CurtinâHammett-Driven Intramolecular Cyclization of Heteroenyne

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Curtin-Hammett Driven Intramolecular Cyclization of Heteroenyneallenes to Phenanthridine-Fused Quinazoliniminiums Pamela S Filby, and Sundeep Rayat J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02643 • Publication Date (Web): 19 Jan 2018 Downloaded from http://pubs.acs.org on January 19, 2018

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The Journal of Organic Chemistry

Curtin-Hammett

Driven

Intramolecular

Cyclization

of

Heteroenyne-allenes

to

Phenanthridine-Fused Quinazoliniminiums

Pamela S. Filby and Sundeep Rayat* Department of Chemistry, Ball State University, Cooper Physical Science Building, Muncie, IN 47304 - 0445, United States. [email protected]

TOC/ABSTRACT GRAPHIC

ABSTRACT Intramolecular

cyclization

of

the

heteroenyne-allene,

2-((biphenyl-2-

ylimino)methyleneamino)benzonitrile 1 to phenanthridine-fused quinazoliniminium salt PQ in the presence of a Lewis acid at room temperature involves formation of two new bonds: a C-C bond and a C-N bond.

In this article, density functional theory (B3LYP and M06-2X) was

employed in conjunction with 6-311G* basis set to gain insights into the mechanism of this 1

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cyclization reaction. The solvent effects were considered using Polarizable Continuum Model with nitromethane as the solvent. Our calculations show that C-C bond formation precedes the C-N bond formation. Precisely, the mechanism involves initial protonation of 1, at Nα and Nβ to form rapidly equilibrating conformers of the tautomers 2a,b and 3a,b. The Curtin-Hammett principle is invoked to determine the course of the reaction from these protonated species, which predicts that the intramolecular Friedel-Crafts type N-acylation (C-C bond formation) occurs between the protonated carbodiimide and biphenyl ring of the isomer 3b to form phenanthridinium cation 6b via transition state TS3b6b. Once 6b is formed, it converts to its most stable tautomers 8R and 9a. Once again, the Curtin-Hammett principle suggests that intramolecular nucleophilic attack is preferred from the tautomer 8R, where phenanthridine Natom (Nβ) attacks the protonated nitrile group (C-N bond formation) and results in the formation of intermediate 11 via TS8R11.

11 then tautomerizes to the most stable cation 13. The

coordination of the latter with the chloride anion yields the phenanthridine-fused heterocyclic salt PQ with overall release of energy. The pathways involving protonation at the nitrile (Nγ) of 1 were found to be energetically unfavorable and thus, insignificant to the mechanism of cyclization.

INTRODUCTION Fused heterocycles are represented in many natural and synthetic compounds that exhibit wide range of medicinal applications.1 As a result, there is a high interest in the pursuit of unique ring-fused structures because of their potential to provide new classes of pharmaceutical 2


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agents. For instance, the phenanthridine ring system is featured in compounds that exhibit anticancer,2-4

antituberculosis,5,6

antitrypanosomiasis,7,8

antihepatitis,9,10

and

pesticidal

activities.11,12 Similarly, the 4(3H)-quinazoliniminium motif is an important pharmacophore with cholinesterase

inhibitory,13-16

antihypertensive,17

antimicrobial18

and

antiproliferative

activities.19,20 This scaffold also represents a key precursor to 4(3H)-quinazolinones, which have emerged as important targets in medicinal chemistry with a myriad of interesting biological activities such as antimicrobial,21 antioxidant,22 antimalarial,23,24 anticonvulsive,25 analgesic and anti-inflammatory,26,27 anticancer,28,29 and antihypertensive.30,31 The fusion of phenanthridine and quinazolinimine cores offers the opportunity to expand the library of biologically active structures, and facilitate drug discovery. However, prior to our work,32 no synthetic routes existed in the literature that united the phenanthridine and quinazolinimine ring systems in one molecular skeleton. We have developed an efficient and versatile protocol to obtain phenanthridine-fused quinazoliniminium salts PQ at room temperature that involved one pot Lewis acid assisted cascade/tandem cyclization of heteroenyne-allenes, specifically, the 2((biphenyl-2-ylimino)methyleneamino)benzonitriles 1 (Scheme 1). The reaction is believed to involve in situ generation of a Bronsted acid (e.g. HX, where X = Cl- or BF4-) from Lewis acid (MX) and trace water. A series of PQ functionalized at various positions on the scaffold were prepared in this way from the corresponding heteroenyne-allenes 1 in moderate to good yields.32 The cyclization of 1 to PQ involves (a) C-N bond formation and (b) a C-C bond formation. The sequence in which C-C and C-N bond formations takes place was not clearly evident. Based on a previous study from our research group,33 it was initially hypothesized that the reaction may involve the formation of intermediate I via the addition of the Bronsted acid, 3



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HX on the carbodiimide moiety of 1 followed by nucleophilic addition of the Nβ on the protonated nitrile group (C-N bond formation).

We envisaged that I would subsequently

undergo intramolecular Friedel-Crafts type N-acylation to form PQ (C-C bond formation). To explore this possibility, I was independently synthesized, and when treated with Lewis acid, it failed to cyclize to PQ.32

This indicated that the formation of PQ may not involve the

intermediate I.

C

γ N

α C N

X β N

NH2

N

N

[HX] CH3NO2

X

NH2

N

N

23 oC

1

PQ

X

I

Scheme 1. Phenanthridine-fused quinazoliniminium salt PQ from heteroenyne-allene 1 in the presence of a Bronsted acid (where X = Cl-, BF4-).

In this article, we report a systematic computational investigation of several mechanistic avenues that could be invoked involving the cyclization of 1 to the fused heterocyclic salt PQ. Our primary goal was to identify critical reactive intermediates and the nature of transition states involved in the formation of the final product that may subsequently aid in substrate selection in our future work, or enable us to modify or improve experimental conditions to increase the efficiency and scope of this reaction. The identification of key intermediates may also suggest opportunities to access other chemical frameworks of high importance using these reaction conditions. 4


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COMPUTATIONAL METHODS All calculations were performed using the Gaussian 09 suite of programs.34 Optimized geometries of the stationary points on the potential energy surface were obtained using Density Functional Theory (B3LYP35,36 and M06-2X37) with the employment of the 6-311G*38,39 basis set. Optimizations were followed by vibrational analyses to ensure an imaginary frequency of zero for the ground states and one for the transition states. Each transition state connecting the corresponding reactant and product was confirmed by following the Intrinsic Reaction Coordinate40-43

(IRC) path in both directions. Solvent effect on the reaction energies and

activation barriers were considered by performing single point Polarized Continuum Model (PCM)44 calculations for nitromethane (ε = 38.2) on optimized gas phase geometries. Thermochemical data obtained in gas phase was used with the corresponding single point solvation energies to calculate Gibbs free energies in the presence of solvent (∆G(solv)) at both the levels of theory. The discussion below is based on ∆G(solv) for the level indicated.

The

conformational entropy effect was expected to be small45 and thus not considered in our computations.

RESULTS AND DISCUSSION Reaction Energetics at B3LYP Level of Theory The various possible pathways for the reaction of heteroenyne-allene 1 to phenanthridinefused heterocyclic salt PQ in the presence of HCl as Bronsted acid are discussed below.

5



Protonation of heteroenyne-allene 1 In the presence of HCl, there are three possible sites for protonation of 1, at Nα, Nβ and Nγ, to form tautomers 2, 3 and 4, respectively (Figure 1). Protonation at Nα and Nβ may produce different conformers of 2 and 3, respectively. We consider two synclinal conformers of 2 with respect to the protonated C-Nα bond, in which the –NCN fragment displayed a dihedral angle of 23o (2a) and -44.5o (2b) with the plane of the benzonitrile ring, respectively. Similarly, two conformers are considered for 3. In 3a, ring A of the biphenyl is oriented nearly perpendicular with respect to the carbodiimide, while in 3b, the ring A is in the same plane as the carbodiimide. In case of protonation at the nitrile (at Nγ ), the optimized structure of the conformer 4a is also shown in Figure 1. The highest occupied molecular orbital (HOMO) of heteroenyne-allene 1 was analyzed to determine the preferred sites of protonation (Figure 2). We note that the molecular orbital component is mostly localized on the carbodiimide moiety (-N=C=N-) and on the biphenyl ring attached to the Nβ. There is a little contribution of the molecular orbital from the −CN group. This implies that Nα and Nβ of 1 are more basic than Nγ, and therefore protonation at the former is expected to be thermochemically more favorable than the latter. This hypothesis is also supported by literature precedence that reports carbodiimides to exhibit higher proton affinities than nitriles.46 A preference for protonation at carbodiimide was also noted in our previous mechanistic study.47 Analogously, our current data indicates that protonation of 1 at Nα to form isomers 2a and 2b (+22.3 and +21.7 kcal/mol), and at Nβ to form the isomers 3a and 3b (+23.2 and +24.8 kcal/mol) is more favorable than protonation at Nγ to give 4a (+30.5 kcal/mol) as 6


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shown in Figure 1. There is also not a significant difference in the ∆G(solv) values for the protonation of Nα and Nβ, even though the frontier molecular orbital suggests that Nβ is slightly more basic than Nα and hence, more likely to get protonated (Figure 2).

C

γ N C

β N

α C N

A

+HCl -Cl

αN H

B

γ N C

C

β N

A

αN

γ N C

C

Hβ N

β N

A

B

3a,b

2a,b

γ NH

α C N

A

B

B

1

4a γ

4a (+30.5)

Β

γ

A

4a

∆G(solv), kcal/mole

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


3b (+24.8) 3a (+23.2)

2a (+22.3) 2b (+21.7)

β

A Β

+HCl -Cl

A

β

3b

+HCl -Cl

+HCl -Cl

β

β Α Β

3a 1

α

Α

α

0.0 γ

Β

α

Α

α

α

Α

2a

β

1

Β

Β

2b

Figure 1. Protonation of heteroenyne-allene 1. Energies are computed at B3LYP/6-311G* and include the free chloride ion. Optimized structures of 2a,b, 3a,b and 4a are also shown.

7



Figure 2. HOMO of heteroenyne-allene 1 at B3LYP/6-311G*.

Chemistry from protonated carbodiimide C-C bond formation. Based on the ∆G(solv) values, we predict that protonation of 1 occurs at both Nα and Nβ leading to the formation of more stable tautomers 2b and 3a, respectively, which are expected to rapidly interconvert (Figure 3).

2b also undergoes fast conversion to its

conformer 2a which is only 0.6 kcal/mole higher in energy. The intramolecular Friedel-Crafts type N-acylation involving the protonated carbodiimide and the ring B of 2a and 3a leads to the formation of syn arenium ions 5a and 6a via transition states TS2a5a and TS3a6a, respectively (Figure 4). This process is slightly endergonic for 2a→5a (+0.7 kcal/mole), while exergonic for 3a→6a (-3.0 kcal/mole), and occurs with an activation barrier of 15.8 and 17.8 kcal/mole, respectively. Note that in 5a and 6a, the benzonitrile group is syn to the C=N and C-N bond of the phenanthridine ring system. Similarly, the conversion of 3a to its slightly higher energy conformer 3b (+1.6 kcal/mole) is expected to be fast, and intramolecular Friedel-Crafts type N-acylation from 2b and 3b leads to the formation the anti arenium ions 5b and 6b via transition states TS2b5b and 8


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TS3b6b (Figures 3 and 4). The benzonitrile group in 5b and 6b is anti to the C=N bond and C-N bond of the phenanthridine ring, respectively. The C-C bond formation from 2b→5b and 3b→6b is endergonic by +5.4 and +0.8 kcal/mole, respectively. The transitions states TS2b5b and TS3b6b are found to be +20.6 and +11.5 kcal/mole higher in energy with respect to the corresponding 2b and 3b. The Curtin-Hammett principle is employed to predict the reaction pathway.

This principle states that the product ratio (e.g. 5a,b and 6a,b) from rapidly

interconverting isomers (e.g. 2a,b and 3a,b) is derived by the relative energies of the transition states, (e.g. TS2a5a, TS2b5b, TS3a6a and TS3b6b) and is not significantly affected by the relative energies of the interconverting isomers.48,49 Therefore, we propose that the tautomer 6b is predominantly formed as the energy of TS3b6b is the lowest on the potential energy surface (Figure 4).

9



N

C

2a 2b

N

N

N H H

HN B

H CN

5a

5b

N C HN

3a 3b

HN N

N

H

B

6b +42.3 TS2b5b

+41.0 TS3a6a TS3b6b

TS2a5a +38.1

+36.3

+25.6 6b

H CN

6a


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+27.1 5b

+24.8 3b

+22.3 2a

3a +23.2

2b +21.7

6a +20.2

5a +23.0

Figure 3. Energy diagram computed at B3LYP/6-311G* for C-C bond formation from protonated carbodiimide species 2a,b and 3a,b. Energies are relative to the reactants (1 + HCl), and thus, include the free chloride ion.

10


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TS2a5a

TS3a6a

TS2b5b

TS3b6b

Figure 4. Transition states TS2a5a, TS2b5b, TS3a6a and TS3b6b for the C-C bond formation (B3LYP/6-311G*).

Tautomerizations on the potential energy surface and C-N bond formation. Once 6b is formed, it has the option of undergoing conformational change to form 6a or tautomerization/ conformational change to 5a,b, 7a,b, and 9a,b (Figure 5). The structures 5a,b, and 7a,b can further tautomerize to 8a,b and 10a,b, respectively as shown. We were able to obtain minimum structures for 9a and 9b. However, we were unable to obtain 7a,b, 8a,b and 10a,b. Instead, we obtained the rotamers 7R, 8R and 10R, featuring the benzonitrile group syn to the C=N of the phenanthridine ring analogous to 5a and 6a, however, its –CN group is oriented opposite to the C=N of the phenanthridine ring (Figure 5). The tautomer 9a is predicted to be most stable. The structures 7R and 10R are considerably higher in energy (+46.8 and +37.9 kcal/mole, 11



respectively) from 9a, owing to their highly unstable quinoid-type structure. The tautomers 8R and 9b are only 0.7 and 1.8 kcal/mole less stable than 9a. Thus, we predict that 8R and 9a,b predominate on the potential energy surface. Our search for transition states for C-N bond formation from these tautomers revealed that 8R undergoes rotational change to 8a which then undergoes intramolecular nucleophilic attack from Nβ to its protonated –CN to yield 11 via TS8R11 with an activation barrier of 5.5 kcal/mole (Figures 6). The cyclization of 8R→11 is highly exergonic by -24.8 kcal/mole. Similarly, 9b undergoes E to Z isomerism with respect to its C=Nα bond to form slightly more stable 9a via TS9b9a (Ea = +2.4 kcal/mole) (See supporting information) which then ring closes to yield 12 via transition state TS9a12 (Ea = +15.8 kcal/mole) (Figure 6). This process is endergonic by +14.2 kcal/mole. Since 8R and 9a are rapidly interconverting isomers, once again, the Curtin-Hammett principle48,49 suggests that the pathway 8R→11 will be favored because transition state TS8R11 is -9.6 kcal/mole lower in energy compared to TS9a12 (Figure 6).

Once 11 is formed, it tautomerizes to its most stable

tautomer 13 (-6.4 kcal/mole more stable). The coordination of a chloride anion to 13 gives the phenanthridine-fused heterocyclic salt PQ with -8.5 kcal/mole free energy decrease. (Figure 7).

12


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β N

NH C γ β N α N H

5a (+23.0) 5b (+27.1)

α HN C NH γ

8a

8b

C HN β N α

β N α N

C γ NH

H

9b (+5.9)

βN α N C NH2 γ

7b

α N

α N

NH2 C γ Nβ α N

C NH γ

7a

8R (+4.8)

C NH γ

9a (+4.1)

NH C γ Nβ α N H

Nβ

β HN

γ NH 6a (+20.2) 6b (+25.6)

C γ NH

α N H

10a

10b

Nβ

α N

H

Nβ

C γ NH2

7R (+50.9)

10R (+42.0)

Figure 5. Energies of the various tautomers computed at B3LYP/6-311G*. Structures in blue could not be obtained as stationary points. All energies are in kcal/mole and are relative to the reactants (1 + HCl), and thus, include the free chloride ion.

13



TS9a12 (19.9) 12 (18.3) NH

H N


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TS8R11 (+10.3) 8a

N 9b (+5.9) TS9b9a (+8.3)

8R (+4.8)

9a (+4.1)

NH N N H 11 (-20.0)

Figure 6. Energy diagram for C-N bond formation computed at B3LYP/6-311G*. Reaction energies are relative to the reactants (1 + HCl), and thus, include the free chloride ion. Cl NH

NH

N N H 11 (-20.0)

NH2

NH2

H N

N

N

N

12 (+18.3)

13 (-26.4)

+Cl

-

N N PQ (-34.9)

Figure 7. Tautomerization of 11 and 12 to the final cation 13, and its coordination with chloride to form the product PQ (B3LYP/6-311G*). All energies are relative to the reactants (1 + HCl), and include the free chloride ion (except the salt PQ).

14


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The transition states for the C-N bond formation from tautomers 5a,b to 11 were also located.

These pathways occur via conversion to tautomers 8a,b which is spontaneously

followed by nucleophilic attack from Nβ to the protonated –CN to form the C-N bond. Similarly, the C-N bond formation from the high energy tautomer 10R to 13 was also investigated, which occurred via rotation to 10a followed by cyclization. All of these pathways involve transition states that are considerably higher in energy on the potential energy surface compared to the pathway from tautomer 8R to11. For instance, transition states TS5a11 and TS5b11 are +24.6 kcal/mole and +26.2 kcal/mole, and TS10R13 is +62.2 kcal/mole higher than TS8R11 on the potential energy surface and are therefore, not expected to play any significant role (See supporting information).

Chemistry from protonated nitrile group Since the protonation of heteroenyne-allene 1 at Nγ to form 4a is less favored (Figure 1) compared to protonation at Nα, and Nβ, any further chemistry emanating from this species is expected to have a minor contribution. Our exploration of the potential energy surface reveals that the formation of the arenium ion 15 from 4a occurs in a stepwise fashion (Figure 8). If the C-C bond formation (Friedel-Crafts type N-acylation) occurs prior to C-N bond formation (electrocyclization) via transition state TS4a15 (Ea = +30.5 kcal/mole) intermediate 7a is involved. However, if C-N bond formation (intramolecular nucleophilic attack) occurs before CC bond formation (Friedel-Crafts type N-acylation) via transition state TS4a15ꞌ (Ea = +32.1 kcal/mole), then intermediate 14a is involved.

The process 4→15 is exergonic by -5.9

15



kcal/mole. We note that 15 is a tautomer of 11, 12 and 13, albeit very unstable. Thus, once 15 forms, it would undergo proton migration to form the most stable tautomer 13 with a free energy decrease of-50.9 kcal/mole. The latter upon coordination to chloride anion would yield the final product PQ, as shown in Figure 7. Both 7a and 14a are not viable intermediates on the potential energy surface.

These high energy structures form during the cyclization of 4a→15, and

spontaneously undergo ring closure. The pathway 4a→15 is energetically demanding as the high energy points involving transition states TS4a15 or TS4a15ꞌ are significantly higher on the potential energy surface (at +61.0 kcal/mole and +62.6 kcal/mole relative to the reactants, see Supporting Information) compared to high energy points on the pathway from protonated carbodiimide involving transition states TS3b6b and TS8R11 (at +36.3 kcal/mole and +10.3 kcal/mole, respectively relative to the reactants). Therefore, we deduce that cyclization 1→PQ does not occur from the protonated nitrile intermediate 4a. γ C

NH β N

α C N

A

NH C γ Nβ α N H

TS4a15 (+61.0)

B

7a

4a (+30.5) TS4a15' (+62.6) NH

NH

N N 14a

NH2

N N

N N

H

13 (-26.4)

15 (+24.6)

16


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Figure 8. High energy pathways from protonated nitrile 4a computed at B3LYP/6-311G*. Energies are relative to the reactants (1 + HCl) and thus, include free chloride ion (except for the salt PQ).

Reaction Energetics at M06-2X level of theory The major pathways involved in the cyclization of 1 to PQ were also investigated using dispersion corrected functional M06-2X with the employment of 6-311G* basis set. Although, M06-2X energies were lower than B3LYP (See supporting information), the overall conclusions remain the same at both the levels of theory. Briefly, the protonation at nitrile group of 1 is found to be less favorable than protonation at the carbodiimide, as tautomer 4a (+21.1 kcal/mole) is significantly higher in energy than 2a (+12.3 kcal/mole) and 2b (+13.4 kcal/mole) as well as 3a (+12.1 kcal/mole) and 3b (+11.5 kcal/mole) at M06-2X/6-311G* (Figure S21). The C-C bond formation is predicted to take place from 3b via transition state TS3b6b (+26.0 kcal/mole) to form 6b in accordance with Curtin-Hammett principle as the other transition states TS2a5a (+27.8 kcal/mole), TS2b5b (+30.0 kcal/mole) and TS3a6a (+32.8 kcal/mole) are higher in energy (Figure S22).

Once 6b is formed, it tautomerizes to the more stable tautomers 9a (-9.2

kcal/mole), 9b (-5.7 kcal/mole) and 8R (-6.5 kcal/mole). Analogous to B3LYP, the tautomers 7R (+41.9 kcal/mole) and 10R (+29.1 kcal/mole) are found to be significantly higher in energy at M06-2X/6-311G* (Figure S23). 9b undergoes E-Z isomerism to more stable 9a via TS9b9a (0.7 kcal/mole). Again, the Curtin-Hammett principle suggests that C-N bond formation takes place from 8R via transition state TS8R11 (-3.4 kcal/mole) because it is lower in energy 17



compared to TS9a12 (+6.5 kcal/mole) (Figure S24). Once 11 (-35.8 kcal/mole) is formed, it tautomerizes to more stable 13 (-41.7 kcal/mole) which upon coordination with chloride anion forms the salt PQ (-41.8 kcal/mole) (Figure S25).

CONCLUSION In this article, density functional theory has been employed to investigate the mechanism of tandem/cascade cyclization of hetero-enyne allene 1 to the phenanthridine-fused quinazoliniminium salt PQ through the formation of C-C and C-N bonds. Our work reveals that C-C bond formation (Friedel-Crafts type N-acylation) precedes the C-N bond formation (nucleophilic attack), and the reaction involves initial protonation of 1 at the carbodiimide unit to form 2a,b and 3a,b. The mechanism is driven by the Curtin-Hammett principle which suggests that C-C bond formation involves the pathway 1→2b→3a→3b→ TS3b6b →6b. Once 6b is formed, it tautomerizes to its most stable tautomers 9a,b and 8R. Again, the Curtin-Hammett principle guides the C-N bond formation from 8R→11 via transition state TS8R11. Once 11 is formed, it tautomerizes to the more stable structure 13. The capture of Cl anion by the latter, gives the salt PQ.

Overall, the formation of PQ is predicted to occur with a -34.9 and -41.8

kcal/mole free energy decrease from the reactants 1 and HCl at B3LYP and M06-2X levels, respectively. Our investigation reveals that cyclization from the protonated nitrile intermediate 4a is unlikely at room temperature due to the high energetics computed for this pathway. In summary, the mechanistic insights gained herein suggest that this chemistry could be exploited to construct unique fused heterocycles by careful choice of the aromatic substituent on 18


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Nβ of 1 or even the electrophilic units on the scaffold. To our knowledge, this is the first report of Friedel-Crafts type reaction employing protonated carbodiimides as N-acylating agents, and thus, may provide a viable route to synthesize N,N-disubstituted amidines, which are a prominent class of nitrogen-containing functional groups exhibiting a wide range of biological and pharmaceutical profiles50-54 as well as material applications.55,56 This work is under investigation and will be reported in the future.

ACKNOWLEGDMENTS The authors acknowledge the College of Sciences and Humanities Beowulf Cluster at Ball State University funded by the Office of Sponsored Program for computational time and support. S. Rayat is also grateful for the Senior Research Grant from the Indiana Academy of Science and the ASPiRE Junior Faculty Award from Ball State University for the partial support of this work.

SUPPORTING INFORMATION Proposed mechanistic pathway; optimized structures of the reactants, intermediates, transition states and products; total energies and vibrational data of all optimized structures, and single point PCM energies; high energy pathways computed at B3LYP/6-311G*; all energy diagrams computed at M06-2X/6-311G*; optimized Cartesian coordinates of relevant structures. This material is available free of charge via the Internet at http://pubs.acs.org. 19



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