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Oxidative Aza-Annulation of Enynyl Azides to 2-Keto/Formyl-1H-Pyrroles Chada Raji Reddy, Sujatarani A Panda, and Andhavaram Ramaraju J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02468 • Publication Date (Web): 28 Dec 2016 Downloaded from http://pubs.acs.org on December 28, 2016

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The Journal of Organic Chemistry

Oxidative Aza-Annulation of Enynyl Azides to 2-Keto/Formyl-1H-Pyrroles Chada Raji Reddy,*,†,‡ Sujatarani A. Panda†,‡ and Andhavaram Ramaraju† †

Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500607, India ‡

Academy of Scientific and Innovative Research, New Delhi, India E-mail: [email protected]

RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required according to the journal that you are submitting your paper to)

ABSTRACT: A method for the construction of pyrroles bearing 2-keto or formyl group through the intramolecular oxidative aza-annulation of enynyl azides is reported for the first time. It involves a sequential carbon-nitrogen/carbon-oxygen bond formations and the combination of AuCl3 with AgSbF6 was identified as suitable reagent system to promote the present reaction. The required enynyl azides are readily prepared from Morita-Baylis-Hillman (MBH) acetates of acetylenic aldehydes.

KEYWORDS: Pyrrole, Formylpyrrole, Aza-annulation, Enynyl azide, Gold(III)chloride.

ACS Paragon Plus Environment


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INTRODUCTION Pyrrole is an important structural motif occurring frequently in natural products and synthetic molecules with diverse pharmacological properties.1,2 Precisely, pyrroles containing C-2 carbonyl (keto or formyl) group are of great synthetic significance due to their presence as a prevalent structure in several natural products with potential biological activities3-7 as well as handy building blocks in organic synthesis.8 For instance (Figure 1), longanlactone (I) was isolated from the seeds of Longan (Dimocarpus longan) tree, which are being used as a traditional medicine in China for treating various diseases.4

Zomepirac (II, Zomax)5 and

ketorolac (III)6 are effective non-steroidal anti-inflammatory drugs (NSAID), marketed as analgesic agents. 2-Formyl pyrrole is also a key sub-unit of several bio-active natural products possessing pharmacological activities, for eg. pollenopyrroside A (IV).7 As a result, the synthesis of pyrrole rings bearing 2-keto/formyl patterns is highly valuable. Conventionally, these compounds are made from the parent pyrroles in a step wise manner involving acylation/formylation reactions,9 wherein regioselectivity is a formidable challenge in the case of unsymmetrical pyrroles. Very limited numbers of methods reported for direct construction of 2keto pyrroles as well as 2-formyl pyrroles10 and the development of such methods are highly desirable.

Figure 1. Denoted bio-active natural products and drugs having 2-keto/formylpyrroles


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Enynyl azides, generated from Morita-Baylis-Hillman adduct of acetylenic aldehydes, have proven to be suitable starting materials for the synthesis of pyridines (3 and 4) and pyrroles (6) by our research group.11,12 Similar enynyl azides were utilized by Lee and coworkers for the synthesis of 6H-pyrrolo[1,2-c][1,2,3]triazoles (5).13 In our recent work, the aza-annulation reaction of enynyl azides for the synthesis of substituted pyridines (3), the formation of ketopyrrole (2a) was observed in few cases depending the electronic nature of the substituent under I2-mediated conditions.12 This result prompted us to explore the possibility to find the suitable condition for the synthesis of 2-keto pyrrole as the exclusive product from enynyl azides irrespective of the substitution on the aryl ring tethered to alkyne. Based on the literature knowledge on gold salts and complexes, which emerged as the most powerful catalysts for the electrophilic activation of alkynes toward a variety of nucleophiles,14 we explored the goldcatalyzed reactions of enynyl azides to the straightforward access to 2-keto pyrroles (Scheme 1).

Scheme 1. Synthesis of nitrogen heterocycles from enynyl azide



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With our enduring interest in the construction of structurally important heterocycles and carbocycles starting from Morita-Baylis-Hillman (MBH) adducts of acetylenic aldehydes,15 herein, we report a new route for the synthesis of 2-keto-pyrroles through an oxidative intramolecular aza-annulation of enynyl azides under Au/Ag-mediated reaction conditions. RESULTS AND DISCUSSION To optimize the reaction condition, the annulation of methyl (E)-2-(azidomethyl)-5-phenylpent-

Table 1: Condition optimization for the aza-annulation of of 1a to 2aa


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2-en-4-ynoate (1a) was chosen as a model reaction (Table 1). Firstly, the use of AuCl3 (5 mol%) in CH3CN led to no reaction at room temperature (entry 1), however the reaction at 80 oC for 24 h provided the desired acyl pyrrole 2a in 51% yield (entry 2). Increasing the AuCl3 loading to 10 mol% did not improve the yield of the product 2a (entry 3). In further optimization, the addition of the silver salt AgSbF6 (15 mol%) in combination with AuCl3 (5 mol% or 10 mol%) helps in reducing the reaction time, to obtain the pyrrole 2a (entry 4 & 5). The yield of annulation product 2a was found to increase (82%) with increased AgSbF6 loading to 30 mol% at 80 oC (entry 6). However, the annulation reaction of 1a was not observed with AgSbF6 alone (entry 7). The solvents were then screened using toluene, 1,2-dichloroethane (DCE) and tetrahydrofuran (THF) solvents (entries 8 to 10) and CH3CN proved to be the best solvent (entry 6). Therefore, the subsequent annulation reactions were performed in the presence of AuCl3 (10 mol%)/AgSbF6 (30 mol%) in CH3CN at 80 oC.

With the optimized conditions reaction conditions in hand, we explored scope of the azaannulation with various enynyl azides and the results are summarized in Scheme 2. Aryl enyne, 1-naphthyl enynyl azide 1b and heteroaryl enyne, 2-thiophenyl enynyl azide 1c were tolerated well in the reaction, delivering the corresponding desired products 2b (89%) and 2c (83%), respectively. Furthermore, enynyl azides tethered to 4-phenyl with a wide range of electronic properties, such as electron donating methyl (1d), methoxy (1e) groups and electronwithdrawing groups, chloro (1f), cyano (1g), nitro (1h) and acyl (1i), all participated smoothly in the aza-annulation reaction under Au/Ag-catalyzed condition to afford the corresponding 2-keto pyrroles 2d to 2i in excellent yields. Similarly, 2-iodo-phenyl- and 3-trifluoromethyl-phenyl enynyl azides 1j and 1k underwent the annulations to give the pyrroles 2j and 2k, in 98% and 81% yields, respectively. The investigation of aliphatic enynyl azide 1l, having 1-hexyl group



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tethered to alkyne, was found to be successful in aza-annulation to deliver the product 2l 64% yield.

Scheme 2: Substrate Scope for Aza-Annulation of Enynyl Azides a,b

The reactivity of enynyl aizdes 1m and 1n, bearing methyl ketone and cyclohexanone in the structure, respectively, were also examined for the present annulation reaction.

The

corresponding C-2 keto-pyrrole products 2m and 2n were obtained in 53% and 51% yield, respectively (Scheme 3).


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Scheme 3: Transformation of Enynyl Azides 1m and 1n

We were curious whether the same aza-annulation could be extended to enynyl azide 1o having terminal alkyne to deliver the corresponding 2-formylpyrrole 2o (Table 2). When, the treatment of 1o in an open flask with AuCl3 (10 mol%)/AgSbF6 (30 mol%) in CH3CN at 80 oC, disappointingly, decomposition of starting material was observed (entry 1a). Based on the earlier observations, we turned our attention to examine the reactivity of 1o under I2/NaHCO3 conditions12 for the possible formation of 2-formylpyrrole. To our satisfaction, the reaction of 1o under I2/NaHCO3 in CH2Cl2 at room temperature provided 2-formylpyrrole 2o in 45% yield (entry 1b). The reactivity of enynyl azide 1p bearing tert-butyldimethyl silyl (TBS) group on alkyne was also tested and found that under both the reaction conditions, AuCl3 (10 mol%)/AgSbF6 (30 mol%) in CH3CN at 80 oC (entry 2a) and I2/NaHCO3 in CH2Cl2 at room temperature (entry 2b), delivered 2-silylketo pyrrole 2p in 34% and 48% yield, respectively. Acyl silanes are versatile intermediates and to the best of our knowledge, their synthesis is less explored, mainly heteroacyl silanes.16 Noteworthy to perceive that the enynyl azide 1q, prepared from a non MBH-product, was successful in providing the corresponding 2-keto pyrrole 2q in the presence of AuCl3 (10 mol%)/AgSbF6 (30 mol%) in CH3CN at 80 oC, albeit in low yield (38%, entry 3a). However, no reaction was observed for the treatment of 1q under I2/NaHCO3



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conditions (entry 3b). All new products were identified through their NMR and HRMS data, as well as IR spectra. Table 2: Oxidative aza-annulations of enynyl azides 1o to 1q

A plausible mechanism for the present gold-catalysed oxidative cyclization of 1a is shown in Scheme 4. Based on the literature precedence, the activity of Au(III)-catalyst will be enhanced by Ag-catalyst.17 After the coordination of internal alkyne of 1a with gold-catalyst (A), we presume that the enyne will undergo regioselective hydration18 to give B, which facilitate the CN bond formation to obtain the acyl pyrrole 2a via intermediates C and D. To verify the source of oxygen for the newly formed carbonyl group, the reaction of 1a was conducted independently in the presence of O2 as well as H2O under the optimized reaction conditions. The reaction in the presence of H2O progressed well in 4h to provide 2a in 82% yield, whereas in the presence of


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oxygen, only 10% conversion was observed even after 48 h. Further, under inert atmosphere there was no progress in the reaction (48 h). These results suggest that the source of oxygen for carbonyl group is H2O.

Scheme 4: Proposed reaction mechanism for the conversion of 1a to 2a CONCLUSION In conclusion, we have demonstrated a facile and direct oxidative aza-annulation approach to access structurally important 2-keto/formylpyrrole derivatives for biological and pharmaceutical chemistry. The method uses commercially available catalysts (AuCl3 and AgSbF6) and delivers the product through a cascade C-N/C-O bond formation reactions of enynyl azides. This paper presents a noteworthy application of enynyl-azides that were easily accessible from Morita-Baylis-Hillman acetates of acetylenic aldehydes, as a handy synthon for the synthesis of 2-keto/formyl pyrroles. EXPERIMENTAL SECTION: Reactions were monitored by thin-layer chromatography carried out on silica plates using UVlight, anisaldehyde and β-napthol for visualization. Column chromatography was performed on silica gel (60–120 mesh) using petroleum ether and ethyl acetate as eluents. Evaporation of



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solvents was done under reduced pressure at temperature less than 40 °C. IR spectra were recorded as neat compound. 1H and

13

C NMR spectra were recorded in CDCl3 and DMSO-d6

solvents on a 300 MHz, 500 MHz and 400 MHz NMR spectrometer. Chemical shifts δ and coupling constants J are given in ppm (parts per million) and Hz (hertz) respectively. Chemical shifts are reported relative to residual solvent as an internal standard for 1H and 7.26 ppm for 1H, and 77.0 ppm for

13

C (CDCl3: δ

13

C, DMSO-d6: δ 2.50 ppm for 1H, and 39.5 ppm for

13

C).

Mass spectra recorded on micro mass VG 70–70H or LC/MSD trap SL spectrometer operating at 70 eV using direct inlet system. HRMS data were recorded by electrospray ionization with a QTOF mass analyzer. Substituted azides 1a-1p have been prepared using the literature procedure from the corresponding Morita-Baylis-Hillman acetates of acetylenic aldehydes,12,13 and spectral data compared with the reported data. Characterization data for new compounds is given below. Methyl (E)-2-(azidomethyl)-5-(2-iodophenyl)pent-2-en-4-ynoate (1j): 0.70 g, 98%, pale yellow solid, mp: 49–51 oC, Rf = 0.5 (petroleum ether:EtOAc = 9:1); 1H NMR (500 MHz, CDCl3): δ 7.91 (dd, J = 8.0, 1.0 Hz, 1H), 7.53 (dd, J = 7.8, 1.6 Hz, 1H), 7.38 (td, J = 7.6, 1.1 Hz, 1H), 7.16 (s, 1H), 7.11 (td, J = 7.8, 1.6 Hz, 1H), 4.45 (s, 2H), 3.89 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 165.9, 139.0, 136.6, 133.5, 130.8, 128.6, 128.0, 124.0, 105.1, 101.1, 87.7, 52.6, 48.3; IR (KBr): νmax = 2095, 1716, 1256, 1110, 1016, 833, 754 cm-1; MS (ESI): m/z 390 (M+Na)+; HRMS (ESI): m/z calcd for C13H10INaN3O2 (M+Na)+: 389.9710, found: 389.9704. (E)-Methyl 2-(azidomethyl)pent-2-en-4-ynoate (1o): 0.35 g, 40%, pale yellow liquid, Rf = 0.5 (petroleum ether:EtOAc = 24:1); 1H NMR (400 MHz, CDCl3) δ 6.77 (t, J = 2.4 Hz, 2H), 4.17 (s, 5H), 3.77 (s, 7H), 3.62 (d, J = 2.5 Hz, 2H). 13C NMR (75 MHz, CDCl3): δ 165.6, 138.6, 123.2,


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91.7, 78.3, 52.6, 47.9. MS (ESI): m/z 166 (M+H)+; HRMS (ESI): m/z calcd for C7H8N3O2(M+H)+: 166.0611, found: 166.0625. Methyl (E)-2-(azidomethyl)-5-(tert-butyldimethylsilyl)pent-2-en-4-ynoate (1p): 0.80 g, 85%, pale yellow liquid , Rf = 0.5 (petroleum ether:EtOAc = 24:1); 1H NMR (500 MHz, CDCl3): δ 6.70 – 6.69 (m, 1H), 4.05 (s, 2H), 3.66 – 3.65 (m, 3H), 0.80 (s, 9H), 0.01 (s, 6H); 13C NMR (100 MHz, CDCl3): δ 165.9, 137.1, 124.4, 110.2, 99.9, 52.6, 48.0, 26.1, 16.7, -4.9; IR (KBr): νmax = 2095, 1719, 1250, 1070, 823, 776 cm-1; MS (ESI): m/z 280 (M+H)+; HRMS (ESI): m/z calcd for C13H22N3O2Si (M+H)+: 280.1476, found: 280.1470. (Z)-(5-Azido-3-methylpent-3-en-1-yn-1-yl)benzene

(1q):

To

a

stirred

solution

of

the

corresponding known alcohol (prepared using the literature protocol),19 (5.8 mmol) in 10 mL of toluene was added, DBU (6.9 mmol) and DPPA (diphenylphosphoryl azide, 6.9 mmol), at 0 oC and stirred at room temperature for 3 h. After the completion of reaction (monitered by TLC), the mixture was diluted with 3N HCl (10 mL) and extracted with EtOAc (2 X 10 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether:EtOAc = 24:1) to afford the corresponding product 1q. 0.80 g, 70 %, brown liquid, Rf = 0.5 (petroleum ether:EtOAc = 24:1); 1H NMR (300 MHz, CDCl3): δ 7.46 (dd, J = 6.7, 2.9 Hz, 2H), 7.36–7.31 (m, 3H), 5.86–5.77 (m, 1H), 4.06 (d, J = 7.2 Hz, 2H), 2.03 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 131.6, 129.3, 128.6, 128.4, 124.3, 122.8, 95.1, 86.9, 50.4, 23.2; IR (KBr): νmax = 2922, 2089, 1442, 1242, 754 cm-1; MS (ESI): m/z 198 (M+H)+; HRMS (ESI): m/z calcd for C12H12N3 (M+H)+: 198.1026, found: 198.1031. General procedure for the aza-annulation of enynyl azides to 2-keto/formyl ppyrroles (2a-2q): To a stirred solution of alkynyl azide 1a-1n, 1p & 1q (0.20 mmol) in CH3CN (3.0 mL) was



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added AuCl3 (10 mmol %), AgSbF6 (30 mmol %) in an open flask and the mixture stirred at 80 o

C for the given time (see schemes 2 & 3 and table 2). After completion of the reaction

(monitered by TLC), the mixture cooled to room temperature and solvent was evaporated. The residue was purified through silicagel column chromatography (petroleum ether/EtOAc as eluents) to afford the corresponding 2-keto/formyl pyrroles 2a to 2n, 2p & 2q. Spectral data for known compounds 2a, 2f, 2g and 2m spectral data was compared with our earlier reported data.12 Characterization data for new compounds is provided below. Methyl 5-(2-naphthoyl)-1H-pyrrole-3-carboxylate (2b): 111 mg, 89%, white solid, mp 192-194 o

C, Rf = 0.4 (petroleum ether:EtOAc = 8:2); 1H NMR (400 MHz, CDCl3): δ 10.18 (s, 1H), 8.22 –

8.12 (m, 1H), 7.96 (d, J = 8.3 Hz, 1H), 7.88 – 7.81 (m, 1H), 7.75 (dd, J = 7.1, 1.2 Hz, 1H), 7.67 (dd, J = 3.2, 1.4 Hz, 1H), 7.52 – 7.41 (m, 3H), 7.02 (dd, J = 2.4, 1.4 Hz, 1H), 3.74 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 186.7, 164.3, 134.9, 133.8, 133.1, 131.8, 130.6, 129.2, 128.5, 127.7, 127.4, 126.6, 125.3, 124.4, 120.3, 118.5, 51.5; IR (KBr): νmax = 3241, 2952, 1720,1610, 1209, 759 cm-1; MS (ESI): m/z 280 (M+ H)+ HRMS (ESI): m/z calcd for C17H13NNaO3. 302.0788, found: 302.0806. Methyl 5-(thiophene-2-carbonyl)-1H-pyrrole-3-carboxylate (2c): 79 mg, 83%, white solid, mp 131-133 oC, Rf = 0.4 (petroleum ether:EtOAc = 8:2); 1H NMR (500 MHz, CDCl3): δ 9.98 (s, 1H), 7.91 (dd, J =3.8, 1.1 Hz, 1H), 7.71 – 7.59 (m, 2H), 7.48 (dd, J = 2.5, 1.3 Hz, 1H), 7.14 (dd, J =4.9, 3.8 Hz, 1H), 3.0 (s, 3H);

13

C NMR (100 MHz, CDCl3): δ 175.9, 164.4, 141.9, 133.4,

132.9, 131.0, 128.7, 128.2, 118.5, 117.6, 51.4; IR (KBr): νmax = 3265, 2952, 1719, 1601, 759 cm1

; MS (ESI): m/z 236 (M+H)+; HRMS (ESI): m/z calcd for C11H10NO3S(M+H)+: 236.0376,

found: 236.0379.


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Methyl 5-(4-methylbenzoyl)-1H-pyrrole-3-carboxylate (2d): 76 mg, 79%, white solid, mp 161163

o

C,

Rf =0.4 (petroleum

ether:EtOAc=

8:2);

1

H NMR

(500 MHz, CDCl3):

δ 10.07 (s, 1H), 7.77 (d, J = 8.2 Hz, 2H), 7.63 (dd, J = 3.3, 1.3 Hz, 1H), 7.31 – 7.21 (m, 3H), 3.78 (s, 3H), 2.38 (s, 3H);.

13

C NMR (100 MHz, CDCl3): δ 185.1, 164.5, 143.4, 134.7, 131.6,

129.3, 128.9, 119.4, 118.2, 51.6, 21.7; IR (KBr): νmax = 3248, 2855, 1720, 1714, 1624, 753 cm-1; MS (ESI): m/z 244 (M+H)+; HRMS (ESI): m/z calcd for C14H14NO3 (M+H)+: 244.0968, found: 244.0960. Methyl 5-(4-methoxybenzoyl)-1H-pyrrole-3-carboxylate (2e): 83 mg, 86%, yellow solid, mp 165 -167 oC. Rf = 0.4 (petroleum ether:EtOAc = 8:2); 1H NMR (500 MHz, CDCl3): δ 9.98 (s, 1H), 7.92 – 7.86 (m, 2H), 7.61 (dd, J = 3.3, 1.4 Hz, 1H), 7.23 (dd, J = 2.5, 1.4 Hz, 1H), 6.9 –6.89 (m, 2H), 3.83 (s, 3H), 3.78 (s, 3H);

13

C NMR (125 MHz, CDCl3): δ 183.8, 164.5, 163.3, 131.5,

131.3, 129.9, 128.4, 118.6, 118.1, 113.8, 55.5, 51.4; IR (KBr): νmax = 3296, 2925, 1694, 1287, 762cm-1; MS (ESI): m/z 260 (M+H)+; HRMS (ESI): m/z calcd for C14H13NNaO4(M+Na)+: 282.0737, found: 282.0740. Methyl 5-(4-nitrobenzoyl)-1H-pyrrole-3-carboxylate (2h): 97 mg, 84%, yellow solid, mp 234236 oC, Rf = 0.4 (petroleum ether:EtOAc = 8:2); 1H NMR (300 MHz, DMSO-d6): δ 12.88 (s, 1H), 8.38 (d, J = 8.6 Hz, 2H), 8.06 (d, J = 8.6 Hz, 2H), 7.83 (s, 1H), 7.10 (s, 1H), 3.74 (s, 3H); 13

C NMR (75 MHz, DMSO-d6): δ 182.4, 163.2, 149.1, 142.6, 130.6, 130.4, 129.6, 123.5, 119.7,

116.8, 50.9; IR (KBr): νmax = 3274, 1697, 1630, 1290, 765cm-1; MS (ESI): m/z 273 (M- H)+ ; HRMS (ESI): m/z calcd for C13H9N2O5(M-H)-: 273.0517, found: 273.0510. Methyl 5-(4-acetylbenzoyl)-1H-pyrrole-3-carboxylate (2i): 41 mg, 87%, white solid, mp 176-178 o

C, Rf = 0.4 (petroleum ether:EtOAc = 8:2); 1H NMR (400 MHz, CDCl3): δ 10.00 (s, 1H), 8.02

(d, J = 8.3 Hz, 2H), 7.92 (d, J = 8.3 Hz, 2H), 7.68 (dd, J = 3.1, 1.2 Hz, 1H), 7.23–7.21 (m, 1H),



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3.78 (s, 3H), 2.61 (s, 3H);

13

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C NMR (125 MHz, CDCl3): δ 197.5, 184.2, 164.1, 140.9, 139.6,

131.2, 129.3, 129.2, 128.4, 119.7, 118.7, 51.6, 26.9; IR (KBr): νmax = 3261, 1722, 1688, 1636, 1218, 764 cm-1; MS (ESI): m/z 272 (M+H)+ HRMS (ESI): m/z calcd for C15H14NO4 (M+H)+: 272.0917, found: 272.0925. Methyl 5-(2-iodobenzoyl)-1H-pyrrole-3-carboxylate (2j): 190 mg, 98%, white solid, mp 172-174 o

C, Rf = 0.5 (petroleum ether:EtOAc = 7:3); 1H NMR (400 MHz, CDCl3): δ 10.26 (s, 1H), 7.98

(d, J = 7.9 Hz, 1H), 7.78 (dd, J = 3.2, 1.3 Hz, 1H), 7.49 – 7.46 (m, 2H), 7.23 (ddd, J = 8.0, 5.5, 3.7 Hz, 1H), 7.00 (dd, J = 2.3, 1.4 Hz, 1H), 3.84 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 186.6, 164.1, 142.5, 140.2, 131.6, 131.2, 130.4, 128.8, 127.7, 121.5, 118.6, 92.6, 51.5; IR (KBr): νmax = 3266, 2950, 1712, 1633, 1291, 895, 750 cm-1; MS (ESI): m/z 356 (M+H)+; HRMS (ESI): m/z calcd for C13H10INNaO3 (M+Na)+: 377.9598, found: 377.9581. Methyl 5-(trifluoromethylbenzoyl)-1H -pyrrole-3-carboxylate (2k): 157 mg, 81%, pale yellow solid, mp 136-138 oC, Rf = 0.4 (petroleum ether:EtOAc = 8:2); 1H NMR (400 MHz, CDCl3): δ 10.07 (s, 1H), 8.09 (s, 1H), 8.03 (d, J = 7.8 Hz, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.69 (dd, J = 3.3, 1.3 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H), 7.21 (dd, J = 2.5, 1.3 Hz, 1H), 3.79 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 183.5, 164.1, 137.9, 132.1, 131.3 (q, 2JC-F = 32.5 Hz), 130.9, 129.2, 129.1, 128.9 (q, 3JC-F = 3.6 Hz), 125.7 (q, 3JC-F = 3.6 Hz), 123.6 (q, 1JC-F = 271.2 Hz), 119.5, 118.8, 51.6; IR (KBr): νmax = 3383, 1704, 1626, 1271, 752 cm-1; MS (ESI): m/z 298 (M+H)+HRMS (ESI): m/z calcd for C14H11O3NF3(M+H)+: 298.0685, found: 298.0690. Methyl 5-heptanoyl-1H-pyrrole-3-carboxylate (2l): 61 mg, 64%, white solid, mp 66-68 oC, Rf = 0.5 (petroleum ether:EtOAc = 9:1); 1H NMR (500 MHz, CDCl3): δ 9.63 (s, 1H), 7.51 (dd, J = 3.2, 1.4 Hz, 1H), 7.26–7.21 (m, 1H), 3.82–3.71 (m, 3H), 2.70 (dd, J = 17.0, 9.4 Hz, 2H), 1.64 (dt, J = 15.1, 7.5 Hz, 2H), 1.35–1.19 (m, 6H), 0.88–0.75 (m, 3H);


13

C NMR (75 MHz, CDCl3): δ

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191.6, 164.4, 132.4, 127.9, 118.1, 115.9, 51.4, 38.1, 31.6, 29.1, 24.9, 22.5, 14.0; IR (KBr): νmax = 3260, 2925, 1715, 1646, 1207, 766 cm-1; MS (ESI): m/z 238 (M+H)+; HRMS (ESI): m/z calcd for C13H20NO3(M+H)+: 238.1438, found: 238.1442. 2-Benzoyl-1,5,6,7-tetrahydro-4H-indol-4-one (2n): 32 mg, 51%, brown solid, mp 182-184 oC, Rf = 0.5 (petroleum ether:EtOAc = 7:3); 1H NMR (400 MHz, CDCl3): δ 9.73 (s, 1H), 7.87–7.76 (m, 2H), 7.56–7.49 (m, 1H), 7.42 (dd, J = 10.4, 4.7 Hz, 2H), 7.17 (d, J = 2.1 Hz, 1H), 2.88 (t, J = 6.2 13

Hz, 2H), 2.53–2.39 (m, 2H), 2.22–2.03 (m, 2H).;

C NMR (75 MHz, CDCl3): δ 194.4, 185.3,

147.8, 137.3, 132.6, 131.0, 128.9, 128.6, 122.5, 115.9, 38.0, 23.4, 23.0; IR (KBr): νmax = 3240, 2926, 1726, 1608, 842 cm-1; MS (ESI): m/z 240 (M+H)+; HRMS (ESI): m/z calcd for C15H14NO2(M+H)+: 240.1019, found: 240.1017. Methyl 5-((tert-butyldimethylsilyl)carbonyl)-1H-pyrrole-3-carboxylate (2p): 92 mg, 48%, white solid, mp 164-166 oC, Rf = 0.5 (petroleum ether:EtOAc = 9:1); 1H NMR (500 MHz, CDCl3) δ 9.98 (s, 1H), 7.56 (dd, J = 3.2, 1.2 Hz, 1H), 7.30 (dd, J = 2.4, 1.3 Hz, 1H), 3.85 (d, J = 4.2 Hz, 3H), 0.98 – 0.96 (m, 9H), 0.38–0.36 (m, 6H);

13

C NMR (100 MHz, CDCl3): δ 221.1, 164.5,

138.9, 127.5, 118.3, 118.2, 51.4, 26.6, 16.7, -5.5; IR (KBr): νmax = 3339, 2935, 1688, 1543, 804 cm-1; MS (ESI): m/z 268 (M+H)+; HRMS (ESI): m/z calcd for C13H22NO3Si(M+H)+: 268.1363, found: 268.1369. (Methyl-1H-pyrrol-yl)methanone (2q): 72 mg, 38%, brown liquid, Rf

= 0.5 (petroleum

ether:EtOAc = 9:1); 1H NMR (400 MHz, CDCl3): δ 9.20 (s, 1H), 7.60–7.57 (m, 2H), 7.48–7.42 (m, 1H), 7.38 (ddt, J = 5.0, 4.3, 1.3 Hz, 2H), 6.90 (t, J = 2.8 Hz, 1H), 6.07 (t, J = 2.4 Hz, 1H), 1.96 (s, 3H).; 13C NMR (100 MHz, CDCl3): δ 186.7, 139.8, 131.2, 129.2, 128.7, 128.4, 128.3, 123.9, 113.8, 13.9; IR (KBr): νmax = 3294, 2923, 1601, 1573, 1261,884, 699 cm-1; MS (ESI): m/z 186 (M+H)+; HRMS (ESI): m/z calcd for C12H12NO(M+H)+: 186.0913, found: 186.0911.



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Page 16 of 20

Methyl 5-formyl-1H-pyrrole-3-carboxylate (2o): Following our earlier reported procedure,12 azide 1o was allowed to react with NaHCO3 (34 mg, 0.41 mmol) and iodine (524 mg, 2.07 mmol) for 2 h. After the workup, the residue was purified by column chromatography on silica gel (10 % EtOAc in petroleum ether) to afford the acyl pyrrole 2o. 85 mg, 45%, brown solid, mp 128-130 oC, Rf = 0.5 (petroleum ether:EtOAc = 3:2); 1H NMR (400 MHz, CDCl3): δ 10.18 (s, 1H), 9.49 (d, J = 1.1 Hz, 1H), 7.64 (dt, J = 3.2, 1.2 Hz, 1H), 7.33 (dd, J = 2.5, 1.4 Hz, 1H), 3.79 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 180.0, 164.0, 133.1, 129.8, 121.4, 118.8, 51.6; IR (KBr): νmax = 3250, 1719, 1659, 849 cm-1; MS (ESI): m/z 176 (M+Na)+; HRMS (ESI): m/z calcd for C7H7NNaO3(M+Na)+: 176.0318, found: 176.0319. ACKNOWLEDGEMENTS SAP and AR thank Council of Scientific and Industrial Research, New Delhi for research fellowships. CRR is grateful to CSIR, New Delhi for financial support as part of XII-five year plan project under title ORIGIN (CSC-108). Supporting Information Available. Structures of enynyl azides 1a to 1l and copies of 1H & 13C NMR spectra of all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org References and Notes: 1.

For representative references, see: (a) Gupton, J.T.; “Pyrrole Natural Products with Antitumor Properties” in Heterocyclic Antitumor Antibiotics, Topics in Heterocyclic Chemistry, vol. 2 (Ed.: M. Lee), Springer, Heidelberg, Berlin, 2006, pp. 53–92. (b) Hu, D. X.; Withall, D. M.; Challis, G. L.; Thomson, R. J. Chem. Rev. 2016, 116, 7818-7853. (c) Ding, X.-B.; Brimble, M. A.; Furkert, D. P. Org. Biomol. Chem. 2016, 14, 5390-5401. (d) Motuhi, S.-E.; Mehiri, M.; Payri, C. E.; Barre, S. L.; Bach, S. Mar. Drugs 2016, 14, 1-60. (e)


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Formyl-1H

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