Rh-Catalyzed Annulations of N-Methoxybenzamides and Ketenimines

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Rh-catalyzed annulations of N-methoxybenzamides and ketenimines: Stericand electronic-controlled synthesis of isoquinolinones and isoindolinones Xiaorong Zhou, Zhiyin Zhang, Hongyang Zhao, Ping Lu, and Yanguang Wang J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 24 Mar 2017 Downloaded from http://pubs.acs.org on March 25, 2017

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The Journal of Organic Chemistry

Rh-catalyzed annulations of N-methoxybenzamides and ketenimines: Steric- and electronic-controlled synthesis of isoquinolinones and isoindolinones

Xiaorong Zhou, Zhiyin Zhang, Hongyang Zhao, Ping Lu,* and Yanguang Wang* Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China

ABSTRACT: Rhodium-catalyzed C-H activation/annulation reactions of ketenimines with N-methoxybenzamides are reported. The outcome of reactions is dependent on the structure of ketenimines. The β-alkyl-substituted ketenimines furnish 3-iminoisoquinolin-1(2H)-ones through a formal [4+2] annulation manner, while the β-ester substituted ketenimines afford 3-aminoisoindolin-1-ones through a formal [4+1] annulation manner. The synthesized [4+2] products undergo an intramolecular Cu-catalyzed C-N coupling to be converted to benzo[4,5]imidazo[1,2-b]isoquinolin-11-ones, which

can be directly prepared from

ketenimines and N-methoxybenzamides by a one-pot Rh-catalyzed annulation /Cu-catalyzed C-N coupling sequence.

ACS Paragon Plus Environment


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INTRODUCTION

Aza-heterocycles are privilege scaffolds in a variety of natural compounds and biologically active molecules.1 They play important roles in the pharmaceutical and agrochemical industries. Both benzimidazole2 and isoquinolinone3 are well known structural motifs in medicinal chemistry. Benzo[4,5]imidazo[1,2-b]isoquinolin-11-one derivatives, the fused form of isoquinolinone and benzimidazole frameworks, exhibited diverse bioactivties and some of them have been demostrated as potential anti-Trypanosoma Cruzi agents,4 PDE inhibitors 45 and anticancer agents (Figure 1).6 However, most biological properties of this class of compounds remain unexplored due to the lack of accessible synthetic methods for these skeletons. Consequently, developing convenient methods for the synthesis of such molecules has attracted much attention from medicinal and synthetic chemists. The published approaches to the benzo[4,5]imidazo[1,2-b]isoquinolin-11-one ring system include the condesention of benzene-1,2-diamines with 2-(carboxymethyl)benzoic acids or their analogues

(Scheme

1,

route

a),7

the

copper(I)-catalyzed

cross-coupling

of

2-halo-N-(2-halophenyl)benzamides with alkyl 2-cyanoacetates or malononitrile (Scheme 1, route b),8 the Ugi-type multicomponent reaction (Scheme 1, route c),9 and the Amberlyst-15 mediated intramolecular cyclization of 3-amino-2-(2-aminophenyl)isoquinolin-1(2H)-ones (Scheme 1, route d).5


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Figure 1. Examples of biolobically active benzo[4,5]imidazo[1,2-b]isoquinolin-11-ones O NC +

O N H Br

R1NH2

N

+

OEt Cu(I)

Br

NHBoc

C

OHC R2CO2H

c

b

MeO2C

O N

a

CO2H

d

N H

O

CO2H +

NH2 NH2

N

This work

NH NH2 2

O

R N H

OMe Br +

H3C

C

N

Ph

Scheme 1. Construction of benzo[4,5]imidazo[1,2-b]isoquinolin-11-ones Ketenimines have been demonstrated as an important and vesatile synthesis intermediates in organic synthesis.10 Their chemical properties have been widely explored and they can undergo various reactions like nucleophilic/electronphilic additions, cycloadditions and sigmatropic rearrangements. To the best of our knowledge, the insertions of transition metal to the C=C bond of ketenimine moleculars have never been reported although these reactions have been explored and applied in other C=C bond containing compounds, such as regular alkene, allene,11 and thus afforded a variety of useful products. Rhodium (III)-catalyzed C-H



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activation/annulation is becoming a successful strategy in constructing aza-heterocycles.12 Recently, we reported a Rh(III)-catalyzed annulations of N-methoxybenamides and ketenimines, furnishing the formal [4+1] and [3+2] annulation products. In these cases, the insertion of C-Rh bond to C=N bond occured.13 In continuation of our interest in the chemistry of ketenimines,14 we herein reported a Rh(III)-catalyzed C-H activation/insertion of C=C bond/annulation reaction between N-methoxybenzamide and ketenimines. This reaction led to the formal [4+2] annulation products, 3,4-dihydroisoquinolin-1(2H)-ones, which could be further converted to benzo[4,5]imidazo[1,2-b]isoquinolin-11(6H)-ones.

RESULT AND DISCUSSION

To start with, we probed the reaction conditions for the envisioned rhodium-catalyzed C-H activation. In our primary test, the reaction of N-methoxybenzamide (1a) with 2-methyl-2-phenyl-N-(p-tolyl)ethenimine (2a) under [Cp*RhCl2]2 (5 mol %) and Cl3CCO2Cs (30 mol %) in 1,2-dichloroethane (DCE) at 80 oC for 10 hours afforded a [4+2] annulation product 3a in 40% yield (Table 1, entry 1). The structure of 3a was established by its single crystal analysis.15 We screened other solvents (e.g. CH2Cl2, acetone, toluene, and 1,4-dioxane), but no better result was afforded (Table 1, entries 2-5). We then screened other bases, such as PivOCs, CsOAc, NaOAc, K2CO3 as well as Cs2CO3, and Cs2CO3 was found to give a better yield (45%) (Table 1, entries 6-10). A decreased yield was observed when the loading of Cs2CO3 was increased (Table 1, entry 11). The results were not improved when the ratio of 1a was added or adding 1,2,3,4-tetraphenylcyclopentdiene as a steric ligand (Table 1, entries 12 and 13 ). [Cp*RhCl2]2 was found to be indispensiable catalyst to this reaction,


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while no desired product was obtained using [Cp*IrCl2]2 or [Ru(cymene)Cl2]2 as the catalyst (Table 1, entries 14 and 15). Finally, the optimized conditions were confirmed: 1a (0.36 mmol), 2a (0.3 mmol), [Cp*RhCl2]2 (0.015 mmol) , Cs2CO3 (0.09 mmol) and 4Å MS (60 mg) in DCE (2 mL) at 80 oC for 10 h (Table 1, entry 10). We also tried other benzamide

substances such as N-pivaloylbenzamide, but no better yields were obtained.

Table 1 Optimization of the [4+2] reaction conditionsa

entry

base

catalyst

solvent

yield (%)b

1

Cl3CCO2Cs

[Cp*RhCl2]2

DCE

40

2

Cl3CCO2Cs

[Cp*RhCl2]2

DCM

32

3

Cl3CCO2Cs

[Cp*RhCl2]2

acetone

30

4

Cl3CCO2Cs

[Cp*RhCl2]2

toluene

35

5

Cl3CCO2Cs

[Cp*RhCl2]2

1,4-dioxane

19

6

PivOCs

[Cp*RhCl2]2

DCE

38

7

CsOAc

[Cp*RhCl2]2

DCE

25

8

NaOAc

[Cp*RhCl2]2

DCE

17

9

K2CO3

[Cp*RhCl2]2

DCE

30

10

Cs2CO3

[Cp*RhCl2]2

DCE

45



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11c

Cs2CO3

[Cp*RhCl2]2

DCE

30

12d

Cs2CO3

[Cp*RhCl2]2

DCE

45

13e

Cs2CO3

[Cp*RhCl2]2

DCE

44

14

Cs2CO3

[Cp*IrCl2]2

DCE

N.D.

15

Cs2CO3

[Ru(cymene)Cl2]2

DCE

N.D.

a

The reaction conditions: 1a (0.36 mmol), 2a (0.3 mmol), catalyst (0.015 mmol), base (0.09

mmol), 4 Å MS (60 mg), solvent (2 mL), N2, 80 oC, 10 h. bIsolated yield refers to 2a. cCs2CO3 (0.3 mmol) was used. d1a (0.6 mmol) was used. e1,2,3,4-Tetraphenylcyclopentdiene (10 mol %) was added.

With the optimized conditon in hand, we invesitgated the substrate scope. As shown in Scheme 2,3-imino-isoquinolin-1(2H)-ones 3b-n were obtained in moderate to good yields when 2-alkyl-2-aryl-N-arylethenimines 2b-n were used as the reaction component. The yields of products 3b-f were found to be relatively lower. The situation changed as the aryl on nitrogen atom of ketenimine changed from p-methylphenyl to m-bromophenyl and o-methylphenyl. Thus, 3f and 3g were obtained in 49% and 67% yields, respectively. Higher yields were also obtained for those with N-(o-ethyl)phenyl ketenimine (product 3h, 66% yield) and N-(o-bromo)phenyl ketenimine (product 3i, 70% yield). However, the less steric and more electron-deficient o-fluorophenyl substituted ketenimine afforded rather lower yield (39%) of the desired product 3j. In the cases where 3i and 3k-l were produced, tautomerism could be identified in their NMR spectra. The alkyl group on the terminal carbon of ketenimine could be methyl or ethyl. As the steric hindrance of the alkyl group increased


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from methyl (products 3k and 3m, 54% and 58% yields) to ethyl (products 3l and 3n, 38% and 46% yields), the yields decreased.

Scheme 2. Synthesis of 3-imino-isoquinolin-1(2H)-ones 3 a

a

Reaction conditions: 1a (0.36 mmol), 2 (0.3 mmol), [Cp*RhCl2]2 (0.015 mmol), Cs2CO3

(0.09 mmol), 4 Å MS (60 mg), DCE (2 mL), N2, 80 oC, 10 h; Isolated yields refer to 2.



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As next step, we turned our sight to the derivation of products 3. We envisioned that 3 could be easily transformed to benzo[4,5]imidazo[1,2-b]isoquinolin-11(6H)-one by an intramolecular C-N bond coupling. The most easily prepared compound 3i was chosen as the ideal candidate for the intramolecular N-Arylation. By screened some classical Buchward-Hartwig reaction and Ullmann reaction conditions (Table 2), we obtained the desired cyclization product 4a in almost quantitative yield (Table 2, entry 3). A slight decrease in yield was observed when the solvent was changed from toluene to DCE (Table 2, entry 4). However, using DCE as solvent, we could conveniently conduct a two-step one-pot procedure for the preparation of benzo[4,5]imidazo[1,2-b]isoquinolin-11(6H)-ones by directly adding the catalyst and additives after the C-H activation/annulation reaction.

Table 2. Optimization of the intramolecular N-arylation of compound 3ia

entry

reaction conditions

yield (%)

1

5 mol % Pd(OAc)2, 7.5 mol % dppf, 2 equiv of t-BuONa,

63

toluene, reflux, 10 h 2

10 mol % CuI, 20 mol % L-proline, 2 equiv of NaH, toluene, reflux,10 h


90

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3

10 mol % CuI, 20 mol % TMEDA, 2 equiv of

Cs2CO3,

98

Cs2CO3,

92

toluene, reflux,10 h 4

10 mol % CuI, 20 mol % TMEDA, 2 equiv of DCE, reflux, 10 h

a

All

the

reactions

were

conducted

in

0.1

mmol

scale.

TMEDA

=

N1,N1,N2,N2-tetramethylethane-1,2-diamine. We then tried to combine the two step reaction in one pot by adding CuI, TMEDA and Cs2CO3 after the annulation of 1 and 2. As shown in Scheme 3, the one-pot preparation of benzo[4,5]imidazo[1,2-b]isoquinolin-11(6H)-one 4a was achieved successfully with a total yield up to 60%. Subsequently, we investigated the substrate scope for this procedure. Several substituted N-methoxybenzamides were examined. The substituent on 4-position in phenyl ring of 1 could be either electron-donating (e.g. MeO and Me) or electron-withdrawing (e.g. Cl and CF3). Thus, the corresponding products 4b-e were obtained with the yields ranging from 42% to 61%. The substituent on 3-position of 1 could be Me (4f), Cl (4g) and NO2 (4h). Substitution on the 2-position of N-methoxybenzamides might retard the reaction due to steric hindrance and poor yields of the corresponding products 4i and 4j were isolated. N-Methoxy-1-naphthamide (1b) was also examined and the desired product 4k was obtained in 25% yield. The substituent on the terminal carbon of ketenimine could be either p-methylphenyl

or

m-chlorophenyl.

In

this

case,

the

desired

benzo[4,5]imidazo[1,2-b]isoquinolin-11(6H)-ones 4l and 4m were isolated in 55% and 60%, respectively.



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Scheme 3. One-pot preparation of benzo[4,5]imidazo[1,2-b]isoquinolin-11(6H)-ones 4a

a

Reaction conditions: 1) 1 (0.24 mmol), 2 (0.2 mmol), [Cp*RhCl2]2 (0.01 mmol), Cs2CO3

(0.06 mmol), 4Å MS (40 mg), DCE (2 mL), N2, 80 oC, 10 h; 2) 10 mol% CuI (0.02 mmol), TMEDA (0.04 mmol), Cs2CO3 (0.4 mmol), N2, 80 oC, 10 h; Isolated yield refer to 2.

Interestingly，by further extending the substrate scope of ketenimines, we found that β-ester group substituted ketenimines 5 were suitable for the standard reaction conditions, but they resulted in a different reaction pathway to give the [4+1] annulation products (Table 3).


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In these cases, 3-aminoindolin-1-ones 6a~6i were obtained along with their stereoisomers 6a'~6i' in moderate to excellent yields. For 6a and 6d~6g, the corresponding stereoisomers 6a' and 6d'~6g' could be isolated and pure products were obtained. For 6b, 6c, 6h and 6i, however, we just isolated a mixture of these compounds and their stereoisomers 6b', 6c', 6h' and 6i', respectively. The (2R,3S)/(2S,3R)-configuration of 6e was established by its single crystal analysis.15 Both R1 and R2 in ketenimines 5 could be either alkyl or aryl. Altering R1 from methyl to aryl (5d~5i), higher dr values were obtained for products 6d~6i (Table 3, entries 4~9). When the alkyl group (R2) on nitrogen of ketenimine became bulkier, from ethyl to isopropyl, the yield decreased (Table 3, entries 8 and 9). When the alkyl was tert-butyl, no reaction occurred (Table 3, entry 10). Formation of the enantiomeric pair with absolute configuration of (2R,3S)-6 and (2S,3R)-6 was found to be dominant in all cases as illustrated in Figure 2. The steric hindrance raised when products 6 adopted the conformation of (2S,3S)-6 and (2R,3R)-6.

Table 3. Synthesis of 3-aminoisoindolin-1-ones 6a

entry

5 (R1/R2/R3)

1

5a (CH3/4-ClC6H4/Et)

2

5b (CH3/4-ClC6H4/n-Bu)

yield of

yield of

(2R,3S)/(2S,3R)-6b

(2R,3R) /(2S,3S)-6'b

6a/64%

6a'/20% (6b + 6b')/ 72%


dr

3.3:1 2.3:1c


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3

5c (CH3/4-ClC6H4/CH2Ph)

4

5d (Ph/4-ClC6H4/Et)

6d/74%

6d'/ 12%

6.4:1

5

5e (4-BrC6H4/4-ClC6H4/Et)

6e/76%

6e'/15%

5:1

6

5f (4-MeOC6H4/4-ClC6H4/Et)

6f/35%

6f'/ 7%

5:1

7

5g (Ph/4-CH3C6H4/Et)

6g/67%

6g'/13%

5.1:1

8

5h (Ph/Et/Et)

(6h + 6h')/98%

5.5:1 c

9

5i (Ph/i-Pr/Et)

(6i + 6i')/57%

6.5:1 c

10

5j (Ph/t-Bu/Et)

N.R.

a

(6c + 6c')/ 46%

2.2:1 c

Reaction conditions: 1a (0.36 mmol), 5 (0.3 mmol), [Cp*RhCl2]2 (0.015 mmol), Cl3CCO2Cs

(0.09 mmol), 4Å MS (60 mg), DCE (2 mL) under N2, 80 oC, 10 h. bIsolated yields refer to 2. c Determined by 1H NMR.

Figure 2. Predominant formation of (2R,3S)-6 and (2S,3R)-6


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To probe the reaction mechanism for the formation of compounds 3, the reactions of 1a with 2a were examined using 5 mol % [Cp*RhCl2]2 and 15 mol % AgNTf2 (Scheme 4, eq 1). The addition product 7 was isolated in 95% yield. Further investigation revealed that imidamide 7 was stable to the standard conditions. Furthermore, when the reaction of 1a was conducted with the addition of 1 equivalent of D2O under the standard conditions in the absence of ketenimine, a deuterium incorporated product was obtained. This result indicated that the C-H activation was reversible (Scheme 4, eq 2). Kinetic isotope effect (KIE) was carried out in parallel experiments (Scheme 4, eq 3). 16 By treatment of 1a or 1a-d5 under standard reaction conditions for 30 minutes, KIE of the [4+2] reaction was determined to be 1.1. This value indicated that the C-H activation was not the rate determining step.

Scheme 4. Mechanistic Experiments



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On the basis of the above experiments, a possible mechanism is proposed in Scheme 5. In the presence of Cs2CO3 or Cl3CCO2Cs, catalyst [Cp*RhCl2]2 is activated to species A. Subsequent arene electrophilic rhodation of 1 provides the complex B, followed by its coordination to ketenimine. Thereafter, there are two distinct reaction pathways depending on the nature of substituents on ketenimine. When methyl or primary alkyl occupied on the terminal carbon of ketenimine (R1 = Me or CH2R), the formation of π-complex C is dominant. Subsequently, the migratory insertion into C=C bond leads to the formation of D, which undergoes an intramolecular oxidation/reductive elimination to form E.17 After metal-H exchange, E undoubtedly generates in the [4+2] annulation product 3. When one ester group or two aryls13 occupies on the terminal carbon of ketenimine (i.e., R1 = COOR or R1 = R2 =aryl), Rh coordinates to the nitrogen atom of ketenimine to afford σ-complex F. Upon migratory insertion into C=N bond, complex G is generated. Then, G undergoes a migratory insertion into C=C bond to form complex H. Finally, the [4+1] annulation product 6 is generated by the metal-H exchange.


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[Cp*RhCl2]2 [ 4+1] product

[ 4+2] product

CsX

6

3 Cp*RhX2 A

O

R3

HX

N OMe Rh Cp* X NH R2 1 R H

Cp* Rh N OMe R3 N Ar CH2 R O

1

HX

HX O

E

HX O

OMe

R1

N Rh Cp* N R3

R1 G

R3 C N

N OMe Rh Cp* B

X = CO32- or Cl3CCO2-

R2 R1 = CO2R or O R1 = R2 = aryl

R2

N OMe Rh Cp* R1 R2

C

N

O N OMe Rh Cp*

R1 = aryl, R2 = alkyl RCH2

R3

F

O

OMe N Rh Cp*

3 Ar CH N R 2 R D

R3 C N

Ar C

Scheme 5. Possible mechanism for steric-and electronic-controlled formation of 3 and 6

Competitive formations between π-complex C and σ-complex F play an important role in the outcome of reaction. Geometry of 2c, 5a, and 2,2-diphenyl-N-(p-tolyl)ethen-1-imine (8)13 was obtained by B3LYP/6-31G method on Gaussian 09 program (Figure 3). For ketenimine 8, coordination of C=C bond to rhodium is effectively inhibited by two twisted aryl groups. As a result, the nitrogen of ketenimine coordinates to rhodium with higher priority. When one of the two aryls is altered into methyl, especially when the nitrogen bears a steric ortho-substituted phenyl, the C=C bond of 2c could coordinate to rhodium. For ketenimine 5a, the electron-withdrawing effect of ester group is dominant which induced double Michael additions on the central carbon of ketenimine.



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Figure 3. Geometry of 2c, 5a and 8

CONCLUSION

In conclusion, we have developed the rhodium-catalyzed C-H activation/annulations of ketenimines with N-methoxybenzamides. The reaction outcomes were found to be dependent on the molecular structure of the ketenimine component. The β-alkyl substituted ketenimines furnished 3-iminoisoquinolin-1(2H)-ones through a formal [4+2] annulation manner, while the β-ester group substituted ketenimines afforded 3-aminoisoindolin-1-ones through a formal [4+1] annulation manner. Possible mechanism for the selective formation of [4+2] and [4+1] annulations products was proposed on the basis of experimental and computational results. Furthermore, the synthesized [4+2] products could undergo an intramolecular Cu-catalyzed C-N coupling to be converted to benzo[4,5]imidazo[1,2-b]isoquinolin-11-ones, which could be directly prepared from ketenimines and N-methoxybenzamides by a one-pot Rh-catalyzed annulation /Cu-catalyzed C-N coupling sequence. The resulted heterocyclic products are an important in medicinal chemistry.


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EXPERIMENTAL SECTION

General considerations. Unless otherwise mentioned, solvents and reagents were purchased from commercial sources and used as received. THF and toluene were distilled from Na before use. MeCN, CH2Cl2 and DCE were distilled from CaH2. Melting points were measured with a micro melting point apparatus. Infrared spectra were obtained with an FTIR spectrometer. NMR spectra were operating at 500 MHz or 400 MHz for 1H NMR, 125 MHz or 100 MHz for

13

C NMR. Unless otherwise noted, all the NMR spectra were recorded at

room temperature. Chemical shifts were quoted in parts per million (ppm) referenced to the appropriate solvent peak or 0.0 ppm for tetramethylsilane. Chemical shifts (in ppm) were referenced to tetramethylsilane (δ = 0 ppm) in CDCl3 and d6-DMSO as an internal standard. 13

C NMR spectra were obtained by using the same NMR spectrometers and chemical shifts

were reported in ppm referenced to the center line of a triplet at 77.0 ppm of CDCl3 or the center line of a heptet at 39.52 ppm of d6-DMSO. The following abbreviations are used to describe peak patterns as appropriate: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet. Coupling constants J were reported in hertz unit (Hz). High-resolution mass spectra (HRMS) data were obtained with an electron ionization time-of-flight (EI-TOF) mass spectrometer. Flash column chromatography was performed employing 300-400 mesh silica gel. Thin layer chromatography (TLC) was performed on silica gel HSGF254. Compounds 1a–k and 1a-d5 were prepared according to the literature procedures.17, 18



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General Procedure for the Preparation of Ketenimines 2. To a mixture of the coresponding N-(triphenylphosphoranylidene)anilines (2 mmol), Et3N (2.4 mmol) in CH2Cl2 (5 mL) was added a solution of 2-phenylpropanoyl chloride (2 mmol) in CH2Cl2 (5 mL) dropwise. The mixture was stirred at room temperature for 15 min and then evaporated on vacuum. The residue was subjected to silica gel column chromatography with petroleum ether as eluent (The column should be eluted previously with petroleum ether/Et3N (10:1, v/v). N-(2-Ethylphenyl)-2-phenylprop-1-en-1-imine (2b). Yellow oil; 70 % (329 mg). 1H NMR (400 MHz, CDCl3) δ 7.31 (t, J = 7.7 Hz, 2H), 7.27 – 7.21 (m, 3H), 7.21 – 7.15 (m, 3H), 7.11 (t, J = 7.2 Hz, 1H), 2.86 (q, J = 7.5 Hz, 2H), 2.12 (s, 3H), 1.27 (t, J = 7.5 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 192.6, 139.5, 139.2, 135.9, 129.4, 128.6, 127.3, 126.8, 124.9, 124.3, 122.6, 66.4, 24.9, 15.3, 12.3 . IR (ATR): 2967, 2004, 1597, 1489, 1449, 1373, 1257, 1063, 756, 694 cm-1. HRMS (EI) m/z calcd for C17H17N [M+]: 235.1361; found: 235.1365. 2-Phenyl-N-(o-tolyl)prop-1-en-1-imine (2c). Yellow oil; 60 % (266 mg). 1H NMR (400 MHz, CDCl3) δ 7.35 – 7.28 (m, 2H), 7.26 – 7.21 (m, 3H), 7.21 – 7.08 (m, 4H), 2.45 (d, J = 1.9 Hz, 3H), 2.12 (d, J = 1.8 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 192.6, 140.1, 135.8, 133.1, 131.0, 128.6, 127.1, 126.8, 124.9, 124.3, 122.5, 66.2, 18.0, 12.3. IR (ATR): 3023, 2919, 2000, 1583, 1488, 1445, 1373, 1254, 1108, 1065, 754, 691 cm-1. HRMS (EI) m/z calcd for C16H15N [M+]: 221.1204; found: 221.1201. N-(2-Bromophenyl)-2-phenylprop-1-en-1-imine (2h). Yellow oil; 54 % (310 mg). 1H NMR (400 MHz, CDCl3) δ 7.62 (dd, J = 8.0, 1.3 Hz, 1H), 7.36 – 7.23 (m, 6H), 7.17 – 7.07 (m, 2H), 2.14 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 195.7, 140.6, 134.8, 133.4, 128.7, 128.3, 128.1, 125.5, 124.6, 123.7, 118.6, 67.5, 12.2. IR (ATR): 3059, 2922, 2000, 1583, 1469, 1439, 1372,


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1257, 1067, 1027, 753, 692, 663 cm-1. HRMS (EI) m/z calcd for C15H12NBr [M+]: 285.0153; found: 285.0153. N-(2-Fluorophenyl)-2-phenylprop-1-en-1-imine (2i). Yellow oil; 83 % (373 mg).1H NMR (400 MHz, CDCl3) δ 7.36 – 7.28 (m, 3H), 7.27 – 7.23 (m, 2H), 7.23 – 7.18 (m, 1H), 7.17 – 7.09 (m, 3H), 2.13 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 196.9, 156.2 (d, J = 252.4 Hz), 135.0, 129.5 (d, J = 10.3 Hz), 128.7, 128.3 (d, J = 7.7 Hz), 125.2 (d, J = 9.2 Hz), 124.6, 124.6 (d, J = 4.1 Hz), 116.6 (d, J = 19.5 Hz), 66.5, 12.2. IR (ATR): 2000, 1596, 1493, 1452, 1374, 1259, 1128, 1101, 1066, 1027, 837, 754, 693 cm-1. HRMS (EI) m/z calcd for C15H12NF [M+]: 225.0954; found: 225.0956. N,2-Di-p-tolylprop-1-en-1-imine (2j). Yellow oil; 49 % (230 mg). 1H NMR (400 MHz, CDCl3) δ 7.21 (d, J = 8.3 Hz, 2H), 7.16 (d, J = 8.3 Hz, 2H), 7.12 (s, 4H), 2.35 (s, 3H), 2.32 (s, 3H), 2.10 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 194.7, 139.1, 137.3, 134.8, 132.4, 130.0, 129.4, 124.3, 123.6, 67.3, 21.1, 21.0, 12.3. IR (film): 3022, 2922, 1997, 1605, 1579, 1512, 1504, 1371, 1252, 1061, 813 cm-1. HRMS (EI) m/z calcd for C17H17N [M+]: 235.1361; found:235.1360. N-(o-Tolyl)-2-(p-tolyl)prop-1-en-1-imine (2k). Yellow oil; 37 % (176 mg). 1H NMR (400 MHz, CDCl3) δ 7.25 – 7.20 (m, 1H), 7.19 – 7.11 (m, 7H), 2.45 (s, 3H), 2.32 (s, 3H), 2.10 (d, J = 0.8 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 193.6, 140.4, 134.6, 133.1, 132.5, 130.9, 129.4, 126.9, 126.8, 124.2, 122.4, 66.2, 21.0, 18.0, 12.4. IR (ATR): 2923, 2000, 1512, 1487, 1456, 1373, 1257, 1110, 1060, 813, 758, 673 cm-1. HRMS (EI) m/z calcd for C17H17N [M+]: 235.1361; found: 235.1357.



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N-(o-Tolyl)-2-(p-tolyl)but-1-en-1-imine (2l). Yellow oil; 45 % (233 mg). 1H NMR (400 MHz, CDCl3) δ 7.25 – 7.19 (m, 2H), 7.17 – 7.10 (m, 6H), 2.51 (qd, J = 7.4, 1.1 Hz, 2H), 2.45 (s, 3H), 2.32 (s, 3H), 1.24 (td, J = 7.3, 1.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 193.4, 140.6, 134.7, 133.1, 132.0, 130.9, 129.4, 126.9, 126.8, 124.6, 122.0, 74.0, 21.0, 19.9, 18.0, 12.9. IR (ATR): 2966, 2925, 1999, 1512, 1488, 1456, 817, 759 cm-1. HRMS (EI) m/z calcd for C18H19N [M+]: 249.1517; found: 249.1514. N-(2-Bromophenyl)-2-(p-tolyl)prop-1-en-1-imine (2m). Yellow oil; 39 % (193 mg). 1H NMR (400 MHz, CDCl3) δ 7.62 (dd, J = 8.0, 1.4 Hz, 1H), 7.31 – 7.22 (m, 2H), 7.18 – 7.08 (m, 5H), 2.33 (s, 3H), 2.13 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 196.7, 140.9, 135.2, 133.4, 131.5, 129.5, 128.3, 128.0, 124.6, 123.7, 118.7, 67.5, 21.0, 12.3. IR (film): 2921, 2000, 1583, 1513, 1472, 1437, 1372, 1255, 1044, 1028, 814, 755 cm-1. HRMS (EI) m/z calcd for C16H14NBr [M+]: 299.0310; found: 299.0309. N-(2-Bromophenyl)-2-(p-tolyl)but-1-en-1-imine (2n). Yellow oil; 43 % (269 mg). 1H NMR (400 MHz, CDCl3) δ 7.65 – 7.60 (m, 1H), 7.31 – 7.25 (m, 2H), 7.20 – 7.01 (m, 6H), 2.53 (q, J = 7.4 Hz, 2H), 2.32 (s, 3H), 1.26 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 196.6, 141.1, 135.3, 133.4, 131.0, 129.5, 128.3, 128.1, 124.9, 123.3, 118.9, 75.2, 21.0, 20.0, 12.8. IR (ATR): 2967, 2925, 2000, 1687, 1584, 1513, 1468, 1028, 816, 755 cm-1. HRMS (EI) m/z calcd for C17H16NBr [M+]: 313.0466; found: 313.0468.

General procedure for the preparation of 3-imino-3,4-dihydroisoquinolin-1(2H)-ones 3: To an oven-dried Schlenk tube equipped with a magnetic stirring bar were added sequentially 1 (0.36 mmol), 2 (0.3 mmol), [Cp*RhCl2]2 (0.015 mmol), Cs2CO3 (0.09 mmol),


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4Å MS (60 mg) and dry DCE (2 mL) under N2 atmosphere. The reaction vessel was heated to 80 oC in oil bath for 10 hours. Upon completion, the reaction mixture was cooled to room temperature and then the solvent was evaporated in vacuum. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 10:1) to give pure product. 4-Methyl-4-phenyl-3-(p-tolylimino)-3,4-dihydroisoquinolin-1(2H)-one (3a). White solid; yield 45% (46 mg); mp 146 – 148 oC. 1H NMR (400 MHz, CDCl3) δ 8.20 (dd, J = 7.8, 1.5 Hz, 1H), 7.76 (s, 1H), 7.59 (td, J = 7.6, 1.5 Hz, 1H), 7.45 (td, J = 7.6, 1.2 Hz, 1H), 7.34 – 7.26 (m, 3H), 7.26 – 7.20 (m, 3H), 7.12 (d, J = 8.0 Hz, 2H), 6.64 (d, J = 8.2 Hz, 2H), 2.31 (s, 3H), 2.17 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 162.6 , 155.8 , 145.6 , 145.3 , 143.9 , 134.0 , 133.7 , 130.4 , 128.4 , 128.1 , 127.8 , 127.4 , 127.1 , 126.9 , 125.0 , 120.0 , 49.4 , 27.9 , 20.8 . IR (ATR): 3361, 3195, 2924, 1689, 1655, 1603, 1503, 1461, 1361, 1285, 1150, 1032, 910, 759, 731, 703 cm-1. HRMS (EI) calcd for C23H20N2O [M+] 340.1576, found 340.1580. 3-((4-Bromophenyl)imino)-4-methyl-4-phenyl-3,4-dihydroisoquinolin-1(2H)-one (3b). White solid; yield 43% (52 mg); mp 170 – 172 oC. 1H NMR (400 MHz, CDCl3) δ 8.20 (dd, J = 7.8, 1.5 Hz, 1H), 7.66 (s, 1H), 7.60 (td, J = 7.7, 1.5 Hz, 1H), 7.50 – 7.40 (m, 3H), 7.34 – 7.28 (m, 2H), 7.28 – 7.24 (m, 2H), 7.23 – 7.19 (m, 2H), 6.67 – 6.59 (m, 2H), 2.17 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 162.5 , 156.5 , 145.7 , 145.3 , 134.2 , 132.9 , 128.5 , 128.2 , 127.8 , 127.6 , 127.2 , 127.0 , 124.7 , 122.1 , 117.2 , 49.5 , 28.1 . IR (ATR): 3191, 3066, 2924, 2854, 1687, 1654, 1461, 1362, 1288, 1211, 1150, 1069, 909, 840, 759, 732 cm-1. HRMS (EI) calcd for C22H17N2OBr [M+] 404.0524, found 404.0520.



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3-((4-Methoxyphenyl)imino)-4-methyl-4-phenyl-3,4-dihydroisoquinolin-1(2H)-one

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(3c).

White solid; yield 41% (44 mg); mp 147 – 148 oC. 1H NMR (500 MHz, CDCl3) δ 8.20 (d, J = 7.7 Hz, 1H), 7.82 (s, 1H), 7.59 (td, J = 7.6, 1.5 Hz, 1H), 7.45 (t, J = 7.5 Hz, 1H), 7.33 – 7.26 (m, 3H), 7.26 – 7.19 (m, 3H), 6.87 (d, J = 8.7 Hz, 2H), 6.69 (d, J = 8.7 Hz, 2H), 3.78 (s, 3H), 2.17 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 162.6 , 156.4 , 156.0 , 145.6 , 145.3 , 139.5 , 134.0 , 128.4 , 128.1 , 127.7 , 127.4 , 127.0 , 126.9 , 124.9 , 121.2 , 115.1 , 55.5 , 49.4 , 27.9 . IR (ATR): 3361, 3199, 3063, 2933, 1689, 1654, 1604, 1503, 1462, 1362, 1285, 1240, 1034, 911, 841, 756, 705, 644 cm-1. HRMS (EI) calcd for C23H20N2O2 [M+] 356.1525, found 356.1528. 4-Methyl-4-phenyl-3-(phenylimino)-3,4-dihydroisoquinolin-1(2H)-one (3d). White solid; yield 41% (40 mg); mp 108 – 110 oC. 1H NMR (400 MHz, CDCl3) δ 8.21 (dd, J = 7.8, 1.5 Hz, 1H), 7.71 (br, 1H), 7.60 (td, J = 7.6, 1.5 Hz, 1H), 7.46 (td, J = 7.6, 1.2 Hz, 1H), 7.36 – 7.27 (m, 5H), 7.27 – 7.20 (m, 3H), 7.13 – 7.06 (m, 1H), 6.74 (dd, J = 8.3, 1.1 Hz, 2H), 2.19 (s, 3H). 13

C NMR (100 MHz, CDCl3) δ 162.6 , 155.8 , 146.6 , 145.5 , 145.3 , 134.1 , 129.9 , 128.5 ,

128.2 , 127.8 , 127.5 , 127.1 , 127.0 , 124.9 , 124.3 , 120.1 , 49.4 , 27.9 . IR (ATR): 3363, 3216, 3061, 2925, 1692, 1656, 1597, 1490, 1461, 1360, 1284, 1211, 1149, 1071, 1030, 909, 759, 700 cm-1. HRMS (EI) calcd for C22H18N2O [M+] 326.1419, found 326.1415. 4-Methyl-4-(p-tolyl)-3-(p-tolylimino)-3,4-dihydroisoquinolin-1(2H)-one (3e). White solid; yield 42% (45 mg); mp 154 – 157 oC. 1H NMR (500 MHz, CDCl3) δ 8.19 (dd, J = 7.8, 1.5 Hz, 1H), 7.74 (s, 1H), 7.59 (td, J = 7.7, 1.5 Hz, 1H), 7.44 (td, J = 7.6, 1.2 Hz, 1H), 7.28 (d, J = 7.9 Hz, 1H), 7.12 (d, J = 8.1 Hz, 2H), 7.10 (s, 4H), 6.64 (d, J = 8.1 Hz, 2H), 2.31 (s, 6H), 2.15 (s, 3H).

13

C NMR (125 MHz, CDCl3) δ 162.7 , 155.9 , 145.5 , 144.0 , 142.7 , 136.7 , 134.0 ,


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133.7 , 130.4 , 129.1 , 128.1 , 127.7 , 127.3 , 126.8 , 124.9 , 120.0 , 49.1 , 27.9 , 20.9 , 20.8 . IR (ATR): 2924, 2855, 1693, 1658, 1510, 1461, 1374, 1281, 817, 753 cm-1. HRMS (EI) calcd for C24H22N2O [M+] 354.1732, found 354.1730. 3-((3-Bromophenyl)imino)-4-methyl-4-phenyl-3,4-dihydroisoquinolin-1(2H)-one

(3f).

White solid; yield 49% (59 mg); mp 125 – 126 oC. 1H NMR (400 MHz, CDCl3) δ 8.20 (dd, J = 7.8, 1.5 Hz, 1H), 7.71 (br, 1H), 7.60 (td, J = 7.6, 1.5 Hz, 1H), 7.46 (td, J = 7.6, 1.2 Hz, 1H), 7.34 – 7.28 (m, 2H), 7.28 – 7.16 (m, 6H), 6.91 (t, J = 1.9 Hz, 1H), 6.67 (dt, J = 7.3, 1.7 Hz, 1H), 2.17 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 162.5 , 156.7 , 148.1 , 145.3 , 145.2 , 134.2 , 131.1 , 128.5 , 128.2 , 127.8 , 127.5 , 127.20 , 127.18 , 126.9 , 124.6 , 123.4 , 123.3 , 118.9 , 49.4 , 28.1 . IR (ATR): 3194, 3061, 1688, 1653, 1584, 1460, 1360, 1286, 1150, 1031, 994, 877, 758, 736, 701, 677 cm-1. HRMS (EI) calcd for C22H17N2OBr [M+] 404.0524, found 404.0526. 4-Methyl-4-phenyl-3-(o-tolylimino)-3,4-dihydroisoquinolin-1(2H)-one (3g). Yellow oil; yield 67% (68 mg). 1H NMR (400 MHz, CDCl3) δ 8.21 (dd, J = 7.8, 1.5 Hz, 1H), 7.68 (s, 1H), 7.56 (td, J = 7.7, 1.5 Hz, 1H), 7.43 (td, J = 7.6, 1.2 Hz, 1H), 7.34 – 7.23 (m, 5H), 7.20 (d, J = 7.7 Hz, 1H), 7.14 (t, J = 7.9 Hz, 2H), 6.98 (td, J = 7.5, 1.3 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 2.23 (s, 3H), 1.89 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 162.5 , 155.4 , 145.9 , 145.4 , 144.8 , 134.1 , 131.1 , 128.7 , 128.4 , 128.0 , 127.3 , 127.2 , 127.09 , 127.06 , 124.5 , 124.3 , 119.3 , 49.3 , 28.5 , 17.4 . IR (ATR): 3359, 3213, 3062, 1691, 1657, 1599, 1488, 1458, 1357, 1285, 1148, 1113, 1033, 808, 757, 702 cm-1. HRMS (EI) calcd for C23H20N2O [M+] 340.1576, found 340.1579.



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3-((2-Ethylphenyl)imino)-4-methyl-4-phenyl-3,4-dihydroisoquinolin-1(2H)-one

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(3h).

White solid; yield 66% (70 mg); mp 95 – 97 oC. 1H NMR (400 MHz, CDCl3) δ 8.22 (dd, J = 7.9, 1.5 Hz, 1H), 7.72 (s, 1H), 7.57 (td, J = 7.6, 1.5 Hz, 1H), 7.44 (td, J = 7.6, 1.2 Hz, 1H), 7.34 – 7.11 (m, 8H), 7.02 (td, J = 7.5, 1.4 Hz, 1H), 6.60 (dd, J = 7.7, 1.3 Hz, 1H), 2.23 (s, 3H), 2.21 (q, J = 7.5 Hz, 2H), 0.91 (t, J = 7.5 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 162.5 , 155.2 , 145.9 , 145.4 , 144.3 , 135.1 , 134.1 , 129.5 , 128.3 , 128.0 , 127.9 , 127.3 , 127.2 , 127.1 , 127.0 , 124.6 , 124.5 , 119.3 , 49.3 , 28.4 , 24.6 , 14.2 . IR (ATR): 3359, 3205, 3062, 2967, 1691, 1656, 1599, 1487, 1457, 1358, 1285, 1215, 1148, 1117, 1031, 755, 702 cm-1. HRMS (EI) calcd for C24H22N2O [M+] 354.1732, found 354.1731. 3-((2-Bromophenyl)imino)-4-methyl-4-phenyl-3,4-dihydroisoquinolin-1(2H)-one

(3i).

White solid; yield 70% (85 mg); mp 123 – 124 oC. 1H NMR (400 MHz, CDCl3) δ 8.22 – 8.19 (1H), 7.73 (br, 0.17H), 7.64 – 7.52 (m, 2.65 H), 7.49 – 7.41 (1H), 7.36 – 7.16 (m, 7H), 7.09 (t, J = 7.5 Hz, 0.17 H), 6.95 (td, J = 7.8, 1.6 Hz, 0.87 H), 6.73 (1H), 2.25 (s, 2.55 H), 2.18 (s, 0.46 H). IR (ATR): 3357, 3194, 3063, 2924, 1691, 1658, 1602, 1460, 1360, 1289, 1149, 1029, 909, 757, 730, 701 cm-1. HRMS (EI) calcd for C22H17N2OBr [M+] 404.0524, found 404.0529. 3-((2-Fluorophenyl)imino)-4-methyl-4-phenyl-3,4-dihydroisoquinolin-1(2H)-one

(3j).

White solid; yield 39% (40 mg); mp 138 – 139 oC. 1H NMR (500 MHz, CDCl3) δ 8.20 (d, J = 7.7 Hz, 1H), 7.72 (s, 1H), 7.59 (td, J = 7.7, 1.5 Hz, 1H), 7.45 (t, J = 7.5 Hz, 1H), 7.34 – 7.29 (m, 2H), 7.28 – 7.22 (m, 4H), 7.12 – 7.02 (m, 3H), 6.82 – 6.76 (m, 1H), 2.20 (s, 3H).

13

C

NMR (125 MHz, CDCl3) δ 162.5 , 157.8 , 152.8 (d, J = 245.5 Hz), 145.5 , 145.1 , 134.2 , 133.9 (d, J = 12.8 Hz), 128.4 , 128.1 , 127.8 , 127.4 , 127.2 , 127.1 , 125.4 (d, J = 7.2 Hz), 125.0 (d, J = 3.6 Hz), 124.5 , 122.9 (d, J = 2.1 Hz), 116.6 (d, J = 19.5 Hz), 49.8 , 28.4 . IR


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(ATR): 3364, 3196, 3067, 1691, 1658, 1603, 1491, 1460, 1363, 1289, 1251, 1150, 1101, 1031, 910, 756, 648 cm-1. HRMS (EI) calcd for C22H17N2OF [M+] 344.1325, found 344.1329. 3-((2-Bromophenyl)imino)-4-methyl-4-(p-tolyl)-3,4-dihydroisoquinolin-1(2H)-one

(3k).

Pale yellow oil; yield 58% (73 mg). 1H NMR (400 MHz, CDCl3) δ 8.19 (dd, J = 7.8, 1.5 Hz, 1H), 7.73 (br, 0.19 H), 7.61 (br, 0.8 H), 7.59 – 7.54 (2H), 7.47 – 7.39 (1H), 7.35 – 7.16 (4H), 7.15 – 7.10 (2H), 7.10 – 7.05 (m, 0.20 H), 6.94 (td, J = 7.7, 1.6 Hz, 0.87 H), 6.76 – 6.68 (1H), 2.32 –2.31 (d, J = 2.8 Hz, 3H), 2.22 (s, 2.49 H), 2.16 (s, 0.50 H). IR (ATR): 3361, 3197, 3065, 1691, 1657, 1601, 1512, 1460, 1360, 1288, 1149, 1027, 909, 820, 758, 730 cm-1. HRMS (EI) calcd for C23H19N2OBr [M+] 418.0681, found: 418.0678. 3-((2-Bromophenyl)imino)-4-ethyl-4-(p-tolyl)-3,4-dihydroisoquinolin-1(2H)-one (3l). Pale yellow oil; yield 46% (60 mg). 1H NMR (400 MHz, CDCl3) δ 8.21 (dt, J = 7.8, 1.9 Hz, 1H), 7.87 (br, 0.26 H), 7.73 (br, 0.71 H), 7.58 – 7.52 (m, 1.68 H), 7.46 – 7.38 (m, 1H), 7.31 (t, J = 7.9 Hz, 0.57 H), 7.27 – 7.09 (m, 6H), 7.08 – 7.04 (m, 0.23 H), 6.93 (td, J = 7.7, 1.6 Hz, 0.75 H), 6.71 (d, J = 8.1 Hz, 0.51 H), 6.66 (d, J = 7.8 Hz, 0.69 H), 3.25 – 3.01 (1H), 2.50 – 2.36 (m, 1H), 2.30 (s, 3H), 0.92 – 0.85 (3H). IR (ATR): 3359, 3199, 3065, 2970, 1690, 1653, 1600, 1512, 1459, 1362, 1306, 1267, 1229, 1148, 1027, 909, 816, 756, 729 cm-1. HRMS (EI) calcd for C24H21N2OBr [M+] 432.0837, found 432.0837. 4-Methyl-4-(p-tolyl)-3-(o-tolylimino)-3,4-dihydroisoquinolin-1(2H)-one (3m). Pale yellow oil; yield 54% (57 mg). 1H NMR (500 MHz, CDCl3) δ 8.20 (dd, J = 7.8, 1.4 Hz, 1H), 7.66 (s, 1H), 7.56 (td, J = 7.7, 1.5 Hz, 1H), 7.42 (t, J = 7.2 Hz, 1H), 7.21 (d, J = 7.9 Hz, 1H), 7.17 – 7.09 (m, 6H), 6.98 (t, J = 7.5 Hz, 1H), 6.61 (d, J = 7.6 Hz, 1H), 2.31 (s, 3H), 2.20 (s, 3H), 1.92 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 162.6 , 155.6 , 146.1 , 144.9 , 142.5 , 136.7 ,



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134.0 , 131.1 , 129.1 , 128.7 , 127.94 , 127.90 , 127.3 , 127.1 , 124.5 , 124.2 , 119.4 , 49.1 , 28.6 , 20.9 , 17.5 . IR (ATR): 3359, 3213, 2925, 1693, 1659, 1599, 1511, 1460, 1359, 1286, 1189, 1149, 1113, 1038, 910, 822, 755, 730 cm-1. HRMS (EI) calcd for C24H22N2O [M+] 354.1732, found 354.1735. 4-Ethyl-4-(p-tolyl)-3-(o-tolylimino)-3,4-dihydroisoquinolin-1(2H)-one (3n). Pale yellow oil; yield 38% (42 mg). 1H NMR (400 MHz, CDCl3) δ 8.22 (dd, J = 7.9, 1.5 Hz, 1H), 7.77 (s, 1H), 7.56 (td, J = 7.7, 1.5 Hz, 1H), 7.42 (td, J = 7.6, 1.2 Hz, 1H), 7.18 – 7.08 (m, 7H), 6.98 (td, J = 7.5, 1.3 Hz, 1H), 6.59 (d, J = 7.7 Hz, 1H), 3.17 (dq, J = 14.4, 7.2 Hz, 1H), 2.42 (dq, J = 14.0, 6.9 Hz, 1H), 2.30 (s, 3H), 1.86 (s, 3H), 0.87 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 162.6 , 154.7 , 145.0 , 144.5 , 143.4 , 136.7 , 134.2 , 131.2 , 129.1 , 129.0 , 128.2 , 127.7 , 127.17 , 127.15 , 125.8 , 124.3 , 119.4 , 53.6 , 34.0 , 21.0 , 17.5 , 9.5 . IR (ATR): 2926, 1692, 1657, 1600, 1459, 1362, 1307, 1265, 1149, 1041, 911, 814, 755, 731 cm-1. HRMS (EI) calcd for C25H24N2O [M+] 368.1889, found 368.1887.

General procedure for the preparation of benzo[4,5]imidazo[1,2-b]isoquinolin11-ones 4: To an oven-dried Schlenk tube equipped with a magnetic stirring bar were added sequentially 1 (0.24 mmol), 2 (0.2 mmol), [Cp*RhCl2]2 (0.01 mmol), Cs2CO3 (0.06 mmol), 4Å MS (40 mg) and dry DCE (2 mL) under N2 atmosphere. The reaction vessel was heated to 80 oC in oil bath for 10 hours. Then, to the reaction mixture was added CuI (0.02 mmol), TMEDA (0.04 mmol) and Cs2CO3 (0.4 mmol), and the reaction was refluxed under N2 atmosphere for another 10 hours. Upon completion, the reaction mixture was cooled to room temperature and the solvent was evaporated in vacuum. The residue was purified by column


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chromatography on silica gel (petroleum ether/ethyl acetate = 10:1) to give pure product. 6-Methyl-6-phenylbenzo[4,5]imidazo[1,2-b]isoquinolin-11(6H)-one (4a). White solid; yield 60% (39 mg); mp 118 – 120 oC. 1H NMR (400 MHz, CDCl3) δ 8.55 – 8.44 (m, 2H), 7.76 – 7.74 (m, 1H), 7.67 – 7.60 (m, 1H), 7.57 – 7.49 (m, 1H), 7.75 – 7.37 (m, 2H), 7.35 – 7.18 (m, 6H), 2.30 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 160.6, 159.0, 146.7, 144.6, 143.0, 134.6, 131.2, 128.7, 128.4, 127.7, 127.3, 127.1, 125.4, 125.0, 124.9, 119.8, 115.7, 46.2, 29.5. IR (ATR): 3061, 2926, 2870, 1704, 1604, 1538, 1481, 1450, 1370, 1342, 1268, 1232, 1149, 970, 890, 793, 750, 698 cm-1. HRMS (EI) calcd for C22H16N2O [M+] 324.1263, found 324.1266. 6,8-Dimethyl-6-phenylbenzo[4,5]imidazo[1,2-b]isoquinolin-11(6H)-one (4b). Pale yellow solid; yield 61% (41 mg); mp 118 – 120 oC. 1H NMR (500 MHz, CDCl3) δ 8.49 (dd, J = 7.3, 1.3 Hz, 1H), 8.35 (d, J = 8.1 Hz, 1H), 7.76 – 7.71 (m, 1H), 7.43 – 7.36 (m, 2H), 7.34 – 7.31 (m, 1H), 7.30 – 7.20 (m, 6H), 7.08 (s, 1H), 2.38 (s, 3H), 2.29 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 160.7, 159.1, 146.6, 145.7, 144.7, 142.9, 131.2, 128.9, 128.8, 128.70, 128.67, 127.2, 127.1, 125.2, 124.8, 122.4, 119.7, 115.7, 46.0, 29.3, 22.0. IR (ATR): 3059, 2926, 1706, 1611, 1537, 1451, 1365, 1343, 1230, 1148, 971, 890, 842, 794, 769, 746, 699 cm-1. HRMS (EI) calcd for C23H18N2O [M+] 338.1419, found 338.1422. 8-Methoxy-6-methyl-6-phenylbenzo[4,5]imidazo[1,2-b]isoquinolin-11(6H)-one (4c). Pale yellow solid; yield 58% (41 mg); mp 202 – 204 oC. 1H NMR (400 MHz, CDCl3) δ 8.51 – 8.46 (m, 1H), 8.42 (d, J = 8.8 Hz, 1H), 7.77 – 7.71 (m, 1H), 7.43 – 7.35 (m, 2H), 7.32 – 7.18 (m, 5H), 7.04 (dd, J = 8.8, 2.5 Hz, 1H), 6.72 (d, J = 2.5 Hz, 1H), 3.82 (s, 3H), 2.29 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 164.5, 160.3, 159.1, 149.1, 144.6, 142.9, 131.3, 131.2, 128.8,



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127.3, 127.0, 125.1, 124.8, 119.7, 117.9, 115.7, 113.6, 113.5, 55.6, 46.4, 29.5. IR (ATR): 2924, 2846, 1701, 1605, 1574, 1535, 1494, 1450, 1364, 1338, 1281, 1257, 1232, 1148, 1032, 970, 888, 848, 767, 737, 698 cm-1. HRMS (EI) calcd for C23H18N2O2 [M+] 354.1368, found 354.1367. 8-Chloro-6-methyl-6-phenylbenzo[4,5]imidazo[1,2-b]isoquinolin-11(6H)-one (4d). Pale yellow solid; yield 59% (42 mg); mp 168 – 170 oC. 1H NMR (400 MHz, CDCl3) δ 8.49 – 8.45 (m, 1H), 8.41 (d, J = 8.4 Hz, 1H), 7.76 – 7.71 (m, 1H), 7.50 (dd, J = 8.4, 2.0 Hz, 1H), 7.46 – 7.37 (m, 2H), 7.34 – 7.21 (m, 6H), 2.30 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 159.8, 158.4, 148.4, 143.8, 143.0, 141.2, 131.1, 130.3, 129.0, 128.48, 128.46, 127.6, 127.0, 125.5, 125.2, 123.4, 119.9, 115.7, 46.3, 29.4. IR (ATR): 2925, 2854, 1706, 1596, 1539, 1451, 1411, 1364, 1339, 1230, 1149, 1099, 971, 886, 842, 765, 746, 696 cm-1. HRMS (EI) calcd for C22H15N2OCl [M+] 358.0873, found 358.0876. 6-Methyl-6-phenyl-8-(trifluoromethyl)benzo[4,5]imidazo[1,2-b]isoquinolin-11(6H)-one (4e). White solid; yield 42% (33 mg); mp 161 – 163 oC. 1H NMR (500 MHz, CDCl3) δ 8.61 (d, J = 8.2 Hz, 1H), 8.51 – 8.45 (m, 1H), 7.81 – 7.73 (m, 2H), 7.56 (s, 1H), 7.47 – 7.40 (m, 2H), 7.34 – 7.29 (m, 2H), 7.28 – 7.20 (m, 3H), 2.34 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 159.4, 158.2, 147.4, 143.6, 143.0, 136.0 (q, J = 33.0 Hz), 131.1, 129.6, 129.0, 127.80, 127.76, 127.0, 125.8, 125.4 (q, J = 3.8 Hz), 125.3, 124.5 (q, J = 3.6 Hz), 123.1 (q, J = 273.3 Hz), 120.0, 115.7, 46.4, 29.4. IR (ATR): 2956, 2925, 2855, 1711, 1672, 1595, 1541, 1453, 1425, 1373, 1334, 1266, 1231, 1174, 1135, 1073, 1024, 751, 700 cm-1. HRMS (EI) calcd for C23H15N2OF3 [M+] 392.1136, found 392.1140. 6,9-Dimethyl-6-phenylbenzo[4,5]imidazo[1,2-b]isoquinolin-11(6H)-one (4f). Pale yellow


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solid; yield 64% (43 mg); mp 170 – 172 oC.1H NMR (400 MHz, CDCl3) δ 8.54 – 8.45 (m, 1H), 8.26 (d, J = 0.8 Hz, 2H), 7.78 – 7.70 (m, 1H), 7.47 – 7.35 (m, 3H), 7.31 – 7.16 (m, 6H), 2.48 (s, 3H), 2.28 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 160.8, 159.2, 144.8, 143.8, 143.0, 137.7, 135.7, 131.3, 128.8, 128.7, 128.3, 127.2, 127.1, 125.3, 124.9, 124.7, 119.8, 115.8, 45.9, 29.4, 21.0 . IR (ATR): 2925, 2856, 1706, 1614, 1538, 1495, 1451, 1422, 1363, 1343, 1271, 1246, 1177, 1149, 830, 798, 768, 748, 700 cm-1. HRMS (EI) calcd for C23H18N2O [M+] 338.1419, found 338.1421. 9-Chloro-6-methyl-6-phenylbenzo[4,5]imidazo[1,2-b]isoquinolin-11(6H)-one (4g). Pale yellow solid; yield 61% (44 mg); mp 173 – 175 oC. 1H NMR (400 MHz, CDCl3) δ 8.49 – 8.45 (m, 1H), 8.43 (d, J = 2.3 Hz, 1H), 7.77 – 7.71 (m, 1H), 7.58 (dd, J = 8.5, 2.4 Hz, 1H), 7.46 – 7.37 (m, 2H), 7.33 – 7.20 (m, 6H), 2.28 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 159.4, 158.5, 145.0, 144.0, 143.0, 134.7, 134.1, 131.1, 130.1, 128.9, 128.3, 127.5, 127.0, 126.4, 125.6, 125.2, 119.9, 115.7, 46.0, 29.4 . IR (ATR): 2926, 2856, 1708, 1603, 1540, 1480, 1452, 1420, 1364, 1342, 1265, 1229, 1150, 1094, 831, 750, 699 cm-1. HRMS (EI) calcd for C22H15N2OCl [M+] 358.0873, found 358.0878. 6-Methyl-9-nitro-6-phenylbenzo[4,5]imidazo[1,2-b]isoquinolin-11(6H)-one

(4h).

Pale

yellow solid; yield 30% (22 mg); mp 223 – 225 oC. 1H NMR (500 MHz, CDCl3) δ 9.30 (d, J = 2.5 Hz, 1H), 8.53 – 8.46 (m, 1H), 8.43 (dd, J = 8.7, 2.5 Hz, 1H), 7.79 – 7.72 (m, 1H), 7.50 (d, J = 8.7 Hz, 1H), 7.47 (td, J = 7.6, 1.5 Hz, 1H), 7.44 (td, J = 7.6, 1.5 Hz, 1H), 7.36 – 7.30 (m, 2H), 7.30 – 7.26 (m, 1H), 7.25 – 7.21 (m, 2H), 2.34 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 158.5, 157.7, 152.8, 147.3, 143.1, 143.0, 130.9, 130.3, 129.2, 128.4, 128.0, 127.0, 126.3, 126.0, 125.5, 124.2, 120.1, 115.8, 46.7, 29.5 . IR (ATR): 2955, 2924, 1709, 1613, 1530, 1452,



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1436, 1369, 1346, 1262, 1231, 1152, 1102, 986, 927, 749, 697 cm-1. HRMS (EI) calcd for C22H15N3O3 [M+] 369.1113, found 369.1113. 10-Chloro-6-methyl-6-phenylbenzo[4,5]imidazo[1,2-b]isoquinolin-11(6H)-one (4i). Pale yellow oil; yield 20% (14 mg).1H NMR (500 MHz, CDCl3) δ 8.54 – 8.48 (m, 1H), 7.76 – 7.71 (m, 1H), 7.56 (dd, J = 7.9, 1.3 Hz, 1H), 7.49 (t, J = 7.9 Hz, 1H), 7.44 – 7.38 (m, 2H), 7.32 – 7.27 (m, 2H), 7.26 – 7.21 (m, 4H), 2.29 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 158.3, 157.6, 149.8, 144.3, 142.9, 136.6, 134.0, 131.8, 131.5, 128.9, 127.7, 127.5, 127.1, 125.4, 125.0, 122.1, 119.8, 115.8, 46.7, 30.0. IR (ATR): 2957, 2927, 1709, 1590, 1542, 1450, 1346, 1259, 1212, 1150, 973, 903, 864, 808, 747, 698 cm-1. HRMS (EI) calcd for C22H15N2OCl [M+] 358.0873, found 358.0872. 10-Fluoro-6-methyl-6-phenylbenzo[4,5]imidazo[1,2-b]isoquinolin-11(6H)-one (4j). White solid; yield 37% (25 mg); mp 182 – 184 oC. 1H NMR (500 MHz, CDCl3) δ 8.53 – 8.47 (m, 1H), 7.76 – 7.71 (m, 1H), 7.60 (td, J = 8.1, 5.0 Hz, 1H), 7.45 – 7.37 (m, 2H), 7.33 – 7.28 (m, 2H), 7.26 – 7.19 (m, 4H), 7.12 (d, J = 8.0 Hz, 1H), 2.30 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 163.1 (d, J = 268.0 Hz), 158.0, 157.5 (d, J = 4.1 Hz), 149.2, 144.3, 142.9, 135.7 (d, J = 10.4 Hz), 131.3, 128.9, 127.5, 127.0, 125.4, 125.1, 124.5 (d, J = 4.1 Hz), 119.8, 116.1 (d, J = 21.7 Hz), 115.8, 114.2 (d, J = 4.6 Hz), 46.3, 29.8. IR (ATR): 2926, 2854, 1714, 1664, 1612, 1540, 1452, 1363, 1343, 1263, 1212, 814, 751, 699 cm-1. HRMS (EI) calcd for C22H15N2OF [M+] 342.1168, found 342.1169. 7-Methyl-7-phenylbenzo[h]benzo[4,5]imidazo[1,2-b]isoquinolin-14(7H)-one (4k). Pale yellow oil; yield 25% (19 mg). 1H NMR (400 MHz, CDCl3) δ 9.97 (d, J = 8.8 Hz, 1H), 8.66 – 8.57 (m, 1H), 8.04 (d, J = 8.7 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.84 – 7.79 (m, 1H), 7.78 –


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7.74 (m, 1H), 7.67 – 7.62 (m, 1H), 7.45 (td, J = 7.6, 1.5 Hz, 1H), 7.40 (td, J = 7.5, 1.5 Hz, 1H), 7.33 – 7.21 (m, 7H), 2.36 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 161.6, 158.3, 149.0, 144.0, 143.1, 135.9, 132.8, 131.6, 131.5, 129.6, 128.9, 128.7, 127.5, 127.4, 127.1, 125.4, 125.2, 124.7, 119.7, 119.0, 116.0, 46.7, 29.6. IR (ATR): 2960, 2927, 1735, 1697, 1599, 1542, 1509, 1449, 1374, 1339, 1243, 1194, 1153, 1099, 1044, 873, 830, 791, 697 cm-1. HRMS (EI) calcd for C26H18N2O [M+] 374.1419, found 374.1422. 6-Methyl-6-(p-tolyl)benzo[4,5]imidazo[1,2-b]isoquinolin-11(6H)-one (4l). Pale yellow oil; yield 55% (37 mg). 1H NMR (400 MHz, CDCl3) δ 8.50 – 8.45 (m, 2H), 7.74 (d, J = 7.7 Hz, 1H), 7.62 (t, J = 7.5 Hz, 1H), 7.51 (t, J = 7.5 Hz, 1H), 7.46 – 7.35 (m, 2H), 7.30 (d, J = 7.9 Hz, 1H), 7.14 – 7.07 (m, 4H), 2.27 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 160.7, 159.2, 146.9, 143.0, 141.6, 137.0, 134.5, 131.2, 129.4, 128.7, 128.4, 127.6, 127.0, 125.3, 124. 9, 124.8, 119.8, 115.7, 45.9, 29.5, 20.9. IR (ATR): 2924, 1705, 1605, 1539, 1453, 1370, 1342, 1268, 1233, 1149, 970, 819, 750, 700 cm-1. HRMS (EI) calcd for C23H18N2O [M+] 338.1419, found 338.1421. 6-(3-Chlorophenyl)-6-methylbenzo[4,5]imidazo[1,2-b]isoquinolin-11(6H)-one (4m). Pale yellow oil; yield 60% (43 mg). 1H NMR (400 MHz, CDCl3) δ 8.51 – 8.46 (m, 2H), 7.80 – 7.70 (m, 1H), 7.65 (td, J = 7.7, 1.4 Hz, 1H), 7.55 (td, J = 7.6, 1.2 Hz, 1H), 7.46 – 7.39 (m, 2H), 7.30 – 7.24 (m, 2H), 7.23 – 7.12 (m, 2H), 7.11 – 7.06 (m, 1H), 2.27 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 160.3, 158.2, 146.4, 145.9, 142.9, 134.8, 134.7, 131.2, 130.0, 128.9, 128.3, 128.0, 127.6, 127.4, 125.7, 125.5, 125.2, 124.8, 119.9, 115.8, 46.0, 29.7. IR (ATR): 2957, 2926, 1706, 1559, 1539, 1453, 1371, 1345, 1268, 1234, 1149, 972, 884, 751, 698 cm-1. HRMS (EI) calcd for C22H15N2OCl [M+] 358.0873, found 358.0874.



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General Procedure for the Preparation of Ketenimines 5. The following procedure is adapted from our previously reported method.14b,14d Method A (5a-g): The mixture of the corresponding ylides (2 mmol) and isocyanate (2 mmol) in CH2Cl2 (5 mL) was stirred at room temperature for 30 minutes for 5a-c or stirred at reflux over night for 5d-g. Then, the solvent was removed in vacuum and the residue was purified by flash column chromatography on silica gel with petroleum ether/ethyl acetate (20:1, v/v) as eluent. Method B (5h and 5i): The mixture of the corresponding ylides (2 mmol) and isocyanate (2 mmol) in CH2Cl2 (5 mL) was stirred at 80 oC in a pressure tube overnight. Then, the solvent was removed in vacuum and the residue was purified by flash column chromatography on silica gel with petroleum ether as eluent. Butyl 3-((4-chlorophenyl)imino)-2-methylacrylate (5b). Pale yellow oil; 64 % (339 mg). 1

H NMR (400 MHz, CDCl3) δ 7.39 – 7.34 (m, 2H), 7.23 – 7.18 (m, 2H), 4.16 (t, J = 6.6 Hz,

2H), 1.87 (s, 3H), 1.64 – 1.55 (m, 2H), 1.40 – 1.29 (m, 2H), 0.89 (t, J = 7.4 Hz, 3H).

13

C

NMR (100 MHz, CDCl3) δ 185.3, 169.7, 137.1, 133.7, 129.7, 125.2, 64.6, 61.5, 30.8, 19.1, 13.7, 10.0. IR (film): 2959, 2933, 2020, 1705, 1487, 1266, 1122, 1014, 824, 756, 645 cm-1. HRMS (EI) m/z calcd for C14H16NO2Cl [M+]: 265.0870; found: 265.0872. Benzyl 3-((4-chlorophenyl)imino)-2-methylacrylate (5c). Pale yellow oil; 64 % (383 mg). 1

H NMR (400 MHz, CDCl3) δ 7.37 – 7.26 (m, 7H), 7.19 – 7.14 (m, 2H), 5.21 (s, 2H), 1.89 (s,

3H). 13C NMR (100 MHz, CDCl3) δ 184.4, 169.4, 136.9, 136.3, 133.8, 129.7, 128.5, 128.0, 127.8, 125.2, 66.2, 61.2, 10.0. IR (film): 2971, 2018, 1701, 1487, 1375, 1264, 1089, 751, 696 cm-1. HRMS (EI) m/z calcd for C17H14NO2Cl [M+]: 299.0713; found: 299.0710.


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Ethyl 3-((4-chlorophenyl)imino)-2-phenylacrylate (5e). Pale yellow solid; 65 % (389 mg); m.p. 77 -78oC. 1H NMR (400 MHz, CDCl3) δ 7.56 – 7.50 (m, 2H), 7.43 – 7.38 (m, 2H), 7.37 – 7.32 (m, 2H), 7.32 – 7.27 (m, 2H), 7.24 – 7.19 (m, 1H), 4.30 (q, J = 7.1 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 181.7, 167.4, 135.5, 134.5, 130.0, 129.7, 128.7, 127.5, 126.6, 125.7, 70.9, 60.7, 14.5. IR (ATR): 2925, 2037, 1711, 1487, 1280, 1187, 1131, 1093, 1047, 834, 767 cm-1. HRMS (EI) m/z calcd for C17H14NO2Cl [M+]: 299.0713; found: 299.0716. Ethyl 2-(4-bromophenyl)-3-((4-chlorophenyl)imino)acrylate (5f). Pale yellow solid; 63 % (475 mg); m.p. 103 -104oC. 1H NMR (400 MHz, CDCl3) δ 7.48 – 7.38 (m, 6H), 7.32 – 7.27 (m, 2H), 4.29 (q, J = 7.2 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 180.2, 167.1, 134.9, 134.7, 131.7, 130.0, 128.8, 125.8, 120.2, 70.0, 60.9, 14.4. IR (ATR): 2925, 2034, 1708, 1485, 1281, 1187, 1132, 1092, 1040, 1012, 829, 759 cm-1. HRMS (EI) m/z calcd for C17H13NO2ClBr [M+]: 376.9818; found: 376.9814. Ethyl 3-((4-chlorophenyl)imino)-2-(4-methoxyphenyl)acrylate (5g). Pale yellow solid; 68 % (447 mg); m.p. 94 -95oC. 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 8.9 Hz, 2H), 7.39 (d, J = 8.7 Hz, 2H), 7.28 (d, J = 8.7 Hz, 2H), 6.90 (d, J = 8.9 Hz, 2H), 4.29 (q, J = 7.1 Hz, 2H), 3.80 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 183.3, 167.7, 158.5, 135.9, 134.3, 129.9, 129.0, 125.6, 121.3, 114.2, 70.6, 60.7, 55.3, 14.4. IR (ATR): 2925, 2014, 1707, 1512, 1485, 1279, 1248, 1176, 1092, 1033, 831, 760 cm-1. HRMS (EI) m/z calcd for C18H16NO3Cl [M+]: 329.0819; found: 329.0816. Ethyl 3-(ethylimino)-2-phenylacrylate (5h). Colorless oil; 48 % (208 mg). 1H NMR (400 MHz, CDCl3) δ 7.53 – 7.47 (m, 2H), 7.35 – 7.29 (m, 2H), 7.16 (ddt, J = 8.6, 7.0, 1.2 Hz, 1H),



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4.25 (q, J = 7.1 Hz, 2H), 3.80 (q, J = 7.2 Hz, 2H), 1.44 (t, J = 7.2 Hz, 3H), 1.30 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 172.4, 168.6, 131.2, 128.4, 126.9, 125.6, 67.9, 60.1, 46.1, 15.7, 14.4. IR (film): 2981, 2055, 1698, 1598, 1497, 1448, 1337, 1290, 1156, 1050, 770, 694 cm-1. HRMS (EI) m/z calcd for C13H15NO2 [M+]: 217.1103; found:217.1103. Ethyl 3-(isopropylimino)-2-phenylacrylate (5i). Colorless oil; 56 % (259 mg). 1H NMR (400 MHz, CDCl3) δ 7.54 – 7.48 (m, 2H), 7.35 – 7.28 (m, 2H), 7.18 – 7.11 (m, 1H), 4.24 (q, J = 7.1 Hz, 2H), 4.12 (hept, J = 6.5 Hz, 1H), 1.43 (d, J = 6.5 Hz, 6H), 1.30 (t, J = 7.1 Hz, 3H). 13

C NMR (100 MHz, CDCl3) δ 171.6, 168.6, 131.3, 128.4, 126.7, 125.5, 68.3, 60.0, 54.9, 23.6,

14.4. IR (film): 2978, 2933, 2049, 1699, 1598, 1495, 1450, 1367, 1286, 1155, 1101, 1049, 1029, 771, 694, 661 cm-1. HRMS (EI) m/z calcd for C14H17NO2 [M+]: 231.1259; found:231.1259.

General procedure for the preparation of 3-aminoisoindolin-1-ones 6: To an oven-dried Schlenk tube equipped with a magnetic stirring bar were added 1 (0.36 mmol), 5 (0.3 mmol), [Cp*RhCl2]2 (0.015 mmol), Cl3CCO2Cs (0.09 mmol), 4Å MS (60 mg) and dry DCE (2 mL). The mixture was stirred at 80 oC under N2 atmosphere for 10 hours. Upon completion, the reaction mixture was cooled to room temperature and then the solvent was evaporated in vacuum. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 5:1) to give the product. [(R,S)+(S,R)]

Ethyl

2-(1-((4-chlorophenyl)amino)-2-

methoxy-3-oxoisoindolin-1-yl)

propanoate (6a). Colorless oil; yield 64% (74 mg). 1H NMR (400 MHz, CDCl3) δ 8.00 – 7.90 (m, 1H), 7.61 – 7.50 (m, 2H), 7.32 – 7.21 (m, 1H), 6.97 – 6.88 (m, 2H), 6.24 – 6.14 (m, 2H),


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5.99 (s, 1H), 4.36 – 4.19 (m, 2H), 3.78 (s, 3H), 3.16 (q, J = 7.0 Hz, 1H), 1.34 (t, J = 7.1 Hz, 3H), 0.95 (d, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 173.4 , 164.9 , 142.0 , 140.0 , 132.6 , 130.0 , 128.9 , 124.4 , 124.1 , 123.8 , 121.1 , 116.6 , 80.6 , 64.8 , 61.5 , 46.4 , 14.1 , 12.2 . IR (ATR): 3350, 2925, 1718, 1599, 1494, 1308, 1261, 1185, 1095, 1009, 822, 749 cm-1. HRMS (EI) calcd for C20H21N2O4Cl [M+] 388.1190, found 388.1193. [(S,S)+(R,R)]

Ethyl

2-(1-((4-chlorophenyl)amino)-2-methoxy-3-oxoisoindolin-1-yl)-

propanoate (6a'). White solid; yield 20% (23 mg); mp 110-116 oC. 1H NMR (400 MHz, CDCl3) δ 7.97 – 7.89 (m, 1H), 7.61 (td, J = 7.5, 1.4 Hz, 1H), 7.57 (td, J = 7.5, 1.3 Hz, 1H), 7.41 (d, J = 6.9 Hz, 1H), 7.06 (s, 1H), 6.92 (dt, J = 9.2, 2.8 Hz, 2H), 6.15 (dt, J = 8.8, 2.6f Hz, 2H), 4.23 (qd, J = 7.2, 0.8 Hz, 2H), 3.68 (s, 3H), 3.15 (q, J = 7.1 Hz, 1H), 1.31 (t, J = 7.1 Hz, 3H), 0.79 (d, J = 7.1 Hz, 3H).

13

C NMR (100 MHz, CDCl3) δ 173.2, 164.9, 142.5, 142.2,

133.5, 130.2, 130.0, 128.9, 124.3, 124.1, 122.0, 116.8, 81.1, 64.5, 61.8, 46.0, 13.9, 10.7 . IR (film): 3344, 2926, 1732, 1722, 1713, 1598, 1525, 1494, 1467, 1268, 1182, 1094, 1069 cm-1. HRMS (EI) calcd for C20H21N2O4Cl [M+] 388.1190, found 388.1191. Butyl 2-(1-((4-chlorophenyl)amino)-2-methoxy-3-oxoisoindolin-1-yl)propanoate (6b+6b'). Colorless oil; yield 72% (90 mg). 1H NMR (400 MHz, CDCl3) δ 7.94 (1H), 7.63 – 7.51 (2H), 7.42 – 7.39 (m, 0.45 H), 7.26 – 7.22 (0.66 H), 7.09 (s, 0.31 H), 6.94 – 6.91 (2H), 6.21 – 6.12 (2H), 5.96 (s, 0.70 H), 4.28 – 4.13 (m, 2H), 3.78 (s, 2.11 H), 3.67 (s, 0.90 H), 3.22 – 3.11 (1H), 1.71 – 1.62 (2H), 1.46 – 1.35 (2H), 0.98 – 0.91 (5.10 H), 0.79 (d, J = 7.0 Hz, 0.93 H). IR (ATR): 3348, 2959, 1716, 1599, 1521, 1494, 1464, 1345, 1309, 1264,1182, 1094, 1007, 822, 753 cm-1. HRMS (EI) calcd for C22H25N2O4Cl [M+] 416.1503, found 416.1497.



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Benzyl

2-(1-((4-chlorophenyl)amino)-2-methoxy-3-oxoisoindolin-1-yl)propanoate

(6c+6c'). Colorless oil; yield 46% (62 mg). 1H NMR (400 MHz, CDCl3) δ 7.97 – 7.87 (1H), 7.63 – 7.30 (7.37 H), 7.07 (d, J = 7.6 Hz, 0.69 H), 6.98 (s, 0.30 H), 6.95 – 6.84 (m, 2H), 6.11 – 6.00 (m, 2H), 5.78 (s, 0.67 H), 5.34 – 5.14 (2H), 3.74 (s, 2.03 H), 3.53 (s, 0.89 H), 3.27 (q, J = 7.0 Hz, 0.68 H), 3.20 (q, J = 7.1 Hz, 0.33 H), 0.91 (d, J = 7.0 Hz, 2.02 H), 0.81 (d, J = 7.1 Hz, 0.91 H). IR (ATR): 3353, 2932, 1717, 1598, 1495, 1461, 1309, 1262, 1171, 1006, 908, 821, 750, 699 cm-1. HRMS (EI) calcd for C25H23N2O4Cl [M+] 450.1346, found 450.1343. [(R,S)+(S,R)]

Ethyl

2-(1-((4-chlorophenyl)amino)-2-methoxy-3-oxoisoindolin-1-yl)-2-

phenylacetate (6d). White solid; yield 74% (100 mg); mp 130 – 130 oC. 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 7.5 Hz, 1H), 7.47 (td, J = 7.5, 0.7 Hz, 1H), 7.34 – 7.24 (m, 2H), 7.18 (t, J = 7.7 Hz, 2H), 7.07 (d, J = 7.5 Hz, 2H), 6.92 (d, J = 8.9 Hz, 2H), 6.77 (s, 1H), 6.63 (d, J = 7.7 Hz, 1H), 6.19 (d, J = 8.9 Hz, 2H), 4.32 – 4.13 (m, 2H), 3.89 (s, 1H), 3.76 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 172.2, 164.7, 142.1, 140.2, 132.14, 132.10, 130.1, 130.0, 129.3, 128.8, 128.6, 128.0, 124.9, 124.6, 124.0, 116.9, 81.5, 64.9, 61.8, 58.1, 13.9 . IR (film): 3345, 2982, 2938, 1719, 1715, 1597, 1494, 1305, 1197, 1075, 1006, 908, 820, 731 cm-1. HRMS (EI) calcd for C25H23N2O4Cl [M+] 450.1346, found 450.1353. [(S,S)+(R,R)] Ethyl 2-(1-((4-chlorophenyl)amino)-2-methoxy-3-oxoisoindolin-1-yl)-2phenylacetate (6d'). White solid; yield 12% (16 mg); mp 152 – 153 oC. 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 7.5 Hz, 1H), 7.46 (td, J = 7.5, 1.2 Hz, 1H), 7.35 – 7.28 (m, 2H), 7.12 – 7.06 (m, 3H), 7.02 – 6.98 (m, 3H), 6.95 – 6.88 (m, 2H), 6.19 – 6.13 (m, 2H), 4.37 – 4.09 (m, 3H), 3.79 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 171.3 , 164.8 , 142.3 , 141.5 , 132.6 , 131.3 , 130.8 , 129.8 , 129.6 , 128.9 , 127.9 , 127.8 , 124.4 , 123.6 ,


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122.5 , 116.9 , 81.4 , 64.8 , 62.1 , 57.7 , 13.8 . IR (film): 3352, 2926, 2853, 1732, 1713, 1597, 1520, 1494, 1467, 1307, 1263, 1180, 1073, 1007, 908, 820, 731 cm-1. HRMS (EI) calcd for C25H23N2O4Cl [M+] 450.1346, found 450.1356. [(R,S)+(S,R)]

ethyl

2-(4-bromophenyl)-2-(1-((4-chlorophenyl)amino)-2-methoxy-3-

oxoisoindolin-1-yl)acetate (6e). White solid; yield 76% (120 mg); mp 155 – 157 oC. 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 7.5 Hz, 1H), 7.50 (td, J = 7.5, 0.9 Hz, 1H), 7.39 (td, J = 7.6, 1.1 Hz, 1H), 7.30 (d, J = 8.7 Hz, 2H), 6.99 – 6.87 (m, 4H), 6.77 (d, J = 7.6 Hz, 1H), 6.56 (s, 1H), 6.22 – 6.14 (m, 2H), 4.34 – 4.13 (m, 2H), 3.93 (s, 1H), 3.76 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 171.6, 164.5, 141.9, 139.8, 132.3, 131.7, 131.1, 131.0, 130.2, 129.4, 128.9, 124.8, 124.2, 123.0, 117.0, 81.2, 65.0, 62.0, 57.4, 13.9. IR (film): 3337, 2925, 1732, 1721, 1709, 1596, 1492, 1462, 1300, 1265, 1170, 1074, 1012, 820 cm-1. HRMS (EI) calcd for C25H22N2O4ClBr [M+] 528.0451, found 528.0447. [(S,S)+(R,R)]

Ethyl

2-(4-bromophenyl)-2-(1-((4-chlorophenyl)amino)-2-methoxy-3-

oxoisoindolin -1-yl)acetate (6e'). White solid; yield 15% (24 mg); mp 175 – 177 oC. 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 7.4 Hz, 1H), 7.48 (td, J = 7.6, 1.0 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.34 (d, J = 7.5 Hz, 1H), 7.19 (d, J = 8.6 Hz, 2H), 7.17 (s, 1H), 6.96 – 6.89 (m, 2H), 6.84 (d, J = 8.4 Hz, 2H), 6.18 – 6.13 (m, 2H), 4.38 – 4.10 (m, 3H), 3.77 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 171.0, 164.7, 142.2, 141.5, 132.9, 132.5, 131.0, 130.3, 129.9, 129.6, 128.9, 124.5, 123.9, 122.24, 122.19, 116.9, 81.3, 64.8, 62.3, 57.3, 13.8. IR (film): 3348, 2925, 1738, 1732, 1713, 1597, 1493, 1467, 1301, 1259, 1074, 1012, 820, 735 cm-1. HRMS (EI) calcd for C25H22N2O4ClBr [M+] 528.0451, found 528.0457.



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[(R,S)+(S,R)] Ethyl 2-(1-((4-chlorophenyl)amino)-2-methoxy-3-oxoisoindolin-1-yl)-2-(4methoxyphenyl)acetate (6f). White solid; yield 35% (51 mg); mp 140 – 142 oC. 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 7.5 Hz, 1H), 7.48 (td, J = 7.5, 0.5 Hz, 1H), 7.36 (td, J = 7.6, 0.9 Hz, 1H), 6.96 (d, J = 8.2 Hz, 2H), 6.95 – 6.90 (m, 2H), 6.75 (d, J = 7.6 Hz, 1H), 6.69 (d, J = 8.9 Hz, 2H), 6.63 (s, 1H), 6.22 – 6.15 (m, 2H), 4.34 – 4.11 (m, 2H), 3.90 (s, 1H), 3.76 (s, 3H), 3.75 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 172.2, 164.6, 159.6, 142.1, 140.1, 132.1, 131.2, 129.9, 129.3, 128.8, 124.9, 124.5, 123.92, 123.86, 116.8, 113.2, 81.5, 64.9, 61.7, 57.2, 55.1, 13.9. IR (film): 3344, 2937, 2838, 1738, 1732, 1714, 1610, 1515, 1495, 1468, 1307, 1254, 1181, 1034, 1006, 909, 821, 735 cm-1. HRMS (EI) calcd for C26H25N2O5Cl [M+] 480.1452, found 480.1451. [(S,S)+(R,R)] Ethyl 2-(1-((4-chlorophenyl)amino)-2-methoxy-3-oxoisoindolin-1-yl)-2-(4methoxyphenyl)acetate (6f'). White solid; yield 7% (10 mg); mp 199 – 200 oC. 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 7.5 Hz, 1H), 7.46 (td, J = 7.5, 1.0 Hz, 1H), 7.34 (td, J = 7.5, 0.8 Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H), 6.96 (s, 1H), 6.93 – 6.92 (m, 2H), 6.91 – 6.90 (m, 2H), 6.62 (d, J = 8.8 Hz, 2H), 6.19 – 6.12 (m, 2H), 4.36 – 4.08 (m, 3H), 3.79 (s, 3H), 3.70 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 171.5, 164.8, 159.0, 142.3, 141.6, 132.6, 131.9, 129.8, 129.6, 128.9, 124.3, 123.7, 123.2, 122.4, 116.8, 113.2, 81.5, 64.8, 62.0, 57.0, 55.1, 13.9. IR (film): 3352, 2927, 1730, 1714, 1611, 1598, 1514, 1494, 1467, 1254, 1182, 1034, 908, 821, 740 cm-1. HRMS (EI) calcd for C26H25N2O5Cl [M+] 480.1452, found 480.1455. [(R,S)+(S,R)] Ethyl 2-(2-methoxy-3-oxo-1-(p-tolylamino)isoindolin-1-yl)-2-phenylacetate (6g). White solid; yield 67% (87 mg); mp 125-126oC. 1H NMR (400 MHz, CDCl3) δ 7.78 (d,


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J = 7.5 Hz, 1H), 7.45 (td, J = 7.5, 0.8 Hz, 1H), 7.31 (td, J = 7.6, 1.0 Hz, 1H), 7.28 – 7.21 (m, 1H), 7.16 (t, J = 7.7 Hz, 2H), 7.08 (d, J = 7.4 Hz, 2H), 6.77 (d, J = 8.3 Hz, 2H), 6.74 (d, J = 7.8 Hz, 1H), 6.45 (s, 1H), 6.16 (d, J = 8.5 Hz, 2H), 4.34 – 4.11 (m, 2H), 3.95 (s, 1H), 3.76 (s, 3H), 2.13 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 172.0, 164.6, 141.0, 140.6, 132.2, 131.9, 130.2, 129.7, 129.4, 129.0, 128.5, 127.8, 125.0, 123.7, 115.8, 81.8, 64.9, 61.7, 58.1, 20.3, 14.0. IR (film): 3334, 2983, 2938, 1721, 1715, 1616, 1520, 1302, 1278, 1197, 1158, 1075, 1005, 909, 810, 732, 702 cm-1. HRMS (EI) calcd for C26H26N2O4 [M+] 430.1893, found 430.1889. [(S,S)+(R,R)] Ethyl 2-(2-methoxy-3-oxo-1-(p-tolylamino)isoindolin-1-yl)-2-phenylacetate (6g'). White solid; yield 13% (17 mg); mp 162 – 164 oC. 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 7.5 Hz, 1H), 7.45 (td, J = 7.5, 0.8 Hz, 1H), 7.31 (td, J = 7.6, 1.0 Hz, 1H), 7.28 – 7.22 (m, 1H), 7.16 (t, J = 7.7 Hz, 2H), 7.08 (d, J = 7.4 Hz, 2H), 6.77 (d, J = 8.3 Hz, 2H), 6.74 (d, J = 7.8 Hz, 1H), 6.44 (s, 1H), 6.16 (d, J = 8.5 Hz, 2H), 3.95 (s, 1H), 3.76 (s, 3H), 2.13 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 172.0, 164.6, 140.9, 140.5, 132.2, 131.9, 130.2, 129.7, 129.4, 128.9, 128.5, 127.8, 125.0, 123.7, 115.8, 81.8, 64.9, 61.7, 58.1, 20.3, 13.9. IR (film): 3348, 2925, 1730, 1721, 1715, 1615, 1519, 1467, 1372, 1302, 1196, 1075, 809, 693, 668 cm-1. HRMS (EI) calcd for C26H26N2O4 [M+] 430.1893, found 430.1898. Ethyl 2-(1-(ethylamino)-2-methoxy-3-oxoisoindolin-1-yl)-2-phenylacetate (6h+6h'). Pale yellow oil; yield 46% (51 mg). 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 7.3 Hz, 0.84 H), 7.55 (d, J = 7.5 Hz, 0.14H), 7.47 – 7.28 (2H), 7.21 – 7.14 (1H), 7.13 – 6.99 (5H), 4.36 – 4.01 (6H), 3.10 (br, 1H), 2.60 – 1.93 (m, 2H), 1.26 (t, J = 7.1 Hz, 2.67 H), 1.17 (t, J = 7.1 Hz, 0.48



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H), 1.06 (3H). IR (film): 3346, 2976, 2937, 1721, 1466, 1371, 1311, 1263, 1156, 1076, 1005, 699 cm-1. HRMS (EI) calcd for C21H24N2O4 [M+] 368.1736, found 368.1745. Ethyl 2-(1-(isopropylamino)-2-methoxy-3-oxoisoindolin-1-yl)-2-phenylacetate (6i+6i'). Pale yellow oil; yield 57% (65 mg). 1H NMR (400 MHz, CDCl3) δ 7.67 – 7.54 (1H), 7.43 – 7.29 (2H), 7.24 – 6.94 (6H), 4.31 – 4.03 (5H), 3.92 – 3.89 (1H), 3.38 (br, 1H), 2.76 – 2.56 (1H), 1.26 (t, J = 7.1 Hz, 2.71 H), 1.17 (t, J = 7.1 Hz, 0.44 H), 1.10 – 1.07 (3H), 0.75 (d, J = 6.3 Hz, 2.59 H), 0.61 (d, J = 6.2 Hz, 0.41 H). IR (film): 3352, 2973, 1721, 1466, 1371, 1311, 1278, 1197, 1156, 1079, 1049, 880, 699 cm-1. HRMS (EI) calcd for C22H26N2O4 [M+] 382.1893, found 382.1897.

Preparation of N-methoxy-N-(2-phenyl-1-(p-tolylimino)propyl)benzamide (7): To an oven-dried Schlenk tube equipped with a magnetic stirring bar were added 1a (0.45 mmol), 2a (0.3 mmol), [Cp*RhCl2]2 (0.015 mmol), AgNTf2 (0.045 mmol), 4A MS (60 mg) and dry DCE (2 mL) under N2 atmosphere. The reaction vessel was heated to reflux in oil bath for 10 hours. Upon completion, the reaction mixture was cooled to room temperature and then the solvent was evaporated in vacuum. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 10:1) to give the product 7 (106 mg, 95 %) as a brown oil. 1H NMR (400 MHz, CDCl3) δ 7.27 – 7.10 (m, 10H), 6.91 (d, J = 7.9 Hz, 2H), 6.73 (d, J = 7.4 Hz, 2H), 4.44 (q, J = 7.3 Hz, 1H), 3.80 (s, 3H), 2.24 (s, 3H), 1.60 (d, J = 7.3 Hz, 3H).

13

C NMR (100 MHz, CDCl3) δ 171.5 , 157.9 , 140.5 , 138.5 , 136.4 , 135.6 , 129.9 ,

129.3 , 128.7 , 128.5 , 128.0 , 127.6 , 127.0 , 126.7 , 62.2 , 40.8 , 20.9 , 17.3 . IR (ATR): 2938, 2819, 1661, 1601, 1509, 1451, 1326, 1296, 1181, 1042, 957, 916, 798, 699 cm-1. HRMS (EI)


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m/z calcd for C24H24N2O2 [M+]: 372.1838; found: 372.1841.

ASSOCIATED CONTENT

Supporting Information The supporting information is available free of charge on the ACS Publications website at DOI: 1

H NMR and 13C NMR spectra for all new compounds. (PDF)

X-ray crystallography of 3a and 6e. (CIF)

AUTHOR INFORMATION

Corresponding authors *E-mail: [email protected]; [email protected] Notes The authors declare no competing financial interest.

ACKNOWLEDGEMENTS

We thank the National Natural Science Foundation of China (Nos. 21632003; 21472164) for financial support.



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15

For ORTEPs of products 3a and 6e, please see the Supporting Information. CCDC 1405391(3a) and 1405392(6e) contain supplementary crystallographic data for this paper.


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Rh-Catalyzed Annulations of N-Methoxybenzamides and Ketenimines

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