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Stereoselective Palladium Catalyzed Synthesis of Indolines via Intramolecular Trapping of N-Ylides with Alkenes Angula Chandra Shekar Reddy, Venkata Surya Kumar Choutipalli, Jayanta Ghorai, Venkatesan Subramanian, and Pazhamalai Anbarasan ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b02072 • Publication Date (Web): 08 Aug 2017 Downloaded from http://pubs.acs.org on August 8, 2017

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ACS Catalysis

Stereoselective Palladium Catalyzed Synthesis of Indolines via Intramolecular Trapping of N-Ylides with Alkenes Angula Chandra Shekar Reddy,† Venkata Surya Kumar Choutipalli,‡ Jayanta Ghorai,† Venkatesan Subramanian‡ and Pazhamalai Anbarasan*†. †

Department of Chemistry, Indian Institute of Technology Madras, Chennai – 600036, India.

‡

Chemical Laboratory, CSIR-Central Leather Research Institute, Chennai – 600020, India.

ABSTRACT: Metal catalyzed in-situ functionalization of ammonium ylides has emerged as mild and atom/step economy strategy for the construction of complex building blocks. Despite the success, these trapping reactions are limited to activated polar double bonds such as (α,βunsaturated) carbonyl derivatives. Trapping of ammonium ylides with non-polar double bonds, which allows the all carbon quaternary center, is unprecedented. In this article, an efficient stereoselective palladium catalyzed intramolecular trapping of N-ylides derived from orthovinylaniline and α-diazocarbonyl compounds have been accomplished, a carbenylative hydroamination of alkenes.

The present reaction allows the synthesis of various tri and

tetrasubstituted indolines in good yield with high diastereoselectivity. Important features are the construction of two contiguous quaternary carbon centers via the formation of C-N and C-C

ACS Paragon Plus Environment

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bond in single operation, high diastereoselectivity, wide functional group tolerance and high atom and step economy. Reaction mechanism has also been explored by a combination of experimental and DFT studies, which revealed the formation of N-ylide followed by cyclization through metallo-ene type reaction involving six-membered cyclic transition state, where the diastereoselectivity is also established.

R1

R1 + N 2

R

CO2R 3

Pd(II)-cat

Ar

R

N CO2R 3 R2

Ar

NH R2

N2

metalloene reaction R1

R1 R

[Pd] CO2R N H R 2 Ar

⋅ no additive ⋅ highly diastereoselective ⋅ N 2 sole byproduct

R 3

Ar OR3 N H R 2 O[Pd]

DFT-studies

⋅ two contiguous quaternary stereocenters ⋅ wide functional group tolerance ⋅ excellent step & atom economy

KEYWORDS: carbenylative hydroamination, ylide, palladium, indoline, metalloene reaction, alkene, DFT

Introduction Donor-acceptor metal carbenoids derived from α-diazocarbonyl compounds have emerged as highly reactive and valuable intermediates in organic chemistry.1 These metal carbenoids, derived from dirhodium and copper complexes, were demonstrated to possess highly electrophilic character2 that undergoes numerous transformations3 such as cyclopropanation,4 insertion into C/heteroatom-H bond,5 and functionalization via generation of ylide6. Besides, cross-coupling reactions of palladium carbenoids were also reported.7 Among these reactions, multicomponent reactions8 of diazocarbonyl compounds and amines/alcohols with reactive electrophiles, via generation and trapping of N/O-ylides, have gained significant attention in


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recent years due to the high atom and step economy and possible construction of complex molecules with high diversity and selectivity (Scheme 1a, right side).9 Till today, reactive electrophiles that were utilized are polar double bonds such as aldehydes/ketones,10 imines11 and α,β-unsaturated carbonyl/nitro compounds12. However, trapping of ylides with non-polar double bonds, i.e. simple alkene, is not documented and highly challenging for the following reasons: 1) low reactivity of non-polar double bonds towards the trapping of ylides and 2) fast 1,2-proton transfer in ylides would result in the formation of inserted product (Scheme 1a). Scheme 1. a) Transition metal catalyzed functionalization of ylide; b) Proposed Pd catalyzed carbenylative hydroamination of alkenes.

a)

R1

R3

R Ar

R2

R4

R4

R2 R3

R4

Ar

X

R2 R3

R1

Ar

X R1 CO2R

N2 Ar

R2

X R3

[M], Additive

[M] Ar

H X R1 R

proton transfer

CO2R 3

R

R1

H

R2 R3 polar double bonds

proton transfer

R Ar

R3

Known

[M] Y R2

X

R3

R Ar

Y = O, NR, CH-EWG

R1

R1

[Pd]

HY R2

Y

H

NH R2

[M]

R3 R4 non-polar double bonds

R Ar

R

+ R1 XH

R2

R1

X = N, O, C etc. b)

R

This work!

H [M]

N2

[M]

proton transfer

R1

Y

X

[Pd] 5-exo-trig R

Ar

N CO2R 3 3 CO R 2 N R2 Ar Challenging trapping of R2 H ammonium ylide with non-polar double bonds

To increase the reactivity of simple alkene and to suppress the 1,2-proton transfer, we envisioned an intramolecular reaction with ortho-vinylaniline and diazo compound employing suitable


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palladium catalyst (Scheme 1b), well established to insert a alkene into Pd-C/heteroatom bond under Heck type reaction13. Successful demonstration of this trapping would provide novel transformation, viz. carbenylative hydroamination of alkene14 and would also allow the synthesis of polysubstituted indolines15, which are ubiquitous subunits present in various biologically relevant molecules16. Based on these challenges, importance and as part of our ongoing interest in exploring the new reactivity of metal carbenoids,17 we herein disclose the first diastereoselective palladium catalyzed intramolecular carbenylative hydroamination of orthovinylaniline for the construction of tri and tetrasubstituted indolines and its mechanistic insight. Results and Discussion Based on the hypothesis, ortho-vinylanilines 1a-1e having electronically different substitution at nitrogen were synthesized and subjected under the palladium catalyzed carbenylative hydroamination conditions with diazo compound 2a. After the initial screening of various catalyst and critical parameters, [Pd(cinnamyl)Cl]2 was chosen as suitable catalyst in toluene at 100 °C (see supporting information). Electron rich aniline 1a on reaction with 2a did not afford either the expected product 3a or the inserted product 4a, instead lead to the rapid decomposition of diazo compound 2a (Table 1). Similar result was observed with related electron donating, (pmethyl)benzyl and electron withdrawing, carbamate, amide and sulfonamide containing orthovinylanilines 1b and 1c-1e, respectively. To our delight, slow addition of 2a to the mixture of 1b and [Pd(cinnamyl)Cl]2 in toluene at 100 °C gave the expected product 3b in 50% isolated yield as single diastereoisomer, other diastereoisomer was not detected in both 1H NMR and HPLC analysis, and no inserted product 4b was observed. On the other hand, slow addition of 2a with other anilines 1a, 1c-1e under above conditions also did not afford any expected products.


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Table 1. Palladium catalyzed carbenylative hydroamination of o-vinylaniline 1 and diazo compound 2a: Optimization.[a] Ph

Ph O + 1

N2

NH R

O Ph [Pd(cinnamyl)Cl] 2 O (X mol%) R Ph N CO2Me Ligand (10 mol%) N CO Me toluene, 100 °C, 8 h 2 MeO2C Ph 2a 3a-e R 4a-e Ph

Entry

R

X mol%

Ligand

Yield of 3 (%)[b]

1

H (1a)

3

-

0

2

p-MeC6H4CH2 (1b)

3

-

0 (50)[c]

3

COOEt (1c)

3

-

0

4

COCF3 (1d)

3

-

0

5

p-MeC6H4SO2 (1e)

3

-

0

6

p-MeC6H4CH2 (1b)

3

PPh3

47[c]

7

p-MeC6H4CH2 (1b)

3

(2-Furyl)3P

45[c]

8

p-MeC6H4CH2 (1b)

3

(o-Tolyl)3P

48[c]

9

p-MeC6H4CH2 (1b)

3

X-Phos

48[c]

10

p-MeC6H4CH2 (1b)

6

-

66[c] (84)[d]

[a] Reaction conditions: 1a (1 equiv), 2a (2 equiv), [Pd(cinnamyl)Cl]2 (X mol%), Ligand (10 mol%), toluene, 100 °C, 8 h. [b] All are isolated yield. [c] Slow addition of 2a. [d] At 120 °C. Next, to improve the yield of 3b, influence of ligands were examined with various electronically and sterically different phosphine, such as PPh3, (2-furyl)3P, (o-tolyl)3P, X-Phos and etc. All the ligands furnished 3b in ~48% yield, suggesting that ligands do not show any significant influence on the present reaction; hence, ligand free palladium system was chosen for further optimization. Similarly, introduction of additive like base and copper salts also did not


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improve the reaction (see supporting information). Successfully, increasing the reaction temperature to 120 °C and catalyst loading to 6 mol% gave the product 3b in 84% yield. Scheme 2. Palladium catalyzed carbenylative hydroamination: Scope of anilines. Ph CO2Me R

N2

+ 1

Ph

NH R1

2a

Ph

R R Ph R N CO2Me R R R1 R

R

Si

O

Ph N CO2Me 3k: 68% R1

Ph Ph

O

N CO2Me R1

Ph N CO2Me R1 3m: 69% Ph

Ph

N CO2Me 1 3n: 69% R H 3C Ph Ph

Ph

TsO

Ph

H 3C

3

N CO2Me R1

Ph

= OMe; 3b: 84% (81%)* = H; 3f: 71% = Me; 3g: 73% = tBu; 3h: 76% = Ph; 3i: 78% = OBn; 3j: 72%

F

O

AcO

Ph

R

R1 = p-MeC6H 4CH2

Ph

3l: 51%

Ph

[Pd(cinnamyl)Cl] 2 (6 mol%) toluene, 120 °C 8h

Ph N CO2Me 1 3o: 80% R Ph

Ph

N CO2Me R1 3q: 77%

EtO 2C

Ph

3r: 52%

N CO2Me R1

Ph

N CO2Me 3p: 80% Bn Ph R

Ph N CO2Me R1 R = 5-OH; 3s: 0% R = 7-F; 3t: 0%

Reaction conditions: 1 (1 equiv), 2a (2 equiv), [Pd(cinnamyl)Cl]2 (6 mol%), toluene, 120 °C, 8 h. All the compounds are isolated as single diastereomer. *Yield of gram scale (1 g of 1b) reaction. Having successfully optimized the palladium catalyzed carbenylative hydroamination, scope and limitation of diazo compounds and ortho-vinylanilines were investigated. At first, diverse substitutions on the aryl moiety of aniline 1 were examined (Scheme 2). Simple phenyl and alkyl


6

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substituted aniline derivatives afforded 3f-3i in good yield. Reactive functional groups such as benzyloxy (3j), acetoxy (3n), tosyloxy (3o), TBDMS ether (3k), acetal (3l), carboxylic ester (3p), fluoro (3m) and vinyl (3r) were well tolerated under the optimized conditions. The structure and diastereoselectivity, cis relation of both phenyl groups, was unambiguously confirmed by single crystal X-ray analysis of 3m.18 Introduction of steric hindrance at ortho to vinyl group was well accepted and led to the formation of 3q in 77%, on the other hand, substitution at ortho to nitrogen did not afford the indoline 3t. Subsequently, varying the nucelophilicity of amine by substituting with electronically different benzyl moiety was well tolerated to give the products 3u-3x in good yield (Scheme 3). Introduction of methyl group at benzylic position and replacing benzyl with alkyl moiety, like iso-propyl and cycloalkyl, also furnished corresponding indolines. However, amine being part of fused ring did not afford the cyclized product, possibly due to the ring stain during cyclization. It is important to note that gram scale reaction of 1b and 2a afforded the indoline 3b with no loss in the yield (81%, Scheme 2),‡ which highly important with respect to synthetic applicability and scalability. Next, changing phenyl group on alkene moiety with p-tolyl, p-tert-butylphenyl, p-fluorophenyl and thiophen-2-yl afforded the indolines 3af-3ai in ~80% yield (Scheme 3). Interestingly, alkenyl and alkyl substituents on alkenes were well tolerated to furnish 3aj-3an in comparable yield. Unsubstituted alkene was also successfully converted to corresponding 2,2,3-trisubstituted indoline 3ao and 3ap in good yield. Similar to α-substituted styrenes, α,β-disubstituted styrene also underwent efficient reaction to furnish 3aq in 71% yield and it was unambiguously confirmed by X-ray analysis.19 Unfortunately, ortho-alkenylaniline 1ar and 1as, which has bulky group at β-position and β,β-disubstituion, respectively, did not give the expected cyclized products.


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Scheme 3. Palladium catalysed carbenylative hydroamination: Scope of anilines. R O

CO2Me + N2 Ph

NH R1

1

2a

O

Ph

Ph

O

Ph CO2Me

O

Ph CO2Me

N N 1 R 3x: 72% = C6H 5CH2; 3u: 69% O = p-MeOC 6H 4CH2; 3v: 77% Ph = p-NO2C6H 4CH2; 3w: 58%† Ph = iPr; 3z: 56% = c-C5H 9; 3aa: 73% N CO2Me = c-C6H11; 3ab: 71% 3ad: 0% = c-C7H13; 3ac: 41% Me

N 3af: 80% R1

3y: 43%†

3ag: 78%

N

N R1

Ph CO2Me

S

N R1 3ah: 86%

Ph CO2Me

N R1 3aj: 75%

N Bn

Ph CO2Me

3ai: 86% Me

Ph CO2Me

Ph CO2Me

Ph CO2Me 3ae: 0%

R O

Ph

Ph

O

O Ph CO2Me

Ph CO2Me

N

F

tBu

O

N CO2Me R1

3

Ph

Ph O

R1 R1 R1 R1 R1 R1 R1

R

[Pd(cinnamyl)Cl] 2 (6 mol%) toluene, 120 °C 8h

N Bn R = nBu; 3ak: 56% R = nHex; 3al: 58%

N Bn 3am: 47%

Ph CO2Me

Me Ph N CO2Me Bn 3an: 91%

H

H

N 3ao: 61% Bn Me

Ph CO2Me

N CO2Me 3ap: 64%† Bn

Ph

CO2Me

N Bn

Ph N H

Bn 1ar

1as

NH Bn

3aq: 71%


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ACS Catalysis

Reaction conditions: 1 (1 equiv), 2a (2 equiv), [Pd(cinnamyl)Cl]2 (6 mol%), toluene, 120 °C, 8 h. All the compounds are isolated as single diastereomer. † 1H NMR Yield Next, scope and limitation of diazo compounds was examined. Similar to methyl ester, ethyl ester gave the product 3at in 83% yield (Scheme 4). But, bulky iso-propyl and tert-butyl esters and additional co-ordination containing allyl ester were failed to furnish expected indolines 3au3aw, instead N-H inserted products 4au-4aw was observed in 72%, 62% and 68% yield, respectively. Scheme 4. Palladium catalysed carbenylative hydroamination: Scope of diazo compounds. Ph O

CO2R1

+ N 2

Ar

NH R 1a Ph O N CO2R1 R Ph

2 R1 R1 R1 R1 R1

O

tBu

Ph

Ar N CO2R1 R

3

= Me; 3b: 84% O = Et; 3at: 83% = iPr; 3au: 0%; 4au: 72% = tBu; 3av: 0%; 4av: 62% = allyl; 3aw: 0%; 4aw: 68%

Me

Ph

N CO2Me R 3ax: 72% OBn Ph

OMe O

O O

Ph

[Pd(cinnamyl)Cl] 2 (6 mol%) toluene, 120 °C 8h R = p-MeC6H 4CH2

OMe N CO2Me R 3az: 69% F Ph

N CO2Me R 3ay: 78% OTs Ph

O

O N CO2Me R 3bb: 78% Ph

O

N CO2Me R 3ba: 70% Ph O

O CF 3

N CO2Me R 3be: 52%

Me N CO2Me R 3bd: 78% PhMe

N CO2Me R 3bc: 71% Ph O NO 2

N CO2Me R 3bf: 50%

N CO2Me R 3bg: 0%

Reaction conditions: 1a (1 equiv), 2 (2 equiv), [Pd(cinnamyl)Cl]2 (6 mol%), toluene, 120 °C, 8 h. All the compounds are isolated as single diastereomer.


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Electronically different aryl groups on 2 were well tolerated under the present conditions to afford 3ax-3bf in good yield. Interestingly, pharmaceutically important trifluoromethyl substituted indoline 3be was also achieved from corresponding diazo compound 2. Similar to the previous observation, sterically demanding ortho substituted aryl containing diazo compounds did not afford the cyclized product. To understand the mechanism of reaction, 1b and 2a were treated under standard conditions in the presence of excess of D2O. The reaction afforded the mixture of 3b and deutrated indoline 3b' in 1:0.3 ratio (Scheme 5). Analysis of the reaction mixture after 1 h, gave 52% of mixture of 3b and 3b' along with 40% of 1b. Although, ratio of 3b and 3b' remained comparable, no deuterium incorporation was observed in the recovered 1b. Scheme 5. Control experiments. Ph O

CO2Me

Ph

Standard Conditions

O

H/D Ph

+ N2 N CO2Me D 2O NH Ph R 2a 1b R After 8 h: 3b/3b': 81% (H/D = 1/0.3 ratio) R = p-MeC6H 4CH2 After 1 h: 3b/3b': 52% (H/D = 1/0.3 ratio) + 1b: 40% Ph No reaction

Toluene O

Ph

120 °C w/wo LDA

4b

N R

[Pd(Cinnamyl)Cl] 2

CO2Me

Toluene, 120 °C

No reaction

w/wo LDA

These results suggest the formation of 3b' is not due to the Pd catalyzed C–H bond activation, instead the catalytic palladium ends up at the methylene carbon after cyclization. Next, to assess the feasibility 4 being the intermediate in the present transformation, various attempts were made to cyclize to corresponding indoline. All attempts have failed, suggesting that 4 may not an


10

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ACS Catalysis

intermediate and could be formed from N-ylide when the trapping is slow or unfavourable conditions. Next, number of NMR experiments was performed at variable temperature to identify the potential intermediate and reaction mechanism, which also failed to provide any conclusive information. It remained as question about the possible intermediate and the observed diastereoselectivity, which sought the help of DFT studies. Based on the preliminary mechanistic investigation and to gain the mechanistic details, we postulated the following mechanism and evaluated by theoretical studies at DFT level. As shown in Scheme 6, initial formation of N-ylide B from 1, 2 and Pd-catalyst could be achieved through either carbenoid A or amine complex A' (Path X and Y). Similarly, formation of cyclized D from B can also be rationalized in two pathways: 1) Pd-C bond in B could undergo intramolecular Heck-type reaction under 5-exo-trig mode of cyclization and 2) metalloene reaction of palladium species C, generated from B via the 1,3-Pd shift. Final protonation of D would furnish the observed indoline 3 along with regeneration of palladium catalyst to continue the catalytic cycle.


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ACS Catalysis

Scheme 6. Plausible mechanism. R1 CO2R 3

N2

CO2R 3

1R

[Pd]

2 Ar

Ar

NH R2

R1

th

X

A

Pa

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R

ath

Y

P

A'

H [Pd] N 2 R2

R1

1 CO2R 3 N Ar H R2 B R1 R1 Ar

R 3

N R2

CO2R 3

[Pd]

R

[Pd]

R D

[Pd]

trig xo - yp e ) e 5 k-t c (He

Ar

R1

N CO2R 3 H R2

R

metallo-ene reaction

1,3-Pd shift Ar

OR3 N H R 2 O[Pd] C

This postulated mechanism has been comprehensively investigated employing DFT calculations and the energy profiles and all the optimized geometries are depicted in Figure 1 and Figure S1-3 (see supporting information). The reaction starts with initial formation of N-ylide B occurs via pathway X with lowest overall activation barriers (19.11 kcal/mol, Figure S1). Subsequent cyclization could follow two possible pathways: 1) Heck-type of cyclization and 2) metallo-ene kind of reaction. Figure 1 shows the free energy profiles calculated for both the possible pathways proposed.


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29.85

TS5ExT Ph H Bn

TS5ExT

∆G (kcal/mol)

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

ACS Catalysis

19.68

TS@Ebt

16.84

TS@Ech

N

Ph Bn

O

MeO

H

Cl –

TS@Ebt

Ph

N

Ph O

MeO

Ph

Pd Ph

Pd

Cl –

TS@Ech

C B

3.92

D –17.6

3 –20.61

Figure 1. Energy profile diagram for the cyclization of N-ylide B to indoline 3. As the energy difference between B and C is very low (3.92 kcal/mol), N-ylide B isomerizes to intermediate C rapidly from which metallo-ene type of reaction is initiated. Metallo-ene reactions of C, proceed through six membered ring transition states of both chair-like and boatlike conformations (TS@Ech and TS@Ebt) where both of them predominantly result to both phenyl group (Ph) in same side, which in turn afford the excellent diastereoselectivity. TS@Ech has low activation barrier compare to TS@Ebt, which is possibly due to the formation of relatively stable cyclic chair-like six-membered transition state. As suggested by J. M. Knapp et. al,20 stepwise mechanistic pathways initiated from both B and C intermediates are also investigated. In the complex C, attack of alkene at electrophilic Pd is endothermic in nature by 18.62 kcal/mol with activation barrier of 20.49 kcal/mol (Figure S4 in supporting information). Hence, stepwise mechanism is unfavorable when compared to concerted mechanism. On the


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other hand, transition states TS5ExT is associated with Heck type reaction with 5-exo-trig mode of cyclisation reactions initiated from the intermediate B, which requires high activation barrier (29.85 kcal/mol) compared to the metallo-ene reactions (in the range of 16-20 kcal/mol), possibly due to the high steric crowed in the transition state (TS5EXT). Thus, these studies reveal that the final cyclization of N-ylide B and observed diastereoselectivity occurs through the rapid isomerization to C and concomitant metallo-ene type reaction. Conclusions In conclusion, we have designed and successfully demonstrated an efficient stereoselective palladium catalyzed intramolecular carbenylative hydroamination of ortho-vinylaniline with αdiazocarbonyl compounds. A broad substrate scope has been established to afford various tri and tetrasubstituted indolines in good yields with excellent diastereoselectivity. Important features of the present methodology include the construction of two contiguous quaternary carbon centers via the formation of C-N and C-C bond in single operation, wide functional group tolerance, excellent diastereoselectivity, high atom and step economy, trapping without assistance of any additives and gram scale synthesis. Furthermore, the reaction mechanism has been explored by a combination of experimental and DFT studies, which unveiled the initial formation of N-ylide followed by cyclization via metallo-ene type reaction involving six-membered cyclic transitionstate, which also establishes the observed diastereoselectivity.

ASSOCIATED CONTENT The Supporting Information is available free of charge on the ACS Publications website.


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ACS Catalysis

Experimental details, characterization data, geometries of optimized structure/transition states and 1H and 13C NMR spectra of isolated compounds (PDF) Crystallographic information file for 3m (CIF) Crystallographic information file for 3aq (CIF) AUTHOR INFORMATION Corresponding Author * [email protected] ACKNOWLEDGMENT P.A. thanks DST-SERB (Project No. EMR/2016/003677/OC) for financial support. V.S. and C.V.S.K. thank CSIR for funding via multi-scale modeling project (No. CSC0129). A.C.S.R. thanks CSIR for fellowship.

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(19) CCDC 1438962 contains the supplementary crystallographic data for the compound 3aq. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/data_request/cif. (20) Knapp, J. M.; Zhu, J. S.; Tantillo, D. J.; Kurth, M. J. Angew. Chem., Int. Ed. 2012, 51, 10588-10591.


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