Visible-Light-Induced C (sp3)-H Functionalization of Tosylhydrazones: Synthesis of Polysubstituted Pyrroles under Metal-Free Conditions

Article abstract of DOI:10.1021/acs.joc.8b00878

Iodine catalyzed C (sp³)-H functionalization of tosylhydrazones with β-enamino esters under visible light irradiation for the synthesis of trisubstituted pyrroles has been described. The present method is also applicable to α- substituted tosyl

Full text of DOI:10.1021/acs.joc.8b00878

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Note
Visible-Light Induced C (sp3)–H Functionalization of Tosylhydrazones:
Synthesis of Polysubstituted Pyrroles under Metal-free Conditions
N Naresh Kumar Reddy, Deepa Rawat, and Subbarayappa Adimurthy
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00878 • Publication Date (Web): 19 Jul 2018
Downloaded from http://pubs.acs.org on July 19, 2018
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Visible-Light Induced C (sp3)–H Functionalization of Tosylhydrazones: Synthesis of
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Polysubstituted Pyrroles under Metal-free Conditions
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N. Naresh Kumar Reddy, Deepa Rawat, Subbarayappa Adimurthy*
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Academy of Scientific & Innovative Research, CSIR–Central Salt & Marine Chemicals
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Research Institute, G.B. Marg, Bhavnagar-364 002. Gujarat (INDIA).
*E-mail: adimurthy@csmcri.res.in
ABSTRACT:
Iodine catalysed C (sp3)–H functionalization of tosylhydrazones with β-enamino esters under
visible light irradiation for the synthesis of tri-substituted pyrroles has been described. The
present method is also applicable to α- substituted tosylhydrazones to yield the tetra-
substituted pyrroles.
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Pyrroles are important synthetic building blocks in chemistry due to their numerous
applications such as preparation of pharmaceuticals, biologically active molecules, and
natural products.1 Accordingly, the development of new methodologies to access these
valuable molecules is continuously gaining the great importance in synthetic organic
chemistry. The first synthetic method was reported by Paal and Knorr independently by the
condensation of 1, 4- dicarbonyl compounds with primary amines or ammonia.2 Inspired by
the aforementioned methods, particularly in the last decade a significant progress has been
made for the synthesis of pyrroles.3-6 Despite the advances, the development of convenient
and practical method for synthesis of pyrroles under transition metal-free, cheaper and
catalytic conditions still holds its relevance, hence it is a highly desirable and yet to be a
challenging task. In particular, the exploration of novel reagents and strategies for the
synthesis of pyrroles under mild conditions with good functional-group tolerance is vital.
From the view point of green chemistry, it is desirable to update the synthetic transformation
of pyrroles under operationally simple and environmentally benign conditions.
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As part of our ongoing research interest on the development of new methods for the synthesis
of various aza-heterocycles through visible-light induced as well as under metal-free
conditions,7 we report herein a novel visible-light-induced synthesis of highly substituted
pyrrole derivatives (Scheme 1). After careful survey of literature, our attention has been
drawn to employ inexpensive and readily available substrates for the synthesis of pyrroles.
We report herein a novel visible-light-induced iodine catalysed synthesis of highly
substituted pyrrole derivatives (Scheme 1).
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Scheme 1Synthetic strategies for pyrrole synthesis
We have started our studies on pyrrole syntheses with tosylhydrazones and β-enamino esters.
To optimize the conditions we have chosen (E)-N'-(1-(4-methoxyphenyl) ethylidene)-4-
methyl benzene sulfonohydrazide (1a) and ethyl-3-amino-3-phenylacrylate (2a) as the model
substrates with catalytic amount of iodine (10 mol %), aqueous TBHP (1.0 equiv.) and DMF
as solvent at room temperature under visible light (12W Blue LED) conditions (Table 1).
Under these conditions the desired product 3a was obtained in 10% isolated yield after 24 h
reaction time (Table 1, entry 1).When the reaction was carried out in DMSO as solvent under
the same conditions, 51% of 3a was isolated (Table 1, entry 2). To improve the yield of the
product, K2CO3 was added to the reaction mixture, but the yield was declined (Table 1, entry
3). No product formation was observed with other solvents (NMP, DCE, CH3CN, THF, H2O
and 1, 4-dioxane) tested for the reaction (Table 1, entries 4-9). The conditions of entry 2 was
performed under inert atmosphere, the desired product 3a yield was increased to 63% (Table
1, entry 10). As the yield was improved under inert atmosphere, based on this observation,
the reaction was performed with TBHP in decane instead of water, unexpectedly the yield
was dropped to 41% (entry 11). Keeping the solvent as DMSO, the reaction was screened
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with different oxidants (DTBP, K2S2O8, molecular oxygen, and H2O2) and other iodine
sources (NIS, TBAI, KI) but the reaction was unsuccessful under these conditions (entries
12−18). To our delight, by increasing the oxidant TBHP to 1.5 equivalents, the product yield
was increased to 69% (entry 19). Furthermore, when the reaction was performed with 2.0
equivalents of TBHP, the yield of 3a was also increased to 79% (entry 20). When the reaction
was performed without catalyst, without oxidant and without irradiation of LED light no
product formation was observed (entries 21 23). Finally, the reaction conducted with one
and two equivalents of iodine but without TBHP, the comparable yields (61% and 72%) of
desired product 3a was obtained (Table 1, entries 24 & 25).
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Table 1 Optimization of the Reaction Conditionsa
aReaction conditions, unless otherwise stated; 0.2 mmol of 1a,0.2 mmolof 2a, 0.05 mmol of I2, 0.4 mmol of
TBHP inH2O and 2.0 mL of solvent were placed in reaction tube in Ar atmosphere at room temperature, under
irradiation of 12 W blue LED strips, 24 h, isolated yields.bopen air c K2CO3 was used. dwithout irradiation of 12
W blue LED light.
On the basis of the results obtained, the optimized conditionswere set as 0.2 mmol of 1a, 0.2
mmol of 2a, 0.05 mmol of I2, 0.4 mmol of TBHP in H2O and 2.0 mL of DMSO as a solvent
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under N2 atmosphere at room temperature with irradiation of 12 W blue LED light for 24 h,
for the present transformation.
With the optimized conditions in hand (Table 1, entry 20), we investigated the substrate
scope with a diverse set of (E)-N'-(1-arylethylidene)-4-methylbenzenesulfonohydrazides (1)
and ethyl (Z)-3-amino-3-arylacrylates (2) to obtain tri-substituted pyrroles (Scheme 2).
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Scheme 2. Substrate scope for the synthesis of tri-substituted pyrrolesa
aReaction conditions: 0.2 mmol of 1,0.2 mmolof 2, 0.05 mmol of I2, 0.4 mmol of TBHP in H2O and 2.0 mL of
DMSO were placed in reaction tube underAr atmosphere, reaction time 24h, isolated yields. bYield at 1.59 gram
scale (5.0 mmol).
Substrates containing either electrondonating (–OMe, –Et, –Me, –H) or withdrawing (–F, –
Br) groups at the para-position of the phenyl ring 1, were all tolerated under the standard
conditions, and gave the corresponding products (3a–3f) in good yields (63–79%). One of the
products, 3f, was further confirmed by single crystal X-ray diffraction (Figure 1, CCDC. No.
Figure 1. Crystal structure of 3f (probability 50%)
1835841). In the case of strong electron withdrawing group low yield (31%) of the
corresponding product 3g was observed. The presence of methoxy group at meta-position or
at either ortho position of phenyl ring, gave the good (69% and 70%) yields of products 3h
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and 3i. The yield of the product 3i indicates, no steric effect was observed in the present
transformation.Then we focused on the reaction of substituted β-enamino esters 2. The
presence of electron donating (–OMe, –Et, –Me, -H) or -withdrawing (–F, –Br, –NO2) groups
at the para-position of the phenyl ring 2, reacted smoothly with representative substrates of 1
and afford the desired tri-substituted pyrroles (3j–3p) in moderate to good yields (50–85%).
The present system is also applicable to heterocyclic derivatives of 1, and obtained the
corresponding product 3q [ethyl 2-phenyl-5-(thiophen-2-yl)-1H-pyrrole-3-carboxylate], in
54% yield. Unfortunately, with aliphatic enamines it does not yield the desired product 3r.
The optimized conditions were then applied for the synthesis of 2, 3, 4, 5- substituted pyrrole
5a from α-substituted tosylhydrazones [(Z)-N'-(1-phenylpropylidene)-4-methtyl benzene
sulfonohydrazide] 4a and β-enamine ester 2a (Scheme 3). Under the conditions of scheme 2,
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Scheme 3. Synthesis of polysubstituted Pyrroles
only traces of 5a was observed. We further optimised the conditions by screening various
parameters and the best yield of 5a was obtained with one equivalent of iodine (w.r.t. 2a and
4a) in 2.0 mL of DMSO as solvent under argon atmosphere with irradiation of 12 W blue
LED light, at room temperature for 24 h (for details see Table S1, supporting information).
With these optimised conditions, different tetra-substituted pyrroles were synthesised
(Scheme 4).
Scheme 4 Substrate scope for the synthesis of tetra-substituted pyrrolesa
aReaction conditions: 0.2 mmol of 4, 0.2 mmol of 2, 0.2 mmol of I2, 2.0 mL of DMSO were placed in reaction
tube under Ar atmosphere, 24h, isolated yields.
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The presence of electron donating (–OMe), neutral (–H), and withdrawing (–Br) groups at the
para-position of the phenyl ring 2, reacted smoothly with 4a and afford the tetra substituted
pyrroles 5a–c in moderate yields (54-65%). Further the reaction of (Z)-N'-(1, 2-
diphenylethylidene)-4-methyl benzene sulfonohydrazide 4b, with both electron donating and
withdrawing substituents of 2, were also provided the corresponding products 5d–g. Under
these conditions, (Z)-N'-(1-(4-bromophenyl)-2-phenylethylidene) benzene sulfonohydrazide
4c was also reacted with 2 and gave the desired product 5h in 56% yield. The presence of
strong electron withdrawing group (–NO2) on the phenyl ring of β-enamine ester 2 inhibits
the reaction. It may be noted that the halogen (Br, Cl, and F) substituted derivatives were well
tolerated and could be further applied in traditional cross-coupling reactions. While the yields
of these products are moderate, they exemplify the ability to expand the method toward
polysubstituted pyrrole synthesis.
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To gain insight into the reaction mechanism we performed some control experiments
(Scheme 5). In order to know the reaction intermediate, the reaction of 1a with stoichiometric
amount of I2 was subjected under visible light conditions in open air and argon atmosphere
(Scheme 5, eqs. 1 and 2). Under the conditions of eq. 1, the quantitative yield of -iodo
derivative 6 was obtained, however with conditions of eq. 2, 6 was not observed. From the
above conditions, in the former case oxygen from air may act as a initiator, in the latter one,
due to the lack of initiator, no iodo derivative formation was observed. Addition of 2
equivalents of TBHP to the above conditions, the decomposition of 1a was observed (eq. 3).
Further to know the role of -iodo derivative 6, it was reacted with 2a under the optimised
conditions, under these conditions decomposition of 6 was observed with the recovery of 2a
(eq. 4).
Scheme 5. Control experiments
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To assess whether the reaction proceed through radical or ionic path, 1a and 2a was subjected
to the optimised conditions along with TEMPO as a radical scavenger, no desired product 3a
formation was observed (eq. 5). This reaction suggests that, the present reaction may proceed
through a radical pathway. Further, when the reaction of 1a and 2a was subjected to the
optimised conditions with HI (20 mol %) as iodine source, 82% of desired product was
isolated (eq. 6). The equation 6 indicates that, TBHP oxidises HI to I2, which proceeds the
reaction in a similar path.
Based on the above results and literature support,8,9 a plausible reaction mechanism has
proposed (Scheme 6). Initially, I2 in the presence of blue LED generates iodine radical, which
may abstract proton from the substrate 1 generates a radical intermediate I with the
elimination of HI. Reaction of I with enamine 2a generates another intermediate II.
Intermediate II in presence of iodine radical forms intermediate III which upon cyclisation
forms cyclic intermediate IV. With the simultaneous elimination of p-toluenesulfonyl
hydrazide and aromatisation gives the desired product 3.
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Scheme 6. Plausible mechanism
In conclusion, we have demonstrated a new method for the syntheses of tri and tetra-
substituted pyrroles through cyclization of tosylhydrazones and β-enamino esters under
metal-free conditions.
EXPERIMENTAL SECTION
General Information. All commercially available chemicals and reagents were used without
anyfurther purification unless otherwise indicated. 1H and 13C NMR spectra were recorded at
600 and 150 MHz, respectively. The spectra were recorded in CDCl3 and DMSO-d6 as a
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solvent. Multiplicity was indicated as follows: s (singlet); d (doublet); t (triplet); m
(multiplet); dd (doublet of doublets), etc. Coupling constants (J) were given in Hz. Chemical
shifts are reported in δ relative to TMS as an internal standard. The peaks around δ values of
7.26 (1H NMR), 77.0 (13C NMR) correspond to CDCl3.The peaks around δ values of 2.50 (1H
NMR), 39.9 (13C NMR) are corresponding to DMSO. The peak around δ values of 3.35 (1H
NMR) is corresponding to the H2O present in DMSO solvent. Progress of the reactions was
monitored by thin layer chromatography (TLC). Silica gel 100-200 mesh size was used for
column chromatography using a hexane/ethyl acetate eluent unless otherwise indicated.
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Experimental Section. General Procedure for 3a: 63.6 mg (0.2 mmol) of (E)-N'-(1-(4-methoxy
phenyl)ethylidene)-4-methyl benzene sulfonohydrazide 1a, 38.2 mg (0.2 mmol) of (ethyl (E)-
3-amino-3-phenylacrylate 2a, 12.65 mg of (0.05 mmol) of I2 and 36 mg (0.4 mmol) of TBHP
were taken in a 10 mL reaction tube; to it 2.0 mL of DMSO at room temperature, argon
atmosphere, under irradiation with 12W blue LED strips for 24 h. Then, 15 mL of saturated
(Na2S2O3) hypo solution was added and extracted with ethyl acetate (3x15 mL) and dried
with anhydrous Na2SO4. After removal of solvent, the crude mixture was subjected to column
chromatography on silica gel, and 79 % yield of the product tri substituted pyrrole (50.9 mg)
3a was isolated. (All the tosyl hydrazones and β-Enamino esters employed in the present
manuscript were prepared by known procedure10).
Characterization Data:
Ethyl 5-(4-methoxyphenyl)-2-phenyl-1H-pyrrole-3-carboxylate (3a)
(Eluent: 7% EtOAc/hexane); 79% yield (50.9 mg); pale yellow solid; melting point 158 -
1
160 °C. H NMR (600 MHz, CDCl3) δ 8.50 (s, 1H), 7.63 (d, J = 6.5Hz, 2H), 7.42 (m, 4H),
7.35 (t, J = 6.0 Hz, 1H ), 6.92 (d, J = 7.0 Hz, 2H), 6.88 (s, 1H), 4.22 (q, J = 4.5 Hz, 2H), 3.82
(s, 3H), 1.26 (t, J = 5.5 Hz, 3H).13C NMR (150 MHz, CDCl3) δ 164.9, 158.9, 137.2, 132.1,
131.8, 129.0, 128.3, 128.2, 125.5, 124.5, 114.5, 113.7, 108.1, 59.8, 55.5, 14.3. IR: 3433,
3217, 3302, 2939, 1687, 1467, 1296, 1138, 1057, 761, 678, 648. HRMS (ESI-TOF) m/z: [M
+ H]+calcd for C20H20NO3 322.1443; Found 322.1424.
Ethyl 2-phenyl-5-(p-tolyl)-1H-pyrrole-3-carboxylate (3b)
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(Eluent: 7% EtOAc/hexane); 65% yield (39.9 mg); white solid; melting point 173 - 175 °C
1H NMR (600 MHz, CDCl3) δ 8.53 (s, 1H), 7.64 (d, J = 6.0Hz, 2H), 7.42 (q, J = 6.0 Hz, 4H),
7.37 (t, J = 6.0 Hz, 1H), 7.20 (d, J = 6.5 Hz, 2H), 6.96 (s, 1H), 4.23 (q, J = 6.0 Hz, 2H), 2.36
(s, 3H), 1.26 (t, J = 6.0 Hz, 3H).13C NMR (150 MHz, CDCl3) δ 164.9, 137.4, 137.0, 131.9,
129.8, 129.0, 128.4, 128.2, 124.0, 113.3, 108.6, 59.8, 21.2, 14.3. IR: 3476, 3285, 2895, 1664,
1455, 1368, 1265, 1248, 1135, 1039, 822, 745, 701, 623. HRMS (ESI-TOF) m/z: [M +
Na]+calcd for C20H19NO2Na 328.1313; Found 328.1306.
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Ethyl 5-(4-ethylphenyl)-2-phenyl-1H-pyrrole-3-carboxylate (3c)
(Eluent: 7% EtOAc/hexane); 77% yield (49.1 mg); white solid; melting point 133 - 135 °C
1H NMR (600 MHz, CDCl3) δ 8.62 (s, 1H), 7.63 (d, J = 6.5 Hz, 2H), 7.42 (m, 4H), 7.35 (t, J
= 6.0 Hz, 1H), 7.23 (d, J = 6.5 Hz, 2H), 6.96 (s, 1H), 4.22 (q, J = 6.0 Hz, 2H), 2.66 (q, J = 6.5
Hz, 2H), 1.25 (q, J = 6.0 Hz, 6H) 13C NMR (150 MHz, CDCl3) δ 164.9, 143.3, 137.3, 132.0,
131.9, 129.0, 128.5, 128.3, 128.1, 124.0, 113.6, 108.6, 59.7, 28.5, 15.5, 14.3. IR: 3433, 3318,
2969, 1657, 1447, 1266, 1128, 1057, 761, 678, 648. HRMS (ESI-TOF) m/z: [M + Na]+calcd
for C21H21NO2Na 342.1470; Found 342.1468.
Ethyl 2, 5-diphenyl-1H-pyrrole-3-carboxylate (3d)
(Eluent: 7% EtOAc/hexane); 70% yield (41.0 mg);white solid; melting point 167 - 170 °C
1H NMR (600 MHz, CDCl3) δ 8.66 (s, 1H), 7.64 (d, J = 5.5Hz, 2H), 7.51 (d, J = 6.0 Hz, 2H),
7.41 (q, J = 7.0 Hz, 5H), 7.26 (t, J = 6.0 Hz, 1H), 7.00 (s, 1H), 4.22 (q, J = 6.0 Hz, 2H), 1.26
13
(t, J = 5.5 Hz, 3H) C NMR (150 MHz, CDCl3) δ 164.8, 137.7, 131.9, 131.7, 131.4, 129.0,
128.4, 128.1, 127.0, 124.0, 113.7, 109.1, 59.8, 14.3. IR: 3433, 3302, 2939, 1672, 1455, 1291,
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1256, 1138, 1043, 761, 692, 623. HRMS (ESI-TOF) m/z: [M + Na]+calcd for C19H17NO2Na
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314.1157; Found 314.1152.
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Ethyl 5-(4-chlorophenyl)-2-phenyl-1H-pyrrole-3-carboxylate (3e)
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(Eluent: 7% EtOAc/hexane); 63% yield (41.5 mg);white solid; melting point 203 - 205 °C
1H NMR (600 MHz, CDCl3) δ 8.65 (s, 1H), 7.62 (d, J = 5.5Hz, 2H), 7.43 (m, 4H), 7.36 (m,
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3H), 6.98 (s, 1H), 4.23 (q, J = 5.5 Hz, 2H), 1.26 (t, J = 6.0 Hz, 3H) C NMR (150 MHz,
CDCl3) δ 164.7, 138.1, 132.7, 131.7, 130.7, 130.0, 129.2, 129.0, 128.6, 128.2, 125.2, 113.9,
109.6, 59.9, 14.3. IR: 3456, 3217, 2939, 1687, 1467, 1296, 1378, 1250, 1057, 761, 678, 648.
HRMS (ESI-TOF) m/z: [M + Na]+calcd for C19H16ClNO2Na 348.0767; Found 348.0760.
Ethyl 5-(4-bromophenyl)-2-phenyl-1H-pyrrole-3-carboxylate (3f)
(Eluent: 7% EtOAc/hexane); 65% yield (47.8 mg); white solid; melting point 213 - 215 °C
1H NMR (600 MHz, CDCl3) δ 8.57 (s, 1H), 7.62 (d, J = 6.0 Hz, 2H), 7.51 (d, J = 6.5 Hz, 2H),
7.41 (t, J = 6.0 Hz, 2H), 7.37 (d, J = 6.0 Hz, 3H), 6.99 (s, 1H), 4.22 (q, J = 6.0 Hz, 2H), 1.26
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(t, J = 6.0 Hz, 3H) C NMR (150 MHz, CDCl3) δ 164.7, 138.1, 132.2, 131.7, 130.6, 130.5,
129.0, 128.6, 128.2, 125.5, 120.7, 114.0, 109.7, 59.9, 14.3. IR: 3419, 3280, 2964, 1658, 1455,
1385, 1286, 1259, 1178, 1143, 1039, 805, 771, 701. HRMS (ESI-TOF) m/z: [M + Na]+calcd
for C19H16BrNO2Na 392.0262; Found 392.0260.
Ethyl 5-(4-nitrophenyl)-2-phenyl-1H-pyrrole-3-carboxylate (3g)
(Eluent: 25% EtOAc/hexane); 31% yield (21.0 mg); yellow solid; melting point 212 - 215 °C
1H NMR (600 MHz, CDCl3) δ 12.1 (s, 1H), 8.18 (d, J = 7.5Hz, 2H), 8.02 (d, J = 7.5 Hz, 2H),
7.61 (d, J = 6.5 Hz, 2H), 7.42 (m, 3H), 7.26 (s, 1H), 4.10 (q, J = 6.5 Hz, 2H), 1.15 (t, J = 5.5
Hz, 3H) 13C NMR (150 MHz, CDCl3) δ 164.1, 145.6, 140.4, 138.3, 130.2, 130.1, 128.8,
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128.2, 125.0, 124.7, 114.1, 112.9, 59.7, 14.6. IR: 3424, 3276, 2947, 1689, 1368, 1265, 1135,
1031, 788. HRMS (ESI-TOF) m/z: [M-H]- calcd for C19H15N2O4 335.1032; Found 335.1045.
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Ethyl 5-(3-methoxyphenyl)-2-phenyl-1H-pyrrole-3-carboxylate (3h)
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(Eluent: 5% EtOAc/hexane); 69% yield (44.3 mg); white solid; melting point 123 - 125 °C
1H NMR (600 MHz, CDCl3) δ 8.56 (s, 1H), 7.65 (d, J = 7.0 Hz, 2H), 7.43 (t, J = 6.5 Hz, 2H),
7.38 (t, J = 6.0 Hz, 1H), 7.31 (t, J = 7.0 Hz, 1H), 7.09 (d, J = 6.5 Hz, 1H), 7.05 (s, 1H), 7.01
(d, J = 2.5 Hz, 1H), 6.82 (m, 1H), 4.25 (q, J = 6.5 Hz, 2H), 3.85 (s, 3H), 1.28 (t, J = 6.5 Hz,
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3H) C NMR (150 MHz, CDCl3) δ 164.8, 160.2, 137.7, 131.9, 130.2, 129.0, 128.5, 128.2,
116.4, 113.8, 112.6, 109.9, 109.4, 59.8, 55.4, 14.3. IR: 3433, 3345, 2937, 1677, 1467, 1296,
1138, 1057, 761, 678, 648. HRMS (ESI-TOF) m/z: [M + H]+calcd for C20H20NO3 322.1443;
Found 322.1452.
Ethyl 5-(2, 6-dimethoxyphenyl)-2-phenyl-1H-pyrrole-3-carboxylate (3i)
(Eluent: 5% EtOAc/hexane); 70% yield (49.0 mg); white solid; melting point 138 - 140 °C
1H NMR (600 MHz, CDCl3) δ 10.0 (s, 1H), 7.67 (d, J = 6.0 Hz, 2H), 7.43 (t, J = 6.5 Hz,
2H), 7.37 (m, 1H), 7.23 (t, J = 6.0 Hz, 1H), 7.10 (s, 1H), 6.90 (d, J = 7.5 Hz, 1H), 6.74 (m,
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1H), 4.24 (q, J = 5.5 Hz, 2H), 3.89 (s, 3H), 3.82 (s, 3H), 1.29 (t, J = 6.0 Hz, 3H) C NMR
(150 MHz, CDCl3) δ 165.0, 154.3, 149.5, 136.4, 132.4, 129.6, 129.1, 128.95, 128.90, 128.2,
120.5, 113.1, 113.0, 112.7, 111.7, 109.8, 59.8, 56.5, 55.8, 14.4. IR: 3450, 3311, 2947, 1699,
1498, 1378, 1230, 1135, 1031, 761. HRMS (ESI-TOF) m/z: [M + H]+calcd for C21H22NO4
352.1549; Found 352.1530.
Ethyl 2, 5-bis (4-methoxyphenyl)-1H-pyrrole-3-carboxylate (3j)
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(Eluent: 5% EtOAc/hexane); 85% yield (59.7 mg); yellow liquid; melting point 183 - 185 °C
1H NMR (600 MHz, CDCl3) δ 8.42 (s, 1H), 7.56 (d, J = 6.5Hz, 2H), 7.43 (d, J = 5.0 Hz, 2H),
6.93 (m, 4H), 6.85 (s, 1H), 4.22 (q, J = 6.0 Hz, 2H), 3.83 (s, 3H), 3.82 (s, 3H), 1.27 (t, J = 6.0
Hz, 3H) 13C NMR (150 MHz, CDCl3) δ 165.0, 159.7, 158.8, 137.3, 131.4, 130.3, 125.4,
124.5, 114.5, 113.7, 113.1, 107.9, 59.7, 55.4, 14.4. IR: 3476, 3217, 2939, 1687, 1467, 1296,
1138, 1057, 770, 678, 621. HRMS (ESI-TOF) m/z: [M + Na]+calcd for C21H21NO4Na
374.1368; Found 374.1358.
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Ethyl 2-(4-fluorophenyl)-5-(4-methoxyphenyl)-1H-pyrrole-3-carboxylate (3k)
(Eluent: 5% EtOAc/hexane); 82% yield (55.8 mg); white solid; melting point 168 - 170 °C
1H NMR (600 MHz, CDCl3) δ 8.55 (s, 1H), 7.58 (d, J = 5.5Hz, 2H), 7.43 (d, J = 6.0 Hz, 2H),
7.07 (t, J = 6.0 Hz, 2H), 6.91 (d, J = 6.0 Hz, 2H), 6.85 (s, 1H), 4.20 (q, J = 6.0 Hz, 2H), 3.82
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(s, 3H), 1.26 (t, J = 5.5 Hz, 3H) C NMR (150 MHz, CDCl3) δ 164.9, 163.5, (d, J = 247.5
Hz), 161.9, 159.0, 136.2, 131.9, 130.97, (d, J = 9.0 Hz), 130.91, 128.1, 125.5, 124.4, 115.2,
(d, J = 22.5 Hz), 115.1, 114.5, 113.7, 108.0, 59.8, 55.4, 14.3. IR: 3477, 3227, 2941, 1647,
1467, 1296, 1138, 1057, 729, 647. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C20H18FNO3Na 362.1168; Found 362.1162.
Ethyl 5-(4-chlorophenyl)-2-(4-fluorophenyl)-1H-pyrrole-3-carboxylate (3l)
(Eluent: 5% EtOAc/hexane); 69% yield (47.6 mg); white solid; melting point 208 - 210 °C
1H NMR (600 MHz, CDCl3) δ 8.56 (s, 1H), 7.60 (m, 2H), 7.42 (d, J = 6.0 Hz, 2H), 7.36 (d, J
= 6.5 Hz, 2H), 7.10 (t, J = 6.5 Hz, 2H), 6.96 (s, 1H), 4.21 (q, J = 5.5 Hz, 2H), 1.25 (t, J = 6.0
Hz, 3H) 13C NMR (150 MHz, CDCl3) δ 164.6, 163.7 (d, J = 247.5 Hz), 162.1, 137.1, 132.9,
131.0, (d, J = 9.0 Hz), 130.9, 130.7, 129.9, 129.3, 127.8, 125.2, 115.4, (d, J = 21.0 Hz),
115.2, 114.0, 109.5, 60.0, 14.3. IR: 3423, 3332, 2940, 1672, 1467, 1296, 1138, 1057, 761,
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678, 648. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H16ClFNO2 344.0854; Found
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Ethyl 2-(4-bromophenyl)-5-(4-methoxyphenyl)-1H-pyrrole-3-carboxylate (3m)
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(Eluent: 5% EtOAc/hexane); 81% yield (65.0 mg); white solid; melting point 223 – 230 °C
1H NMR (600 MHz, CDCl3) δ 8.48 (s, 1H), 7.52 (q, J = 7.0 Hz, 4H), 7.42 (d, J = 7.0 Hz, 2H),
6.92(q, J = 7.0 Hz, 2H), 6.87 (s, 1H), 4.22 (q, J = 6.0 Hz, 2H), 3.82 (s, 3H), 1.28 (t, J = 6.0
Hz, 3H) 13C NMR (150 MHz, CDCl3) δ 164.8, 159.0, 135.8, 131.4, 130.5, 125.6, 124.2,
122.5, 114.5, 114.0, 108.2, 59.9, 55.4, 14.4. IR: 3420, 3119, 2965, 1658, 1455, 1386, 1289,
1259, 1174, 1143, 1039, 805, 772, 699. HRMS (ESI-TOF) m/z: [M + H]+calcd for
C20H19BrNO3 400.0548; Found 400.0545.
Ethyl 5-(4-bromophenyl)-2-(4-fluorophenyl)-1H-pyrrole-3-carboxylate (3n)
(Eluent: 5% EtOAc/hexane); 70% yield (54.5 mg); white solid; melting point 218 - 220 °C
1H NMR (600 MHz, CDCl3) δ 8.56 (s, 1H), 7.58 (m, 2H), 7.51 (d, J = 6.5 Hz, 2H), 7.36 (m,
2H), 7.09 (t, J = 7.0 Hz, 2H), 6.97 (s, 1H), 4.20 (q, J = 5.5 Hz, 2H), 1.26 (t, J = 6.0 Hz, 3H)
13C NMR (150 MHz, CDCl3) δ 164.6, 163.7 (d, J = 246.0 Hz), 162.1, 137.1, 132.2, 131.0 (d,
J = 6.0 Hz) 130.9, 130.7, 130.4, 125.5, 120.8, 115.3 (d, J = 21.0 Hz), 115.2, 114.1, 109.6,
60.0, 14.3. IR: 3419, 3280, 2939, 1687, 1455, 1378, 1296, 1138, 1057, 761, 678, 648. HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C19H16BrFNO2 388.0348; Found 388.0354.
Ethyl 5-(4-methoxyphenyl)-2-(4-nitrophenyl)-1H-pyrrole-3-carboxylate (3o)
(Eluent: 25% EtOAc/hexane);71% yield (52.0 mg); yellow solid; melting point 218 - 220 °C
1H NMR (600 MHz, CDCl3) δ 8.61 (s, 1H), 8.26 (d, J = 6.0 Hz, 2H), 7.83 (d, J = 6.0 Hz, 2H),
7.48 (d, J = 7.5 Hz, 2H), 6.93 (m, 3H), 4.27 (q, J = 6.0 Hz, 2H), 3.85 (s, 3H), 1.32 (t, J = 6.0
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Hz, 3H) 13C NMR (150 MHz, CDCl3) δ 164.5, 159.4, 147.1, 133.9, 133.6, 129.4, 125.8,
123.7, 123.5, 117.0, 115.7, 114.6, 109.1, 55.4, 14.4. IR: 3424, 3295, 2947, 1689, 1368, 1265,
1298, 1135, 1031, 788, 692, 623. HRMS (ESI-TOF) m/z: [M + H]+calcd for C20H19N2O5
367.1294; Found 367.1277.
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Ethyl 2-(4-nitrophenyl)-5-(p-tolyl)-1H-pyrrole-3-carboxylate (3p)
(Eluent: 25% EtOAc/hexane); 49% yield (34.5 mg); yellow solid; melting point 207 - 210 °C
1H NMR (600 MHz, CDCl3) δ 8.76 (s, 1H), 8.23 (d, J = 7.5Hz, 2H), 7.79 (d, J = 7.0 Hz, 2H),
7.43 (d, J = 6.5 Hz, 2H), 7.23 (t, J = 7.0 Hz, 2H), 6.98 (s, 1H), 4.26 (q, J = 6.5 Hz, 2H), 2.38
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(s, 3H), 1.31 (t, J = 6.0 Hz, 3H) C NMR (150 MHz, CDCl3) δ 164.6, 147.0, 138.1, 137.7,
134.1, 133.7, 129.9, 129.5, 128.1, 124.2, 123.5, 115.6, 109.5, 60.3, 21.3, 14.4. IR: 3425,
3276, 2947, 1691, 1383, 1265, 1281, 1135, 1031, 788, 690, 630. HRMS (ESI-TOF) m/z: [M
+Na]+calcd for C20H18N2O4Na 373.1164; Found 373.1156.
Ethyl 2-phenyl-5-(thiophen-2-yl)-1H-pyrrole-3-carboxylate (3q)
(Eluent: 5% EtOAc/hexane); 54% yield (32.2 mg); grey solid; melting point 158 - 160 °C
1H NMR (600 MHz, CDCl3) δ 8.59 (s, 1H), 7.59 (d, J = 5.5Hz, 2H), 7.36 (m, 3H), 7.19 (s,
1H), 7.09 (s, 1H), 7.02 (s, 1H), 6.87 (s, 1H), 4.19 (q, J = 5.5Hz, 2H), 1.24 (t, J = 5.0 Hz, 3H)
13C NMR (150 MHz, CDCl3) δ 164.7, 137.5, 134.7, 131.7, 129.1, 128.5, 128.2, 127.8, 126.5,
123.7, 122.0, 113.6, 109.7, 59.9, 14.3. IR: 3441, 3276, 1668, 1368, 692. HRMS (ESI-TOF)
m/z: [M + Na]+calcd for C17H15NO2SNa 320.0721; Found 320.0717.
Ethyl 2-(4-methoxyphenyl)-4-methyl-5-phenyl-1H-pyrrole-3-carboxylate (5a)
(Eluent: 3% EtOAc/hexane); 65% yield (43.6 mg); white solid; melting point 130 - 132 °C
1H NMR (600 MHz, CDCl3) δ 8.27 (s, 1H), 7.46 (d, J = 7.5Hz, 2H), 7.42 (m, 4H), 7.29 (m,
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1H), 6.92 (d, J = 7.5 Hz, 2H), 4.19 (q, J = 6.5 Hz, 2H), 3.82 (s, 3H), 2.41 (s, 3H), 1.20 (t, J =
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6.0 Hz, 3H) C NMR (150 MHz, CDCl3) δ 165.9, 159.6, 137.0, 132.6, 130.3, 129.1, 128.8,
127.5, 127.0, 125.3, 118.8, 113.5, 112.7, 59.5, 55.4, 14.3, 11.9. IR: 3449, 3330, 2947, 1689,
1469, 1357, 1286, 1225, 1057, 761, 678, 648. HRMS (ESI-TOF) m/z: [M + Na]+calcd for
C21H21NO3Na 358.1419; Found 358.1415.
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Ethyl 4-methyl-2, 5-diphenyl-1H-pyrrole-3-carboxylate (5b)
(Eluent: 3% EtOAc/hexane); 59% yield (36.2 mg); white solid; melting point 118 - 120 °C
1H NMR (600 MHz, CDCl3) δ 8.25 (s, 1H), 7.53 (d, J = 6.0 Hz, 2H), 7.40 (m, 6H), 7.34 (t, J
= 6.0 Hz, 1H), 7.31 (m, 1H), 4.19 (q, J = 5.5 Hz, 2H), 2.43 (s, 3H), 1.18 (t, J = 6.0 Hz, 3H)
13C NMR (150 MHz, CDCl3) δ 165.8, 136.8, 132.9, 132.5, 129.5, 129.0, 128.8, 128.1, 127.5,
127.1, 119.0, 113.2, 59.6, 14.2, 11.8. IR: 3450, 3311, 2947, 1699, 1499, 1357, 1296, 1245,
1138, 1057, 761, 678, 648. HRMS (ESI-TOF) m/z: [M + Na]+calcd for C20H19NO2Na
328.1313; Found 328.1306.
Ethyl 2-(4-bromophenyl)-4-methyl-5-phenyl-1H-pyrrole-3-carboxylate (5c)
(Eluent: 3% EtOAc/hexane); 54% yield (41.5 mg); white solid; melting point 187 - 189 °C
1H NMR (600 MHz, CDCl3) δ 8.23 (s, 1H), 7.50 (d, J = 7.0 Hz, 2H), 7.43 (d, J = 3.0 Hz, 4H),
7.40 (d, J = 6.5 Hz, 2H), 7.31 (m, 1H), 4.21 (q, J = 6.0 Hz, 2H), 2.40 (s, 3H), 1.21 (t, J = 6.5
Hz, 3H) 13C NMR (150 MHz, CDCl3) δ 165.5, 135.4, 132.3, 131.6, 131.2, 130.5, 129.9,
128.8, 127.5, 127.2, 122.2, 119.1, 113.4, 59.6, 14.2, 11.8.8. IR: 3469, 3250, 2948, 1702,
1498, 1357, 1296, 1245, 1138, 1056, 761, 677, 647. HRMS (ESI-TOF) m/z: [M + Na]+ calcd
for C20H18BrNO2Na 406.0419; Found 406.0405.
Ethyl 2, 4, 5-triphenyl-1H-pyrrole-3-carboxylate (5d)3f
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(Eluent: 3% EtOAc/hexane); 51% yield (37.5 mg); white solid; melting point 143 - 145 °C
1H NMR (600 MHz, CDCl3) δ 8.49 (s, 1H), 7.62 (d, J = 6.0 Hz, 2H), 7.41 (d, J = 6.0 Hz, 2H),
7.38 (m, 1H), 7.29 (m, 5H), 7.21 (m, 5H), 3.97 (q, J = 5.5 Hz, 2H), 0.89 (t, J = 6.0 Hz, 3H)
13C NMR (150 MHz, CDCl3) δ 165.4, 136.1, 135.4, 132.1, 131.9, 130.6, 129.2, 128.7, 128.5,
128.28, 128.24, 127.7, 127.0, 126.5, 124.1, 113.7, 59.7, 13.6. IR: 3450, 3311, 2947, 2500,
1696, 1479, 1357, 1290, 1236, 1138, 1057, 882.
Ethyl 2-(4-methoxyphenyl)-4, 5-diphenyl-1H-pyrrole-3-carboxylate (5e)
(Eluent: 3% EtOAc/hexane); 60% yield (48.0 mg); white solid; melting point 128 – 130 °C
1H NMR (600 MHz, CDCl3) δ 8.37 (s, 1H), 7.57 (d, J = 6.5 Hz, 2H), 7.30 (m, 4H), 7.24 (m,
3H), 7.17 (m, 3H), 6.97 (d, J = 7.0 Hz, 2H) 3.97 (q, J = 5.5 Hz, 2H), 3.84 (s, 3H), 0.89 (t, J =
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5.5 Hz, 3H) C NMR (150 MHz, CDCl3) δ 165.4, 159.7, 135.7, 130.7, 130.2, 128.8, 128.6,
127.8, 127.0, 126.9, 126.5, 124.7, 124.1, 113.8, 59.7, 55.4, 13.7. IR: 3433, 3302, 2936, 2467,
1672, 1479, 1357, 1290, 1236, 1138, 1057, 880, 761. HRMS (ESI-TOF) m/z: [M + Na]+calcd
for C26H23NO3Na 420.1576; Found 420.1569.
Ethyl 5-(4-nitrophenyl)-2, 4-diphenyl-1H-pyrrole-3-carboxylate (5f)
(Eluent: 3% EtOAc/hexane); 50% yield (38.5 mg); white solid; melting point 183 - 185 °C
1H NMR (600 MHz, CDCl3) δ 8.48 (s, 1H), 7.59 (t, J = 4.5Hz, 2H), 7.30 (m, 5H), 7.22 (m,
2H), 7.18 (t, J = 7.0 Hz, 3H), 7.10 (t, J = 7.0 Hz, 2H), 3.97 (q, J = 6.0 Hz, 2H), 0.88 (t, J =
6.0 Hz, 3H) 13C NMR (150 MHz, CDCl3) δ 165.2, 163.5, (d, J = 225 Hz), 162.0, 135.4(d, J =
15 Hz), 135.3, 131.8, 130.75, (d, J = 7.5 Hz), 130.70, 130.6, 129.3, 128.5, 128.3, 127.7,
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127.0, 126.5, 124.2, 115.3, 115.2, 113.7, 59.7, 13.6. IR: 3426, 3280, 2939, 1687, 1455, 1378,
1296, 1138, 1057. HRMS (ESI-TOF) m/z: [M + Na]+calcd for C25H20FNO2Na 408.1376;
Found 408.1378.
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(Eluent: 3% EtOAc/hexane); 51% yield (45.6 mg); white solid; melting point 172 - 175 °C
1H NMR (600 MHz, CDCl3) δ 8.45 (s, 1H), 7.57 (d, J = 7.5 Hz, 2H), 7.50 (m, 2H), 7.30 (m,
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CDCl3) δ 165.1, 135.2, 134.8, 131.6, 131.4, 130.5, 130.3, 129.6, 128.6, 127.1, 127.0, 126.6,
124.3, 122.4, 114.0, 59.8, 13.6. IR: 3426, 3278, 2970, 2478, 1660, 1457, 1357, 1290, 1236,
1138, 1039. HRMS (ESI-TOF) m/z: [M + H]+calcd for C25H21BrNO2 446.0756; Found
446.0745.
Ethyl 5-(4-bromophenyl)-2, 4-diphenyl-1H-pyrrole-3-carboxylate (5h)
(Eluent: 3% EtOAc/hexane); 56% yield (49.9 mg); white solid; melting point 183 - 185 °C
1H NMR (600 MHz, CDCl3) δ 8.49 (s, 1H), 7.61 (d, J = 6.0 Hz, 2H), 7.42 (t, J = 6.0 Hz, 2H),
7.38 (t, J = 6.0 Hz, 1H), 7.31 (m, 3H), 7.29 (m, 4H), 7.02 (d, J = 7.5 Hz, 2H), 3.97 (q, J = 6.0
13
Hz, 2H), 0.88 (t, J = 5.5 Hz, 3H) C NMR (150 MHz, CDCl3) δ 165.2, 136.6, 135.2, 132.0,
131.8, 130.8, 130.6, 128.8, 128.5, 128.4, 128.3, 126.8, 124.8, 120.9, 113.9, 59.8, 13.6. IR:
3426, 3278, 2971, 2478, 1658, 1455, 1357, 1290, 1236, 1138, 1039. HRMS (ESI-TOF) m/z:
[M + Na]+calcd for C25H20BrNO2Na 468.0575; Found 468.0571.
Associated Content
Supporting Information
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Copies of NMR spectra for all compounds and HRMS spectra for new compounds, and
crystallographic data for 3f (CCDC No. 1835841). This material is available free of charge
via the Internet at http://pubs.acs.org.
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Acknowledgements
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CSIR-CSMCRI Communication No. 40/2018. N.N.K.R thankful to AcSIR for his Ph.D.
enrolment and the “Analytical Discipline and Centralized Instrumental Facilities” for
providing instrumentation facilities. We thank DST, Government of India
(EMR/2016/000010), and CSIR-CSMCRI (MLP-027 and OLP-088) for financial support.
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