Lewis Acid-Catalyzed [3+3] Annulation of DonorâAcceptor

Subscriber access provided by Iowa State University | Library

Note

Lewis Acid Catalyzed [3+3] Annulation of Donor-Acceptor Cyclopropanes and Indonyl Alcohols: One Step Synthesis of Substituted Carbazoles with Promising Photophysical Properties Rohit Kumar Varshnaya, and Prabal Banerjee J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 08 Jan 2019 Downloaded from http://pubs.acs.org on January 8, 2019

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

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

The Journal of Organic Chemistry

Lewis Acid Catalyzed [3+3] Annulation of Donor-Acceptor Cyclopropanes and Indonyl Alcohols: One Step Synthesis of Substituted Carbazoles with Promising Photophysical Properties Rohit Kumar Varshnaya and Prabal Banerjee* Department of Chemistry, Indian Institute of Technology Ropar, Nangal Road, Rupnagar, Punjab-140001, India. Abstract

A highly efficient protocol to access carbazole from donor-acceptor cyclopropane and indonyl alcohol via [3+3] annulation in the presence of a Lewis acid has been demonstrated. This method facilitates the post functionalization of the substituted carbazole into a fully conjugated 𝜋-system exhibiting intense emission bands in the visible range of the spectrum and also offers a convenient route toward the synthesis of pityriazole derivatives. It is arguable that polycyclic indoles are one of the most prominent heterocyclic compounds. This privileged moiety remains prime scaffold for pharmaceutical drug discovery and occupies a significant position in the natural product pool.1 Carbazole and its hydroderivative, a subset of polycyclic indoles, has garnered a lot of attention from

ACS Paragon Plus Environment

The Journal of Organic Chemistry 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

organic chemists owing to their presence in several natural products and a large display of bioactivity.2 In the recent years, this moiety has been isolated from various natural sources.3 Out of these, an aromatized carbazole skeleton constitutes the basic unit of many significant natural products, demonstrating a broad spectrum of biological

Figure 1. Bioactive compounds containing carbazole and their derivatives. activities including antimalarial, anticancer, detoxification agents, treatment of skin diseases and efficiency in relieving abdominal pain (Figure 1). 4 Such remarkable and diverse properties compelled us to explore a new pathway towards the synthesis of this ubiquitous ring system. Donor-acceptor cyclopropanes (DACs) have emerged as versatile building blocks in organic synthesis to assemble various carbo- and heterocyclic compounds, including natural compounds and their analogs.5 The high ring strain and donor-acceptor moieties of DACs enable them to undergo a variety of transformations.6 In the presence of a Lewis acid, [3+n] annulation allows to access four, five, six and seven-membered carbo- and heterocyclic skeletons by insertion of dipolar or easily polarizable two-, three- or four atom moieties into the three-membered ring.7 Reports by Johnson, Wang, and other groups demonstrated that various 2𝜋-components react with DACs to afford a wide range of carbocycles and heterocycles. 8 Our group has also explored the cycloaddition and annulation reactions of DACs with epoxides,


Page 2 of 35

Page 3 of 35 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


aziridines, oxaziridines, nitrosocarbonyls, enamines and vinyl azides for the synthesis of carbocyles and heterocycles relevant to biological applications.9 In 2009, Kerr et. al. reported a notable approach to assemble tetrahydrocarbazoles, which involved ring opening of DACs with indole and Conia-ene cyclization.10 Following this report, Tang et al. demonstrated the one pot asymmetric synthesis of tetrahydrocarbazole via enantioselective [3+3] annulation of 2-alkynylindole and DACs.11 Herein, we report the Lewis acid catalyzed [3+3] annulation of DACs and indonyl alcohol, which provides onepot access to a variety of substituted carbazoles. These could be further converted into various elaborated skeletons present in several bioactive natural products. Scheme 1. Synthesis of carbazole derivatives.

The present study began with the optimization of the reaction conditions for the synthesis of substituted carbazole via [3+3] annulation with DAC 1c and indonyl alcohol 2c. The initial experiment was conducted with InCl3 (10 mol %) as the Lewis acid in CH2Cl2 at room temperature, and we were pleased to obtain the targeted substituted carbazole 3cc in moderate yield, 56% (Table 1, entry1). To enhance the product yield, we further



Page 4 of 35

Table 1. Optimization of the reaction conditionsa.

entry

Lewis acid

LA (mol %)

Time (h)

Solvent

Isolated yieldb (%)

1

InCl3

10

4

CH2Cl2

56

2

InCl3

20

2

CH2Cl2

73

3

InCl3

40

1.5

CH2Cl2

60

4

InCl3

100

1

CH2Cl2

20

5

Sc(OTf)3

20

3

CH2Cl2

62

6

Yb(OTf)3

20

4

CH2Cl2

58

7

In(OTf)3

20

4

CH2Cl2

65

8

Cu(OTf)2

20

24

CH2Cl2

n.r.c

9

MgI2

20

24

CH2Cl2

n.r.c

10

Zn(OTf)2

20

24

CH2Cl2

n.r.c

11

Mg(OTf)2

20

24

CH2Cl2

n.r.c

12

Bi(OTf)3

20

1

CH2Cl2

20

13

InI3

20

1

CH2Cl2

45

a Reaction

was carried out under an inert atmosphere using 1c (1 equiv), 2c (1 equiv), Lewis acid (0.2 equiv) and CH2Cl2. b Isolated yield after flash column chromatography. c n.r. = no reaction.

optimized other reaction parameters including the amount of catalyst and solvent (Table 1, entries 2-4 and for solvent variation see supporting information). We found that the yield was increased to 73% in CH2Cl2 when InCl3 was loaded up to 20 mol % (Table 1, entry 2). No further improvement of the yield was achieved with higher loading of InCl3 (40 and 100 mol %, Table 1, entry 3-4). The use of Sc(OTf)3, Yb(OTf)3, and In(OTf)3 provided the desired product in moderate yields (Table 1 entry 5, 6 and 7). Disappointingly, Lewis acids such as MgI2, Cu(OTf)2, Zn(OTf)2, and Mg(OTf)2 did not give


Page 5 of 35 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


any product, while in the case of Bi(OTf)3 and InI3, using a trace amount of the annulated product was formed. Employing the optimized reaction conditions, the scope of the [3+3] annulation was studied with various DACs and indonyl alcohols. Highly activated DACs bearing an electron donating group in the vicinal phenyl ring resulted in an excellent yield of the annulated products (3aa-3ca, Table 2).

A heterocycle containing DAC 3d, when

subjected to the above transformation, afforded the desired product in moderate yield (3da, Table 2). The styryl substituted DAC delivered the corresponding annulated product 3ea in 62% yield. Further, we explored the compatibility of p-fluoro aryl substituted indonyl alcohol with DAC containing an electron donating group (3c)‘ the reaction resulted in the formation of substituted carbazole 3ce in 71% yield. We next examined the generality of the reaction by using N-substituted indonyl alcohol with various DACs. The present transformation was also accomplished by the reaction of N-methyl substituted indonyl alcohol with electron rich and heterocycle containg DACs, which led to the formation of therespective products in good yields (Table 2 entry 3bc-3dc). Excitingly, electron rich DAC 1f containing a N,N-dimethyl group at the p-position of the phenyl ring undergoes [2+3] cycloaddition with N-methyl substituted indonyl alcohol in the presence of InCl3 to produce 3fc’, while with Sc(OTf)3, the [3+3] annulated product 3fc was formed in moderate yield. The reason might be attributed to the isomerization of the 1,3-zwitterionic species generated from DAC into the corresponding propene via prototrophic shift.12 The reaction of p-Br aryl substituted indonyl alcohol 2d with DAC 3c resulted in the corresponding annulated product 3cd in 72% yield. Notably, N-benzyl substituted indonyl alcohol 2e



Page 6 of 35

Table 2. Substrate scope of [3+3] annulation between various DACs and various indonyl alcoholsa

entry

1

2

Ar

R1

R2

R3

3

time (h)

yield [%] b

1

1a

2a

4-methoxy phenyl

Me

H

H

3aa

2

65

2

1b

2a

3,4-dimethoxy phenyl

Me

H

H

3ba

2

66

3

1c

2a

2,4,6-trimethoxy phenyl

Et

H

H

3ca

1

70

4

1d

2a

N-benzyl indole

Et

H

H

3da

2

68

5

1e

2a

styryl

Et

H

H

3ea

3

62

6

1c

2b


Et

H

F

3cb

2

71

7

1b

2c

3,4-dimethoxy phenyl

Me

Me

H

3bc

2

70

8

1c

2c


Et

Me

H

3cc

1

73

9

1d

2c

N-benzyl indole

Et

Me

H

3dc

2

70

10

1f

2c

4-N,N-dimethyl phenyl

Et

Me

H

3fc

3

68

11

1f

2c

4-N,N-dimethyl phenyl

Et

Me

H

3fc’

0.5

67

12

1c

2d


Et

Me

Br

3cd

2

72

13

1d

2e

N-benzyl indole

Et

Bn

H

3de

2

71

aunless

otherwise specified all reactions were carried out in CH2Cl2 at rt with 1 equiv. of 1 and 1 equiv. of 2 in the presence of a InCl3 (20 mol%) at rt. bIn the case of 3fc we have used Sc(OTf)3 instead of InCl3.


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


Scheme 2. Plausible mechanistic pathway A. DAC pathway:

B. indole pathway:

worked well with N-benzyl indole substituted DAC 3d and the product 3de was isolated in 71% yield. In all cases, a single isomer of carbazole was formed. The structure of 3aa was confirmed by single crystal X-ray analysis, and others are confirmed by analogy (Figure 2 and see also the supporting information).13



Figure 2. X-ray structure of 3aa (Hydrogen atoms are omitted for the sake of clarity).

Two plausible mechanistic descriptions for this transformation are depicted in Scheme 2. Option A involves the Lewis acid interaction with DAC 1 to provide the activated Lewis acid- cyclopropane complex A, which could open into the zwitterionic intermediate C. At the same time, the alkylideneindolinium intermediate B generated from indonyl alcohol in the presence of Lewis acid14a undergoes nucleophilic attack by C to form an intermediate D.14 The intermediate D undergoes intramolecular Friedel-Crafts alkylation to form an intermediate E which readily converts into substituted carbazole 3 via C-C ring expanding rearrangement followed by deprotonation.14b Option B involves the Lewis acid activation of the DAC 1 to form intermediate A. Indonyl alcohol 2 undergoes nucleophilic attack on intermediate A, an open chain intermediate B is formed. The intermediate B involved in the alkyl migration from C-3 to C-2 to furnished intermediate C.14d The intermediate C is converted in to intermediate D via deprotonation. The intermediate D form alkylideneindolinium intermediate D by dehydration, which is readily cyclised to substituted carbazole 3 via michael type addition.


Page 8 of 35

Page 9 of 35 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


To explore the potential of this strategy, post functionalizations of the substituted carbazole 3 were carried out (Scheme 3). Carbazole 3 underwent aromatization in the presence of LiCl at 160 °C (Krapcho dealkoxycabonylation) to form the compound 4 in moderate yield. This fully conjugated 𝜋-system also shows intense emission in the visible range and a solvatochromic effect (Scheme 3).15 (See supporting information for detail) Scheme 3. Post functionalization of carbazole into fully aromatized system and their optical properties.

compound

aThe

solvent

λmax abs [nm]

λmax em [nm]

𝜙a

4cc

DMSO

280

396

0.10 ± 0.02

4de

DMSO

279

421

0.12 ± 0.02

4dc

DMSO

281

426

0.11± 0.02

4fc

DMSO

273

484

0.10 ± 0.02

quantum yield of the 4cc, 4de, 4dc, 4fc (c = 0.37 µM, ± 0.02) in DMSO using anthracene as a standard.



Page 10 of 35

Scheme 4. Hydrolysis of aromatized carbazole.

Additionally, it is anticipated that the framework could be useful as a fluorescent marker in biological systems. Upon refluxing, this fully aromatized system underwent hydrolysis in the presence of alcoholic KOH to give the corresponding monoacid 5 in excellent yield. This monoacid 5 is an analog of the natural product pityriazole (Scheme 4).

The

successful construction of these polycyclic skeletons promises an efficient and general strategy towards the synthesis of biologically important carbazole alkaloids. 4 In conclusion, we have successfully developed an efficient method for producing substituted tetrahydrocarbazoles via Lewis acid catalyzed [3+3] annulation of DACs and indonyl alcohol. Additionally, we have also demonstrated the chemical conversion of substituted carbazole into a fully conjugated 𝜋-system, which might exhibit biological activity and also shows a solvatochromic effect. The synthetic potential of the current protocol demonstrated by a three-step synthesis of an analog of natural product pityriazole. Further, studies are underway to delineate the impact of these subtle structural changes on the photophysical properties, and biological activity of the natural product analog.


Page 11 of 35 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


Experimental section General information All reactions were carried out under inert atmosphere using oven dried glassware. All solvents and reagents were obtained from commercial sources and were purified using standard procedure prior to use. The developed chromatogram was analyzed by UV lamp (254 nm), or p-anisaldehyde solution. Products were purified by flash chromatography on silica gel (mesh size 230-400).The 1H and Chemical shifts of 1H and

13C-NMR

13C-NMR

spectra were recorded in CDCl3.

spectra are expressed in parts per million (ppm). All

coupling constants are given in absolute values and are expressed in Hz. The description of the signals include: s = singlet, d = doublet, dd = doublet of doublet, t = triplet, dt = doublet of triplet, q = quartet, pent = pentet, br = broad and m = multiplet. 2. General procedure for synthesis of cyclopropane-1,1-diester derivatives.16 Sodium hydride (2.5 equiv) was taken in a two-neck, round-bottom flask and washed three to four times with dry hexane. Trimethylsulfoxonium iodide (2.5 equiv) was added and the mixture suspended in anhydrous DMSO under nitrogen atmosphere. The mixture was cooled to 0 °C and stirred for 30 min. A solution of the appropriate benzylidenemalonate (1 equiv) in anhydrous DMSO was added, and the reaction mixture was allowed to stir at room temperature. Upon completion of the reaction (as determined by TLC analysis), the solution was poured into ice and extracted with diethyl ether. The combined organic layers were washed once with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography with ethyl acetate/hexane as eluent 1. Dimethyl 2-(4-methoxyphenyl)cyclopropane-1,1-dicarboxylate (1a).16(d)



Dimethyl 2-(4-methoxybenzylidene)malonate (0.5 g, 1.99 mmol), NaH (0.1 g, 4.99 mmol), trimethyl sulfoxonium iodide (1.0 g, 4.99 mmol), dry DMSO (11 mL), reaction time = 5h, 1a (0.39 g, Yield: 74%), colorless oil. 1H NMR (CDCl3, 400 MHz)  7.11 (m, 2H), 6.80 (m, 2H), 3.77 (s, 3H), 3.86(s, 6H), 3.18 (t, 1H), 2.15 (dd, 1H), 1.72 (dd, 1H) ppm. 2. Dimethyl 2-(3,4-dimethoxyphenyl)cyclopropane-1,1-dicarboxylate (1b).16(d) Dimethyl 2-(3,4-dimethoxybenzylidene)malonate (0.5 g, 1.78 mmol), NaH (0.1 g, 4.46 mmol), trimethylsulfoxonium iodide (0.9 g, 4.46 mmol), dry DMSO (11 mL), reaction time = 6h, 1b (0.37 g, yield: 72%), white solid m.p. 70-72 °C; 1H NMR (CDCl3, 400 MHz): δ 6.77-6.71 (m, 3H), 3.85 (s, 6H), 3.78 (s, 3H), 3.40 (s, 3H), 3.18 (t, 1H), 2.15 (dd, 1H), 1.72(dd, 1H) ppm. 3. Diethyl 2-(2, 4, 6-trimethoxyphenyl) cyclopropane-1, 1-dicarboxylate (1c).16(d) Diethyl 2-(2,4,6-trimethoxybenzylidene)malonate (0.5 g, 1.47 mmol), NaH (0.09 g, 3.67 mmol), trimethylsulfoxonium iodide (0.8 g, 3.67 mmol), dry DMSO (9 mL), reaction time = 7h, 1c (0.34 g, yield: 65%), white solid, m.p. 65-67 °C; 1H NMR (CDCl3, 400 MHz): δ 6.05 (s, 2H), 4.30-4.18 (m, 2H), 3.91-3.83 (m, 2H), 3.78 (s, 3H), 3.75 (s, 6H), 2.84 (t, 1H), 2.40 (dd, 1H), 1.79 (dd, 1H), 1.29 (t, 3H), 0.97 (t, 3H) ppm. 4. Diethyl 2-(1-benzyl-1H-indol-3-yl)cyclopropane-1,1-dicarboxylate (1d).16(d) Diethyl 2-((1-benzyl-1H-indol-3-yl)methylene)malonate (0.5 g, 1.32 mmol), NaH (0.08 g, 3.67 mmol), trimethylsulfoxonium iodide (0.7 g, 3.67 mmol), dry DMSO (11 mL), reaction time = 7h, 1d (0.32 g, yield: 62%), white solid, m.p. 79-80 °C; 1H-NMR (CDCl3, 400 MHz): δ 7.70 (d, 1H), 7.38 (d, 2H), 7.23-7.03(m, 6H), 6.88 (s, 1H), 5.23 (d, 2H), 4.33-4.16 (m, 2H), 3.78-3.61 (m, 2H), 3.29 (t, 1H), 2.08 (dd, 1H), 1.75 (dd, 1H), 1.31 (t, 3H), 0.63(t, 3H) ppm.


Page 12 of 35

Page 13 of 35 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


5. (E)-Diethyl 2-styrylcyclopropane-1, 1-dicarboxylate (1e).16(e) (E)-Diethyl 2-(3-phenylallylidene)malonate (0.5 g, 2.04 mmol), NaH (0.08 g, 2.20 mmol), trimethyl sulfoxonium iodide (0.8 g, 2.24 mmol), dry DMF (5 mL), reaction time = 15 min at 0 °C, 1e (0.43 g, yield: 81%), colorless oil. 1H-NMR (CDCl3, 400 MHz): δ 7.30-727 (m, 4H), 7.23(s, 1H) 6.63 (d, 1H), 5.81 (dd, 1H), 4.27-4.14 (m, 4H), 2.73 (q, 1H), 1.81 (dd, 1H), 1.66 (dd, 1H), 1.28 (t, 3H), 1.22 (t, 3H) ppm. 6. Diethyl 2-(4-(dimethylamino)phenyl)cyclopropane-1,1-dicarboxylate (1f).16(d) Diethyl 2-(4-(dimethylamino)benzylidene)malonate (0.5 g, 1.71 mmol), NaH (0.1 g, 3.67 mmol), trimethylsulfoxonium iodide (0.9 g, 3.67 mmol), dry DMSO (11 mL), reaction time = 4h, 1f (0.31 g, yield: 60%), yellow oil. 1H-NMR (CDCl3,400 MHz): δ 7.06 (d, 2H), 6.62 (d, 2H), 4.27-4.15 (m, 2H), 3.90-3.83 (m,2H), 3.14 (t, 1H), 2.90 (s, 6H), 2.12 (dd, 1H), 1.66 (dd, 1H), 1.28 (t, 3H), 0.92 (t, 3H) ppm. General procedure for the synthesis of 3-(α-hydroxyaryl)indoles.17 A mixtrure of benzaldehyde, indole, and Cs2CO3 with a molar ratio of 1:1.2:1 was stirred in 10 volumes of DMF for 6-7 h, and then diluted with 20 mL of water and evaporated under reduced pressure. The residue thus obtained was purified by column chromatography on silica gel and was eluted with ethyl acetate/hexanes mixture to provide the corresponding 3-(α-hydroxyaryl)indole. 1. (1H-indol-3-yl)(phenyl) methanol (2a).17 Benzaldehyde (0.5 g, 4.76 mmol), indole (0.5 g, 5.64 mmol), Cs2CO3 (1.8 g, 4.76 mmol), dry DMF (11 mL), reaction time = 7h, 2a (0.35 g, yield: 32%), white solid, m.p. 80-83 °C; (ethyl acetate/hexane) 4:10 (v/v). 1H-NMR (CDCl3, 400 MHz): δ 7.98 (s, 1H), 7.59 (d, 1H),



7.50 (d, 2H), 7.37-7.28 (m, 3H), 7.18 (m, 1H), 7.08 (m, 1H), 6.92 (s, 1H), 6.16 (s, 1H) ppm. 2. (4-Fluorophenyl)(1H-indol-3-yl)methanol (2b).17 4-Fluorobenzaldehyde (0.5 g, 4.02 mmol), indole (0.5 g, 4.83 mmol), Cs2CO3 (1.3 g, 4.02 mmol), dry DMF (11 mL), reaction time = 7h, 2b (0.35 g, yield: 35%), white solid, m.p. 7980 °C; (ethyl acetate/hexane) 4:10 (v/v). 1H-NMR (CDCl3, 400 MHz): δ 7.93 (br s, 1H), 7.36 (m, 2H), 7.31-7.27 (m, 2H), 7.18 (m, 1H), 7.03 (s, 2H), 6.99-6.96 (m, 1H), 6.64 (d, 1H) 5.87 (s, 1H) ppm. General procedure for Friedel−Crafts silyloxyalkylation of N-alkylindoles.18 To an oven-dried round-bottomed flask under a N2 atmosphere were added diethyl ether (10 mL), N-alkyl indole (1.0 mmol), i-Pr2NEt2 (250 μL, 186 mg, 1.44 mmol), and aldehyde (1.40 mmol). The reaction mixture was cooled to −78 °C in a dry ice/ acetone bath, and trimethylsilyl trifluoromethanesulfonate (270 μL, 332 mg, 1.50 mmol) was added dropwise. The orange reaction mixture was stirred for 1 h and then quenched with pyridine (210 μL). The reaction mixture was passed through a column of silica gel (2 cm × 1 cm) eluting with Et2O. The solvent was removed in vacuo, and the residue was redissolved in tetrahydrofuran (10 mL). To the solution was added tetrabutylammonium fluoride as a 1.0 M solution in THF (1.10 mL, 1.10 mmol). The reaction mixture was stirred for 5 min and then partitioned between diethyl ether (20 mL) and saturated sodium bicarbonate (20 mL). The layers were separated, and the organic layer was washed with water (20 mL). The organic layer was diluted with hexanes (60 mL) and dried with sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated in vacuo. Column


Page 14 of 35

Page 15 of 35 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


chromatography of the residue (0−20% ethyl acetate/hexanes with 1% diethylamine) provided the product, which was stored at −20 °C after isolation. (1-Methyl-1H-indol-3-yl)(phenyl)methanol (2c).18 N-methylindole (128 μL, 135 mg 1.03 mmol) and benzaldehyde(140 μL, 146 mg, 1.40 mmol). The product was isolated as a yellow solid (164 mg, 68%), m.p. 65-70 °C; 1H-NMR (400 MHz, CDCl3) δ 7.62 (dt,1H), 7.51 (d, 2H), 7.39-7.34 (m, 2H), 7.30 (d, 2H), 7.23 (ddd, 1.1 Hz, 1H), 7.12-7.08 (m, 1H), 6.79 (s, 1H), 6.17 (s, 1H), 3.76 (s, 3H) ppm. (4-Bromophenyl)(1-methyl-1H-indol-3-yl)methanol (2d).18 N-methylindole (128 μL, 135 mg 1.03 mmol) and 4-bromobenzaldehyde (259 mg, 1.40 mmol). The product was isolated as an off-white solid (254 mg, 78%), m.p. 90-92 °C; 1H-NMR (400 MHz, CDCl3) δ 7.57 (dt, 1H),7.48 (dt, 2H), 7.38 (d, 2H), 7.30 (d, 1H), 7.23 (ddd, 1H), 7.12-7.08 (m, 1H), 6.79 (s, 1H), 6.12 (s, 1H), 3.73 (s, 3H ppm. (1-Benzyl-1H-indol-3-yl)(phenyl)methanol (2e).18 A, using N-benzylindole (206 mg, 1.00 mmol) and benzaldehyde (142 μL, 149 mg, 1.40 mmol). The product was isolated as a pale yellow oil (235 mg, 75%): 1H-NMR (400 MHz, CDCl3) δ 7.60 (d,1H), 7.51 (d, 2H), 7.38-7.33 (m, 2H), 7.31-7.24 (m, 5H), 7.18-7.14 (m, 1H), 7.11-7.05 (m, 3H), 6.93 (s, 1H), 6.18 (d, 1H), 5.26 (s, 2H) ppm. General procedure for the synthesis of tetra-hydrocarbazoles To a round-bottom flask equipped with a magnetic stir bar was added the donor-acceptor cyclopropane (1 equiv.) and the indonyl alcohol (1 equiv.) and a Lewis acid (0.2 equiv.) under a nitrogen atmosphere. DCM was added as a solvent to the reaction mixture, which was stirred at room temperature until consumption of starting material (as monitored by TLC).The reaction mixture was passed through a small pad of Celite and the solvent was



Page 16 of 35

evaporated in a rotary evaporator. The crude mixture was further purified by flash column chromatography on silica gel with ethyl acetate/hexane as the eluent. Dimethyl1-(4-methoxyphenyl)-4-phenyl-4,9-dihydro-1H-carbazole-3,3(2H)dicarboxylate (3aa): Reaction time: 2 h, 1a (0.100 g, 0.37 mmol), 2a (0.084 g, 0.37 mmol), white solid, m.p. 111-115 °C, 0.115 g, yield: 65 %, Rf value 0.65 (ethyl acetate/hexane) 4:10 (v/v). (3aa) 1H-NMR (400 MHz): δ 7.52 (s, 1H), 7.30-7.26 (m , 4H), 7.23-7.16 (m, 3H), 7.11 (d, J = 7.74 Hz, 1H), 7.05 (m, 1H), 6.96-6.89 (m, 3H), 5.26 (s, 1H), 3.96 (q, J = 4.87, 6.07 Hz, 1H), 3.84 (s, 3H), 3.78 (s, 3H), 3.46 (s, 3H), 2.64 (dd, J = 6.02, 8.17 Hz, 1H ), 2.57 (dd, J = 11.47, 2.29 Hz, 1H) ppm.

13C {1H}

NMR (100 MHz): δ

171.1, 170.2, 159.1, 140.1, 135.3, 135.9, 129.4, 128.2, 127.4, 121.9, 119.4, 119.0, 114.5, 110.6, 60.5, 55.4, 53.1, 52.2, 42.9, 38.2, 34.1 ppm. IR: νmax 2961, 1683, 1452, 1328, 1074, 908, 733 cm-1. HRMS (ESI) calcd for C29H27NNaO5 [M+Na]+ 492.1787; found 492.1788. Dimethyl1-(3,4-dimethoxyphenyl)-4-phenyl-4,9-dihydro-1H-carbazole-3,3(2H)dicarboxylate (3ba): Reaction time: 2 h, 1b (0.100 g, 0.33 mmol), 2a (0.075 g, 0.33 mmol), white solid, m.p. 117-121 °C, 0.112 g, yield: 66%, Rf value 0.63 (ethyl acetate/hexane) = 4:10 (v/v) (3ba) 1H-NMR (400 MHz): δ 7.55 (s, 1H), 7.29 (m, 2H), 7.25-7.18 (m, 4H), 7.14 (d, J = 7.70 Hz, 1H), 7.07 (m, 1H), 6.92 (m, 3H), 6.85 (s, 1H), 5.27 (s, 1H), 3.96 (q, J = 5.79, 5.62 Hz, 1H), 3.91(s, 3H), 3.89 (s ,3H), 3.79 (s, 3H), 3.48 (s, 3H), 2.67 (q, J = 5.36, 7.95 Hz, 1H), 2.58 (q, J = 11.24, 2.42 Hz, 1H) ppm.

13C {1H}

NMR (100 MHz): δ 171.1, 170.1, 149.4, 148.5, 129.4, 128.2, 127.4, 122.0, 120.3, 119.5, 111.6, 111.3, 110.7, 60.5, 56.1, 56.0, 53.2, 52.3, 42.8, 38.6, 34.0 ppm. IR: ν max 2921, 2853, 1734, 1375, 1067, 923, 749 cm-1. HRMS (ESI, Q-TOF) m/z: calcd for C30H30NO6 [M+H]+ 500.2073; found 500.2089.


Page 17 of 35 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


Diethyl

4-phenyl-1-(2,4,6-trimethoxyphenyl)-4,9-dihydro-1H-carbazole-3,3(2H)

dicarboxylate (3ca): Reaction time: 2 h, 1c (0.100 g, 028 mmol), 2a (0.063 g, 0.28 mmol), white solid, m.p. 122-124 °C, 0.110 g, yield: 70%, Rf value 0.50 (ethyl acetate/hexane) = 4:10 (v/v). (3ca) 1H-NMR (400 MHz): δ 7.48 (s, 1H), 7.42 (m, 2H), 7.217.14 (m, 3H), 7.09 (q, J = 6.28, 7.78 Hz, 2H), 6.96 (m, 1H), 6.85 (m, 1H), 6.23 (d, J = 2.19 Hz, 1H), 6.18 (d, J = 2.19 Hz, 1H), 5.15 (s, 1H), 4.64 (q, J = 4.83, 7.28 Hz, 1H), 4.40-4.33 (m, 1H), 4.19-4.13 (m, 1H), 3.97-3.90 (m, 1H), 3.85 (s, 3H), 3.85-3.83 (m, 1H), 3.82(s, 3H), 3.62 (s, 3H), 3.06 (t, J = 12.71 Hz, 1H), 2.35 (q, J = 4.88, 8.27 Hz, 1H), 1.30 (t, J = 7.33 Hz, 3H), 1.10 (t, J = 7.28, 3H) ppm. 13C {1H} NMR (100 MHz): δ 171.0, 170.2, 160.6, 159.5, 141.6, 136.9, 136.0, 129.9, 127.8, 127.5, 126.8, 120.6, 118.8, 118.4, 110.2, 110.0, 91.3, 90.7, 61.4, 61.0, 60.7, 56.0, 55.5, 55.4, 42.9, 29.1, 27.7, 14.2, 13.9 ppm. IR: ν max 2925, 2851,2355, 1733, 1418, 1060, 948, 742 cm-1. HRMS (ESI, Q-TOF) m/z: calcd for C33H35 NNaO7 [M+Na]+ 580.2311; found 580.2311. Diethyl

1-(1-benzyl-1H-indol-3-yl)-4-phenyl-4,9-dihydro-1H-carbazole-3,3(2H)-

dicarboxylate (3da): Reaction time: 2 h, 1d (0.100 g, 0.25 mmol), 2a (0.057 g, 0.25 mmol), viscous liquid, 0.103 g, yield: 68%, Rf value 0.66 (ethyl acetate/hexane) = 4:10 (v/v) (3da) 1H-NMR (400 MHz): δ 7.77 9s,1H), 7.56 (d, J = 7.77 Hz, 1H), 7.37-7.27 ( m, 6H), 7.24-7.10 (m, 10H), 7.02 (t, J = 7.13 Hz, 1H), 6.89 (t, J = 7.39 Hz, 1H), 5.35 (d, J = 32.49 Hz, 2H), 4.39 (t, J = 8.98 Hz, 1H), 4.29 ( q, J = 6.81, 7.07 Hz, 2H), 3.98-3.90 (m, 1H), 3.87-3.79 (m 1H), 2.78 (m, 2H), 1.31 (t, J = 7.83 Hz, 3H), 1.09 (t, J = 7.38 Hz, 3H) ppm. 13C {1H} NMR (100 MHz): δ 170.6, 169.9, 140.5, 137.7, 136.9, 136.3, 135.5, 129.7, 128.9, 128.1,127.8, 127.5, 127.2, 127.0, 126.8, 126.0, 122.4, 121.6, 119.8, 119.3, 115.6, 111.2, 110.7, 110.2, 61.7, 61.3, 60.5, 50.3, 42.9, 32.8, 29.8, 29.6, 14.3, 13.9 ppm. IR:



Page 18 of 35

νmax 3026, 2836, 2354, 1737, 1451, 1027, 918, 756 cm-1. HRMS (ESI, Q-TOF) m/z: calcd for C39H37 N2O4 [M+H]+ 597.2753; found 597.2743. (E)-Diethyl

4-phenyl-1-styryl-4,9-dihydro-1H-carbazole-3,3(2H)-dicarboxylate

(3ea): Reaction time: 3 h, 1e (0.100 g, 0.34 mmol), 2a (0.069 g, 0.34 mmol), viscous liquid, 0.106 g, yield: 62%, Rf value 0.54 (ethyl acetate/hexane) = 4:10 (v/v). (3ea) 1HNMR (400 MHz): δ 7.84 (s, 1H), 7.47 (d, J = 7.70 Hz, 1H), 7.37 (t, J = 7.57 Hz, 2H), 7.29 (m, 2H), 7.23-7.18 (m, 5H), 7.12-7.03 (m, 2H), 6.91 (q, J = 7.01, 7.43 Hz, 1H), 6.76 (d, J = 15.69 Hz, 1H), 6.33 (q, J = 8.67, 6.74 Hz, 1H), 5.21 (s, 1H), 4.27-4.16 (m, 2H), 4.013.92 (m, 1H), 3.91-3.78 (m, 1H), 3.71-3.62 (m, 1H), 2.59 (dd, J = 5.36, 8.53 Hz, 1H), 2.49 (dd, J= 11.14, 2.75 Hz, 1H), 1.23 (t, J = 6.98 Hz, 3H), 1.12 (t, J = 7.13 Hz, 3H) ppm.

13C

{1H} NMR (100 MHz): 170.4, 169.8, 132.9, 130.1, 129.5, 128.8, 128.1, 128.0, 127.3, 126.5, 121.9, 119.0, 110.6, 61.7, 61.3, 59.9, 42.7, 36.6, 31.0, 14.2, 13.9 ppm. IR: νmax 3025, 2924, 1723, 1453, 1295, 1173, 1095, 965, 743 cm-1. HRMS (ESI, Q-TOF) m/z: calcd for C32H32 NO4 [M+H]+ 494.2331; found 494.2340. Diethyl

4-(4-fluorophenyl)-9-methyl-1-(2,4,6-trimethoxyphenyl)-4,9-dihydro-1H-

carbazole-3,3(2H)-dicarboxylate (3cb): Reaction time: 2 h, 1c (0.100 g, 0.28 mmol), 2b (0.67 g, 0.28 mmol), white solid, m.p. 137-140 °C, 0.115 g, yield: 71%, Rf value 0.51 (ethyl acetate/hexane) = 4:10 (v/v). (3cb) 1H-NMR (400 MHz): δ 7.49 (s, 1H), 7.41-7.36 (m, 2H), 7.12 (d, J = 8.11 Hz, 1H), 7.05 (d, J = 7.71 Hz, 1H), 6.98 (m, 1H), 6.91-6.86 (m, 3H), 6.23 (d, J = 2.10 Hz, 1H), 6.18 (d, J = 2.40 Hz, 1H), 5.14 (s, 1H), 4.69 (q, J = 3.80, 7.11 Hz, 1H), 4.40 (m, 1H), 4.20-4.13 (m, 1H), 4.00-3.94 (m, 1H), 3.86 (s, 3H), 3.85-3.83 (m, 1H), 3.82 (s, 3H), 3.59 (s, 3H), 2.99 (t, J = 12.62 Hz, 1H), 2.35 (q, J = 4.81, 8.31 Hz, 1H), 1.29 (t, J = 7.31 Hz, 3H), 1.12 (t, J = 7.11 Hz, 3H) ppm.


13C {1H}

NMR (100 MHz):

Page 19 of 35 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


170.8, 170.1, 160.6, 160.1, 159.5, 137.4, 136.9, 136.0, 131.3 (d, JC-F = 7.91), 131.2, 119.8 (d, JC-F = 179.09), 118.3, 114.7 (d, JC-F = 21.63), 110.3, 91.3, 90.8, 61.5, 61.2, 56.0, 55.6, 55.4, 42.1, 31.7, 29.0, 27.6, 14.2, 13.9 ppm. IR: νmax 3390, 2925, 2355, 2189, 1733, 1461, 1159, 1096, 948, 742 cm-1. HRMS (ESI, Q-TOF) m/z: calcd for C33H35 FNO7 [M+H]+ 576.2398; found 576.2390. Dimethyl

1-(3,4-dimethoxyphenyl)-9-methyl-4-phenyl-4,9-dihydro-1H-carbazole-

3,3(2H)-dicarboxylate (3bc): Reaction time: 2 h, 1b (0.100 g, 0.33 mmol), 2c (0.078 g, 0.33 mmol), white solid, m.p. 180-182 °C, 0.122 g, yield: 70%, Rf value 0.61 (ethyl acetate/hexane) = 4:10 (v/v). (3bc) 1H-NMR (400 MHz): δ 7.32 (m, 2H), 7.24-7.18 (m, 5H), 7.15-7.11 (m, 1H), 6.97-6.93 (m, 1H), 6.86 (t, J = 7.36 Hz, 3H), 5.32 (s, 1H), 4.06 (q, J = 5.81, 5.16 Hz, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 3.76 (s, 3H), 3.47 (s, 3H), 3.23 (s, 3H), 2.73 (q, J = 5.48, 7.77 Hz, 1H)), 2.47 (q, J = 11.23, 2.74 Hz, 1H) ppm. 13C {1H} NMR (100 MHz): δ170.9, 170.1, 149.5, 148.1, 140.1, 138.2, 136.3, 135.8, 129.4, 128.2, 127.3, 126.2, 121.7, 119.1, 118.8, 112.0, 111.7, 108.8, 60.2, 56.0, 53.1, 52.3, 43.3, 38.2, 35.4, 31.1 ppm. IR: νmax 2937, 1729, 1608, 1141, 1024, 962, 744 cm-1. HRMS (ESI, Q-TOF) m/z: calcd for C31H31 NNaO6 [M+Na]+ 536.2049; found 536.2045. Diethyl

9-methyl-4-phenyl-1-(2,4,6-trimethoxyphenyl)-4,9-dihydro-1H-carbazole-

3,3(2H)-dicarboxylate (3cc): Reaction time: 2 h, 1c (0.100 g, 0.28 mmol), 2c (0.066 g, 0.28 mmol), white solid, m.p. 170-172 °C, 0.118 g, yield: 73%, Rf value 0.60 (ethyl acetate/hexane) = 4:10 (v/v). (3cc) 1H-NMR (400 MHz): δ 7.40 (d, J = 6.87 Hz, 2H), 7.217.14 (m, 3H), 7.10 (q, J = 3.81, 3.94 Hz, 2H), 7.02(m, 1H), 6.86 (m, 1H), 6.23 (d, J = 2.41 Hz, 1H), 6.15 (d, J = 2.41 Hz, 1H), 5.17 (s, 1H), 4.66 (q, J = 4.70, 6.74 Hz, 1H), 4.39-4.31 (m, 1H), 4.18-4.11 (m, 1H), 3.98-3.91 (m, 1H), 3.85 (d, J = 2.77 Hz, 6H), 3.84 (m, 1H),



3.58(s, 3H), 3.17(s, 3H), 2.91 (q, J = 11.92, 1.47 Hz, 1H), 2.39 (q, J = 4.86, 8.38 Hz, 1H), 1.30 (t, J = 7.27 Hz, 3H), 1.09 (t, J = 7.27 Hz, 3H) ppm. 13C {1H} NMR (100 MHz): δ170.9, 170.3, 160.3, 159.7, 158.5, 141.7, 137.6, 129.9, 127.7, 126.8, 120.2, 118.4, 118.3, 110.4, 109.5, 108.2, 91.1, 90.9, 61.3, 61.0, 60.2, 56.0, 55.5, 55.4, 43.2, 30.4, 30.3, 27.7, 14.2, 13.9 ppm. IR: νmax 3052, 2936, 2343, 1727, 1450, 1248, 1174, 1040, 952, 742 cm -1. HRMS (ESI, Q-TOF) m/z: calcd for C34H37 NNaO7 [M+Na]+ 594.2468; found 594.2449. Diethyl

1-(1-benzyl-1H-indol-3-yl)-9-methyl-4-phenyl-4,9-dihydro-1H-carbazole-

3,3(2H)-dicarboxylate (3dc): Reaction time: 2 h, 1d (0.100 g, 0.25 mmol), 2c (0.080 g, 0.25 mmol), white solid, m.p. 124-126 °C, 0.109 g, yield: 70%, Rf value 0.64 (ethyl acetate/hexane) = 4:10 (v/v). (3dc) 1H-NMR (400 MHz): δ 7.81 (d, J = 7.08 Hz, 1H), 7.29 (d, J = 7.16 Hz, 2H), 7.24-7.12 (m, 14H), 6.94 (t, J = 7.16 Hz, 1H), 6.28 (s, 1H), 5.26 (s, 1H), 5.11 (q, J = 15.78, 9.71 Hz, 2H), 4.84 (d, J = 5.77 Hz, 1H), 3.92-3.84 (m, 1H), 3.753.66 (m, 1H), 3.48 (s, 3H), 3.32-3.24 (m, 1H), 3.09 (d, J = 14.24 Hz, 1H), 2.99 (q, J = 5.77, 8.03 Hz, 1H), 2.29 (m, 1H), 1.04 (t, J = 7.08 Hz, 3H), 0.219 (t, J = 7.16 Hz, 3H) ppm. 13C {1H} NMR (100 MHz): δ 170.6, 170.3, 141.0, 137.8, 137.4, 136.8, 135.3, 129.6, 128.6, 128.0, 127.6, 122.0, 119.3, 118.9, 109.8, 108.7, 61.0, 60.3, 57.3, 50.1, 42.2, 29.7, 29.5, 28.3, 13.8, 12.7 ppm. IR: νmax

2925, 2343, 1732, 1468, 1264, 1060, 899, 738, cm -1.

HRMS (ESI, Q-TOF) m/z: calcd for C40H39N2O4 [M+H]+ 611.2910; found 611.2905. Diethyl 1-(4-(dimethylamino)phenyl)-9-methyl-4-phenyl-4,9-dihydro-1H-carbazole3,3(2H)-dicarboxylate (3fc): Reaction time: 3 h, 1f (0.100 g, 0.32 mmol), 2c (0.077 g, 0.32 mmol), viscous liquid, 0.116 g, yield: 68%, Rf value 0.61 (acetone/hexane) = 4:10 (v/v). (3fc) 1H-NMR (400 MHz): δ 7.35 (d, J = 7.29 Hz, 2H), 7.24-7.15 (m, 7H), 7.10 (t, J = 6.43 Hz, 1H), 6.92 (t, J= 7.23 Hz, 1H), 6.75 (d, J = 8.57 Hz, 2H), 5.27 (s, 1H), 4.25-4.20


Page 20 of 35

Page 21 of 35 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


(m, 2H), 4.01 (q, J = 6.29, 4.82 Hz, 1H), 3.92-3.83 (m, 2H), 3.21 (s, 3H), 2.96 (s, 6H), 2.69 (q, J = 5.62, 8.17 Hz, 1H), 2.47 (q, J = 11.25, 2.94 Hz, 1H), 1.23 (t, J = 6.96 Hz, 3H), 1.04 (t, J = 7.23 Hz, 3H) ppm.

13C {1H}

NMR (100 MHz): δ 170.4, 169.9, 149.7, 140.4, 138.1,

136.3, 131.4, 129.7, 128.3, 128.1, 127.1, 126.3, 121.4, 118.9, 118.7, 113.2, 112.0, 108.6, 61.6, 61.2, 60.2, 43.2, 40.7, 37.7, 35.5, 31.1, 14.2, 13.8 ppm. IR: νmax 2985, 2801, 1717, 1454, 1273, 1167, 1066, 943, 750 cm-1. HRMS (ESI, Q-TOF) m/z: calcd for C33H37N2O4 [M+H]+ 525.2753; found 525.2756. Diethyl

2-(3-(4-(dimethylamino)phenyl)-4-methyl-1-phenyl-1,2,3,4

tetrahydrocyclopenta[b]indol-2-yl)malonate (3fc’): Reaction time: 30 min, 1f (0.100 g, 0.32 mmol), 2c (0.077 g, 0.32 mmol), viscous liquid, 0.104 g, yield: 67%, Rf value 0.59 (acetone/hexane) = 4:10 (v/v). (3fc’) 1H-NMR (400 MHz): δ 7.20-7.29 (m, 8H), 6.99-6.94 (m, 3H), 6.67 (d, J = 9.0 Hz, 2H), 4.90 (d, J = 7.97 Hz, 1H), 4.45 (d, J = 8.09 Hz, 1H), 4.02-3.91 (m, 3H), 3.69 (m, 1H), 3.32 (m, 1H), 3.21 (s, 3H), 3.15 (d, J = 11.55 Hz, 1H), 2.91 (s, 6H), 1.09 (t, J = 7.09 Hz, 3H), 0.826 (t, J = 7.05 Hz, 3H) ppm. 13C {1H} NMR (100 MHz): δ 168.4, 168.2, 149.9, 146.4, 141.7, 141.2, 129.4, 129.3, 129.1, 128.2, 126.7, 123.2, 120.6, 119.8, 119.1, 118.9, 112.8, 109.3, 61.1, 57.5, 54.4, 47.1, 46.6, 40.8, 30.1, 13.9, 13.5 ppm. IR: νmax 2903, 1744, 1720, 1520, 1368, 1286, 1054, 946, 748 cm-1. HRMS (ESI, Q-TOF) m/z) calcd for C33H37N2O4 [M+H]+ 525.2753; found 525.2756. Diethyl

4-(4-bromophenyl)-9-methyl-1-(2,4,6-trimethoxyphenyl)-4,9-dihydro-1H-

carbazole-3,3(2H)-dicarboxylate (3cd): Reaction time: 2 h, 1c (0.100 g, 0.28 mmol), 2d (0.088 g, 0.28 mmol), white solid, m.p. 177-180 °C, 0.132 g, yield: 72%, Rf value 0.55 (ethyl acetate/hexane) = 4:10 (v/v). (3cd) 1H-NMR (400 MHz): δ 7.37-7.30 (m, 4H), 7.117.01 ( m, 3H), 6.88 (m, 1H), 6.23 (d, J = 2.27 Hz, 1H), 6.15 (d, J = 2.35 Hz, 1H), 5.13 (s,



1H), 4.65 (q, J = 5.23, 6.70 Hz, 1H), 4.39-4.31 (m, 1H), 4.02-3.95 (m, 1H), 3.90-3.86 (m, 1H), 3.85 (d, J = 2.35 Hz, 6H), 3.59 (s, 3H), 3.16 (s, 3H), 2.82 (q, J = 11.78, 1.78 Hz, 1H), 2.40 (q, J = 5.41, 8.07 Hz, 1H), 1.29 (t, J = 6.98 Hz, 3H), 1.12 (t, J = 7.33 Hz, 3H) ppm. 13C {1H} NMR

(100 MHz): δ170.6, 170.1, 160.4, 159.6, 158.5, 141.0, 137.6, 131.7, 130.9,

126.4, 120.8, 120.4, 118.5, 118.0, 110.1, 109.0, 108.3, 91.1, 90.9, 61.5, 61.2, 56.0, 55.5, 55.4, 42.6, 30.4, 30.1, 27.5, 14.2, 13.9 ppm. IR: νmax 2937, 2839, 1725, 1469, 1293, 1150, 1069, 951, 743 cm-1. HRMS (ESI, Q-TOF) m/z: calcd for C34H36BrNNaO7 [M+Na]+ 672.1573; found 672.1563. Diethyl

9-benzyl-1-(1-benzyl-1H-indol-3-yl)-4-phenyl-4,9-dihydro-1H-carbazole-

3,3(2H)-dicarboxylate (3de): Reaction time: 2 h, 1d (0.100 g, 0.25 mmol), 2e (0.80 g, 0.25 mmol), white solid, m.p. 128-130 °C, 0.124 g, yield: 71%, Rf value 0.64 (ethyl acetate/hexane) = 4:10 (v/v). (3de) 1H-NMR (400 MHz): δ 7.68 (d, J = 7.93 Hz, 1H) 7.28 (d, J = 7.11 Hz, 2H), 7.24-7.05 (m, 17H), 6.95 (m, 1H), 6.84 (m, 2H), 6.36 (s, 1H), 5.30 (s, 1H), 5.17-5.02 (q, J = 16.79, 23.79 Hz , 4H), 4.68 (d, J = 5.48 Hz,1H), 3.86 (m, 1H), 3.70 (m, 1H), 3.25 (m, 1H), 2.96 (m, 1H), 2.24 (m, 1H), 1.04 (t, J = 7.27 Hz, 3H), 0.201 (t, J = 7.15 Hz, 3H) ppm.

13C

{1H} NMR (100 MHz): δ 170.6, 170.2, 140.9, 138.3, 137.3,

135.3, 129.5, 128.7, 128.6, 128.0, 127.7, 127.2, 127.1, 126.8, 125.9, 122.0, 121.6, 119.5, 119.4, 119.3, 119.2, 114.5, 112.3, 109.8, 109.5, 61.0, 60.4, 57.3, 50.2, 46.6, 42.2, 29.4, 28.3, 13.8, 12.7 ppm. IR: νmax 2927, 1730, 1452, 1363, 1212, 1060, 961, 778, 736 cm-1. HRMS (ESI, Q-TOF) m/z: calcd for C46H42N2NaO4 [M+Na]+ 709.3042; found 709.3015. General procedure for Krapcho dealkxoycarbonylation To the solution of adduct 3 (1 equiv) in DMSO (4 mL) were added LiCl ( 6 equiv) and H2O (1 drop), and the reaction mixture was heated at 160 °C until consumption of starting


Page 22 of 35

Page 23 of 35 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


material (as monitored by TLC). Three milliliters of water were added to the mixture, and the mixture was extracted with diethyl ether, dried over Na 2SO4, and purified by flash column chromatography using a 10−20% acetone/hexane solvent system. Ethyl

9-methyl-4-phenyl-1-(2,4,6-trimethoxyphenyl)-9H-carbazole-3-carboxylate

(4cc) Reaction time: 72 h, 3cc (0.100 g, 0.17 mmol), LiCl (0.044 g, 1.04 mmol), white solid, m.p. 156-160 °C, 0.055 g, yield: 64%, Rf value 0.61 (acetone/hexane) = 4:10 (v/v). (4cc) 1H-NMR (400 MHz): δ 7.91 (s, 1H), 7.52-7.48 (m, 3H), 7.45-7.42 (m, 2H), 7.36-7.32 (m, 1H), 7.27 (d J = 7.96 Hz, 1H), 6.89-6.85 (m, 1H), 6.55 (d, J = 8.30 Hz, 1H), 6.28 (s, 1H), 4.04 (q, J = 7.07, 7.32 Hz, 2H), 3.92 (s, 3H), 3.71 (s, 6H), 3.45 (s, 1H), 0.986 (t, J = 7.07 Hz, 3H) ppm.

13C {1H}

NMR (100 MHz): δ 168.2, 161.5, 159.3, 142.2, 132.3, 128.7,

128.3, 127.0, 125.5, 122.5, 120.4, 119.2, 108.4, 90.4, 60.2, 55.9, 55.5, 30.3, 13.9 ppm. IR: νmax 2922, 2851, 2351, 1696, 1557, 1365, 1188, 1016, 950 cm-1. HRMS (ESI, Q-TOF) m/z: calcd for C31H29NNaO5 [M+Na]+ 518.1943; found 518.1963. Ethyl 1-(4-(dimethylamino)phenyl)-9-methyl-4-phenyl-9H-carbazole-3-carboxylate (4fc): Reaction time: 60 h, 3fc (0.100 g, 0.31 mmol), LiCl (0.044 g, 1.11 mmol), viscous oil, 0.021 g, yield: 25%, Rf value 0.58 ((acetone/hexane) = 4:10 (v/v). (4fc) 1H-NMR (400 MHz): δ 7.98 (s, 1H), 7.53-7.50 (m, 3H), 7.42-7.36 (m, 5H), 7.31 (d, J = 8.19 Hz, 1H), 6.92-6.83 (m, 3H), 6.58 (d, J = 7.74 Hz, 1H), 4.07 (q, J = 7.70, 7.20 Hz, 2H), 3.47 (s, 3H), 3.06 (s, 6H), 1.01 (t, J = 6.87 Hz, 3H) ppm.

13C

{1H} NMR (100 MHz): δ 168.0, 142.8,

140.8, 130.8, 128.7, 128.4, 127.2, 125.9, 122.6, 119.5, 111.9, 108.8, 60.3, 40.6, 32.8, 13.9 ppm. IR: νmax 2921, 2853, 1734, 1459, 1275, 1077, 972, 742 cm -1. HRMS (ESI, QTOF) m/z: calcd for C30H29N2O2 [M+H]+ 449.2229; found 449.2234.



Ethyl

1-(1-benzyl-1H-indol-3-yl)-9-methyl-4-phenyl-9H-carbazole-3-carboxylate

(4dc): Reaction time: 72 h, 3dc (0.100 g, 0.163 mmol), LiCl (0.041 g, 0.98 mmol), white solid, m.p. 163-165 °C, 0.052 g, yield: 60%, Rf value 0.61 (acetone/hexane) = 4:10 (v/v). (4dc) 1H-NMR (400 MHz): δ 8.08 (s, 1H), 7.56-7.50 (m, 3H), 7.47-7.40 (m, 4H), 7.38-7.27 (m, 7H), 7.23 (m, 2H), 7.13 (m, 1H), 6.91 (m, 1H), 6.61 (d, J = 7.74 Hz, 1H), 5.46 (s, 2H), 4.06 (q, J = 6.79, 7.08 Hz, 2H), 3.45 (s, 3H), 0.991 (t, J = 7.04 Hz, 3H) ppm. 13C {1H} NMR (100 MHz): δ 168.1, 142.7, 140.8, 138.4, 137.4, 136.1, 132.2, 129.0, 128.7, 128.4, 127.9, 127.5, 127.3, 126.9, 125.9, 119.6, 116.7, 114.6, 109.9, 108.8, 60.4, 50.3, 31.6, 13.9 ppm. IR: νmax 2920, 2852, 1711, 1460, 1306, 1060, 892, 738 cm-1. HRMS (ESI, Q-TOF) m/z: calcd for C37H31N2O2 [M+H]+ 535.2386; found 535.2364. Ethyl

9-benzyl-1-(1-benzyl-1H-indol-3-yl)-4-phenyl-9H-carbazole-3-carboxylate

(4de): Reaction time: 72 h, 3de (0.100 g, 0.14 mmol), LiCl (0.036 g, 0.85 mmol), white solid, m.p. 194-197 °C, 0.069 g, yield: 62%, Rf value 0.61 (acetone/hexane) = 4:10 (v/v). (4de) 1H-NMR (400 MHz): δ 8.05 (s, 1H), 7.58-7.53 (m, 3H), 7.49 (m, 2H), 7.42 (d, J = 7.82 Hz, 1H), 7.34-7.27 (m, 3H), 7.25-7.23 (m, 3H), 7.16-7.09 (m, 5H), 7.02-6.98 (m, 2H), 6.91 (m, 1H), 6.80 (s, 1H), 6.63 (m, 3H), 5.25-5.02 (m, 4H), 4.09-4.04 (m, 2H), 1.00 (t, J = 7.26 Hz, 3H) ppm.

13C {1H} NMR

(100 MHz): δ 168.1, 128.4, 127.6, 127.0, 126.8, 126.1,

125.5, 122.7, 123.3, 120.2, 120.1, 109.9, 109.5, 60.4, 50.1, 47.4, 13.9 ppm. IR: νmax 2921, 2853, 1680, 1450, 1256, 1073, 964, 733 cm-1. HRMS (ESI, Q-TOF) m/z: calcd for C43H35N2O2 [M+H]+ 611.2699; found 611.2678. General procedure for hydrolysis of aromatized carbazoles Compound 4 (1equiv.) and KOH (4 equiv.) were dissolved in dry methanol under an inert atmosphere and stirred at 70 °C until consumption of starting material (as monitored by


Page 24 of 35

Page 25 of 35 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


TLC). The reaction mixture was cooled to room temperature and acidified with 1N HCl solution. The aqueous layer was extracted with CH2Cl2, dried with Na2SO4 and evaporated in vacuo. The compound was purified by silica gel coloum chromatography (ethyl acetate/hexane). 9-Benzyl-1-(1-benzyl-1H-indol-3-yl)-4-phenyl-9H-carbazole-3-carboxylic acid (5dc): Reaction time: 3 h, 4dc (0.100 g, 0.187 mmol), KOH (0.041 g, 0.74 mmol), white solid, m.p. 186-188 °C, 0.068 g, yield: 72%, Rf value 0.39 (ethyl acetate/hexane) = 6:10 (v/v). (5dc) 1H-NMR (400 MHz): δ 8.17 (s, 1H), 7.58-7.52 (m, 3H), 7.47-7.40 (m, 4H), 7.387.27 (m, 7H), 7.24 (m, 2H), 7.12 (m, 1H), 6.91 (m, 1H), 6.51 (d, J = 8.17 Hz, 1H), 5.45 (s, 2H), 3.46 (s, 3H) ppm.

13C

{1H} NMR (100 MHz): δ 170.3, 142.7, 139.2, 136.1, 133.0,

129.7, 129.0, 128.6, 128.5, 127.9, 127.6, 127.5, 126.9, 126.0, 126.6, 122.6, 122.5, 119.8, 110.0, 108.9, 50.3, 31.6 ppm. IR: νmax 3022, 2905, 1668, 1555, 1256, 1069, 970, 904, 726 cm-1. HRMS (ESI, Q-TOF) m/z: calcd for C35H27N2O2 [M+H] + 507.2073; found 507.2064. 9-Benzyl-1-(1-benzyl-1H-indol-3-yl)-4-phenyl-9H-carbazole-3-carboxylic acid (5de): Reaction time: 3 h, 4de (0.100 g, 0.16 mmol), KOH (0.103 g, 0.65 mmol), white solid, m.p. 191-194 °C, 0.070 g, yield: 74%, Rf value 0.38 (ethyl acetate/hexane) = 6:10 (v/v). (5de) 1H-NMR (400 MHz): δ 8.14 (s, 1H), 7.57-7.53 (m, 3H), 7.48 (m, 2H), 7.42 (d, J = 7.87 Hz, 1H), 7.34-7.27 (m, 3H), 7.25-7.23 (m, 3H), 7.15-7.09 (m, 5H), 7.01-6.99 (m, 2H), 6.91 (m, 1H), 6.79 (s, 1H), 6.63 (m, 2H), 6.54 (d, J = 7.47 Hz, 1H), 5.28-5.02 (m, 4H) ppm. 13C {1H} NMR (100 MHz): δ 171.0, 133.5, 128.8, 128.6, 128.4, 127.7, 127.6, 127.0, 126.9, 126.2, 125.5, 122.7, 122.4, 120.3, 120.1, 120.0, 119.1, 116.9, 109.9, 109.6, 50.1,



47.4 ppm. IR: νmax 3027, 2961, 2922, 1683, 1452, 1255, 1020, 908, 733 cm-1. HRMS (ESI, Q-TOF) m/z: calcd for C41H31N2O2 [M+H]+ 583.2386; found 583.2367. ASSOCIATED CONTENT Supporting Information Copies of 1H,

13C

NMR spectra, mass data of all new compounds, and single crystal X-

ray data. The supporting information are available free of charge on the Internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]. Notes The authors declare no competing financial interests. ACKNOWLEDGMENT R.K.V. thanks to the University Grants Committee (UGC), New Delhi for a research fellowship. P.B. acknowledges the Department of Science and Technology, New Delhi (Project no. EMR/2015/002332) and the Council of Scientific and Industrial Research (CSIR-India). REFERENCES 1. (a) Kam, T.-S.; Sim, K.-M.; Lim, T.-M. Tronoharine, a Novel Hexacyclic Indole Alkaloid from a Malayan Tabernaemontana. Tetrahedron Lett. 1999, 40, 5409 – 5412. (b) Marco, B.; Astrid, E. Catalytic Functionalization of Indoles in a New Dimension. Angew. Chem. Int. Ed. 2009, 48, 9608–9644. (c) Campbell, N.; Barclay, B. M. Recent Advances in the Chemistry of Carbazole. Chem. Rev. 1947, 40, 359–380. (d) Mobilio, D.; Humber, L. G.;


Page 26 of 35

Page 27 of 35 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


Katz, A. H.; Demerson, C. A.; Hughes, P.; Brigance, R.; Conway, K.; Shah, U.; Williams, G. and. Structure-Activity Relationships among Analogues of Pemedolac, Cis-1-Ethyl1,3,4,9-Tetrahydro-4(Phenylmethyl)

Pyrano[3,4-b]Indole-1-Acetic

Acid,

a

Potent

Analgesic Agent. J. Med. Chem. 1988, 31, 2211–2217. (e) Cai, X.-H.; Du, Z.-Z.; Luo, X.D. Unique Monoterpenoid Indole Alkaloids from Alstonia Scholaris. Org. Lett. 2007, 9, 1817–1820. (f) Liang‐Wen, F.; Hai, R.; Hu, X.; Pan, W.; Lijia, W.; Yong, T. Reaction of Donor‐Acceptor Cyclobutanes with Indoles: A General Protocol for the Formal Total Synthesis of (±)‐Strychnine and the Total Synthesis of (±)‐Akuammicine. Angew. Chem. Int. Ed. 2017, 56, 3055–3058. 2. (a) Knölker, H.-J.; Reddy, K. R. Isolation and Synthesis of Biologically Active Carbazole Alkaloids. Chem. Rev. 2002, 102, 4303–4428. (b) Schmidt, A. W.; Reddy, K. R.; Knölker, H.-J. Occurrence, Biogenesis, and Synthesis of Biologically Active Carbazole Alkaloids. Chem. Rev. 2012, 112, 3193–3328. (c) Kalyan, D.; Tirtha, M.; Joydeb, D.; Jyotirmayee, D. Synthesis of

Carbazole Alkaloids by Ring‐Closing Metathesis and Ring

Rearrangement–Aromatization. Angew. Chem. Int. Ed. 2015, 54, 15831–15835. (d) Wang, Y.-S.; He, H.-P.; Shen, Y.-M.; Hong, X.; Hao, X.-J. Two New Carbazole Alkaloids from Murraya Koenigii. Journal of Natural Products 2003, 66, 416–418. (e) Maneerat, W.; Ritthiwigrom, T.; Cheenpracha, S.; Promgool, T.; Yossathera, K.; Deachathai, S.; Phakhodee, W.; Laphookhieo, S. Bioactive Carbazole Alkaloids from Clausena Wallichii Roots. J. Nat. Prod. 2012, 75, 741–746. 3. (a) Ito, C.; Katsuno, S.; Ruangrungsi, N.; Furukawa, H. Structures of clausamine-A,B,-C, three novel carbazole alkaloids from Clausena anisate. Chem. Pharm. Bull. 1998, 46, 344-346. (b) Ito, C.; Katsuno, S.; Ohta, H.; Omura, M.; Kajiura, I.; Furukawa, H.



Constituents of Clausena Excavata. Isolation and Structural Elucidation of New Carbazole Alkaloids. Chem. Pharm. Bull. 1997, 45, 48–52. (c) Beccalli, E. M.; Clerici, F.; Marchesini, A. A New Synthesis of Furostifoline. Tetrahedron 1998, 54, 11675 – 11682. (d) Bhattacharyya, P.; Chakraborty, A. Mukonal, a Probable Biogenetic Intermediate of Pyranocarbazole Alkaloids from Murraya Koenigii. Phytochemistry 1984, 23, 471 – 472. (e) Wu, T.-S.; Huang, S.-C.; Wu, P.-L.; Lee, K.-H. Structure and Synthesis of Clausenaquinone-a. A Novel Carbazolequinone Alkaloid and Bioactive Principle from Clausena Excavata. Bioorg. & Med. Chem. Lett. 1994, 4, 2395 – 2398. 4. (a) Forke, R.; Jager, A.; Knölker, H.-J. First Total Synthesis of Clausine L and Pityriazole, a Metabolite of the Human Pathogenic Yeast Malassezia Furfur. Org. Biomol. Chem. 2008, 6, 2481–2483. (b) Yu, Q.; Xin‐Xing, W.; Yupeng, Z.; Yongqing, S.; Baoguo, L.; Shufeng, C. Copper‐Catalyzed Successive C−C Bond Formations on Indoles or Pyrrole: A Convergent Synthesis of Symmetric and Unsymmetric Hydroxyl Substituted N‐ H Carbazoles. Adv. Synth. & catal. DOI 10.1002/adsc.201800154. (c) Qiu, Y.; Ma, D.; Fu, C.; Ma, S. An Efficient Au-Catalyzed Synthesis of Isomukonidine, Clausine L, Mukonidine, Glycosinine, Mukonal, and Clausine V from Propadienyl Methyl Ether. Org. Biomol. Chem. 2013, 11, 1666–1671. (d) Gupta, A. K.; Bluhm, R.; Summerbell, R. Pityriasis Versicolor. J. Eur. Acad. Dermatol. Venereol. 2002, 16, 19–33. (e) Irlinger, B.; Bartsch, A.; Krämer, H.-J.; Mayser, P.; Steglich, W. New Tryptophan Metabolites from Cultures of the Lipophilic Yeast Malassezia Furfur. Helv. Chim. Acta. 2005, 88, 1472–1485. (f) Knölker,H.-J.; Reddy, K. R. in ¨The Alkaloids, ed. G. Cordell, Academic Press, Amsterdam, 2008, vol. 65, p. 1. (g) Knölker, H.-J. Occurrence, Biological Activity, and


Page 28 of 35

Page 29 of 35 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


Convergent Organometallic Synthesis of Carbazole Alkaloids Top.Curr. Chem. 2005, 244, 115-148. 5. (a) Reissig, H.-U.; Zimmer, R. Donor−Acceptor-Substituted Cyclopropane Derivatives and Their Application in Organic Synthesis. Chem. Rev. 2003, 103, 1151–1196. (b) Yu, M.; Pagenkopf, B. L. Recent Advances in Donor–acceptor (DA) Cyclopropanes. Tetrahedron 2005, 61, 321 – 347. (c) Rubin, M.; Rubina, M.; Gevorgyan, V. Transition Metal Chemistry of Cyclopropenes and Cyclopropanes. Chem. Rev. 2007, 107, 3117– 3179. (d) De Simone, F.; Waser, J. Cyclization and Cycloaddition Reactions of Cyclopropyl Carbonyls and Imines. Synthesis 2009, 2009, 3353–3374. (e) Carson, C. A.; Kerr, M. A. Heterocycles from Cyclopropanes: Applications in Natural Product Synthesis. Chem. Soc. Rev. 2009, 38, 3051–3060. (f) Ivanova, O. A.; Budynina, E. M.; Chagarovskiy, A. O.; Trushkov, I. V.; Melnikov, M. Y. (3 + 3)-Cyclodimerization of Donor– Acceptor Cyclopropanes. Three Routes to Six-Membered Rings. J. Org. Chem. 2011, 76, 8852–8868. (g) Schneider, T. F.; Kaschel, J.; Werz, D. B. A New Golden Age for Donor–Acceptor Cyclopropanes. Angew. Chem. Int. Ed. 2014, 53, 5504–5523. (h) de Nanteuil, F.; De Simone, F.; Frei, R.; Benfatti, F.; Serrano, E.; Waser, J. Cyclization and Annulation Reactions of Nitrogen-Substituted Cyclopropanes and Cyclobutanes. Chem. Comm. 2014, 50, 10912–10928. (i) Pandey, A. K.; Ghosh, A.; Banerjee, P. Reactivity of Donor‐Acceptor

Cyclopropanes

with

Saturated

and

Unsaturated

Heterocyclic

Compounds. Isr. J. Chem. 2016, 56, 512–521. 6. (a) Brand, C.; Rauch, G.; Zanoni, M.; Dittrich, B.; Werz, D. B. Synthesis of [n,5]Spiroketals by Ring Enlargement of

Donor-Acceptor-Substituted Cyclopropane

Derivatives. J. Org. Chem. 2009, 74, 8779–8786. (b) Schneider, T. F.; Kaschel, J.;



Page 30 of 35

Dittrich, B.; Werz, D. B. Anti-Oligoannelated THF Moieties: Synthesis via Push−PullSubstituted Cyclopropanes. Org. Lett. 2009, 11, 2317–2320. (c) Schmidt, C. D.; Kaschel, J.; Schneider, T. F.; Kratzert, D.; Stalke, D.; Werz, D. B. Donor-Substituted Nitrocyclopropanes: Immediate Ring-Enlargement to Cyclic Nitronates. Org. Lett. 2013, 15, 6098–6101. (d) Lücht A. ; Patalag, L. J.; Augustin, A. U.; Jones, P. G.; Werz, D. B Reactions of Donor–Acceptor Cyclopropanes with Naphthoquinones: Redox and Lewis Acid Catalysis Working in Concert. Angew. Chem. Int. Ed. 2017, 56, 10587–10591. 7. (a) Ivanova, O. A.; Budynina, E. M.; Chagarovskiy, A. O.; Rakhmankulov, E. R.; Trushkov, I. V.; Semeykin, A. V.; Shimanovskii, N. L.; Melnikov, M. Y. Domino Cyclodimerization

of

Indole-Derived

Donor–Acceptor

Cyclopropanes:

One-Step

Construction of the Pentaleno[1,6-a,b]Indole Skeleton. Chem. Eur. J. 2011, 11738– 11742. (b) Korotkov, V. S.; Larionov, O. V.; Hofmeister, A.; Magull, J.; de Meijere, A. GaCl3-Catalyzed Insertion of Diazene Derivatives into the Cyclopropane Ring. J. Org. Chem. 2007, 72, 7504–7510. (c) Zhu, W.; Fang, J.; Liu, Y.; Ren, J.; Wang, Z. Lewis Acid Catalyzed Formal Intramolecular [3+2] Cross-Cycloaddition of Cyclopropane 1,1-Diesters with Alkenes: General and Efficient Strategy for Construction of Bridged [n.2.1] Carbocyclic Skeletons. Angew. Chem., Int. Ed. 2013, 52, 2032–2037. (d) Racine, S.; de Nanteuil, F.; Serrano, E.; Waser, J. Synthesis of (Carbo) Nucleoside Analogues by [3+2] Annulation of Aminocyclopropanes. Angew. Chem. Int. Ed. 2014, 53, 8484–8487. (e) Chakrabarty, S.; Chatterjee, I.; Wibbeling, B.; Daniliuc, C. G.; Studer, A. Stereospecific Formal [3+2] Dipolar Cycloaddition of Cyclopropanes with Nitrosoarenes: An Approach to Isoxazolidines. Angew. Chem. Int. Ed. 2014, 53, 5964–5968. (f) Racine, S.; Hegedüs, B.; Scopelliti, R.; Waser, J. Divergent Reactivity of Thioalkynes in Lewis Acid Catalyzed


Page 31 of 35 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


Annulations with Donor–Acceptor Cyclopropanes. Chem. Eur. J. 2016, 22, 11997–12001. (g) Sabbatani, J.; Maulide, N. Temporary Generation of a Cyclopropyl Oxocarbenium Ion Enables Highly Diastereoselective Donor–Acceptor Cyclopropane Cycloaddition. Angew. Chem. Int. Ed. 2016, 55, 6780–6783. (8) (a) Young, I . S.; Kerr, M. A. Homo [3+2] Dipolar Cycloaddition: The Reaction of Nitrones with Cyclopropanes. Angew. Chem. Int. Ed. 2003, 115, 3131–3134. (b) Sanders, S. D.; Ruiz-Olalla, A.; Johnson, J. S. Total Synthesis of (+)-VirgatusinviaAlCl3-Catalyzed [3+2] Cycloaddition. Chem. Commun. 2009, 34, 5135–5137. (c) Parsons, A. T.; Campbell, M. J.; Johnson, J. S. Diastereoselective Synthesis of Tetrahydrofurans via Palladium (0)-Catalyzed [3 + 2] Cycloaddition of Vinylcyclopropanes and Aldehydes. Org. Lett. 2008, 10, 2541–2544. (d) Smith, A. G.; Slade, M. C.; Johnson, J. S. Cyclopropane−Aldehyde Annulations at Quaternary Donor Sites: Stereoselective Access to Highly Substituted Tetrahydrofurans. Org. Lett. 2011, 13, 1996–1999. (e) Zhu, W.; Fang, J.; Liu, Y.; Ren, J.; Wang, Z. Lewis Acid Catalyzed Formal Intramolecular [3+2] Cross-Cycloaddition of Cyclopropane 1,1-Diesters with Alkenes: General and Efficient Strategy for Construction of Bridged [n.2.1] Carbocyclic Skeletons. Angew. Chem. Int. 2013, 52, 2032–2037. (f) Augustin, A. U.; Sensse, M.; Jones, P. G.; Werz, D. B. Stereospecific Reactions of Donor–Acceptor Cyclopropanes with Thioketones: Access to Highly Substituted Tetrahydrothiophenes. Angew. Chem. Int. Ed. 2017, 56, 14293– 14296. (g) Lücht, A.; Patalag, L. J.; Augustin, A. U.; Jones, P. G.; Werz, D. B. Reactions of Donor–Acceptor Cyclopropanes with Naphthoquinones: Redox and Lewis Acid Catalysis Working in Concert. Angew. Chem. Int. Ed. 2017, 56, 10587–10591.



Page 32 of 35

9. (a) Ghosh, A.; Pandey, A. K.; Banerjee, P. Lewis Acid Catalyzed Annulation of Donor– Acceptor Cyclopropane and N-Tosylaziridinedicarboxylate: One-Step Synthesis of Functionalized 2H-Furo[2,3-c]Pyrroles. J. Org. Chem. 2015, 80, 7235–7242. (b) Pandey, A.

K.;

Ghosh,

A.;

Banerjee,

P.

Lewis-Acid-Catalysed

Tandem

Meinwald

Rearrangement/Intermolecular [3+2]-Cycloaddition of Epoxides with Donor–Acceptor Cyclopropanes: Synthesis of Functionalized Tetrahydrofurans. Eur. J. Org. Chem. 2015, 2517–2523. (c) Varshnaya, R. K.; Banerjee, P. Construction of Isoxazolidines through Formal [3+2] Cycloaddition Reactions of in Situ Generated Nitrosocarbonyls with Donor– Acceptor Cyclopropanes: Synthesis of α-Amino γ-Butyrolactones. Eur. J. Org. Chem. 2016, 4059–4066. (d) Verma, K.; Banerjee, P. Lewis Acid-Catalyzed [3+2] Cycloaddition of Donor-Acceptor Cyclopropanes and Enamines: Enantioselective Synthesis of Nitrogen-Functionalized Cyclopentane Derivatives Adv. Synth. & Catal. 2016, 358, 2053– 2058. (e) Ghosh, A.; Mandal, S.; Chattaraj, P. K.; Banerjee, P. Ring Expansion of Donor– Acceptor Cyclopropane via Substituent Controlled Selective N-Transfer of Oxaziridine: Synthetic and Mechanistic Insights. Org. Lett. 2016, 18, 4940–4943. (f) Verma, K.; Banerjee, P. Lewis Acid Catalyzed Formal [3+2] Cycloaddition of Donor-Acceptor Cyclopropanes and 1-Azadienes: Synthesis of Imine Functionalized Cyclopentanes and Pyrrolidine Derivatives. Adv. Synth. & catal. 2017, 359, 3848–3854. (g) Dey, R.; Banerjee, P. Lewis Acid Catalyzed Diastereoselective Cycloaddition Reactions of Donor–Acceptor Cyclopropanes and Vinyl Azides: Synthesis of Functionalized Azidocyclopentane and Tetrahydropyridine Derivatives. Org. Lett. 2017, 19, 304–307.


Page 33 of 35 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


10. Grover, H. K.; Lebold, T. P.; Kerr, M. A. Tandem Cyclopropane Ring-Opening/ConiaEne Reactions of 2-Alkynyl Indoles: A [3 + 3] Annulative Route to Tetrahydrocarbazoles. Org. Lett. 2011, 13, 220–223. 11. Liu, Q.-J.; Yan, W.-G.; Wang, L.; Zhang, X. P.; Tang, Y. One-Pot Catalytic Asymmetric Synthesis of Tetrahydrocarbazoles. Org. Lett. 2015, 17, 4014–4017. 12. (a) Chagarovskiy, A. O.; Ivanova, O. A.; Rakhmankulov, E. R.; Budynina, E. M.; Trushkov, I. V.; Melnikov, M. Y. Lewis Acid-Catalyzed Isomerization of 2Arylcyclopropane-1,1-Dicarboxylates: A New Efficient Route to 2-Styrylmalonates. Adv. Synth. & catal. 2010, 352, 3179–3184. (b) Zhu, M.; Liu, J.; Yu, J.; Chen, L.; Zhang, C.; Wang, L. AlCl3-Promoted Formal [2 + 3]-Cycloaddition of 1,1-Cyclopropane Diesters with N-Benzylic Sulfonamides To Construct Highly Stereoselective Indane Derivatives. Org. Lett. 2014, 16, 1856–1859. 13. CCDC1825186 contains the supplementary crystallographic data of this

paper.

These data can be obtained free of charge from The Cam-bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. 14. (a) Harrison, C.-A.; Leineweber, R.; Moody, C. J.; Williams, J. M. J. Cyclopenta[b]Indoles. Part 1. Synthesis of Cyclopenta[b]Indoles by Formal [3 + 2] Addition of Indolylmethyl Cations to Alkenes. J. Chem. Soc., Perkin Trans. 1 1995, No. 9, 1127–1130. (b) Ganosan, A.; Heathcock, C. H. A Stereochemical Test of the Mechanism of Electrophilic Substitution in 3-Substituted Indoles. Tetrahedron Lett. 1993, 34, 439– 440. (c) Liu, J.; Wang, L.; Wang, X.; Xu, L.; Hao, Z.; Xiao, J. Fluorinated Alcohol-Mediated [4 + 3] Cycloaddition Reaction of Indolyl Alcohols with Cyclopentadiene. Org. Biomol.



Page 34 of 35

Chem. 2016, 14, 11510–11517.(d) Mari, M.; Lucarini, S.; Bartoccini, F.; Piersanti, G.; Spadoni, G. Synthesis of 2-Substituted Tryptophans via a C3- to C2-Alkyl Migration. Beilstein J. Org. Chem. 2014, 10, 1991–1998. 15. (a) Fakhari M., A.; Rokita, S. E. A New Solvatochromic Fluorophore for Exploring Nonpolar Environments Created by Biopolymers. Chem. Comm. 2011, 47, 4222–4224. (b) Benedetti, E.; Kocsis, L. S.; Brummond, K. M. Synthesis and Photophysical Properties of a Series of Cyclopenta[b] Naphthalene Solvatochromic Fluorophores. J. Am. Chem. Soc. 2012,134, 12418–12421. 16. (a) Corey, E. J.; Chaykovsky, M. Dimethyloxosulfonium Methylide ((CH3)2SOCH2) and Dimethylsulfonium Methylide ((CH3)2SCH2). Formation and Application to Organic Synthesis. J. Am. Chem. Soc. 1965, 87, 1353–1364. (b) Fraser, W.; Suckling, C. J.; Wood, H. C. S. Latent Inhibitors. Part 7. Inhibition of Dihydro-Orotate Dehydrogenase by Spirocyclopropanobarbiturates. J. Chem. Soc., Perkin Trans. 1 1990, No. 11, 3137–3144. (c) Goldberg, A. F. G.; O’Connor, N. R.; Craig, R. A.; Stoltz, B. M. Lewis Acid Mediated (3 + 2) Cycloadditions of Donor–Acceptor Cyclopropanes with Heterocumulenes. Org. Lett. 2012, 14, 5314–5317. (d) He, X.; Qiu, G.; Yang, J.; Xiao, Y.; Wu, Z.; Qiu, G.; Hu, X. Synthesis

and

Anticonvulsant

Activity

of

New

6-Methyl-1-Substituted-4,6-

Diazaspiro[2.4]Heptane-5,7-Diones. Eur. J. Med. Chem.

2010, 45, 3818—3830. (e)

Talukdar, R.; Tiwari, D. P.; Saha, A.; Ghorai, M. K. Diastereoselective Synthesis of Functionalized Tetrahydrocarbazoles via a Domino-Ring Opening–Cyclization of Donor– Acceptor Cyclopropanes with Substituted 2-Vinylindoles. Org. Lett. 2014, 16, 3954–3957. (f) Appel, R.; Hartmann, N.; Mayr, H. Scope and Limitations of Cyclopropanations with Sulfur Ylides. J. Am. Chem. Soc. 2010, 132, 17894–17900. (g) S. Christie, D. R.; Davoile,


Page 35 of 35 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


R. J.; Elsegood, M. R. J.; Fryatt, R.; Jones, R. C. F.; Pritchard, G. J. Novel formation and use of a Nicholas carbocation in the synthesis of highly substituted tetrahydrofurans Chem. Comm. 2004, 2474–2475. 17. Elayaraja, R.; Karunakaran, R. J. Cesium Carbonate Mediated Synthesis of 3-(αHydroxyaryl)Indoles. Tetrahedron Lett. 2012, 53, 6901–6904. 18. Downey, C. W.; Poff, C. D.; Nizinski, A. N. Friedel–Crafts Hydroxyalkylation of Indoles Mediated by Trimethylsilyl Trifluoromethanesulfonate J. Org. Chem. 2015, 80, 10364– 10369.


Lewis Acid-Catalyzed [3+3] Annulation of DonorâAcceptor

Recommend Documents

Lewis Acid-Catalyzed [3+3] Annulation of DonorâAcceptor