chapter 2a base-mediated hydroamination of...

Chapter 2A Base-Mediated Hydroamination of

Symmetrical Internal Alkynes

Chapter 2 Part A: Base-mediated hydroamination of symmetrical internal alkynes

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2A.1 INTRODUCTION

The addition of amines onto C−C multiple bonds is rising as a powerful technique for the synthesis of imines, enamines or other nitrogen containing molecules used in diverse biological activities.1 Hydroamination of alkynes has been reported as both an intra- and intermolecular reaction proceeding in the presence of various metals, including lanthanides, transition metals and alkaline earth metals.2 The use of late transition-metals as catalysts is thought to facilitate the attack of nitrogen nucleophiles onto unsaturated carbon substrates through activation of the double or triple bond such that the electron-rich alkyne is transformed into an electrophile.3

The products formed can not only be used in a number of synthetically useful transformations but also can be reduced to stable secondary amines. Not only this, alkyne hydroaminations have been employed as key steps in total syntheses of a number of natural products (Figure 2a.1).4

NHMeO

OMe

OMe

MeO

I (+)-preussin II (+)-(S)-laudanosine III (–)-(S)-xylopinine

Figure 2a.1. Natural Products Synthesized by the Hydroamination of Alkynes

A significant progress has been done by Knochel5a-b and Ackermann5c-g for the synthesis of diversely substituted indoles using inter- or intramolecular hydroamination of alkynes (Scheme 2a.1).

Scheme 2a.1. Applications of Inter- or Intramolecular Hydroamination in the Synthesis of indoles


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With these successful reports on the synthesis of biologically important molecules via hydroamination and strong demand for the development of general, flexible, and regioselective methodologies motivated us to explore the addition of heterocyclic amines onto alkynes. 2A.2 HYDROAMINATION OF INTERNAL ALKYNES: REVIEW OF

LITERATURE Enamines are versatile substrates and are known for the synthesis of wide variety of simple and complex heterocycles from several years.6 These molecules possess numerous medicinal and pharmaceutical properties and hence used by the mankind for its therapeutic value.7 The construction of nitrogen containing molecules or their substrates by hydroamination of C−C multiple (double or triple) bonds is rising as a powerful technique in organic synthesis. Due to some thermodynamical and kinetic constraints, direct addition of amines onto C−C multiple bonds is difficult.8 Therefore, a variety of catalysts has been reported in the literature for the hydroamination to occur under mild conditions.2 While a great number of metal catalysts of the periodic table have now been described for the inter- or intramolecular hydroamination, still the more entropically demanding intermolecular variant of this reaction remains a significant challenge.

Many research groups like Cossy et al.,9 Jacobi et al.,10 Trost et al.,11 Hartwig et al.12 and Barluenga et al.13 contributed significantly for the inter- or intramolecular addition of nitrogen nucleophiles with alkynes.8b Due to the amount and toxicity of the catalysts employed, these reactions could not be considered very practical. Remarkable contribution to this field was made by Knochel et al., reporting the CsOH.H2O catalyzed intermolecular addition of anilines and heterocyclic amines to phenylacetylene.14 From then, catalytic hydroamination of alkynes has been performed in a variety of ways, using different types of catalysts or initiators and under different reaction conditions.15

In 2010, Xie et.al. reported a direct and efficient reactions catalyzed by titanium amides with excellent regioselectivity for the preparation of a series of substituted isoindoles, isoquinolines, and imidazoles (Scheme 2a.2).16


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Scheme 2a.2. Titanium catalyzed Intramolecular Hydroamination

RN + HNR'R''

N

HR

NR'R''

RN

+N

NH

HR

R' CNR'

Ti Complex

Ti Complex

X XI XII

XIII XIV XV

A similar approach has been made to furnish functionalized five-, six-, and seven-membered N-heterocycles XIX in excellent yields via a Cu(I)-catalyzed, one-pot, tandem hydroamination/alkynylation process (Scheme 2a.3).17

Scheme 2a.3. Cyclization Triggered alkynylation

Ackermann and co-workers have reported a titanium and palladium-catalyzed, one-pot protocol for the highly regioselective annulation reactions of unsymmetrically substituted alkynes by primary 2-bromo or 2-chloroanilines (Scheme 2a.4).18

Scheme 2a.4. Regioselective annulation of internal alkynes

The TiCl4-catalyzed intermolecular hydroamination and a subsequent palladium- catalyzed intramolecular aza-Heck reaction provided diversely functionalized indoles, with a regioselectivity that is complementary to the one obtained when employing Larock’s annulation reaction.19


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In a recent study, zirconium-catalyzed hydroamination of both internal and terminal alkynes with sterically demanding and less demanding primary amines was achieved successfully in moderate to good yields but the reaction failed with secondary amines (Scheme 2a.5).20

Scheme 2a.5. Hydroamination/reduction sequence

In 2010, Stradiato and co-workers have reported stereoselective hydroamination of internal aryl alkynes with dialkylamines to afford E-enamine products by using an efficient P, N-ligand and gold complex.21 This catalytic system was found to accommodate a diverse range of functional groups on both the amine and alkyne with synthetically useful regioselectivity.

A gold(I)-catalyzed tandem reaction of alkynes with secondary amines has been developed for the synthesis of tertiary amines (Scheme 2a.6).22 In the presence of ethyl Hantzsch ester and catalytic amount of [{(tBu)2(o-biphenyl)P}AuCl]/AgBF4 a variety of secondary amines bearing electron-deficient and electron-rich substituents and a wide range of alkynes, including terminal and internal aryl alkynes, aliphatic alkynes, and electron-deficient alkynes, underwent a tandem reaction to afford the corresponding tertiary amines in up to 99% yield.

Scheme 2a.6.

All of these organic transformations were conducted in one-pot reaction from simple and readily available starting materials without the need of isolation of air/moisture sensitive enamine intermediates, and under mild reaction conditions. The


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proposed reaction pathway was found to follow with the formation of gold(I)-coordinated enamine complex as a key intermediate generated by the hydroamination of cationic gold(I)–alkyne and amine substrate. Subsequent hydrogenation followed by the protodemetallation affords tertiary amines and regeneration of the gold(I) catalyst were proved by NMR spectroscopy, ESI-MS, isotope labelling studies, and DFT calculations.22

2A.3 OBJECTIVE OF THE WORK

Due to the broad applications of the hydroamination reaction in the synthesis of nitrogen containing heterocycles which are being used as intermediates and in pharmaceutical industries encouraged the scientific community to produce new catalytic methods for this nucleophilic addition. Among the number of intermolecular hydroamination reactions stereo- and regioselective addition of N-heterocycles onto alkynes was important and challenging.

In our recent report on copper-catalyzed tandem synthesis of indolo- and pyrrolo[2,1-a]isoquinolines XXXII (Scheme 2a.7).23

Scheme 2a.7.

This reaction was proposed to follow a reaction mechanism with the formation of a hydroaminated key intermediate followed by intramolecular cyclization (Scheme 2a.8).

A plausible catalytic cycle for the above transformation was presumably that CuI with ligand L generates the copper complex I1, which on oxidative addition, followed by complexation with the alkyne, results in the formation of intermediate I2. л-complexation of the alkyne by copper renders haloalkyne complex I3 susceptible to attack by the heterocyclic nucleophile. Thus, copper complex I3 is formed by intermolecular attack of nucleophile XXX, which subsequently undergoes intramolecular attack of tethered C-2 of the N-heterocycle, resulting in the formation


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of intermediate I6 by eliminating HBr from complex I5. Reductive elimination of I6 affords the product XXXII and regenerates copper complex I1. The other possibility for the formation of I3 involves oxidative addition of I5 to I1. Intermediate I5 could be obtained by hydroamination of bromoalkyne XXXI with XXX.23

Scheme 2a.8. Plausible catalytic cycle for the synthesis of tandem synthesis of indolo- and pyrrolo[2,1-a]isoquinolines

The formation of unexpected indolo- and pyrrolo[2,1-a]isoquinolines via hydroaminated key intermediate I5 and the literature survey for the hydroamination reaction suggested that the catalytic systems used so far were derived from complex and expensive molecules. Thus, our objective was not only to provide an efficient methodology for the synthesis of novel enamines but also helpful in the creation of a diverse library for medicinal chemists. With only one report on the addition of N-heterocycles onto internal alkynes,24 we targeted the addition of N-heterocycles onto arylalkynes.25


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2A.4 RESULTS AND DISCUSSION 2A.4.1. Synthesis of symmetrical internal alkynes: For the hydroamination of internal alkynes, the substrates were synthesized by the conventional Sonogashira coupling reaction of commercially available terminal alkynes 1 (1.0 mmol) with aryl halides 2 and using 5 mol % PdCl2(PPh3)2, Et3N (4.0 equiv) in MeCN at 60 ºC under nitrogen atmosphere for 2h (Table 2a.1) and the spectral data of the products 3a–f was found to be identical with the previous reports.26

Table 2a.1. Synthesis of 1,2-disubstituted ethyne.

entry alkyne arylhalide product yield (%)b

1 1a

2a

3a

85

2 1b

2b

3b

92

3 1c

I

Me

2c

3c

95

4 OMe

1d

2d

3d

90

5 1e

2e

3e

89

6 1f

SI 2f

3f

90

aAll reactions were performed with 1 (1.0 mmol) with 2 1.1 equiv, 5 mol % PdCl2(PPh3)2, Et3N 4.0 equiv in 2.0 mL of MeCN at 60 ºC under an nitrogen atmosphere for 2h. bIsolated yields.


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2A.4.2. Establishment of reaction conditions: Encouraged by our previous efforts to synthesize indolo- and pyrrolo[2,1-a]isoquinolines, when indole 4a and alkyne 1,2-dip-tolylethyne 3b were treated with CuI (5.0 mol %), ligand BtCH2OH (10 mol %) and KOtBu (1.4 equiv) in DMSO at 110 °C for 24 h, a mixture of E/Z isomers of (E)-1-(1,2-dip-tolylvinyl)-1H-indole 5a and (Z)-1-(1,2-dip-tolylvinyl)-1H-indole 6a was obtained in 68% yield with 40:60 stereoselectivity (Table 2a.2, entry 1). When the reaction was carried without CuI and ligand, mixture of 5a and 6a was obtained in 45% yield in 20:80 stereoselectivity (entry 2). Increase in the amount of 4a from 1.0 to 2.0 equiv and base from 1.4 to 2.5 equiv afforded the hydroaminated product in 55 and 62% yields respectively (entries 3 and 4).

Table 2a.2. Optimization of the Reaction Conditions.a

entry base solvent time (h) t °C yield (%)b Isomeric ratio

(5a:6a)c 1d KOtBu DMSO 24 110 68 40:60 2e KOtBu DMSO 24 110 45 20:80 3f KOtBu DMSO 24 120 55 30:70 4g KOtBu DMSO 24 120 62 20:80 5 KOH DMSO 24 120 76 5:95 6 Cs2CO3 DMSO 24 120 - - 7 TEA DMSO 24 120 - - 8 K2CO3 DMSO 24 120 - - 9 KOH DMSO 24 30 - - 10 KOH DMSO 24 80 - - 11 KOH DMSO 05 120 10 0:100 12 KOH DMSO 12 120 50 2:98 13 KOH DMSO 48 120 60 50:50 14 KOH DMF 24 120 35 10:90 15 KOH Toluene 24 110 - - 16 KOH DMA 24 120 - - 17h KOH DMSO 24 120 - -

a Reactions were carried out using 4a (2.0 equiv), 3b (1.0 mmol) and base (2.5 equiv) in solvent (2.0 mL). b Total yield of two isomers. c Stereoisomeric ratio. d 1 (1.0 equiv), 2 (1.0 equiv), CuI (5 mol %), BtCH2OH (10 mol %) and base (1.4 equiv) were added. e 1a (1.0 equiv), 2 (1.0 equiv). f 1a (2.0 equiv), 2 (1.0 equiv). g Base (2.5 equiv) h Base (0.20 equiv) was taken.


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When different bases were tested in this reaction, KOH proved to be the most effective and provided the hydroaminated product 5a in 76% yield in high stereoselectivity (entry 5), other bases like Cs2CO3, Et3N and K2CO3 were found to be ineffective (entries 6−8). With a selective base in hand, other parameters such as temperature and solvent were investigated. At lower temperatures, 30 and 80 °C, hydroaminated products 5a/6a were not observed (entries 9 and 10). The reaction was found to proceed smoothly at elevated temperatures and it is worth noting that longer reaction times led to the conversion of Z-isomer in to E-isomer (entries 11−13). Amongst different solvents such as DMSO, DMF, toluene and dimethylacetamide, DMSO was found to be most effective (entries 14−16). The reaction was not found to occur under the catalytic amounts of KOH (entry 17). 2A.4.3. Characterization of compound 5a: (Z)-1-(1,2-di-p-tolylvinyl)-1H-indole

Compound 5a was prepared by the addition of 2.5 mmol of KOH in the solution of indole 4a and 1,2-dip-tolylethyne 3b in DMSO. The reaction mixture was heated at 120 °C for 14–16h. The structure of compound 5a was established on the basis of its spectral data analysis. Its high resolution mass spectrum showed [M]+ peak at m/z 233.1205, which confirmed its molecular formula to be C17H15N. In the 1H NMR spectrum in CDCl3 at 400 MHz, the characteristic peaks of methyl groups attached to para-position of the phenyl rings at C4" and C4"' appeared at δ 2.34 and 2.32 as singlet for 3 protons each. The vinyl proton at C2 should be at δ 6.64 ppm. The two protons of indole at C2' and C3' were at 6.67 and 6.99 ppm with a coupling constant of 3.2 Hz (Figure 2a.1).


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Similarly, in its 13C NMR spectrum in CDCl3 at 75 MHz, the characteristic peak of methyl carbons attached with C4" and C4"' appeared at δ 21.2. shows the formation of an addition product. The presence of vinylic carbons, C1 and C2 were observed to be present at δ 131.9 and 103.6 ppm respectively (Figure 2a.2) The peaks of all other protons and carbons of the molecule were present in 1H and 13C NMR spectra of the molecule. But, this information did not revealed the stereochemistry of the product formed.

H2

Figure 2a.1. 1H NMR of (Z)-1-(1,2-dip-tolylvinyl)-1H-indole (5a)


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C2

Figure 2a.2. 13C NMR of (Z)-1-(1,2-dip-tolylvinyl)-1H-indole (5a)

NOESY experiments (5a): Hence, the Z-configuration was established based on the NOESY studies (Figure 2a.3). NOEs between vinyl-Hx [δ = 6.64 ppm and ortho-hydrogens Ha , Hb [δ = 7.12–7.09 ppm] of the phenyl groups of 5a was seen while the NOEs between


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vinyl- Hx [(δ = 6.64 ppm] and hydrogen of indole Hc [δ = 6.99 ppm (J = 3.2 Hz)] is not observed in the NOESY spectra of 5a (Figure 2a.3).

Figure 2a.3. NOESY spectra of (Z)-1-(1,2-dip-tolylvinyl)-1H-indole (5a)


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X-ray crystallography studies: Finally the stereochemistry of the product was confirmed by X-ray crystallographic studies (Figure 2a.4).

Figure 2a.4. X-ray crystallographic ORTEP drawing of compound 5a drawn at the 50% probability level

The single-crystal X-ray data of 5a was collected on an Oxford XCalibur CCD diffractometer using graphite monochromated Mo Kα radiation (λ = 0.71073 Å). The structure was solved using SIR-92 and refined by full matrix least squares teqchnique on F2 using the SHELXL-97 program within the WinGX v 1.70.01 software package. All hydrogen atoms were fixed at the calculated positions with isotropic thermal parameters and all non-hydrogen atoms were refined anisotropically.27 The main crystallographic data and structural refinement details are given in Table 2a.3.

Atomic coordinates, bond lengths, bond angles, and thermal parameters for compound 5a have been deposited at the Cambridge Crystallographic Data Centre and CCDC deposit no. 802285 was obtained. In the crystal structure of compound 5a, two carbon atoms C19 and C20 were disordered. Intensity data for 5a was collected for three times using crystals from three different batches, both at 100K as well as 298K and noticed the same disorder in every crystal structure. However, the overall topology of the molecule shows (Z)-olefinic stereochemistry.


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Table 2a.3. Crystal data for 5a 5a

Formula C24H21N Fw 323.4302 T (K) 293 K λ (Å) 0.71073 Crystal system Monoclinic Space group P 21/c a (Å) 7.001(5) b (Å) 15.566(7) c (Å) 17.278(6) α (°) 90 β (°) 97.18(5) γ (°) 90 V (Å3) 1868.2(17) Z 4 Abs.coefficient (Mu (mm-1)) 0.066 F [000] 688.0 R(int.) 0.1547( 1387) Final R indices [I > 2sigma(I)] R1 = 0.1547( 1387)

wR2 = 0.4651( 4238) a R1 = Σ||Fo| – |Fc||/ Σ|Fo|; wR = {[Σ[w(Fo

2 –Fc2)2]/Σ[wFo

4]}1/2

2A.4.4. Scope of the reaction: Under optimized reaction conditions, the scope and limitations of this process were next examined with various substituted N-heterocycles 4a–h and alkynes 3a–g (Table 2a.4, entries 1–19). Indoles with an electron-donating group afforded the addition products with Z-stereoselectivity in good yields. 3-Methylindole 4b, 2-methylindole 4c and 5-methoxyindole 4d reacted well under the given reaction conditions and yielded the desired products in 50–77% yields (entries 3–11).


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Table 2a.4. Synthesis of Z- styryl enamines a

entry N-Heterocycle 4 alkyne 3 product 5 yield (%)b

1 4a 3b

5a

70

2 4a 3c

5b

69

3

4b 3a

5c

70

4 4b 3b

5d

76

5 4b 3c

5e

74

6 4b 3e

5f

52c


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7 4b 3d

5g

76

8 4b 3f

5h

50c

9 4b 3g

nr -

10 4c

3a

5i

69

11 4d

3d

5j

75

12 4d 3b

5k

77

13 4e

3a

5l

74


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14 4e 3c

5m

70

15 4f

3b

5n

75d

16 4f 3a

5o

76d

17 4f 3d

5p

79c

18 4g

3a nr -

19 4h

3a nr -

a The reactions were performed using N-heterocycle 4 (2.0 equiv), 1.0 mmol of the alkyne 3 and 2.5 equiv of KOH in 1.5 mL of DMSO at 120 oC for 24 h unless otherwise noted b Yield of isolated product. c CuI (5 mol %) and ligand / BtCH2OH (10 mol %). d Time = 18–20 h.

5-Bromoindole 4e afforded the addition products with 3a and 3c in 74 and 70% yields respectively (entries 13 and 14). Pyrrole 4f being more nucleophilic yielded the products 5o–q in lesser reaction time (entries 15–17). Electron-deficient heterocycles imidazole 4g and 2-ethyl-4-methylimidazole 4h did not reacted with 3a under the optimized reaction conditions (entries 18 and 19).


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Positioning of the groups on the aromatic ring in alkyne substrate affected the product formation (entries 3–9). Presence of electron-donating group at the para- position of alkynyl phenyl ring 3b improved the yield of the product in comparison to those attached at meta- position 3c (entries 3–5). Sterically hindered 1, 2-di-o-tolylethyne 3e did not reacted in the presence of KOH. So, catalytic amount of CuI (5 mol %) and BtCH2OH (10 mol %) were added in the reaction and desired addition product was obtained in 52% yield (entry 6). Highly electron-rich substrate 1,2-di(thiophen-3-yl)ethyne 3f also reacted with 4b under catalytic conditions and provided 5i in 50% yield (entry 8). Aliphatic alkyne, 3-hexyne 3g did not react with 1a (entry 9). The stereochemistry of the products formed by the addition of amines onto internal alkynes was confirmed on the basis of NMR spectroscopy and NOESY experiments.27 This approach to a variety of styryl enamines is quite useful for the synthesis of additional more highly substituted indolo- and pyrroloisoquinolines, particularly when one considers that there are many ways to transform the halide functional group into other substituents.

For example, (Z)-5-bromo-1-(1,2-diphenylvinyl)-1H-indole 5l produced by the addition of 5-bromoindole 4e and diphenylacetylene 3a can be further functionalized by applying palladium-catalyzed coupling reactions. Suzuki29, Heck30 and Sonogashira26 coupling of 5l with corresponding substrates 6, 8 and 1f afforded the products 7, 9 and 10 in 85%, 81% and 70% yields respectively (Scheme 6).

Scheme 2a.6. Palladium Catalyzed Diversification of (Z)-5-bromo-1-(1,2-diphenylvinyl)-1H-indole, 5l


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2A.5 CONCLUSION In summary, an efficient base mediated regio- and stereoselective hydroamination of alkynes has been developed to synthesise a wide array of (Z)-vinyl-enamines that are useful in organic synthesis. Stereoselectivity was largely affected by the nature of the base and reaction time. The developed protocol avoids the use of expensive catalysts and ligands. Based upon this stereoselective hydroamination, we should be able to develop new synthetic methods to a variety of fused heterocycles. 2A.6 EXPERIMENTAL SECTION 2A.6.1. General procedure for hydroamination of internal alkynes: In an oven dried pressure tube, to a solution of N-heterocycle (2.0 equiv) in DMSO and finely crushed KOH (2.5 equiv), alkyne (1.0 mmol) was added. The resulting reaction mixture was heated at 120 °C. Progress of the reaction was monitored by TLC, while noticing complete consumption of alkynes, reaction mixture was brought to room temperature. The reaction mixture was extracted with ethyl acetate (5 mL x 3), and evaporated under reduced pressure. The crude reaction mixture was purified using silica gel column chromatography.

2A.6.2. Analytical data

(Z)-1-(1,2-dip-tolylvinyl)-1H-indole (5a): The product was obtained as a white solid, mp: 130–135 °C; 1H NMR (400 MHz, CDCl3): δ 7.67 (d, J = 8.2 Hz, 1H), 7.12–7.09 (m, 5H), 7.05–7.01(m, 2H), 6.99 (d, J = 3.2 Hz, 1H), 6.94 (dd, J = 0.9, 7.4 Hz,

1H), 6.90 (d, J = 7.8 Hz, 2H), 6.67 (d, J = 4.6 Hz, 2H), 6.64 (s, 1H), 2.34 (s, 3H), 2.22 (s, 3H); 13C NMR (CDCl3, 75 MHz): δ 138.6, 137.6, 135.6, 135.5, 135.3, 131.9, 129.4, 129.1, 128.9, 128.6, 128.5, 125.9, 124.1, 122.1, 120.7, 120.1, 111.8, 103.6, 21.2. HRMS (ESI): [M]+ Calcd for [C24H21N] : 323.1674, found : 323.1673.


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(Z)-1-(1,2-dim-tolylvinyl)-1H-indole (5b): The product was obtained as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.66 (d, J = 7.8 Hz, 1H), 7.23–7.08 (m, 5H), 7.07–6.95 (m, 4H), 6.94–6.89 (m, 2H), 6.66 (d, J = 3.0 Hz, 1H), 6.61 (s, 1H), 6.47 (d, J =

6.9 Hz, 1H), 2.31 (s, 3H), 2.12 (s, 3H); 13C NMR (CDCl3, 75 MHz): δ 138.5, 138.3, 137.7, 136.1, 135.5, 134.6, 129.8, 129.6, 128.8, 128.54, 128.52, 128.2, 128.0, 126.7, 125.6, 124.9, 123.4, 122.0, 120.6, 120.1, 111.8, 103.1, 21.5, 21.3. HRMS (ESI): [M]+ Calcd for [C24H21N] : 323.1674, found : 323.1674.

(Z)-1-(1,2-diphenylvinyl)-3-methyl-1H-indole (5c): The product was obtained as white crystals, mp: 109–112 °C; 1H NMR (400 MHz, CDCl3): δ 7.60 (d, J = 7.3 Hz, 1H), 7.33–7.28 (m, 4H), 7.25–7.22 (m, 2H), 7.13–7.09 (m, 4H), 7.03–6.99 (m, 2H), 6.85 (d, J = 8.0

Hz, 1H), 6.84–6.81 (m, 1H), 6.77 (s, 1H), 2.35 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 138.7, 136.2, 135.7, 134.9, 129.4, 128.7, 128.3, 127.6, 126.3, 125.8, 124.2, 122.0, 119.5, 118.7, 113.1, 111.7, 9.7. HRMS (ESI): [M]+ Calcd for [C23H19N] : 309.1517, found : 309.1514.

(Z)-1-(1,2-dip-tolylvinyl)-3-methyl-1H-indole (5d): The product was obtained as a yellow oil. 1HNMR (300 MHz, CDCl3): δ 7.61 (d, J = 7.8 Hz, 1H), 7.15–7.07 (m, 5H), 7.04–6.99 (m, 1H), 6.95 (s, 1H), 6.89 (t, J = 7.2 Hz, 3H), 6.77 (s, 1H), 6.68 (d, J = 8.1 Hz, 2H),

2.34 (s, 6H), 2.22 (s, 3H). 13C NMR (CDCl3, 75 MHz): δ 138.6, 137.5, 136.0, 135.7, 135.3, 132.2, 129.3, 129.0, 128.6, 126.1, 125.8, 123.5, 122.0, 119.4, 118.7, 112.9, 111.7, 21.3, 9.8. HRMS (ESI): [M]+ Calcd for [C25H23N] : 337.1830, found : 337.1830.

(Z)-1-(1,2-dim-tolylvinyl)-3-methyl-1H-indole (5e): The product was obtained as a white oil. 1H NMR (300 MHz, CDCl3): δ 7.52 (d, J = 7.8 Hz, 1H), 7.14–7.01 (m, 4H), 6.99–6.95 (m, 2H), 6.88 (t, J = 7.8 Hz, 3H), 6.78 (d, J = 8.4 Hz, 1H), 6.67 (s,

1H), 6.54 (s, 1H), 6.43 (d, J = 6.9 Hz, 1H), 2.28 (s, 3H), 2.23 (s, 3H), 2.65 (s, 3H);

N

Me Me

Me


43

13C NMR (CDCl3, 75 MHz ): δ 138.8, 138.2, 137.6, 136.2, 135.8, 134.9, 130.4, 129.5, 129.3, 128.5, 128.3, 128.1, 126.8, 125.8, 125.5, 124.3, 123.6, 121.9, 119.4, 118.6, 112.9, 111.7, 21.5, 21.3, 9.7. HRMS (ESI): [M]+ Calcd for [C25H23N] : 337.1830, found : 337.1830.

(Z)-1-(1,2-di-o-tolylvinyl)-3-methyl-1H-indole (5f): The product was obtained as yellow crystals, mp: 110–115 °C; 1H NMR (400 MHz, CDCl3): δ 7.47 (m, 2H), 7.29 (dd, J = 1.5, 5.9 Hz, 1H), 7.15–7.12 (m, 3H), 7.04–6.99 (m, 2H), 6.90 (d, J = 8.0 Hz, 1H), 6.81 (d, J

= 8.0 Hz, 1H), 6.65 (t, J = 7.7 Hz, 2H), 6.59 (s, 1H), 6.52 (s, 1H), 2.32 (s, 3H), 2.22 (s, 3H), 1.81 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 138.9, 137.7, 137.4, 136.2, 135.3, 134.8, 130.8, 130.2, 129.9, 129.5, 128.8, 128.1, 127.2, 125.7, 125.6, 121.8, 121.3, 119.8, 119.4, 118.5, 113.1, 111.8, 20.4, 19.7, 9.6. HRMS (ESI): [M]+ Calcd for [C25H23N] : 337.1830, found : 337.1832.

(Z)-1-(1,2-bis(3-methoxyphenyl)vinyl)-3-methyl-1H-indole (5g): The product was obtained as a yellow semi–solid; 1H NMR (400 MHz, CDCl3): δ 7.57 (d, J = 7.3 Hz, 1H), 7.26–7.21 (m, 2H), 7.11–7.00 (m, 3H), 6.91–6.82 (m, 4H), 6.78 (s, 1H), 6.65 (dd, J = 2.2,

5.9 Hz, 1H), 6.57 (d, J = 10.2 Hz, 1H), 6.04 (s, 1H), 3.76 (s, 3H), 3.29 (s, 3H), 2.34 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 159.8, 159.3, 140.1, 136.1, 135.9, 135.7, 129.6, 129.2, 129.0, 125.6, 124.6, 122.1, 122.0, 119.6, 118.9, 118.6, 114.9, 114.1, 113.0, 111.9, 111.6, 55.3, 54.6, 9.7. HRMS (ESI): [M]+ Calcd for [C25H23NO2] : 369.1729, found : 369.1728.

(Z)-1-(1,2-di(thiophen-3-yl)vinyl)-3-methyl-1H-indole (5h): The product was obtained as a dark yellow oil; 1H NMR (400 MHz, CDCl3): δ 7.63 (d, J = 7.3 Hz, 1H), 7.31–7.29 (m, 1H), 7.18 (dd, J = 1.5 Hz, 1H), 7.16 (s, 1H), 7.13 (td, J = 1.5, 6.6 Hz, 1H), 7.07 (t, J =

8.0 Hz, 1H), 7.02–6.99 (m, 2H), 6.85 (s, 1H), 6.79–6.73 (m, 2H), 6.22 (d, J = 5.1 Hz, 1H), 2.39 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 140.9, 135.7, 130.6, 128.9, 127.5,


44

126.4, 125.3, 125.2, 124.9, 122.4, 122.2, 119.5, 119.0, 118.8, 112.8, 111.1, 9.8. HRMS (ESI): [M]+ Calcd for [C19H15NS2] : 321.0646, found : 321.0645.

(Z)-1-(1,2-diphenylvinyl)-2-methyl-1H-indole (5i): The product was obtained as a brown oil; 1H NMR (400 MHz, CDCl3): δ 7.58 (d, J = 8.0 Hz, 1H), 7.31–7.29 (m, 4H), 7.20–7.18 (m, 2H), 7.12–7.09

(m, 3H), 7.06 (dd, J = 1.5, 6.6 Hz, 1H), 6.97–6.96 (m, 2H), 6.76–6.74 (m, 2H), 6.46 (s, 1H), 2.08 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 138.4, 136.4, 136.2, 134.7, 134.2, 128.8, 128.6, 128.1, 127.5, 125.4, 121.2, 120.0, 119.5, 110.8, 102.0, 12.7. HRMS (ESI): [M]+ Calcd for [C23H19N] : 309.1517, found : 309.1517.

(Z)-1-(1,2-bis(3-methoxyphenyl)vinyl)-5-methoxy-1H-

indole (5j): The product was obtained as a yellow oil. 1HNMR (400 MHz, CDCl3): δ 7.24 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 2.3 Hz, 1H)¸ 7.07– 7.03 (m, 2H), 6.96 (d, J

=3.2 Hz, 1H), 6.88 (dt, J = 8.2, 1.4 Hz, 1H), 6.84– 6.82 (m, 3H), 6.69 (d, J = 2.3 Hz, 1H), 6.68– 6.67 (m, 1H), 6.58 (d, J = 3.2 Hz, 1H), 6.54 (d, J = 7.8 Hz, 1H), 6.10 (t, J = 1.8 Hz, 1H), 3.83 (s, 3H), 3.75 (s, 3H), 3.36 (s, 3H); 13C NMR (100 MHz, CDCl3) : δ 159.9, 159.3, 154.5, 139.9, 136.2, 135.8, 130.7, 129.6, 129.3, 129.1, 128.9, 124.8, 121.9, 118.8, 114.8, 114.2, 112.4, 112.28, 112.25, 111.8, 103.6, 102.4, 55.7, 55.3, 54.7. HRMS (ESI): [M]+ Calcd for [C25H23NO3] : 385.1678, found : 385.1678. NOESY experiments (5j)

Results: The Z–configuration of 5j was established based on the NOESY studies; NOEs between vinyl-Hx [δ = 6.10 ppm (J = 1.8 Hz)] and ortho-hydrogens Ha , Hb [δ

N

MeO

OMe

OMe


45

= 7.07–7.03 ppm] of the phenyl groups of 5j is clearly seen while the NOEs between vinyl- Hx [(δ = 6.10 ppm (J = 1.8 Hz)] and hydrogen of indole Hc [δ = 6.96 ppm (J = 3.2 Hz)] was not observed.

(Z)-1-(1,2-dip-tolylvinyl)-5-methoxy-1H-indole (5k): The product was obtained as a yellow solid, mp: 105–110 °C; 1H NMR (400 MHz, CDCl3): δ 7.12–7.10 (m, 5H), 6.97 (s, 1H), 6.96 (d, J = 3.2 Hz, 1H), 6.91 (d, J = 7.8 Hz, 2H), 6.82 (d, J =

8.7 Hz, 1H), 6.69–6.64 (m, 3H), 6.58 (dd, J = 3.2, 0.9 Hz, 1H), 3.84 (s, 3H), 2.35 (s, 3H), 2.23 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 154.4, 138.7, 137.6, 135.8, 135.4, 132.1, 130.7, 129.4, 129.3, 129.1, 128.6, 126.0, 123.9, 112.6, 112.2, 103.3, 102.3, 55.7, 21.3. HRMS (ESI): [M]+ Calcd for [C25H23NO] : 353.1780, found : 353.1782.

(Z)-5-bromo-1-(1,2-diphenylvinyl)-1H-indole (5l): The product was obtained as yellow crystals, mp: 130–132 °C; 1H NMR (400 MHz, CDCl3): δ 7.78 (d, J = 2.2 Hz, 1H), 7.34–7.29 (m, 3H),

7.23–7.19 (m, 2H), 7.14–7.09 (m, 5H), 6.99 (d, J = 3.6 Hz, 1H), 6.80–6.76 (m, 3H), 6.60 (d, J = 2.2 Hz, 1H); 13C NMR (CDCl3, 100 MHz): δ 137.9, 135.7, 134.4, 134.1, 130.5, 129.7, 128.9, 128.8, 128.6, 128.5, 128.0, 126.0,125.2, 125.1, 123.3, 113.6, 113.1, 103.4. HRMS (ESI): [M+1]+ Calcd for [C22H16BrN] : 373.0466, found : 373.0465.

(Z)-5-bromo-1-(1,2-dim-tolylvinyl)-1H-indole (5m): The product was obtained as a white solid, mp: 135–140 °C; 1H NMR (300 MHz, CDCl3): δ 7.78 (s, 1H), 7.72–6.94 (m, 9H), 6.79 (d, J = 8.7 Hz, 1H), 6.60 (s, 2H), 6.46 (d, J = 6.6 Hz,

1H), 2.31 (s, 3H), 2.14 (s, 3H); 13C NMR (CDCl3, 75 MHz): δ 138.5, 138.1, 137.9, 135.7, 134.4, 134.2, 130.5, 129.8, 129.7, 128.8, 128.7, 128.3, 128.1, 126.6, 125.4, 125.3, 125.0, 123.3, 123.2, 113.5, 113.2, 103.2, 21.5, 21.3. HRMS (ESI): [M]+ Calcd for [C24H20BrN] : 401.0779, found : 401.0777.


46

(Z)-1-(1,2-dip-tolylvinyl)-1H-pyrrole (5n): The product was obtained as a brown oil; 1H NMR (300 MHz, CDCl3): δ 7.26–7.21 (m, 1H), 7.16–7.06 (m, 4H), 6.99 (d, J = 7.5 Hz, 1H), 6.80 (s, 1H), 6.61–6.56 (m, 4H), 6.30–6.29 (m, 2H), 2.34 (s, 3H), 2.23 (s, 3H); 13C NMR

(CDCl3, 75 MHz): δ 138.6, 137.5, 137.4, 136.2, 132.0, 129.4, 129.2, 129.1, 128.7, 122.2, 121.3, 120.7, 109.5, 21.3, 21.2. HRMS (ESI): [M]+ Calcd for [C20H19N] : 273.1517, found : 273.1517.

(Z)-1-(1,2-diphenylvinyl)-1H-pyrrole (5o): The product was obtained as a white semi–solid; 1H NMR (400 MHz, CDCl3): δ 7.36–7.33 (m, 3H), 7.29–7.27 (m, 2H), 7.25–7.18 (m, 3H), 6.85–6.82 (m, 3H), 6.58 (t,

J = 2.2 Hz, 2H), 6.30 (t, J = 2.2 Hz, 2H); 13C NMR (CDCl3, 100 MHz): δ 138.8, 134.8, 130.5, 129.1, 128.8, 128.5, 128.3, 127.7, 126.3, 122.9, 121.4, 120.7, 117.9, 109.7. HRMS (ESI): [M]+ Calcd for [C18H15N] : 245.1204, found : 245.1203.

(Z)-1-(1,2-bis(3-methoxyphenyl)vinyl)-1H-pyrrole (5p): The product was obtained as a dark brown oil; 1H NMR (400 MHz, CDCl3): δ 7.28–7.25 (m, 1H), 7.14 (t, J = 7.3 Hz, 1H), 6.92–6.88 (m, 2H), 6.86 (s, 1H), 6.83–6.81 (m, 1H), 6.75 (dd, J = 2.9, 5.1

Hz, 1H), 6.60 (t, J = 2.2 Hz, 3H), 6.30 (t, J = 2.2 Hz, 2H), 6.19 (t, J = 2.2 Hz, 1H), 3.79 (s, 3H), 3.61 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 159.8, 159.4, 140.2, 138.2, 135.9, 129.5, 129.1, 123.3, 122.1, 121.4, 118.7, 114.7, 114.3, 112.2, 111.8, 109.8, 55.3, 54.9. HRMS (ESI): [M]+ Calcd for [C20H19NO2] : 305.1416, found : 305.1411.

(Z)-5-(2,5-dimethoxyphenyl)-1-(1,2-diphenylvinyl)-1H-

indole (14): The product was obtained as an orange semi–solid; 1H NMR (400 MHz, CDCl3): δ 7.83 (s, 1H), 7.35–7.33 (m, 3H), 7.29–7.28 (m, 2H), 7.23 (dd, J = 1.4 Hz, 1H), 7.15–

7.13 (m, 3H), 7.06 (s, 1H), 6.99 (d, J = 2.9 Hz, 1H), 6.97 (d, J = 2.9 Hz, 1H), 6.93 (d, J = 4.4 Hz, 1H), 6.91 (d, J = 4.4 Hz, 1H), 6.87–6.84 (m, 2H), 6.83–6.80 (m, 1H), 6.69 (d, J = 3.7 Hz, 1H), 3.81 (s, 3H), 3.75 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 153.7, 150.8, 138.3, 136.3, 134.7, 132.6, 130.4, 128.9, 128.8, 128.6, 128.4, 127.8, 126.3,


47

124.8, 124.1, 121.5, 117.0, 112.6, 112.4, 111.7, 104.3, 56.3, 55.8. HRMS (ESI): [M]+ Calcd for [C30H25NO2] : 431.1885, found : 431.1885.

(E)-methyl-3-(1-((Z)-1,2-diphenylvinyl)-1H-indol-5-

yl)acrylate (16): The product was obtained as white crystals, mp: 130–135 °C; 1H NMR (400 MHz, CDCl3): δ

7.84 (dd, J = 1.6, 15.6 Hz, 2H), 7.37–7.33 (m, 3H), 7.28–7.24 (m, 3H), 7.16–7.14 (m, 4H), 7.05 (d, J = 3.2 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.83–6.80 (m, 2H), 6.73 (d, J = 3.2 Hz, 1H), 6.39 (d, J = 14.0 Hz, 1H), 3.82 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 167.9, 146.4, 144.9, 137.9, 136.7, 135.7, 134.4, 130.3, 129.7, 129.1, 129.0, 128.9, 128.8, 128.6, 128.5, 128.0, 126.9, 126.0, 125.3, 122.4, 121.8, 117.8, 114.8, 112.2, 104.7, 51.5. HRMS (ESI): [M]+ Calcd for [C26H21NO2] : 379.1572, found : 379.1572.

(Z)-1-(1,2-diphenylvinyl)-5-(thiophen-3-ylethynyl)-

1H-indole (17): The product was obtained as a brown oil; 1H NMR (400 MHz, CDCl3): δ 7.86 (s, 1H), 7.47 (d, J = 2.2 Hz, 1H), 7.35–7.33 (m, 2H), 7.29–7.22 (m, 5H), 7.19–

7.16 (m, 1H), 7.13–7.10 (m, 3H), 7.02 (d, J = 3.7 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 6.79–6.77 (m, 2H), 6.71 (s, 1H), 6.66 (d, J = 2.9 Hz, 1H); 13C NMR (CDCl3, 100 MHz): δ 138.1, 135.8, 135.3, 134.6, 129.9, 129.4, 128.9, 128.7, 128.6, 128.4, 127.9, 127.8, 126.1, 125.8, 125.2, 125.1, 124.6, 122.9, 116.2, 114.7, 111.8, 104.1, 90.2, 82.3. HRMS (ESI): [M]+ Calcd for [C28H19NS] : 401.1238, found : 401.1238.

NOTE: All the data mentioned here has been published in Org. Lett. 2011, 13, 1630 and J. Org. Chem. 2012, Manuscript jo-2012-00782n (Revisions submitted to Editorial Office). Therefore, selected spectras has been added in Appendix-I to avoid the wastage of paper.


48

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