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Article

Sequential Annulations to Interesting Novel Pyrrolo[3,2-c]carbazoles

by
Alice Benzi
,
Lara Bianchi
,
Massimo Maccagno
,
Angela Pagano
,
Giovanni Petrillo
and
Cinzia Tavani
*
Department of Chemistry and Industrial Chemistry, Università di Genova, Via Dodecaneso 31, I-16146 Genova, Italy
*
Author to whom correspondence should be addressed.
Molecules 2019, 24(20), 3802; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24203802
Submission received: 30 September 2019 / Revised: 16 October 2019 / Accepted: 18 October 2019 / Published: 22 October 2019
(This article belongs to the Special Issue Indole Derivatives: Synthesis and Application)
Browse Figures
Versions Notes

Abstract

:
Herein we report a significant, valuable extension of a recently implemented pyrrole benzannulation methodology that, employing versatile nitrodienes from our lab as useful C4 building blocks, led to indole derivatives characterized by unusual patterns of substitution. The 6-nitro-7-arylindoles resulting from suitably derivatized, non-symmetric dienes are of foreseeable synthetic interest in search for new polyheterocyclic systems. As an example, pyrrolocarbazoles with a rarely reported ring fusion were synthesized with the classical Cadogan protocol. Furthermore, the proven easy reducibility of the nitro group to amine will surely open the way to further interesting elaborations.

Graphical Abstract

1. Introduction

Due to the outstanding importance of indole derivatives in many applicative fields—as natural products, pharmaceuticals, fine chemicals and materials, as well as core structures in more complex heterocyclic systems—their synthesis [1,2,3] keeps on being a very active research subject. Among the plethora of more or less recent methods, benzannulation has been surely less practiced with respect to heteroannulation. Actually, classic syntheses tend to build up the penta-atomic heteroring, exploiting the functionalities of properly derivatized benzene substrates [4], rather than assembling the hexa-atomic ring onto a pyrrolic starting material [4,5,6]. Only in recent years, some examples of benzannulating procedures in which a C4 building block is involved have been reported: an approach to be generally preferred when specific substituents are needed at the 4–7 positions, as they can be conveniently placed in the appropriate positions of the employed reagent. Examples of pericyclic processes are limited in number, including classic Diels-Alder reactions of electron-poor dienophiles like nitropyrroles [7], or hetero-Diels-Alder reactions of electron-rich N-methylpyrroles with 4,5-dicyanopyridazine [8]; more frequently, ionic processes have been reported, where various sources of the C4 fragment were used, combined with the appropriate pyrrole derivative. Beside traditional double electrophiles like 4-chloro-4-arylthiobutanoate [9], more recently, 2-butoxy-2,3-dihydrofurans [10], or γ-carbonyl-tert-butylperoxides [11] were employed; other methods rely on the efficiency of transition metal catalysis [12,13,14,15]. It should be also mentioned that the benzene ring of the final indole can be also built up starting from pyrrolic intermediates that already contain all, or some, of the carbon atoms of the eventual new ring.
In this context it should be placed our recent work on the benzannulation of indole [16,17], employing versatile nitrobutadienic building blocks (3, 4 in Scheme 1, parts a and c, respectively) obtained from the initial ring opening of suitably substituted nitrothiophenes (1, 2) [18,19,20]. Thus, mixtures of 2- and 3-nitro-, or 2,3-dinitro-1,4-diarylcarbazoles were obtained from indole by action of 2,3-dinitrobutadienes 3, while when employing mononitrobutadienes 4, 4-aryl-3-nitrocarbazoles were generated as the main products.
It should be said that the practical interest of such benzannulation processes was somehow diminished by their modest selectivity, leading in every case to mixtures of compounds. Interestingly enough, when we applied the same procedure on pyrrole [21] with the 2,3-dinitrobutadienes 3, the method’s outcomes were more gratifying from both the mechanistic and the synthetic point of view, thanks to the unexpected interception of a key intermediate (5, Scheme 1, part b), that allowed a definitely better selectivity to the whole process: actually, from the isolated 5, suitable procedures were optimized to generate either mononitro- or dinitro-indoles substituted in positions that are not easily accessible, for instance, by means of SEAr reactions.
Such interesting results encouraged us to proceed in that research by adding another tile to the picture. We present here, our very recent results obtained in the benzannulation of pyrrole with the non-symmetric 2-nitro-1,3-dienes 4, which opens the door to possible further elaborations, aimed at building-up new polyheterocyclic derivatives.

2. Results

2.1. Search for the Best Experimental Conditions

We started our research applying to the model substrate 4a (Ar = p-Tol) the same reaction conditions previously applied [21] to diene 3 (2 mol equiv of pyrrole, TFE, 50 °C). Here again, 24 h were necessary to observe, by TLC, the complete disappearance of 4a; the analysis of the chromatographed final reaction mixture highlighted the formation of three different indole derivatives (6a–8a, Scheme 2), 6a being by far the prevalent one (Table 1, entry 1). We considered satisfying the balance and good the selectivity, in favor of the derivative probably most appealing thanks to the preservation of the versatile nitro group.
Increasing the molar equivalents of pyrrole from 2 to 4, we obtained a faster reaction (Table 1, entry 2) with almost unchanged results. A gradual decrease of the temperature caused a progressive slowdown (entries 3 and 4), maintaining again almost unchanged absolute and relative yields. It should be noted that neither at 30 °C nor at 0 °C it was possible to observe and isolate an unsaturated intermediate analogous to the dihydroindole 5 of Scheme 1. At T = 0 °C no change in the reaction mixture occurred within 48 h, and the unreacted substrate was quantitatively recovered.
At the end of this screening, we judged those of entry 3 as the conditions of choice, as they allow a reasonable reaction time and a better yield of 6a.

2.2. Verifying the Scope

We proceeded, then, to verify the scope of the reaction, applying the same conditions to a series of 2-nitro-1,3-butadienes substituted at position 1 with different Ar groups. Results are reported in Table 2. It can be observed that the good selectivity and the satisfying balance evidenced for 4a were not exhibited by the whole series, being maintained only when Ar = Ph, m-ClPh, and, somewhat less so, p-MeO- and p-Cl-Ph, and 1-naphthyl. Particularly negative was the result from 4f, while for 4g a fourth product, 9g, originated in a yield comparable to 6g. A longer reaction time was required by 4i, and after 7 h the control TLC still showed traces of substrate. The data obtained until now seem to definitely reveal a non-negligible effect, in particular on the yield of 6, exerted both by EWG and EDG aryl substituents.

2.3. A Possible Elaboration of 7-Aryl-6-nitroindole 6 to Pyrrolo[3,2-c]carbazoles

The 7-aryl-6-nitroindoles 6 obtained herein as the principal products appear of sure interest, as they have never been reported so far: evidence of a pattern of substitution not easy to be obtained otherwise. Actually, the position occupied by the nitro group, ortho to the aryl substituent and meta-like (i.e., not directly conjugated) to the electron-donating pyrrolic nitrogen atom, is promising, e.g., for further elaborations starting with a reductive step of the nitro group itself.
For instance, the application of the classic Cadogan reaction [22] could hopefully build up unusual pyrrolo[3,2-c]carbazoles (Scheme 3), very rarely reported before in the literature [23]; that notwithstanding, many other similar scaffolds, different from the kind of fusion between pyrrole and carbazole, have been described. For instance, some pyrrolo[2,3-a]carbazoles have been recently synthesized and tested for their pharmacological properties (Pim kinase inhibitory potencies [24]), while the pyrrolo[2,3-c]carbazole scaffold characterizes the biologically active natural compounds dictyodendrines [25]. Encouraged by the wide diffusion of fused carbazole scaffolds among natural or synthetic biologically active compounds, we submitted compound 6a to reflux in triethyl phosphite. The reaction went on smoothly to give the expected compound 10a, in a 75% yield.
For the extension of the Cadogan reaction to other derivatives, we selected nitroindoles 6a–e and 6h–i, excluding those items for which, because of the poorer results of the benzannulation, the two-step procedure would be inconvenient. The compounds obtained and relative yields are reported in Table 3.

2.4. Reduction of the Nitro- to Amino Group in Compounds 6: A First Step to Further Elaborations

Still in the field of polyheterocyclic synthesis, we envisaged in the reduction of 6-nitro to 6-amino group another potential application for our 7-aryl-6-nitroindoles 6, in the light of the easy reducibility of the nitro group testified by the results of the Cadogan reaction. In this regard, it should be recalled that in our experience, nitroindoles and nitrocarbazoles are not easily reduced when the nitro groups are positioned on C5 and C3, respectively, as expected when considering the electron-donating effect of the ring nitrogens. Particularly representative of this noteworthy different reducibility was the result [16] obtained from 1,4-diaryl-2,3-dinitrocarbazole (Ar = p-Tol, Scheme 4), for which the reduction of the two nitro groups proceeded with such different rates as to reveal a high regioselectivity.
Beside to the interest in obtaining merely the corresponding amino derivatives, we intend in the future, to investigate their possible utilization to obtain different polyheterocyclic systems (Scheme 5) involving the nucleophilic primary amino group in further reactions. A preliminary test on the model substrate 6a showed the expected reduction to occur smoothly in satisfactory yield (11a: 61% of isolated compound; Scheme 5a) and in a reasonable reaction time (overnight), in conditions (SnCl2·2H2O, EtOH 60 °C, under Ar) [26] that were not as efficient when previously tried on diaryldinitroindoles (from [21]; Scheme 5b): an encouraging result in the above mentioned perspective of widening the scope of the reduction of 6 towards the synthesis of new N-heterocycles.

3. Mechanistic Aspect Discussion

As far as the benzannulation reaction is concerned, some considerations can be advanced in order to rationalize the formation and distribution of the observed products, also comparing the present system to the previously studied reaction with indole as a nucleophile (Scheme 1, part c). However, it should be specified that, in the absence of any isolable intermediate, the discussion herein has just a speculative significance.
As already ascertained in other processes, we found, in recent years [27,28], that the more reactive electrophilic site within 4-type butadienes is the nitrovinylic moiety, presumably leading, as a first intermediate, to the Michael adduct 12 (Scheme 6), analogous to that (13) hypothesized for the reaction with indole [16]. Of course, due to the different site-selectivity of the considered heterocycles, the new bond involves C2 of pyrrole, while in the case of indole involves C3.
Among the many conceivable evolutions of 12, it is very difficult to individuate which could be the most reasonable to justify the observed products. The cyclization step could, in principle, generate (Scheme 7) the tetrahydroindole 14 (through a 6-endo-trig Michael addition) or the dihydroindole 15 (through an overall SNV 6-exo-trig process). A third possible way (SNV with ICD [29,30]) to 16 could be labeled again as a 6-endo-trig process. The main products (6–8) actually observed can find in 15 an obvious common precursor, while 14 could be the precursor not only of 6–8 but also of 9, observed in our system only in a few cases (4g–i). As far as 16 is concerned, it could be at most a competitive precursor only of 8.
As a matter of fact, experimental results in previously studied systems, as well as Baldwin’s rules [31], encouraged us to consider the intermediate 15 as the most likely one, although it is only through 14 that 9 can originate. Thus, the observed distribution could be the result of a competition between these two alternative cyclization ways, rather than the consequence of different evolutions of 14, with 15 playing a significant role anyway: In this regard, it is worth mentioning what we observed in the reactions with indole, where a trisubstituted derivative analogous to 9 was generally the main product (Scheme 8, results from [16]).
Admitting analogous competitions in the pyrrole and indole systems, one should deduce that for indole the double Michael addition pathway should be favoured. This is not unexpected, considering that in analogy with the mechanism hypothesized for the well-known Pictet–Spengler reactions [32,33], formation of the new hexa-atomic ring (18) passes probably through a spiro precursor (17 in Scheme 9), whose stability and evolution could be disadvantaged in the case of an unsaturated system (17′) generated by SNV with loss of MeSO2H.
On the other hand, an alternative cyclization mechanism that we considered in the analogous reactions of dinitrobutadienes 3 (Scheme 1, part b) also, cannot be, in principle, excluded: The initially formed zwitterionic form of 12 (12′) could evolve through an ionic cycloaddition in which the hexa-atomic ring closes with an inversion of polarity, generating 19, not yet aromatic in the penta-atomic ring (Scheme 10). From this tetrahydroindole, processes involving tautomerizations, elimination(s) of acid and oxidative aromatizations (not necessarily in this sequence) would generate all the observed products.
While in the cited case of dinitrobutadienes 3 that eventuality better fits with the isolation of intermediate 5 (Scheme 1), it should be recalled that no intermediates were ever isolated herein, although a zwitterion would be perhaps more justified than in the previous system. Actually, the presence of the electron-withdrawing –SO2Me group on C4 would increase the stabilization of the negative charge delocalized by the nitrovinylic moiety, making intermediate 12′ a better nucleophile and a weaker base. This last hypothesis seems more intriguing, but only the interception of 19, possibly by trapping with a suitable diene, could furnish an adequate evidence.

4. Materials and Methods

1H NMR and 13C NMR spectra were recorded with a Varian Mercury 300 Plus spectrometer, at 300 and 75 MHz, respectively; chemical shifts (TMS as internal reference) are reported as δ values (ppm). Signals are designated as follows: s, singlet; d, doublet; dd, doublet of doublets; ddd, doublet of doublet of doublets; t, triplet; dt, doublet of triplets; tt, triplet of triplets; td, triplet of doublets; m, multiplet; br, broad; app, apparent. High-resolution mass spectra (HRMS) were obtained with an Agilent MSD TOF mass spectrometer, and recorded in positive ion mode with an electrospray (ESI) source. Melting points were determined with a Büchi 535 apparatus and are uncorrected. IR spectra were recorded on a Perkin Elmer Spectrum 65 FT-IR and wave numbers are reported in cm−1. Petroleum ether and light petroleum refer to the fractions with bp 40–60 °C and 80–100 °C, respectively. Silica gel 230–400 mesh Acros Organics (50–200 μm) were used for column chromatography, all solvents being used as received. TLC analyses were performed on commercially prepared 60 F254 silica gel plates and visualized by UV irradiation (eluent: petroleum ether/ethyl acetate). All commercially available reagents were used as received.

4.1. Substrates

The employed substrates 4a–c,h–i [34], 4e [16] and 4g [27] were known compounds, prepared according to the reported procedures. Sulfones 4d and 4f, and the corresponding precursors, sulfides 4′d and 4”f, are new compounds, prepared following the same protocols and obtained with yields from good to satisfactory (60%–90%; details in the Supporting Information).
1-Chloro-3-[(1E,3E)-4-(methylsulfonyl)-2-nitro-3-(phenylsulfonyl)buta-1,3-dien-1-yl]benzene (4d)
Yellow solid, mp 129–131 °C (taken-up with petroleum ether/DCM). 1H NMR (CDCl3, 300 MHz): δ (ppm) 3.08 (3H, s), 7.20–7.42 (6H, m), 7.51–7.58 (1H, m), 7.71–7.75 (2H, m), 7.99 (1H, s), 8.27 (1H, s). 13C NMR (CDCl3, 75 MHz): δ (ppm) 42.57, 128.49, 129.40, 129.56, 130.32, 130.52, 130.88, 132.01, 135.07, 135.36, 135.80, 136.95, 139.64, 142.44, 144.92. HRMS (ESI) m/z calculated [M + H]+ C17H15ClNO6S2+ 428.0024, found 428.0102.
[(1E,3E)-4-(3-chlorophenyl)-3-nitro-2-(phenylsulfonyl)buta-1,3-dien-1-yl](methyl)sulfane (4′d)
Yellow solid, mp 144–146 °C (taken-up with petroleum ether/DCM). 1H NMR (CDCl3, 300 MHz): δ (ppm) 2.55 (3H, s), 7.19–7.25 (1H, m), 7.30–7.39 (5H, m), 7.43–7.50 (1H, m), 7.71–7.77 (2H, m), 8.18 (1H, s), 8.30 (1H, s). 13C NMR (CDCl3, 75 MHz): δ (ppm) 17.69, 125.09, 128.10, 128.47, 129.11, 129.97, 130.12, 131.39, 131.69, 133.64, 134.82, 138.98, 139.22, 140.54, 156.45. HRMS (ESI) m/z calculated [M + H]+ C17H15ClNO4S2+ 396.0126, found 396.0178.
1-(Methylsulfonyl)-4-[(1E,3E)-4-(methylsulfonyl)-2-nitro-3-(phenylsulfonyl)buta-1,3-dien-1-yl]benzene (4f)
White solid, mp 183–185 °C (ethanol). 1H NMR (acetone-d6, 300 MHz): δ (ppm) 3.20 (3H, s), 3.35 (3H, s), 7.43–7.51 (2H, m), 7.59–7.66 (1H, m), 7.73 (2H, half AA’BB’, J = 8.2 Hz), 7.79–7.87 (4H, m), 8.49 (1H, s), 8.57 (1H, s). 13C NMR (acetone-d6, 75 MHz): δ (ppm) 42.95, 44.01, 128.51, 130.42, 130.75, 132.28, 135.25, 136.44, 137.70, 139.34, 139.89, 143.75, 144.26, 145.98. HRMS (ESI) m/z calculated [M + H]+ C18H18NO8S3+ 472.0189, found 472.0205.
Methyl{4-[(1E,3E)-4-(methylthio)-2-nitro-3-(phenylsulfonyl)buta-1,3-dien-1-yl]phenyl}sulfane (4”f)
Yellow solid, mp 118–119 °C (ethanol). 1H NMR (CDCl3, 300 MHz): δ (ppm) 2.50 (3H, s), 2.52 (3H, s), 7.10–7.20 (4H, m), 7.37–7.49 (4H, m), 7.52 (1H, d, J = 7.5 Hz), 7.74–7.83 (2H, m), 8.25 (1H, s), 8.27 (1H, s). 13C NMR (CDCl3, 75 MHz): δ (ppm) 14.68, 17.65, 125.43, 125.72, 125.99, 128.24, 129.11, 131.36, 133.62, 137.77, 139.59, 140.88, 145.62, 155.60. HRMS (ESI) m/z calculated [M + H]+ C18H18NO4S3+ 408.0392, found 408.0444.

4.2. General Procedure for the Synthesis of 7-arylsubstituted indoles (6–8 a–h)

To a stirred suspension of the suitable nitrobutadiene 4a–h (0.245 mmol) in TFE (5 mL, 0.05 M), pyrrole (4 mol equiv) was added. Temperature and time are reported in Table 2. After the time necessary for the disappearance of 4 (5–7 h), the solvent was removed under reduced pressure and the residue purified by flash chromatography over a silica gel column (petroleum ether/ethyl acetate gradients).
6-Nitro-7-(p-tolyl)-1H-indole (6a)
Waxy solid. IR (ATR): ῦ = 3407 (m, br), 1592 (m), 1508 (s), 1483 (s), 1436 (m), 1413 (m), 1339 (s), 1315 (s), 1255 (m), 1149 (s), 1107 (m), 1092 (m), 1037 (m), 1022 (m) cm−1. 1H NMR (CDCl3, 300 MHz): δ (ppm) 2.43 (3H, s), 6.67 (1H, dd, J = 3.2, 2.1 Hz), 7.29 (4H, AA’BB’), 7.37 (1H, dd, J = 3.2, 2.6 Hz), 7.66 (1H, d, J = 8.7 Hz), 7.85 (1H, d, J = 8.7 Hz), 8.28 (1H, br s). 13C NMR (CDCl3, 75 MHz): δ (ppm) 21.30, 103.55, 116.61, 119.59, 122.02, 128.25, 129.31, 129.84, 130.99, 131.14, 134.57, 138.21, 142.57. HRMS (ESI) m/z calculated [M + H]+ C15H13N2O2+ 253.0972, found 253.0993.
6-Nitro-5-phenylsulfonyl-7-(p-tolyl)-1H-indole (7a)
Yellow solid, mp 141–142 °C (ethanol). IR (ATR): ῦ = 3289 (m, br), 1534 (s), 1446 (m), 1368 (m), 1350 (m), 1306 (s), 1288 (m), 1259 (m), 1141 (s), 1082 (s) cm−1. 1H NMR (CDCl3, 300 MHz): δ (ppm) 2.39 (3H, s), 6.82 (1H, dd, J = 3.3, 2.0 Hz), 7.26 (4H, AA’BB’), 7.42 (1H, dd, J = 3.2, 2.5 Hz), 7.47–7.62 (3H, m), 7.96–8.02 (2H, m), 8.54 (1H, br s), 8.55 (1H, s). 13C NMR (CDCl3, 75 MHz): δ (ppm) 21.34, 105.28, 116.15, 120.21, 123.79, 124.96, 127.29, 127.93, 128.68, 128.95, 129.29, 130.14, 133.17, 136.20, 139.75, 141.81, 149.47. HRMS (ESI) m/z calculated [M + H]+ C21H17N2O4S+ 393.0909, found 393.0993.
5-Phenylsulfonyl-7-(p-tolyl)-1H-indole (8a)
Yellow oil. IR (ATR): ῦ = 3293 (m, br), 1708 (m), 1614 (m), 1512 (m), 1446 (m), 1301 (m), 1180 (m), 1149 (s), 1088 (s), 1038 (m), 1019 (m). 1H NMR (CDCl3, 300 MHz): δ (ppm) 2.35 (3H, s), 6.65 (1H, dd, J = 3.3, 2.1 Hz), 7.15–7.30 (4H, m), 7.35–7.49 (4H, m), 7.65 (1H, d, J = 1.7 Hz), 7.88-7.92 (2H, m), 8.22 (1H, d, J = 1.6 Hz), 8.60 (1H, br s). 13C NMR (CDCl3, 75 MHz): δ (ppm) 21.25, 104.66, 120.28, 120.81, 126.56, 126.66, 127.35, 127.95, 128.06, 129.08, 130.06, 132.54, 133.16, 134.37, 136.02, 138.28, 142.92. HRMS (ESI) m/z calculated [M + H]+ C21H18NO2S+ 348.1053, found 348.1103.
7-(4-Phenyl)-6-nitro-1H-indole (6b)
Orange oil. IR (ATR): ῦ = 3285 (m, br), 1598 (w), 1587 (w), 1509 (w), 1490 (s), 1443 (w), 1362 (m), 1343 (m), 1307 (s), 1282 (s), 1252 (s), 1204 (m), 1151 (m), 1102 (s), 1071 (m), 1031 (m) cm−1. 1H NMR (CDCl3, 300 MHz): δ (ppm) 6.68 (1H, dd, J = 3.2, 2.1 Hz), 7.35–7.42 (3H, m), 7.43–7.56 (3H, m), 7.67 (1H, d, J = 8.7 Hz), 7.87 (1H, d, J = 8.7 Hz), 8.30 (1H, br s). 13C NMR (CDCl3, 75 MHz): δ (ppm) 103.62, 116.64, 119.80, 121.99, 128.38, 128.43, 129.13, 129.41, 131.13, 134.32, 134.51, 142.48. HRMS (ESI) m/z calculated [M + H]+ C14H11N2O2+ 239.0815, found 239.0873.
7-(4-Methoxyphenyl)-6-nitro-1H-indole (6c)
Yellow solid, mp 175–177 °C (taken-up with petroleum ether/DCM). IR (ATR): ῦ = 3356 (m, br), 1610 (m), 1502 (s), 1483 (m), 1412 (w), 1361 (m), 1311 (s), 1257 (m), 1233 (s), 1176 (m), 1148 (m), 1110 (s), 1022 (s) cm−1. 1H NMR (CDCl3, 300 MHz): δ (ppm) 3.87 (3H, s), 6.67 (1H, dd, J = 3.2, 2.1 Hz), 7.03 (2H, half AA’BB’), 7.32 (2H, half AA’BB’), 7.37 (1H, dd, J = 3.2, 2.6 Hz), 7.65 (1H, d, J = 8.7 Hz), 7.82 (1H, d, J = 8.7 Hz), 8.32 (1H, br s). 13C NMR (CDCl3, 75 MHz): δ (ppm) 55.33, 103.62, 114.64, 116.65, 119.57, 121.67, 126.10, 129.23, 129.70, 130.93, 134.77, 142.77, 159.62. HRMS(ESI) m/z calculated [M + H]+ C15H13N2O3+ 269.0921, found 269.0997.
7-(3-Chlorophenyl)-6-nitro-1H-indole (6d)
Yellowish solid, mp 122–125 °C (taken-up with petroleum ether/DCM). IR (ATR): ῦ = 3326 (m, br), 1586 (m), 1567 (m), 1510 (m), 1490 (s), 1360 (m), 1350 (m), 1314 (s), 1282 (s), 1251 (s), 1203 (m), 1152 (m), 1104 (s), 1079 (s) cm−1. 1H NMR (CDCl3, 300 MHz): δ (ppm) 6.70 (1H, dd, J = 3.2, 2.0 Hz), 7.28 (1H, app td), 7.40–7.50 (4H, m), 7.70 (1H, d, J = 8.7 Hz), 7.91 (1H, d, J = 8.7 Hz), 8.23 (1H, br s). 13C NMR (CDCl3, 75 MHz): δ (ppm) 103.85, 116.75, 120.32, 120.51, 126.82, 128.55, 128.63, 129.67, 130.45, 131.42, 134.34, 135.02, 136.23, 142.26. HRMS (ESI) m/z calculated [M + H]+ C14H10ClN2O2+ 273.0425, found 273.0615.
7-(4-Chlorophenyl)-6-nitro-1H-indole (6e)
Yellow solid, mp 110–113 °C (taken-up with petroleum ether/DCM). IR (ATR): ῦ = 3306 (m, br), 1598 (w), 1511 (w), 1487 (s), 1360 (m), 1334 (m), 1309 (s), 1281 (m), 1255 (m), 1206 (w), 1150 (m), 1106 (m), 1092 (m), 1016 (m) cm−1. 1H NMR (CDCl3, 300 MHz): δ (ppm) 6.69 (1H, t, J = 2.5 Hz), 7.33 (2H, d, J = 8.4 Hz), 7.40 (1H, t, J = 2.9 Hz), 7.50 (2H, d, J = 8.3 Hz), 7.70 (1H, d, J = 8.7 Hz), 7.89 (1H, d, J = 8.7 Hz), 8.23 (1H, s). 13C NMR (CDCl3, 75 MHz): δ (ppm) 103.79, 116.77, 120.19, 120.78, 129.44, 129.63, 129.92, 131.34, 132.81, 134.42, 134.55, 142.35. HRMS (ESI) m/z calculated [M + H]+ C14H10ClN2O2+ 273.0425, found 273.0453.
7-(4-(Methylsulfonyl)phenyl)-6-nitro-1H-indole (6f)
Yellow solid, mp 248–249 °C (taken-up with petroleum ether/DCM). IR (ATR): ῦ = 3314 (m, br), 1590 (w), 1513 (m), 1494 (m), 1360 (m), 1321 (s), 1293 (s), 1279 (s), 1257 (s), 1209 (m), 1184 (m), 1137 (s), 1109 (s), 1081 (s), 1017 (m) cm−1. 1H NMR (CDCl3, 300 MHz): δ (ppm) 3.17 (3H, s), 6.72 (1H, dd, J = 3.1, 2.0 Hz), 7.44 (1H, dd, J = 3.2, 2.6 Hz), 7.62 (2H, half AA’BB’, J = 8.5 Hz), 7.75 (1H, dd, J = 8.7, 0.8 Hz), 7.98 (1H, d, J = 8.7 Hz), 8.10 (2H, half AA’BB’, J = 8.4 Hz), 8.24 (1H, br s). 13C NMR (CDCl3, 75 MHz): δ (ppm) 44.53, 104.01, 116.86, 120.13, 120.83, 128.23, 129.75, 130.17, 131.84, 134.14, 140.46, 140.88, 141.96. HRMS (ESI) m/z calculated [M + H]+ C15H13N2O4S+ 317.0591, found 317.0703.
7-(3,5-Bis(trifluoromethyl)phenyl)-6-nitro-1H-indole (6g)
Yellow solid, mp 143–145 °C (taken-up with petroleum ether/DCM). IR (ATR): ῦ = 3353 (m, br), 1513 (m), 1491 (m), 1380 (m), 1361 (m), 1325 (m), 1308 (m), 1276 (s), 1241 (m), 1171 (m), 1167 (m), 1147 (s), 1128 (s), 1108 (s), 1097 (s) cm−1. 1H NMR (CDCl3, 300 MHz): δ (ppm) 6.75 (1H, dd, J = 3.3, 2.1 Hz), 7.46 (1H, dd, J = 3.3, 2.7 Hz), 7.78 (1H, dd, J = 8.8, 0.8 Hz), 7.87 (2H, app s), 7.99-8.05 (2H, m), 8.08 (1H, br s). 13C NMR (CDCl3, 75 MHz): δ (ppm) 104.28, 117.05, 118.89, 121.24, 122.45 (app quint, J = 3.72 Hz), 123.07 (q, J = 273.16 Hz), 129.06 (app d, J = 3.74 Hz), 130.34, 132.07, 132.58 (q, J = 33.30 Hz), 134.28, 137.13, 141.95. HRMS(ESI) m/z calculated [M + H]+ C16H9F6N2O2+ 375.0563, found 375.0635.
7-(3,5-Bis(trifluoromethyl)phenyl)-2-methylsulfonyl-6-nitro-1H-indole (9g)
Brown solid, mp 222–224 °C (taken-up with petroleum ether/DCM). IR (ATR): ῦ = 3480 (w), 3308 (w, br), 1580 (w), 1520 (m), 1491 (m), 1379 (m), 1348 (m), 1314 (m), 1280 (s), 1245 (m), 1177 (m), 1128 (s), 1109 (s) cm−1. 1H NMR (acetone-d6, 300 MHz): δ (ppm) 3.33 (3H, s), 7.19 (1H, dd, J = 3.3, 1.8 Hz), 7.97 (1H, t, J = 3.0 Hz), 8.25 (1H, app q, J = 0.8 Hz), 8.29 (2H, app br s), 8.55 (1H, s), 11.34 (1H, br s). 13C NMR (acetone-d6, 75 MHz): δ (ppm) 43.06, 102.68, 117.18, 122.52 (app. quint., J = 3.77 Hz), 123.50 (q, J = 273.08 Hz), 124.38, 128.23, 129.66 (app. d, J = 3.64 Hz), 131.36, 131.74 (q, J = 33.33 Hz), 134.69, 136.50, 136.89, 140.65. HRMS(ESI) m/z calculated [M + H]+ C17H11F6N2O4S+ 453.0265, found 453.0289.
7-(Naphthalen-1-yl)-6-nitro-1H-indole (6h)
Orange oil. IR (ATR): ῦ = 3410 (m, br), 1589 (m), 1514 (s), 1507 (s), 1492 (s), 1437 (m), 1334 (s), 1309 (s), 1268 (s), 1245 (m), 1208 (m), 1181 (m), 1150 (m), 1129 (m), 1102 (m), 1067 (m), 1036 (m), 1015 (m) cm−1. 1H NMR (CDCl3, 300 MHz): δ (ppm) 6.70 (1H, dd, J = 3.2, 2.0 Hz), 7.30 (1H, app. t), 7.34 (2H, app. d), 7.43–7.54 (3H, m), 7.58 (1H, dd, J = 8.3, 7.0 Hz), 7.79 (1H, dd, J = 8.7, 0.8 Hz), 7.93–7.99 (2H, m), 8.05 (1H, d, J = 8.7 Hz). 13C NMR (CDCl3, 75 MHz): δ (ppm) 103.53, 116.77, 120.20, 120.42, 124.86, 125.65, 126.33, 126.37, 126.82, 128.58, 128.87, 129.55, 131.29, 131.42, 132.01, 133.80, 135.05, 143.25. HRMS (ESI) m/z calculated [M + H]+ C18H13N2O2+ 289.0972, found 289.0792.
6-Nitro-7-(thiophen-2-yl)-1H-indole (6i)
Yellow solid, mp 112–114 °C (taken-up with petroleum ether/DCM). IR (ATR): ῦ = 3349 (m, br), 3297 (m, br), 1592 (m), 1504 (s), 1487 (s), 1443 (m), 1355 (m), 1327 (s), 1311 (s), 1279 (s), 1240 (s), 1214 (m), 1191 (m), 1152 (m), 1104 (s), 1085 (s), 1039 (m) cm−1. 1H NMR (CDCl3, 300 MHz): δ (ppm) 6.68 (1H, dd, J = 3.2, 2.1 Hz), 7.14–7.23 (2H, m), 7.42 (1H, t, J = 2.9 Hz), 7.53 (1H, dd, J = 5.0, 1.4 Hz), 7.70 (1H, d, J = 8.7 Hz), 7.82 (1H, d, J = 8.7 Hz), 8.53 (1H, br s). 13C NMR (CDCl3, 75 MHz): δ (ppm) 103.77, 114.16, 116.60, 120.70, 127.42, 127.75, 127.92, 129.32, 130.92, 133.46, 135.13, 143.73. HRMS (ESI) m/z calculated [M + H]+ C12H9N2O2S+ 245.0379, found 245.0409.

4.3. General Procedure for the Cadogan Reaction: Synthesis of Pyrrolo[3,2-c]carbazoles 10

A 5 mL flame-dried, round-bottomed flask, equipped with a condenser, was charged with 0.11 mmol of the relevant 6 and 2.2 mL of triethylphosphite (d = 0.969 g/mL, 2.13 g, 12.8 mmol). The resulting mixture was heated at reflux under nitrogen for 5 h, and then the excess of triethylphosphite was partly removed under reduced pressure (bath temperature 80 °C). The residue was dissolved in ethyl acetate and washed with HCl 5% solution, and water, then dried. The crude was purified by column chromatography (ethyl acetate/petroleum ether 4:1) to isolate compound 10.
8-Methyl-1,6-dihydropyrrolo[3,2-c]carbazole (10a)
Grey solid, mp 238–240 °C (taken-up with petroleum ether/DCM). IR (ATR): ῦ = 3426 (m), 3388 (s), 1622 (m), 1590 (w), 1521 (m), 1455 (m), 1418 (m), 1366 (s), 1329 (m), 1282 (m), 1254 (m), 1179 (m), 1075 (m), 1064 (m), 1036 (w) cm−1. 1H NMR (acetone-d6, 300 MHz): δ (ppm) 2.51 (3H, s), 6.62 (1H, dd, J = 3.1, 2.0 Hz), 7.05 (1H, ddt, J = 8.0, 1.4, 0.7 Hz), 7.23–7.30 (2H, m), 7.35 (1H, dt, J = 1.5, 0.8 Hz), 7.58 (1H, dd, J = 8.5, 0.8 Hz), 8.30 (1H, d, J = 8.0 Hz), 10.25 (1H, br s), 10.68 (1H, br s). 13C NMR (acetone-d6, 75 MHz): δ (ppm) 22.12, 103.70, 105.52, 108.46, 111.65, 119.40, 120.60, 121.07, 121.36, 122.29, 122.45, 130.85, 134.29, 138.06, 140.34. HRMS (ESI) m/z calculated [M + H]+ C15H13N2+ 221.1073, found 221.1125.
1,6-Dihydropyrrolo[3,2-c]carbazole (10b) [35]
Grey glassy solid. IR (ATR): ῦ = 3399 (m, br), 1637 (m), 1611 (m), 1424 (m), 1369 (m), 1330 (m) cm−1. 1H NMR (acetone-d6, 300 MHz): δ (ppm) 6.63 (1H, dd, J = 3.2, 2.0 Hz), 7.21 (1H, ddd, J 8.1, 7.2, 1.1 Hz), 7.28–7.32 (2H, m), 7.35 (1H, ddd, J = 8.2, 7.2, 1.2 Hz), 7.56 (1H, dt, J = 8.1, 1.0 Hz), 7.64 (1H, dd, J = 8.5, 0.8 Hz), 8.43 (1H, ddd, J = 7.8, 1.3, 0.7 Hz), 10.38 (1H, br s), 10.72 (1H, br s). 13C NMR (acetone-d6, 75 MHz): δ (ppm) 130.78, 105.51, 108.43, 111.54, 119.50, 120.03, 121.63, 122.47, 122.53, 122.75, 124.62, 130.94, 138.15, 139.82. HRMS (ESI) m/z calculated [M + H]+ C14H11N2+ 207.0917, found 207.0975.
8-Methoxy-1,6-dihydropyrrolo[3,2-c]carbazole (10c)
Whitish solid, mp 214–217 °C (taken-up with petroleum ether/DCM). IR (ATR): ῦ = 3444 (w, br), 3390 (m, br), 1617 (s), 1522 (w), 1501 (m), 1459 (m), 1439 (m), 1419 (m), 1368 (s), 1339 (m), 1324 (m), 1304 (m), 1253 (m), 1230 (m), 1220 (m), 1196 (m), 1176 (m), 1161 (m), 1121(m), 1079 (m), 1061 (m), 1041 (m), 1022 (m) cm−1. 1H NMR (acetone-d6, 300 MHz): δ (ppm) 3.88 (3H, s), 6.61 (1H, dd, J = 3.2, 1.9 Hz), 6.86 (1H, dd, J = 8.6, 2.3 Hz), 7.09 (1H, d, J = 2.4 Hz), 7.25 (1H, d, J = 8.7 Hz), 7.28 (1H, dd, J = 3.0, 2.4 Hz), 7.55 (1H, dd, J = 8.5, 0.7 Hz), 8.30 (1H, d, J = 8.6 Hz), 10.27 (1H, br s), 10.68 (1H, br s). 13C NMR (acetone-d6, 75 MHz): δ (ppm) 55.78, 95.41, 103.63, 105.44, 107.52, 107.78, 116.80, 118.52, 122.21, 122.50, 122.62, 130.58, 137.97, 141.13, 158.86. HRMS (ESI) m/z calculated [M + H]+ C15H13N2O+ 237.1022, found 237.1092.
7-Chloro- (10d) and 9-Chloro-1,6-dihydropyrrolo[3,2-c]carbazole (10d’)
The product obtained (yellow solid) was revealed, upon the 1H NMR analysis, to be a mixture of 7-chloro and 9-chloro isomers, in a ratio of about 1:1. Only the 7-chloro derivative (10d) was obtained pure: 1H NMR (acetone-d6, 300 MHz): δ (ppm) 6.66 (1H, dd, J = 3.1, 2.0 Hz), 7.23 (1H, t, J = 7.8 Hz), 7.34 (1H, dd, J = 3.2, 2.4 Hz), 7.37–7.44 (2H, m), 7.71 (1H, dd, J = 8.6, 0.8 Hz), 8.42 (1H, dt, J = 7.8, 0.9 Hz), 10.68 (1H, s), 10.84 (1H, s). The 1H NMR spectrum of 10d’ was deduced by difference from that of the mixture: 1H NMR (acetone-d6, 300 MHz): δ (ppm) 6.61–6.69 (1H, m), 7.30 (1H, d, J = 8.7 Hz), 7.32–7.35 (2H, m), 7.55 (1H, d, J = 8.6 Hz), 7.68 (1H, d, J = 8.5 Hz), 8.47 (1H, d, J = 2.1 Hz), 10.56 (1H, s), 10.90 (1H, s).
8-Chloro-1,6-dihydropyrrolo[3,2-c]carbazole (10e)
Yellow solid, mp 177–180 °C (taken-up with petroleum ether/DCM). IR (ATR): ῦ = 3444 (m), 3400 (m, br), 1707 (w), 1638 (m), 1604 (m), 1584 (m), 1522 (m), 1477 (w), 1451 (m), 1427 (m), 1415 (m), 1363 (s), 1326 (m), 1290 (m), 1272 (m), 1249 (s), 1175 (m), 1108 (m), 1064 (m), 1033 (m) cm−1. 1H NMR (CDCl3, 300 MHz): δ (ppm) 6.66 (1H, dt, J = 3.8, 2.0 Hz), 7.22 (1H, dt, J = 8.4, 2.0 Hz), 7.28–7.37 (2H, m), 7.59 (1H, t, J = 1.7 Hz), 7.68 (1H, dd, J = 8.5, 1.8 Hz), 8.43 (1H, dd, J = 8.4, 1.5 Hz), 10.55 (1H, s), 10.81 (1H, s). 13C NMR (CDCl3, 75 MHz): δ (ppm) 103.85, 103.94, 105.56, 107.98, 111.37, 119.72, 120.64, 121.52, 122.64, 122.87, 129.82, 130.61, 138.61, 140.37. HRMS (ESI) m/z calculated [M + H]+ C14H10ClN2+ 241.0527, found 241.0597.
1,6-Dihydrobenzo[c]pyrrolo[2,3-g]carbazole (10h)
Grey solid, mp 227–230 °C (taken-up with petroleum ether/DCM). IR (ATR): ῦ = 3480 (m), 3382 (m, br), 1699 (w, br), 1613 (m), 1582 (m), 1530 (m), 1392 (m), 1368 (m), 1349 (s), 1302 (s), 1259 (m) cm−1. 1H NMR (acetone-d6, 300 MHz): δ (ppm) 6.74 (1H, dd, J = 3.2, 1.8 Hz), 7.37 (1H, dd, J = 3.2, 2.6 Hz), 7.43–7.50 (2H, m), 7.65–7.72 (2H, m), 7.84 (2H, AB, J 17.6, 8.8 Hz), 8.05 (1H, dm, J = 8.0 Hz), 9.06 (1H, ddt, J = 8.4, 1.3, 0.7 Hz), 10.60 (1H, br s), 10.99 (1H, br s), 13C NMR (acetone-d6, 75 MHz): δ (ppm) 104.61, 106.37, 109.87, 114.24, 116.12, 119.57, 122.56, 123.33, 123.67, 124.88, 126.52, 126.97, 130.11, 130.19, 130.30, 130.38, 137.09, 137.53. HRMS (ESI) m/z calculated [M + H]+ C18H13N2+ 257.1073, found 257.1097.
1,6-Dihydropyrrolo[2,3-e]thieno[3,2-b]indole (10i)
Whitish solid, mp 181–182 °C (taken-up with petroleum ether/DCM). IR (ATR): ῦ = 3389 (s, br), 1710 (w), 1628 (w), 1517 (w), 1432 (m), 1389 (s), 1372 (s), 1318 (m), 1294 (m), 1263 (m), 1249 (m), 1234 (m), 1182 (m), 1097 (m), 1075 (m), 1062 (m), 1042 (m), 1030 (m) cm−1. 1H NMR (CDCl3, 300 MHz): δ (ppm) 6.59 (1H, dd, J = 3.1, 2.0 Hz), 7.21 (1H, d, J = 5.2 Hz), 7.24–7.30 (2H, m), 7.42–7.48 (2H, m), 10.51 (1H, br s), 10.68 (1H, br s). 13C NMR (CDCl3, 300 MHz): δ (ppm) 103.77, 106.83, 108.46, 112.68, 115.34, 117.05, 122.00, 122.27, 126.26, 128.71, 139.53, 142.98. HRMS (ESI) m/z calculated [M + H]+ C12H9N2S+ 213.0481, found 213.0499.

4.4. Procedure for the Reduction of the Nitro- to Amino- Group in Compound 6a

To a solution of 6a (85 mg, 0.34 mmol) in dry ethanol (3.5 mL), SnCl2·2H2O (768 mg, 10.0 mmol) was added. The reaction mixture was left overnight at 60 °C under an argon atmosphere. After removal of the solvent under reduced pressure, the crude residue was partitioned between ethyl acetate and KOH 2M. The aqueous layer was extracted with ethyl acetate (3 × 10 mL), and the combined organic extracts washed with brine (2 × 10 mL) and water (3 × 10 mL), then dried (Na2SO4), and concentrated under reduced pressure. A flash silica-gel column chromatography (petroleum ether/DCM 1:1) of the crude residue gave compound 11a (46 mg, 61%).
7-(p-Tolyl)-1H-indol-6-amine (11a)
Whitish solid, mp 127–129 °C (taken-up with petroleum ether/DCM). IR (ATR): ῦ = 3368 (m, br), 3313 (w, br) 1618 (s), 1503 (m), 1432 (s), 1335 (m), 1248 (m), 1185 (w), 1106 (m), 1060 (w), 1022 (w) cm−1. 1H NMR (CDCl3, 300 MHz): δ (ppm) 2.45 (3H, s), 3.25 (2H, br), 6.47 (1H, app t, J = 2.5 Hz), 6.69 (1H, d, J = 8.3 Hz), 6.94 (1H, app t, J = 2.7 Hz), 7.32–7.45 (5H, m), 7.82 (1H, br). 13C NMR (CDCl3, 300 MHz): δ (ppm) 21.26, 102.70, 110.22, 111.17, 120.34, 120.98, 122.10, 129.74, 130.23, 132.34, 135.94, 137.39, 138.36. HRMS(ESI) m/z calculated [M + H]+ C15H15N2+ 223.1230, found 223.1322.

5. Conclusions

In conclusion, in the present research we have explored a pyrrole-to-indole benzannulation procedure making use of non-symmetric nitrobutadienic C4 building blocks, that allowed us to obtain, in satisfactory yields and good selectivity, unusual nitroindolic derivatives still unknown in the literature, and further amenable to interesting elaborations. Thanks to the easy reducibility of the nitro group and to the relative position of substituents, novel and interesting pyrrolo[3,2-c]carbazoles could be obtained applying a reported protocol for the Cadogan reaction (non-optimized for our compounds), while the promising easy reduction of nitro to amino derivatives opens the way to further elaborations of 6 to other polyheterocyclic systems; for instance, pyrrolo[2,3-a]phenanthridines, by means of the Pictet–Spengler protocol [32,33].

Supplementary Materials

The following are available online: Detailed description on preparative procedures of substrates 4d, 4f, and the corresponding precursors, 4′d, 4”f: 1H NMR and 13C NMR spectra for all new compounds.

Author Contributions

Conceptualization: C.T. and G.P.; methodology, synthesis and characterization: A.B. and A.P.; data curation: L.B. and C.T.; analysis of the results: all the authors; writing—original draft preparation, C.T.; writing—review and editing, C.T., G.P. and M.M.

Funding

Financial support was provided by grants by Genoa University (FRA 2017).

Acknowledgments

We thank Michele Ghisolfo for skillful contribution with the experimental work; Walter Sgroi and Cinzia Bottinelli are also gratefully acknowledged for performing IR analyses.

Conflicts of Interest

The authors declare no conflict of interest.

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Sample Availability: Samples of all compounds are available from the authors.
Molecules 24 03802 sch001 550
Scheme 1. Pyrrole and indole benzannulation reactions.
Scheme 1. Pyrrole and indole benzannulation reactions.
Molecules 24 03802 sch001
Molecules 24 03802 sch002 550
Scheme 2. Results from the reaction between the 2-nitrodiene 4a and pyrrole at 50 °C in TFE.
Scheme 2. Results from the reaction between the 2-nitrodiene 4a and pyrrole at 50 °C in TFE.
Molecules 24 03802 sch002
Molecules 24 03802 sch003 550
Scheme 3. Classic conditions for the Cadogan reaction ([22]) applied to 6a.
Scheme 3. Classic conditions for the Cadogan reaction ([22]) applied to 6a.
Molecules 24 03802 sch003
Molecules 24 03802 sch004 550
Scheme 4. Progressive/regioselective reduction from dinitro- to diamino-carbazole derivatives.
Scheme 4. Progressive/regioselective reduction from dinitro- to diamino-carbazole derivatives.
Molecules 24 03802 sch004
Molecules 24 03802 sch005 550
Scheme 5. (a) Reduction of the nitro group in 6a to obtain 11a, a possible precursor for new polyheterocyclic targets.; (b) the same reducing agent proves less efficient in the reduction of nitro groups in a 4,7-diaryl-5,6-dinitroindole reported in ref [21].
Scheme 5. (a) Reduction of the nitro group in 6a to obtain 11a, a possible precursor for new polyheterocyclic targets.; (b) the same reducing agent proves less efficient in the reduction of nitro groups in a 4,7-diaryl-5,6-dinitroindole reported in ref [21].
Molecules 24 03802 sch005
Molecules 24 03802 sch006 550
Scheme 6. Probable first step of the process under study, and an analogy of the reaction with indole.
Scheme 6. Probable first step of the process under study, and an analogy of the reaction with indole.
Molecules 24 03802 sch006
Molecules 24 03802 sch007 550
Scheme 7. Conceivable evolutions of 13 according to the observed products.
Scheme 7. Conceivable evolutions of 13 according to the observed products.
Molecules 24 03802 sch007
Molecules 24 03802 sch008 550
Scheme 8. Pertinent results from [16].
Scheme 8. Pertinent results from [16].
Molecules 24 03802 sch008
Molecules 24 03802 sch009 550
Scheme 9. Evolution from 14 to tetrahydrocarbazole 19 through the hypothetic spiro precursor 18.
Scheme 9. Evolution from 14 to tetrahydrocarbazole 19 through the hypothetic spiro precursor 18.
Molecules 24 03802 sch009
Molecules 24 03802 sch010 550
Scheme 10. Alternative ionic cycloaddition to tetrahydroindole 19.
Scheme 10. Alternative ionic cycloaddition to tetrahydroindole 19.
Molecules 24 03802 sch010
Table
Table 1. Search for conditions of choice in the reactions of nitrobutadiene 4a with pyrrole 1.
Table 1. Search for conditions of choice in the reactions of nitrobutadiene 4a with pyrrole 1.
EntryT (°C)Mol Eq. of Pyrroletime (h) Molecules 24 03802 i001
6a (Yield %)		 Molecules 24 03802 i002
7a (Yield %) 		Molecules 24 03802 i003
8a (Yield %) 		Overall Balance
15022452161482%
25042.553211791%
3404557171286%
43042457161992%
50448---100% of 4a
1 Yields reported are for chromatographically isolated compounds.
Table
Table 2. Results obtained in the reactions of nitrobutadienes 4a–i with pyrrole in TFE at 40 °C for 5 h 1.
Table 2. Results obtained in the reactions of nitrobutadienes 4a–i with pyrrole in TFE at 40 °C for 5 h 1.
EntryAr in 4 Molecules 24 03802 i004
6 (Yields %)		 Molecules 24 03802 i005
7 (Yields %)		 Molecules 24 03802 i006
8 (Yields %)		 Molecules 24 03802 i007
9 (Yields %)		Overall Balance
1p-Tol: 4a6a: 577a: 178a: 129a: nq286%
2Ph: 4b6b: 607b: 108b: 109b: -380%
3p-MeOC6H4: 4c6c: 447c: 178c: 139c: -374%
4m-ClC6H4: 4d6d: 537d: 118d: 189d: -381%
5p-ClC6H4: 4e6e: 427e: 88e: 159e: 1883%
6p-MeSO2C6H4: 4f6f: 197f: nq28f: nq29f: nq2nq
73,5-(CF3)2C6H3: 4g6g: 227g: 108g: 119g: 2568%
81-Naphthyl: 4h6h: 407h: 148h: 139h: 1380%
92-Thienyl:4 4i6i: 337i: 78i: 119i: 1465%
1 Yields reported are for chromatographically isolated compounds, unless otherwise specified. 2 Observed by TLC and hypothesized on the grounds of 1H NMR signals, but not quantified. 3 Not evidenced by TLC. 4 Reaction time: 7h.
Table
Table 3. Results obtained in the Cadogan reaction (triethyl phosphite at reflux, 5 h, under Ar) applied to 7-aryl-6-nitroindoles 6 1.
Table 3. Results obtained in the Cadogan reaction (triethyl phosphite at reflux, 5 h, under Ar) applied to 7-aryl-6-nitroindoles 6 1.
EntrySubstrate ProductYield
1 Molecules 24 03802 i0086a Molecules 24 03802 i00910a: 75%
2 Molecules 24 03802 i0106b Molecules 24 03802 i01110b: 50%
3 Molecules 24 03802 i0126c Molecules 24 03802 i01310c: 53%
4 Molecules 24 03802 i0146d Molecules 24 03802 i01510d and 10d’:
75% ca. 1:1
5 Molecules 24 03802 i0166e Molecules 24 03802 i01710e: 51%
6 Molecules 24 03802 i0186h Molecules 24 03802 i01910h: 65%
7 Molecules 24 03802 i0206i Molecules 24 03802 i02110i: 38%
1 Yields reported are for chromatographically isolated compounds.

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Benzi, A.; Bianchi, L.; Maccagno, M.; Pagano, A.; Petrillo, G.; Tavani, C. Sequential Annulations to Interesting Novel Pyrrolo[3,2-c]carbazoles. Molecules 2019, 24, 3802. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24203802

AMA Style

Benzi A, Bianchi L, Maccagno M, Pagano A, Petrillo G, Tavani C. Sequential Annulations to Interesting Novel Pyrrolo[3,2-c]carbazoles. Molecules. 2019; 24(20):3802. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24203802

Chicago/Turabian Style

Benzi, Alice, Lara Bianchi, Massimo Maccagno, Angela Pagano, Giovanni Petrillo, and Cinzia Tavani. 2019. "Sequential Annulations to Interesting Novel Pyrrolo[3,2-c]carbazoles" Molecules 24, no. 20: 3802. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24203802

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