Influence of Non-Covalent Interactions in the Exo- and Regioselectivity

Subscriber access provided by Stockholm University Library

Article

Influence of Non-Covalent Interactions in the Exo- and Regioselectivity of Aza-Diels-Alder Reactions: Experimental and DFT calculations Sebastian Gallardo-Fuentes, Nicolás Lezana, Susan Lühr, Antonio Galdámez, and Marcelo Vilches Herrera J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01390 • Publication Date (Web): 14 Aug 2019 Downloaded from pubs.acs.org on August 20, 2019

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 7 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry

Influence of Non-Covalent Interactions in the Exo- and Regioselectivity of Aza-Diels-Alder Reactions: Experimental and DFT calculations Sebastián Gallardo-Fuentes‡, Nicolás Lezana‡, Susan Lühr, Antonio Galdámez, Marcelo VilchesHerrera* Faculty of Sciences, University of Chile, Department of Chemistry, Las Palmeras 3425, Ñuñoa, Santiago, Chile. Supporting Information Placeholder via NCIs

O 2N

regioselective

CO2Et O 2N

+

NC N

N

H 2O 200ºC MW 20 min

CH-π interaction π-π interaction

CO2Et NC N

NH

stereoselective

69 %

ABSTRACT: A systematic experimental and theoretical study of the intermolecular Aza-Diels-Alder reaction using 5aminopyrrole as building block, shows that the commonly accepted endo selectivity, ruled by controversial secondary orbital interactions are overcome by non-covalent interactions affording to the unusual exo adduct. Additionally, the regioselectivity is also influenced for such interactions. Starting materials are easily to be prepared and the use of water as solvent is a great achievement for the development of cleaner synthetic methodologies.

INTRODUCTION The Aza-Diels-Alder (ADA) reaction is a well-established synthetic method finding application in the synthesis of several compounds with relevant biological activities, as well in natural products.1 As in all Diels-Alder (DA) reactions, the Aza version shows a high regio- and stereoselectivity.2 Commonly, the relative energies of the molecular orbitals of the interacting pair are used to describe the mechanism and charge transfer patterns, whereas the relative size of the atomic coefficients of the corresponding Frontier Molecular Orbital (FMO) appears as the main criterion to predicts the regiochemical outcome.3-4 Additionally, the so-called secondary orbital interactions (SOIs) have been widely invoked to rationalize stereoselectivities in these processes. In this context, there is a wide choice of examples in the literature where the corresponding endo/exo pathways are referred to the position of the electron-withdrawing group attached to the dienophile relative to the diene moiety at the transition state (TS) region.5 Nonetheless, the prevalence of these elusive secondary interactions in determining the stereochemical outcome has been subject to controversy in the past few years.6 On contrary, a combination of well-known mechanisms such as solvent effects, steric interactions, hydrogen bonds, electrostatic forces, and others would be the reason behind the observed endo/exo selectivity.7 Since the Diels-Alder reaction is one of the most relevant reactions for

the organic synthetic chemist all contributions that allow a better understanding of the factors that govern the selectivity and consequently a more rational and efficient synthetic design are necessary. On our previous work a highly diastereoselective synthesis of tetrahydropyridines and annulated 7-azaindoles was achieved using an intramolecular ADA reaction.8 However, because the HOMO and LUMO concerned were in the same molecule, the mechanism could not be unequivocally established by the frontier molecular orbital theory and the observed stereoselectivity was not fully investigated. Thus, we decided to study the intermolecular version from the experimental and theoretical point of view. RESULTS AND DISCUSSION Initially we study the reaction between the aldimine 1a and the ethyl cinnamate derivative 2a in water under microwave irradiation. To our delight, 3a was obtained as the only product in 55% yield. Considering that Aza-Diels-Alder reactions are normally conducted in apolar solvents such as benzene9 or xylene10 in order to facilitate the solubility and compatibility of the required reagents and catalysts, this is a great achievement to the use of more environmentally friendly processes (Scheme 1). Moreover, considering that one of the most interesting features of 7-azaindoles is the variability of their biological properties regarding to the substitution pattern,11 the use of the aldimine 1a allows the introduction of

ACS Paragon Plus Environment

The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

two versatile groups in the final product. The nitrile group that can be converted to other functional group and the phenyl group derived from benzaldehyde that can be substituted by other aldehydes derivatives. On the other hand, 2a enables also the desirable partial or full functionalization of 7azaindoles.12 The configuration of the new stereocenters in 3a was deduced from the 1D and 2D NMR analysis. Independently, the X ray structure of 3a was fully in accordance with the trans assigned configuration (SI). All attempts to carried out the reaction under milder conditions failed and no reaction took place Scheme 1. Model reaction for the stereoselective cycloaddition reaction between 1a (1mmol) and 2a (1mmol)

O 2N N

t

N

t

1a

100/0

63

0/100

100/0

59

0/100

100/0

39

0/100

100/0

40

66/33a

-

25

66/33a

-

49

Ph

66/33a

-

23

Ph

66/33a

-

47

-

-

53

-

-

73

NO2

3-O2N-Ph

Ph

NC

2

NH N

3b

t

Bu

CO2Et

4-NC-Ph

Ph NH N

NH

CHO Ph

NC

3a

Bu

3c

Bu

4

69 %

NH N

3d

t

Bu

ortho/meta

CN

Ph

Ph

NC

5

NH N

3e

t

Bu

CN Ph

NC

6

NH N

3f

t

Bu

NC Ph

NC NH

7

N

3f`

t

Bu

CO2Et NC

8

NH N

3g

t

Bu

EtO2C NC NH

9

N t

Bu

10

3g`

CO2Me

MeO2C

Ph

NC NH N

Table 1. Scope of the reaction R

0/100

Bu

t

To test the versatility of our approach, we carried out the reaction with electron poor and electron rich dienophiles. Because only with electron demanding substrates the reaction resulted to be successful, we have assumed a normal electrondemand mechanism and a library of compounds was prepared (Table 1). The original ester group of 2a was conveniently replaced by a nitro, aldehyde or nitrile moiety, all of them easily to be transformed in other functionalities. On the other hand, the nitro group of the electron deficient aromatic ring of 2a was also replaced by a nitrile or an aldehyde group. Other imines in the diene different to those derived from benzaldehyde, such as cinnamaldehyde, 1-naphtaldehyde and cyclohexane carbaldehyde were also tested broadening the scope of the reaction (Table 1, entries 15-17). In all cases regio- and stereoselective products were obtained (Table 1, entries 1-5 and 16-17). Replacement of the aromatic ring of 2a for a hydrogen atom resulted in a completely loss of the regioselectivity of the reaction and a mixture of regioisomers was obtained (Table 1, entries 6-9). After separation by column chromatography, both structures were confirmed by NMR spectroscopy and 3g’ was additionally confirmed by single X-ray crystal. (SI). Depending on the nature of the substituents present in the dienophile the corresponding 7-azaindoles were obtained with good to excellent yields (Table 1, entries 11-15). Although no mechanistic information can be obtained from these reactions, these scaffolds validate the synthetic value of the reaction. Moreover, the use of dimethyl acetylenedicarboxylate resulted to be also a good dienophile (Table 1, entries 10-11) broadening the scope of the reaction to the use of alkynes as dienophiles.

Entry

69

3a

t

Ph

N

Bu

100/0

NH N

NC

200ºC MW 15 min

+

NC

1

CO2Et

H 2O

0/100

Ph

NC

3

CO2Et 2a

CO2Et

4-O2N-Ph

NC

O 2N

a.

Page 2 of 7

3h

t

Bu

exo/endo

CO2Me

MeO2C

Yield [%] 11

Ph

NC N N t

Bu


3i

Page 3 of 7 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry NO2

3-F3C-Ph

12

Ph

NC

Bu

Ph

NC

-

62 1a

3k

t

Bu

NO2

4-NC-Ph

Ph

NC

0/100

-

66

b. TS-2mn

N N t

Bu

3l CO2Et

4-O2N-Ph NC

Sty

0/100

-

2a ester group endo approach

89

N N t

Bu

1a

3m

CO2Et

4-O2N-Ph

Cy

NC

0/100

100/0

44

NH N t

3n

Bu

17

2a ester group exo approach

N N

16

0/100

a. TS-2mx

NO2

4-O2N-Ph

15

86

3j

t

14

-

N N

13

0/100

CO2Et

4-O2N-Ph

Naph

NC

0/100

100/0

47

NH N t

3o

Bu

a Ratio based on the 1H NMR of the raw mixture, which was separated by column chromatography.

As mentioned above, since high regio- and stereochemical control is one of the reasons that Diels-Alder reactions have been largely considered as valuable synthetic tools for the synthesis of complex molecules these results appear to be particularly interesting. Although a similar behavior was observed in the construction of pyrazolopyridine skeletons.13 Despite the extensive literature on the mechanism and selectivity patterns in Diels-Alder reactions, the Aza version has been less studied.14 Moreover, only few reports, based on theoretical and experimental reports exist about the use of amino-heterocycles in [4+2] cycloadditions.14-15 Based on the synthetic potential of our 2-aza-diene system, an in-depth theoretical study at the M06-2X/6-31+G(d,p) level of theory was performed and compared with the experimental data. We started the computational study by exploring the stereochemical outcome. For this purpose, the corresponding endo/exo pathways associated with the favored meta regiochemical mode were computationally addressed. The resulting transition state (TS) structures for the model reaction are depicted in Figure 1.

Figure 1. M06-2X/6-31+G(d,p) optimized transition state structures for the exo (a) and endo (b) stereochemical modes associated with the ADA reaction of 1a with 2a. Distances are given in Å. The computed activation free energies reveal that TS-2mn is higher in energy by 2.7 kcal/mol than TS-2mx predicting an unusual exo/endo selectivity of 18:1 in excellent agreement with our experimental findings. Moreover, the origin of the complete meta observed regioselectivity can be explained by the corresponding Gibbs free energies profile associated to the ortho and meta reactions paths for the model reaction which show that the lowest energy is associated with the TS-2mx (SI). Exo selectivity has already been observed and interpreted as consequence of electrostatic repulsion between electron withdrawing group in the dienophile and π electrons in the diene,16 steric effects by silyl groups present in the diene17 or due to the addition of bulky borane complexes.18 In our case, the reason for this unusual selectivity could be ascribed to two main factors arising from the geometrical arrangement of the interacting pair at the TS region: An attractive dispersion interaction between the nitrophenyl group of 2a and the electron-rich pyrrole moiety of 1a in conjunction with a weak CH-π interaction between the ethyl functionality of 2a and the phenyl group of 1a. However, considering the electronic nature of 1a and 2a, a charge transfer (CT) interaction or complex formation, whose role in other Diels-Alder reactions has been studied, could be also be involved.19 Moreover, the good results obtained in our reactions using water as solvent, are consistent with literature reports where favorable interactions (including donor-acceptor interactions) have been observed in reactions involving heterocycles and hydrocarbon aromatic units in aqueous solution.20 We rationalized that if a CT interaction would be present, the selectivity of the reaction, rather than the reactivity would be influenced for the polarity of the solvent.21 Thus, we performed the reaction using xylene as solvent with representative reactions and



additionally CPCM (conductor-like polarizable continuum model) calculations were carried out. In all cases any noticeable effect on the selectivity was observed, ruling out the idea of a CT formation. To unravel the existence of the non-covalent interactions previously mentioned, we performed a topological analysis based on the NCI-index introduced by Johnson and co-workers (Figure 2).22 This analysis enables the visualization of these weak interactions in the real space, allowing the characterization of both the strength and nature of these interactions. The following color codes are used to characterize nonbonding interaction through NCI index: (i) blue for highly attractive interactions, (ii) green for week interactions and (iii) red for repulsive interactions. From the NCI analysis, it is possible to confirm the existence of weak CH-π attractive interactions in both TS structures. This result strongly suggests that the π-π interactions, which are prevailing in the exo approach, are responsible for the significant energy barrier lowering predicted by the TS-2mx structure.

(a)

(b)

Figure 2. Isosurfaces for all non-covalent interactions presents at the TS-2mx (a) and TS-2mn (b) transition structures. In order to obtain further mechanistic information we interpret the reactivity patterns of the tittle reactions by means of the distortion-interaction model, also called distortion-strain model, introduced independently by Houk and Bickelhaupt.23 The central premise in these models is that the activation barrier can be described as the sum of the energy required for the geometrical deformation of the interacting pair to reach the TS structure (distortion energy), and the interactions between the two distorted reactants (interaction energy) at the TS region. The corresponding activation energy (green arrows), diene and dienophile distortion energies (red and blue arrows) and the resulting interaction energies (black arrows) are summarized in Figure 3. The results reveal that the distortion energies are quite similar for the transition states associated with the major and minor regioisomers, with values which range from 32.2 to 32.7 kcal/mol. These values suggest that the high activation barriers computed for the reaction between 1a and 2a are controlled mainly by the distortion energy of the interaction pair. In this context, the distortion/interaction model nicely agree with the analysis based on the NCI-index, revealing that the energetically low- lying TS-2mx structure ≠ exhibit a Δ𝐸𝑖𝑛𝑡 value much more favorable, highlighting the crucial role of the π-π interactions in controlling both regioand stereoselectivity patterns for the title reactions.

Page 4 of 7

CN N

CN N

CO2Et N

CN

N

Ph TS-2on

13.0

19.3

-17.9

14.4

NO2

TS-2ox

NO2

N N

Ph

NO2

CN

NO2

N

CO2Et

CO2Et

N

CO2Et

Ph

Ph

TS-2mn

TS-2mx

13.3

-19.6

13.6

-17.0

13.4

-20.4

19.4

13.2

18.6

15.3

19.4

12.3

Figure 3 Distortion/interaction analyses for the aza-DA reaction between 1a and 2a. Red: diene distortion, blue: dienophile distortion, black: interaction energy and green: activation energy. All the values are given in kcal mol-1. Finally, we were interested to evaluate the influence or not, of NCIs in the formation of the regioisomeric mixture for the reaction between 1a and 2f and 2g respectively. The calculated activation free energies for the reaction of 1a with 2g associated with the four isomeric reaction pathways predicts that the meta regioisomeric channel is energetically favored by 1.3 kcal/mol with an endo/exo selectivity of 1:1 (SI), in contrast to the experimental results where two regioisomers were formed, 3g and 3g´. We rationalize this divergence in terms of a thermodynamic versus kinetic control. In this context, the presence of the phenyl group in compounds 2a-f allows that the reaction proceeds under kinetic control which is favoured by these NCIs. However, when the phenyl group is removed, a thermodynamic control would be also present. To validate this idea, a full geometry optimization for the four possible products associated with the ortho and meta reaction paths was performed. The computed relative energies (SI) for the regioisomeric compounds 3g and 3g` show that the ortho regioisomer is 0.9 kcal/mol lower in energy than the meta isomer, predicting a 3g:3g` product ratio of 18:82, that resembles the experimental product distribution.

CONCLUSION In summary, we have elucidated the high regio- and stereoselective intermolecular Aza-Diels-Alder reaction in terms of non-covalent interactions. DFT calculations revealed that the attractive π-π interactions at the TS region play a key role by modulating the regio- and stereoselectivity patterns of the title reactions. When these non-covalent interactions are precluded the thermodynamic control prevailing. The insights presented herein can be used as a key piece of information to inspire the rational design of new elements of stereocontrol.

EXPERIMENTAL SECTION All microwave reactions were performed in a microwave reactor (Monowave 300), in sealed reaction vessels. The temperature was controlled using an IR sensor. The reactions were monitored by thin-layer chromatography (TLC) performed on silica gel 60 F254 plates. HPLC-ESI-MS experiments were performed on an Exactive Plus Orbitrap MS Thermo Fischer Scientific (Bremen, Germany). The accurate mass measurements were performed at a


Page 5 of 7 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry resolution of 140.000 in positive mode, AGC target: 3e6, Max. inject time: 200. HESI source: Sheath gas flow: 10, Aux gas flow rate: 3, Sweep gas flow rate: 0, Capillary temp.: 320°C, S-lens RF level: 0, Heater temp: 100°C. 1H NMR (200 and 400 MHz) and 13C NMR (50 and 100 MHz) spectra were recorded on a Bruker Biospin GmbH NMR. Procedure for the preparation of imine (1a) To a solution of 5amino-1-(tert-butyl)-1H-pyrrole-3-carbonitrile (1 mmol, 1eq.) in toluene (60 mL), DBU (2 mmol, 2eq) and the salicylaldehyde (1 mmol, 1 eq.) were added. The mixture was refluxed in a heating mantle for 6-8 hours and left overnight at room temperature. The solvent was evaporated and the mixture was extracted with AcOEt (8 mL) and water (12 mL). The organic phase was separated, and the aqueous layer was extracted with AcOEt (2 x 12 mL). The combined organic phases were dried over Na2SO4 anhydrous, filtered and concentrated under reduce pressure, dissolved in 5 mL of methanol for crystallization and left overnight. The formed crystals were filtered to give the corresponding product 1a. General procedure for the cycloaddition and obtaining of tetrahydro-1H-pyrrolo-[2,3-b]-pyridine (3a-h) and 7azaindoles (3i-m). Imine 1a (1mmol, 1 eq.) and the corresponding substituted dienophiles 2a-m (1.0 mmol, 1.0 eq.) and water (5 mL) were introduced in a microwave reaction vial, which was sealed with a PTFE-coated silicone septum and closed with a PEEK cap. The solution was heated for 20 minutes at 200°C. After the aqueous solution was extracted with 1 mL (x2) of ethyl acetate, dried over Na2SO4 anhydrous, concentrated and crystallized from methanol or column chromatography when necessary (3f, 3f`and 3g, 3g`). ethyl (4S,5R,6R)-1-(tert-butyl)-3-cyano-4-(4-nitrophenyl)-6phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridine-5carboxylate (3a). Yield 69.2% (104 mg), orange solid. mp. 232234 °C. 1H NMR (400 MHz, CDCl3) δ= 8.16 (d, J = 8.0 Hz, 1H), 7.45 – 7.32 (m, 4H), 6.97 (s, 1H), 4.58 (d, J = 10.3 Hz, 1H), 4.48 (dd, J = 9.9, 6.2 Hz, 1H), 3.76 – 3.56 (m, 1H), 3.44 (d, J = 6.0 Hz, 1H), 2.87 (t, J= 10.2 Hz, 1H), 1.60 (s, 8H), 0.68 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 171.9, 149.0, 147.27, 138.9, 135.9, 129.2, 128.9, 128.8, 127.5, 123.9, 121.4, 115.9, 105.7, 88.6, 61.2, 60.5, 57.1, 56.2, 43.8, 29.6, 13.6. HRMS (ESI): Mass calculated for C27H29N4O4 [M+H]+ 473.2188. Found: 473.2176. (4S,5R,6S)-1-(tert-butyl)-5-nitro-4-(3-nitrophenyl)-6-phenyl4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (3b). Yield 62.5% (106 mg), orange solid. mp. 203-205 °C. 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 8.1 Hz, 1H), 8.09 (s, 1H), 7.58 (d, J = 7.7 Hz, 1H), 7.52 (t, J = 7.9 Hz, 1H), 7.40 (s, 5H), 7.02 (s, 1H), 4.99 – 4.91 (m, 1H), 4.89 (d, J = 9.7 Hz, 1H), 4.85 – 4.74 (m, 1H), 3.58 (d, J = 6.7 Hz, 1H), 1.61 (s, 10H). 13C{1H} NMR (101 MHz, CDCl3) δ 149.2, 147.4, 139.1, 136.1, 129.4, 129.0, 128.9, 127.7, 124.0, 121.6, 116.1, 105.9, 88.8, 61.4, 60.7 (s), 57.3 (s), 56.4 (s), 43.9, 29.7. ethyl (4S,5R,6R)-1-(tert-butyl)-3-cyano-4-(4-cyanophenyl)-6phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridine-5carboxylate (3c). Yield 58.6% (116 mg), orange solid. mp. 243245 °C. 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 8.0 Hz, 2H), 7.35 (dd, J = 16.4, 8.2 Hz, 7H), 6.96 (s, 1H), 4.51 (d, J = 10.7 Hz, 1H), 4.48–4.44 (m, 1H), 3.72 – 3.57 (m, 1H), 3.42 (d, J = 5.8 Hz, 1H), 2.85 (t, J = 10.2 Hz, 1H), 1.59 (s, 9H), 0.68 (t, J =7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 172.0, 146.9, 139.0, 135.9, 132.4, 129.1, 128.8, 128.75, 127.5, 121.3, 118.9, 115. 9, 111.3, 105.8, 88.6, 61.2, 60.4, 57.1, 56.2, 44.0, 29.6, 13.6. HRMS (ESI): Mass calculated for C28H29N4O2 [M+H]+ 453.2290. Found: 453.2281.

(4S,5R,6R)-1-(tert-butyl)-5-formyl-4,6-diphenyl-4,5,6,7tetrahydro-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (3d). Yield 38.7%, (59 mg), orange solid. mp. 145-148 °C. 1H NMR (400 MHz, CDCl3) δ 9.40 (s, 1H), 7.42 – 7.13 (m, 10H), 6.95 (s, 1H), 4.51 (d, J = 9.6 Hz, 1H), 4.49 – 4.40 (m, 1H), 3.36 – 3.28 (m, 1H), 3.25 (d, J = 9.7 Hz, 1H), 1.59 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 202.7, 141.1, 138.9, 135.4 129.2, 128.9, 128.7, 128.5, 127.5, 127.3, 121.4, 116.0, 107.9, 89.0, 60.2, 59.9, 56.9, 40.9, 29.6. HRMS (ESI): Mass calculated for C25H26N3O [M+H]+ 384.2076. Found: 384.2068 (4S,5R,6R)-1-(tert-butyl)-4,6-diphenyl-4,5,6,7-tetrahydro-1Hpyrrolo[2,3-b]pyridine-3,5-dicarbonitrile (3e). Yield 40.1% (60 mg), white solid. mp. 256-258 °C. 1NMR (400 MHz, CDCl3) δ 7.48–7.29 (m, 10H), 6.97 (s, 1H), 4.49 (dd, J = 10.2, 6.5 Hz, 1H), 4.37 (d, J = 10.7 Hz, 1H), 3.37 (d, J = 6.2 Hz, 1H), 3.02 (t, J = 10.5 Hz, 1H), 1.58 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 139.5, 138.4, 135.3, 129.4, 129.3, 129.0, 128.9, 128.9, 128.3, 128.3, 128.2, 127.3, 121.8, 118.9, 106.2, 89.1, 60.9, 57.1, 44.7, 44.1, 29.6. HRMS (ESI): Mass calculated for C25H25N4 [M+H]+ 381.2079. Found: 381.2068 (5R,6R)-1-(tert-butyl)-6-phenyl-4,5,6,7-tetrahydro-1Hpyrrolo[2,3-b]pyridine-3,5-dicarbonitrile (3f). Yield 48.5% (in ratio 2:1 with his isomer, 59mg), white solid. mp. 168-170 °C. 1H NMR (400 MHz, CDCl3) δ 7.45 – 7.37 (m, J = 15.2 Hz, 5H), 7.02 (s, 1H), 4.26 (dd, J = 10.7, 5.3 Hz, 1H), 4.08 (dd, J = 10.5, 6.2 Hz, 1H), 3.38 (d, J= 4.8 Hz, 1H), 2.53 (dd, J = 13.1, 6.0 Hz, 1H), 2.26 (dd, J = 23.8, 11.2 Hz, 1H), 1.59 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 140.7, 136.8, 129.1, 129.0, 128.5, 128.2, 126.6, 121.3, 119.1, 97.4, 57.3, 57.1, 34.5, 29.5, 24.1. HRMS (ESI): Mass calculated for C19H21N4 [M+H]+ 305.1766. Found: 305.1751. (4S,6R)-1-(tert-butyl)-6-phenyl-4,5,6,7-tetrahydro-1Hpyrrolo[2,3-b]pyridine-3,4-dicarbonitrile (3f´). Yield 25% (30mg, in ratio 1:2 with his isomer), white powder, mp. 187191°C. 1H NMR (400 MHz, CDCl3) δ 7.42 (s, 5H), 6.99 (s, 1H), 4.76 – 4.46 (m, 1H), 3.92 (d, J = 5.2 Hz, 1H), 3.61 (d, J = 2.9 Hz, 1H), 2.36 (d, J = 13.5 Hz, 1H), 2.29 – 2.05 (m, 1H), 1.59 (s, 9H). 13C{1H} NMR (101 MHz, CDCl ) δ 141.1, 137.2, 129.0, 128.4, 3 126.6, 120.7, 120.3, 115.5, 96.8, 88.7, 57.1, 55.2, 34.0, 29.5, 23.1. HRMS (ESI): Mass calculated for C19H21N4 [M+H]+ 305.1766. Found: 305.1766. ethyl (5R,6R)-1-(tert-butyl)-3-cyano-6-phenyl-4,5,6,7tetrahydro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (3g). Yield 47.2% (65 mg), white solid (in ratio 2:1 with his isomer), mp. 198-200 °C. 1H NMR (400 MHz, CDCl3) δ 7.51– 7.30 (m, 5H), 6.98 (s, 1H), 4.57–4.43 (m, 1H), 4.32 – 4.14 (m, 1H), 3.72 (dd, J = 5.8, 1.6Hz, 1H), 3.48 (d, J = 3.6 Hz, 1H), 2.43 (d, J = 13.6 Hz, 1H), 1.96 – 1.78 (m, 1H), 1.59 (s, 9H), 1.35 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 173.6, 142.8, 137.0, 128.8, 127.8, 126.7, 120.5, 117.0, 100.2, 89.8, 61.2, 56.7, 55.1, 36.6, 32.7, 29.5, 14.2. HRMS (ESI): Mass calculated for C21H26N3O2 [M+H]+ 352.2025. Found: 352.2022. ethyl (4R,6S)-1-(tert-butyl)-3-cyano-6-phenyl-4,5,6,7tetrahydro-1H-pyrrolo[2,3-b]pyridine-4-carboxylate (3g´). Yellow solid.Yield of the raw mixture 47.2%, (in ratio 2:1 with his isomer), mp. 198-200 °C. 1H NMR (400 MHz, CDCl3) δ 7.51– 7.30 (m, 5H), 6.98 (s, 1H), 4.57–4.43 (m, 1H), 4.32 – 4.14 (m, 1H), 3.72 (dd, J = 5.8, 1.6Hz, 1H), 3.48 (d, J = 3.6 Hz, 1H), 2.43 (d, J = 13.6 Hz, 1H), 1.96 – 1.78 (m, 1H), 1.59 (s, 9H), 1.35 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 173.6, 142.8, 137.1, 128.8, 127.8, 126.7, 120.5, 117.0, 100.2, 89.8, 61.2, 56.7, 55.1, 36.6, 32.7, 29.5, 14.2. Mass calculated for C21H26N3O2 [M+H]+ 352.2025. Found: 352.2022. dimethyl (4S,5S,6S)-1-(tert-butyl)-3-cyano-6-phenyl-4,5,6,7tetrahydro-1H-pyrrolo[2,3-b]pyridine-4,5-dicarboxylate (3h). Yield 53,4% (83 mg), yellow solid. mp. 234-236 °C. 1H NMR (400 MHz, CDCl3) δ 7.39 – 7.28 (m, 5H), 7.07 (s, 1H), 4.62 (d, J



= 8.9 Hz, 1H), 3.99 (d, J = 3.3 Hz, 1H), 3.88 (d, J = 9.0 Hz, 1H), 3.84 (s, 3H), 3.66 (t, J = 3.1 Hz, 1H), 3.57 (s, 3H), 1.63 (s, 9H). 13C{1H} NMR (101 MHz, CDCl ) δ 172.7, 171.5, 139.6, 136.3, 3 128.6, 127.7, 126.2, 122.2, 116.7, 101.9, 89.3, 57.3, 56.2, 52.4, 51.8, 43.3, 39.9, 29.5. HRMS (ESI): Mass calculated for C22H26N3O4 [M+H]+ 396.1923. Found 396.1913 Dimethyl 1-(tert-butyl)-3-cyano-6-phenyl-1H-pyrrolo[2,3b]pyridine-4,5-dicarboxylate (3i). Yield 72.6% (112 mg), yellow solid. mp. 162-165 °C. 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 7.60 (d, 2H), 7.46 (m, 3H), 4.07 (s, 3H), 3.70 (s, 3H), 1.82 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 168.6, 165.3, 151.9, 147.5, 139.4, 137.6, 131.8, 128.9, 128.8, 128.7, 128.4, 122.8, 115.3, 115.2, 84.5, 59.4, 52.8, 52.3, 29.2. HRMS (ESI): Mass calculated for C22H22N3O4 [M+H]+ 392.1610. Found: 392.1599. 1-(tert-Butyl)-5-nitro-6-phenyl-4-(3-(trifluoromethyl)phenyl)1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (3j). Yield 85.7 % (157 mg), orange solid. mp. 205-207 °C. NMR (400 MHz, CDCl3) δ 8.12 (d, J = 3.1 Hz, 2H), 7.89 (s, 1H), 7.86 (d, J = 7.9 Hz, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.65 (t, J = 7.8 Hz, 1H), 7.55 (d, J = 2.7 Hz, 3H), 7.49 (s, 1H), 1.91 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 180.3, 167.4, 162.3, 158.9, 148.6, 137.4, 135.3, 132.3, 131.3, 129.1, 129.1, 127.7 (s), 115.5 (s), 107.3, 59.9 (s), 28.9 (s). HRMS (ESI): Mass calculated for C25H20F3N4O2 [M+H]+ 465.1538. Found: 465.1539 1-(tert-Butyl)-5-nitro-4-(3-nitrophenyl)-6-phenyl-1Hpyrrolo[2,3-b]pyridine-3-carbonitrile (3k). Yield 62,3% (107 mg), orange solid, mp. 148-151 ºC. 1H NMR (400 MHz, CDCl3) δ 8.42 (d, J = 8.5 Hz, 2H), 8.14 (d, J = 7.5 Hz, 2H), 7.98 (s, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.68 (s, 1H), 7.50 (dt, J = 12.6, 7.3 Hz, 3H), 1.94 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 167.4, 162.6, 158.7, 148.8, 147.6, 140.7 (s), 137.2 (s), 131.5, 129.9, 129.2, 127.7, 123.8, 115.4, 60.0, 28.9. HRMS (ESI): Mass calculated for C24H19N5O4 [M]+ 441.1437. Found: 441.1438. 1-(tert-Butyl)-4-(4-cyanophenyl)-5-nitro-6-phenyl-1Hpyrrolo[2,3-b]pyridine-3-carbonitrile (3l). Yield 88,6 % (147 mg), yellow solid. mp. 217-220 °C. 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 7.6 Hz, 2H), 7.94 (s, 1H), 7.82 (d, J = 8.1 Hz, 2H), 7.73 (d, J = 8.1 Hz, 2H), 7.63 (s, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.43 (d, J = 7.3 Hz, 1H), 1.91 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 152.2, 147.8, 141.9, 141.3, 138.9, 135.5, 132.3, 130.1, 129.2, 129.0, 128.9, 128.2, 126.9, 125.3, 118.6, 116.7, 115.8, 115.2, 112.9, 82.5, 59.0, 29.3 Ethyl (E)-1-(tert-butyl)-2-cyano-4-(4-nitrophenyl)-6-styryl-1Hpyrrolo[2,3-b]pyridine-5-carboxylate (3m). Yield 65,6% (70 mg), yellow color, mp. 138-141 ºC. 1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 8.25 (d, J = 7.9 Hz, 2H), 7.93 (s, 1H), 7.67 (d, J = 9.2 Hz, 3H), 7.63 – 7.48 (m, 4H), 7.17 (s, 1H), 6.56 (d, J = 16.0 Hz, 1H), 4.29 (s, 3H), 1.86 (s, 9H), 1.35 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 166.0, 148.5, 143.9, 141.6, 140.6, 134.8, 129.3, 128.9, 128.6, 128.3, 124.2, 122.6, 118.2, 60.9, 29.2, 14.3. Ethyl (4S,5R,6S)-1-(tert-butyl)-3-cyano-6-cyclohexyl-4-(4nitrophenyl)-4,5,6,7-tetrahydro 1H-pyrrolo[2,3-b]pyridine-5carboxylate (3n). Yield 44% (78 mg), light brown powder, mp. 205-209 °C.. 1H NMR (400 MHz, CDCl3) δ 8.17 – 8.13 (tt, 2H), 7.36 – 7.33 (tt, 2H), 6.94 (s, 1H), 4.43 (dd, J = 10.3, 1.6 Hz, 1H), 4.16 – 4.08 (m, 1H), 3.97 (dq, J = 10.8, 7.1 Hz, 1H), 3.29 – 3.23 (m, 1H), 2.77 (d, J = 8.1 Hz, 1H), 2.56 (t, J = 10.1 Hz, 1H), 1.61 (s, 9H), 1.10 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 193.4, 173.1, 149.5, 147.2, 135.8, 129.1, 123.8, 121.6, 115.9, 107.4, 88.2, 61.3, 60.7, 57.0, 53.0, 43.9, 39.8, 31.1, 29.5, 26.5, 26.3, 25.8, 14.2. HRMS (ESI): Mass calculated for C27H35N4O4 [M+H]+ 479.2658. Found: 479.2653 Ethyl (4S,5R,6R)-1-(tert-butyl)-3-cyano-6-(naphthalen-1yl)-4(4-nitrophenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridine5-carboxylate (3o). Yield 47 % (81 mg), orange powder, mp. 152-156 °C. 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 8.3 Hz, 1H), 8.22 – 8.16 (m, 2H), 7.90 – 7.83 (m, 2H), 7.64 (d, J = 7.1 Hz,

1H), 7.55 (dtd, J = 14.6, 6.9, 1.3 Hz, 2H), 7.48 – 7.41 (m, 3H), 7.02 (s, 1H), 5.34 (d, J = 7.9 Hz, 1H), 4.68 (dd, J = 10.3, 1.4 Hz, 1H), 3.67 – 3.51 (m, 2H), 3.30 (dd, J = 17.2, 9.0 Hz, 1H), 3.23 (d, J = 10.1 Hz, 1H), 1.56 (s, 8H), 0.57 (t, J = 7.0 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 172.1, 149.0, 147.3, 135.7, 134.0, 131.5, 129.3, 128.9, 126.6, 126.0, 125.1, 123.9, 123.3, 121.7, 115.9, 88.5, 60.5, 57.2, 54.5, 44.4, 29.5, 13.5. HRMS (ESI): Mass calculated for C31H31N4O4 [M+H]+ 523.2345. Found: 523.2339

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. 1H-

and 13C{1H} NMR spectral data for synthesized compounds. Computational data and X-ray crystallography data and CIF files of 3a and 3g`.

AUTHOR INFORMATION Corresponding Author * E-mail: [email protected].

Author Contributions ‡These authors contributed equally.

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT We acknowledge the financial support by the CONICYT project FONDECYT Iniciación Nº 11160465 and FONDECYT postdoctoral grant N°3170653 for S.G.F.

REFERENCES 1. 2. 3. 4.

5.

6.

Cao M. H; Green, N.; Xu, S. Z. Application of the azaDiels–Alder reaction in the synthesis of natural products Org. Biomol. Chem., 2017, 15, 3105–3129. Fleming, I., Pericyclic Reactions. Oxford University Press: 2015. Fleming, I., Frontier orbitals and organic chemical reactions. Wiley: 1976. (a) Woodward, R. B.; Hoffmann, R., The Conservation of Orbital Symmetry. Elsevier Science: 2013; (b) Hoffmann, R.; Woodward, R. B., Orbital Symmetries and endo-exo Relationships in Concerted Cycloaddition Reactions. J. Am. Chem. Soc. 1965, 87 (19), 4388-4389. a) Sakata, K.; Fujimoto, H. Origin of the Endo Selectivity in the Diels-Alder Reaction Between Cyclopentadiene and Maleic Anhydride. Eur. J. Org. Chem. 2016, 4275–4278; b) Gotoh, H.; Hayashi, Y. Diarylprolinol Silyl Ether as Catalyst of an exoSelective, Enantioselective Diels-Alder Reaction. Org. Lett., 2007, 9 (15) 2859-2862; c) Payette, J.N.; Yamamoto, H. Regioselective and Asymmetric DielsAlder Reaction of 1and 2-Substituted Cyclopentadienes Catalyzed by a Brønsted Acid Activated Chiral Oxazaborolidine. J. Am. Chem. Soc. 2007, 129, 9536-9537. a); García, J. I.; Mayoral, J. A.; Salvatella, L. The Source of the endo Rule in the Diels Alder Reaction: Are Secondary Orbital Interactions Really Necessary?. Eur. J. Org. Chem. 2005, 85-90; b) Fernández, I.; Bickelhaupt, F.M. Origin of the “Endo rule” in Diels Alder reactions. Journal of Computational Chemistry, 2014, 35, 371-376.


Page 6 of 7

Page 7 of 7 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry 7. 8.

9.

10.

11.

12.

13.

14.

García, J. I.; Mayoral, J. A.; Salvatella, L. Do Secondary Orbital Interactions Really Exist? Acc. Chem. Res. 2000, 33 (10), 658-664. a) Lezana, N.; Galdámez, A.; Lühr, S.; Vilches-Herrera, M.; Highly stereoselective and catalyst free synthesis of annulated tetrahydropyridines by intramolecular imino Diels-Alder reaction under microwave irradiation in water. Green Chem., 2016, 18, 3712-3717; b) Becerra‐Ruiz, M.; Vargas, V.; Jara, P.; Tirapegui, C.; Carrasco, C.; Nuñez, M.; Lezana, N.; Galdámez, A.; Vilches‐Herrera, M. Blue‐Fluorescent Probes for Lipid Droplets Based on Dihydrochromeno‐Fused Pyrazolo‐ and Pyrrolopyridines. Eur. J. Org. Chem. 2018, 34, 4795-4801. Ceulemans, E.; Voets, M.; Emmers, S.; Uytterhoeven, K.; Van Meervelt, L.; Dehaen, W.; Diasteroselective intramolecular hetero Diels-Alder approach towards polycyclic heterocycles. Tetrahedron, 2002, 58, 531544. Tietze, L.; Utecht, J.; Inter‐ and intramolecular hetero diels‐alder reactions, 40. Effect of high pressure on the stereoselectivity of intermolecular hetero diels‐alder reactions. Chem. Ber., 1992, 125, 2249-2258. a) Bandarage, U.K; Clark, M.P.; Perola, E.; Gao, H.; Jacobs, M.D.; Tsai, A.; Gillespie, J.; Kennedy, J.M.; Maltais, F.; Ledeboer, M.W.; Davies, I.; Gu, W.; Byrn, R.A.; Nti Addae, K.; Bennett, H.; Leeman, J.R.; Jones, S.M.; O'Brien, C.; Memmott, C.; Bennani, Y.; Charifson, P. Novel 2-Substituted 7-Azaindole and 7Azaindazole Analogues as Potential Antiviral Agents for the Treatment of Influenza. ACS Med. Chem. Lett. 2017, 8, 261-265; b) Kwiatkowski, J.; Liu, B.; Ying Tee, D.H.; Chen, G.; Binte, Ahmad, N.H..; Wong, Y.X.; Poh, Z. Y.; Ang, S.H.; Wai Tan, E.S.; Ong, E.; Dinie, N.; Poulsen, A.; Kanda Sangthongpitag, V.P.; Lee, M.A.; Sepramaniam, S.; Ho, S.Y.; Cherian, J.; Hill, J.; Keller, T.H.; Hung, A.W. Fragment-Based Drug Discovery of Potent Protein Kinase C Iota Inhibitors. J. Med. Chem. 2018, 61, 4386-4396; c) Mérour J.Y.; Buron, F.; Plé, K.; Bonnet, P.; Routier, S. The Azaindole Framework in the Design of Kinase Inhibitors. Molecules, 2014, 19, 19935-19979. Barl, N.; Sansiaume-Dagousset, E.; karaghiosoff, K.; Knochel, P.; Full Functionalization of the 7-Azaindole Scaffold by Selective Metalation and Sulfoxide/Magnesium Exchange. Angew. Chem. Int. Ed., 2013, 52, 10093-10096. Díaz-Ortiz, A.; Carrillo, J.R.; Cossío, F.; GómezEscalonilla, M.; de la Hoz, A.; Moreno, A.; Prieto, P. Synthesis of Pyrazolo[3,4-b]pyridines by Cycloaddition Reactions under Microwave Irradiation. Tetrahedron, 2000, 56, 1569-1577. Teixeira, F.; Rodríguez-Borges, J.; Melo, A.; Cordeiro, N. Stereoselectivity of the aza-Diels–Alder reaction between cyclopentadiene and protonated phenylethylimine derived from glyoxylates. A density functional theory study. Chem. Phys. Lett., 2009, 477, 60–64.

15. Tietze, L.; Fennen, J.; Geißler, H.; Schulz, G.; Anders, E. L. Ab initio and semiempirical calculations of the hetero‐Diels‐Alder reaction of 1‐aza‐1,3‐butadiene with ethene. Liebigs. Ann. Chem., 1995, 1681-1687. 16. Jia, Z-J.; Zhou, Q.; Zhou, Q.Q; Chen, P-Q.; Chen, Y-Ch. Diels–Alder Reaction exo-Selective Asymmetric Diels– Alder Reaction of 2,4-Dienals and Nitroalkenes by Trienamine Catalysis. Angew. Chem. Int. Ed., 2011,50, 8638 –8641. 17. Liu, Z.; Lin, X.; Yang, N.; Su, Z.; Hu, Ch.; Xiao, P.; He, Y.; Song, Z. Unique Steric Effect of Geminal Bis(silane) To Control the High Exoselectivity in Intermolecular Diels−Alder Reaction. J. Am. Chem. Soc. 2016, 138, 1877−1883. 18. a) Yepes, D.; Pérez, P.; Jaquea, P.; Fernández, I. Effect of Lewis acid bulkiness on the stereoselectivity of Diels–Alder reactions between acyclic dienes and α,βenals. Org. Chem. Front., 2017, 4, 1390-1399; b) Zhou, J-H.; Jiang, B.; Meng, F.F.; Xu, Y-H.; Loh,T-P. B(C6F5)3: A New Class of Strong and Bulky Lewis Acid for Exo Selective Intermolecular Diels−Alder Reactions of Unreactive Acyclic Dienes with α,β-Enals. Org. Lett. 2015, 17, 4432−4435. 19. a) Berionni, G.; Bertelle, P-A.; Marrot, J.; Goumont, R. X-ray Structure of a CT Complex Relevant to DielsAlder Reactivity of Anthracenes. J. Am. Chem. Soc., 2009, 131, 18224–18225; b) (a) Konovalov, A. I.; Kiselev, V. D. Diels-Alder Reaction. Effect of Internal and External Factors on the Reactivity of DieneDienophile Systems. Russ. Chem. Rev. 2003, 52, 293311; c) Shihab, M. S. Study of Solvent Effects in DielsAlder Reaction through Charge Transfer Formation by Using Semi-empirical Calculations Bull. Korean Chem. Soc., 2008, 29, 1898–1904. 20. McKay, S.; Haptonstall, B.; Gellman, S. Beyond the Hydrophobic Effect: Attractions Involving Heteroaromatic Rings in Aqueous Solution. J. Am. Chem. Soc. 2001, 123, 1244-1245. 21. Pardo, L.; Branchadell, V.; Oliva, A.; Bertrán, J. Solvent Effect in the Diels-Alder Reaction. J. Mol. Struct. 1983, 93, 255-260. 22. a) Johnson, E. R.; Keinan, S.; Mori-Sánchez, P.; Contreras-García, J.; Cohen, A. J.; Yang, W., Revealing Noncovalent Interactions. J. Am. Chem. Soc. 2010, 132 (18), 6498-6506; b) Contreras-García, J.; Johnson, E. R.; Keinan, S.; Chaudret, R.; Piquemal, J.-P.; Beratan, D. N.;Yang, W., NCIPLOT: A Program for Plotting Noncovalent Interaction Regions. J. Chem.Theory Comput. 2011, 7 (3), 625-632. 23. a) Bickelhaupt, F. M.; Houk, K. N. Analyzing Reaction Rates with the Distortion/Interaction-Activation Strain Model. Angew. Chem., Int. Ed. 2017, 56, 10070−10086; b) Fernández I.; Bickelhaupt, F. M. The activation strain model and molecular orbital theory: understanding and designing chemical. Chem Soc Rev. 2014, 43,4953-67.


Influence of Non-Covalent Interactions in the Exo- and Regioselectivity

Recommend Documents