Annulation of a Highly Functionalized Diazo Building Block with

Subscriber access provided by University of Sunderland

Article

Annulation of a Highly Functionalized Diazo Building Block with Indoles Under Sc(OTf)3/Rh2(OAc)4 Multicatalysis Through Michael Addition/Cyclization Sequence Shanmugam Sakthivel, and Rengarajan Balamurugan J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02127 • Publication Date (Web): 04 Sep 2018 Downloaded from http://pubs.acs.org on September 5, 2018

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 37 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

Annulation of a Highly Functionalized Diazo building block with Indoles Under Sc(OTf)3/Rh2(OAc)4 Multicatalysis Through Michael Addition/Cyclization Sequence. Shanmugam Sakthivel and Rengarajan Balamurugan* School of Chemistry, University of Hyderabad, Gachibowli, Hyderabad – 500046, INDIA

ABSTRACT: A highly functionalized and easily accessible 6-carbon diazo building block has been developed and utilized as a 1,4-diacceptor for an efficient synthesis of functionalized tetrahydrocarbazoles, carbazoles, tetrahydropyrido[1,2-a]indoles. The synthesis involves concurrent tandem catalysis by Sc(OTf)3 and Rh2(OAc)4. The role of Sc(OTf)3 is critical as it facilitates both the initial intermolecular Michael reaction of indole and the subsequent Rh(II)-catalyzed intramolecular annulation. The products tetrahydrocarbazoles and tetrahydropyridoindoles are equipped with a

β-ketoester and an ester functionalities which can be utilized for further synthetic elaborations. KEYWORDS: carbazole; tetrahydropyridoindole; annulation; multicatalysis; indole.

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

INTRODUCTION: α-Diazo carbonyl compounds are highly useful compounds having diverse reactivities and potential synthetic utilities.1 Diazo compounds find applications in chemical biology as well these days.2 Easy generation of reactive intermediates such as carbenes, carbenoids, and ylides are viable with diazo compounds. The advent of new methods for their generation, regiochemistry of their reactions and new catalysts to tune their reactivities, keep the field vibrant over the last three decades. Having attained such an advancement in the field of organic synthesis, development of functionalized diazo compounds is obviously a demanding aspect as quite complex structures could be accessed at ease using them. There are a few prominent diazo building blocks such as enoldiazoacetate, vinyldiazoacetate, diazoenal and α,β−unsaturated diazocarbonyl compound which show potential applications.3 Despite their widespread applications, their usage in tandem one pot reactions is limited.3,4 Mainly C-H functionalization/nucleophilic attack followed by Cope rearrangement has been used. Synthesis of some of the functionalized diazo carbonyl compounds involve multistep processes and, in some cases, is difficult to make such as α,β−unsaturated diazoketones.3j Further, individual diazo precursors have to be made to make products with different substitutions. Herein, we report an easily accessible 6-carbon diazo building block 1 which has a range of functionalities with different reactivities (Figure 1). To elaborate, it has two different ester functionalities, a β-keto ester moiety, a diazo moiety, Michael acceptor, trans-dienophile. Hence this building block can be utilized in tandem reactions to form cyclic compounds by making use of the rich functionalities it has. After cyclization, once incorporated as rings, the product will still possess functional groups which could be used in subsequent synthetic elaborations. More importantly, this building block could be synthesized in multigram quantities starting from ethyl propiolate in 72% overall yield in three steps.5 Also, it is quite stable and can be stored for months.


Page 2 of 37

Page 3 of 37 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


Figure 1. 6-carbon diazo building block.

Scheme 1. One-pot annulation of diazo building block with indoles

RESULTS AND DISCUSSION: In this manuscript, we present one possibility of utilization of the 6-carbon diazo building block 1 by making use of Michael reaction on the double bond followed by annulation using the diazo carbon (Scheme 1). This way the building block can act either as a 1,4- or a 1,3-diacceptor unit. Indole, being a good substrate in Michael additions,6 was subjected to reaction with the building block 1 under Lewis acidic conditions followed by rhodium-catalyzed cyclization via annulation. Among the catalysts attempted for this two-step one-pot protocol 1 mol% Sc(OTf)3/2 mol% Rh2(OAc)4 resulted the tetrahydrocarbazole 3 in 80% yield along with less than 2% of the corresponding aromatized product (Table 1, entry 16). The product 3a existed in its enolic form exclusively. Catalyst Sc(OTf)3 was added to the reaction mixture first to effect the Michael reaction. After completion of the Michael addition, Rh2(OAc)4 was added to the reaction mixture to effect the cyclization. Although the substrate 1 has two sites for Michael reaction, indole added exclusively at the carbon β-to the keto group through its 3rd position. While a complex product mixture was obtained when the reaction was attempted with Rh2(OAc)4 alone, Michael adduct 5 was the sole product even after 5 h when Sc(OTf)3 was used (Table 1, entries 1 and 11).



Page 4 of 37

Table 1. Optimization for direct annulation of diazo building block 1 with indolea

time yield (%) (3a:4a)b

entry

catalyst (mol %)

solvent

Michael addition/ annulation

1

Rh2(OAc)4 (2)

(CH2)2Cl2

1h

−c

2

Cu(OTf)2 (5)/Rh2(OAc)4 (2)

(CH2)2Cl2

23 h/1 h

trace

3

AgOTf (5)/Rh2(OAc)4 (2)

(CH2)2Cl2

23 h/1 h

−c

4

Sc(OTf)3 (5)/Rh2(OAc)4 (2)

(CH2)2Cl2

30 min/2 h 30 min

57 (98:2)

5

In(OTf)3 (5)/Rh2(OAc)4 (2)

(CH2)2Cl2

6 h/18 h

44 (95:5)

6

Bi(OTf)3 (5)/Rh2(OAc)4 (2)

(CH2)2Cl2

24 h/2 h

--c

7

Ln(OTf)3 (5)/Rh2(OAc)4 (2)

(CH2)2Cl2

24 h/2 h

--c

8

Yb(OTf)3 (5)/Rh2(OAc)4 (2)

(CH2)2Cl2

24 h/2 h

--c

9

Binol phosphoric acid (5)

(CH2)2Cl2

33 h

d

10

CSA (5)

(CH2)2Cl2

20 h/4 h

--c

11

Sc(OTf)3 (5)

(CH2)2Cl2

30 min/4h 30 min

e

12

Sc(OTf)3 (2)/Rh2(OAc)4 (2)

(CH2)2Cl2

45 min/6 h 15 min

70 (98:2)

13

Sc(OTf)3 (2)/Rh2(OAc)4 (2)

CH2Cl2

45 min/7 h 15 min

79 (97:3)

14

Sc(OTf)3 (2)/Rh2(OAc)4 (2)

Toluene

24 h/2 h

18 (96:4)

15

Sc(OTf)3 (2)/Rh2(OAc)4 (2)

CHCl3

1 h/23 h

63 (97:3)

16

Sc(OTf)3 (1)/Rh2(OAc)4 (2)

CH2Cl2

1 h/16 h

80 (98:2)


Page 5 of 37 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


17

Sc(OTf)3 (1)/Rh2(oct)4 (2)

CH2Cl2

1 h/9 h

72 (97:3)

18

Sc(OTf)3 (1)/Rh2(TFA)4 (2)

CH2Cl2

1 h/18 h

23(98:2)

19

Sc(OTf)3 (1)/Rh2(esp)2 (2)

CH2Cl2

1 h/4 h

66 (98:2)

20

Sc(OTf)3 (1)/Rh2(hfb)4 (2)

CH2Cl2

1 h/21 h

41 (97:3)

a

Reaction condition: 1 (0.21 mmol), 2a (0.21 mmol), Lewis acid (1-5 mol%), Rh(II) salt (2 mol%), solvent (1.5 ml), room temperature. bcalculated based on 1H NMR spectra of the product, ccomplex reaction mixture, disolated 6% of Michael addition product. eisolated 92% of Michael addition product.

In order to check whether Sc(OTf)3 has played any role in the Rh-catalyzed annulation step, the Michael adduct 5a was prepared separately and treated with different Rh catalysts. Surprisingly, except Rh2(Oct)4 no other rhodium catalyst including Rh2(OAc)4 resulted the expected carbazole product in an appreciable amount even at reflux (Table 2, entries 1-3). The worst thing is that the reaction resulted in a complex mixture of products. Whereas, interestingly, the substrate 5a in the presence of Sc(OTf)3 and Rh2(OAc)4 combination in DCE at room temperature resulted in smooth conversion into 3a indicating a certain role of Sc(OTf)3 in the formation of carbazole product (Table 2, entries 5, 9 and 17). Recently, it has been reported that Lewis/Brønsted acids to promote the reactions of Rh-azavinylcarbene intermediates.7 To the best of our knowledge, facilitation of Rh-carbenoid generated from α-diazocarbonyl compounds in annulation reactions has not been reported so far. Perhaps, the Lewis acid increases the reactivity of the rhodium carbenoid by complexing to the β-keto ester moiety. The above statement was evaluated with the annulation reaction already reported by Doyle and co-workers.9b It was reported that the reaction took 16 h at 40 °C by using Rh2(oct)4 alone as the catalyst. When we carried out the same reaction using 1 mol% of Sc(OTf)3 and 2 mol% of Rh2(OAc)4 catalyst system it completed in 11 h at room temperature itself resulting the product in 60% yield. It has to be noted that the reaction resulted in a trace amount of the product after 24 h of reflux in CH2Cl2 in the presence of 2 mol% of Rh2(OAc)4 catalyst alone. Further, 30% of the starting material was recovered back. Hence it is believed that there is a dual activation by Rh2(OAc)4 and Sc(OTf)3 catalysts during annulation step. It has to be mentioned that other Lewis acids such as Cu(OTf)2, In(OTf)3 and Ln(OTf)3 also assisted the Rh-catalyzed annulation; but slightly less effective than Sc(OTf)3 (Table 2, entries 10, 11, 13, 14 and 16). Intermolecular carbenoid insertion on indole’s C-2/C-3



Page 6 of 37

carbons are known for the preparation of substituted indoles.8 However, there are a very few reports on making carbazoles that utilize the annulation of rhodium-carbenoid on indole. Both inter and intramolcular annulations have been utilized.9 Our approach has its own advantage as the product is equipped with a β-keto ester and an ester moieties which can be utilized for later stage functionalization using classical carbanion chemistry. Table 2. Intramolecular annulation of indolyl α-diazo acetate 5aa

yield (%)

entry

catalyst (mol %)

solvent

1

Rh2(OAc)4 (2)

(CH2)2Cl2

reflux

24

trace

2

Rh2(esp)4 (2)

(CH2)2Cl2

reflux

3

--c

3

Rh2(Oct)4 (2)

(CH2)2Cl2

reflux

3

15 (98:2)

4

Sc(OTf)3 (5)

(CH2)2Cl2

reflux

7

NR

5

Sc(OTf)3 (5)/Rh2(OAc)4 (2)

(CH2)2Cl2

reflux

1

72 (98:2)

6

Rh2(OAc)4 (2)

CH2Cl2

reflux

24

--c

7

SiO2

CH2Cl2

reflux

24

NR

8

Cu(OTf)2 (10)

CHCl3

reflux

2

trace

9

Sc(OTf)3 (5)/Rh2(OAc)4 (2)

(CH2)2Cl2

rt

2

78 (trace)

10

Cu(OTf)2 (5)/Rh2(OAc)4 (2)

(CH2)2Cl2

rt

6

43 (37:63)

11

Bi(OTf)3 (5)/Rh2(OAc)4 (2)

(CH2)2Cl2

rt

23

63 (95:5)

12

Cu(OAc)2 (5)/Rh2(OAc)4 (2)

(CH2)2Cl2

rt

24

NR

13

In(OTf)3 (5)/Rh2(OAc)4 (2)

(CH2)2Cl2

rt

4

71 (96:4)

14

Ln(OTf)3 (5)/Rh2(OAc)4 (2)

(CH2)2Cl2

rt

22

69 (92:8)

15

AgOTf (5)/Rh2(OAc)4 (2)

(CH2)2Cl2

rt

24

NR

16

Yb(OTf)3 (5)/Rh2(OAc)4 (2)

(CH2)2Cl2

rt

4

61 (95:5)

17

Sc(OTf)3 (1)/Rh2(OAc)4 (2)

(CH2)2Cl2

rt

5

79 (99:1)

temp (˚C) T (h)

a

(3a:4a)b

Reaction condition: 5a (0.14 mmol), Lewis acid (1-5 mol%), Rh(II) salt (2 mol%), solvent (1.5 mL). bcalculated based on 1H NMR signals, ccomplex mixture, NR no


Page 7 of 37 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


reaction

A wide range of indoles having substituents with different electronic effects at different positions on the phenyl ring were subjected to direct one-pot annulation with functionalized diazo compound 1 using the condition mentioned in entry 16 of table 1. These starting indoles are either commercially available or easily obtainable via trivial synthetic protocols.10 Indoles with substituents such as cyano, ester, fluoro, bromo, chloro, methyl, methoxy, benzyloxy underwent one-pot sequential Sc(OTf)3/Rh2(OAc)4 catalyzed Michael addition/annulation to give corresponding tetrahydrocarbazole products (Figure 2). Protection of indole nitrogen is not required. In all the cases, except with the substrate having CN group, the yields were moderate to good. Indoles with CN, CO2Me and 4-Cl required more time for the initial Sc(OTf)3-catalyzed Michael reaction. Notably, 5-CN and 4-Cl substituted indoles required 5 mol% of Sc(OTf)3 in order to complete the Michael reaction in a reasonable time. However, the other substrates took less than 1 to 10 h for the Michael reactions with 1 mol% of Sc(OTf)3 (Figure 2). In most of the cases some amount of aromatized products were also obtained which is inseparable from the actual tetrahydrocarbazole product. The extend of aromatization was noticed up to 10% for the substrates which required longer reaction time for annulation reactions (Figure 2, products 3d, 3f and 3m). 5-Carbomethoxy indole took less time for both Michael and annulation reactions when the amount of Sc(OTf)3 was enhanced to 5 mol% (Figure 2, product 3e). N-Substituted indoles resulted in the expected products in moderate yields and interestingly the obtained products existed in their keto forms as a mixture of diastereomers mostly along with small amounts of the corresponding enol forms (Figure 2, products 3r-3t).




Page 8 of 37

Page 9 of 37 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


Figure 2. Substrate scope. aratio of tetrahydrocarbazole and carbazole from 1H NMR signals. b

reaction time for Michael reaction. creaction time for annulation. d keto/enol ratio from 1H NMR

spectra. ediastereomeric ratio of the keto form. It was observed that the tertahydrocarbazole derivative 3a in the presence of 2 equiv. of triethyl amine in dichloromethane in open air at room temperature resulted in the formation of carbazole derivative 4a (Scheme 2).

Since carbazoles are important class of biologically active

heterocyclic compounds and their functionalized derivatives find applications as optical materials

we

pursued

the

aromatization

of

the

tetrahydrocarbazoles.11

Selected

tetrahydrocarbazole derivatives were subjected to treatment with trimethylamine under open atmosphere to get their corresponding carbazole derivatives (4a, 4c, 4h, 4j, 4l-n, 4p-q) in good yields (Scheme 2). Scheme 2. Aromatization of tetrahydrocarbazoles



In fact the annulation and aromatization can be carried out in one-pot by adding 2 equivalents of trimethylamine to the reaction flask after the completion of the Michael and annulation reactions (Scheme 3). Scheme 3. One-pot direct benzannulation of indole to carbazole

The aromatization strategy of tetrahydrocarbazoles can be extended to an interesting class of compounds containing indole fused anthrananilic acids. Anthranilic acid and their derivatives have been found to display a wide spectrum of biological activities.12 To mention few, mefenamic acid, tranilast, etofenamate and furosemide are some of the commercially drugs available in the market having anthranilic acid in their structures. Treatment of compound 3a with a primary amine in the presence of Yb(OTf)3 catalyst resulted in the corresponding derivatives of anthranilic acid fused indole 6b and 6c (Scheme 4). On the other hand, reaction of 3a with ammonium acetate in acetic acid gave the aminocarbazole 6a along with 4a. It is believed that the synthesized indole anthranilic acid hybrid scaffold13 is expected to possess some interesting bioactivities. Moreover, these aminocarbazoles are fluorescent as well. It is known that aminocarbazoles find extensive application in material chemistry.14 Scheme 4. Synthesis of anthranilic acid fused indoles

The 1,3-dicarbonyl incorporated in the product provides an opportunity for the regioselective functionalization. To demonstrate this alkylation was attempted on 3a. This compound


Page 10 of 37

Page 11 of 37 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


underwent smooth C-alkylation at the active methylene carbon using K2CO3 base and alkylating agents (Scheme 5).

Scheme 5. Alkylation of tetrahydrocarbazole 3a.

Fischer indole synthesis was attempted on compounds 3a and 7a with phenylhydrazine in DMU:L-tartaric acid eutectic mixture.15 While 3a resulted in the corresponding indolo[2,3b]carbazole 8a, compound 7a resulted in a diastereomeric mixture of fused tetracyclic compounds 9a and 9b (Scheme 6). The indolo[2,3-b]carbazole derivatives are important class of compounds having applications in treating different type of cancers (SR13668), and viral infections (RSV and HCMV).16 They find applications in DSSC as dyes as well.17 Scheme 6. Synthesis of indolo, pyrazolo[4,3-a]carbazoles.



We then pursued the reactions of the building block 1 with 3-substituted indoles to make the 2nd position of the indole to take part in the initial Michael reaction. Interestingly this reaction underwent smooth Michael addition through the 2nd position followed by insertion on N-H bond of the indole to generate tetrahydropyridoindoles (Scheme 7). Indole alkaloids with tetrahydropyrido[1,2-a]indole core such as goniomitine, vinpocetine, vincamine etc. display interesting bioactivities.18 Scheme 7. Synthesis of tetrahydropyrido[1,2-a]indole

CONCLUSION In conclusion, we have developed a highly functionalized diazo building block and demonstrated its utility to make functionalized tetrahydrocarbazoles, carbozoles and tetrahydropyrido[1,2a]indole. The functionalities present in the cyclized product could be advantageously used in further synthetic manipulations. Involvement of the catalyst Sc(OTf)3 in both the steps i.e., Michael addition of indole on the building block and subsequent Rh-catalyzed annulation favors a concurrent tandem catalysis mechanism. Exploration of synthetic possibilities such as asymmetric Michael reaction using different nucleophiles followed by annulation sequence and


Page 12 of 37

Page 13 of 37 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


other tandem processes like Diels-Alder/annulation using this 6-carbon diazo building block is currently being pursued in our lab.

EXPERIMENTAL SECTION

General information: Chemicals and solvents were obtained from various commercial sources. Starting materials were prepared by following known literature procedures. THF and toluene were dried over sodium and freshly distilled before use. Dichloromethane and dichloroethane were dried over CaH2 and freshly distilled before use. 1H and 13C spectra were recorded on 400 and 500 MHz spectrometers using solution in CDCl3 with tetramethylsilane (TMS) as an internal standard. IR spectra were recorded using a FT-IR spectrometer. High-resolution mass spectra (HRMS) were recorded using ESI-Q-TOF technique. Melting points were determined by using a melting range apparatus and are uncorrected. For TLC, silica gel plates 60 F254 were used and compounds were visualized by UV light and/or by treatment with Seebach solution (phosphomolybdic acid (2.5 g), Ce(SO4)2 (1 g), Conc. H2SO4 (6 mL) and H2O (94 mL)) followed by heating. Column chromatography was performed on silica gel (100-200 mesh) using ethyl acetate and hexanes mixture as eluent.

Procedure for the synthesis of (E)-diethyl 5-diazo-4-oxohex-2-enedioate 1 To the solution of (E)-diethyl 4-oxohex-2-enedioate5b (1.6 g, 7.47 mmol) and p-toluene sulfonyl azide19 (1.36 g, 7.47 mmol) in dry CH2Cl2 (30 mL, 4 mL/mmol) at 0 ˚C, triethyl amine (1.2 mL, 8.96 mmol) was added dropwise. The reaction temperature was brought to room temperature slowly and maintained at the same temperature for 5 h. After completion of the reaction as monitored by TLC, the reaction mass was evaporated under reduced pressure at room temperature. The obtained crude was purified by column chromatography using a mixture of 10 % ethyl acetate in hexanes. Yield (1.53 g, 85%); light yellow liquid; Rf = 0.35 in 1:10



EtOAc/hexanes; 1H NMR (400 MHz, CDCl3): δ 8.08 (d, J = 15.6 Hz, 1H), 6.85 (d, J = 15.6 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 4.3 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H), 1.33 (t, J = 7.1 Hz, 3H);

13

C{1H} NMR (100 MHz, CDCl3) : δ 180.8, 165.2, 160.7, 135.8, 131.1, 78.2, 62.0,

61.3, 14.3, 14.2; IR (neat, cm-1): υ 3370, 3266, 2975, 2142, 1715, 1643, 1298, 1163, 811; HRMS (ESI-Q-TOF) m/z calcd for C10H12N2NaO5+ (M + Na)+ 263.0638, found 263.0643.

Indoles 2a-2i were purchased from commercially available source and used as such. Indoles 2jl,10a,b 2m-2o,10c,d 2p-2q10e,f and 2r-2t10g,h,i were prepared by following the literature procedure. General procedure for the synthesis of diethyl 2-hydroxy-4,9-dihydro-3H-carbazole-1,4dicarboxylate 3a To a solution of (E)-diethyl 5-diazo-4-oxohex-2-enedioate (1) (100 mg, 0.42 mmol ) and indole (2a) (48.8 mg, 0.42 mmol) in dry CH2Cl2, (3 mL, 7 mL/mmol) Sc(OTf)3 (2.0 mg, 0.004 mmol) was added at room temperature and maintained till the completion starting material 1, then Rh2(OAc)4 (3.7 mg, 0.008 mmol) was added. After completion of the reaction, solvent was removed under reduced pressure and the product was isolated by column chromatography using 12% ethyl acetate in hexanes. Yield (110 mg, 80%); Yellow solid; m.p. = 86-87 ℃; Rf = 0.56 in 1:3 EtOAc/hexanes; 1H NMR (400 MHz, CDCl3): δ 13.03 (br s, 1H), 8.86 (br s, 1H), 7.59-7.57 (m, 1H), 7.34-7.32 (m, 1H), 7.16-7.10 (m, 2H), 4.51-4.45 (m, 2H), 4.22-4.03 (m, 3H), 3.13 (dd, J = 17.5, 3.3 Hz, 1H), 3.06 (dd, J = 17.6, 8.4 Hz, 1H), 1.49 (t, J = 7.2 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 177.0, 172.9, 169.4, 135.7, 130.4, 126.3, 120.7, 120.1, 118.0, 110.8, 99.8, 94.4, 61.5, 61.0, 36.0, 32.4, 14.6, 14.2; IR (KBr, cm-1): υ 3468, 2982, 2899, 1722, 1645, 1593, 1448, 1221, 1076; HRMS (ESI-Q-TOF) m/z calcd for C18H20NO5 (M + H)+ 330.1336, found 330.1340. The above procedure was followed for the synthesis of other tetrahydrocarbazoles 3b-3t using 100 mg of 1 in each case. Diethyl 2-hydroxy-6-methoxy-4,9-dihydro-3H-carbazole-1,4-dicarboxylate (3b): Yield (96 mg, 65%); Yellow solid; m.p. = 122-123 ˚C; Rf = 0.48 in 1:3 EtOAc/hexanes; 1H NMR (500 MHz, CDCl3): δ 13.00 (br s, 1H), 8.74 (br s, 1H), 7.19 (d, J = 8.7 Hz, 1H), 7.02 (d, J = 2.4 Hz, 1H), 6.75 (dd, J = 8.7, 2.4 Hz, 1H), 4.48-4.40 (m, 2H), 4.18-4.03 (m, 3H), 3.87 (s, 3H) 3.10 (dd,


Page 14 of 37

Page 15 of 37 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


J = 17.5, 3.1 Hz, 1H), 3.04 (dd, J = 17.5, 8.4 Hz, 1H), 1.46 (t, J = 7.1 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H);

13

C{1H} NMR (125 MHz, CDCl3): δ 172.9, 169.5, 154.5, 131.1, 130.8, 126.8, 111.5,

110.6, 100.1, 99.6, 94.5, 61.6, 61.0, 55.8, 36.0, 32.3, 14.5, 14.2; IR (KBr, cm-1): υ 3401, 2972, 2931, 1717, 1640, 1211, 1149, 1082; HRMS (ESI-Q-TOF) m/z calcd for C19H22NO6 (M + H)+ 360.1442, found 360.1441. Diethyl 6-bromo-2-hydroxy-4,9-dihydro-3H-carbazole-1,4-dicarboxylate (3c): Yield (122 mg, 72%); Yellow solid; m.p. = 152-153 ˚C; Rf = 0.71 in 1:2 EtOAc/hexanes;

1

H NMR (400

MHz, CDCl3): δ 13.06 (br s, 1H), 8.84 (br s, 1H), 7.66 (s, 1H), 7.2-7.13 (m, 2H), 4.46 (q, J = 7.1 Hz, 2H), 4.15-4.04 (m, 2H), 4.01 (dd, J = 8.5, 3.2 Hz, 3H) 3.11 (dd, J = 17.7, 3.2 Hz, 1H), 3.03 (dd, J = 17.7, 8.6 Hz, 1H), 1.50 (t, J = 7.1 Hz, 3H), 1.20 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 172.7, 134.4, 131.8, 128.2, 123.4, 120.7, 113.5, 112.3, 99.4, 94.2, 61.8, 61.3, 35.9, 32.3, 14.6, 14.2; IR (KBr, cm-1): υ 3375, 2977, 1712, 1645, 1226, 1200, 1087; HRMS (ESIQ-TOF) m/z calcd for C18H19BrNO5 (M + H)+ 408.0441, found 408.0439. Diethyl 6-cyano-2-hydroxy-4,9-dihydro-3H-carbazole-1,4-dicarboxylate (3d): Yield (48 mg, 32%); Yellow solid; m.p. = 188-189 ˚C; Rf = 0.23 in 1:3 EtOAc/hexanes; 1H NMR (400 MHz, CDCl3): δ 13.08 (br s, 1H), 9.15 (br s, 1H), 7.87 (s, 1H), 7.36 (d, J = 8.4 Hz 1H), 7.30 (dd, J = 8.4, 1.4 Hz, 1H), 4.49 (q, J = 7.1 Hz, 2H), 4.18-4.03 (m, 3H), 3.16 (dd, J = 17.7, 3.1 Hz, 1H), 3.07 (dd, J = 17.8, 8.7 Hz, 1H), 1.48 (t, J = 7.1 Hz, 3H), 1.18 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 172.3, 137.5, 133.1, 126.3, 123.7, 123.4, 121.0, 111.7, 103.2, 100.2, 93.9, 61.9, 61.4, 35.8, 32.2, 14.6, 14.2; IR (KBr, cm-1): 3416, 2972, 2931, 2208, 1717, 1650, 1206, 1082; HRMS (ESI-Q-TOF) m/z calcd for C19H19N2O5 (M + H)+ 355.1288, found 355.1285. 1, 4-Diethyl 6-methyl 2-hydroxy-4, 9-dihydro-3H-carbazole-1, 4, 6-tricarboxylate (3e): Yield (104 mg, 65%); Yellow solid; m.p. = 129-130 ˚C; Rf = 0.29 in 1:3 EtOAc/hexanes; 1H NMR (500 MHz, CDCl3): δ 12.99 (br s, 1H), 9.05 (br s, 1H), 8.30 (s, 1H), 7.78 (d, J = 8.5 Hz 1H), 7.28 (dd, J = 8.4, 0.8 Hz, 1H), 4.47-4.42 (m, 2H), 4.15-4.06 (m, 3H), 3.92 (s, 3H), 3.14 (dd, J = 17.6, 3.2 Hz, 1H), 3.04 (dd, J = 17.7, 8.9 Hz, 1H), 1.45 (t, J = 7.1 Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H);

13

C{1H} NMR (125 MHz, CDCl3): δ 172.2, 172.7, 169.2, 168.3, 138.4, 132.0, 126.0,

122.2, 122.1, 121.0, 110.5, 100.8, 94.2, 66.7, 61.3, 51.8, 36.0, 32.3, 14.6, 14.1; IR (KBr, cm-1): υ 3416, 2982, 2946, 1722, 1696, 1655, 1206, 1097; HRMS (ESI-Q-TOF) m/z calcd for C20H22NO7 (M + H)+ 388.1381, found 388.1394.



Diethyl 6-fluoro-2-hydroxy-4,9-dihydro-3H-carbazole-1,4-dicarboxylate (3f): Yield (77 mg, 54%); Yellow solid; m.p. = 137-138 ˚C; Rf = 0.33 in 1:3 EtOAc/hexanes; 1H NMR (400 MHz, CDCl3): δ 13.04 (br s, 1H), 8.81 (br s, 1H), 7.22-7.17 (m, 2H), 6.81 (td, J = 9.1, 2.5 Hz 1H), 4.50-4.44 (m, 2H), 4.18-4.00 (m, 3H), 3.11 (dd, J = 17.6, 3.3 Hz, 1H), 3.04 (dd, J = 17.6, J2 = 8.4 Hz, 1H), 1.46 (t, J = 7.1 Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 172.8, 158.3 (d, J = 232 Hz), 132.3, 132.2, 126.9 (d, J = 11 Hz ), 112.0, 111.3 (d, J = 9.9 Hz), 108.8 (d, J = 26 Hz), 103.1 (d, J = 24.1 Hz), 100.0 (d, J = 4.7 Hz), 94.3, 61.7, 61.2, 36.0, 32.3, 14.6, 14.2; IR (KBr, cm-1): υ 3452, 3390, 2977, 2905, 1717, 1645, 1216, 1149, 1082; HRMS (ESI-Q-TOF) m/z calcd for C18H19FNO5 (M + H)+ 348.1242, found 348.1239. Diethyl 6-chloro-2-hydroxy-4,9-dihydro-3H-carbazole-1,4-dicarboxylate (3g): Yield (100 mg, 66%); Yellow solid; m.p. = 142-143 ˚C; Rf = 0.33 in 1:3 EtOAc/hexanes; 1H NMR (400 MHz, CDCl3): δ 13.04 (br s, 1H), 8.87 (br s, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.18 (d, J = 8.6 Hz, 1H), 6.98 (dd, J = 8.6, 1.7 Hz, 1H), 4.40 (q, J = 7.0 Hz, 2H), 4.18-3.99 (m, 3H), 3.06 (dd, J = 17.6, 3.1 Hz, 1H), 3.02 (dd, J = 17.7, 8.6 Hz, 1H), 1.46 (t, J = 7.1 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 177.3, 172.7,169.2, 134.1, 131.9, 127.4, 125.8, 120.8, 117.5, 111.8, 99.4, 94.2, 61.7, 61.2, 35.9, 32.2, 14.5, 14.2; IR (KBr, cm-1): υ 3375, 2982, 1722, 1645, 1237, 1206, 1082, 1030; HRMS (ESI-Q-TOF) m/z calcd for C18H18ClNNaO5 (M + Na)+ 386.0766, found 386.0765. Diethyl 8-methyl-2-oxo-2, 3, 4, 9-tetrahydro-1H-carbazole-1,4-dicarboxylate (3h): Yield (108 mg, 76%); Yellow solid; m.p. = 125-126 ˚C; Rf = 0.58 in 1:3 EtOAc/hexanes; 1H NMR (400 MHz, CDCl3): δ 12.93 (br s, 1H), 8.78 (br s, 1H), 7.42 (d, J = 7.9 Hz, 1H), 7.05 (t, J = 7.7 Hz, 1H), 6.92 (d, J = 7.2, 1H), 4.47 (q, J = 7.1 Hz, 2H), 4.16-4.00 (m, 3H), 3.12 (dd, J = 17.5, 3.6 Hz, 1H), 3.05 (dd, J = 17.5, 8.2 Hz, 1H), 2.48 (s, 3H), 1.51 (t, J = 7.2 Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H);

13

C{1H} NMR (100 MHz, CDCl3): δ 173.0, 169.6, 135.2, 130.1, 125.9, 121.5,

120.4, 119.8, 116.0, 100.4, 94.5, 61.5, 61.1, 36.3, 32.5, 16.4, 14.4, 14.3; IR (KBr, cm-1): υ 3277, 3132, 2967, 1738, 1655, 1619, 1485, 1206, 1087; HRMS (ESI-Q-TOF) m/z calcd for C19H22NO5 (M + H)+ 344.1492, found 344.1497. Diethyl 8-bromo-2-hydroxy-4,9-dihydro-3H-carbazole-1,4-dicarboxylate (3i): Yield (113 mg, 68%); Yellow solid; m.p. = 154-155 ˚C; Rf = 0.61 in 1:3 EtOAc/hexanes; 1H NMR (400 MHz, CDCl3): δ 12.96 (br s, 1H), 9.01 (br s, 1H), 7.47 (d, J = 7.9 Hz, 1H), 7.21 (d, J = 7.6 Hz,


Page 16 of 37

Page 17 of 37 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


1H), 6.97 (t, J = 7.8, 1H), 4.45 (q, J = 7.1 Hz, 2H), 4.16-4.0 (m, 3H), 3.12 (dd, J = 17.6, 3.4 Hz, 1H), 3.04 (dd, J = 17.6, 8.4 Hz, 1H), 1.52 (t, J = 7.1 Hz, 3H), 1.17 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 177.3, 172.6, 169.4, 134.4, 131.2, 127.6, 122.9, 121.3, 117.3, 104.4, 100.8, 94.2, 61.8, 61.2, 36.2, 32.3, 14.4, 14.2; IR (KBr, cm-1): υ 3277, 3132, 2967, 1738, 1655, 1619, 1485, 1206, 1087; HRMS (ESI-Q-TOF) m/z calcd for C18H18BrNO5Na (M + Na)+ 430.0261, found 430.0268. Diethyl

7-bromo-2-hydroxy-8-methyl-4,9-dihydro-3H-carbazole-1,4-dicarboxylate

(3j):

Yield (115 mg, 66%); Yellow solid; m.p. = 150-151 ˚C; Rf = 0.62 in 1:3 EtOAc/hexanes; 1H NMR (500 MHz, CDCl3): δ 12.94 (br s, 1H), 8.78 (br s, 1H), 7.25-7.23 (m, 2H), 4.46 (q, J = 7.1 Hz, 2H), 4.15-4.0 (m, 3H), 3.11 (dd, J = 17.6, 3.2 Hz, 1H), 3.04 (dd, J = 17.6, 8.6 Hz, 1H), 2.45 (s, 3H), 1.5 (t, J = 7.1 Hz, 3H), 1.17 (t, J = 7.1 Hz, 3H);

13

C{1H} NMR (100 MHz, CDCl3): δ

172.8, 135.7, 130.8, 125.2, 124.5, 119.6, 117.0, 116.5, 100.5, 94.3, 61.7, 61.2, 36.1, 32.3, 16.6, 14.5, 14.3; IR (KBr, cm-1): υ 3277, 3132, 2967, 1738, 1655, 1619, 1485, 1206, 1087; HRMS (ESI-Q-TOF) m/z calcd for C19H21BrNO5 (M + H)+ 422.0598, found 422.0595. Diethyl

5-chloro-2-hydroxy-8-methyl-4,9-dihydro-3H-carbazole-1,4-dicarboxylate

(3k):

Yield (80 mg, 51%); Yellow solid; m.p. = 138-139 ˚C; Rf = 0.66 in 1:3 EtOAc/hexanes; 1H NMR (500 MHz, CDCl3): δ 12.93 (br s, 1H), 8.86 (br s, 1H), 6.94 (d, J = 7.7 Hz, 1H), 6.77 (d, J = 7.7 Hz, 1H), 4.56 (dd, J = 8.2, 2.5 Hz, 1H), 4.45 (q, J = 7.2 Hz, 2H), 4,17-4.11 (m, 1H), 4.064.0 (m, 1H), 3.13 (dd, J = 17.6, 8.3 Hz, 1H), 3.08 (dd, J = 17.5, 2.4 Hz, 1H), 2.41 (s, 3H), 1.49 (t, J = 7.2 Hz, 3H), 1.18 (t, J = 7.1 Hz, 3H);

13

C{1H} NMR (100 MHz, CDCl3): δ 177.0, 173.2,

136.1, 131.3, 123.3, 122.4, 122.0, 120.8, 118.5, 101.0, 94.6, 61.7, 61.1, 35.9, 33.2, 16.0, 14.4, 14.2; IR (KBr, cm-1): υ 3473, 2982, 2926, 1722, 1655, 1603, 1232, 1102, 860, 798; HRMS (ESIQ-TOF) m/z calcd for C19H21ClNO5 (M + H)+ 378.1103, found 378.1106. Diethyl 9-hydroxy-8,11-dihydro-7H-benzo[a]carbazole-7,10-dicarboxylate (3l): Yield (112 mg, 71%); Yellow solid; m.p. = 177-178 ˚C; Rf = 0.64 in 1:3 EtOAc/hexanes; 1H NMR (400 MHz, CDCl3): δ 12.88 (br s, 1H), 9.50 (br s, 1H), 7.90 (t, J = 7.8 Hz, 2H), 7.69 (d, J = 8.6 Hz, 1H), 7.53-7.49 (m, 2H), 7.40- 7.36 (m, 1H), 4.51 (q, J = 7.2 Hz, 2H), 4.18-4.02 (m, 3H), 3.16 (dd, J = 17.5, 3.5 Hz, 1H), 3.09 (dd, J = 17.5, 8.1 Hz, 1H), 1.58 (t, J = 7.1 Hz, 3H), 1.18 (t, J = 7.1 Hz, 3H);

13

C{1H} NMR (100 MHz, CDCl3): δ 176.2, 173.0, 169.6, 129.8, 129.1, 128.7,

125.6, 123.4, 122.4, 121.6, 121.0, 118.9, 118.7, 102.0, 94.7, 61.7, 61.2, 36.3, 32.4, 14.6, 14.2;



Page 18 of 37

IR(KBr, cm-1): υ 3473, 2981, 1729, 1652, 1609, 1382, 1226, 1073, 1027, 851, 805, 744; HRMS (ESI-Q-TOF) m/z calcd for C22H21NNaO5+ (M + Na)+ 402.1312, found 402.1318. Diethyl 2-hydroxy-6-(4-methoxyphenyl)-4,9-dihydro-3H-carbazole-1,4-di carboxylate (3m): Yield (111 mg, 61%); Yellow gum; Rf = 0.46 in 1:3 EtOAc/hexanes;

1

H NMR (400 MHz,

CDCl3): δ 13.06 (br s, 1H), 8.80 (br s, 1H), 7.71 (s, 1H), 7.54 (d, J = 8.7 Hz, 2H), 7.38-7.30 (m, 2H), 7.00 (d, J = 8.7 Hz, 2H), 4.51 (q, J = 7.1 Hz, 2H), 4.17-4.05 (m, 3H), 3.86 (s, 3H), 3.13 (dd, J = 17.6, 3.6 Hz, 1H), 3.17 (dd, J = 17.5, 8.1 Hz, 1H), 1.49 (t, J = 7.1 Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H);

13

C{1H} NMR (100 MHz, CDCl3): δ 173.0, 169.6, 158.6, 135.4, 134.9, 133.4, 131.1,

128.5, 128.4, 126.9, 120.4, 116.1, 114.3, 114.2, 111.0, 100.1, 94.5, 61.7, 61.1, 55.5, 36.1, 32.5, 14.7, 14.3; IR (neat, cm-1): υ 3478, 3416, 2982, 2931, 1722, 1645, 1598, 1278, 1035, 803; HRMS (ESI-Q-TOF) m/z calcd for C25H25NNaO6 (M + Na)+ 458.1574, found 458.1579. Diethyl 2-hydroxy-6-(p-tolyl)-4,9-dihydro-3H-carbazole-1,4-dicarboxylate (3n): Yield (120 mg, 69%); Yellow solid; m.p. = 97-98 ˚C; Rf = 0.61 in 1:3 EtOAc/hexanes; 1H NMR (500 MHz, CDCl3): δ 13.05 (br s, 1H), 8.81 (br s, 1H), 7.7 (s, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.36-7.32 (m, 2H), 7.25 (m, 2H), 4.50-4.46 (m, 2H), 4.16-4.03 (m, 3H), 3.12 (dd, J = 17.4, 3.2 Hz, 1H), 3.06 (dd, J = 17.5, 8.4 Hz, 1H), 2.40 (s, 3H), 1.50 (t, J = 7.2 Hz, 3H), 1.19 (t, J = 7.1 Hz, 3H); 13

C{1H} NMR (100 MHz, CDCl3): δ 173.0, 139.9, 136.0, 135.2, 133.7, 131.1, 129.6, 129.5,

127.4, 127.2, 126.9, 120.6, 116.3, 111.0, 100.2, 94.5, 61.7, 61.2, 36.1, 32.5, 21.2, 14.7, 14.3; IR (KBr, cm-1): υ 3473, 3427, 2982, 1727, 1645, 1593, 1226, 798; HRMS (ESI-Q-TOF) m/z calcd for C25H26NO5 (M + H)+ 420.1805, found 420.1811. Diethyl

6-(4-chlorophenyl)-2-hydroxy-4,9-dihydro-3H-carbazole-1,4-dicarboxylate

(3o):

Yield (140 mg, 76%); Yellow solid; m.p. = 133-134 ˚C; Rf = 0.45 in 1:3 EtOAc/hexanes; 1H NMR (400 MHz, CDCl3): δ 13.08 (br s, 1H), 8.91 ( br s, 1H), 7.75 (s, 1H), 7.59 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 7.0 Hz, 2H), 7.30 (d, J = 8.3 Hz, 1H), 4.47 (q, J = 7.0 Hz, 2H), 4.21-4.05 (m, 3H), 3.15 (dd, J = 17.6, 3.1 Hz, 1H), 3.07 (dd, J = 17.5, 8.6Hz, 1H), 1.48 (t, J = 7.1 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 177.1, 172.8, 169.4, 141.1, 135.4, 132.3, 131.3, 128.8, 128.7, 128.6, 128.4, 126.9, 120.2, 116.3, 111.2, 100.0, 94.4, 61.6, 61.1, 36.0, 32.4, 14.5, 14.2; IR (KBr, cm-1): ߭ 3473, 2982, 1732, 1717, 1649, 1221, 1086, 519;

HRMS (ESI-Q-TOF) m/z calcd for C24H23ClNO5 (M + H)+440.1259, found

440.1258.


Page 19 of 37 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

7-(benzyloxy)-2-hydroxy-6-methoxy-4,9-dihydro-3H-carbazole-1,4-dicarboxylate

(3p): Yield (150 mg, 77%); Yellow gum; Rf = 0.41 in 1:3 EtOAc/hexanes; 1H NMR (400 MHz, CDCl3): δ 12.90 (br s, 1H), 8.64 (br s, 1H), 7.42 (t, J = 7.5 Hz, 2H), 7.35-7.24 (m, 3H), 7.03 (s, 1H), 6.84 (s, 1H), 5.11 (s, 2H), 4.40 (q, J = 7.0 Hz, 2H), 4.16-3.99 (m, 3H), 3.93 (s, 3H), 3.31 (dd, J = 17.5, 3.2 Hz, 1H), 2.99 (dd, J = 17.6, 8.4 Hz, 1H), 1.42 (t, J = 7.1 Hz, 3H), 1.19 (t, J = 7.1 Hz, 3H);

13

C{1H} NMR (125 MHz, CDCl3): δ 175.7, 172.9, 169.4, 146.1, 145.0, 137.7,

129.9, 129.2, 128.6, 128.5, 127.7, 127.3, 127.2, 120.1, 100.9, 99.7, 98.1, 94.7, 71.9, 61.5, 61.0, 56.6, 36.2, 32.3, 14.6, 14.3; IR (neat, cm-1): υ 3395, 2982, 2931, 1722, 1645, 1242, 1211, 1020; HRMS (ESI-Q-TOF) m/z calcd for C26H27NNaO7 (M + Na)+ 488.1680, found 488.1685. Diethyl

7-hydroxy-8,9-dihydro-5H-[1,3]dioxolo[4,5-b]carbazole-6,9-dicarboxylate

(3q):

Yield (107 mg, 67%); Yellow solid; m.p. = 153-154 ˚C; Rf = 0.48 in 1:3 EtOAc/hexanes; 1H NMR (400 MHz, CDCl3): δ 12.86 (br s, 1H), 8.66 (br s, 1H), 6.94 (s, 1H), 6.79 (s, 1H), 5.91 (s, 2H), 4.47-4.42 (m, 2H), 4.18-4.02 (m, 2H), 3.96 (dd, J = 8.1, 3.7 Hz, 1H), 3.08 (dd, J = 17.5, 3.6 Hz, 1H), 3.01 (dd, J = 17.6, 8.1 Hz, 1H), 1.46 (t, J = 7.2 Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H); 13

C{1H} NMR (100 MHz, CDCl3): δ 175.6, 172.9, 169.5, 143.8, 143.1, 130.4, 129.0, 120.6,

100.6, 100.2, 97.1, 94.7, 92.2, 61.5, 61.1, 36.2, 32.3, 14.6, 14.3; IR (KBr, cm-1): υ 3468, 3430, 2981, 2879, 1726, 1648, 1597, 1460, 1327, 1258, 1036; HRMS (ESI-Q-TOF) m/z calcd for C19H20NO7 (M + H)+ 374.1234, found 374.1234. Diethyl 9-methyl-2-oxo-2,3,4,9-tetrahydro-1H-carbazole-1,4-dicarboxylate (3r): Yield (77 mg, 54%); dr = 1:0.8; Keto/enol forms = 94:6; Yellow solid; m.p. = 109-110 ˚C; Rf = 0.39 in 1:3 EtOAc/hexanes; 1H NMR (500 MHz, CDCl3) Major isomer : δ 7.68 (d, J = 3.7 Hz, 1H), 7.337.25 (m, 2H), 7.19-7.15 (m, 1H), 4.66 (s, 1H), 4.42 (dd, J = 6.8, 2.2 Hz, 1H), 4.29-4.17 (m, 2H), 4.14-4.01 (m, 2H), 3.63 (s, 3H), 3.15 (dd, J = 14.3, 6.7 Hz, 1H), 2.95 (dd, J = 14.3, 1.8 Hz, 1H), 1.30-1.26 (m, 3H), 1.22-1.17 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3) : δ 199.7, 173.1, 166.9, 138.1, 131.0, 125.3, 122.6, 120.1, 119.3, 109.4, 107.8, 62.6, 61.5, 54.8, 40.1, 39.0, 29.9, 14.1; 1H NMR (500 MHz, CDCl3) Minor isomer : δ 7.70 (d, J = 3.7 Hz, 1H), 7.33-7.25 (m, 2H), 7.197.15 (m, 1H), 4.65 (s, 1H), 4.31 (dd, J = 6.7, 3.5 Hz, 1H), 4.29-4.17 (m, 2H), 4.14-4.01 (m, 2H), 3.64 (s, 3H), 3.24 (dd, J = 15.0, 3.6 Hz, 1H), 2.79 (dd, J = 15.0, 6.8 Hz, 1H), 1.30-1.26 (m, 3H), 1.22-1.17 (m, 3H);

13

C{1H} NMR (100 MHz, CDCl3): δ 200.2, 172.3, 167.0, 138.0, 131.0,

125.4, 122.6, 120.1, 119.3, 109.5, 107.9, 62.4, 61.4, 54.5, 40.8, 38.4, 29.8, 14.1; IR (KBr, cm-1):



υ 3050, 2972, 2931, 1727, 1588, 1469, 1175, 1030;

Page 20 of 37

HRMS (ESI-Q-TOF) m/z calcd for

C19H21NNaO5 (M + Na)+ 366.1312, found 366.1312. Diethyl 9-benzyl-2-oxo-2,3,4,9-tetrahydro-1H-carbazole-1,4-dicarboxylate (3s): Yield (87 mg, 50%); dr = 1:0.68; Keto/enol forms = 94:6; Yellow solid; m.p. = 111-112 ˚C; Rf = 0.45 in 1:3 EtOAc/hexanes; 1H NMR (400 MHz, CDCl3) Major isomer : δ 7.76-7.73 (m, 1H), 7.24-7.16 (m, 6H), 6.90-6.88 (m, 2H), 5.37-5.14 (m, 2H), 4.57 (s, 1H), 4.47 (dd, J = 6.7, 2.0 Hz, 1H), 4.153.88 (m, 2H), 3.80-3.73 (m, 2H), 3.27-3.20 (m, 1H), 2.93 (dd, J = 14.3, 1.9 HZ, 1H), 1.22-1.03 (m, 6H);

13

C{1H} NMR (100 MHz, CDCl3) : δ 199.6, 172.9, 166.6, 137.9, 136.7, 131.1, 128.7,

127.5, 125.6, 125.4, 122.9, 120.3, 119.4, 110.2, 108.6, 62.5, 61.4, 54.8, 46.8, 39.9, 39.0, 14.0, 13.7; 1H NMR (400 MHz, CDCl3) Minor isomer: δ 7.76-7.73 (m, 1H), 7.24-7.16 (m, 6H), 6.966.94 (m, 2H), 5.37-5.14 (m, 2H), 4.51 (s, 1H), 4.33 (dd, J = 6.7, 3.5 Hz, 1H), 4.15-3.88 (m, 2H), 3.80-3.73 (m, 2H), 3.27-3.20 (m, 1H), 2.73 (dd, J = 15.2, 6.8 HZ, 1H), 1.22-1.03 (m, 6H); 13

C{1H} NMR (100 MHz, CDCl3) : δ 200.1, 172.1, 166.7, 137.9, 136.8, 130.9, 128.8, 127.6,

126.1, 125.6, 122.8, 120.3, 119.4, 110.0, 108.7, 62.1, 61.3, 54.4, 46.8, 40.5, 38.3, 14.1, 13.8; IR (KBr, cm-1): υ 3050, 2972, 1738, 1717, 1562, 1469, 1185, 1154, 1036; HRMS (ESI-Q-TOF) m/z calcd for C25H25NNaO5 (M + Na)+ 442.1625, found 442.1624. Diethyl 9-allyl-2-oxo-2,3,4,9-tetrahydro-1H-carbazole-1,4-dicarboxylate (3t): Yield (46 mg, 60%); dr = 1:0.67; Keto/enol forms = 97:3; Yellow gum; Rf = 0.64 in 1:3 EtOAc/hexanes; 1H NMR (500 MHz, CDCl3): Major isomer : δ 7.73 (d, J = 7.7 Hz, 1H), 7.34-7.25 (m, 2H), 7.227.19 (m, 1H), 5.93-5.84 (m, 1H), 5.17-5.14 (m, 1H), 4.87-4.83 (m, 1H), 4.75-4.72 (m, 1H), 4.674.60 (m, 2H), 4.47 (dd, J = 6.7, 2.0 Hz, 1H), 4.29-4.13 (m, 2H), 4.10 (q, J = 7.1 Hz, 2H), 3.24 (dd, J = 14.3, 6.8 Hz, 1H), 2.96 (dd, J = 14.3, 2.1 Hz, 1H), 1.30-1.18 (m, 6H);

13

C{1H} NMR

(100 MHz, CDCl3): δ 199.8, 172.0, 166.9, 137.6, 132.6, 130.8, 125.5, 122.8, 120.2, 119.4, 116.8, 110.1, 108.3, 62.7, 61.5, 54.9, 45.9, 40.0, 39.1, 14.1; 1H NMR (500 MHz, CDCl3): Minor isomer : δ 7.75 (d, J = 7.2 Hz, 1H), 7.34-7.25 (m, 2H), 7.22-7.19 (m, 1H), 5.93-5.84 (m, 1H), 5.17-5.14 (m, 1H), 4.95-4.91 (m, 1H), 4.78-4.75 (m, 1H), 4.67-4.60 (m, 2H), 4.35 (dd, J = 6.8, 3.4 Hz, 1H), 4.29-4.13 (m, 2H), 3.29 (dd, J = 15.2, 3.5 Hz, 1H), 2.80 (dd, J = 15.2, 6.8 Hz, 1H), 1.30-1.18 (m, 6H);

13

C{1H} NMR (100 MHz, CDCl3): δ 200.3, 172.2, 166.9, 137.5, 132.8,

130.6, 125.7, 122.7, 120.3, 119.4, 117.0, 110.0, 108.4, 62.4, 61.5, 54.5, 45.8, 40.7, 38.3, 14.2; HRMS (ESI-Q-TOF) m/z calcd for C21H23NNaO5 (M + Na)+ 392.1468, found 392.1465.


Page 21 of 37 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


General procedure for the synthesis of carabzoles (4a, 4c, 4h, 4j, 4l-n, 4p-q): To a solution of tetrahydrocarbazole (3a) (50 mg, 0.15 mmol ) in dry CH2Cl2, (1 mL, 7 mL/mmol) triethyl amine (43 µL, 0.30 mmol ) was added at room temperature and stirred for 2 h. After completion of the reaction, as monitored by 1H NMR signal of the reaction mixture, solvent was evaporated and the obtained crude was purified using mixture of ethyl acetate/hexanes by silica gel column chromatography. Diethyl 2-hydroxy-9H-carbazole-1,4-dicarboxylate (4a): Yield (39 mg, 76%); Yellow solid; m.p. = 124-125 ˚C; Rf = 0.56 in 1:3 EtOAc/hexanes; 1H NMR (400 MHz, CDCl3): δ 10.86 (br s, 1H), 9.33 (br s, 1H), 8.54 (d, J = 8.1 Hz, 1H), 7.39-7.36 (m, 2H), 7.23-7.20 (m, 2H), 4.57-4.48 (m, 4H), 1.54 (t, J = 7.1 Hz, 3H), 1.47 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 169.5, 167.0, 160.3, 140.2, 139.4, 131.9, 125.7, 124.2, 121.6, 120.5, 114.9, 111.5, 110.5, 98.8, 62.5, 61.7, 14.6, 14.4; IR (KBr, cm-1): υ 3478, 2982, 1717, 1665, 1459, 1371, 1025; HRMS (ESI-Q-TOF) m/z calcd for C18H18NO5+ (M + H)+ 328.1179, found 328.1189. Diethyl 6-bromo-2-hydroxy-9H-carbazole-1,4-dicarboxylate (4c): The reaction was carried out using 28 mg of 3c. Yield (21 mg, 72%); Yellow solid; m.p. = 178-179 ˚C; Rf = 0.46 in 1:3 EtOAc/hexanes; 1H NMR (400 MHz, CDCl3): δ 10.89 (br s, 1H), 9.38 (br s, 1H), 8.73 (d, J = 1.9 Hz, 1H), 7.45 (dd, J = 8.5, 2.0 Hz, 1H), 7.32 (s, 1H), 7.24 (d, J = 8.6 Hz, 1H), 4.62 (q, J = 7.1 Hz, 2H), 4.52 (q, J = 7.1 Hz , 2H), 1.58 (t, J = 7.1 Hz, 3H), 1.50 (t, J = 7.1 Hz, 3H);

13

C{1H}

NMR (100 MHz, CDCl3): δ 169.2, 166.5, 160.8, 140.4, 137.9, 131.9, 128.3, 127.0, 123.3, 113.9, 113.4, 112.4, 111.8, 99.0, 62.7, 61.9, 14.6, 14.4; IR (KBr, cm-1): υ 3469, 2987, 1721, 1671, 1589, 1450, 1291, 1206, 1156, 1084, 1028; HRMS (ESI-Q-TOF) m/z calcd for C18H17BrNO5+ (M + H)+ 406.0285, found 406.0289. Diethyl 2-hydroxy-8-methyl-9H-carbazole-1,4-dicarboxylate (4h): The reaction was carried out using 27 mg of 3h. Yield (24 mg, 71%); Yellow solid; m.p. = 135-136 ˚C; Rf = 0.64 in 1:3 EtOAc/hexanes; 1H NMR (400 MHz, CDCl3): δ 10.82 (br s, 1H), 9.34 (br s, 1H), 8.40 (d, J = 7.8 Hz, 1H), 7.30 (s, 1H), 7.20-7.13 (m, 2H), 4.58 (q, J = 7.1 Hz, 2H), 4.52 (q, J = 7.1 Hz , 2H), 2.49 (s, 3H), 1.59 (t, J = 7.1 Hz, 3H), 1.48 (t, J = 7.1 Hz, 3H);

13

C{1H} NMR (100 MHz,

CDCl3): δ 169.5, 167.0, 160.2, 140.1, 138.7, 132.1, 126.3, 121.8, 121.1, 120.6, 119.2, 115.4, 111.5, 98.8, 61.4, 61.7, 16.5, 14.4, 14.3; IR (KBr, cm-1): υ 3480, 2974, 1719, 1663, 1579, 1424,



1372, 1282, 1220, 1166, 1103, 1046, 863, 776, 747; HRMS (ESI-Q-TOF) m/z calcd for C19H20NO5+ (M + H)+ 342.1336, found 342.1334. Diethyl 7-bromo-2-hydroxy-8-methyl-9H-carbazole-1,4-dicarboxylate (4j): The reaction was carried out using 31 mg of 3j. Yield (28 mg, 89%); Yellow solid; m.p. = 209-210 ˚C; Rf = 0.67 in 1:3 EtOAc/hexanes; 1H NMR (400 MHz, CDCl3): δ 10.78 (br s, 1H), 9.22 (br s, 1H), 8.26 (d, J = 8.7 Hz, 1H), 7.34 (d, J = 8.7 Hz, 1H), 7.35-7.26 (m, 1H), 4.57 (q, J = 7.1 Hz, 2H), 4.49 (q, J = 7.1 Hz, 2H), 2.47 (s, 3H), 1.59 (t, J = 7.1 Hz, 3H), 1.48 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 169.2, 166.5, 160.2, 140.1, 139.1, 131.7, 124.5, 123.1, 121.6, 120.3, 119.0, 115.1, 112.3, 98.9, 62.6, 61.8, 16.6, 14.4; IR (KBr, cm-1): υ 3474, 1727, 1669, 1583, 1425, 1376, 1226, 1167, 1097, 1040, 1015; HRMS (ESI-Q-TOF) m/z calcd for C19H19BrNO5+ (M + H)+ 420.0441, found 420.0442. Diethyl 9-hydroxy-11H-benzo[a]carbazole-7, 10-dicarboxylate (4l): The reaction was carried out using 24 mg of 3l. Yield (21 mg, 90%); Yellow solid; m.p. = 215-216 ˚C; Rf = 0.59 in 1:3 EtOAc/hexanes; 1H NMR (400 MHz, CDCl3): δ 10.75 (br s, 1H), 9.86 (br s, 1H), 8.56 (d, J = 8.9 Hz, 1H) 7.96-7.93 (m, 1H), 7.8-7.92 (m, 1H), 7.58 (d, J = 8.9 Hz, 1H), 7.54-7.49 (m, 2H), 7.31 (s, 1H), 4.58-4.49 (m, 4H), 1.61 (t, J = 7.2 Hz, 3H), 1.50 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 169.4, 166.9, 159.8, 138.7, 134.7, 132.0, 131.4, 128.8, 125.6, 125.5, 122.8, 120.6, 120.4, 120.0, 117.1, 115.8, 112.6, 99.2, 62.5, 61.7, 14.5, 14.4; IR (KBr, cm-1): υ 3471, 1721, 1666, 1585, 1511, 1423, 1371, 1283, 1219, 1169, 1115, 1081; HRMS (ESI-Q-TOF) m/z calcd for C22H20NO5+ (M + H)+ 378.1336, found 378.1334. Diethyl 2-hydroxy-6-(4-methoxyphenyl)-9H-carbazole-1,4-dicarboxylate (4m): The reaction was carried out using 60 mg of 3m. Yield (46 mg, 76%); Yellow solid; m.p. = 146-147 ˚C; Rf = 0.41 in 1:3 EtOAc/hexanes; 1H NMR (400 MHz, CDCl3): δ 10.91 (br s, 1H), 9.55 (br s, 1H), 8.79 (s, 1H), 7.64-7.61 (m, 3H), 7.49 (d, J = 8.4 Hz, 1H), 7.38 (s, 1H), 7.02 (d, J = 8.4 Hz , 2H), 4.68 (q, J = 7.0 Hz , 2H), 4.54 (q, J = 7.0 Hz , 2H), 3.88 (s, 3H), 1.62 (t, J = 7.0 Hz, 3H), 1.48 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 169.5, 167.0, 160.4, 158.7, 140.7, 138.5, 135.0, 133.6, 132.1, 128.4, 125.0, 122.3, 122.1, 115.0, 114.3, 111.6, 110.7, 98.9, 62.6, 61.8, 55.5, 14.6, 14.4; IR (KBr, cm-1): υ 3462, 2971, 1716, 1670, 1582, 1468, 1293, 1236, 1200; HRMS (ESI-Q-TOF) m/z calcd for C25H23NNaO6+ (M + Na)+ 456.1418, found 456.1418.


Page 22 of 37

Page 23 of 37 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 2-hydroxy-6-(p-tolyl)-9H-carbazole-1,4-dicarboxylate (4n): The reaction was carried out using 40 mg of 3n. Yield (30 mg, 79%); Yellow solid; m.p. = 120-121 ˚C; Rf = 0.51 in 1:3 EtOAc/hexanes; 1H NMR (400 MHz, CDCl3): δ 10.91 (br s, 1H), 9.50 (br s, 1H), 8.80 (d, J = 1.5 Hz, 1H), 7.63 (dd, J = 8.4, 1.7 Hz, 1H), 7.60 (d, J = 8.9 Hz, 2H), 7.47 (d, J = 8.4 Hz, 1H), 7.34 (s, 1H), 7.28 (d, J = 7.9 Hz , 2H), 4.64 (q, J = 7.2 Hz, 2H), 4.53 (q, J = 7.2 Hz , 2H), 2.42 (s, 3H), 1.59 (t, J = 7.2 Hz, 3H), 1.47 (t, J = 7.2 Hz, 3H);

13


169.5, 167.0, 160.5, 140.8, 139.5, 138.7, 136.3, 134.0, 132.3, 129.6, 127.4, 125.2, 122.6, 122.2, 115.1, 111.7, 110.7, 99.0, 62.6, 61.8, 21.2, 14.7, 14.5; IR (KBr, cm-1): υ 3471, 3421, 2981, 2925, 1723, 1670, 1587, 1470, 1415, 1374, 1293, 1203, 1153, 801; HRMS (ESI-Q-TOF) m/z calcd for C25H24NO5+ (M + H)+ 418.1649, found 418.1648. Diethyl

7-(benzyloxy)-2-hydroxy-6-methoxy-9H-carbazole-1,4-dicarboxylate

(4p):

The

reaction was carried out using 23 mg of 3p. Yield (16 mg, 69%); Yellow solid; m.p. = 163-164 ˚C; Rf = 0.41 in 1:3 EtOAc/hexanes; 1H NMR (400 MHz, CDCl3): δ 10.76 (br s, 1H), 9.33 (br s, 1H), 8.29 (s, 1H), 7.46 (d, J = 7.2 Hz, 2H), 7.39-7.35 (m, 3H), 7.32-7.30 (m, 1H), 6.93 (s, 1H), 5.24 (s, 2H), 4.62 (q, J = 7.1 Hz, 2H), 4.51 (q, J = 7.1 Hz, 2H), 4.02 (s, 3H), 1.56 (t, J = 7.1 Hz, 3H), 1.48 (t, J = 7.1 Hz, 3H);

13

C{1H} NMR (100 MHz, CDCl3): δ 169.6, 167.0, 159.2, 148.4,

145.2, 140.2, 137.2, 134.4, 130.7, 128.7, 128.0, 127.3, 115.8, 114.6, 111.4, 107.7, 99.1, 96.4, 71.3, 62.5, 61.7, 56.8, 14.7, 14.5; IR (KBr, cm-1): υ 3472, 3404, 2985, 2941, 2900, 1721, 1668, 1590, 1480, 1423, 1374, 1345, 1204, 1146, 1014; HRMS (ESI-Q-TOF) m/z calcd for C26H26NO7+ (M + H)+ 464.1704, found 464.1707. Diethyl 7-hydroxy-5H-[1,3]dioxolo[4,5-b]carbazole-6,9-dicarboxylate (4q): The reaction was carried out using 40 mg of 3q. Yield (24 mg, 60%) Yellow solid; m.p. = 208-209 ˚C; Rf = 0.41 in 1:3 EtOAc/hexanes; 1H NMR (400 MHz, CDCl3): δ 10.74 (br s, 1H), 9.33 (br s, 1H), 8.04 (s, 1H), 7.31 (s, 1H), 6.85 (s, 1H), 6.01 (s, 2H), 4.63 (q, J = 7.1 Hz, 2H), 4.50 (q, J = 7.2 Hz , 2H), 1.58 (t, J = 7.1 Hz, 3H), 1.48 (t, J = 7.2 Hz, 3H);

13

C{1H} NMR (100 MHz, CDCl3): δ 169.5,

167.1, 159.1, 147.1, 143.1, 140.0, 135.1, 130.7, 115.6, 115.0, 111.4, 103.6, 101.3, 99.0, 91.6, 62.5, 61.7, 14.7, 14.4; IR (KBr, cm-1): υ 3473, 1714, 1671, 1583, 1494, 1283, 1188, 1148; HRMS (ESI-Q-TOF) m/z calcd for C19H18NO7+ (M + H)+ 372.1078, found 372.1074. Synthesis of diethyl 2-diazo-5-(1H-indol-3-yl)-3-oxohexanedioate (5a):



To a solution of (E)-diethyl 5-diazo-4-oxohex-2-enedioate (1) (500 mg, 2.10 mmol) and indole (2a) (245.0 mg, 2.10 mmol) in dry CH2Cl2, (12.6 mL, 6 mL/mmol), Sc(OTf)3 (20.0 mg, 0.042 mmol) was added at room temperature and stirred for 1 h. Then solvent was evaporated under reduced pressure and the obtained crude was purified by silica gel column chromatography using 1:3 mixture of ethyl acetate/hexanes. Yield (744 mg, 96%); Brown solid; m.p. = 86-87 ℃; Rf = 0.56 in 1:3 EtOAc/hexanes; 1H NMR (400 MHz, CDCl3): δ 8.41 (br s, 1H), 7.75 (d, J = 7.7 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.21-7.12 (m, 2H), 7.07 (s, 1H), 4.49 (dd, J = 10.8, 3.9 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 4.22-4.04 (m, 2H), 3.96 (dd, J = 18.5, 10.8 Hz, 1H), 3.27 (dd, J = 18.4, 4.0 Hz, 1H), 1.31 (t, J = 7.1 Hz, 3H), 1.19 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 191.1, 174.0, 161.4, 136.3, 126.3, 122.4, 122.2, 119.7, 119.3, 112.6, 111.4, 76.3, 61.6, 61.1, 43.2, 37.9, 14.4, 14.1; IR (KBr, cm-1): υ 3377, 2982, 2936, 2134, 1171, 1650, 1300, 1172, 1094; HRMS (ESI-Q-TOF) m/z calcd for C18H19N3NaO5 (M + Na)+ 380.1217, found 380.1218. Synthesis of diethyl 2-amino-9H-carbazole-1,4-dicarboxylate (6a): Tetrahydrocarbazole (3a) (50 mg, 0.15 mmol), NH4OAc (234 mg, 3.0 mmol ) and acetic acid (3.5 µL, 0.15 mmol) was taken in ethanol (2 mL, 14 mL/mmol) and refluxed for 20 h. The reaction was cooled and 10 mL of water was added. Then, the reaction mass was extracted using ethyl acetate (6 mL). The combined organic layer was dried using anhydrous sodium sulfate and evaporated under reduced pressure. The obtained crude product was purified by silica gel chromatography using mixture of ethyl acetate/hexanes. Yield (15 mg, 30%); Yellow solid; m.p. = 125-126 ˚C; Rf = 0.46 in 1:3 EtOAc/hexanes; 1H NMR (500 MHz, CDCl3): δ 10.03 (br s, 1H), 8.48 (d, J = 2.7 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.35 (td, J= 7.1, 1.0 Hz 1H), 7.22-7.19 (m, 1H), 7.05 (s, 1H), 5.88 (br s, 2H), 4.58-4.51 (m, 4H), 1.54 (t, J = 7.1 Hz, 3H), 1.49 (t, J = 7.1 Hz, 3H);

13

C{1H} NMR (100 MHz, CDCl3): δ 168.0, 167.5, 149.1, 142.4, 139.0, 131.2, 124.8,

123.4, 122.0, 120.2, 112.5, 111.6, 110.5, 97.0, 61.6, 61.4, 14.8, 14.5; IR (KBr, cm-1): υ 3365, 2977, 2910, 1738, 1459, 1231, 1030, 751; HRMS (ESI-Q-TOF) m/z calcd for C18H19N2O4+ (M + H)+ 327.1339, found 327.1341. Synthesis of diethyl 2-(phenylamino)-9H-carbazole-1,4-dicarboxylate (6b): Tetrahydrocarbazole (3a) (40 mg, 0.12 mmol), benzyl amine (16 µL, 0.26 mmol) and Yb(OTf)3 (3.7 mg, 0.006 mmol) were taken in benzene (1.0 mL, 8 mL /mmol) in a round bottom flask fitted with a DS apparatus. The reaction mixture was heated to reflux temperature for 13 h. The


Page 24 of 37

Page 25 of 37 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


reaction mass was cooled and the solvent was evaporated under reduced pressure to get the crude product. The obtained crude product was purified by silica gel column chromatography using mixture of ethyl acetate/hexanes. Yield (39 mg, 80%); Yellow solid; m.p. = 172-173 ˚C; Rf = 0.56 in 1:3 EtOAc/hexanes; 1H NMR (400 MHz, CDCl3): δ 9.90 (br s, 1H), 9.59 (br s, 1H), 8.45 (d, J = 8.0 Hz, 1H), 7.61 (s, 1H), 7.44-7.31 (m, 5H), 7.25-7.20 (m, 1H), 7.14 (t, J = 7.3 Hz, 1H), 4.60 (q, J = 7.2 Hz, 2H), 4.47 (q, J = 7.2 Hz, 2H), 1.57 (t, J = 7.1 Hz, 3H), 1.41 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 168.1, 167.7, 146.8, 142.3, 140.8, 139.2, 131.1, 129.6, 125.1, 124.1, 123.4, 122.6, 121.9, 120.3, 113.3, 110.4, 109.0, 97.9, 61.7, 61.6, 14.7, 14.4; IR (KBr, cm-1): υ 3466, 3450, 1722, 1679, 1593, 1497, 1322, 1257, 1147; HRMS (ESI-Q-TOF) m/z calcd for C24H23N2O4+ (M + H)+ 403.1652, found 403.1647. Diethyl 2-(benzylamino)-9H-carbazole-1,4-dicarboxylate (6c): The above procedure was followed using 40 mg of 3a. It took 16 h for the completion of the reaction. Yield (36 mg, 74%) ; Yellow gum; Rf = 0.50 in 1:3 EtOAc/hexanes; 1H NMR (400 MHz, CDCl3): δ 9.94 (br s, 1H), 8.43 (d, J = 8.1 Hz, 1H), 8.22 (br s, 1H), 7.43-7.28 (m, 7H), 7.20 (t, J = 8.0 Hz, 1H), 7.10 (s, 1H), 4.55 (s, 2H), 4.53-4.47 (m, 4H), 1.48 (t, J = 7.1 Hz, 3H), 1.45 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 168.4, 167.9, 149.9, 142.8, 139.0, 138.6, 131.5, 128.9, 127.6, 124.8, 123.2, 122.0, 120.1, 111.9, 110.3, 106.6, 96.0, 61.6, 61.3, 48.0, 14.7, 14.4; IR (KBr, cm-1): υ 3470, 3427, 2978, 1722, 1677, 1603, 1462, 1256, 1172; HRMS (ESI-Q-TOF) m/z calcd for C25H25N2O4+ (M + H)+ 417.1809, found 417.1808. Synthesis of diethyl 1-methyl-2-oxo-2,3,4,9-tetrahydro-1H-carbazole-1,4-dicarboxylate (7a): Tetrahydrocarbazole (3a) (50 mg, 0.15 mmol) and K2CO3 (48 mg, 0.34 mmol) were taken in dry CH3CN, (1 mL, 7 mL/mmol) and stirred at room temperature. After stirring the reaction for 30 min, methyl iodide (lot-1) (40 µL, 0.30 mmol) was added and continued stirring for 1 h. Again, methyl iodide (lot-2) (40 µL, 0.30 mmol) was added and stirred for 1.5 h. Then, the reaction mas was filtered. The obtained filtrate was evaporated and the crude product was purified by silica gel column chromatography using mixture of ethyl acetate/hexanes. Yield (44.0 mg, 85%); dr = 1:0.88; Yellow gum; Rf = 0.45 in 1:3 EtOAc/hexanes; Major isomer : 1H NMR (500 MHz, CDCl3): δ 8.65 (br s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.40-7.37 (m, 1H), 7.28-7.16 (m, 2H), 4.31 (t, J = 6.0 Hz, 1H), 4.32-4.08 (m, 4H), 3.32 (dd, J = 14.6, 5.8 Hz, 1H), 2.96 (dd, J = 14.7, 6.5 Hz,



1H), 1.79 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) : δ 204.2, 172.3, 170.7, 137.0, 134.0, 125.7, 123.0, 120.5, 120.4, 119.4, 119.0, 111.5, 107.7, 62.5, 61.4, 55.7, 38.8, 38.6, 22.0, 14.2, 13.9; Minor isomer : 1H NMR (500 MHz, CDCl3): δ 8.66 (br s, 1H), 7.72 (d, J = 7.7 Hz, 1H), 7.40-7.37 (m, 1H), 7.28-7.16 (m, 2H), 4.38 (dd, J = 6.4, 1.8 Hz, 1H), 4.26-4.08 (m, 4H), 3.17 (dd, J = 14.7, 6.6 Hz, 1H), 3.04 (dd, J = 14.6, 1.6 Hz, 1H), 1.79 (s, 3H), 1.22-1.19 (m, 6H);

13

C{1H} NMR (125 MHz, CDCl3) : δ 203.8,

173.0, 170.9, 136.7, 134.8, 125.7, 123.0, 120.4, 119.0, 111.4, 107.8, 62.6, 61.5, 55.0, 41.2, 40.0, 22.0, 14.1, 14.0; IR (KBr, cm-1): υ 3377, 2983, 1736, 1458, 1242, 1180, 1099, 1029; HRMS (ESI-Q-TOF) m/z calcd for C19H21NNaO5+ (M + Na)+ 366.1312, found 366.1316. Synthesis of C-alkylated carbazoles (7b-d): The reactions were carried out using 50 mg of 3a in each experiment and 1.1 equiv. of corresponding alkyl bromide using in single lot. It took, respectively, 5 h, 5h and 6h for the synthesis of 7b, 7c and 7d. Diethyl 1-allyl-2-oxo-2,3,4,9-tetrahydro-1H-carbazole-1,4-dicarboxylate (7b): Yield (49 mg, 88%); dr = 1 : 0.61; Colourless gum; Rf = 0.64 in 1:3 EtOAc/hexanes; Major isomer : 1H NMR (500 MHz, CDCl3): δ 8.56 (br s, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.37-7.35 (m, 1H), 7.25-7.21 (m, 1H), 7.18-7.14 (m, 1H), 5.46-5.38 (m, 1H), 5.07-4.96 (m, 2H), 4.25 (t, J = 6.2 Hz, 1H), 4.22-4.04 (m, 4H), 3.26-3.20 (m, 1H), 3.11-2.98 (m, 2H), 2.77 (dd, J = 15.0, 6.3 Hz, 1H), 1.26-1.15 (m, 6H);

13

C{1H} NMR (125 MHz, CDCl3) : δ 203.5, 172.3, 169.9, 137.1, 132.5, 132.0, 125.8,

123.0, 120.4, 119.4, 119.2, 111.5, 109.5, 62.5, 61.4, 59.9, 41.9, 40.1, 38.4, 14.3, 13.9; Minor isomer : 1H NMR (500 MHz, CDCl3): δ 8.51 (br s, 1H), 7.71 (d, J = 7.9 Hz, 1H), 7.37-7.35 (m, 1H), 7.25-7.21 (m, 1H), 7.18-7.14 (m, 1H), 5.61-5.52 (m, 1H), 5.03-4.96 (m, 2H), 4.89-4.86 (m, 1H), 4.34 (dd, J = 6.1, 2.8 Hz, 1H), 4.22-4.04 (m, 4H), 3.24-3.20 (m, 1H), 3.11-2.98 (m, 2H), 1.26-1.15 (m, 6H);

13

C{1H} NMR (125 MHz, CDCl3) : δ 202.3, 172.6, 169.9, 136.9, 132.5,

132.0, 125.9, 123.0, 120.1, 119.4, 119.2, 111.4, 109.4, 62.7, 61.4, 59.4, 41.1, 39.3, 38.5, 14.2, 14.0; IR (KBr, cm-1): υ 3370, 3091, 2987, 1727, 1459, 1024, 850; HRMS (ESI-Q-TOF) m/z calcd for C21H24NO5 (M + H)+ 370.1649, found 370.1644. Diethyl 1-(3-methylbut-2-en-1-yl)-2-oxo-2,3,4,9-tetrahydro-1H-carbazole-1,4-dicarboxylate (7c): Yield (54 mg, 90%); dr = 1 : 0.46; Colorless gum; Rf = 0.56 in 1:3 EtOAc/hexanes; Major isomer : 1H NMR (400 MHz, CDCl3): δ 8.21 (br s, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.24-7.22 (m, 1H), 7.12-7.14 (m, 1H), 4.76-4.72 (m, 1H), 4.24-4.03 (m, 5H), 3.19


Page 26 of 37

Page 27 of 37 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


(dd, J = 15.0, 5.4 Hz, 1H), 3.15-3.08 (m, 1H), 2.86 (dd, J = 14.5, 5.3 Hz, 1H), 2.72 (dd, J = 15.0, 6.4 Hz, 1H), 1.52 (s, 6H), 1.26-1.16 (m, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 204.1, 172.4, 170.3, 137.0, 136.8, 132.6, 125.9, 122.8, 120.2, 117.4, 111.4, 109.2, 62.4, 61.4, 59.7, 41.8, 38.3, 34.8, 25.9, 18.0, 14.2, 13.9; Minor isomer : 1H NMR (400 MHz, CDCl3): δ 8.29 (br s, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.26-7.21 (m, 1H), 7.12-7.14 (m, 1H), 4.884.84 (m, 1H), 4.32 (dd, J = 5.9, 3.0 Hz, 1H), 4.24-4.03 (m, 5H), 3.15-3.08 (m, 1H), 3.05-3.00 (m, 2H), 2.93 (dd, J = 14.6, 6.6 Hz, 1H), 1.56 (s, 6H), 1.26-1.16 (m, 6H);

13

C{1H} NMR (100 MHz,

CDCl3): δ 202.8, 172.5, 170.3, 136.9, 135.8, 133.0, 126.0, 122.9, 119.4, 118.0, 111.4, 109.1, 62.5, 61.3, 59.4, 41.1, 38.3, 33.9, 25.9, 17.9, 14.2, 14.0; IR (KBr, cm-1): υ 3370, 2982, 2915, 1732, 1459, 1226, 1025, 741; HRMS (ESI-Q-TOF) m/z calcd for C23H28NO5 (M + H)+ 398.1962, found 398.1961. Diethyl 2-oxo-1-(prop-2-yn-1-yl)-2,3,4,9-tetrahydro-1H-carbazole-1,4-dicarboxylate (7d): Yield (46 mg, 83%); dr = 1 : 0.59; Colorless gum; Rf = 0.61 in 1:3 EtOAc/hexanes; Major isomer: 1H NMR (500 MHz, CDCl3): δ 8.65 (br s, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.39 (d, J = 7.7 Hz, 1H), 7.30-7.25 (m, 1H), 7.23-7.17 (m, 1H), 4.36 (t, J = 6.0 Hz, 1H), 4.31-4.07 (m, 4H), 3.35-3.28 (m, 2H), 3.14-2.90 (m, 2H), 2.01 (t, J = 2.6 Hz, 1H), 1.30-1.18 (m, 6H); 13C{1H} NMR (125 MHz, CDCl3): δ 202.4, 172.2, 168.7, 137.0, 131.5, 125.6, 123.2, 120.4, 119.5, 111.6, 109.8, 79.3, 72.5, 62.9, 61.5, 59.0, 41.2, 38.5, 25.6, 14.3, 13.9; Minor isomer : 1H NMR (500 MHz, CDCl3): δ 8.80 (br s, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.41 (d, J = 7.9 Hz, 1H), 7.30-7.25 (m, 1H), 7.23-7.17 (m, 1H), 4.40 (dd, J = 6.2, 2.4 Hz, 1H), 4.29-4.07 (m, 4H), 3.54 (dd, J = 17, 2.7 Hz, 1H), 3.14-2.90 (m, 2H), 2.13 (t, J = 2.6 Hz, 1H), 1.30-1.18 (m, 6H); 13C{1H} NMR (125 MHz, CDCl3): δ 200.7, 172.7, 168.1, 136.7, 132.6, 125.4, 123.2, 120.4, 119.3, 111.6, 109.3, 79.3, 72.5, 63.0, 61.6, 58.9, 40.6, 38.7, 25.0, 14.2, 14.0; IR (neat, cm-1): υ 3375, 3282, 2981, 2937, 2906, 1723, 1456, 1231, 1184, 1030; HRMS (ESI-Q-TOF) m/z calcd for C21H21NNaO5+ (M + Na)+ 390.1312, found 390.1312. Synthesis of Diethyl 5,7-dihydroindolo[2,3-b]carbazole-6,12-dicarboxylate (8a): A 70:30 mixture of dimethyl urea and L-tartaric acid (1.5 g) was taken in a round bottom flask and heated to 85 ˚C till the solids melt to liquid. Then phenyl hydrazine hydrochloride (47.5 mg, 0.33 mmol) and compound 3a (100 mg, 0.30 mmol) were added in sequence at 85 ˚C and maintained at the same temperature for 2 h. After completion of the reaction as monitored by



TLC, H2O (5 mL) was added to the reaction mass at 85 ˚C and stirred for another 10 minutes and brought to room temperature. Then, the product from the reaction mass was extracted using ethyl acetate (10 mL). The organic layer was dried using anhydrous sodium sulfate and evaporated under reduced pressure to get the crude product. The obtained crude product was purified by silica gel column chromatography using mixture of ethyl acetate/hexanes. Yield (42 mg, 35%); Fluorescent yellow solid; m.p. = 232-233 ˚C; Rf = 0.51 in 1:3 EtOAc/hexanes; 1H NMR (400 MHz, CDCl3): δ 9.94 (br s, 2H), 8.01-7.99 (m, 2H), 7.53-7.51 (m, 2H), 7.46-7.42 (m, 2H), 7.297.25 (m, 2H), 4.82 (q, J = 7.2 Hz, 2H), 4.68 (q, J = 7.2 Hz, 2H), 1.64 (t, J = 7.2 Hz, 3H), 1.57 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 169.0, 167.4, 140.3, 140.0, 125.9, 125.6, 121.7, 121.1, 120.4, 114.8, 111.0, 94.3, 62.4, 61.7, 15.0, 14.4; IR (KBr, cm-1): υ 3465, 3424, 2981, 1725, 1686, 1605, 1461, 1322, 1244, 1179, 1025; HRMS (ESI-Q-TOF) m/z calcd for C24H20N2NaO4+ (M + Na)+ 423.1315, found 423.1316. Synthesis of pyrazolo[4,3-a] carbazole (9a and 9b) A 70:30 mixture of dimethyl urea and L-tartaric acid (1.5 g) was taken in a round bottom flask and heated to 85 ˚C till the solids melt to liquid. Then phenyl hydrazine hydrochloride (35.2 mg, 0.24 mmol) and compound 7a (76 mg, 0.22 mmol) were added in sequence at 85 ˚C and reacted at the same temperature for 2 h. After completion of the reaction as monitored by TLC, H2O (5 mL) was added to the reaction mass at 85 ˚C and stirred for another 10 minutes and brought to room temperature. Then, the product from the reaction mass was extracted using (2 × 5 mL) ethyl acetate. The combined organic layer was dried using anhydrous sodium sulfate and evaporated under reduced pressure to get the crude product. The obtained crude product was purified by silica gel column chromatography using mixture of ethyl acetate/hexanes to separate 9a and 9b in (40 mg (48%) and 36 mg (42%) respectively. 9a: Colorless solid; m.p. = 199-200 ˚C; Rf = 0.67 in 1:3 EtOAc/hexanes; 1H NMR (400 MHz, CDCl3): δ 9.03 (br s, 1H), 7.91 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 8.0 Hz, 1H), 7.43-7.39 (m, 2H), 7.36 (d, J = 8.1 Hz, 1H), 7.23-7.18 (m, 2H), 7.13-7.10 (m,1H), 4.36-4.24 (m, 3H), 3.39-3.28 (m, 2H), 1.87 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 173.9, 173.3, 164.4, 137.9, 137.0, 131.5, 129.1, 125.7, 125.6, 123.0, 120.4, 119.4, 119.1, 111.8, 107.6, 61.8, 50.7, 41.8, 26.8, 23.6, 13.4; IR (KBr, cm-1): υ 3355, 2978, 1697, 1596, 1496,1456, 1179, 1032; HRMS (ESI-Q-TOF) m/z calcd for C23H22N3O3+ (M + H)+ 388.1656, found 388.1655.


Page 28 of 37

Page 29 of 37 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


9b: Yield Colorless solid; m.p. = 185-186 ˚C; Rf = 0.54 in 1:3 EtOAc/hexanes; 1H NMR (400 MHz, CDCl3): δ 8.74 (br s, 1H), 7.92 (d, J = 7.7 Hz, 2H), 7.62 (d, J = 7.9 Hz, 1H), 7.43-7.37 (m, 3H), 7.24-7.18 (m, 2H), 7.15-7.11 (m, 1H), 4.39-4.37 (m, 1H), 4.12-4.04 (m, 2H), 3.35-3.31 (m, 1H), 3.12-3.07 (m, 1H), 1.76 (s, 3H), 1.45 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 173.9, 172.3, 163.9, 138.1, 137.2, 131.8, 129.0, 126.0, 125.5, 123.0, 120.3, 119.6, 119.3, 111.8, 107.3, 61.4, 50.8, 40.4, 26.7, 24.4, 14.2; IR (KBr, cm-1): υ 3340, 2980, 2269, 1695, 1497, 1367, 1319, 1284, 1779; HRMS (ESI-Q-TOF) m/z calcd for C23H22N3O3+ (M + H)+ 388.1656, found 388.1653. Synthesis

of

diethyl

10-methyl-7-oxo-6,7,8,9-tetrahydropyrido[1,2-a]indole-6,9-

dicarboxylate (11a): To a solution of (E)-diethyl 5-diazo-4-oxohex-2-enedioate (1) (50 mg, 0.21 mmol) and 3-methyl indole (10a) (32.8 mg, 0.25 mmol) in dry CH2Cl2, (1.5 mL, 7 mL/mmol) Sc(OTf)3 ( 2.0 mg, 0.004 mmol) was added at room temperature and heated to reflux. The reaction mass was maintained at reflux for 3 h. The reaction mass was cooled to room temperature. Rh2(Oct)4 (3.3 mg, 0.004 mmol) was added to the reaction mass at room temperature and maintained at the same temperature for 1 h. Then, the solvent was removed under reduced pressure and the product was isolated by column chromatography using mixture of ethyl acetate and hexanes. Yield (48 mg, 67%); Brown solid; m.p. = 127-128 ˚C; Rf = 0.57 in 1:3 EtOAc/hexanes; 1H NMR (400 MHz, CDCl3) Major isomer : δ 7.60-7.56 (m, 1H), 7.23-7.15 (m, 2H), 7.08 (d, J = 7.9, 1H), 5.53 (s, 1H), 4.40 (dd, J = 5.8, 1.9 Hz, 1H), 4.30-4.17 (m, 2H), 4.15-4.05 (m, 2H), 3.20 (dd, J = 16.6, 1.7 Hz, 1H), 2.73 (dd, J = 16.5, 5.7 Hz, 1H), 2.41 (s, 3H), 1.28-1.19 (m, 6H);

13

C{1H}

NMR (100 MHz, CDCl3): δ 196.9, 170.9, 165.1, 135.8, 129.3, 126.9, 122.5, 120.5, 119.4, 109.7, 109.1, 108.4, 65.0, 62.8, 62.1, 39.4, 37.4, 14.0, 8.7; Minor isomer : 1H NMR (400 MHz, CDCl3): δ 7.60-7.56 (m, 1H), 7.23-7.15 (m, 2H), 7.08 (d, J = 7.9, 1H), 5.50 (s, 1H), 4.50 (dd, J = 5.5, 2.9 Hz, 1H), 4.30-4.17 (m, 2H), 4.15-4.05 (m, 2H), 3.10 (dd, J = 15.0, 5.6 Hz, 1H), 3.01 (dd, J = 15.0, 2.9 Hz, 1H), 2.36 (s, 3H), 1.28-1.19 (m, 6H);

13


197.0, 171.2, 165.9, 135.6, 129.4, 126.8, 125.9, 122.7, 120.5, 119.4, 109.6, 109.1, 66.9, 63.1, 62.1, 39.1, 38.7, 14.2, 8.6; IR(KBr, cm-1): υ 2982, 2931, 1738, 1459, 1367, 1335, 1299, 1190, 1020, 746; HRMS (ESI-Q-TOF) m/z calcd for C19H22NO5 (M + H)+ 344.1492, found 344.1492.



Diethyl

2-methoxy-10-methyl-7-oxo-6,7,8,9-tetrahydropyrido[1,2-a]indole-6,9-

dicarboxylate (11b): To a solution of (E)-diethyl 5-diazo-4-oxohex-2-enedioate (1) (60 mg, 0.25 mmol) and 3-methyl indole (10b) (48 mg, 0.30 mmol ) in dry CH2Cl2, (1.8 mL, 7 mL/mmol) Sc(OTf)3 ( 2.5 mg, 0.005 mmol) was added at room temperature and heated to reflux. The reaction mass was maintained at reflux for 6 h. The reaction mass was cooled to room temperature. Rh2(Oct)4 (3.9 mg, 0.005 mmol) was added to the reaction mass at room temperature and maintained at the same temperature for 2 h. Then, the solvent was removed under reduced pressure and the product was isolated by column chromatography using mixture of ethyl acetate and hexanes. Yield (60 mg, 65%); Brown gum; Rf = 0.42 in 1:3 EtOAc/hexanes; Major isomer : 1H NMR (400 MHz, CDCl3): δ 7.03-6.97 (m, 3H), 5.48 (s, 1H), 4.39 (dd, J = 5.7, 2.0 Hz, 1H), 4.31-4.16 (m, 2H), 4.14-4.03 (m, 2H), 3.87 (s, 3H), 3.18 (dd, J = 16.5, 2.0 Hz, 1H), 2.73 (dd, J = 16.5, 5.7 Hz, 1H), 2.37 (s, 3H), 1.27-1.19 (m, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 197.0, 171.2, 165.1, 154.9, 131.0, 129.8, 127.6, 112.5, 109.9, 109.2, 101.6, 65.0, 62.7, 62.1, 56.1, 39.3, 37.5, 14.1, 8.8; Minor isomer : 1H NMR (400 MHz, CDCl3): δ 6.87-6.83 (m, 3H), 5.44 (s, 1H), 4.47 (dd, J = 5.8, 2.9 Hz, 1H), 4.31-4.16 (m, 2H), 4.14-4.03 (m, 2H), 3.86 (s, 3H), 3.09 (dd, J = 15.1, 5.7 Hz, 1H), 2.98 (dd, J = 15.0, 3.0 Hz, 1H), 2.32 (s, 3H), 1.27-1.19 (m, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 197.1, 171.2, 166.0, 154.9, 130.8, 129.9, 126.6, 112.5, 109.9, 109.4, 101.5, 66.9, 63.0, 62.1, 56.0, 39.2, 38.6, 14.2, 8.7; IR(neat, cm-1): υ 3360, 2978, 2931, 1737, 1680, 1620, 1482, 1370, 1236, 1190, 1030, 859, 806; HRMS (ESI-Q-TOF) m/z calcd for C20H24NO6 (M + H)+ 374.1598, found 374.1592.

ASSOCIATED CONTENT Supporting Information NMR data of all the prepared compounds with spectra and X-ray crystallographic data of 3l, 8a and 9a. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author *[email protected]


Page 30 of 37

Page 31 of 37 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


ACKNOWLEDGMENT The authors thank UPE II-UGC, PURSE-DST and SERB for financial support. S.S thanks the Council of Scientific and Industrial Research (CSIR), India for a fellowship.

REFERENCES 1) For reviews on diazo chemistry, see: (a) Guttenberger, N.; Breinbauer, R. C-H and C-C Bond Insertion Reactions of Diazo Compounds into Aldehydes. Tetrahedron 2017, 73, 6815-6829. (b) Santiago, J. V.; Machado, A. H. L. Enantioselective Carbenoid Insertion into C(sp3)–H Bonds. Beilstein J. Org. Chem. 2016, 12, 882-902. (c) Fructos, M. R.; Diáz-Requejo, M. M.; Pérez, P. J. Gold and Diazo Reagents: A Fruitful Tool for Developing Molecular Complexity. Chem. Commun. 2016, 52, 7326-7335. (d) Candeias, N. R.; Paterna, R.; Gois P. M. P. Homologation Reaction of Ketones with Diazo Compounds. Chem. Rev. 2016, 116, 2937-2981. (e) Gillingham, D.; Fei, N. Catalytic X– H Insertion Reactions Based on Carbenoids. Chem. Soc. Rev. 2013, 42, 4918-4931. (f) Davies, H. M. L.; Morton, D. Guiding Principles for Site Selective and Stereoselective Intermolecular C-H Functionalization by Donor/Acceptor Rhodium Carbenes. Chem. Soc. Rev. 2011, 40, 1857-1869. (g) Ford, A.; Miel, H.; Ring, A.; Slattery, C. N.; Maguire, A. R.; McKervey, M. A. Modern Organic Synthesis with α Diazocarbonyl Compounds. Chem. Rev. 2015, 115, 9981-10080. (h) Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L. Catalytic Carbene Insertion into C-H Bonds. Chem. Rev. 2010, 110, 704-724. 2) Mix, K. A.; Aronoff, M. R.; Raines, R. T. Diazo Compounds: Versatile Tools for Chemical Biology. ACS Chem. Biol. 2016, 11, 3233-3244. 3) (a) Cheng, Q. Q.; Yu, Y.; Yedoyan, J.; Doyle, M. P. Vinyldiazo Reagents and Metal Catalysts: A Versatile Toolkit for Heterocycle and Carbocycle Construction. ChemCatChem 2018, 10, 488-496. (b) Cheng, Q. Q.; Deng, Y.; Lankelma, M.; Doyle, M. P. Cycloaddition Reactions of Enoldiazo Compounds. Chem. Soc. Rev. 2017, 46, 54255443. (c) Parr, B. T.; Davies, H. M. L. Stereoselective Synthesis of Highly Substituted Cyclohexanes by a Rhodium-Carbene Initiated Domino Sequence. Org. Lett. 2015, 17, 794-797. (d)

Parr, B. T.; Davies, H. M. L. Highly Stereoselective Synthesis of

Cyclopentanes Bearing Four Stereocentres by a Rhodium Carbene-Initiated Domino Sequence. Nat. Commun. 2014, 5, 1-12. (e) Spangler, J. E.; Lian, Y.; Raikar, S. N.;



Page 32 of 37

Davies, H. M. L. Synthesis of Complex Hexacyclic Compounds via a Tandem Rh(II)Catalyzed Double-Cyclopropanation/Cope Rearrangement/Diels-Alder Reaction. Org. Lett. 2014, 16, 4794-4797. (f) Dawande, S. G.; Lad, B. S.; Prajapati, S.; Katukojvala, S. Rhodium-Catalyzed Pyridannulation of Indoles with Diazoenals: A Direct Approach to Pyrido[1,2-A]-indoles. Org. Biomol. Chem. 2016, 14, 5569-5573. (g) Dawande, S. G.; Kanchupalli, V.; Kalepu, J.; Chennamsetti, H.; Lad, B. S.; Katukojvala, S. Rhodium Enalcarbenoids: Direct Synthesis of Indoles by Rhodium(II)-Catalyzed [4+2] Benzannulation of Pyrroles. Angew. Chem., Int. Ed. 2014, 53, 4076-4080. (h) Burtoloso, A. C. B.; Dias, R. M. P.; Bernardim, B. α,β-Unsaturated Diazoketones as Useful Platforms in the Synthesis of Nitrogen Heterocycles. Acc. Chem. Res. 2015, 48, 921-934. 4) (a) Davies, H. M. L.; Lian, Y. The Combined C-H Functionalization/Cope Rearrangement: Discovery and Applications in Organic Synthesis. Acc. Chem. Res. 2012, 45, 923-935. (b) Xu, X.; Wang, X.; Zavalij, P. Y.; Doyle, M. P. Straightforward Access to

the

[3.2.2]Nonatriene

Structural

Framework

via

Intramolecular

Cyclopropenation/Buchner Reaction/Cope Rearrangement Cascade. Org. Lett. 2015, 17, 790-793. (c) Wang, X.; Abrahams, Q. M.; Zavalij, P. Y.; Doyle, M. P. Highly Regio- and Stereoselective Dirhodium Vinylcarbene Induced Nitrone Cycloaddition with Subsequent Cascade Carbenoid Aromatic Cycloaddition/N-O Cleavage and Rearrangement. Angew. Chem., Int. Ed. 2012, 51, 5907-5910. (d) Liu, Y.; Doyle, M. P. Michael Addition/Pericyclization/Rearrangement - A Multicomponent Strategy for the Synthesis of Substituted Resorcinols. Org. Biomol. Chem. 2012, 10, 6388-6394. (e) Egger, L.; Guénée, L.; Bürgi, T.; Lacour, J. Regioselective and Enantiospecific Synthesis of Dioxepines by (Cyclopentadienyl)ruthenium-Catalyzed Condensations of Diazocarbonyls and Oxetanes. Adv. Synth. Catal. 2017, 359, 2918-2923. (f) Poggiali, D.; Homberg, A.; Lathion, T.; Piguet, C.; Lacour, L. Kinetics of Rh(II)-Catalyzed α‑Diazo-β-ketoester Decomposition and Application to the [3+6+3+6] Synthesis of Macrocycles on a Large Scale and at Low Catalyst Loadings. ACS Catal. 2016, 6, 4877-4881. (g) Alamsetti, S. H.; Spanka, M.; Schneider, C. Synergistic Rhodium/Phosphoric Acid Catalysis for the Enantioselective Addition of Oxonium Ylides to ortho-Quinone Methides. Angew. Chem., Int. Ed. 2016, 55, 2392-2396. (h) Rix, D.; Rafael, B.-G.; Zeghida, W.; Besnard,


Page 33 of 37 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


C.; Lacour, J. Macrocyclization of Oxetane Building Blocks with Diazocarbonyl Derivatives under Rhodium(II) Catalysis. Angew. Chem., Int. Ed. 2011, 50, 7308-7311. 5) (a) Ramachandran, P. V.; Rudd, M. T.; Reddy, M. V. R. Stereoselective Synthesis of Hex-2-(E)-En-4-Yn-1,6-Dioates and E,Z-Muconic Acid Diesters via Organo-Catalyzed Self-Coupling of Propiolates. Tetrahedron Lett. 2005, 46, 2547-2549. (b) Chandrahas, T.; Thota, G. K.; Balamurugan, R. Efficient Synthesis of Functionalized β-Keto Esters and β -Diketones through Regioselective Hydration of Alkynyl Esters and Alkynyl Ketones by Use of a Cationic NHC–AuI Catalyst. Eur. J. Org. Chem. 2016, 5855-5861. 6) (a) Bartoli, G.; Bartolacci, M.; Bosco, M.; Foglia, G.; Giuliani, A.; Marcantoni, E.; Sambri, L.; Torregiani. E. The Michael Addition of Indoles to α,β-Unsaturated Ketones Catalyzed by CeCl3.7H2O-NaI Combination Supported on Silica Gel. J. Org. Chem. 2003, 68, 4594-4597. (b) Austin, J. F.; MacMillan, D. W. C. Enantioselective Organocatalytic Indole Alkylations. Design of a New and Highly Effective Chiral Amine for Iminium Catalysis. J. Am. Chem. Soc. 2002, 124, 1172-1173. (c) Evans, D. A.; Scheidt, K. A.; Fandrick, K. R.; Lam, H. W.; Wu, J. Enantioselective Indole FriedelCrafts

Alkylations

Catalyzed

by

Bis(oxazolinyl)pyridine-Scandium(III)

Triflate

Complexes. J. Am. Chem. Soc. 2003, 125, 10780-10781. (d) Rasappan, R.; Hager, M.; Gissibl, A.; Reiser, O. Highly Enantioselective Michael Additions of Indole to Benzylidene

Malonate

Using

Simple

Bis(oxazoline)

Ligands:

Importance

of

Metal/Ligand Ratio. Org. Lett. 2006, 8, 6099-6102. 7) (a) Lu, X.-L.; Liu, Y.-T.; Wang, Q.-X.; Shen, M.-H.; Xu, H.-D. Straightforward Regioselective Construction of 3,4-Dihydro-2H-1,4-Thiazine by Rhodium Catalyzed [3 + 3] Cycloaddition of Thiirane with 1-Sulfonyl-1,2,3-Triazole: A Pronounced Acid Additive Effect. Org. Chem. Front. 2016, 3, 725-729. (b) Wang, Y.; Leia, X.; Tang, Y. Rh(II)-Catalyzed

Cycloadditions

of

1-Tosyl

1,2,3-Triazoles

with

2H-Azirines:

Switchable Reactivity of Rh-Azavinylcarbene as [2C]- or Aza-[3C]-Synthon. Chem. Commun. 2015, 51, 4507-4510. (c) Zhang, Y.-S.; Tang, X.-Y.; Shi, M. Divergent Synthesis of Indole-Fused Polycycles via Rh(II)-Catalyzed Intramolecular [3 + 2] Cycloaddition and C-H Functionalization of Indolyltriazoles. Org. Chem. Front. 2015, 2, 1516-1520.



8) (a) Gao, X.; Wu, B.; Yan, Z.; Zhou, Y-G. Copper-Catalyzed Enantioselective C–H Functionalization of Indoles with an Axially Chiralbipyridine Ligand. Org. Biomol. Chem. 2016, 14, 8237-8240. (b) Gao, X.; Wu, B.; Huang, W-X.; Chen, M-W.; Zhou, YG. Enantioselective Palladium-Catalyzed C-H Functionalization of Indoles Using an Axially Chiral 2,2ʹ-Bipyridine Ligand. Angew. Chem., Int. Ed. 2015, 54, 11956-11960. (c) Xing, D.; Jing, C.; Li, X.; Qiu, H.; Hu, W. Highly Efficient Synthesis of Mixed 3,3ʹBisindoles via Rh(II)-Catalyzed Three-Component Reaction of 3‑Diazooxindoles with Indoles and Ethyl Glyoxylate. Org. Lett. 2013, 15, 3578-3581. (d) Lian, Y.; Davies, H. M. L. Rh2(S-biTISP)2-Catalyzed Asymmetric Functionalization of Indoles and Pyrroles with Vinylcarbenoids. Org. Lett. 2012, 14, 1934-1937. (e) Qiu, H.; Zhang, D.; Liu, S.; Qiu, L.; Zhou, J.; Qian, Y.; Zhai, C.; Hu, W. Asymmetric C-H Functionalization of Indoles via Enantioselective Protonation. Acta Chim. Sinica 2012, 70, 2484-2488. (f) DeAngelis, A.; Shurtleff, V. W.; Dmitrenko, O.; Fox, J. M. Rhodium(II)-Catalyzed Enantioselective C-H Functionalization of Indoles. J. Am. Chem. Soc. 2011, 133, 16501653. (g) Johansen, M. B.; Kerr, M. A. Direct Functionalization of Indoles: CopperCatalyzed Malonyl Carbenoid Insertions. Org. Lett. 2010, 12, 4956-4959. For reviews on carbenoid insertion on electron rich heterocycles, see: (h) Li, Yi-P.; Li, Z-Q.; Zhu, S.-F. Recent Advances in Transition-Metal-Catalyzed Asymmetric Reactions of Diazo Compounds with Electron-Rich (Hetero-) Arenes. Tetrahedron Lett. 2018, 59, 23072316. (i) Davies, H. M. L.; Hedley, S. J. Intermolecular Reactions of Electron-Rich Heterocycles with Copper and Rhodium Carbenoids. Chem. Soc. Rev. 2007, 36, 11091119. 9) (a) James, M. J.; O’Brien, P.; Taylor, R. J. K.; Unsworth, W. P. Selective Synthesis of Six Products from a Single Indolyl α-Diazocarbonyl Precursor. Angew Chem., Int. Ed. 2016, 55, 9671-9695. (b) Shanahan, C. S.; Truong, P.; Mason, S. M.; Leszczynski, J. S.; Doyle, M. P. Diazoacetoacetate Enones for the Synthesis of Diverse Natural Product-like Scaffolds. Org. Lett. 2013, 15, 3642-3645. (c) Wu, J.-Q.; Yang, Z.; Zhang, S.-S.; Jiang, C.-Y.; Li, Q.; Huang, Z.-S.; Wang, H. From Indoles to Carbazoles: Tandem Cp*Rh(III)Catalyzed C−H Activation/Brønsted Acid-Catalyzed Cyclization Reactions. ACS Catal. 2015, 5, 6453-6457. (d) Rathore, K. S.; Harode, M.; Katukojvala, S.


Page 34 of 37

Page 35 of 37 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


Regioselective Π-Extension of Indoles with Rhodium Enalcarbenoids-Synthesis of Substituted Carbazoles. Org. Biomol. Chem. 2014, 12, 8641-8645. 10) (a) Muratore, M. E.; Shi, L.; Pilling, A. W.; Storerc R. I.; Dixon, D. J. Exploiting a Novel Size Exclusion Phenomenon for Enantioselective Acid/Base Cascade Catalysis. Chem. Commun. 2012, 48, 6351-6353. (b) Fürstner, A.; Mamane, V. Flexible Synthesis of Phenanthrenes by a PtCl2-Catalyzed Cycloisomerization Reaction. J. Org. Chem. 2002, 67, 6264-6267. (c) Prieto, M.; Zurita, E.; Rosa, E.; Muñoz, L.; Lloyd-Williams, P.; Giralt, E. Arylboronic Acids and Arylpinacolboronate Esters in Suzuki Coupling Reactions Involving Indoles. Partner Role Swapping and Heterocycle Protection. J. Org. Chem. 2004, 69, 6812-6820. (d) Bose, A.; Mal, P. Using Weak Interactions to Control CH Mono-Nitration of Indolines. Chem. Commun. 2017, 53, 11368-11371. (e) Sinhababu, A. K.; Borchardt, R. T. Silica Gel Assisted Reductive Cyclization of Alkoxy-2,βdinitrostyrenes to Alkoxyindoles. J. Org. Chem. 1983, 48, 3347-3349. (f) LlabresCampaner, P. J.; Ballesteros-Garrido, R.; Ballesteros, R.; Abarca, B. Straight Access to Indoles from Anilines and Ethylene Glycol by Heterogeneous Acceptorless Dehydrogenative Condensation. J. Org. Chem. 2018, 83, 521-526. (g) Su, Y.-M.; Hou, Y.; Yin, F.; Xu, Y.-M.; Li, Y.; Zheng, X.; Wang, X.-S. Visible Light-Mediated C-H Difluoromethylation of Electron-Rich Heteroarenes. Org. Lett. 2014, 16, 2958-2961. (h) Greulich, T. W.; Daniliuc, C. G.; Studer, A. N‑Aminopyridinium Salts as Precursors for N‑Centered Radicals -Direct Amidation of Arenes and Heteroarenes. Org. Lett. 2015, 17, 254-257. (i) Xu, S.; Huang, X.; Hong, X.; Xu, B. Palladium-Assisted Regioselective C-H Cyanation of Heteroarenes Using Isonitrile as Cyanide Source. Org. Lett. 2012, 14, 4614-4617. 11) (a) Schmidt, A. W.; Reddy, K. R.; Knӧlker, H.-J. Occurrence, Biogenesis, and Synthesis of Biologically Active Carbazole Alkaloids. Chem. Rev. 2012, 112, 3193-3328. (b) Knӧlker, H.-J.; Reddy, K. R. Isolation and Synthesis of Biologically Active Carbazole Alkaloids. Chem. Rev. 2002, 102, 4303-4427. (c) Barea, E. M.; Zafer, C.; Gultekin, B.; Aydin, B.; Koyuncu, S.; Icli, S.; Santiago, F. F.; Bisquert, J. Quantification of the Effects of Recombination and Injection in the Performance of Dye-Sensitized Solar Cells Based on N-Substituted Carbazole Dyes. J. Phys. Chem. C 2010, 114, 19840-19848.



12) (a) Merk, D.; Lamers, C.; Weber, J.; Flesch, D.; Gabler, M.; Proschak, E.; Manfred, S.Z. Anthranilic Acid Derivatives as Nuclear Receptor Modulators-Development of Novel PPAR Selective and Dual PPAR/FXR Ligands. Bioorg. Med. Chem. 2015, 23, 499-514. (b) Cheng, Y.-D.; Hwang, T.-L.; Wang, H.-H.; Pan, T.-L.; Wu, C.-C.; Chang, W.-Y.; Liu, Y.-T.; Chu, T.-C.; Hsieh, P.-W. Anthranilic Acid-Based Inhibitors of Phosphodiesterase: Design, Synthesis, and Bioactive Evaluation. Org. Biomol. Chem. 2011, 9, 7113-7125. 13) For reviews on biologically active hybrid natural products, see: (a) Choudhary, S.; Singh, P. K.; Verma, H.; Singh, H.; Silakari, O. Success Stories of Natural Product-Based Hybrid Molecules for Multifactorial Diseases. Eur. J. Med. Chem. 2018, 151, 62-97. (b) Fershtat, L. L.; Makhova, N. N. Molecular Hybridization Tools in the Development of Furoxan-Based NO-Donor Prodrugs. ChemMedChem 2017, 12, 622-638. (c) Klahn, P.; Brӧnstrup, M. Bifunctional Antimicrobial Conjugates and Hybrid Antimicrobials. Nat. Prod. Rep. 2017, 34, 832-885. (d) Tietze, L. F.; Bell, H. P.; Chandrasekhar, S. Natural Product Hybrids as New Leads for Drug Discovery. Angew. Chem., Int. Ed. 2003, 42, 3996-4028. 14) (a) Wang, H.; Zhang, X.; Li, J. Structure and Fluorescent Performance of Waterborne Polyurethane-Acrylate Based on a Carbazole Derivative. Adv. Polym. Tech. 2018, 37, 16. (b) Chen, Z.; Li, H.; Zheng, X.; Zhang, Q.; Li, Z.; Hao, Y.; Fang, G. Low-Cost Carbazole-Based Hole-Transport Material for Highly Efficient Perovskite Solar Cells. ChemSusChem 2017, 10, 3111-3117. (c) Saritha G.; Mangalaraja, R. V.; Anandan, S. High-Efficiency Dye-Sensitized Solar Cells Fabricated Using D-D-P-A (Donor-Donor/πSpacer-Acceptor) Architecture. Solar Energy, 2017, 146, 150-160. (d) Wang, W.-D.; Hu, Y.; Li, Q.; Hu, S.-Li. A Carbazole-Based Turn-On Fluorescent Probe for the Detection of Hydrazine in Aqueous Solution. Inorg. Chim. Acta 2018, 477, 206-211. (e) Mishra, A. K.; Jacob, J.; Müllen, K. Synthesis of Aminocarbazol-Anthraquinone Fused Dyes and Polymers. Dyes Pigm. 2007, 75, 1-10. 15) Gore, S.; Baskaran, S.; Kӧnig, B. Fischer Indole Synthesis in Low Melting Mixtures. Org. Lett. 2012, 14, 4568-4571. 16) (a) Chao, W.-R.; Yean, D.; Amin, K.; Green, C.; Jong, L. Computer-Aided Rational Drug Design: A Novel Agent (SR13668) Designed to Mimic the Unique Anticancer Mechanisms of Dietary Indole-3-Carbinol to Block Akt Signaling. J. Med. Chem. 2007,


Page 36 of 37

Page 37 of 37 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


50, 3412-3415. (b) Janosik, T.; Wahlstrӧm, N.; Bergman, J. Recent Progress in the Chemistry and Applications of Indolocarbazoles. Tetrahedron 2008, 64, 9159-9180. 17) Su, J.-Y.; Lo, C.-Y.; Tsai, C.-H.; Chen, C.-H.; Chou, S.-H.; Liu, S.-H.; Chou, P.-T.; Wong, K.-T. Indolo[2,3‑b]carbazole Synthesized from a Double-Intramolecular Buchwald-Hartwig Reaction: Its Application for a Dianchor DSSC Organic Dye. Org. Lett. 2014, 16, 3176-3179. 18) (a) Taylor, D. L.; Ahmed, P. S.; Chambers, P.; Tyms, A. S.; Bedard, J.; Duchaine, J.; Falardeau, G.; Lavallee, J. F.; Brown, W.; Rando, R. F.; Bowlin, T. Pyrido [1,2a] Indole Derivatives Identified as Novel Non-Nucleoside Reverse Transcriptase Inhibitors of Human Immunodeficiency Virus Type 1. Antiviral Chem. Chemother. 1999, 10, 79-86. (b) Khdour, O.; Skibo, E. B. Chemistry of Pyrrolo[1,2-a]indole- and Pyrido[1,2-a]indoleBased

Quinone

Methides.

Mechanistic

Explanations

for

Differences

in

Cytostatic/Cytotoxic Properties. J. Org. Chem. 2007, 72, 8636-8647. (c) Molinaro, C.; Bulger, P. G.; Lee, E. E.; Kosjek, B.; Lau, S.; Gauvreau, D.; Howard, M. E.; Wallace, D. J.; O’Shea, P. D. CRTH2 Antagonist MK-7246: A Synthetic Evolution from Discovery through Development. J. Org. Chem. 2012, 77, 2299-2309. 19) Kim, H.; Choi, T.-L. Preparation of a Library of Poly(N‑sulfonylimidates) by CuCatalyzed Multicomponent Polymerization. ACS Macro Lett. 2014, 3, 791-794.


Annulation of a Highly Functionalized Diazo Building Block with

Recommend Documents