DFT Studies on Metal-Controlled Regioselective Amination of N

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DFT Studies on Metal-Controlled Regioselective Amination of N-acylpyrazoles with Azodicarboxylates Shujuan Lin, and Zhenyang Lin J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01863 • Publication Date (Web): 03 Sep 2019 Downloaded from pubs.acs.org on September 3, 2019

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The Journal of Organic Chemistry

DFT Studies on Metal-Controlled Regioselective Amination of N-acylpyrazoles with Azodicarboxylates Shujuan Lin and Zhenyang Lin* Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China Author e-mail: [email protected] TOC Graphics

Ag(I)

O

Amine N N

+

N ROOC

ROOC



Amine R = alkyl

N

NH COOR

? Zn(II)

N

N

(major)

COOR N

O



O

N N N ROOC N COOR H (major)

Abstract DFT calculations were carried out to study the reaction mechanisms of Ag(I)- and Zn(II)catalyzed amination of unsaturated N-acylpyrazoles with azodicarboxylates. Our theoretical investigation focused on the origin of the metal-controlled regioselectivity (- versus amination). Through our calculations, it was found that the amination reactions occur via metaldienolate intermediates, in which the Ag(I) center prefers to coordinate with the -carbon or the pyrazolyl N-donor site of the dienolate ligand, while the Zn(II) center prefers to coordinate with the O-donor of the dienolate ligand. The different site preferences for coordination with dienolate between the Ag(I) and Zn(II) metal centers play the key roles for the different regioselectivity observed experimentally. 1 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

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INTRODUCTION Amino-carbonyls are important structural motifs present in many natural, biological and pharmaceutical relevant compounds.1 Thus, various synthetic methods have been developed to access amino-carbonyl compounds.2 Direct amination of organic carbonyl compounds represents one of the most general and straightforward approaches to construct amino-carbonyl substructures.3-8 Many -amino carbonyl products have been successfully obtained through this strategy (-amination).3,4 Experimentally, an -amination often involves formation of an enolate species followed by reaction with electrophilic nitrogen sources (such as azodicarboxylates,5 azides,6 nitroso compounds,7 etc.), as summarized in Scheme 1(a). Amination of organic carbonyl compounds at a -position is more challenging and less reported. A general platform involving enolization of unsaturated carbonyl has been designed to enable -amination, as shown in Scheme 1(b).8 This approach to -amination of organic carbonyl compounds has found limited application, due to the fact that -amination of the formed vinylogous intermediates is competing and generally easier to access.8 Scheme 1. General strategies of electrophilic amination of carbonyls

(a) -amination of carbonyls using electrophilic nitrogen source R3 N O

O cat

cat.

R1

R1 R2

R2

R or R3

N

R3 N3 or N

R3

O

3

N

R1 R2

O

O N

3

N H

R or R1 R

N

2

(b) -amination of carbonyls using electrophilic nitrogen source O R1

R2

O cat

cat. R1

R

[NR2]+

2

O R2

R1

NR2

O

[NR2]+

R2

R1 NR2

2 ACS Paragon Plus Environment

R3

O or N

R1

N R2

OH

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Recently, Zhang and co-workers reported a metal-controlled regioselective amination of unsaturated N-acylpyrazoles with azodicarboxylates.9 Under a silver catalyst, the reaction gives -amination product with high selectivity (eq. 1). Interestingly, -amination product is generated as the major product when a zinc catalyst was used (eq. 2). Scheme 2 presents the plausible mechanisms proposed by the authors who reported these interesting and important findings.9 O



N AgOAc 20 mol% TMG 20 mol%, rt

ROOC

NH

N N

N

+

N



ROOC Zn(OAc)2 20 mol%

R = alkyl

(1)

COOR (major)

COOR

O

N

N

DIPEA 20 mol%, rt

ROOC

N H

N

O N N

(2)

COOR

(major)

For the Ag-catalyzed cycle (Cycle A in Scheme 2), it starts with deprotonation of Nacylpyrazole by the base tetramethylguanidine (TMG), generating the Ag(I)-dienolate intermediate I. In the Ag(I)-dienolate intermediate (I), it was believed that the silver(I) metal center coordinates only with the carbonyl oxygen but not the azo-nitrogen atom, which allows an anti-to-syn rearrangement in the N-acylpyrazole diene moiety, followed by a [4+2] cycloaddition with azodicarboxylate (I  II). Finally, protonation of II leads to the -amino product. The essential steps proposed for the Zn-catalyzed cycle (Cycle B in Scheme 2) also include deprotonation (by the base N,N-Diisopropylethylamine (DIPEA)), C-N bond formation and protonation. The primary difference lies in the C-N bond formation step. The Zn(II)-dienolate intermediate species (III) is proposed to adopt a five-membered ring structure with Zn(II) coordinating with the carbonyl oxygen and azo-nitrogen atoms. Next, azodicarboxylate adds to the -position of the Zn(II)-dienolate intermediate III to construct a new C-N bond, giving the



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intermediate IV. Finally, protonation of the intermediate IV gives the -amino product and regenerates the Zn(II) catalyst.

Scheme 2. Catalytic cycles for the regioselective amination reactions proposed by Zhang et al.9 O

TMGH OAc

DIPEAH OAc N N

O Ag



O



N



O

N

III

I COOR

Zn N

N



AgOAc +

Cycle A: Ag-catalyzed -amination

N N

O

TMG

Zn(OAc)2 Cycle B: Zn-catalyzed -amination

+ DIPEA

COOR N N

ROOC ROOC



N COOR N COOR

 II

R = alkyl

ROOC

N N

Ag O

N

N

N N

ROOC TMGH OAc



DIPEAH OAc O

NH TMG =

O

NCOOR

N N

HN COOR



O





O

Zn N

O

N

IV

N NCOOR N

DIPEA =

N

HN COOR

According to the proposed mechanisms (Scheme 2), the regioselectivity is related to the two different C-N bond formation steps (I  II and III  IV) and originated from the different coordination capabilities of the silver(I) and zinc(II) metal centers in the dienolate intermediates I and III, respectively. In coordination chemistry, it has been well known that Ag(I) complexes often have a linear coordination geometry, while higher and variable coordination numbers (4, 5 and 6) are usually observed for a Zn(II) center. Therefore, the metal-controlled selectivity was believed to be a result of the different coordination capabilities of silver(I) and zinc(II).9 In view of the complexity mentioned above related to the coordination chemistry of Ag(I) and Zn(II), we feel the need to do a more comprehensive theoretical study to reveal the reaction mechanisms and understand how different coordination affects the regioselectivity. In this work, we report the results of our DFT calculations for the amination reactions shown in eqs. 1 and 2. We hope to gain deep insight into the interesting results experimentally observed. 4 ACS Paragon Plus Environment

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RESULTS AND DISCUSSION As mentioned in the Introduction, the difference in the regioselectivity is closely related to the different coordination capability of Ag(I) and Zn(II) with dienolate. Thus, it is important and crucial to examine and understand how Ag(I) and Zn(II) coordinate with dienolate under the reaction conditions (in the presence of amines). According to the general coordination chemistry, we all know that both Ag(I) and Zn(II) have very strong affinity for coordination with N- and/or O-donor ligands. Therefore, to discuss the selectivity issue, we first calculated various dienolate complexes of Ag(I) and Zn(II), considering amine molecules as possible coordinating ligands. In the calculations, we used trimethyl amine as the model amine and MeOOC-N=N-COOMe as the model azodicarboxylate for the computational convenience. The simplification should not affect the major qualitative conclusions made. And then the selectivity issue can be addressed if we know how dienolate interacts with azodicarboxylate (electrophilic nitrogen source) to form a new C-N bond on the basis of the structures calculated for the metal-dienolate species. Dienolate complexes of Ag(I). For dienolate complexes of Ag(I), we located 4 local minimum structures (I1 – I4) which are shown in Figure 1. Three of the four structures adopt two-coordinate, linear arrangement around Ag(I), consistent with our common knowledge regarding the coordination chemistry for Ag(I). Interestingly, I1 is found to be the most stable among the four isomeric structures. Instead of coordinating with the O-donor, the metal center Ag(I) in the most stable isomer binds with the -carbon of the dienolate ligand, a result consistent with the common notion that Ag(I) is a soft metal cation (Lewis acid). In I1, a negative charge associated with the Ag(I)-bonded carbon is stabilized by the nearby electron-withdrawing carbonyl group. I2 has similar coordination arrangement as I1, but is less stable because the carbonyl group is further away from the Ag(I)-bonded carbon that is associated with a negative charge. I4 is the least stable, suggesting that Ag(I) shows weaker affinity for O than for N. 5 ACS Paragon Plus Environment


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2.27

2.29

2.23

2.34

2.30

3.31

2.21

2.17

2.10

2.16

NMe3

NMe3

Me3N

Ag

Ag

Me3N Ag

O

N

N

O

O

O

I4 9.3 (8.2)

I3 2.1 (2.1)

I2

I1 0.0 (0.0)

N N

N

N

N

Ag N

6.4 (5.2)

Figure 1. Optimized structures for the Ag(I) dienolate complexes with selected structural parameters (bond lengths in angstroms). The relative free energies and electronic energies (in parentheses) are given in kcal/mol, taking the lowest-energy structure (I1) as the reference energy point.

NMe3

N N

NMe3

Ag

N

O

N

Ag

O TSI1-I4 15.9 (16.1)

NMe3 TSI3-I4

Ag

N N O TSI1-I2 12.6 (11.3)

10.8 (8.8) 9.3 (8.2)

6.4 (5.2)

Me3N 2.1 (2.1)

N

Ag

NMe3

N

Me3N

0.0 (0.0)

O

O

Ag N

Me3N

I4

Ag N

N O

Ag

N

N

I2

N I3

O I1

Figure 2. Energy profile calculated for isomerization among the four Ag(I) dienolate complexes located. The relative free energies and electronic energies (in parentheses) are given in kcal/mol.

Our DFT results also indicate that the four structures for Ag(I)-dienolate species shown in Figure 1 can isomerize to each other. The energy profiles calculated for isomerization processes are shown in Figure 2. Starting from the lowest-energy structure I1, isomerization to I2 occurs through an 3-allylic transition state (TSI1-I2), which has a barrier of 12.6 kcal/mol. I1 can also undergo isomerization via TSI1-I4 to I4 in which the Ag(I) center coordinates to the carbonyl


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oxygen. This step needs a barrier of 15.9 kcal/mol. I4 is the least stable, and easily isomerizes to the more stable isomer I3. The barrier for this process is 1.5 kcal/mol via TSI3-I4. We also explored structures with two amine ligands and one dienolate ligand on the basis of I1, I2 and I4. The calculated structures show T-shape arrangement around Ag(I) and are in general less stable (Figure S1). We do not consider these structures further because they are not expected to play a role in the amination reactions. Ag(I)-catalyzed amination processes. The next issue that needs to be addressed is the selectivity in C-N bond formation step (I  II in Scheme 2). Figure 2 shows that there exist equilibria among the four Ag(I) dienolate intermediates, thus all of which are in theory potentially capable of undergoing amination reactions with azodicarboxylate in the reaction system. We first consider the amination processes which start from the most stable Ag(I)-dienolate species I1. To form C-N bond, the first step is that a molecule of azodicarboxylate coordinates via one diazo-nitrogen atom to the Ag(I) center of the Ag(I)-dienolate species I1. Such coordination, which gives I1a (Figure 3), makes the two diazo-nitrogen atoms in azodicarboxylate distinct, distinguished as coordinated and uncoordinated in the following discussion. In the C-N bond formation step, both of the - and -carbons of the dienolate ligand in I1a are available for electrophilic attack by the uncoordinated or coordinated diazo-nitrogen atom of azodicarboxylate to form a new C-N bond. Thus, in theory there exist four possible C-N bond formation paths: (i) coupling of the -carbon with the uncoordinated diazo-nitrogen to give II1; (ii) coupling of the -carbon with the coordinated diazo-nitrogen to give II1′; (iii) coupling of the -carbon with the uncoordinated diazo-nitrogen to give II2; (iv) coupling of the -carbon with the coordinated diazo-nitrogen to give II2′. The first two paths (to give II1 and II1′) would produce the -amination product after protonation, and the last two paths (to give II2 and II2′) produce the -amination product. 7 ACS Paragon Plus Environment


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N2R'2

L

R'

L N Ag

R'

R'

0.0 (0.0)

N

N

R'

N O I1

Ag

R'

N

-11.2 (-29.1)

N N

L

I1a

N

Ag

N

N O

Ag N N

N

TSI1b-II2 -9.8 (-27.8)

O TSI1b-II1' -9.2 (-27.9)

N

O TSI1a-II1 -12.3 (-30.2)

R'

R'

N

R'

R' N

L Ag

N

-11.1 (-29.5)

N

R'

N O

-14.6 (-34.2) TSI1b-II1

N N

O

R'

L

-16.3 (-34.2)

Ag

R'

N

N

R'

N

Ag

N

L

O TSI1a-I1b -12.7 (-29.0)

L

N

L

TSI1b-II2' MeO

N N R'

I1b

L

R' N

L

Ag

-26.8 (-48.5)

N R'

N N

O II2'

II2'

NMe3

N

-22.2 (-42.1)

O

Ag R'

N

N

R' = COOMe

O

C

Ag N

L=

L

N

II1'

N

MeO C N

O

Ag R'

N

N N

-29.2 (-48.4)

O TSI1b-II1 L

N

II1' L

-37.4 (-57.7)

Ag R'

O

II2

Ag

II1 N

R'

N N

II1

O

R'

N

R' N

N

N

O II2

Figure 3. Energy profile calculated for Ag(I) catalyzed -amination (in black lines) and amination (in red lines) processes from the most stable Ag(I)-dienolate complex (I1). The relative free energies and electronic energies (in parentheses) are given in kcal/mol. As shown in Figure 3, from I1 to I1a, there is no transition state for this coordination step, as all of geometry optimization calculations lead to I1a regardless what starting geometry was used. Starting from this azodicarboxylate-coordinated species I1a, we however only located the first pathway discussed above, which is very facile and involves coupling of the -carbon with the uncoordinated diazo-nitrogen to give II1 via TSI1a-II1. Attempt to locate other transition state structures leads to the following interesting finding: isomerization of I1a to I1b (a linkage isomer) from which the four pathways were all located (Figure 3). The linkage isomer I1b allows structural flexibility making all of the four pathways possible. Clearly, it is the geometric


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constraint in I1a that resulted in only the first pathway being located. Selected structures related to Figure 3 are presented in Figure S2 (Supporting Information). Figure 3 clearly shows that the -amination involving coupling of the -carbon with the uncoordinated diazo-nitrogen to form II1 is the most favorable path both kinetically and thermodynamically. In I1a and I1b, the uncoordinated diazo-nitrogen atom of the coordinated azodicarboxylate is directly lying above the -carbon of the dienolate (Figure S2). Thus, the coupling between the two atoms in the transition states (TSI1a-II1 and TSI1b-II1) causes the least structural change when compared to other coupling pathways, facilitating the C-N bond formation to make the -amination precursor complex II1 kinetically the most favorable, consistent with the experimental observation. Experimentally, a : product ratio of over 20:1 was observed,9 indicating that the relative barriers are qualitatively consistent. It is here worth commenting that in Cycle A of Scheme 2, I  II corresponds to a [4 + 2] cycloaddition process.8a,9 We attempted to examine if we were able to see such a [4 + 2] cycloaddition process for the transformation from I1b to II1. The cycloaddition process first requires a trans-to-cis isomerization in the dienolate moiety in I1b, which has a significant barrier. In addition, our attempt to locate a cis intermediate for the [4 + 2] cycloaddition always leads to the C()-N(uncoordinated) bond formation. In view of the very small barrier for the direct transformation of I1b to II1 (Figure 3) together with the additional calculations mentioned here, we conclude that a [4 + 2] cycloaddition process is not responsible for the -amination. As mentioned above, other isomers (I2 – I4) (Figure 1) could also potentially undergo amination processes. However, when we examine both Figures 2 and 3, we clearly see that the barriers leading to the formation of the -amination precursor complex II1 are small. When the relative stabilities among the different isomers (I1 – I4) and the barriers for isomerization from one to the other are taken into account, we conclude that the isomers I2, I3 and I4 are not participating the C-N coupling that leads to the -amination.9 9 ACS Paragon Plus Environment


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Dienolate complexes of Zn(II). It is well known that Zn(II) is capable of adopting three coordination numbers - 4, 5 and 6. Thus, we considered structures of Zn(II) dienolate complexes with different coordination numbers. For 4-coordinate complexes, considering that Zn(II) has a charge of +2, we have the following possible ligand combinations: (i) two bidentate ligands (dienolate and acetate), (ii) one bidentate ligand + one 1-bidentate ligand + one amine ligand, and (iii) two 1-bidentate ligands + two amine ligands. For the first combination, we located three isomers (III1, III2 and III3) shown in Figure 4(a). These three isomers are derived from the fact that the dienolate ligand has several donor atoms, including azo-nitrogen, carbonyl oxygen, and the - or -carbon. Among the three isomers shown in Figure 4(a), the 2-N,O-dienolate species III1 is found to be the most stable structure, consistent with our knowledge that Zn(II) shows high affinity to N- and O-donor ligands over a C-donor ligand. The second combination gives only one 4-coordinate local minimum structure (III4). The acetate ligand shows high preference to be 2-coordinated to the Zn(II) metal center, giving no chance to have a species having an 1acetate, an 2-dienolate and an amine. The third combination does not give 4-coordinate species, again because the acetate ligand shows high preference to be 2-coordinated. We then calculated 5-coordinate structures having ligand sets as (i) an 2-acetate, an 2dienolate and one amine ligand; and (ii) an 2-acetate, an 1-dienolate and two amine ligands. For (i), we added one amine ligand to the most stable 4-coordinate structure III1 and used different starting structures for geometry optimization. As shown in Figure 4(b), the lowest-energy 5coordinate structure is a distorted square-pyramidal structure III5, which is more stable than III1 + NMe3 by 13.4 kcal/mol. All the possible stereoisomers having square-pyramidal (SP) or trigonal-bipyramidal (TBP) structures (Figure S3), are also considered and eventually converged to III5 in all of our geometry optimization calculations. For (ii), the 5-coordinate structure, having an 2-acetate, an 1-dienolate and two amine ligands, lies >10 kcal/mol higher in free energy than III5 (Figure S4). 10 ACS Paragon Plus Environment

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For 6-coodination dienolate complexes, we do not consider cases containing two amine molecules in view of the fact that in the catalytic reactions reported Zn(II) and amine are all in catalytic amount with the same equivalent quantities. Thus, when azodicarboxylate is included, we have three possible scenarios shown in Figure 5(a), (b) and (c) in which one amine is present. We also consider Zn(II) dienolate complexes without amine (Figure 5(d)). However, they are not as stable as those having one amine. Up to this point, we examined all the feasible dienolate complexes of Zn(II). Among these dienolate complexes, III5b-1 is not only the most stable species but also significantly more stable than any other species calculated (Figures 4 and 5).

(a) 4-coordination Zn(II)-dienolate-acetate complexes 2.05 2.12

1.90

N

2.05

2.00

2.02

N

1.87 2.09

2.06

2.01

1.98 2.05

O Zn

O

O

2.08

2.14

2.04

N

N

O Zn

N

O

O Zn

O

O

III2 2.6 (3.1)

III1 0.0 (0.0)

N

2.04

N

O

N

O

O

Zn

Me3N

O

III4 1.5 (-11.1)

III3 8.2 (9.5)

(b) Structure of III5 2.06 N

N O

NMe3 Zn

O O

N

NMe3

2.16 O

O

2.13

140.6 163.7 2.05

O

1.97

III5

Figure 4. Optimized structures for (a) 4-coordinate dienolate-acetate Zn(II) complexes and (b) 5coordinate dienolate-acetate Zn(II) complex (III5) with selected structural parameters (bond lengths in angstroms and bond angles in degree). Note that the relative free energies and electronic energies (in parentheses) are given in kcal/mol taking the lowest-energy structure (III1) (+NMe3) as the energy reference point.

Zn(II)-catalyzed amination processes. As discussed above, III5b-1, having an 2azodicarboxylate, an 1-O-dienolate, an 2-acetate and one amine, is much more stable than any other structures (Figures 4 and 5). It is more stable by 7.3 kcal/mol than the second most stable 11 ACS Paragon Plus Environment


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structure III5a-1, and by 10.8 kcal/mol than the third most stable structure III5. As we will see clearly later, III5b-1 plays the key role in the amination processes.

(a) 1- azodicarboxylate + 2- dienolate + - acetate + amine

N

O

Zn

O O N

MeO

NMe3

NMe3

N

N

O

O

N

N

R'

N

O

Zn

O

O

N

MeO

N

N

Zn

R'

O N

MeO

N

NMe3

N N

NMe3 O

III5a-2 -12.2 (-39.8)

III5a-1 -16.8 (-47.3)

(c) 2- azodicarboxylate + 2- dienolate + - acetate + amine

(b) 2- azodicarboxylate + 1- dienolate + - acetate + amine

O

O O

O

MeO

O

Zn N N

R'

N

O

O

R'

R'

III5b-2

III5b-1 -24.1 (-58.0)

N

NMe3 O Zn O O OMe N N

III5c -13.6 (-44.3)

-14.8 (-47.6)

(d) 2- azodicarboxylate + 2- dienolate + - acetate

N

N O

O Zn O

O N N

N R'

MeO

III5d-1 -5.9 (-22.1)

N O

R'

O Zn

O

N N

N

O OMe

N O

N Zn

MeO

N

OMe O O

O

N

N O

R'

III5d-2 -6.8 (-23.7)

III5d-3 -6.1 (-21.1)

O Zn

N N

R'

O O

III5d-4 -2.8 (-17.9)

R' = COOMe

Figure 5. Structures calculated for 6-coordinate dienolate-acetate Zn(II) complex involving azodicarboxylate. The relative free energies and electronic energies (in parentheses) are given in kcal/mol. The lowest-energy 4-coordinate structure (III1) + azodicarboxylate (+ NMe3) (Figure 4a) was taken as the energy reference point.

Indeed, we have been able to find an extremely facile pathway leading to the formation of the most stable dienolate complex III5b-1 (Figure 6). To achieve charge neutrality, we first start with the 4-coordinate Zn(II)(dienolate)(acetate) species III1. Considering the high affinity of Zn(II) for amine, we expect that III5 is then easily formed from III1 and NMe3 (III5 is more stable by 13.4 kcal/mol than III1 + NMe3). Inclusion of azodicarboxylate into III5 conveniently leads to III5a-1 and then to III5b-1 (Figure 6). In view of the very facile nature of the transformation leading to III5b-1 and the remarkably high stability of III5b-1 (when compared to other isomeric structures), we conclude that III5b-1 is the precursor complex for C-N bond formation, and we do not expect other dienolate species are actually involved in the product formation processes.


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L

N

N Zn

N

O

O

N

L

O

Zn

O

N

N

0.0 (0.0) N O

O

R'

III1

L Zn N

O

MeO

O R'

N

TSIII5-III5a N2R'2 -13.4 (-27.9)

N Zn O III5

L O

R'

O

TSIII5a-III5b

N

-8.0 (-40.5)

N

R'

N

L

O O

O OMe

N

O

TSII

N

O O N

N

Zn

MeO

N

N

OMe

N

L O

-20.0 (-54.9)

L

O

R' N

TSIII5b-IV1

-15.6 (-48.9)

-16.8 (-47.3)

O

Zn

N

I5b-I -9.1

(-42.7) V2'

O O

O R'

N

O

Zn N

O OMe

N

N

O

TSIII5b-IV2

-24.1 (-58.0)

O R' N

III5a-1

N

-22.4 (-56.4) L

L O

O

O

O

N

N

MeO

O

Zn

O

N

R'

N

O

Zn

O

R' = COOMe N

R'

N

N

Zn

R N

-29.8 (-65.6)

O O N

IV2'

OMe

O

R' N

N

IV2'

IV1'

O O

-41.2 (-73.1)

OMe

O

Zn

R' N

N

OMe

L

III5b-1 O

O

Zn

R' N

N

OMe

L O

Zn O R' N

IV2 OMe

O N

IV1'

-44.5 (-76.6)

O

O

N

IV1

N

O N

L -34.9 (-69.9)

O

O

Zn

N

O

TSIII 1'

N

L O

5b-IV

L

L = NMe3

Zn

-12.7 (-42.0)

L N

N

O O

O O N

N

OMe

N

N IV2

IV1

Figure 6. Energy profiles calculated for the very facile pathway leading to the formation of the most stable dienolate complex III5b-1 Zn(II) from the 4-coordinate Zn(II)(dienolate)(acetate) species III1, and for the -amination (in black lines) and -amination (in red lines) processes from III5b-1. The relative free energies and electronic energies (in parentheses) are given in kcal/mol. Note that the lowest-energy 4-coordinate structure (III1) + azodicarboxylate + NMe3 was taken as the energy reference point.

The calculated energy profiles for Zn(II)-catalyzed amination processes from III5b-1 are also shown in Figure 6. Similar to the situation for Ag(I)-catalyzed amination processes, there are four possible paths to form C-N bond from III5b-1. They are: (i) coupling of the -carbon with the uncoordinated diazo-nitrogen to give IV1; (ii) coupling of the -carbon with the coordinated diazo-nitrogen to give IV1′; (iii) coupling of the -carbon with the uncoordinated diazo-nitrogen to give IV2; (iv) coupling of the -carbon with the coordinated diazo-nitrogen to give IV2′. Figure 6 shows that the most favored pathway is -amination of III5b-1 to IV1′, which only needs a very small barrier of 1.7 kcal/mol (TSIII5b-IV1′). The barriers for other paths to give IV1, IV2 and IV2′ (TSIII5b-IV1, TSIII5b-IV2 and TSIII5b-IV2′) are higher than that of the path to give IV1′. In the intermediate III5b-1, the -carbon of dienolate ligand is close to the coordinated nitrogen 13 ACS Paragon Plus Environment


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atom of the azodicarboxylate (Figure S5). Thus, the coupling path to give IV1′ is facilitated due to the structural advantage. We also consider other possible coupling pathways from III5 and/or III5a-1 directly. The barrier of the pathway for the direct amination from III5 is remarkably high (Figure S6). The transition states of the direct amination from III5a-1 could not be located after a lot of attempts. The failure (location of transition states) is due to the fact that in III5a-1 the diazo-nitrogen atoms in the azodicarboxylate and the -carbon atoms in the coordinated dienolate are far apart from each other. Clearly, under the Zn(II)-catalysis condition, the reaction proceeds through the 6-coordianted Zn(II)-dienolate precursor complex III5b-1, from which the -amination to form IV1′ is most favored having a barrier of 1.7 kcal/mol (Figure 6). Generating -amination product needs a barrier of 4.1 kcal/mol, which is competing with -amination (Figure 6). The calculation results are again consistent with the experimental observation that -amination product is the major product.9 Experimentally, an : product ratio in the range of 2:1 to 11:1 was observed,9 indicating that the relative barriers are again qualitatively consistent. 9 Ag(I)- versus Zn(II)-catalyzed amination. Our calculation results above show that for the Ag(I)-catalyzed amination, the dienolate intermediates I1a and I1b are the key species for C-N bond formation, while for the Zn(II)-catalyzed amination, III5b-1 is the key intermediate for amination. Figure 7 summarizes the calculation results presented in Figures 3 and 6 regarding the relative C-N bond coupling preferences. From Figure 7, we can easily observe the following. The preferential coordination of Ag(I) with either the carbon-donor or pyrazolyl N-donor site of dienolate creates a favorable situation for both C and the uncoordinated N of azodicarboxylate to be in very close proximity, giving the C-N coupling the most favorable coupling (Figure 7(a)). For the Zn(II)-catalyzed amination, the preferential coordination of Zn(II) with the O-donor site 14 ACS Paragon Plus Environment

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of dienolate makes the C carbon easily accessible for the coordinated N of azodicarboxylate, facilitating C-N coupling. R N N R 

R N

[Ag] N N





[Ag] N R



O

I1a only C()-N(uncoordinated) coupling is located





N N

O I1b

Coupling type: (1) C()-N(uncoordinated) Most favorable (2) C()-N(coordinated) (3) C()-N(uncoordinated) Least favorable (4) C()-N(coordinated)

[Ag] = AgNMe3 R = COOMe (a)

O

RN

N N

[Zn]





O N

OMe



Coupling type: (1) C()-N(coordinated) Most favorable (2) C()-N(uncoordinated) (3) C()-N(uncoordinated) Least favorable (4) C()-N(coordinated)

III5b-1 [Zn] = Zn(NMe3)(2-OAc) R = COOMe (b)

Figure 7. Schematic illustration of relative preferences among the various C-N couplings on the basis of calculation results presented in Figures 3 and 6.

CONCLUSION In this work, we carried out DFT calculations to study the mechanisms of Ag(I)- and Zn(II)catalyzed amination reactions of N-acylpyrazoles with azodicarboxylates. Experimentally, the Ag(I)-catalyzed reaction gives -amination as the major product while the Zn(II)-catalyzed reaction gives -amination as the major product. Through our systematic calculations, we have been able to identify the precursor dienolate complexes that are responsible for the favorable C-N bond formation leading to the final products. We found that Ag(I) prefers to coordinate with either the carbon-donor or pyrazolyl N-donor site of dienolate, while Zn(II) prefers to coordinate with the O-donor site of dienolate. It is the different preferential coordination between Ag(I) and 15 ACS Paragon Plus Environment


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Zn(II) in the precursor complexes that makes the regioselectivity difference observed experimentally. COMPUTATIONAL DETAILS All molecular geometries were fully optimized at the DFT level using the B3LYP functional.10 The metal atom Ag is described by the effective core potentials (ECPs) of Hay and Wadt with a double- vanlence basis set (lanl2dz) 11 and addition of one set of f-type polarization functions (f = 1.611).12 For Zn, 6-311G** basis set was used. For other atoms including H, C, N, O, the 6-31G* basis set was used. Vibrational frequency calculations were performed at the same level of theory to verify the nature of the stationary points as local minima (which have no imaginary frequency) or transition states (which have only one imaginary frequency). Intrinsic reaction coordinate (IRC) calculations were also carried out to make sure that the transition states could connect two relevant minima.13 To take into account the effects of solvation, dispersion and basis set, single-point calculations were carried out using DFT-D314 together with the PCM solvation model.15 For single-point calculations, Ag was described by Stuttgart/Dresden ECPs (SDD)16 with addition of one set of f-type polarization functions, while Zn was described by the polarization triple- basis set Def2TZV.17 6-31G** was used for other atoms. The solvent is specified as diethyl ether. All of the DFT calculations were performed with the Gaussian 09 software package.18 Optimized structures of selected intermediates and transition states were visualized by the XYZviewer software developed by de Marothy.19


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ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.***. 5-coordinated Zn(II)-dienolate complex with two amine ligand, optimized structures for selected species in Figures 3 and 6, energy profiles for direct amination from III5, and Cartesian coordinates for all optimized structures (PDF) AUTHOR INFORMATION Corresponding Author ORCID Zhenyang Lin: 0000-0003-4104-8767 Notes The authors declare no competing financial interest. ACKNOWLEDGMENTS This work is supported by the Research Grants Council of Hong Kong (HKUST16304617).

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DFT Studies on Metal-Controlled Regioselective Amination of N

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