Site-Selective Functionalization of Pyridinium Derivatives via Visible

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Site-Selective Functionalization of Pyridinium Derivatives via Visible Light Driven Photocatalysis with Quinolinone Inwon Kim, Gyumin Kang, Kangjae Lee, Bohyun Park, Dahye Kang, Hoimin Jung, Yu-Tao He, Mu-Hyun Baik, and Sungwoo Hong J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 24 May 2019 Downloaded from http://pubs.acs.org on May 24, 2019

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Journal of the American Chemical Society

Site-Selective Functionalization of Pyridinium Derivatives via Visible Light Driven Photocatalysis with Quinolinone Inwon Kim, Gyumin Kang, Kangjae Lee, Bohyun Park, Dahye Kang, Hoimin Jung, Yu-Tao He, MuHyun Baik* and Sungwoo Hong* Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Korea Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 34141, Korea Supporting Information Placeholder

ABSTRACT: The selective installation of phosphinoyl and carbamoyl moieties on the pyridine scaffold is an important transformation in synthetic and medicinal chemistry. By employing quinolinone as an efficient organic photocatalyst, we developed a catalytic system driven by visible light that forms phosphinoyl and carbamoyl radicals, which react with various heteroarenium derivatives under mild, transition-metal-free conditions. This straightforward and environmentally friendly synthetic method represents a new approach to site-divergent pyridine functionalization that offers considerable advantages in both simplicity and efficiency. Ambient temperature is sufficient for the formation of the reactive radicals, and the site-selectivity can be switched from C2 to C4 by changing the radical coupling sources. Under standard reaction conditions, phosphinoyl radicals give access to C4 products, while carbamoyl radicals selectively give C2 products. We found that the carbamoyl radical overcomes the intrinsic preference for forming the ortho-product by allowing the oxo functionality of the carbamoyl radical to electrostatically engage the nitrogen of the pyridinium substrate, which preferentially gives the ortho-product. The phosphinoyl radical cannot engage in the same interaction, because the phosphorus is too large. This novel synthetic route tolerates a broad range of substrates and provides a convenient and powerful synthetic tool for accessing the core structures of numerous privileged scaffolds.

INTRODUCTION The site-selective modification of heteroarenes bearing multiple reactive sites requires the selective recognition of often very subtle steric and electronic differences between them. The successful exploitation of these differences can afford powerful synthetic methodologies.1 The direct functionalization of pyridine using metal catalysts or photocatalysts has been studied extensively,2 because it promises convenient and cost-effective access to core structures of many privileged heterocycles that are important in medicinal chemistry3 and materials science.4 However, directly and regio-selectively installing functional groups onto pyridine scaffolds remains a difficult challenge. Current methods are often problematic in industrial applications due to the use of expensive and toxic metal catalysts and harsh reaction conditions.5 As a result, there is a growing demand for methods that can efficiently and site-selectively functionalize pyridine derivatives in a predictable and controllable manner under mild, transition-metal-free conditions. Recently, Herzon reported an elegant method for stoichiometric cobalt-mediated reductive coupling of alkenes with Nmethoxypyridinium salts under hydrogen-atom transfer (HAT) conditions to afford alkylpyridine products.6 Important advances have been made by Cho in the base-promoted deborylative alkylation of pyridine N-oxides in a C2 selective manner using 1,1diborylalkanes.7 Furthermore, Kanai successfully explored C2 and C4 selective fluoroalkylation of the pyridine core via a stepwise sequence involving direct activation of substrates with a borane Lewis acid, fluoroalkylation, and oxidation for rearomatization.8 Furthermore, McNally disclosed regioselective nickel-catalyzed cross-coupling of pyridines using phosphonium salts as pseudohalides.9 However, these approaches and previous Minisci-type reactions remain largely limited to

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the introduction of alkyl groups to the pyridine core. The site-selective installation of other functionalities such as amide and phosphinoyl moieties on the pyridine scaffold are highly valuable and particularly so, if mild and transition-metal-free conditions could be used. Recently, photoredox catalysis mediated by visible light emerged as a powerful tool in organic synthesis,10,11 and we imagined that it may offer a convenient platform to develop such a solution for the direct functionalization of pyridine.

quinolinone as photocatalyst

MeO H N OEt

P

R R

R N

H R

O

O R H P R

N

O P Ph Ph O

C4 selective phosphinoylation

Q1 1 mol %

mild conditions broad scope

R

O

20 oC H

NR2

N O

NR2

C2 selective carbamoylation

Figure 1. Design and development of visible-light-induced site-selective functionalization of pyridines. Previously, Lakhdar reported an intermolecular HAT reaction of alkoxy radicals generated from N-ethoxypyridinium salts for the efficient phosphonation of arylphosphine oxides with alkynes12 and we demonstrated that quinolinone and coumarin derivatives are capable of forming reactive alkoxy radicals from N-alkoxypyridinium salts upon excitation by light to develop synthetically useful transformations.13 Inspired by these studies, we questioned whether pyridinium salts may undergo visiblelight-induced cross-dehydrogenative coupling (CDC) reactions with reactive radical species to afford functionalized pyridines. We speculated that by carefully choosing the radical species and controlling the reaction conditions we may invoke regioselectivity by exploiting subtle differences of the pyridinium salts.14 As outlined in Figure 1, we discovered that the siteselectivity can be determined by the judicial selection of the radical source. Phosphinoyl radicals display a strong preference for the C4-position, whereas carbamoyl radicals favor addition to the C2-position. The origin of these remarkably regioselective radical additions is studied in detail by combining experimental and computational methods. This powerful transformation establishes a new synthetic method that allows for site-divergent functionalizations of pyridine derivatives driven by visible light and offers considerable advantages in both simplicity and efficiency under transition metal-free conditions. Ambient temperature is sufficient for the formation of the phosphinoyl and carbamoyl radicals and they can be incorporated directly into synthetically and biologically important pyridine scaffolds.

RESULTS AND DISCUSSION Initial studies revealed that the photoreduction of the pyridinium salt 1a (Ered = –0.60 V vs the saturated calomel electrode)12,15 by the excited state of 3-phosphonated quinolinones (Q1*, E*red = –1.29 V vs SCE)13c is feasible. The exposure of quinolinone to visible light produces ethoxy radicals via single electron transfer (SET) that leads to the cleavage of the N–O bond of the N-ethoxypyridinium salt under very mild conditions. Moreover, installation of the phosphinoyl group into the quinolinone scaffold at the C3 position induces a red-shift in the emission wavelength reaching up to 520 nm, as detailed in the Supporting Information, and enables a more efficient photocatalysis under visible-light illumination. Based on these results, we first examined the envisioned direct phosphonylation of the N-ethoxypyridinium salt (1a) with diphenylphosphine oxide (2a) under blue LED irradiation at 20 °C and the results are summarized in Table 1. To our delight, the pyridinium ion 1a was found to undergo a C4-selective phosphonation. Among the solvents screened, 1,2-DCE was most


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efficient in this reaction, and the desired product was obtained in 62% yield (entry 4). A range of C3-phosphinoylated quinolinones that were efficiently prepared using our recent protocol13d were tested, and Q1 was most effective. Thus, Q1 was chosen for further exploration (entries 6-10). In the absence of a base, the yield of the desired product was only 24%, presumably due to the increasing acidification of the medium as the reaction proceeds. Under the same reaction condition, the inorganic oxidant K2S2O8 promoted the transformation more efficiently (70%, entry 6). Using these conditions, several common photocatalysts including Ru and Ir complexes, and an organic dye Eosin Y were tested and found to be less efficient than Q1 (entries 11-13). Control experiments confirmed the essential role of the catalyst and visible light in this reaction (entries 14 and 15). We also conducted control reactions using alternating intervals of light and dark, and observed that product was formed only upon irradiation (see the SI for details). The inhibition of the reactivity when 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) was added (entry 16) and detection of the corresponding TEMPO-adduct by mass spectrometry suggests that a radical process is involved. We next surveyed the counterions of the pyridinium complex, including I– and EtSO3–, and found that BF4– provided optimal yields (see the SI for details). Through systematic screening of the reaction conditions, a stirred solution of 1a, diphenylphosphine oxide, NaHCO3 (1.2 equiv), and K2S2O8 (1.5 equiv) in 1,2-DCE at 20 °C for 16 h gave 3a in 70% yield with regioselectivity of >40:1 (para:ortho). Table 1. Optimization of Visible-Light-Induced C4 Selective Phosphonylation.a

Me

+

N BF 4 OEt 1a

Ph O P Ph

PC (1 mol %) NaHCO3 (1.2 equiv)

O Ph P H Ph

blue LED 20 oC, 16 h

2a

Me

photocatalyst R1

3

R2

N

O P Ph Ph

CF3

F N

O

F F

Q1, R1 = OMe, R2 = H Q2, R1 = H, R2 = OMe Q3, R1 = H, R2 = H Q4, R1 = H, R2 = NEt2 Q5, R1 = NEt2, R2 = H

N 3a +

PF6-

N

IrIII N N

N

F

CF3 [Ir(dFCF3ppy)2(bpy)](PF6) (A) 2+

2ClN N

Ru

N N

CO2H Br

N Br

II

N O

O Br

[Ru(bpy)3]Cl2 (B)

OH Br

Eosin Y (C)

photocat. (1.0 mol %)

oxidant (1.5 equiv)

solvent

yield (%)b

1

Q1

-

toluene

12

2

Q1

-

MeCN

34

3

Q1

-

DCM

54

4

Q1

-

1,2-DCE

62

5

Q1

TBHP

1,2-DCE

11

6

Q1

K2S2O8

1,2-DCE

70

Entry


3


aReactions

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7

Q2

K2S2O8

1,2-DCE

36

8

Q3

K2S2O8

1,2-DCE

33

9

Q4

K2S2O8

1,2-DCE

46

10

Q5

K2S2O8

1,2-DCE

55

11

A

K2S2O8

1,2-DCE

58

12

B

K2S2O8

1,2-DCE

20

13

C

K2S2O8

1,2-DCE

40

14

-

K2S2O8

1,2-DCE

trace

15c

Q1

K2S2O8

1,2-DCE

trace

16d

Q1

K2S2O8

1,2-DCE

trace

were performed by using 1a (0.1 mmol), 2a (3.0 equiv), oxidant (1.5 equiv), NaHCO3 (1.2 equiv), photocatalyst (1.0

mol %) and solvent (1.0 mL) under light irradiation using a blue LED at 20 oC under N2 for 16 h. bYields were determined by 1H NMR. cThe reaction was conducted in the dark. dTEMPO (2.0 equiv) was added. To gain mechanistic insight, a number of luminescence quenching experiments were conducted. Stern-Volmer fluorescence studies demonstrated that the Q1* excited state is quenched by the pyridinium salt 1a, and the quenching was found to be linearly dependent on the concentration of 1a. This observation suggests that the excited state Q1* is capable of directly activating the N–O bond of 1a. On the other hand, no color change nor any bathochromic displacement was detected upon mixing the reaction components, excluding the possibility of any electron donor-acceptor (EDA) association between Q1 and 1a. With the optimized condition in hand, we next explored the scope of the reaction. As illustrated in Table 2, under blue light and in the presence of Q1, a wide range of pyridinium substrates bearing electron-rich or electron-deficient groups such as methyl, methoxy, chloro, ester, benzyl, phenyl, and trifluoromethyl are selectively phosphonated at the C4 position. In all cases, mono-phosphonated products were obtained exclusively. The structures of 3a and 3n were unambiguously confirmed by X-ray crystallographic analysis and details are given in the supporting information.16 The optimized conditions were compatible with chloro-substituents at the C2 position to provide 2-chloro pyridyl product 3e, thus, enabling further synthetic elaboration. Considering the importance of 2-aryl-C4-phosphonated pyridines as key moieties within various ligands, we subsequently assessed the applicability of our method to substrates bearing various aryl groups at the C2 position. Indeed, these prominent structural motifs were conveniently accessed, while maintaining the selectivity for the 4-positions consistently (3h, 3i, 3j, and 3k). Furthermore, the current protocol could be applied to functionalize 2,2’-bipyridine that is widely used in materials science17 and catalysis18 to prepare the C4-phosphonated product 3l. The reaction with a 3-substituted pyridinium salt proceeded to afford 3m in modest yield. By expanding the scope of the reaction to other heteroarenium substrates, such as quinolinium and pyridazinium ions, the products 3n, 3o, and 3p could be prepared. Interestingly, the pyridazinium ion was selectively functionalized at the C3 position. The scope of the phosphine oxide coupling partners was subsequently examined, and a relatively broad range of phosphine oxides (3q–3t) worked well in the optimized system. Table 2. Substrate Scope for Phosphonylation.a


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R

+

N BF 4 OEt 1a

Ar O P Ar

Q1 (1.0 mol %) K2S2O8 (1.5 equiv) NaHCO3 (1.2 equiv)

O Ar P H Ar 2

R

20 oC, blue LED, N2 1,2-DCE (0.1 M)

N 3a

O P Ph Ph

MeO N

O

Q1 Ph O P Ph

Ph O P Ph

N

Me

N

Me

3b, 73% (23:1)

3a, 73% (42:1) Ph O P Ph

MeO

3i, 64% (8.1:1) Ph O P Ph

Ph O P Ph

N Bn 3g, 73% (>50:1)

Ph N 3h, 77% (13:1)

Ph O P Ph

Ph O P Ph

N

N

N Me

F3C

3j, 70% (6.3:1)

Ph O P Ph

3k, 62% (6.1:1)

Ph O P Ph

Me

N

N

N

N 3l, 65% (5.2:1)

N

3m, 52% (7.3:1) F

Cl

O

O Cl P Ph N Ph from quinoxyfen 3p, 41% (single) aReactions

Me

R P R

N

O P Ph Ph

3o, 54% (single)

3n, 75% (single)

R=

O

N

3d, 71% (20:1)

Ph O P Ph

N MeO 3f, 51% (2.5:1)

Ph O P Ph

MeO2C

Me

N

3c, 75% (single)

Ph O P Ph

N Cl 3e, 57% (14:1)

Ph O P Ph

Ph O P Ph

Me 3q, 67% (10:1)

OMe 3s, 81% (10:1) Me

Cl Ph

N 3r, 57% (7.6:1)

Me 3t, 70% (20:1)

were performed by using 1 (0.2 mmol), 2 (3.0 equiv), oxidant (1.5 equiv), NaHCO3 (1.2 equiv), and Q1 (1.0 mol %)

in 1,2-DCE (2.0 mL) under light irradiation using a blue LED at 20 oC under N2 for 16-24 h. Yields of isolated products. Product isomer ratios were determined by GC/MS analysis (C4:C2) of the unpurified product mixture. Pyridine derivatives bearing amide groups at C2 position are privileged motifs in ligand19 and drug development.20 Thus, we sought to extend this methodology to the direct carbamoylation of N‑ethoxypyridinium (1a) with N,N-dimethylformamide for the introduction of an amide functionality into the pyridine core.21 Interestingly, a carbamoyl radical was formed under slightly altered reaction conditions in which DMF was employed as the solvent leading to the efficient cross-coupling of a carbamoyl radical unit with a pyridinium salt. Under blue LED irradiation at 20 oC, carbamoylation proceeds in a highly efficient fashion without suffering from decarbonylation. Under photocatalytic conditions,22 the Csp3–H bond adjacent to the nitrogen atom of Nalkyl amide engaged in hydrogen-atom transfer to afford amido radicals, wherein the reactions occurred at the N-alkyl group. Therefore, this protocol can be utilized to straightforwardly photo-catalyze the activation of the carbonyl Csp2–H bond of formamide and furnish cross-coupling reactions with the resulting carbamoyl radicals. Remarkably, in contrast to the C4 selectivity for the phosphonylation described above, the carbamoyl radical underwent the CDC reaction preferentially at the C2 position, providing a powerful and convenient tool for exquisite regiocontrol of the radical addition.


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Table 3. Substrate Scope for Carbamoylation.a Q1 (1.0 mol %) K2S2O8 (1.5 equiv) NaHCO3 (1.2 equiv)

O

R +

N BF 4 OEt 1

H

NR2

O

Me

N 5a, 57% (6.3:1)

Me

5d, 57% (10:1)

O

Ni i Pr Pr 5i, 72% (22:1) O

N N

N

5j, 74% (6.7:1)

5k, 52% (19:1) O

N

O

N

O

N

HN

N

5f, 74% (15:1)

N Et Et 5h, 79% (10:1)

O

N

N

MeO

N

5g, 70% (13:1)

O

N

5e, 75% (15:1)

N

F3C

N 5c, 43% (9:1)

N

O

N

NR2

O

N

Bn

O

N

N

5

N 5b, 42% (13:1)

O

N

Cl

O

N

O

N

20 oC, blue LED, N2

4

N

R

5l, 44% (15:1) O

N

MeO2C

N

MeO

O

N

N

N

5n, 68% (5.4:1)

5m, 60% (7:1)

O

5o, 51% (15:1) MeO

O

N

O

N

N 5p, 72% (15:1)

N

5q, 72% (10:1)

Cl

Cl

O

N

N

F 5r, 78% (9:1)

O

O

N N 5s, 66% (11:1)

Cl

O

N

from quinoxyfen 5t, 65% (single)

N

aReactions

were performed using 1 (0.2 mmol), 4 (2.0 mL), K2S2O8 (1.5 equiv), NaHCO3 (1.2 equiv) and Q1 (1.0 mol %) at 20

oC under N

2 for 20-24 h with light irradiation using a blue LED. Yields of isolated products. Product isomer ratios were determined

by 1H NMR analysis (C2:C4) of the unpurified product mixture. Having the optimized reaction conditions for the carbamoylation, we investigated the scope of pyridinium salts to extend the utility and generality of this methodology, as enumerated in Table 3. Again, high ortho-regioselectivity was obtained with pyridine-based heteroarenes. We were pleased to observe that pyridinium substrates bearing both electron-rich or electrondeficient groups such as methyl, methoxy, chloro, ester, benzyl, phenyl, and trifluoromethyl are amenable to this carbamoylation protocol and provide the desired products. The structures of 5f were unambiguously confirmed by X-ray crystallographic analysis (see the SI for details).16 The reaction of other formamide derivatives also worked well in the optimized system to afford the corresponding adducts (5h, 5i, 5j, 5k, and 5l). The scope of the reaction was further extended to quinoline derivatives to give access to the corresponding quinoline-2-carboxamide products (5q, 5r, 5s, and 5t). Similarly, 2,2’-bipyridine derivatives can also be used to generate the corresponding product 5m. To further highlight the broad applicability of this site-selective synthetic method, we carried out the late-stage modifications of medicinally relevant molecules. Various pharmaceutically important compounds contain a pyridine core. As depicted in Scheme 1, when the pyridinium intermediates 6, 9, and 12 derived from bisacodyl, vismodegib, and pyriproxyfen


6

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were subjected to the standard reaction conditions, site-selective C–H phosphonylation and carbamoylation occurred under the present catalytic systems to yield the corresponding products with good functional group tolerance. Scheme 1. Late-Stage Site-Selective Functionalization of Complex Molecules a Ph O P Ph

from Bisacodyl OAc

OAc condition A

N OEt BF4

N

58% (14:1)

6 OAc

OAc 7 OAc O

condition B

N NMe2

61% (11:1)

8 from Vismodegib

NH

Cl

O

N

50% (22:1)

10

HN

OEt

Cl

Cl

BF4

9

Cl

condition A

Cl N

Ph O P Ph

O Me S O

O

OAc

O N

condition B

HN NMe2

Cl

11 from Pyriproxyfen

O

Ph O P Ph N O BF4 OEt PhO

O

S

O

condition A 42% (12:1)

N

O

O 13

O Ph

12 condition B 57% (10:1)

aCondition

O

O

O

38% (7:1)

S

O

N NMe2

O

O 14

O Ph

A: reactions were performed by using pyridinium salt (0.2 mmol), 2 (3.0 equiv), K2S2O8 (1.5 equiv), NaHCO3 (1.2

equiv), and Q1 (1.0 mol %) in 1,2-DCE (2.0 mL) under light irradiation using a blue LED at 20 oC under N2. Condition B: reactions were performed using pyridinium salt (0.2 mmol), 4 (2.0 mL), K2S2O8 (1.5 equiv), NaHCO3 (1.2 equiv) and Q1 (1.0 mol %) at 20 oC under N2 with light irradiation using a blue LED. To determine whether the pyridine species was generated in situ as a result of SET, mixtures of pyridinium salts and pyridines were subjected to the standard reaction conditions (Scheme 2a and 2b). Indeed, phosphonylation occurred only at the C4 of pyridinium salts, leading to the formation of the corresponding products. Also, we examined the phosphonation and carbamoylation of 2-methylpyridine with trifluoroacetic acid (1.1 equiv) in the absence of N-ethoxypyridinium salts. Under the reaction conditions, only trace amounts of the desired C4-phosphonated or C2-carbamoylated products could be detected (Scheme 2c and 2d). Scheme 2. Control experiments


7


(a)

(b)

N BF4 OEt 1a

N BF4 OEt 1b

(c)

standard conditions

+ N

+ N

N

O H P Ph Ph O

N

Ph O P Ph +

N 3a, 64%

N 3b, trace

Ph O P Ph

Ph O P Ph +

2a

N

N 3b, 65%

3a, trace

+

(d)

Ph O P Ph

2a

standard conditions

Page 8 of 17

+

H

N

Q1 (1.0 mol %) K2S2O8 (1.5 equiv) TFA (1.1 equiv) blue LED, N2 DCE, 14 h Q1 (1.0 mol %) K2S2O8 (1.5 equiv) TFA (1.1 equiv)

O

Ph P Ph

N 3a, trace

O

N

blue LED, N2, 14 h

N 5b, trace

Whereas the demonstrated regioselectivity in combination with the mild reaction conditions that afforded the reactive radicals are undoubtedly useful, these findings are puzzling. Conventional chemical intuition does not offer a simple rationale for how radical reactions can be designed to exhibit selectivities at the level found in these reactions. To better understand this intriguing phenomenon, we carried out a full-scale computational study of the mechanism and investigated the inner workings of the regioselective addition of the photo-generated radical reactants. The most plausible mechanism suggested by density functional calculations is summarized in Figure 2a, and the computed reaction energy profiles are shown in Figure 2b and 2c. The catalytic cycle starts with the photoexcitation of Q1 to Q1*, which undergoes a SET event with a sacrificial quantity of 1a to yield an ethoxy radical that engages in intermolecular HAT with phosphine oxide and formamide. Addition of the persulfate anion, which has a redox potential of Ered = +1.75 V vs. SCE,23 improves the reaction efficiency because the sulfate radical anion generated by the action of Q1* can abstract a hydrogen atom from phosphine oxide and formamide, forming the corresponding free radicals that promote the reaction. As demonstrated previously,13c both radicals follow the identical reaction sequence when reacting with pyridinium: (i) radical addition, (ii) deprotonation and (iii) N–O cleavage. Once the radical is formed, it reacts with pyridinium via radical addition to generate the radical cation species X2. The radical addition step governs the overall regioisomer distribution of the product. For the phosphinoyl radical, the transition state p-P1-TS affording the para-product is 1.4 kcal/mol lower in energy than o-P1-TS, resulting para-preference of radical addition, as illustrated in Figure 2b. Interestingly, calculations show a reversed energy ordering for the carbamoyl reaction. As shown in Figure 2c, the transition state o-C1-TS is found to be 1.1 kcal/mol lower in energy than p-C1-TS, suggesting that the carbamoyl radical addition is ortho-selective. This finding is in excellent agreement with the experimental observations discussed above. The reaction proceeds by deprotonation mediated by sodium bicarbonate to generate the neutral radical species X3, which undergoes facile N–O cleavage to extrude an ethoxy radical and furnishing final products. The regenerated ethoxy radical formed during the reaction can start a new reaction cycle. This radical chain pathway explains the exceedingly high reaction quantum yield of Φ = 9.9 for phosphonylation and Φ = 8.4 for carbamoylation (see the SI for details).24


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(a)

Radical Extrusion

SET N OEt 1b

Q1*

N OEt 1b*

Q1+

HAT

OEt

O

O

XH

N OEt X2

1b

EtOH

X = PAr2, C–NMe2

(b)

Deprotonation

X

X

O

pyridine

Radical Addition

X

O Radical Extrusion

N OEt X3

HCO3– H2CO3

O X N

OEt

X-pdt

(c) G(sol) (kcal/mol)

G(sol) (kcal/mol)

O

N 1b*-TS 1b* (36.14) (35.87)

N

OEt 1b*-TS 2a-TS (14.33)

Q1+ Q1*

O Ph P H Ph OEt

Ph O P Ph

2a-TS o-P1-TS (0.93) p-P1-TS (–0.47)

2a 1b

H

OEt 4a-TS p-C1-TS 4a-TS (11.97) (15.47) o-C1-TS (10.90)

O

O

N OEt p-P1-TS

Ph O P Ph

EtOH

4a

N OEt 1b*

1b

O P

Ph Ph

P1

O Ph P H Ph

Ph O P Ph

2a

SET& Radical Extrusion

HCO3– P1 (–18.41) Ph O P Ph H N OEt p-P2

N p-3b

HAT

OEt p-P3-TS

1b

OEt (0.00)

o-P3-TS (–18.87) p-P3-TS (–22.30)

O

C1

HCO3–

C1 (–7.78) N OEt

Me2N

N OEt p-P3

Radical Addition

o-C2

o-3b (–55.38) p-3b (–56.74)

OEt O N

O H

4a

Deprotonation & Radical Extrusion

Regioselectivity Determining Step

HAT

p-C3-TS (–8.79)

H2CO3

O

o-P3 (–19.02) p-P3 (–27.17)

o-C3-TS (–2.43)

p-C2 (2.02) o-C2 (0.94)

N

H2CO3

Ph O P Ph

OEt o-C3-TS

N

* o-P2 (–3.27) p-P2 (–5.24)

N OEt 1b

**

*

N

Me2N

EtOH OEt (0.00)

N NMe2 OEt o-C1-TS

N NMe2 o-5a

Radical Addition

OEt

o-C3 (–6.34) p-C3 (–12.51)

O N Me2N OEt o-C3

o-5a (–43.19) p-5a (–43.38)

Deprotonation & Radical Extrusion

Regioselectivity Determining Step

Figure 2. (a) Generalized mechanistic scheme. (b) Reaction energy profile for the phosphinoyl radical. (c) Reaction energy profile for the carbamoyl radical. With a computer model in hand that reproduced the experimentally observed regioselectivities correctly, we conducted detailed analyses of these results to identify the origin of the different regiochemical outcomes seen for the two radical reactants. We firstly focused on the phosphonylation and found that the energetic trend of radical addition TSs are consistent with those of products, thus Hammond postulate can be applied. As the intermediate o-P2 has higher free energy than p-P2 by ~2.0 kcal/mol, as highlighted in Figure 2b, the transition state o-P1-TS is late in comparison to p-P1-TS. Because the radical addition converts a sp2 carbon into a sp3 carbon, o-P1-TS should display a more pronounced structural distortion than p-P1-TS at the bond forming carbon center.


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Figure 3. (a) Distortion-interaction analysis of phosphinoyl radical addition. (b) DFT-optimized transition state geometry of oP1-TS and p-P1-TS. Hydrogen atoms are omitted for clarity. (c) Representative parameters and their relationship between structure and electronic energy.

To validate and quantify the simple Hammond analysis, the two transition states were subjected to a fragment energy decomposition analysis, where the structural distortion and interaction energies25 were calculated for the molecular fragments, as summarized in Figure 3. As the phosphinoyl radical attacks, the pyridinium ring undergoes a structural distortion that is associated with 4.0 and 2.5 kcal/mol to adopt the geometry found in the transition states o-P1-TS and p-P1-TS, respectively. And these structural distortions are dominated by the distortion of the bond forming center, as expected, with distinct ethoxy group distortions in o-P1-TS playing a minor role. This distortion is due to an interaction between the C–H σ-bond of ethoxy group and the phenyl ring, as further detailed in the supporting information. The interaction between the two molecular fragments are found to be –12.3 and –12.2 kcal/mol for o-P1-TS and p-P1-TS, respectively, implying that the electronic interaction between the two fragments gives no regioselectivity. This is in good agreement with the conventional thought that the radicals show little sensitivity to subtle electronic differences of their reaction partners. Thus, the attack of the phosphinoyl radical prefers the paraposition because the structural distortion that the substrate 1b has to undergo at the para-position is ~1.5 kcal/mol less pronounced than at the ortho-position, in good agreement with the Hammond postulate.


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Figure 4. (a) Distortion-interaction analysis of carbamoyl radical addition. (b) Comparison of transition state geometry between phosphinoyl radical and carbamoyl radical. Interestingly, our DFT calculations show a very different mechanistic scenario for the carbamoyl radical addition. In contrast to the general stability trend discussed above, the ortho-intermediate o-C2 is ~1.1 kcal/mol lower in energy than the para-intermediate p-C2, as illustrated in Figure 2c. At 19.8 kcal/mol the p-C1-TS is about 1.1 kcal/mol higher in energy than oC1-TS, which was located at 18.7 kcal/mol. Figure 4a summarizes the results of an energy decomposition analysis of the two transition states. Starting from the reactant state, the substrate 1b and the carbamoyl radical must undergo structural changes to adopt the geometry found in the transition. As expected for a radical addition mechanism, very little change is needed for the carbamoyl radical and our calculations indicate structural distortion energies in the range of 0.6 and 0.9 kcal/mol. The substrate distortions amount to 5.1 and 4.9 kcal/mol for o-C1-TS and p-C1-TS, respectively. The interaction energies of the two fragments are –9.0 and –7.7 kcal/mol, as illustrated in Figure 4a, resulting in the transition state o-C1-TS being ~1.5 kcal/mol lower in energy than p-C1-TS. These energy components are entirely different from what was seen for the phosphinoyl radical addition discussed above. Most importantly, these calculated numbers suggest that it is the different magnitude of the fragment interaction energies that dictates the overall energy ordering. These calculated numbers indicate that there are favorable electronic interactions between the molecular fragments in o-C1-TS that are absent in p-C1-TS. Moreover, the electronic interaction of the two radicals with the pyridinium substrate is fundamentally different. A closer inspection of the computed structures offers very plausible explanations. Because of the larger size of the phosphorus atom, the C–P distances at the two transition states o-P1-TS and p-P1-TS are 2.596 and 2.613 Å, respectively. In comparison, the C–C’ distances in the two transition states o-C1-TS and o-P1-TS are nearly 0.4 Å shorter at 2.218 and 2.204 Å, respectively, which is of course due to the smaller size of the carbon compared to the phosphorus atom. One decisive consequence of the relatively short C–C’ distance in o-P1-TS is that the oxo functionality that is directly connected to C’, as illustrated in Figure 4b, is close enough to the N1 of the pyridinium moiety. And because N1 carries a positive partial charge, there is an electrostatic attraction between the partially negatively charged oxo group and the nitrogen center of the pyridinium, contributing several kcal/mol additional energy. Of course, no such interaction is possible in the transition state leading to the para-products (See supporting information for a detailed description of electrostatic charges). In o-P1-TS the C–P distance of nearly 2.6 Å is too far to allow the oxo moiety to engage in a similar electrostatic interaction. As a result, this secondary interaction plays no notable role when the phosphinoyl radical attacks. In summary, the short C–C’ distance in the transition state o-C1-TS enables an electrostatic interaction between the oxo functionality of the carbamoyl species and the nitrogen of the pyridinium substrate,


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which helps to make the carbamoyl addition at the ortho-position preferable over the intrinsically-preferred para-position. This mechanism of complete regiocontrol by the radical is interesting and demonstrates how secondary interactions leads to the lowering of the barrier to overturn the intrinsically programmed para-preference.

CONCLUSIONS We have developed a novel catalytic platform that uses visible light as the driving force to form phosphinoyl or carbamoyl radicals that subsequently engage N-ethoxyheteroarenium derivatives at room temperature. The C3-phosphonated quinolinone Q1 provides high levels of photocatalytic activity and the regioselectivity is controlled completely by the radical source. Phosphinoyl radicals predominantly provide C4 products, while carbamoyl radicals selectively form C2 products. The origin of this useful regioselectivity between phosphinoyl and carbamoyl radicals was revealed by combining experimental and computational methods. We found that an electrostatic attraction between the oxo-functionality of the formamide and the nitrogen of the pyridinium substrate directs the carbamoyl radical addition to the ortho-position. In the phosphinoyl radical this secondary interaction is not possible because the larger size of the phosphorus atom does not allow the oxo and nitrogen atoms to come close enough in geometry. The utility of this mild protocol was further demonstrated by the site-selective late-stage functionalization of bisacodyl, pyriproxyfen, and vismodegib. The current method provides a strategically new approach to the site-selective functionalization of pyridine derivatives and will expand the medicinal chemist toolbox for accessing valuable privileged scaffolds.

ASSOCIATED CONTENT Supporting Information Experimental procedure and characterization of new compounds (1H and 13C NMR spectra). Computational details, optimized Cartesian coordinates of all structures, vibrational frequencies, and energy component. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected], [email protected] ORCID Mu-Hyun Baik: 0000-0002-8832-8187 Sungwoo Hong: 0000-0001-9371-1730

ACKNOWLEDGMENT This research was supported financially by Institute for Basic Science (IBS-R010-A2 and IBS-R010-A1). We thank Dr. Jung Hee Yoon (IBS) for XRD analysis and Mr. Juhyeong Lee for helpful discussions.

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(22) Dai, C.; Meschini, F.; Narayanam, J. M. R.; Stephenson, C. R. J. Friedel–Crafts Amidoalkylation via Thermolysis and Oxidative Photocatalysis. J. Org. Chem. 2012, 77, 4425. (23) (a) Memming, R. Mechanism of the Electrochemical Reduction of Persulfates and Hydrogen Peroxide. J. Electrochem. Soc. 1969, 116, 785. (b) White, H. S.; Bard, A. J. Electrogenerated Chemiluminescence. 41. Electrogenerated Chemiluminescence and Chemiluminescence of the Ru(2,21-bpy)32+-S2O82- System in Acetonitrile-Water Solutions. J. Am. Chem. Soc. 1982, 104, 6891. (c) Nickel, U.; Chen, Y.-H.; Schneider, S.; Silva, M. I.; Burrows, H. D.; Formosinho, S. J. Mechanism and Kinetics of the Photocatalyzed Oxidation of p-Phenylenediamines by Peroxydisulfate in the Presence of Tri-2,2'-bipyridylylruthenium(II). J. Phys. Chem. 1994, 98, 2883. (24) Cismesia, M. A.; Yoon, T. P. Characterizing Chain Processes in Visible Light Photoredox Catalysis. Chem. Sci. 2015, 6, 5426. (25) Bickelhaupt, F. M.; Houk, K. N. Analyzing Reaction Rates with the Distortion/Interaction-Activation Strain Model. Angew. Chem. Int. Ed. 2017, 56, 10070.


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TOC Graphic H R H N OEt 20 oC O R

NR2

N O

H

NR2

Q1 photocatalysis

O

O R H P R

P

R R

R N


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Site-Selective Functionalization of Pyridinium Derivatives via Visible

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