Mechanistic Studies on Bioinspired Aerobic CâH Oxidation of Amines

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Mechanistic Studies on Bioinspired Aerobic C-H Oxidation of Amines with an ortho-Quinone Catalyst Ruipu Zhang, Yan Qin, Long Zhang, and Sanzhong Luo J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 12 Feb 2019 Downloaded from http://pubs.acs.org on February 13, 2019

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The Journal of Organic Chemistry

Mechanistic Studies on Bioinspired Aerobic C-H Oxidation of Amines with an ortho-Quinone Catalyst Ruipu Zhang,†,§ Yan Qin,†,§ Long Zhang,*,†, ‡,¶ and Sanzhong Luo*,†,‡,¶ †Key

Laboratory of Molecular Recognition and Function, Institute of Chemistry, The Chinese Academy of Sciences, Beijing

100190, China and University of Chinese Academy of Sciences, Beijing, 100049, China ‡Center

of Basic Molecular Science (CBMS), Department of Chemistry, Tsinghua University, Beijing, 100084, China

¶Collaborative

Innovation Center of Chemical Science and Engineering, Tianjin, 300071, China

NH2 Ar

tBu

O

MeO

O

N

Nu-H Ar

NH

Transamination

R

Hydride Transfer Ar

N

Ar

O2

N R N

Ar

Nu

ABSTRACT: We report herein our mechanistic studies of the ortho-quinone-catalyzed aerobic oxidation of primary, secondary, and tertiary amines. Two different catalytic pathways were discovered for the reductive half reactions: for primary amines, the reaction was found to proceed via a transamination pathway, while the reactions with secondary amines and tertiary amines proceeded via hydride transfer. We also found that the amine substrates could significantly promote the regeneration of the ortho-quinone catalyst in the oxidative half reaction, in which a proton transfer occurs between the amine substrates and catechol derivatives (the reduced form of the ortho-quinone catalyst).

Introduction Natural enzymatic transformations provide a great source of inspiration for developing new catalysts and reactions. The copper amine oxidases (CuAOs), which are involved in the metabolism of amines,1 have been the basis for developing the biomimetic amine oxidation process. In 1990, Klinman2 first identified the cofactor of CuAOs, isolated from bovine serum amine oxidase, as TPQ (2,4,5-trihydroxyphenylalanine quinone). Similar cofactors can be found in all bacteria, yeasts, plants, and animals. Unlike the

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dissociable PQQ (pyrroloquinoline quinone) cofactors found in alcohol and glucose dehydrogenases from Gram-negative bacteria,3 which bind to the quinone proteins through ionic interactions, TPQ is generated directly from the Tyr side chain and hence is covalently bound to the protein backbone (Scheme 1A). The aerobic oxidation catalyzed by CuAOs consists of two distinct half reactions (based on the redox process of catalysts): in the reductive half reaction, TPQ gains two electrons to reach its reductive state, oxidizing amines to aldehydes; in the oxidative half reaction, reductive TPQ is oxidized by oxygen to the resting state, releasing NH4+ and H2O2 with the assistance of a cupric ion.1c The quinone cofactors are the only active species promoting amine oxidation; the cupric ion simply assists oxygen to recycle the quinone cofactors. Mechanistic works reported by Klinman,1b-d, 2, 4 Sayre,5 and others6 demonstrated that the reductive half reaction proceeds through a transamination pathway (Scheme 1B). In a much earlier study, Corey7 reported oxidation of primary amines to ketones using 3,5-di-t-butyl-1,2-benzoquinone via a transamination pathway. Recently, notable advances have been made in the development of bioinspired ortho-quinone catalysts (Scheme 1C).8 For example, Largeron9 achieved the oxidation of a large number of primary amines with o-iminoquinone recycled using electrochemical conditions or air in the presence of cupric ions. A natural Purpurogallin-derived ortho-quinone catalyst has also been developed to promote primary amine oxidation under air condition without the assistance of any metal cocatalysts. 9g Stahl and colleagues10 also made a great contribution to this field by developing several quinone-based catalysts, which enabled efficient dehydrogenation of primary amines, secondary amines, and even nitrogen heterocycles with the assistance of metal cocatalysts under mild reaction conditions. Furthermore, they showed that secondary amines were oxidized by the ortho-quinone catalyst (1,10-phenanthroline-5,6dione, phd) via an “addition-elimination” pathway involving a hemiaminal intermediate.10b Kobayashi11 proposed the involvement of hemiaminal intermediates in secondary amine oxidation reactions by a cooperative catalytic system of Pt/Ir nanoclusters and 4-tertbutylcatechol. Oh and co-workers reported that an ortho-naphthoquinone could catalyze aerobic oxidation of primary and secondary amines in the presence of trifluoroacetic acid or Cu(OAc)2.12 Recently, we developed a simple bio-inspired ortho-quinone catalyst (Scheme 1, o-Q1) that enabled effective oxidative dehydrogenation of the difficult α-branched primary amines without any cocatalyst.13a We13b and others14 reported oxidative C-H functionalizations of primary amines to afford aza-heterocycles via in-situ formed imine intermediates. Further investigation showed that the oxidation of cyclic secondary amines and tertiary amines were also viable using the same ortho-quinone catalyst. Herein, we report a full account of mechanistic studies on our ortho-quinone catalysis.


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The Journal of Organic Chemistry COO-

A -

OOC

B

O

HN

O -

OOC

OH

O

N

O

O PQQ C

CuII

TPQ

NH2

OH O HN

OH O

H 2O

O

Ph

O

O Largeron "o-iminoquinone" O

OH

Kobayashi "4-tBu-o-quinone" O

NH3

O

O H 2N

OH O Stahl "TBHBQ"

N

R

R

OH Cu

Largeron "pyrogallol" tBu

OH

O

O

OH OH

CuII N

N

Stahl "phd" O

OH

R

Ph Oh "o-naphthoquinone"

II

Transamination Mechanism

NH

OH CuII

H 2O 2

O Luo o-Q1, R = Me o-Q2, R = Et

R H 2O

OH

O

RO

N

O O2 OH

R

H

CuII NH2

Scheme 1. (A) Structures of two quinone cofactors: PQQ (pyrroloquinoline quinone) and TPQ (2,4,5-trihydroxyphenylalanine quinone). (B) Mechanism of amine oxidation mediated by CuAOs via a transamination pathway. (C) Recent biomimetic quinonebased catalysts developed by Largeron, Kobayashi, Stahl, Oh, and Luo.

Results and Discussion α-Branched primary amine. In our previous reports, we developed a bioinspired ortho-quinone catalyst for the aerobic oxidation of α-branched primary amines (Scheme 2).13b 1-Phenylethanamines bearing electron-donating or electron-withdrawing groups were well tolerated and produced secondary imines with high to excellent yields and good E/Z ratio. Substrates with a bulky group such as diphenylmethanamine also gave the desired imine. It should be mentioned that the catalytic reaction by using para-quinone (TBHBQ) as catalyst was nearly inert, highlighting the unique catalytic ability of our ortho-quinone catalyst. Moreover, a higher temperature would afford oxidative trimerization adducts, imidazolinones (Scheme 2). Control experiments showed that the quinone catalyst was also involved in the later stages of oxidation, as no product was observed in the absence of catalyst when using imine as the starting material. Overall, this oxidative trimerization provided a novel method for the synthesis of imidazolinones.


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The Journal of Organic Chemistry A

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

NH2 Ar

1

R

R

o-Q1 (10 mol %)

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R

Ar

N Ar 2 up to 99% yield

CH3CN, rt, O2, 48 h

R

B

NH2

R

O

o-Q2 (2 mol %) o

CH3CN (0.3 M), 60 C O2, 48 h - 72 h

1

N N

R R

3 up to 65% yield

Scheme 2. (A) Aerobic oxidation of primary amines. (B) Oxidative trimerization of 1-phenylethanamines.

Cyclic secondary amines. In previous work, biomimetic oxidative dehydrogenation of secondary amines usually required transition metal salts as cocatalysts.10b, 10c, 11, 15 To our delight, we found that the ortho-quinone catalyst also promoted the oxidation of tetrahydroisoquinoline to 3,4-dihydroisoquinoline under an oxygen atmosphere and slightly higher temperature, and no metal additive was needed (Scheme 3; for full substrate scope see Table S1 in SI).13b 1-Phenyl-substituted tetrahydroisoquinolines bearing halogen or alkyl groups worked well in this catalytic system. Meanwhile, 1-phenyl-substituted tetrahydro-β-carbolines exhibited good reactivity under the same conditions. Ar

NH R 4

o-Q1 (10 mol %) CH3CN, 60 oC, O2

Ar

N

R 5 up to 99% yield 14 examples

Scheme 3. Aerobic oxidation of secondary amines.

Cyclic tertiary amines. The direct oxidation of tertiary amines is widely used in cross-dehydrogenative coupling (CDC) reactions.16 Besides the commonly used transition metal catalysis17 and photoredox procedure,18 small organic molecules such as DDQ are able to catalyze the oxidation of tertiary amines.19 We wondered whether the ortho-quinone catalyst could also be applied to tertiary amine oxidation. As an initial trial, the aerobic oxidation of N-phenyl-tetrahydroisoquinoline with o-Q1 was examined in acetonitrile at 60 °C. An oxidative amide product 7a was isolated in 48% yield after 48 h; this was determined to be the side product of the CDC reaction (Scheme 4).20 The addition of water showed no effect on the yield of amide product, indicating that the oxygen atom might come from molecular oxygen. This observation prompted us to further examine CDC-type coupling in the presence of nucleophiles. After condition optimization (see Table S2 in SI), 2-equivalent nitromethane and 10% ortho-quinone catalyst under neat conditions were employed as the optimal conditions to test the substrate scope (Scheme 5). To our delight, the scope of the bioinspired metal-free organocatalytic CDC reaction was tolerated with various tertiary amines and nitroalkanes (see Table S3 in SI). A series of N-aryl 1,2,3,4-tetrahydroisoquinoline derivatives with electron-donating or electron-withdrawing groups on the phenyl ring were tolerated to undergo the CDC reaction with nitroalkanes to form the desired coupling products in good to excellent yields.


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Other nucleophiles could also react smoothly with N-phenyltetrahydroisoquinoline 6a, affording another method for C–X bond formation. o-Q1 (10 mol %) N

N

MeCN (0.1 M), O2 60 oC, 16 h

Ph

6a

Ph

O 7a

18% (48% within 48 h) with H2O (1 eq.): 13% with H2O (5 eq.): 19%

Scheme 4. Aerobic oxidation of N-phenyltetrahydroisoquinoline with o-Q1.

R1

N

+ R3

R

2

NO2 or Nu-H

o-Q1 (10 mol %) 60 oC, O2 12 h or 24 h

R1

N O2 N

6

or R1

R2

R3

8 up to 89% yield 14 examples

N Ph Nu 9 up to 90% yield 12 examples

MeO N

Ph

NO2

86%

MeO

90%

N

OMe

NO2

73% N

O

N

O

NO2

Cl

N

N

Ph

NH

64%

N

42%

O2N

Ph

Ph

NO2

67%

N

Ph

N

N Me

77%

83%

Ph OMe

N

MeO

MeO P O MeO

N Ph

Ph

Ph

62%

O

63%

Scheme 5. Aerobic oxidation of tertiary amines.

Mechanism Studies. In 1995, Klinman investigated the mechanism of topaquinone-dependent amine oxidases by using model systems, and a transamination reaction mechanism was verified.4f However, the oxidation of secondary amine and tertiary amine could not proceed via the transamination pathway; therefore other possible reaction pathways should be considered. In general, four possible pathways were proposed for the bioinspired oxidation (Scheme 6): noncovalent pathways including (1) direct hydride transfer and (2) single electron oxidation, covalent pathways including (3) addition−elimination and (4) transamination. To elucidate the catalytic mechanism with ortho-quinone, we carried out detailed experimental and theoretical studies.


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Noncovalent pathway

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

I: Direct Hydride Transfer NH2 Ph

H

O

MeO

o-Q1

NH2 NH

1a

Me

Ph

NH

O H Ph

Me

N

Ph

Ph

Ph

Product

II: Single Electron Oxidation NH2 Ph

Me

O

MeO

o-Q1

+

SET

NH

Ph

O

1a

NH2

HAT or PCET

NH2

Ph

Me

Ph

N

Ph

Ph

Product

Covalent pathway NH2 Ph

tBu

o-Q1

Me

HO H N O

MeO

1a

tBu

Ph - H2O H

N

MeO

O

Ph H

tBu

N

MeO

O

Ph H

11

10

IV: transamination

tBu

HO H N

MeO

O

Ph Ph H

III: addition-elimination

NH

tBu

Ph

NH2 Ph

Me

Ph

N Product

Ph

NH2 Ph

Me

N

MeO

OH 12

Scheme 6. Possible oxidation pathway of α-branched primary amine oxidation.

Exclusion of the single electron transfer process. Quinones such as DDQ (2,3-dichloro-5,6-dicynobenzoquinone) are widely used as single electron oxidants in organic synthesis. The oxidation of tertiary amines with DDQ has also been reported in the past few years.19 Recently, Todd and co-workers revealed that the DDQ oxidation of N-phenyltetrahydroisoquinolines proceeded via a single-electron-transfer (SET) pathway.21 To verify whether o-Q1 oxidized amines via a SET procedure, we first investigated the oxidation potential of the amine substrates and the reduction potential of the o-Q1 catalyst via cyclic voltammetry (Figure 1). The oxidation potential of primary, secondary and tertiary amine were determined to be 1.47 V, 1.19 V, and 0.89 V (vs Ag/AgCl), respectively, while the reduction potential of the ortho-quinone catalyst was found to be -0.45 V (vs Ag/AgCl), thus the energy gap of these oxidative process was 1.92 V, 1.64 V, and 1.34 V, respectively. According to the general accepted criteria,22 an electrontransfer-initiated process would occur if the energy gap was well below the empirical energy limit (1.0 V, i.e., 23.1 kcal/mol). However, the gap between three amine compounds and quinone catalyst was much higher than the limit. Therefore, the single electron transfer was likely unfavorable for the catalytic reactions. We also calculated the energy difference between the starting materials and the radical ions by using Gaussian 0923 with the same computational methods as Todd described21 (Scheme 7), the free energy changes were 44.1, 41.1, and 32.6 kcal/mol, respectively (corresponding to 1.91 V, 1.78 V, and 1.41 V), which were in agreement with the experimental results above. The reason for the difference in the SET process between o-Q1 and DDQ could be ascribed to the electron-rich nature of o-Q1, which led to an unstable quinone radical anion. In addition, kinetic isotope effect (KIE) experiments


6

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showed primary KIEs for all three types of amines (Scheme 8), indicating that C–H bond cleavage was involved in the ratedetermining step of these oxidation processes.24

Figure 1. Cyclic voltammetry of amines and ortho-quinone catalyst (1 mmol/L) in electrolyte solution (0.1 M TBAPF6 in CH3CN), using glassy carbon as the working electrode, and Ag/AgCl (0.1 M) as counter and reference electrode at a 100 mV/s scan rate.

NH2

O + MeO

O

N

1a 0.0

o-Q1

+

N

O o-Q1

Ph

6a 0.0

NH2

O MeO

N

H

4a 0.0

44.1 kcal/mol

H

41.1 kcal/mol

N

Ph

32.6 kcal/mol

Scheme 7. Energy differences between starting materials and the corresponding radical ions (ΔG in kcal/mol. calculation method: M06-2X/6-311+G(3df,2p)// B3LYP/6-31G(2df,p)).


7


X NH2

o-Q1 (10 mol%)

X = H, or D 1a

X CH3CN, rt, O2 Ph

N

(eq. 1)

Ph

X = H or D KIE = 6.5 X X

X X N

o-Q1 (10 mol%) H

X X (> 95%)

X = H, or D 4a X X

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X

KIE = 2.6

X

(> 90%)

N

o-Q1 (10 mol%) Ph

X X (> 95%)

X = H, or D 6a

(eq. 2)

N

CH3CN 60 oC, O2

MeNO2 (2.0 eq.) 60 oC, CH 3CN

X N

X

(eq. 3) Ph

NO2

KIE = 

Scheme 8. KIE experiments for primary, secondary, and tertiary amine oxidation.

Mechanism for the oxidation of α-branched primary amines. In situ electrospray ionization mass spectrometry (ESI-MS) analysis of the oxidation of α-branched primary amines was conducted. Signals corresponding to hemiketal 10, substrate imine 11, and product imine 12 could be clearly observed (Scheme 9A). An attempt to isolate the product imine 12 failed owing to contamination of the final product and other intermediates; however, an aza-ortho-quinone side product 14 (Scheme 9B), an oxidized product of the iminoquinone intermediate, was isolated and fully characterized by 1H and 13C nuclear magnetic resonance (NMR). In addition, the isolation of reductive quinone catalyst 15 further supported the transamination pathway (Scheme 9C). These experimental observations supported the transamination mechanism, in accordance with Klinman’s biomimetic studies.4e,4f Density functional theory (DFT) calculations on the three possible H-transfer pathways were performed using Truhlar’s M06-2X method.25 For the direct hydride transfer process, the electronic differentiation of the two carbonyls on the quinone catalyst was evaluated (TS1 vs TS1a, Scheme 10, I). The results showed that the oxygen atom on the carbonyl meta to MeO group was more electron-rich, and thus would preferentially bond with the positive N-H instead of C-H (see SI, S24 for details). A 29.2 kcal/mol energy barrier (vs 30.8 kcal/mol for TS1a) was obtained for this process. A much higher free energy barrier (46.2 kcal/mol, compared with 1a) was found for the addition-elimination pathway, (Scheme 10, II). In comparison, the energy gap (TS3) for transamination was much lower, only 23.3 kcal/mol, consistent with an ambient-temperature reaction condition. Given that the substrate amine or additional base could facilitate the hydrogen transfer of this transamination, we also calculated the intermolecular hydrogen transfer pathway for the transamination of iminoquinone 11 (TS3a). Owing to the assistance of an additional amine, this process needed a lower energy barrier than direct hydride transfer or addition-elimination, but it was still higher than that of intramolecular hydrogen transfer (TS3). Kinetically, the reaction was determined to be first order for the α-branched primary amine 1a (Scheme 11), consistent with an intramolecular transamination pathway (TS3, Scheme 10, III).


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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

HO H N

tBu

tBu

Ph

H OH

MeO

Ph

H N

MeO

O

Ph

tBu

H

MeO

11

10

N O 12

Exact Mass: 316.19015

298.17972

296.16542

ESI-MS:

298.18016

296.16560

316.19072

B

13

MeO

O CH3CN (0.5 mL) rt, O2

CO2Et MeO + NH2

O

O N

70% yield

o-Q1

14

1:1

CO2Et Ph

C NH2 MeO

O

N2

O

CH3CN

NH2 O

o-Q1

1b

OH 15

Scheme 9. (A) ESI-MS analysis of the oxidation of α-branched primary amines. (B) Stoichiometric reaction of -branched amines with quinone catalysts. (C) Synthesis of reductive quinone catalyst—aminophenol 15.

O

MeO tBu TS1

H

O

tBu NH MeO

O H Ph

TS1a

H

46.2

NH

TS2

O H Ph

tBu

HO H N

MeO

O

Ph H

TS2

30.8

tBu

TS1a

G (kcal/mol) Direct Hydride Transfer

TS1

Addition-elimination

29.2

26.5

MeO

TS3a

Transamination O

MeO

O

6.2

o-Q1 NH2 Ph

1a

Ph

TS3

23.1 tBu

N Ph H O N H TS3a H tBu

N

MeO

O

Ph H

TS3

10

0

-0.2

o-Q1 + 1a tBu

HO H N O

MeO 10

Ph H

11 tBu

N

MeO

O

Ph

Ph

H

tBu

N

-23.1 MeO

11

12

tBu

OH

MeO

NH

-55.7

OH 18

OH 12

Ph

N 2a

Ph

18 + Int-0 Int-0

Scheme 10. Transition states of possible pathways in the oxidation of primary amines (calculation method: UM062x/6311++G(2df, 2pd)//UM06-2X/6-31G(d)). Energy relative to 1a/o-Q1 (kcal/mol).


9


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Scheme 11. Kinetic analysis of primary amine oxidation.

The para-quinone catalyst (TBHBQ), which was identified as an efficient catalyst for the oxidation of benzyl amines10a, was inactive for α-branched primary amines. In a single case, the oxidation of α-branched primary amine was shown to proceed only in the presence of a stoichiometric amount of inorganic base. To disclose the catalytic difference between ortho-quinone and paraquinone, we analyzed the intrinsic properties of these two catalysts. Previously, Zhu and co-workers systematically investigated the hydride affinities and one-electron reduction potentials of various p- and o-quinones.26 The hydride affinities of o-quinones were found to be generally higher than those of p-quinones, indicating that o-quinones would be more suitable for hydride abstraction processes. We calculated the hydride affinity of o-Q1 and TBHBQ based on Zhu’s method (Scheme 12A). The hydride affinity of oQ1 was found to be 3.5 kcal/mol higher than that of TBHBQ. The one-electron reduction potential calculations based on Zhu’s equations also showed that o-Q1 was a stronger oxidant than TBHBQ. We also investigated the stoichiometric reaction of 1phenylethanamine with TBHBQ (Scheme 12B) by 1H NMR. Only the reactant imine 16 was formed; no oxidized product imine 17 was found. The DFT calculations revealed intramolecular O-H…N hydrogen bonding in the reactant imine intermediate TS4, which prevented any further hydrogen-transfer process (Scheme 13). The energy barrier of this intermolecular hydrogen-transfer step (Scheme 13, TS4) was determined to be 29.4 kcal/mol, indicating that a room-temperature reaction was unfavorable. On the other hand, a C-H…O weak interaction was noted in the reactant imine intermediate 11 with o-Q1, facilitating 1,5-H transfer (Scheme 10, III, TS3). Structurally, p-quinone TBHBQ could equilibrate with an ortho-quinone derivative 16a and this equilibrium could be further driven to ortho-quinone anion 16b in the presence of base (Scheme 13). The reactions of the latter two species with α-branched primary amine 1a were explored by DFT. While the energy barrier was even higher for 16a via intramolecular hydrogen-transfer (TS4a, 34.2 kcal/mol), o-quinone 16b showed only a 27.2 kcal/mole barrier via a transition state TS4b (Using HCOO- as base and DMF as solvent) (Scheme 13), similar to TS3 (Scheme 10, III). This result was consistent with the observed base effect.10a Clearly, the presence of base equilibrated p-quinone TBHBQ to its o-quinone isomer, favoring a transamination pathway.


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O

O GH-A = -71.1 kcal/mol - O ENHE(Q/Q  = -0.27 V

OH

O o-Q1 B

GH-A = -67.7 kcal/mol ENHE(Q/Q- = -0.45 V

O TBHBQ O

O NH2

+ Ph

OH

OH

CD3CN (0,5 mL) rt, N2 quant.

OH

OH

N

O TBHBQ

N 16

Ph

Ph 17 no detected

Scheme 12. (A) The calculated hydride affinity of quinone catalysts (the energy and frequency in gas phase was calculated with MP2/ 6-311++g(d,p)//B3LYP/6-31+G(d), the solvation energy in DMSO was calculated with HF/6-31+g(d,p)(IEFPCM)). (B) The stoichiometric reaction of 1-phenylethanamine with TBHBQ.

HO

O

G = 10.1 kcal/mol

Ph H

N O

G = 3.9 kcal/mol (HCOO- as base O in DMF)

N

N

O

O H

H

Ph iminoquinone 16a

+ HCOOH

iminoquinone 16

H

Ph iminoquinone 16b

NH2 Ph

HO

Ph H Ph H H2N N

O N O

H Ph TS4a

Ga = 34.2 kcal/mol

O N O

O H TS4

H

TS4b

Ga = 29.4 kcal/mol

Ph

Ga = 27.2 kcal/mol - HCOO-

HO

Me

N Ph OH product imine intermediate

Scheme 13. The reaction profile of primary amine oxidation using TBHBQ (calculation method: UM062x/6-311++G(2df, 2pd)//UM06-2X/6-31G(d)).


11


Page 12 of 27

Mechanism for the oxidation of secondary amines. Natural quinoproteins such as CuAOs do not work with secondary amines.5 The addition of secondary amines was found to deactivate the enzymes. Mechanistically, the transamination process was not feasible with cyclic secondary amine substrates, leaving addition-elimination and direct hydride transfer as two possible pathways. Stahl and Kobayshi proposed an addition-elimination pathway for the secondary amine oxidation by a p-quinone or o-quinone catalyst.10,11 A hemiacetal intermediate was observed and proposed to support the addition-elimination mechanism by Stahl. We also observed this hemiacetal intermediate Int-1 by high-resolution mass spectrometry (HRMS; see Figure S5 in SI). However, with the catalysis of oQ1, a much higher energy (Figure 2, TS6, 42.6 kcal/mol) had to be overcome for the addition-elimination procedure. It is likely that Int-1 was an off-cycle parasite species that reversibly entered or exited the main cycle. By contrast, the reaction barrier for direct hydride transfer (TS5) was only 25.7 kcal/mol, consistent with a facile reaction. Meanwhile, the kinetic study showed a first-order reaction for the secondary amine substrate (Scheme 14). These results were supportive of a direct hydride transfer process. The primary KIE of 2.2 was also in support of this conclusion.27 Previously, Lumb28 reported the coupling of ortho-quinone and pyrrolidine leading to an N-heterocycle via a covalent pathway. In our case, when tetrahydroisoquinoline 4a was treated with a stoichiometric amount of o-Q1 at 60 °C, the reaction proceeded smoothly to 3,4-dihydroisoquinoline 5a and no quinone-covalent adduct was detected.

NH H tBu

O

MeO

O

NH O

MeO

O

HO

N O

MeO

H

TS6 42.6 (37.1)

TS5

+ tBu

tBu

25.7 (20.2)

tBu -2.0 (-6.1)

-3.6 (-8.3)

OH

MeO

OH +

tBu MeO

HO

N H

N O

Int-1

+ H

tBu MeO

H O O

N -20.2 (-22.5)

Int-2

Figure 2. Reaction profile of aerobic oxidation of secondary amines (calculation method: UM062x/6-311++G(2df, 2pd)//UM062X/6-31G(d). Values in Figure 2 are G (kcal/mol), values in parentheses are H (kcal/mol)).


12

Page 13 of 27 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


Scheme 14. Kinetic analysis of secondary amine oxidation.

Mechanism for the oxidation of tertiary amines. For tertiary amine oxidation, non-covalent pathways may usually be possible. As single-electron oxidation can be excluded, direct hydride transfer might be responsible for this transformation. By DFT, we located the direct hydride-transfer transition state using the B3LYP method and 6-31G(2df,p) basis set, and the activation free energy was determined to be 27.3 kcal/mol. The iminium ion formed in situ then reacted with the nucleophiles to complete the CDC process (Scheme 15).

N N o-Q1 N H 6a

Ph

N

Ph 9

H tBu

O

O

O

TS7 G = 27.3 kcal/mol

Ph

Nu

Ph

Nu H tBu MeO

OH O

Nu tBu

OH

MeO

OH

[O]

o-Q1

TS7

Scheme 15. The cross-dehydrogenative coupling of tertiary amines with nucleophiles (calculation method: M06-2X/6311+G(3df,2p)// B3LYP/6-31G(2df,p)).

Oxidative half reaction of the catalyst. In previous reports, the reduced ortho-quinone catalysts, including catechol derivatives such as 18 (Scheme 16), could be re-oxidized by electrochemical conditions9b-c or metal-promoted9e,10b-c aerobic oxidation to complete the catalytic cycle. To look into this oxidative half reaction (re-oxidation of the reduced catalyst), we investigated the stoichiometric reaction with o-Q1 or its reduced analogue (e.g., 15 and 18) under a nitrogen or oxygen atmosphere, respectively. In the stoichiometric reaction with the primary amine, the performance of an aminophenol 15/O2 combination showed much lower activity than o-Q1, resulting in a 14% yield of homo-coupling imine along with 12% o-Q1 and 83% 1a in 0.5 h. Similar phenomena were observed for the oxidation of secondary and tertiary amines mediated by a catechol 18/O2 system (Scheme 16). Significant amounts of o-Q1 were detected in both cases. In the CDC reaction, the desired adduct was obtained in 17% yield (vs 30% yield with o-Q1) and the catechol


13


Page 14 of 27

was completely oxidized to o-Q1. These results suggest that the reductive half reaction (amine oxidation) was slower than the oxidative half reaction (reduced catalyst re-oxidation) for all the three types of amines, consistent with the KIE results.

Condition A: o-Q1 (1 eq.), N2 O

Stoichiometric Amine Oxidation

O

Condition B: 15 or 18 (1 eq.), O2 O

XH

O

NH2

CH3CN, 0.5 h

N

2a : 87%

rt 2a

1a CH3CN, 0.5 h NH

6a

+ CH3NO2 Ph

CH3CN, 10 h

N

60 oC O2 N

Ph

2a : 14% o-Q1 : 12% 15: 71%

5a : 70%

5a : 29% o-Q1 : 67% 18 : 30%

8a : 30%

8a : 17% o-Q1 : 86% no 18 detected

5a

4a

N

N

60 oC

OH

8a

Scheme 16. Comparison of reaction outcomes in stoichiometric reaction when using quinone catalyst and reductive catalyst.

We next investigated the oxidative half reaction with catechol 18 as a model compound (Table 1). Surprisingly, oxidation of catechol barely proceeded in acetonitrile under aerobic conditions, with only 6% yield after 12 h (Table 1, entry 1). When a catalytic amount of amine was added, the oxidation was significantly accelerated to afford ortho-quinone o-Q1 at moderate to high yield (Table 1, entry 2-5). In general, tertiary amines had the best outcomes compared with secondary and primary amines. Even the imine adduct showed a promoting effect (Table 1, entry 7). The use of inorganic base Na2CO3 also accelerated the oxidation (Table 1, entry 6), indicating a general base catalysis in this oxidative process.29 We also investigated the amine effect on the oxidative half reaction using aminophenol 15. With a catalytic amount of primary amine 1a, a trimerization side product 19 instead of o-Q1 was obtained, along with many other unidentified products (Scheme 17). Increasing the loading of primary amine inhibited the self-condensation and side product 19 was not detected under catalytic conditions (Scheme 17). No obvious base effect was observed in this case.30 Previously, it has been reported that aerobic oxidation of catechol proceeded via radical species (e.g., 20) with a superoxide anion (Scheme 18).31 A similar base effect was noted in cobalt-catalyzed oxidation of catechol.32 Our experiments showed that amines could effectively promote the aerobic oxidation of catechol 18 in a metal-free context. Mechanistically, the amine would serve as an organic base to facilitate the deprotonation of either free catechol or its radical cation, thus promoting the oxidation. Taken together, the whole aerobic ortho-quinone catalysis involves two mutually promoting cycles, wherein the ortho-quinone catalyzes the oxidation of amines, and the amine (or its oxidized product) catalyzes the aerobic re-oxidation of the reduced ortho-quinone. Table 1. Additive effect on the oxidative half reactiona.


14

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

The Journal of Organic Chemistry OH O

O

CH3CN, O2 Amine (10 mol %) 12 h, rt

OH 18

O

O o-Q1

Entry

Amine

Yield (%)

1

--

5

2 3

43

Ph

NH2

Ph

NH2

50

N H

83

4

5

91

N

6

Na2CO3

7

Ph

aGeneral

N

85 Ph

56

conditions: 18 (0.05 mmol), amine (10 mol %), and CH3CN (0.5 mL) with O2 balloon at room temperature for 12 h. Yield

determined by 1H NMR using 1,3,5-trimethoxybenzene as internal standard.

Ph

N 14%

Ph

tBu

O

1a (1 eq.)

tBu

NH2

Amine (10 mol %)

MeO

O

CH3CN, rt, O2 0.5 h

MeO

OH

CH3CN, rt, O2 12 h

15

28%

O

OMe

tBu

N

tBu

MeO

N

tBu

O

OMe

19 8% NMR yield

Scheme 17. The re-oxidation of aminophenol 15.


15


Page 16 of 27

NH2 tBu

X

MeO

O

Ph 1a

tBu

N

Ph

H 2O 2 MeO

NH H tBu MeO

tBu

O TS5

O

11

HO2

O

X

MeO

tBu

H

MeO

O 20

or N

Ph

R'

H2 N

R

N

TS3

tBu

O O

H

O2

H MeO

O

Ph

Ph R'

H N

R

TS7

tBu

O2 tBu

XH

N

MeO

OH 12

MeO Secondary&Tertiary Amine

OH

15 or 18 X = NH, O

1a Primary Amine

Scheme 18. A proposed cycle of ortho-quinone catalysis.

Conclusion In summary, we have disclosed the mechanism of aerobic oxidation of α-branched primary amines, cyclic secondary amines, and cyclic tertiary amines with a simple bioinspired ortho-quinone catalytic system. The transamination pathway was responsible for the oxidation of α-branched primary amines, while secondary and tertiary amines oxidation underwent hydride transfer process. Amine substrate as a return was found to promote the oxidative half reaction via base catalysis of the aerobic oxidation of catechols.

Experimental Section General information. Commercial reagents were used as received unless otherwise indicated. All manipulations were conducted with a standard Schlenk technique. 1H, and 13C NMR spectra were measured on a NMR instrument (300 MHz, 400 MHz, or 500 MHz for 1H NMR; 75 MHz, 101 MHz, or 126 MHz for 13C NMR). Chemical shifts of 1H NMR spectra were recorded relative to TMS (δ 0.00) or residual protonated solvents (CDCl3: δ 7.26; CD3CN: δ 1.94). 13C NMR spectra were obtained at 101 or 126 MHz using a proton-decoupled pulse sequence and were tabulated by the observed peak. Chemical shifts were reported in parts per million (ppm) and referenced to 77.16 ppm. Nuclear Overhauser effect spectroscopy (NOESY), heteronuclear multiple-bond correlation spectroscopy (HMBC), and heteronuclear single-quantum correlation spectroscopy (HSQC) were used to determine the structures of products. The following abbreviations are used to express the multiplicities: s = singlet; d = doublet; t = triplet; q = quartet; m = multiplet; br = broad. Silica gel (300–400 mesh) was used for column chromatography. Unless otherwise noted, reagents obtained


16

Page 17 of 27 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


from commercial suppliers were used without further purification. Infrared spectroscopy was conducted on a Thermo Fisher Nicolet 6700 instrument. HRMS was recorded on a commercial apparatus (ESI and APCl Source). Cyclic voltammograms were collected with a Shanghai Chenhua CH1600D potentiostat. Melting points are uncorrected. Materials. All ortho-quinone catalysts were prepared according to the relevant literature.13 Tetrahydroisoquinolines and 1,2,3,4tetrahydro-β-carbolines were prepared by a Pictet-Spengler reaction in two steps according to the method of Stahl,10b from commercially available 3,4-dimethoxyphenethylamine and 2-(1H-indol-3-yl)ethanamine, whose spectroscopic data matched those previously reported.10b,33 Other cyclic secondary amines were obtained from commercial sources and used without further purification. N-aryltetrahydroisoquinolines were prepared according to the method of Li.17b Nucleophiles were obtained from commercial sources and used without further purification. 1-Phenylethylamine-d1,34 3,4-dihydro-2H-isoquinoline-d2,35 and N-phenyl-1,2,3,4tetrahydroisoquinoline-d436 were prepared according to previously described methods. General procedure for secondary amines oxidation. A flame-dried 10 mL flask was flushed with O2 and equipped with an O2 balloon. o-Q1 (3.88 mg, 0.02 mmol, 10 mol%) in 1.0 mL of CH3CN and secondary amine (0.2 mmol) were added to the flask. The reaction was stirred at 60 °C for 48–72 h. After the reaction was completed, the mixture was concentrated. The yield was determined by 1H NMR analysis by using 1,3,5-trimethoxybenzene as an internal standard. Then the crude reaction product was purified though an Et3N-washed silica gel using 1:10–1:4 EtOAc/petro ether to give a pure product. For known compounds: 3,4-Dihydroisoquinoline (5a)10b, white solid, 19.7 mg, 75% yield; 6,7-Dimethoxy–3,4-dihydroisoquinoline (5b)10b, white solid, 36.3 mg, 95% yield; 1H– indole (5c)10b, yellow solid, 11.7 mg, 50% yield; Quinoline (5d)10c, yellow solid, 9.8 mg, 38% yield; 6,7-Dimethoxy–1–phenyl–3,4dihydroisoquinoline (5e)10b, white solid, 47.6 mg, 89% yield; 1–(4-Chlorophenyl)–6,7-dimethoxy–3,4-dihydroisoquinoline (5f)10b, white solid, 56.1 mg, 93% yield; 1–(4-Bromophenyl)–6,7-dimethoxy–3,4-dihydroisoquinoline (5g)37, yellow solid, 60.9 mg, 88% yield; 6,7-Dimethoxy–1–(p-tolyl)–3,4-dihydroisoquinoline (5h)37, white solid, 54.0 mg, 96% yield; 1–Phenyl–4,9– dihydro-3H–pyrido[3,4-b]indole (5i)10b,white solid, 46.3 mg, 94% yield; 1–(4-Chlorophenyl)–4,9–dihydro-3H–pyrido[3,4b]indole (5j) 0b, white solid, 47.1 mg, 84% yield; 1–(4-Bromophenyl)–4,9–dihydro-3H–pyrido[3,4-b]indole (5k)33, yellow solid, 57.2 mg, 88% yield; 1–(p-Tolyl)–4,9–dihydro-3H–pyrido[3,4-b]indole (5l)38, yellow solid, 44.3 mg, 85% yield. 1-(Thiophen-3-yl)-4,9-dihydro-3H-pyrido[3,4-b]indole (5m): yellow solid, 47.8 mg, 95%. Mp: 231-234 oC. 1H NMR (300 MHz, CDCl3) δ 8.41 (br, 1H), 7.76 – 7.75 (m, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.55 – 7.53 (m, 1H), 7.44 – 7.38 (m, 2H), 7.33 – 7.30 (m, 1H), 7.21 – 7.16 (m, 1H), 4.03 – 3.97 (m, 2H), 2.97 – 2.92 (m, 2H). 13C {1H} NMR (75 MHz, CDCl3) δ 154.7, 139.9, 136.7, 127.3, 126.7, 126.0, 125.8, 124.7, 120.6, 120.1, 118.2, 112.8, 77.5, 77.1, 76.7, 48.6, 19.3. IR (KBr, cm-1): 2931, 1541, 1276, 746, 726. HRMS (ESIOrbitrap) m/z: [M + H]+ Calcd for C15H13N2S 253.0794; Found 253.0792. General procedure for cross-dehydrogenative coupling reaction. A flame-dried 10 mL flask was flushed with O2 and equipped with an O2 balloon. o-Q1 (4.85 mg, 0.025 mmol, 10 mol%), nucleophile (0.50 mmol), and N-aryltetrahydroisoquinoline (0.25 mmol) were added to the flask. The reaction was stirred at 60 °C for 12–24 h. After the reaction was completed, the crude reaction product was purified though a silica gel using 1:20–1:1 EtOAc/petro ether to give a pure product. For known compounds: 1–(Nitromethyl)–2–


17


phenyl–1,2,3,4-tetrahydroisoquinoline

(8a)39,

yellow

oil,

57.7

mg,

Page 18 of 27 86%;

1–(1–Nitroethyl)–2–phenyl–1,2,3,4-

tetrahydroisoquinoline (8b)39, yellow oil, 62.8 mg, 89%; 1–(1–Nitropropyl)–2–phenyl–1,2,3,4-tetrahydroisoquinoline (8c)39, yellow oil, 62.8 mg, 83%; 1–(Nitromethyl)–2–(m–tolyl)–1,2,3,4-tetrahydroisoquinoline (8d)40, yellow oil, 51.5 mg, 73%; 1–(1– Nitroethyl)–2–(m–tolyl)–1,2,3,4-tetrahydroisoquinoline (8e)40, yellow oil, 49.6 mg, 67%; 1–(Nitromethyl)–2–(p-tolyl)–1,2,3,4tetrahydroisoquinoline (8f)39, yellow oil, 60.7 mg, 86%; 1–(Nitromethyl)–2–(p-tolyl)–1,2,3,4-tetrahydroisoquinoline (8g)39, yellow oil, 63.7 mg, 86%; 2–(4-Methoxyphenyl)–1–(nitromethyl)–1,2,3,4-tetrahydroisoquinoline (8h)39, yellow solid, 54.4 mg, 73%; 2–(4-Methoxyphenyl)–1–(1–nitroethyl)–1,2,3,4-tetrahydroisoquinoline (8i)40, yellow solid, 57.8 mg, 74%; 2–(4Chlorophenyl)–1–(nitromethyl)–1,2,3,4-tetrahydroisoquinoline (8j)39, yellow solid, 62.8 mg, 83%; 2–(4-Chlorophenyl)–1–(1– nitroethyl)–1,2,3,4-tetrahydroisoquinoline (8k)41, yellow solid, 64.1 mg, 81%; 2–(4-Bromophenyl)–1–(nitromethyl)–1,2,3,4tetrahydroisoquinoline (8l)39, yellow solid, 73.8 mg, 85%; 2–(4-Bromophenyl)–1–(1–nitroethyl)–1,2,3,4-tetrahydroisoquinoline (8m)39, yellow solid, 65.0 mg, 72%; 2–(3-Methoxyphenyl)–1–(1–nitroethyl)–1,2,3,4-tetrahydroisoquinoline (8n)42, yellow oil, 58.2 mg, 78%; 2–(2–Methoxyphenyl)–1–(nitromethyl)–1,2,3,4-tetrahydroisoquinoline (8o)39, yellow oil, 27.6 mg, 37%; 6,7Dimethoxy–1–(nitromethyl)–2–phenyl–1,2,3,4-tetrahydroisoquinoline (8p)39, yellow oil, 63.2 mg, 77%; Dimethyl 2–(2–phenyl– 1,2,3,4-tetrahydroisoquinolin–1–yl)malonate tetrahydroisoquinolin–1–yl)malonate

(9a)39,

(9b)43,

colorless

colorless

oil,

oil,

76.4

mg,

75.3

mg,

82%;

90%;

Diethyl

2–(2–phenyl–1,2,3,4-

1–(1H–Indol–3-yl)–2–phenyl–1,2,3,4-

tetrahydroisoquinoline (9c)41, yellow solid, 51.9 mg; 1–(5-Methyl–1H–indol–3-yl)–2–phenyl–1,2,3,4-tetrahydroisoquinoline (9d)44, yellow solid, 53.3 mg, 63%; 1–(1–Methyl–1H–indol–3-yl)–2–phenyl–1,2,3,4-tetrahydroisoquinoline (9e)41, yellow solid, 35.5 mg, 42%; Dimethyl (2–phenyl–1,2,3,4-tetrahydroisoquinolin–1–yl)phosphonate (9f)43, colorless oil, 49.2 mg, 62%; Diethyl (2–phenyl–1,2,3,4-tetrahydroisoquinolin–1–yl)phosphonate (9g)19b, colorless oil, 52.7 mg, 61%; Diisopropyl (2–phenyl–1,2,3,4tetrahydroisoquinolin–1–yl)phosphonate

(9h)19b,

colorless

oil,

53.2

mg,

57%;

1–Phenyl–2–(2–phenyl–1,2,3,4-

tetrahydroisoquinolin–1–yl)ethanone (9i)19b, colorless oil, 51.6 mg, 63%. 9–Methyl–1–(nitromethyl)–2–phenyl–2,3,4,9–tetrahydro-1H–pyrido[3,4-b]indole (8q): yellow oil, 54.0 mg, 67% yield. 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 7.9 Hz, 1H), 7.32 – 7.19 (m, 4H), 7.14 – 7.10 (m, 1H), 7.00 (d, J = 7.9 Hz, 2H), 6.86 (t, J = 7.3 Hz, 1H), 5.61 (dd, J = 10.2, 3.3 Hz, 1H), 4.92 (dd, J = 12.5, 10.3 Hz, 1H), 4.65 (dd, J = 12.5, 3.4 Hz, 1H), 3.97 (dd, J = 14.7, 5.6 Hz, 1H), 3.75 (s, 3H), 3.65 –3.62 (m, 1H), 3.03 – 2.98 (m, 1H), 2.69 (dd, J = 15.9, 3.9 Hz, 1H). 13C {1H} NMR (101 MHz, CDCl3) δ 149.6, 137.6, 130.1, 129.4, 126.6, 122.6, 121.0, 119.7, 118.7, 118.1, 110.8, 109.2, 54.9, 42.1, 29.9, 18.8. IR (KBr, cm-1): 3057, 2942, 1601, 1557, 747. HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for C19H20N3O2 322.1550; Found 322.1548. Kinetic isotope effect studies for amine oxidation. Kinetic isotope effect studies for amine oxidation. (a) Primary amine: To a solution of o-Q1 (7.76 mg, 0.04 mmol) and 1,3,5-trimethoxybenzene (11.2 mg, 0.06 mmol) in 1 mL of CD3CN in a NMR tube was added 1-phenylethanamine (48.4 mg, 0.4 mmol) or α-d-1-phenylethanamine (48.8 mg, 0.4 mmol). The NMR tube was flushed with O2. The reaction was monitored by 1H NMR analysis for 0.5 h (

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