Sulfur-Promoted DABCO-Catalyzed Oxidative Trimerization of

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Sulfur-Promoted DABCO-Catalyzed Oxidative Trimerization of Phenylacetonitriles Thanh Binh Nguyen, and Pascal Retailleau J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00408 • Publication Date (Web): 12 Apr 2019 Downloaded from http://pubs.acs.org on April 12, 2019

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The Journal of Organic Chemistry

Sulfur-Promoted DABCO-Catalyzed Oxidative Trimerization of Phenylacetonitriles Thanh Binh Nguyen,* and Pascal Retailleau Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Université Paris-Sud, Université Paris-Saclay, 1 avenue de la Terrasse, 91198 Gif-sur-Yvette, France [email protected] Ar

S (1 equiv) CN

Ar

DMSO (1.5 equiv) DABCO (20 mol %) T °C, 16 h

1

Ar

NC N

NH2

Ar 2

ABSTRACT: By simply heating phenylacetonitriles 1 with elemental sulfur and DMSO in the presence

of a catalytic amount of DABCO, we have performed an oxidative trimerization leading to polysubstituted pyrrole heterocycles 2 in excellent yields and E-configuration.

The rising demands to more efficient chemical processes with reduced environmental impact prompt organic chemists to develop new greener cascade reactions, which is also known as domino or tandem reactions, to achieve complex structures with high atom-, step-, and redox economy while reducing waste, time and work compared to classical approaches involving only sequence of separated simple transformations.1 Most of the reported cascade reactions involve complex starting materials bearing many functional groups that are potentially reactive and thus difficult to install in the same molecules. In this context, using simple compounds as starting materials to develop cascade reaction is inarguably of significant impact but not trivial and highly challenging. For this purpose, we have been developing in recent years the use of elemental sulfur as a versatile tool to promote such a cascade reaction using only simple, inexpensive and readily available starting materials. Despite its apparent simplicity, sulfur displays a wide range of reactivities depending on external activator in both redox and non-redox transformation.2 With new regulations aiming at lowering sulfur contents in fossil fuels, elemental sulfur becomes a waste by-product of oil and gas refinery industry. Consequently, the annual global production of this element exceeds 80 millions of metric tons and exceeds the demand of chemical industry. The long term large scale storage of this surplus was performed by pouring melting sulfur into open air large blocks. Such storage may pose environmental issues (fire risk; air, water and soil acidification). In this context the use of elemental sulfur for other useful purposes may be an excellent green solution.

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

Pyrrole moiety occurs frequently in many natural products, biologically active compounds and molecules with interesting physical properties.3 Scheme 1 presents some selected pyrrole derivatives. Most of the methods of preparation of such molecules of interest are based on challenging multistep sequences, especially for heavily substituted derivatives.4

Scheme 1. Selected examples of pyrroles in natural products and bioactive molecules, and our route to pyrroles 2 via sulfur-promoted oxidative trimerization of arylacetonitriles 1 We report herein an unusual sulfur-promoted oxidative trimerization reaction of arylacetonitriles 1 to provide densely functionalized pyrrole derivatives 2 in excellent yields and diastereoselectivity. At the outset of the finding of this cascade reaction, we have detected accidentally the formation of trimer 2e in moderate yield when 4-methoxyphenylacetonitrile 1e was heated with excess elemental sulfur activated by a stoichiometric amount of N-methylpiperidine (NMP)5 and DMSO at 100 °C for 16 h (Table 1, entry 1). Other nitrogen bases such as pyridine,6 3-picoline,7 N-methylmorpholine (NMM),8 which were known previously to be capable of activating sulfur were found to be totally inefficient in promoting this transformation, even in stoichiometric amounts at 100 °C (entries 2-4). Table 1. Screening of the reaction conditions for trimerization of acetonitrile 1e


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MeO

OMe

S (x equiv) CN DMSO (y equiv)

NC

base (z equiv)

MeO 1e 1mmol 1 equiv

N

T °C, 16 h MeO

a

NH2

2e

X-ray structure of 2e

entrya x

y

base (z equiv)

Temp (°C)

yield (%)d

1

1

1.5

NMP (1)

100

65

2

1

1.5

pyridine (1)

100

0b

3

1

1.5

3-picoline (1)

100

0b

4

1

1.5

NMM (1)

100

0b

5

1

1.5

DABCO (1)

100

70

6

1

1.5

DABCO (0.2)

100

72

7

1

1.5

NMP (0.2)

100

22

8

1

1.5

DABCO (0.2)

80

88e

9

0.5

1.5

DABCO (0.2)

80

45

10

0

1.5

DABCO (0.2)

80

0b

11

1

0c

DABCO (0.2)

80

0b

12

1

1.5

DABCO (1)

60

83

Reaction conditions: 4-methoxyphenylacetonitrile 1e (1 mmol, 147 mg), sulfur (x mmol, 32

mg/mmol), base (z mmol), DMSO (y equiv, 1.5 equiv = 0.1 mL), T °C, 16 h. b Determined by 1H NMR of the crude mixture. c DMF (0.1 mL) was used in place of DMSO. d Unless otherwise noted, the yield referred to isolated yield by column chromatography. e Product isolated by trituration and filtration with methanol.



Interestingly, DABCO displayed an excellent activating effect when being used in stoichiometric amount (entry 5). In this case, after the transformation was completed, the reaction mixture was solidified and a significant amount of solid DABCO was condensed on the cool part of the reaction tube. This observation suggested that the amount of DABCO could be lowered. Indeed, such a reducing of DABCO (0.2 equiv) led to practically the same yield of trimer 2e (entry 6). At this catalytic loading, NMP was found to be much less efficient (entry 7). Gratifyingly, higher yield with cleaner isolated product 2e was obtained by simple trituration and filtration with methanol (entry 8). In this case, the product was formed with E configuration confirmed unambiguously by X-ray diffraction. The trimerization process of 1e became slower with lower sulfur loading (entry 9) or totally stopped in the absence of either sulfur (entry 10) or DMSO (entry 11). Actually, when DMSO was replaced by the same volume of a polar aprotic solvent such as DMF, the starting nitrile 1e remained totally untouched (entry 11). Finally, the reaction could be performed at temperature as low as 60 °C by using a stoichiometric amount of DABCO (entry 12). The optimized reaction conditions were further applied to other phenylacetonitriles 1 and led to the corresponding products 2 presented in Table 2. First, unsubstituted benzyl cyanide 1a underwent the oxidative trimerization to provide pyrrole 2a in excellent yields (entry 1). Similarly, phenylacetonitriles substituted by an electron donating group such as alkyls (entries 2-4), methoxy (entries 5-6), acetamido (entry 7), or phenyl (entry 8) in the para or meta position 1b-1i provided the corresponding pyrroles 2b2i in good to excellent yields. On the other hand, the reactions with phenylacetonitriles 2j-2k bearing an electron attracting group in the para position such as trifluoromethyl, cyano resulted in moderate or low yield (entries 9-10). The reaction failed with phenylacetonitriles substituted in the o-position by a methyl, methoxy or chloro group (results not shown). In these cases, the expected trimers were formed in low yields along with extensive degradation of the starting arylacetonitriles. Actually, this is quite understandable since the presence of an ortho substituent could hinder significantly the formation of C3-C4 bond of the pyrrole ring. Gratifyingly, using 3-pyridylacetonitrile 1l as a heterocyclic example, we obtained also the expected product 2l in high yield (entry 11).


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Table 2. Scope of trimerization of arylacetonitriles 1

a

entrya

1

Ar

2, yield (%)b

1

1a

Ph

2a, 88

2

1b

4-MeC6H4

2b, 89

3

1c

4-i-PrC6H4

2c, 84

4

1d

3-MeC6H4

2d, 81

5

1f

3-MeOC6H4

2f, 80

6

1g

3,4-(MeO)2C6H3

2g, 71

7

1h

4-AcNHC6H4

2h, 78

8

1i

4-PhC6H4

2i, 83

9

1j

4-F3CC6H4

2j, 60

10

1k

4-NCC6H4

2k, 38c

11

1l

3-pyridyl

2l, 85

Reaction conditions: arylylacetonitrile 1 (1 mmol), sulfur (1 mmol, 32 mg), DABCO (0.2 mmol, 22

mg), DMSO (1.5 mmol, 0.1 mL), 80 °C, 16 h. b Unless otherwise noted, the products were isolated by trituration and filtration of the crude mixture with methanol, except for 2k. chromatography on silica gel.


c

Isolated by column


The structures of trimeric products were further confirmed by X-ray crystallography on single crystals of pyrroles 2a and 2c ((See Supporting Information)). Once again, this suggests the high selectivity of E-configuration of the formation of pyrroles. At this stage, we questioned on the reaction mechanism. For this purpose, some control experiments were performed (Scheme 2). First, we noticed that, non-benzylic nitrile such as butyronitrile 1m failed to deliver the similar product and remained unchanged under the reaction conditions (eq 1). Furthermore, in a crossover experiment of 4-methoxyphenylacetonitrile 1e and butyronitrile 1m, the trimerization of 1e was found to proceed independently to provide 2e in excellent yield while 1m remained unchanged (eq 2). This results suggests that the nitrile group of 4-methoxyphenylacetonitrile 1e involving in the formation of heterocycle 2e must be activated beforehand by an oxidation at the neighboring methylene group. Such oxidation is obviously favored only in case of benzylic nitriles.

Scheme 2. Control experiments Based on these observations, we proposed a mechanism of trimerization initiated by an oxidation of the methylene group of 1 with sulfur catalyzed by DABCO into thiobenzoyl cyanide A via iterative dithiolation (Scheme 3). The next step could be a DABCO-catalyzed condensation of the methylene group of 1 with highly reactive thiocarbonyl function of A, leading to dimer B.9 Once again, DABCO could catalyze another condensation of 1 with B to provide trimer C. Trimer C must isomerize to D to achieve a favorable configuration for ultimate cyclization catalyzed by DABCO to yield trimer 2. The success of this cascade of reaction is obviously dependent on the formation of thiobenzoyl cyanide A, which requires and appropriate activation of sulfur. Such activation by a tertiary amine was previously shown to be strongly enhanced by DMSO. 5b


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Scheme 3. Plausible mechanism Finally, we found that the isomerization of 2 from E to Z configuration could occur if the crude mixture was left at rt for one month (Scheme 4). The Z isomer could be easily separated from its E isomer by column chromatography and its structure was elucidated by X-ray crystallography (See Supporting Information). Further study is needed to better understand the mechanism of such isomerization but we can imagine that the Z isomer, with two aryl ring in the same side is stabilized by an additional π stacking interaction.

Scheme 4. Isomerization of 2c to 2c’ in the crude mixture In conclusion, we have developed a set of reaction conditions for oxidative trimerization of arylacetonitriles 1. This cascade of reactions was promoted by sulfur and DMSO in the presence of a catalytic amount of DABCO under mild thermal conditions. A range of tetrasubstituted pyrrole derivatives 2 was obtained in reasonable yields with excellent degree of the selectivity of configuration. Furthermore, most of the trimers could be obtained by simple trituration and filtration of the crude mixture with methanol, which could be amenable to large scale synthesis. We are convinced that this preliminary outcome will open new opportunities for the finding of unusual and nontrivial sulfur-



involved cascade processes leading to novel scaffolds with interesting applications. Experimental Section General Information All reactions were carried out under argon atmosphere in new test tube with oven-dried magnetic stirring. Reagents were obtained from commercial supplier and used without further purification. Analytical thin layer chromatography (TLC) was purchased from Merck KGaA (silica gel 60 F254). Visualization of the chromatogram was performed by UV light (254 nm) or phosphomolybdic acid or vanilline stains. Flash column chromatography was carried out using kieselgel 35-70 μm particle sized silica gel (230-400 mesh). NMR Chemical shifts are reported in (δ) ppm relative to tetramethylsilane (TMS) with the residual solvent as internal reference (CDCl3, δ 7.26 ppm for 1H and δ 77.0 ppm for 13C; DMSO-d6, δ 2.50 ppm for 1H and δ 39.5 ppm for 13C). Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constants (Hz) and integration. High-resolution mass spectra (HRMS) were determined on an AEI MS-9 using electrospray ionization (ESI) and a time-of-flight (TOF) analyzer. General procedure A mixture of arylacetonitrile 1 (1 mmol), elemental sulfur (1 mmol, 32 mg), DABCO (0.2 mmol, 22 mg), and DMSO (0.1 mL, 1.5 mmol) was heated under an argon atmosphere in a 7-mL test tube at 80 °C for 16 h. The reaction mixture was diluted with methanol (2 mL). The resulting yellow slurry was filtered. The yellow solid precipitate was washed with methanol (2 mL  2), then dried in vacuo (0.01 mmHg, 100 °C) to afford the expected trimer 2 as yellow solid. In some cases, because of high solubility of TFA salt of trimer, the 13C NMR was recorded in the presence of a small amount of this acid. In case of 2k, the product was purified by column chromatography on silica gel (CH2Cl2:EtOAc 1:0 to 5:1). (E)-2-(5-Amino-3,4-diphenyl-2H-pyrrol-2-ylidene)-2-phenylacetonitrile (2a)

Yellow solid (102 mg, 88%). mp 254 °C (with decomposition). 1H

NMR (300 MHz, CDCl3) δ 7.68 (d, J = 7.8 Hz, 2H), 7.38-7.27 (m, 10H), 7.22-7.17 (m, 1H), 7.11-


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7.06 (m, 2H). 13C

NMR (75 MHz, CDCl3 + TFA) δ 164.2, 147.1, 146.2, 133.9, 131.8, 131.0, 130.8, 130.0, 130.0,

129.9, 129.7, 129.3, 129.2, 128.3, 126.5, 114.8, 108.1 (1 signal missing due to overlap). HRMS (ESI+) calcd for C24H18N3 [M + H]+ 348.1501. Found 348.1522. (E)-2-(5-Amino-3,4-di-p-tolyl-2H-pyrrol-2-ylidene)-2-(p-tolyl)acetonitrile (2b)

Yellow solid (116 mg, 89%). 1H

NMR (300 MHz, CDCl3) δ 7.59 (d, J = 8.1 Hz, 2H), 7.16-7.10 (m, 8H), 6.98 (d, J = 8.1 Hz, 2H),

2.34 (s, 3H), 2.31 (s, 3H), 2.21 (s, 3H). 13C

NMR (75 MHz, CDCl3 + TFA) δ 163.7, 146.7, 145.6, 142.8, 141.1 (2C), 133.2, 130.6, 130.5, 129.8,

129.6, 129.3, 128.8, 128.0, 125.1, 123.4, 114.6, 107.9, 21.6, 21.4 (2C). HRMS (ESI+) calcd for C27H24N3 [M + H]+ 390.1970. Found 390.1964. (E)-2-(5-Amino-3,4-bis(4-isopropylphenyl)-2H-pyrrol-2-ylidene)-2-(4isopropylphenyl)acetonitrile (2c)


NMR (300 MHz, CDCl3) δ 7.64-7.60 (m, 2H), 7.23-7.12 (m, 8H), 7.00-6.97 (m, 2H), 2.91 (septet, J

= 6.8 Hz, 1H), 2.86 (septet, J = 6.8 Hz, 1H), 2.70 (septet, J = 6.8 Hz, 1H), 1.26 (d, J = 6.8 Hz, 6H), 1.22 (d, J = 6.8 Hz, 6H), 1.02 (d, J = 6.8 Hz, 6H). 13C

NMR (75 MHz, CDCl3) δ 169.3, 161.1, 149.7, 149.5, 149.4, 146.1, 136.5, 132.9, 130.6, 130.1,

129.6, 129.0, 128.0, 127.1, 126.5, 126.4, 118.1, 101.1, 34.0 (3C), 24.1, 23.9 (2C).



HRMS (ESI+) calcd for C33H36N3 [M + H]+ 474.2909. Found 474.2931. (E)-2-(5-Amino-3,4-di-m-tolyl-2H-pyrrol-2-ylidene)-2-(m-tolyl)acetonitrile (2d)


NMR (300 MHz, CDCl3) δ 7.53-7.52 (m, 2H), 7.32-7.04 (m, 7H), 6.99-6.94 (m, 3H), 2.39 (s, 3H),

2.37 (s, 3H), 2.32 (s, 3H). 13C

NMR (75 MHz, CDCl3) δ 169.3, 161.5, 145.8, 138.6, 138.1, 137.0, 135.7, 131.9, 131.2, 130.7,

130.5, 129.9, 129.6 (2C), 129.1, 128.9, 128.3, 128.2, 127.8, 127.2, 126.4, 118.0, 100.5, 21.6, 21.3, 21.0 (1 signal missing due to overlap). HRMS (ESI+) calcd for C27H24N3 [M + H]+ 390.1970. Found 390.1964. (E)-2-(5-Amino-3,4-bis(4-methoxyphenyl)-2H-pyrrol-2-ylidene)-2-(4-methoxyphenyl)acetonitrile (2e)


NMR (300 MHz, CDCl3) δ 7.79-7.73 (m, 2H), 7.25-7.20 (m, 2H), 7.09-7.04 (m, 2H), 6.94-6.84 (m,

6H), 3.83 (s, 3H), 3.82 (s, 3H), 3.76 (s, 3H). 13C

NMR (75 MHz, CDCl3 + TFA) δ 164.5, 162.1, 161.3, 160.9, 145.7, 145.6, 132.5, 131.8, 131.5,

130.6, 123.6, 121.1, 119.3, 115.7, 115.3, 115.2, 114.6, 106.2, 55.6, 55.5, 55.4. HRMS (ESI+) calcd for C27H24N3O3 [M + H]+ 438.1818. Found 438.1797. (E)-2-(5-Amino-3,4-bis(3-methoxyphenyl)-2H-pyrrol-2-ylidene)-2-(3-methoxyphenyl)acetonitrile (2f)


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NMR (300 MHz, CDCl3 + TFA) δ 7.45-7.29 (m, 4H), 7.12-6.92 (m, 5H), 6.85-6.84 (m, 1H), 6.77 (d,

J = 7.5 Hz, 1H), 6.68-6.67 (m, 1H), 3.82 (s, 3H), 3.77 (s, 3H), 3.68 (s, 3H). 13C

NMR (75 MHz, CDCl3 + TFA) δ 163.7, 160.5, 160.4, 160.0, 146.7, 146.3, 133.8, 131.8, 131.2 (2C),

130.6, 129.1, 127.3, 122.2, 121.7, 121.2, 117.2, 116.7, 116.4, 115.6, 115.3, 114.6, 114.2, 107.8, 55.6 (2C), 55.5. HRMS (ESI+) calcd for C27H24N3O3 [M + H]+ 438.1818. Found 438.1802. (E)-2-(5-Amino-3,4-bis(3,4-dimethoxyphenyl)-2H-pyrrol-2-ylidene)-2-(3,4dimethoxyphenyl)acetonitrile (2g)


NMR (300 MHz, CDCl3) δ 7.52 (d, J = 1.5 Hz, 1H), 7.37 (dd, J = 6.9, 1.5 Hz, 1H), 6.88-6.75 (m,

6H), 6.58 (d, J = 1.5 Hz, 1H), 3.91 (s, 3H), 3.88 (s, 3H), 3.87 (s, 3H), 3.83 (s, 3H), 3.81 (s, 3H), 3.63 (s, 3H). 13C

NMR (75 MHz, CDCl3) δ 168.9, 159.3, 149.9, 149.7, 149.4, 149.2, 149.1, 148.5, 145.3, 136.1,

127.7, 124.8, 123.9, 123.3, 123.2, 121.3, 118.2, 113.9, 113.8, 112.3, 111.5, 111.1, 110.8, 100.9, 56.3, 56.2, 56.0 (3C), 55.9. HRMS (ESI+) calcd for C30H30N3O6 [M + H]+ 528.2135. Found 528.2124. (E)-N,N'-((2-((4-Acetamidophenyl)(cyano)methylene)-5-amino-2H-pyrrole-3,4-diyl)bis(4,1phenylene))diacetamide (2h)




NMR (500 MHz, DMSO) δ 10.09 (broad s, 1H), 9.97 (broad s, 2H), 8.43 (broad s, 1H), 8.05 (d, J =

8.0 Hz, 2H), 7.61 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H), 7.51 (broad s, 1H), 7.16 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.0 Hz, 2H), 2.06 (s, 3H), 2.04 (s, 3H), 2.02 (s, 3H). 13C

NMR (75 MHz, DMSO) δ 170.2, 169.0, 168.9, 162.4, 146.9, 139.7, 139.6, 139.5, 137.5, 130.9 (2C),

130.2, 130.0, 128.0, 125.6, 119.1, 118.8 (2C), 118.5, 24.6, 24.5 (2C) (one signal missing due to overlap). HRMS (ESI+) calcd for C30H27N6O3 [M + H]+ 519.2145. Found 519.2119. (E)-2-([1,1'-Biphenyl]-4-yl)-2-(3,4-di([1,1'-biphenyl]-4-yl)-5-amino-2H-pyrrol-2ylidene)acetonitrile (2i)


NMR (500 MHz, CD3OD) δ 7.91-7.89 (m, 2H), 7.81-7.79 (m, 2H), 7.75-7.62 (m, 10H), 7.56-7.49

(m, 4H), 7.46-7.42 (m, 7H), 7.37-7.34 (m, 2H). 13C

NMR (75 MHz, CDCl3) δ 164.6, 146.4, 146.3, 144.3, 143.3, 143.2, 139.9, 139.6, 133.4, 130.5,

130.0, 129.7, 129.2, 129.1, 129.0, 128.4, 128.3, 128.2, 127.7, 127.6, 127.5, 127.3, 127.2, 125.8, 115.4, 106.6 (some carbon signals missing due to overlap). HRMS (ESI+) calcd for C42H30N3 [M + H]+ 576.2440. Found 576.2445.


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(E)-2-(5-Amino-3,4-bis(4-(trifluoromethyl)phenyl)-2H-pyrrol-2-ylidene)-2-(4(trifluoromethyl)phenyl)acetonitrile (2j)


NMR (300 MHz, CDCl3 + 1 drop TFA) δ 11.70 (broad s, 2H), 7.62 (d, J = 8.3 Hz, 2H), 7.28-7.16

(m, 8H), 6.87(d, J = 8.3 Hz, 2H). 13C

NMR (75 MHz, CDCl3 + 1 drop TFA) δ 164.0, 148.3, 145.1, 136.3, 132.6, 130.9, 130.4, 130.2,

129.8, 129.5, 126.9, 125.6, 125.4, 115.6, 105.5 (some signals missing due to overlap). HRMS (ESI+) calcd for C27H15F9N3 [M + H]+ 552.1122. Found 552.1146. (E)-4,4'-(5-Amino-2-(cyano(4-cyanophenyl)methylene)-2H-pyrrole-3,4-diyl)dibenzonitrile (2k)

The product was purified by column chromatography on silica gel (eluent CH2Cl2 to CH2Cl2:EtOAc 9:1). Yellow solid (54 mg, 38%). 1H

NMR (300 MHz, CD3OD + TFA) δ 7.94 (d, J = 8.2 Hz, 2H), 7.84 (d, J = 8.2 Hz, 2H), 7.81 (d, J =

8.2 Hz, 2H), 7.78 (d, J = 8.2 Hz, 2H), 7.65 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 8.2 Hz, 2H). 13C

NMR (75 MHz, CD3OD + TFA) δ 165.9, 147.8, 137.3, 137.1, 134.9, 134.5, 134.0, 133.9, 133.3,

132.8, 132.3, 132.1, 131.9 (2C), 119.1, 119.0, 115.9, 115.7, 115.6, 115.4, 104.5. HRMS (ESI+) calcd for C27H15N6 [M + H]+ 423.1358. Found 423.1325. (E)-2-(5-Amino-3,4-di(pyridin-3-yl)-2H-pyrrol-2-ylidene)-2-(pyridin-3-yl)acetonitrile (2l)




NMR (300 MHz, CD3OD + TFA) δ 9.60 (d, J = 1.9 Hz, 1H), 8.94 (d, J = 1.9 Hz, 1H), 8.81-8.72 (m,

5H), 8.37-8.34 (m, 1H), 8.18-8.14 (m, 1H), 7.99 (dd, J = 8.3, 5.5 Hz, 1H), 7.85 (dd, J = 8.3, 5.5 Hz, 1H), 7.75 (dd, J = 8.3, 5.5 Hz, 1H). 13C

NMR (75 MHz, CD3OD + TFA) δ 169.6, 160.0, 148.5, 147.9, 147.8, 147.5, 146.6, 146.0, 145.0,

144.6, 144.4, 143.4, 138.1, 133.7, 130.6, 127.8, 127.7, 127.3, 127.0, 117.3, 97.4. HRMS (ESI+) calcd for C21H15N6 [M + H]+ 351.1358. Found 351.1335. (Z)-2-(5-amino-3,4-bis(4-isopropylphenyl)-2H-pyrrol-2-ylidene)-2-(4isopropylphenyl)acetonitrile (2c’)

A crude mixture of the reaction starting with 1c left for one month at rt was purified by chromatography on silica gel (eluent CH2Cl2:EtOAc 1:0 to 1:1) led to the first fraction of 2c (103 mg, 65%) and the second fraction of 2c’(16 mg, 10%). 1H

NMR (500 MHz, CDCl3) δ 7.12 (d, J = 8.0 Hz, 2H), 7.01 (d, J = 8.0 Hz, 2H), 6.91 (d, J = 8.0 Hz,

2H), 6.71 (d, J = 8.0 Hz, 2H), 6.66 (d, J = 8.0 Hz, 2H), 6.62 (d, J = 8.0 Hz, 2H), 5.80 (broad s, 2H), 2.83 (septet, J = 6.8 Hz, 1H), 2.65 (septet, J = 6.8 Hz, 1H), 2.64 (septet, J = 6.8 Hz, 1H), 1.19 (d, J = 6.8 Hz, 6H), 1.10 (d, J = 6.8 Hz, 6H), 1.08 (d, J = 6.8 Hz, 6H). 13C

NMR (75 MHz, CDCl3) δ 169.5, 163.3, 149.4, 148.7, 147.8, 144.5, 139.6, 131.7, 130.7, 130.4,

129.6, 129.3, 128.2, 127.2, 126.6, 125.7 (2C), 121.2, 34.0, 33.8 (1C), 24.0 (2C), 23.8. HRMS (ESI+) calcd for C33H36N3 [M + H]+ 474.2909. Found 474.2892. ASSOCIATED CONTENT Supporting information The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.xxxxxxx.


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Copies of 1H and 13C NMR spectra data for all compounds. X-ray crystallographic data for 2a, 2e, 2c, and 2c’ (CCDC 1883985, 1883986, 1846812 and 1844000 respectively). This material is available free of charge via the Internet at http://pubs.acs.org. Acknowledgment We thank ICSN-CNRS for financial support and Dr. A. Marinetti (ICSN) for her helpful support. References

(1) (a) Tietze L. F.; Beifuss, U. Sequential Transformations in Organic Chemistry: a Synthetic Strategy with a Future. Angew. Chemie Int. Ed. 1993, 32, 131-163. (b) Padwa, A.; Bur, S. K. The Domino Way to Heterocycles. Tetrahedron 2007, 63, 5341-5378. (2) For reviews on organic reactions involving elemental sulfur, see: (a) Nguyen, T. B. Recent Advances in Organic Reactions Involving Elemental Sulfur. Adv. Synth. Catal. 2017, 359, 1106-1130. (b) Nguyen, T. B. Elemental Sulfur and Molecular Iodine as Efficient Tools for Carbon‐Nitrogen Bond Formation through Redox Reactions. Asian J. Org. Chem. 2017, 6, 477-491. (3) For selected reviews on pyrroles, see: (a) Domagala, A.; Jarosz, T.; Lapkowski, M. Living on Pyrrolic Foundations - Advances in Natural and Artificial Bioactive Pyrrole Derivatives. Eur. J. Med. Chem. 2015, 100, 176-187. (b) Fan, H.; Peng, J.; Hamann, M. T.; Hu, J. F. Lamellarins and Related Pyrrole-Derived Alkaloids from Marine Organisms. Chem. Rev. 2008, 108, 264-187. (c) Estévez V, Villacampa M, Menéndez J. C. Recent Advances in the Synthesis of Pyrroles by Multicomponent Reactions. Chem. Soc. Rev. 2014, 43, 4633-4657. (d) Multicomponent Reactions for the Synthesis of Pyrroles. Estévez, V.; Villacampa, M.; Menéndez, J. C. Chem. Soc. Rev. 2010, 39, 4402-4421 (4) For selected examples, see : (a) Majhail, M. K.; Ylioja, P. M.; Willis, M. C. Direct Synthesis of Highly Substituted Pyrroles and Dihydropyrroles Usinglinear Selective Hydroacylation Reactions. Chem. Eur. J. 2016, 22, 7879-7884. (b) Vivekanand, T.; Vinoth, P.; Agieshkumar, B.; Sampath, N.; Sudalai, A.; Menéndez, J. Sridharan, C. V. Highly Efficient Regioselective Synthesis of Pyrroles Via A Tandem Enamine Formation–Michael Addition–Cyclization Sequence Under Catalyst- and SolventFree Conditions. Green Chem. 2015, 17, 3415-3423. (c) Mondal, S. K.; Mandal, A.; Manna, S. K.; Ali, S. A.; Hossain, M.; Venugopal, V.; Jana, A.; Samanta, S. Intramolecular Macrolactonization, Photophysical and Biological Studies of New Class of Polycyclic Pyrrole Derivatives. Org. Biomol. Chem. 2017, 15, 2411-2421. (d) Tan, W. W.; Yoshikai, N. Copper-Catalyzed Condensation of Imines and Α-Diazo-Β-Dicarbonyl Compounds: Modular and Regiocontrolled Synthesis of Multisubstituted Pyrroles. Chem. Sci. 2015, 6, 6448-6455. (e) Zhou, A.; He, Q.; Shu, C.; Yu, Y.; Liu, S.; Zhao, T.; Zhang, W.; Lu, X.; Ye, L. Atom-Economic Generation of Gold Carbenes: Gold-Catalyzed Formal [3+2]



Cycloaddition Between Ynamides and Isoxazoles. Chem. Sci. 2015, 6, 1265-1271. (f) Wu, Y.; Zhu, L.; Yu, Y.; Luo, X.; Huang, X. Polysubstituted 2-Aminopyrrole Synthesis Via Gold-Catalyzed Intermolecular Nitrene Transfer from Vinyl Azide To Ynamide: Reaction Scope and Mechanistic Insights. J. Org. Chem. 2015, 80, 11407-11416. (g) Xiao, X.; Zhou, A.; Shu, C.; Pan, F.; Li, T.; Ye, L. Atom‐Economic Synthesis of Fully Substituted 2‐Aminopyrroles Via Gold‐Catalyzed Formal [3+2] Cycloaddition Between Ynamides and Isoxazoles. Chem. Asian. J. 2015, 10, 1854-1858. (h) Zhu, L.; Yu, Y.; Mao, Z.; Huang, X. Gold-Catalyzed Intermolecular Nitrene Transfer from 2H-Azirines to Ynamides: a Direct Approach to Polysubstituted Pyrroles. Org. Lett. 2015, 17, 30-33. (i) Mcgeary, R. P.; Tan, D. T. C.; Selleck, C.; Pedroso, M. M.; Sidjabat, H. E.; Schenk, H. E. G. Structure-Activity Relationship Study and Optimisation of 2-Aminopyrrole-1-Benzyl-4,5-Diphenyl-1H-Pyrrole-3Carbonitrile as a Broad Spectrum Metallo--Lactamase Inhibitor. Eur. J. Med. Chem. 2017, 137, 351364. (5) For our previous works on using n-methylpiperidine as sulfur activator, See: (a) Nguyen, T. B.; Cheung-Lung, J. Iron-Catalyzed Sulfur-Promoted Decyanative Redox Condensation of o-Nitrophenols and Arylacetonitriles: an Unprecedented Route to 2-Arylbenzoxazoles. Eur. J. Org. Chem. 2018, 58155818. (b) Nguyen, T. B.; Retailleau, P. Cooperative Activating Effect of Tertiary Amine-DMSO on Elemental Sulfur: Direct Access to Thioaurones from 2’-Nitrochalcones under Mild Conditions. Org. Lett. 2018, 20, 186-189. (c) Nguyen, T. B.; Retailleau, P. DIPEA-Promoted Reaction of 2Nitrochalcones with Elemental Sulfur: an Unusual Approach to 2-Benzoylbenzothiophenes. Org. Lett. 2017, 19, 4858-4860. (d) Nguyen, T. B.; Retailleau, P. Elemental Sulfur-Promoted Oxidative Rearranging Coupling between o-Aminophenols and Ketones: a Synthesis of 2-Alkylbenzoxazoles under Mild Conditions. Org. Lett. 2017, 19, 3887-3890. (E) Nguyen, T. B.; Ermolenko, L.; Corbin, M.; Almourabit, A. Fe/S-Catalyzed Decarboxylative Redox Condensation of Arylacetic Acids with Nitroarenes. Org. Chem. Front. 2014, 1, 1157-1160. (6) Nguyen, T. B.; Tran, M. Q.; Retailleau, P.; Almourabit, A. Three-Component Reaction between Alkynes, Elemental Sulfur, and Aliphatic Amines: a General, Straightforward, and Atom Economical Approach to Thioamides. Org. Lett. 2014, 16, 310-313. (7) Nguyen, T. B.; Retailleau, P. Redox-Neutral Access to Sultams from 2-Nitrochalcones and Sulfur with Complete Atom Economy. Org. Lett. 2017, 19, 3879-3882. (8) (a) Nguyen, T. B.; Pasturaud, K.; Ermolenko, L.; Almourabit, A. Concise Access to 2Aroylbenzothiazoles by Redox Condensation Reaction between o-Halonitrobenzenes, Acetophenones, and Elemental Sulfur. Org. Lett. 2015, 17, 2562-2565. (b) Nguyen, L. A.; Ngo, Q. A.; Retailleau, P.; Nguyen, T. B. Elemental Sulfur as Polyvalent Reagent in Redox Condensation with o-


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Chloronitrobenzenes and Benzaldehydes: Three-Component access to 2-Arylbenzothiazoles. Green Chem. 2017, 19, 4289-4293. (9) The dimerization of 1 to B was reported to proceed in the presence different oxidants: molecular iodine under various conditions: (a) Villemin, D.; Alloum, A. B. Microwave-Assisted One-Pot Synthesis of 3-Amino-1-aryl-8-bromo-2,4-dicyano-9H-fluorenes in Water. Synth. Commun. 1992, 22, 3169-3179. (b) Yeh, H.; Wu, W.; Wen, Y.; Dai, D.; Wang, J.; Chen, C. Derivative of ,Dicyanostilbene: Convenient Precursor for the Synthesis of Diphenylmaleimide Compounds, E−Z Isomerization, Crystal Structure, and Solid-state Fluorescence. J. Org. Chem. 2004, 69, 6455-6462. Anodic Oxidation: (c) Elinson, M. N.; Dorofeev, A. S.; Feducovich, S. K.; Belyakov, P. A.; Nikishin, G. I. Stereoselective Electrocatalytic Oxidative Coupling of Phenylacetonitriles: Facile and Convenient Way to trans‐,‐Dicyanostilbenes. Eur. J. Org. Chem. 2007, 18, 3023-3027.


Sulfur-Promoted DABCO-Catalyzed Oxidative Trimerization of

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