Theoretical investigation on Iodine (III)-Mediated Selective Csp−Csp2 bond Cleavage from Nitrogenation of alkyne with Nitrone Yielding Functionalized [1,4] Oxazinone

Research Article

Theoretical investigation on Iodine (III)-Mediated Selective Csp−Csp2 bond Cleavage from Nitrogenation of alkyne with Nitrone Yielding Functionalized [1,4] Oxazinone

  • Nan Lu 1*
  • Chengxia Miao

*Corresponding Author: Nan Lu, College of Chemistry and Material Science, Shandong Agricultural University, Taian 271018, P. R. China.

Citation: Nan Lu, and Chengxia Miao, (2024), Theoretical Investigation on Iodine (III)-Mediated Selective Csp−Csp2 bond Cleavage from Nitrogenation of alkyne with Nitrone yielding Functionalized [1,4] Oxazinone, International Journal of Clinical Case Reports and Reviews, 20(5); DOI:10.31579/2690-4861/626

Copyright: © 2024, Nan Lu. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Received: 22 November 2024 | Accepted: 05 December 2024 | Published: 13 December 2024

Keywords: Csp−Csp2 bond cleavage; iodine(III); [1,4]oxazinone; nitrone; [4 + 3] cycloaddition

Abstract

Our DFT calculations provide the first theoretical investigation on iodine(III)-mediated selective Csp−Csp2 bond cleavage of 1-alkynylnaphthol with N-phenyl nitrone. 1-alkynylnaphthol was isomerized to VQM under base NEt3, which underwent [4 + 3] cycloaddition with N-phenyl nitrone affording heptatomic ring. 1,3-rearrangement of N−O vinyl group was determined to be rate-limiting furnishing another heptatomic ring more stable. The ring opening and sequential hydrogen shift gave iminium. The intramolecular 1,4-addition delivered pyrroline through pentacyclic alkene. The intermolecular alcoholysis with MeOH and PhI(OAc)2 pro-vided α-aminoketone. Via oxidative dearomatization and intramolecular cyclization, spirolactam was formed followed by ring opening and ester exchange producing major product [1,4]oxazinone. Alternatively, the in-tramolecular 1,2-addition of O-anion resulted in bridged ring by-product. The positive solvation effect is suggested by decreased absolute and activation energies in solution compared with in gas. These results are supported by Multiwfn analysis on FMO composition of specific TSs, and MBO value of vital bonding, breaking.

Introduction

As privileged method to construct scaffold in drug discovery and add molecular complexity to pharmacophore in chemical synthesis [1,2], reaction of C−C bond cleavage represents attractive strategy with efficient bond reorganization [3,4]. In this aspect, alkynes are most versatile starting materials developed in past decades such as unsaturated, strained Csp−Csp bond easily cleaved with transition metal catalysts, oxidants [5,6] and polar Csp−Csp3 bond cleaved through radical process or retro-1,2-addition with photocatalysts [7]. However, the cleavage of unstrained Csp−Csp2 σ-bond is still difficult requiring assistants to generate stable intermediates [8]. Selective Csp−Csp2 Bond Cleavage: The Nitrogenation of Alkynes to Amides. Up till now, nitrogenation of alkynes was less reported via regioselective Csp−Csp2 bond cleavage. Only Jiao developed aryl-substituted alkynes with TMSN3 catalyzed by gold(I) to access linear amides [9]. Echavarren discovered sequential cycloaddition to afford tetrazoles [10].

In past decades, 1-alkynylnaphthol was applied as precursor of vinylidene−quinone methide [11] such as Rh-catalyzed azide-internal-alkyne cycloaddition in construction of axially chiral 1,2,3-triazoles [12] and Ir(I)/squaramide cooperative catalysis in asymmetric azide−alkyne cycloaddition [13]. On the other hand, nitrone was demonstrated as various N and O sources in synthesis of novel scaffolds. Luo developed diastereoselective assembly of ten-membered N-heterocycles between two 1,3-dipoles then to access fused N-heterocycles [14]. Xu explored stereoselective photoredox catalyzed (3 + 3) dipolar cycloaddition of nitrone with aryl cyclopropane [15]. Zhou discovered enantioselective oxidative multi-functionalization of terminal alkynes with nitrones and alcohols to assemble chiral α-alkoxy-β-amino-ketones [16]. Li realized stereoselective construction of azepine-containing bridged scaffolds via organocatalytic bicyclization of yne-allenone esters, regio- and enantioselective (3 + 3) cycloaddition of 2-Indolylmethanols [17,18]. Recently, powerful hypervalent iodine(III) compounds have attracted much attention owing to high reactivity in cascade transformation. Wang reported α-functionalization of benzylamides with N-nucleophiles via oxidative Umpolung in synthesis of tetrasubstituted 3,3′-oxindoles and regioselective dearomatization of non-activated arenes [19,20]. 

In this field, Mo group has achieved cinchonidine-catalyzed synthesis of various oxazabicyclo [4.2.1] nonanones from N-aryl-α, β-unsaturated nitrone and 1-ethynylnaphthalen-2-ol [21]. Another breakthrough was nitrogenation of 1-alkynylnaphthols with N-aryl nitrones and sequential recombination leading to functionalized [1,4]oxazinone mediated by iodine(III) compounds through regioselective Csp−Csp2 cleavage of alkyne and C=N/N−O bond cleavage of nitrone [22]. [1,4]oxazinone is vital heterocyclic scaffold with extensive pharmacological significance [23,24] also as fluorescence imaging materials [25]. Although a range of [1,4] oxazinones were yielded, many problems still puzzled. There was no report about detailed mechanistic study explaining its vicinal carbon stereocenter with high diastereoselectivity. How vinylidene−quinone methide (VQM) underwent [4 + 3] cycloaddition with N-phenyl nitrone followed by 1,3-rearrangement of N−O vinyl moiety? How pyrroline intermediate was obtained through intramolecular 1,4-addition of iminium intermediate? Why bridged ring by-product resulted from intramolecular 1,2-addition of O-anion was disfavored compared with [1,4] oxazinone via intramolecular cyclization, dearomatization, rearomatization, ring opening of spirolactam and ester exchange? To solve these questions in experiment, an in-depth theoretical study was necessary also focusing on the C−C/C=N/N−O multiple bonds cleavage and recombination.

2 Computational details

The geometry optimizations were performed at the B3LYP/BSI level with the Gaussian 09 package [26,27]. The mixed basis set of LanL2DZ for I and 6-31G(d) for other non-metal atoms [28-32] was denoted as BSI. Different singlet and multiplet states were clarified with B3LYP and ROB3LYP approaches including Becke's three-parameter hybrid functional combined with Lee−Yang−Parr correction for correlation [33,34]. The nature of each structure was verified by performing harmonic vibrational frequency calculations. Intrinsic reaction coordinate (IRC) calculations were examined to confirm the right connections among key transition-states and corresponding reactants and products. Harmonic frequency calculations were carried out at the B3LYP/BSI level to gain zero-point vibrational energy (ZPVE) and thermodynamic corrections at 353 K and 1 atm for each structure in MeOH. The solvation-corrected free energies were obtained at the B3LYP/6-311++G(d,p) (LanL2DZ for I) level by using integral equation formalism polarizable continuum model (IEFPCM) in Truhlar’s “density” solvation model [35-37] on the B3LYP/BSI-optimized geometries. 

As an efficient method of obtaining bond and lone pair of a molecule from modern ab initio wave functions, NBO procedure was performed with Natural bond orbital (NBO3.1) to characterize electronic properties and bonding orbital interactions [38,39]. The wave function analysis was provided using Multiwfn_3.7_dev package [40] including research on frontier molecular orbital (FMO) and Mayer bond order (MBO).

3 Results and Discussion

The mechanism was explored for PhI(OAc)2-mediated Csp−Csp2 bond cleavage of 1-alkynylnaphthol 1, C=N/N−O bond cleavage of N-phenyl nitrone 2, sequential recombination yielding [1,4]oxazinone 3 and bridged ring by-product 4 (Scheme 1). Illustrated by black arrow of Scheme 2, 1-alkynylnaphthol 1 was initially isomerized to VQM under base NEt3, which underwent [4 + 3] cycloaddition with N-phenyl nitrone 2 affording intermediate A. Then 1,3-rearrangement of N−O vinyl group of A furnished intermediate B, the ring opening of which and sequential hydrogen shift gave iminium intermediate C. The intramolecular 1,4-addition of C delivered pyrroline intermediate D, of which the intermolecular alcoholysis with MeOH and PhI (OAc)2 provided α-aminoketone intermediate (red arrow). Then spirolactam F was formed via oxidative dearomatization of naphthol and intramolecular cyclization. Finally [1,4] oxazinone 3 was yielded in high diastereoselectivity from ring opening of F via intermediate G and sequential ester exchange via intermediate H. Alternatively, the intramolecular 1,2-addition of O-anion of D resulted in bridged ring by-product 4, which could be transformed to D by hydrolysis (blue arrow).

The schematic structures of optimized TSs in Scheme 2 were listed by Figure 1. The activation energy was shown in Table 1 for all steps. Supplementary Table S1, Table S2 provided the relative energies of all stationary points. According to experiment, the Gibbs free energies in MeOH solution phase are discussed here.

Scheme 1: PhI(OAc)2-mediated Csp−Csp2 bond cleavage of 1-alkynylnaphthol 1, C=N/N−O bond cleavage of N-phenyl nitrone 2, sequential recombination yielding [1,4]oxazinone 3 and bridged ring by-product 4.

Scheme 2: Proposed mechanism of PhI (OAc)2-mediated Csp−Csp2 bond cleavage of 1, C=N/N−O bond cleavage of 2, sequential recombination yielding 3 and 4. TS is named according to the two intermediates it connects. TS is named according to the two intermediates it connects.

TSΔG≠gasΔG≠sol
ts-i12  23.6 21.3 
ts-i23  11.1 12.3 
ts-i4513.4 11.7 
ts-i5A  14.6 12.8 
ts-AB  31.6 26.9 
ts-BC1  27.2 22.9 
ts-C1C  20.7 15.2 
ts-CD1  29.8 25.8 
ts-D1D  21.7 17.4 
ts-D4  11.4 7.4 
ts-Ei611.1 9.2 
ts-GH9.7 5.9 
ts-Hi7  26.522.4

Table 1: The activation energy (in kcal mol−1) of all reactions in gas and solvent

3.1 Isomerization of 1 to VQM with NEt3

Under the assistance of base NEt3, initial two steps are required for the isomerization of 1-alkynylnaphthol 1 to VQM. From complex i1 between 1 and NEt3, the proton of naphthol hydroxyl group is deprived by negative N of base via ts-i12 in step 1 with the activation energy of 21.3 kcal mol−1 endothermic by 2.4 kcal mol−1 producing reactive i2with (black dash line of Figure 1a). The transition vector indicates proton H1 transfer from O1 to N1 (1.54, 1.36 Å). The C1-O1 is strengthened to be carbonyl group of VQM in i2 along with sp3 hybrid N1 easy to hand over the proton to negative alkyne C4.

Therefore of via ts-i23 in step 2 the proton H1 is shifting from N1 to C4 (1.29, 1.43 Å) with decreased activation energy of 12.3 kcal mol−1 exothermic by -4.2 kcal mol−1 generating stable i3 bindingVQM and recovered NEt3. Not only includes proton transfer, the transition vector also suggests alkyne turning to be reactive conjugated diene (Figure S1a). Here NEt3 functions as bridge transferring proton to facilitate two steps of isomerization.

(a)

(b)

(c)

Figure 1: Relative Gibbs free energy profile in solvent phase starting from complex (a) i1 (b) i4 (c) E, G (Bond lengths of optimized TSs in Å).

3.2 [4+3] cycloaddition/N−O vinyl 1,3-rearrangement/ring opening/hydrogen shift/1,4-addition

Added with N-phenyl nitrone 2, the complex denoted as i4 is taken as starting point of the following seven steps (black dash line of Figure 1b). VQM undergoes [4 + 3] cycloaddition with 2 via ts-i45 in step 3 with activation energy of 11.7 kcal mol−1 affording stable intermediate i5 exothermic by -20.0 kcal mol−1. The transition vector contains nucleophilic addition of O2 to C3 and the cooperative stretching of N2-O2, C3-C2 bond from double to single (1.96, 1.31, 1.37 Å) (Figure S1b). The next step 4 is required to realize the formation of seven-membered intermediate A via ts-i5A with activation energy of 12.8 kcal mol−1 continuously exothermic by -27.2 kcal mol−1. The transition vector corresponds to the approaching of O1 to C5 (1.71 Å). In addition to typical O1-C5 single bond, the closure heptatomic ring A also involves C1-C2, C3-C4 conjugated double bond. Owing to the reactive VQM, both of the two steps are readily accessible in kinetics but favorable from thermodynamics.

Then 1,3-rearrangement of N−O vinyl group of A takes place via ts-ABin step 5 with activation energy of 26.9 kcal mol−1 greatly exothermic by -81.5 kcal mol−1 giving intermediate B. The transition vectoris complicated with a series of atomic motions about cleavage of N2-O2, linkage of N2-C4 bond as well as shortened of C3-O2 from single to double while elongation of C3-C4 from double to single (2.41, 2.65, 1.25, 1.42 Å) (Figure S1c). Obviously, the structure of B is another heptatomic ring much more stable than A supporting 1,3-rearrangement of N−O bond, which is significant and determined to be rate-limiting from kinetics.

Subsequently, the ring opening of occurs via ts-BC1 with mediate activation energy of 22.9 kcal mol−1 exothermic by -59.0 kcal mol−1 in step 6 yielding C1 involving increased relative energy of 22.5 kcal mol−1 compared with B. According to the transition vector, this process is composed of O1-C5 bond breaking along with contraction of C1-O1 and N2-C5 bond from single to double (2.21, 1.28, 1.32 Å) (Figure S1d). Hence a sequential hydrogen shift is easy via ts-C1C in step 7 with decreased activation energy of 15.2 kcal mol−1 exothermic by -55.8 kcal mol−1. The transition vector reveals a proton transfer mode of C4···H1···O1 (1.31, 1.32 Å). An iminium intermediate C is furnished with positive N2 and negative charge focused on C4 ready to initiate the nucleophilic attack afterwards.

Next intramolecular 1,4-addition of C proceeds via ts-CD1 in step 8 with activation energy of 25.8 kcal mol−1 generating stable D1 followed by proton transfer via ts-D1D in step 9 with reduced activation energy of 17.4 delivering pyrroline intermediate D exothermic by -62.8 kcal mol−1. The transition vector suggests nucleophilic addition of C4···C7, stretching C3···C4, C6···C7 (2.65, 1.41, 1.45 Å) (Figure S1e) and then O1···H1···C6 (1.49, 1.21 Å). Finally, the stable pentacyclic alkene D1 with C5=C6 double bond turns to be pyrroline with N2=C5 and sp3 hybrid C6. With relative energy uphill by 9.9 kcal mol−1 from D1, D is more likely to trigger subsequent processes.

3.3 O-anion 1,2-addition or intramolecular cyclization/ring opening/sequential ester exchange

Two feasible paths are located for the formation of two products. On one hand, the intramolecular 1,2-addition of O-anion of D takes place via ts-D4 in step 10 with activation energy of 7.4 kcal mol−1 delivering bridged ring by-product 4, which could be transformed to D by hydrolysis. The transition vector corresponds to a process just reverse to that of ts-BC1 comprising O1-C5 bonding together with extension of C1-O1 and N2-C5 bond from double to single (2.29, 1.29, 1.30 Å). The new seven membered oxygen heterocyclic ketone is obtained in 4 fused with previous five membered nitrogen heterocyclic ring.

Alternatively, with additional MeOH and PhI(OAc)2, the intermolecular alcoholysis of D could provide α-aminoketone intermediate (black dash line of Figure 1c). The intramolecular cyclization happens via ts-Ei6 in step 11 with activation energy of 9.2 kcal mol−1 exothermic by -43.4 kcal mol−1 resulted in quaternary nitrogen heterocyclic ketone i6. The transition vectorcontains detailed atomic motion about nucleophilic addition of negativeN2 to C2 and depriving proton H2 from N2 by OAc (2.28, 1.25, 1.62 Å). Via oxidative dearomatization, spirolactam F is given after the removal of PhI and HOAc from i6.

Then another MeOH molecule is added to C3=O2 of F in forms of MeO and H making it to be C3-O2 single one and sp3 hybrid C3 in G, which is located as new starting point of last two steps (red dash line of Figure 1c). Via ts-GH, the ring opening proceeds in step 12 with low activation energy of 5.9 kcal mol−1 exothermic by -16.0 kcal mol−1 yielding intermediate H. This process is illustrated according to the transition vector composed ofC3-C2 dissociation and proton shift O2···H3···O1 in concerted mode (2.02, 1.08, 1.28 Å) (Figure S1f). There are also cooperated exchange of C3-O2 and C1-O1 beween double and single.

Finally, a sequential ester exchange takes place from via ts-Hi7 with mediate activation energy of 22.4 kcal mol−1 exothermic by -25.8 kcal mol−1 yielding intermediate i7 in last step 13. As shown by the transition vector, this process is collaborative yet asynchronous with proton transfer O1···H3···O3 in front and nucleophilic attack of O1 to C3 as well as resultant O3 cleavage from C3 behind (1.35, 1.17, 1.91, 1.58 Å) (Figure S1g). Once O1-C3 is bonded in i7, a new hexacyclic lactone is realized not only with recovered MeOH but producing [1,4]oxazinone 3 with high diastereoselectivity. 

The relative energy of higher by 28.5 kcal mol−1 than that of 3 is in accordance with 4 as by-product and major one 3 in experiment [22]. To highlight the idea of feasibility for changes in electron density and not molecular orbital interactions are responsible of the reactivity of organic molecules, quantum chemical tool Multiwfn was applied to analyze of electron density such as MBO results of bonding atoms and contribution of atomic orbital to HOMO of typical TSs (Table S3, Figure S2). These results all confirm the above analysis.

4 Conclusions

Our DFT calculations provide the first theoretical investigation on iodine(III)-mediated selective Csp−Csp2 bond cleavage of 1-alkynylnaphthol with N-phenyl nitrone. Under base NEt3, 1-alkynylnaphthol was isomerized to VQM, which underwent [4 + 3] cycloaddition with N-phenyl nitrone affording heptatomic ring. Then 1,3-rearrangement of N−O vinyl group was determined to be rate-limiting furnishing another heptatomic ring much more stable, the ring opening of which and sequential hydrogen shift gave iminium intermediate. The intramolecular 1,4-addition delivered pyrroline through pentacyclic alkene intermediate. The intermolecular alcoholysis with MeOH and PhI(OAc)2 provided α-aminoketone intermediate. Via oxidative dearomatization and intramolecular cyclization, spirolactam was formed followed by ring opening and ester exchange producing major product [1,4]oxazinone with high diastereoselectivity. Alternatively, the intramolecular 1,2-addition of O-anion resulted in bridged ring by-product. The lower yield of by-product is induced by higher relative energy than major one. The positive solvation effect is suggested by decreased absolute and activation energies in MeOH solution compared with in gas. These results are supported by Multiwfn analysis on FMO composition of specific TSs, and MBO value of vital bonding, breaking.

Electronic Supplementary Material

Supplementary data available: [Computation information and cartesian coordinates of stationary points; Calculated relative energies for the ZPE-corrected Gibbs free energies (ΔGgas), and Gibbs free energies (ΔGsol) for all species in solution phase at 353 K.]

Author contributions: 

Conceptualization, Nan Lu; Methodology, Nan Lu; Software, Nan Lu; Validation, Nan Lu; Formal Analysis, Nan Lu; Investigation, Nan Lu; Resources, Nan Lu; Data Curation, Nan Lu; Writing-Original Draft Preparation, Nan Lu; Writing-Review & Editing, Nan Lu; Visualization, Nan Lu; Supervision, Chengxia Miao; Project Administration, Chengxia Miao; Funding Acquisition, Chengxia Miao. All authors have read and agreed to the published version of the manuscript.

Funding: 

This work was supported by National Natural Science Foundation of China (21972079) and Key Laboratory of Agricultural Film Application of Ministry of Agriculture and Rural Affairs, P.R. China.

Conflict of interest: 

The authors declare no conflict of interest.

References

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I am delighted to publish our manuscript entitled "A Perspective on Cocaine Induced Stroke - Its Mechanisms and Management" in the Journal of Neuroscience and Neurological Surgery. The peer review process, support from the editorial office, and quality of the journal are excellent. The manuscripts published are of high quality and of excellent scientific value. I recommend this journal very much to colleagues.

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S Munshi

Dr.Tania Muñoz, My experience as researcher and author of a review article in The Journal Clinical Cardiology and Interventions has been very enriching and stimulating. The editorial team is excellent, performs its work with absolute responsibility and delivery. They are proactive, dynamic and receptive to all proposals. Supporting at all times the vast universe of authors who choose them as an option for publication. The team of review specialists, members of the editorial board, are brilliant professionals, with remarkable performance in medical research and scientific methodology. Together they form a frontline team that consolidates the JCCI as a magnificent option for the publication and review of high-level medical articles and broad collective interest. I am honored to be able to share my review article and open to receive all your comments.

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Tania Munoz

“The peer review process of JPMHC is quick and effective. Authors are benefited by good and professional reviewers with huge experience in the field of psychology and mental health. The support from the editorial office is very professional. People to contact to are friendly and happy to help and assist any query authors might have. Quality of the Journal is scientific and publishes ground-breaking research on mental health that is useful for other professionals in the field”.

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George Varvatsoulias

Dear editorial department: On behalf of our team, I hereby certify the reliability and superiority of the International Journal of Clinical Case Reports and Reviews in the peer review process, editorial support, and journal quality. Firstly, the peer review process of the International Journal of Clinical Case Reports and Reviews is rigorous, fair, transparent, fast, and of high quality. The editorial department invites experts from relevant fields as anonymous reviewers to review all submitted manuscripts. These experts have rich academic backgrounds and experience, and can accurately evaluate the academic quality, originality, and suitability of manuscripts. The editorial department is committed to ensuring the rigor of the peer review process, while also making every effort to ensure a fast review cycle to meet the needs of authors and the academic community. Secondly, the editorial team of the International Journal of Clinical Case Reports and Reviews is composed of a group of senior scholars and professionals with rich experience and professional knowledge in related fields. The editorial department is committed to assisting authors in improving their manuscripts, ensuring their academic accuracy, clarity, and completeness. Editors actively collaborate with authors, providing useful suggestions and feedback to promote the improvement and development of the manuscript. We believe that the support of the editorial department is one of the key factors in ensuring the quality of the journal. Finally, the International Journal of Clinical Case Reports and Reviews is renowned for its high- quality articles and strict academic standards. The editorial department is committed to publishing innovative and academically valuable research results to promote the development and progress of related fields. The International Journal of Clinical Case Reports and Reviews is reasonably priced and ensures excellent service and quality ratio, allowing authors to obtain high-level academic publishing opportunities in an affordable manner. I hereby solemnly declare that the International Journal of Clinical Case Reports and Reviews has a high level of credibility and superiority in terms of peer review process, editorial support, reasonable fees, and journal quality. Sincerely, Rui Tao.

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Rui Tao

Clinical Cardiology and Cardiovascular Interventions I testity the covering of the peer review process, support from the editorial office, and quality of the journal.

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Khurram Arshad

Clinical Cardiology and Cardiovascular Interventions, we deeply appreciate the interest shown in our work and its publication. It has been a true pleasure to collaborate with you. The peer review process, as well as the support provided by the editorial office, have been exceptional, and the quality of the journal is very high, which was a determining factor in our decision to publish with you.

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Gomez Barriga Maria Dolores

The peer reviewers process is quick and effective, the supports from editorial office is excellent, the quality of journal is high. I would like to collabroate with Internatioanl journal of Clinical Case Reports and Reviews journal clinically in the future time.

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Lin Shaw Chin

Clinical Cardiology and Cardiovascular Interventions, I would like to express my sincerest gratitude for the trust placed in our team for the publication in your journal. It has been a true pleasure to collaborate with you on this project. I am pleased to inform you that both the peer review process and the attention from the editorial coordination have been excellent. Your team has worked with dedication and professionalism to ensure that your publication meets the highest standards of quality. We are confident that this collaboration will result in mutual success, and we are eager to see the fruits of this shared effort.

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Maria Dolores Gomez Barriga

Dear Dr. Jessica Magne, Editorial Coordinator 0f Clinical Cardiology and Cardiovascular Interventions, I hope this message finds you well. I want to express my utmost gratitude for your excellent work and for the dedication and speed in the publication process of my article titled "Navigating Innovation: Qualitative Insights on Using Technology for Health Education in Acute Coronary Syndrome Patients." I am very satisfied with the peer review process, the support from the editorial office, and the quality of the journal. I hope we can maintain our scientific relationship in the long term.

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Dr Maria Dolores Gomez Barriga

Dear Monica Gissare, - Editorial Coordinator of Nutrition and Food Processing. ¨My testimony with you is truly professional, with a positive response regarding the follow-up of the article and its review, you took into account my qualities and the importance of the topic¨.

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Dr Maria Regina Penchyna Nieto

Dear Dr. Jessica Magne, Editorial Coordinator 0f Clinical Cardiology and Cardiovascular Interventions, The review process for the article “The Handling of Anti-aggregants and Anticoagulants in the Oncologic Heart Patient Submitted to Surgery” was extremely rigorous and detailed. From the initial submission to the final acceptance, the editorial team at the “Journal of Clinical Cardiology and Cardiovascular Interventions” demonstrated a high level of professionalism and dedication. The reviewers provided constructive and detailed feedback, which was essential for improving the quality of our work. Communication was always clear and efficient, ensuring that all our questions were promptly addressed. The quality of the “Journal of Clinical Cardiology and Cardiovascular Interventions” is undeniable. It is a peer-reviewed, open-access publication dedicated exclusively to disseminating high-quality research in the field of clinical cardiology and cardiovascular interventions. The journal's impact factor is currently under evaluation, and it is indexed in reputable databases, which further reinforces its credibility and relevance in the scientific field. I highly recommend this journal to researchers looking for a reputable platform to publish their studies.

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Dr Marcelo Flavio Gomes Jardim Filho

Dear Editorial Coordinator of the Journal of Nutrition and Food Processing! "I would like to thank the Journal of Nutrition and Food Processing for including and publishing my article. The peer review process was very quick, movement and precise. The Editorial Board has done an extremely conscientious job with much help, valuable comments and advices. I find the journal very valuable from a professional point of view, thank you very much for allowing me to be part of it and I would like to participate in the future!”

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Zsuzsanna Bene

Dealing with The Journal of Neurology and Neurological Surgery was very smooth and comprehensive. The office staff took time to address my needs and the response from editors and the office was prompt and fair. I certainly hope to publish with this journal again.Their professionalism is apparent and more than satisfactory. Susan Weiner

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Dr Susan Weiner

My Testimonial Covering as fellowing: Lin-Show Chin. The peer reviewers process is quick and effective, the supports from editorial office is excellent, the quality of journal is high. I would like to collabroate with Internatioanl journal of Clinical Case Reports and Reviews.

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Lin-Show Chin

My experience publishing in Psychology and Mental Health Care was exceptional. The peer review process was rigorous and constructive, with reviewers providing valuable insights that helped enhance the quality of our work. The editorial team was highly supportive and responsive, making the submission process smooth and efficient. The journal's commitment to high standards and academic rigor makes it a respected platform for quality research. I am grateful for the opportunity to publish in such a reputable journal.

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Sonila Qirko

My experience publishing in International Journal of Clinical Case Reports and Reviews was exceptional. I Come forth to Provide a Testimonial Covering the Peer Review Process and the editorial office for the Professional and Impartial Evaluation of the Manuscript.

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Luiz Sellmann