MeOTf-Mediated Annulation of Alkylnitriles and Arylalkynes Leading to

Article Cite This: J. Org. Chem. 2017, 82, 11391-11398

pubs.acs.org/joc

MeOTf-Mediated Annulation of Alkylnitriles and Arylalkynes Leading to Polysubstituted NH‑Pyrroles Yu Liu,† Xiangli Yi,† Xuewei Luo,† and Chanjuan Xi*,†,‡ †

MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Department of Chemistry, Tsinghua University, Beijing 100084, China ‡ State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China S Supporting Information *

ABSTRACT: A metal-free multicomponent domino reaction for the highly regioselective synthesis of tetrasubstituted NH-pyrroles from readily available alkylnitriles, arylalkynes, and MeOTf has been developed. A variety of NH-pyrroles were obtained in moderate to good yields under mild conditions. In addition, the reactions using diarylalkynes with electron-rich aryl groups were found to afford isoquinolines.

■

INTRODUCTION Pyrrole is an important organic skeleton that exists in many useful compounds such as pharmaceuticals, natural products, and functional materials.1 Thus, a variety of reactions have been created for the synthesis of the pyrroles.,2 Besides the classical methods such as Paal−Knorr pyrrole synthesis and Hantzsch pyrrole synthesis,2a,b a number of efficient synthetic methodologies have been documented in recent years under the promotion of transition metals.3,4 From the viewpoint of sustainable chemistry, the development of metal-free pathways using readily accessible starting materials under mild conditions toward polysubstituted NH-pyrroles are more attractive, especially for the drug screen.5 Consequently, it is still highly desirable to further explore this topic; of particular interest are pyrroles containing a C-2 carbonyl group, which are of great synthetic significance as biologically active molecules6 and as building blocks in organic synthesis,7 although many transition metal-mediated formations of substituted pyrroles have been developed.8 As a part of our ongoing projects on alkyltriflatemediated annulation,9 herein we report a one-pot procedure for the regioselective synthesis of tetrasubstituted NH-pyrroles containing a C-2 keto group via a methyltriflate (MeOTf)triggered domino reaction of alkylnitrile and arylalkynes under mild conditions. Recently, we reported MeOTf-inducted annulation of arylnitriles and aromatic alkynes leading to indenones.9a In this process, MeOTf as an electrophile reacts with arylnitrile to give the N-methylnitirilium A, which is a highly reactive species and can react with alkynes to afford intermediate B. The intermediate B undergoes a Friedel−Crafts reaction to form indenone imine C (Scheme 1). We are curious about the reaction of alkylnitriles, which lacks an aryl ring for the ring closure and may lead to a different ring formation process. To our delight, reaction of alkylnitriles, alkynes, and MeOTf indeed afforded tetrasubstituted NH-pyrroles D (Scheme 1). © 2017 American Chemical Society

Scheme 1. MeOTf-Induced Reaction of Nitriles and Alkynes

■

RESULTS AND DISCUSSION Initially, butyronitrile 1a, 1-phenyl-1-propyne 2a, and MeOTf were chosen as model substrates to optimize the reaction conditions. As shown in Table 1, we first tested a reaction in dichloroethane (DCE) at 60 °C for 24 h with 1:1:1 ratio of the three substrates (entry 1), and 2-acylpyrrole 3aa was obtained as a product in 25% yield after workup. A part of 2a remained, which is probably because the reaction of 2a to afford 3aa entails 2 equiv of butyronitrile and MeOTf. Therefore, 2 equiv of butyronitrile 1a and MeOTf were used, and 3aa was obtained in 87% yield (entry 2). Temperature screening experiments (entries 2−5) revealed that the best reaction temperature was 60 °C (entry 2). Furthermore, different reaction times were examined (entries 2, 6−8), and 24 h was found to be most suitable for this reaction (entry 2). When the reaction was treated in CHCl3, CCl4, and n-hexane, only trace amounts of the product was observed (entries 9−11). Furthermore, other methyl cation sources such as dimethyl sulfate, and methyl 4-(methyl)benzenesulfonate were used, and Received: July 24, 2017 Published: October 17, 2017 11391

DOI: 10.1021/acs.joc.7b01845 J. Org. Chem. 2017, 82, 11391−11398

Article

The Journal of Organic Chemistry Table 1. Optimization of the Reactiona

entry

temp (°C)

time (h)

solvent

ratio [1a:2a:MeOTf]

yield (%)b

1 2 3 4 5 6 7 8 9 10 11 12c 13d

60 60 40 80 120 60 60 60 60 60 60 60 60

24 24 24 24 24 12 18 36 24 24 24 24 24

DCE DCE DCE DCE DCE DCE DCE DCE CHCl3 CCl4 n-hexane DCE DCE

1:1:1 2:1:2 2:1:2 2:1:2 2:1:2 2:1:2 2:1:2 2:1:2 2:1:2 2:1:2 2:1:2 2:1:2 2:1:2

25 87(78) 62 71 70 48 77 81 trace trace trace n.r. n.r.

trace amounts of the corresponding products were observed in GC-MS. Then the substrate scope of alkynes for the synthesis of 2acylpyrroles was also investigated (Scheme 3). First, we tried different alkylarylacetylenes (2b−j). The reaction of 1a with pent-1-yn-1-ylbenzene 2b or hex-1-yn-1-ylbenzene 2c and MeOTf afforded the desired product 3ab or 3ac in 65% and Scheme 3. Substrate Scope of Arylalkynesb

a Reaction condition: 0.3 mmol of 2a, 0.5 mL of solvent, under N2, in a sealed tube. All chemical yields are calculated on the basis of 2a. b NMR yield; isolated yield was given in parentheses. cDimethyl sulfate was used. dMethyl 4-(methyl)benzenesulfonate was used.

the reactions did not proceed (entries 12−13). On the basis of above results, the optimal conditions are shown in entry 2. With the optimized conditions, we initially tried various alkylnitriles as substrates (Scheme 2). Unbranched alkylnitriles, Scheme 2. Substrate Scope of Alkylnitrilesa

a

Reaction conditions: 0.6 mmol 1, 0.3 mmol of 2a, 0.6 mmol of MeOTf, 0.5 mL of solvent, under N2, in a sealed tube. All chemical isolated yields are calculated on the basis of 2a.

including butyronitrile 1a, acetonitrile 1b, n-pentanenitrile 1c, and 3-phenylpropanenitrile reacted with 1-phenyl-1-propyne 2a to afford 2-acylpyrroles 3aa, 3ba, 3ca, and 3da in 78%, 60%, 68%, and 60% yield, respectively. The use of branched alkylnitrile such as isobutyronitrile 1e led to 3ea in 48% yield, which might have resulted from greater steric hindrance. Moreover, when alkylnitriles with a ring structure, such as cyclopropanecarbonitrile 1f and cyclopentanecarbonitrile 1g, were employed, the corresponding products could also be obtained (45% yield for 3fa and 40% yield for 3ga). Unfortunately, when phenylacetonitrile 1h, pivalonitrile 1i, and cyclohexanecarbonitrile 1j were used in this reaction, only

a Reaction temperature at 80 °C. bReaction conditions: 0.6 mmol of 1, 0.3 mmol of 2, 0.6 mmol of MeOTf, 0.5 mL of solvent, under N2, in a sealed tube. All chemical isolated yields are calculated on the basis of 2.

11392


Article

The Journal of Organic Chemistry 68% yield, respectively. The substrates with a methyl group at the para-position of the phenyl reacted smoothly to give desired pyrrole 3ad in 67% yield. However, the reaction did not proceed with substrate 2e bearing a methoxyl group at the paraposition of the phenyl. Halogen substitution such as bromine, fluorine, and chlorine on the para-position of the phenyl led to higher yields (75% for 3af, 78% for 3ag, and 68% for 3ah). Gratifyingly, a crystal of 3af was suitable for a single crystal analysis, and its structure was fully characterized by X-ray diffraction analysis. The structure of 3af clearly shows the formation of substituted pyrrole with aromatic groups neighboring the acyl group on the pyrroles. When the phenyl in the substrate 2i was substituted by trifluoromethyl, the reaction became unproductive. Next, arylalkynes with mchlorine (2j) and o-chlorine (2k) were used, the reaction could also proceed well, and the desired pyrroles (3aj, 3ak, 3bj, and 3bk) were obtained in 52%, 61%, 50%, and 56% yield, respectively. Additionally, unsymmetrical diarylacetylenes (2l− p) were also found to regioselectively furnish the corresponding products in good yields. The reactions with diarylacetylenes such as 1-bromo-4-(p-tolylethynyl)benzene 2l, 1-chloro-4-(ptolylethynyl)benzene 2m, 1-fluoro-4-(p-tolylethynyl)benzene 2n, 1-methyl-4-((4-(trifluoromethyl)phenyl)ethynyl)benzene 2o, and 1-(phenylethynyl)-4-(trifluoromethyl)benzene 2p were treated, and the products were obtained in moderate yields (65% for 3al, 70% for 3am, 58% for 3an, 41% for 3ao, 40% for 3ap) with substituents in high regioselectivity, respectively. It is noteworthy that no other products were obtained. The structure of 3bm was further confirmed by X-ray diffraction analysis, which confirmed that the phenyl with a more electron-donating methyl neighbored an acyl group on the pyrrole. Next, dialkyl-substituted alkynes such as 4-octyne and 5-decyne were employed in this reaction, and the desired products were not observed. Furthermore, when 1,2-bis(4chlorophenyl)ethyne 2q and 1,2-bis(4-fluorophenyl)ethyne 2r were employed, only trace pyrrole 3aq and 3ar were observed by GC-MS. The starting materials remained. Notably, when 1,2-diphenylethyne 2s and 1,2-di-p-tolylethyne 2t were employed under the same reaction conditions, the expected pyrroles were observed by GC-MS in trace amounts but an amount of isoquinolines 4 was obtained. The reaction conditions were further optimized, and we found that the reactions were conducted at 130 °C, isoquinolines 4 were obtained in good yields. The representative results are summarized in Scheme 4. When 1,2-bis(4-fluorophenyl)ethyne was used, the reaction failed to give any product. 1,2-Bis(4fluorophenyl)ethyne still remained. Notably, when diarylacetylenes such as 2l and 2n were employed under the same conditions, a mixture of products (including pyrroles as major and isoquinolines as minor products) were observed. Furthermore, 1,2-di-m-tolylethyne 2u was used, and a mixture of two products 4au (49%) and 4au′ (29%) were obtained. Notably, the two isomers could be easily separated by flash chromatography on silica gel. When 1,2-di-o-tolylethyne 2v and 1,2-bis(4-methoxyphenyl)ethyne 2w were employed, the reactions failed to give the corresponding isoquinolines. Overall, for the formation of isoquinolines 4, the diarylalkynes are limited in a certain scope. When deuterated acetonitrile 1k was used, the product 4ks was obtained in 65% isolated yield, which further indicates the reaction pathway. To further understand this reaction, we tried the reaction of acetonitrile 1b, 1-methyl-4-((4-(trifluoromethyl)phenyl)ethynyl)benzene 2o, and EtOTf (Scheme 5, a). Compound 5

Scheme 4. Substrate Scope of Alkylnitriles with 1,2Diphenylethyne, 1,2-Di-p-tolylethyne, and 1,2-Di-mtolylethynea

a Reaction conditions: 0.3 mmol of 1, 0.3 mmol of 2, 0.3 mmol of MeOTf, 0.5 mL of solvent, under N2, in a sealed tube. All chemical isolated yields are calculated on the basis of 2.

Scheme 5. Mechanistic Experiments

was obtained in 40% isolated yield, and no acylated product was observed. In addition, when deuterated acetonitrile 1k was used, the product 3′ka was obtained in GC-MS. As a result, we finally got a product 6 with only one fully deuterated methyl group in 65% isolated yield after hydrolysis (Scheme 5, b), which may have resulted from the fast exchange between hydrogen and deuterium during the workup. On the basis of above results and reported literature,9a we propose a plausible mechanism as shown in Scheme 6. First, methylation of alkylnitrile by MeOTf gives nitrilium 7, which adds to alkyne to form an alkenyl carbocation 8. Then 1,5-H shift occurs, leading to intermediate 9, which undergoes electrophilic annulation, elimination, and isomerization to 11393


Article

The Journal of Organic Chemistry

and 1,2-bis(4-methoxyphenyl)ethyne 2w were prepared according to reported literature.10 General Procedure for the Synthesis of Product 3. An ovendried sealed tube was charged with a mixture of alkylnitrile 1 (0.60 mmol), MeOTf (0.60 mmol, 69 μL), and aromatic alkyne 2 (0.3 mmol) and then stirred in dichloroethane (0.5 mL) at 60 °C under nitrogen atmosphere for 24 h. The reaction mixture and sodium acetate (0.5 g, 6.1 mmol) in water (3 mL) were heated to 115 °C and refluxed for 15 min.11 Then the reaction was cooled to room temperature and extracted with dichloromethane three times, dried over Na2SO4, evaporated, and purified with 200−300 mesh silica gel (particle size 200−300 mesh) (petroleum ether/ethyl acetate: 10/1) to provide the desired substance. 1-(4-Methyl-3-phenyl-5-propyl-1H-pyrrol-2-yl)butan-1-one (3aa). Faint yellow solid, 63 mg (78% yield), mp: 72−74 °C; 1H NMR (CDCl3, 400 MHz): δ 9.26 (s, 1H), 7.44−7.34 (m, 3H), 7.28 (dd, J = 8.1, 1.4 Hz, 2H), 2.62−2.55 (m, 2H), 2.12 (d, J = 7.7 Hz, 2H), 1.80 (s, 3H), 1.67 (d, J = 7.6 Hz, 2H), 1.46 (dd, J = 15.0, 7.4 Hz, 2H), 0.99 (t, J = 7.3 Hz, 3H), 0.66 (t, J = 7.4 Hz, 3H). 13C NMR (CDCl3, 101 MHz): δ 191.0, 136.5, 135.9, 132.5, 130.3, 128.2, 127.3, 117.7, 40.8, 28.3, 22.5, 18.9, 14.1, 13.9, 9.4. IR (neat) νmax cm−1 1613 (CO); GC-MS: 269.2. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H24NO 270.1852; found: 270.1850. 1-(4, 5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)ethanone (3ba). Faint yellow solid, 38 mg (60% yield); mp: 141−143 °C. 1H NMR (CDCl3, 400 MHz): δ 9.21 (s, 1H), 7.42 (t, J = 7.2 Hz, 2H), 7.37 (d, J = 6.9 Hz, 1H), 7.28−7.26 (m, 2H), 2.26 (s, 3H), 1.89(s, 3H), 1.80 (s, 3H); 13C NMR (CDCl3, 101 MHz): δ 187.7, 136.2, 133.1, 130.3, 128.4, 127.5, 118.1, 27.3, 11.7, 9.3. IR (neat) νmax cm−1 1615 (CO); GC-MS: 213.1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C14H16NO 214.1226; found: 214.1238. 1-(5-Butyl-4-methyl-3-phenyl-1H-pyrrol-2-yl)pentan-1-one (3ca). Faint yellow solid, 61 mg (68% yield), mp: 65−67 °C; 1H NMR (CDCl3, 600 MHz): δ 9.69 (s, 1H), 7.41 (t, J = 7.4 Hz, 2H), 7.37− 7.34 (m, 1H), 7.29−7.26 (m, 2H), 2.64−2.59 (m, 2H), 2.19−2.14 (m, 2H), 1.80 (s, 3H), 1.62 (dt, J = 15.4, 7.6 Hz, 2H), 1.46−1.36 (m, 4H), 1.03 (dd, J = 14.9, 7.4 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H), 0.69 (t, J = 7.4 Hz, 3H).13C NMR (CDCl3, 101 MHz): δ 191.2, 136.6, 136.3, 132.6, 128.2, 127.3, 117.6, 38.7, 31.4, 27.5, 26.1, 22.6, 22.5, 14.0, 13.8, 9.4, 55.6. IR (neat) νmax cm−1 1614 (CO); GC-MS: 297.2. HRMS (ESITOF) m/z: [M + H]+ calcd for C20H28NO 298.2165; found: 298.2170. 1-(4-Methyl-5-phenethyl-3-phenyl-1H-pyrrol-2-yl)-3-phenylpropan-1-one (3da). Yellow solid, 71 mg (60% yield), mp: 158−160 °C; 1 H NMR (CDCl3, 400 MHz): δ 9.77 (s, 1H), 7.45−7.34 (m, 3H), 7.30−7.19 (m, 5H), 7.13 (ddd, J = 14.0, 8.4, 4.1 Hz, 5H), 6.81 (d, J = 7.1 Hz, 2H), 2.94 (s, 4H), 2.81−2.73 (m, 2H), 2.56−2.48 (m, 2H), 1.69 (d, J = 1.3 Hz, 3H). 13C NMR (CDCl3, 101 MHz): δ 189.9, 141.3, 140.9, 136.4, 135.6, 132.8, 130.2, 128.4 (dd, J = 27.4, 11.2 Hz), 127.4 (d, J = 9.5 Hz), 126.4, 125.8, 118.3, 40.3, 35.7, 31.3, 28.4, 9.2. IR (neat) νmax cm−1 1603 (CO); GC-MS: 393.2. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C28H28NO 394.2165; found: 394.2160. 1-(5-Isopropyl-4-methyl-3-phenyl-1H-pyrrol-2-yl)-2-methylpropan-1-one (3ea). Faint yellow solid, 39 mg (48% yield), mp: 132−134 °C; 1H NMR (CDCl3, 400 MHz): δ 9.22 (s, 1H), 7.38 (m, 3H), 7.30− 7.28 (m, 2H), 3.07 (m, 1H), 2.63 (m, 1H), 1.80 (s, 3H), 1.30 (d, J = 7.1 Hz, 6H), 0.90 (d, J = 6.6 Hz, 6H). 13C NMR (CDCl3, 101 MHz): δ 195.5, 141.0, 136.4, 132.3, 130.2, 128.2, 127.3, 116.7, 34.7, 26.0, 21.8, 19.4, 9.3. IR (neat) νmax cm−1 1609 (CO); GC-MS: 269.2. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H24NO 270.1852; found: 270.1860. Cyclopropyl(5-cyclopropyl-4-methyl-3-phenyl-1H-pyrrol-2-yl)methanone (3fa). Yellow solid, 36 mg (45% yield), mp: 160−162 °C; 1 H NMR (CDCl3, 400 MHz): δ 8.81 (s, 1H), 7.40- 7.30 (m, 5H), 1.92 (s, 3H), 1.87−1.81 (m, 1H), 1.66−1.62 (m, 1H), 1.02−1.01 (m, 2H), 0.96−0.94 (m, 2H), 0.73−0.72 (m, 2H), 0.55−0.54 (m, 2H); 13C NMR (CDCl3, 101 MHz): δ 190.3, 136.0, 135.9, 132.4, 130.7, 128.2, 127.3, 118.8, 18.2, 10.9, 9.5, 7.3, 6.6. IR (neat) νmax cm−1 1598 (C O); GC-MS: 265.1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H20NO 266.1539; found: 266.1541.

Scheme 6. Proposed Reaction Mechanisms

form pyrrole 12 via intermediate 10 and 11. Subsequently, the pyrrole 12 reacts with another molecule of the nitrilium 7 via electrophilic substitution to give 14, which leads to the final product 3 after hydrolysis. When R1 is phenyl or p-tolyl or mtolyl on intermediate 9, Friedel−Crafts reaction takes place with priority, which is followed by isomerization to lead to isoquinoline 4. This is consistent with the fact that Friedel− Crafts reaction is favored on electron-rich aryl rings.

■

CONCLUSION We present a MeOTf-induced, highly regioselective, and metalfree method for the synthesis of a series of multiply substituted pyrroles under mild conditions. This route provides a practical and convenient method for the synthesis of multiply substituted 2-acylpyrroles from readily available starting materials in a one-pot reaction. Moreover, the reactions using diarylalkynes with electron-rich aryl groups were found to afford isoquinolines in good yields.

■

EXPERIMENTAL SECTION

General Information. All the reactions were carried out in an oven-dried sealed tube with a Teflon-lined septum under N 2 atmosphere. Unless indicated, all materials were obtained from commercial sources and used as received. DCE was dried with activated 4 Å molecular sieves. Column chromatography was performed on silica gel (particle size 200−300 mesh). 1H NMR and 13 C NMR spectra were recorded at 300 or 400 MHz at ambient temperature with CDCl3 as the solvent. Chemical shifts (δ) were given in ppm, referenced to the residual proton resonance of CDCl3 (7.26), to the carbon resonance of CDCl3 (77.16). Coupling constants (J) were given in hertz (Hz). The term m, q, t, d, s referred to multiplet, quartet, triplet, doublet, singlet. The reaction progress was monitored by GC-MS if applicable. The melting points were measured on an X-4 digital melting point apparatus and were uncorrected. HRMS was carried out with ESI in positive ion mode on an IT-TOF instrument. 1-(Hex-1-yn-1-yl)-4-methylbenzene 2d, 1-(hex-1-yn-1-yl)-4-methoxybenzene 2e, 1-bromo-4-(hex-1-yn-1-yl)benzene 2f, 1-fluoro-4-(hex-1yn-1-yl)benzene 2g, 1-chloro-4-(hex-1-yn-1-yl)benzene 2h, 1-(hex-1yn-1-yl)-4-(trifluoromethyl)benzene 2i, 1-chloro-3-(hex-1-yn-1-yl)benzene 2j, 1-chloro-2-(hex-1-yn-1-yl)benzene 2k, 1-bromo-4-(ptolylethynyl)benzene 2l, 1-chloro-4-(p-tolylethynyl)benzene 2m, 1fluoro-4-(p-tolylethynyl)benzene 2n, 1-methyl-4-((4-(trifluoromethyl)phenyl)ethynyl)benzene 2o, 1-(phenylethynyl)-4-(trifluoromethyl)benzene 2p, 1,2-di-m-tolylethyne 2u, 1,2-di-o-tolylethyne 2v, 11394


Article


0.76 (t, J = 7.1 Hz, 3H), 0.70 (t, J = 7.4 Hz, 3H). 13C NMR (CDCl3, 101 MHz): δ 190.7, 136.3, 135.2, 133.3, 131.7, 130.7, 128.4, 127.6, 123.1, 40.9, 33.7, 28.2, 23.8, 22.9, 22.6, 18.7, 14.2, 13.9. IR (neat) νmax cm−1 1611 (CO); GC-MS: 345.2. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C21H29ClNO 346.1932; found: 346.1933. 1-(4-Butyl-3-(2-chlorophenyl)-5-propyl-1H-pyrrol-2-yl)butan-1one (3aj). Yellow oil, 53.7 mg (52% yield); 1H NMR (CDCl3, 400 MHz): δ 9.22 (s, 1H), 7.41−7.29 (m, 3H), 7.23−7.17 (m, 1H), 2.62− 2.54 (m, 2H), 2.22−2.15 (m, 2H), 2.08 (t, J = 7.5 Hz, 2H), 1.68 (dd, J = 15.2, 7.5 Hz, 2H), 1.52−1.43 (m, 2H), 1.26−1.17 (m, 4H), 1.00 (t, J = 7.3 Hz, 3H), 0.76 (t, J = 7.1 Hz, 3H), 0.69 (t, J = 7.4 Hz, 3H). 13C NMR (CDCl3, 101 MHz): δ 190.7, 138.5, 135.9, 134.0, 131.7, 130.4, 129.4, 128.7, 128.4, 127.5, 123.1, 40.9, 33.6, 28.2, 23.8, 22.7, 22.5, 18.8, 14.2, 13.9, 14.0. IR (neat) νmax cm−1 1616 (CO); GC-MS: 345.2. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C21H29ClNO 346.1932; found: 346.1937. 1-(4-Butyl-3-(2-chlorophenyl)-5-propyl-1H-pyrrol-2-yl)butan-1one (3ak). Yellow oil, 63.2 mg (61% yield); 1H NMR (CDCl3, 400 MHz): δ 9.62 (s, 1H), 7.51−7.46 (m, 1H), 7.36−7.28 (m, 3H), 2.64− 2.58 (m, 2H), 2.22−1.99 (m, 4H), 1.69 (dd, J = 15.2, 7.5 Hz, 2H), 1.48 (dt, J = 15.1, 7.4 Hz, 2H), 1.27−1.11 (m, 4H), 0.99 (t, J = 7.3 Hz, 3H), 0.74 (t, J = 7.1 Hz, 3H), 0.66 (t, J = 7.4 Hz, 3H). 13C NMR (CDCl3, 101 MHz): δ 190.5, 136.2, 135.7, 134.7, 132.3, 129.6, 129.1, 128.6, 127.3, 126.6, 123.1, 40.3, 33.1, 28.2, 24.1, 22.8, 22.5, 18.4, 14.1, 14.0, 13.9. IR (neat) νmax cm−1 1614 (CO); GC-MS: 345.2. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C21H29ClNO 346.1932; found: 346.1940. 1-(4-Butyl-5-methyl-3-phenyl-1H-pyrrol-2-yl)ethanone (3bc). Yellow solid, 51 mg (67% yield), mp: 109−111 °C; 1H NMR (CDCl3, 400 MHz): δ 9.51 (s, 1H), 7.41−7.37 (m, 3H), 7.28−7.26 (m, 2H), 3.28 (s, 3H), 2.22−2.19 (m, 2H), 1.85 (s, 3H), 1.27−1.22 (m, 2H), 1.17−1.15 (m, 2H), 0.76 (t, J = 6.7 Hz, 3H). 13C NMR (CDCl3, 101 MHz): δ 187.7, 136.3, 133.1, 131.7, 128.2, 127.6, 127.4, 123.5, 33.3, 27.3, 23.9, 22.5, 13.9, 11.7. IR (neat) νmax cm−1 1617 (CO); GCMS: 255.2. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H22NO 256.1696; found: 256.1701. (4-Butyl-5-cyclopentyl-3-phenyl-1H-pyrrol-2-yl)(cyclopentyl)methanone (3gc). Yellow solid, 44 mg (40% yield), mp: 88−90 °C; 1 H NMR (CDCl3, 400 MHz): δ 9.04 (s, 1H), 7.41−7.33 (m, 3H), 7.31−7.27 (m, 2H), 3.15−3.06 (m, 1H), 2.72 (m, 1H), 2.25−2.18 (m, 2H), 2.12−2.02 (m, 2H), 1.86−1.80 (m, 2H), 1.74−1.56 (m, 8H), 1.45−1.37 (m, 2H), 1.30−1.21 (m, 4H), 1.18−1.10 (m, 2H), 0.74 (t, J = 7.2 Hz, 3H). 13C NMR (CDCl3, 101 MHz): δ 194.3, 138.8, 136.4, 131.9, 130.4, 127.9, 127.3, 123.2, 45.9, 37.1, 33.9, 33.3, 30.8, 26.4, 25.6, 23.9, 22.6, 13.9. IR (neat) νmax cm−1 1611 (CO); GC-MS: 363.3. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C25H34NO 364.2635; found: 364.2641. 1-(4-Butyl-3-(3-chlorophenyl)-5-methyl-1H-pyrrol-2-yl)ethanone (3bi). Yellow oil, 52 mg (50% yield); 1H NMR (CDCl3, 400 MHz): δ 9.57 (s, 1H), 7.35 (dd, J = 3.5, 1.5 Hz, 2H), 7.28 (t, J = 4.8 Hz, 1H), 7.23−7.16 (m, 1H), 2.27 (s, 3H), 2.19 (d, J = 8.2 Hz, 2H), 1.88 (d, J = 2.0 Hz, 3H), 1.30−1.19 (m, 4H), 0.78 (t, J = 7.1 Hz, 3H).13C NMR (CDCl3, 101 MHz): δ 187.5, 138.3, 134.1, 132.0, 131.2, 131.3, 129.5, 128.7, 127.6, 127.5, 123.4, 33.3, 27.4, 23.8, 22.4, 13.9, 11.69. IR (neat) νmax cm−1 1617 (CO); GC-MS: 289.1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H21ClNO 290.1306; found: 290.1310. 1-(4-Butyl-3-(2-chlorophenyl)-5-methyl-1H-pyrrol-2-yl)ethanone (3bj). Yellow solid, 48.5 mg (56% yield), mp: 133−135 °C; 1H NMR (CDCl3, 400 MHz): δ 9.74 (s, 1H), 7.49 (dd, J = 5.6, 3.4 Hz, 1H), 7.34−7.25 (m, 3H), 2.29 (s, 3H), 2.23−2.08 (m, 2H), 1.85 (d, J = 1.3 Hz, 3H), 1.23 (dd, J = 7.2, 4.3 Hz, 2H), 1.16 (dd, J = 14.7, 6.9 Hz, 2H), 0.76 (dd, J = 7.6, 6.5 Hz, 3H). 13C NMR (CDCl3, 101 MHz): δ 187.4, 135.5, 134.7, 132.1, 129.7, 129.4, 129.2, 127.4, 126.7, 123.3, 32.8, 26.5, 24.1, 22.4, 13.9, 11.8. IR (neat) νmax cm−1 1619 (CO); GC-MS: 289.1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H21ClNO 290.1306; found: 290.1312. 1-(4-(4-Bromophenyl)-5-propyl-3-(p-tolyl)-1H-pyrrol-2-yl)butan1-one (3al). Yellow solid, 83 mg (65% yield), mp: 190−192 °C; 1H NMR (CDCl3, 400 MHz): δ 9.84 (s, 1H), 7.17−7.12 (m, 2H), 7.11− 7.03 (m, 4H), 6.97−6.92 (m, 2H), 2.67−2.59 (m, 2H), 2.34 (s, 3H),

Cyclopentyl(5-cyclopentyl-4-methyl-3-phenyl-1H-pyrrol-2-yl)methanone (3ga). Yellow solid, 39 mg (40% yield), mp: 144−146 °C; 1H NMR (CDCl3, 400 MHz): δ 9.07 (s, 1H), 7.37 (m, 3H), 7.31− 7.26 (m, 2H), 3.16−3.06 (m, 1H), 2.79 (t, J = 7.7 Hz, 1H), 2.12−2.04 (m, 2H), 1.81 (s, 5H), 1.64 (m, 8H), 1.43 (m, 2H), 1.31−1.26 (m, 2H). 13C NMR (CDCl3, 101 MHz): δ 194.3, 138.7, 136.4, 132.4, 130.4, 128.1, 127.3, 126.9, 117.5, 45.9, 37.4, 32.5, 30.8, 26.5, 25.5, 9.6. IR (neat) νmax cm−1 1609 (CO); GC-MS: 321.2. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C22H28NO 322.2165; found: 322.2170. 1-(3-Phenyl-4,5-dipropyl-1H-pyrrol-2-yl)butan-1-one (3ab). Yellow solid, 57.6 mg (65% yield), mp: 76−78 °C; 1H NMR (CDCl3, 400 MHz): δ 9.41 (s, 1H), 7.44−7.36 (m, 3H), 7.32−7.27 (m, 2H), 2.65− 2.55 (m, 2H), 2.27−2.19 (m, 2H), 2.08 (t, J = 7.5 Hz, 2H), 1.69 (d, J = 7.7 Hz, 2H), 1.46 (d, J = 7.5 Hz, 2H), 1.25 (m, 2H), 0.99 (d, J = 7.3 Hz, 3H), 0.89−0.87 (m, 3H), 0.65 (t, J = 7.4 Hz, 3H). 13C NMR (CDCl3, 101 MHz): δ 190.0, 135.5, 134.6, 131.0, 129.3, 127.2, 126.4 (d, J = 17.4 Hz), 123.7, 39.8, 27.2, 21.9, 17.8, 16.4, 15.3, 13.21 12.4. IR (neat) νmax cm−1 1612 (CO); GC-MS: 297.2. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H28NO 298.2165; found: 298.2171. 1-(4-Butyl-3-phenyl-5-propyl-1H-pyrrol-2-yl)butan-1-one (3ac). Yellow solid, 63 mg (68% yield), mp: 56−58 °C; 1H NMR (CDCl3, 400 MHz): δ 9.35 (s, 1H), 7.43−7.35 (m, 3H), 7.29−7.26 (m, 2H), 2.59 (t, J = 7.4 Hz, 2H), 2.20 (t, J = 7.3 Hz, 2H), 2.12−2.05 (m, 2H), 1.69 (dd, J = 14.6, 7.3 Hz, 2H), 1.45 (dd, J = 14.4, 7.1 Hz, 2H), 1.27− 1.18 (m, 4H), 1.00 (t, J = 7.3, 1.0 Hz, 3H), 0.74 (t, J = 6.7 Hz, 3H), 0.64 (t, J = 7.3, 1.1 Hz, 3H). 13C NMR (CDCl3, 101 MHz): δ 191.0, 136.5, 135.8, 132.3, 130.3, 128.1, 127.5, 127.22−127.3, 123.2, 40.8, 33.7, 28.3, 23.8, 22.8, 22.6, 18.9, 14.2, 13.9. IR (neat) νmax cm−1 1612 (CO); GC-MS: 311.2. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C21H30NO 312.2322; found: 312.2324. 1-(4-Butyl-5-propyl-3-(p-tolyl)-1H-pyrrol-2-yl)butan-1-one (3ad). Yellow solid, 65 mg (67% yield), mp: 66−68 °C; 1H NMR (CDCl3, 400 MHz): δ 9.37 (s, 1H), 7.20 (d, J = 7.7 Hz, 2H), 7.15 (d, J = 7.9 Hz, 2H), 2.61−2.56 (m, 2H), 2.41 (s, 3H), 2.22−2.17 (m, 2H), 2.10 (t, J = 7.5 Hz, 2H), 1.68 (dd, J = 15.2, 7.5 Hz, 2H), 1.50−1.43 (m, 2H), 1.26−1.20 (m, 2H), 1.17 (dd, J = 14.4, 7.2 Hz, 2H), 1.00 (t, J = 7.3 Hz, 3H), 0.76 (t, J = 7.3 Hz, 3H), 0.66 (t, J = 7.4 Hz, 3H). 13C NMR (CDCl3, 101 MHz): 13C NMR (151 MHz, CDCl3) δ 191.1, 136.86 (s), 133.4, 132.3, 130.2, 128.8, 127.6, 123.2, 40.7, 33.7, 28.3, 23.9, 22.8, 22.6, 21.4, 18.9, 14.2, 13.9. IR (neat) νmax cm−1 1612 (C O); GC-MS: 325.2. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C22H32NO 326.2478; found: 326.2486. 1-(3-(4-Bromophenyl)-4-butyl-5-propyl-1H-pyrrol-2-yl)butan-1one (3af). Yellow solid, 85 mg (75% yield), mp: 121−123 °C; 1H NMR (CDCl3, 400 MHz): δ 9.83 (s, 1H), 7.55 (dd, J = 8.1, 1.2 Hz, 2H), 7.20−7.14 (m, 2H), 2.60 (t, J = 7.6 Hz, 2H), 2.19 (t, J = 7.2 Hz, 2H), 2.10 (t, J = 7.3 Hz, 2H), 1.68 (dt, J = 14.6, 7.3 Hz, 2H), 1.47 (dd, J = 14.6, 7.3 Hz, 2H), 1.25−1.14 (m, 4H), 1.02−0.95 (m, 3H), 0.77 (t, J = 6.6 Hz, 3H), 0.70 (t, J = 6.9 Hz, 3H). 13C NMR (CDCl3, 101 MHz): δ 190.7, 136.3, 135.7, 132.1, 131.3, 130.7, 127.5, 123.1, 121.5, 40.9, 33.7, 28.2, 23.8, 22.9, 22.6, 18.7, 14.2, 13.9. IR (neat) νmax cm−1 1611 (CO); GC-MS: 389.1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C21H29BrNO 390.1427; found: 390.1432. 1-(4-Butyl-3-(4-fluorophenyl)-5-propyl-1H-pyrrol-2-yl)butan-1one (3ag). Yellow solid, 67 mg (68% yield), mp: 81−83 °C; 1H NMR (CDCl3, 400 MHz): δ 9.84 (s, 1H), 7.28−7.23 (m, 2H), 7.11 (t, J = 8.7 Hz, 2H), 2.63−2.57 (m, 2H), 2.21−2.16 (m, 2H), 2.11−2.07 (m, 2H), 1.69 (dd, J = 15.3, 7.5 Hz, 2H), 1.51−1.45 (m, 2H), 1.24−1.13 (m, 4H), 0.99 (t, J = 7.3 Hz, 3H), 0.76 (t, J = 7.2 Hz, 3H), 0.69 (t, J = 7.4 Hz, 3H). 13C NMR (CDCl3, 101 MHz): δ 190.7, 163.1, 161.5, 136.2, 132.5, 131.9, 131.8, 131.0, 127.7, 123.2, 115.2, 115.1, 40.9, 33.7, 28.2, 23.8, 22.9, 22.6, 18.7, 14.2, 14.0, 13.9. IR (neat) νmax cm−1 1609 (CO); GC-MS: 329.2. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C21H29FNO 330.2228; found: 330.2233. 1-(4-Butyl-3-(4-chlorophenyl)-5-propyl-1H-pyrrol-2-yl)butan-1one (3ah). Yellow solid, 80 mg (78% yield), mp: 94−96 °C; 1H NMR (CDCl3, 400 MHz): δ 9.83 (s, 1H), 7.39 (d, J = 8.4 Hz, 2H), 7.25− 7.21 (m, 2H), 2.63−2.56 (m, 2H), 2.22−2.16 (m, 2H), 2.10 (t, J = 7.4 Hz, 2H), 1.69 (dd, J = 15.2, 7.5 Hz, 2H), 1.49 (dd, J = 14.8, 7.4 Hz, 2H), 1.20 (ddd, J = 21.4, 11.5, 5.3 Hz, 4H), 0.99 (t, J = 7.4 Hz, 3H), 11395


Article

The Journal of Organic Chemistry 2.24−2.17 (m, 2H), 1.65 (dt, J = 15.2, 7.4 Hz, 2H), 1.51 (ddd, J = 14.7, 7.5, 1.4 Hz, 2H), 0.91 (t, J = 7.3 Hz, 3H), 0.70 (t, J = 7.3 Hz, 3H). 13C NMR (CDCl3, 101 MHz): δ 191.8, 137.0, 133.4, 132.3, 131.9, 131.6, 130.6, 128.8, 128.10, 123.7, 40.9, 28.4, 22.9, 21.4, 18.7, 14.00. IR (neat) νmax cm−1 1611 (CO); GC-MS: 423.1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C24H27BrNO 424.1271; found: 424.1279. 1-(4-(4-Chlorophenyl)-5-propyl-3-(p-tolyl)-1H-pyrrol-2-yl)butan1-one (3am). Yellow solid, 80 mg (70% yield), mp: 180−182 °C; 1H NMR (CDCl3, 400 MHz): δ 9.68 (s, 1H), 7.30 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 4.2 Hz, 4H), 6.88 (d, J = 8.0 Hz, 2H), 2.66−2.58 (m, 2H), 2.34 (s, 3H), 2.20 (t, J = 7.4 Hz, 2H), 1.62 (m, 2H), 1.50 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H), 0.69 (t, J = 7.3 Hz, 3H). 13C NMR (CDCl3, 101 MHz): δ 191.8, 137.1, 136.1, 133.9, 132.2, 131.9, 131.1, 130.6, 128.8, 128.0, 123.7, 120.2, 40.9, 28.4, 22.9, 21.4, 18.7, 14.00. IR (neat) νmax cm−1 1611 (CO); GC-MS: 379.2. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C24H27ClNO 380.1776; found: 380.1783. 1-(4-(4-Fluorophenyl)-5-propyl-3-(p-tolyl)-1H-pyrrol-2-yl)butan1-one (3an). Yellow solid, 63 mg (58% yield), mp: 138−140 °C; 1H NMR (CDCl3, 400 MHz): δ 9.89 (s, 1H), 7.09−7.05 (m, 4H), 6.98 (ddd, J = 8.1, 3.7, 1.4 Hz, 2H), 6.90−6.86 (m, 2H), 2.65−2.60 (m, 2H), 2.34 (s, 3H), 2.24−2.20 (m, 2H), 1.65 (dd, J = 15.3, 7.6 Hz, 2H), 1.52 (td, J = 7.8, 0.8 Hz, 2H), 0.91 (t, J = 7.3 Hz, 3H), 0.70 (t, J = 7.4 Hz, 3H). 13C NMR (CDCl3, 101 MHz): δ 191.8, 162.2, 160.6, 136.9, 136.3, 132.4, 131.84 (d, J = 7.7 Hz), 131.4, 130.8, 130.6, 128.8, 127.9, 123.9, 114.87 (d, J = 21.3 Hz), 40.9, 28.4, 22.9, 21.4, 18.7, 14.1, 13.9. IR (neat) νmax cm−1 1609 (CO); GC-MS: 363.2. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C24H27FNO 364.2071; found: 364.2077. 1-(5-Propyl-3-(p-tolyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrol-2yl)butan-1-one (3ao). Yellow solid, 51 mg (41% yield), mp: 178−180 °C; 1H NMR (CDCl3, 400 MHz): δ 7.43 (d, J = 8.3 Hz, 2H), 7.26 (s, 1H), 7.08 (d, J = 3.2 Hz, 6H), 2.68−2.62 (m, 2H), 2.35 (s, 3H), 2.21 (t, J = 7.4 Hz, 2H), 1.66 (dd, J = 15.3, 7.6 Hz, 2H), 1.51 (dd, J = 14.8, 7.4 Hz, 2H), 0.93 (t, J = 7.3 Hz, 3H), 0.70 (t, J = 7.4 Hz, 3H). 13C NMR (CDCl3, 101 MHz): δ 191.9, 138.8, 137.2, 136.1, 131.1, 130.5 (d, J = 16.6 Hz), 128.9, 128.1, 124.91 (d, J = 3.6 Hz), 123.5, 41.0, 28.4, 22.9, 21.4, 18.7, 13.99 (d, J = 15.9 Hz). IR (neat) νmax cm−1 1608 (C = O); GC-MS: 413.2. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C25H27F3NO 414.2039; found: 414.2039. 1-(4-(4-Chlorophenyl)-5-methyl-3-(p-tolyl)-1H-pyrrol-2-yl)ethanone (3bm). Yellow solid, 63 mg (65% yield), mp: 170−172 °C; 1 H NMR (CDCl3, 400 MHz): δ 9.71 (s, 1H), 7.17−7.14 (m, 2H), 7.12−7.05 (m, 4H), 6.96−6.92 (m, 2H), 2.35−2.32 (s, 6H), 1.96 (s, 3H). 13C NMR (CDCl3, 101 MHz): δ 188.6, 137.3, 133.1, 132.1, 131.9, 131.8, 131.4, 130.6, 129.0, 128.3, 128.2, 123.7, 27.6, 21.4, 12.4. IR (neat) νmax cm−1 1617 (CO); GC-MS: 323.1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H19ClNO 324.1150; found: 324.1153. 1-(4-(4-Bromophenyl)-5-methyl-3-(p-tolyl)-1H-pyrrol-2-yl)ethanone (3bl). Yellow solid, 66 mg (60% yield), mp: 179−181 °C; 1 H NMR (CDCl3, 400 MHz): δ 9.62 (s, 1H), 7.33−7.29 (m, 2H), 7.12−7.04 (m, 4H), 6.90−6.86 (m, 2H), 2.35−2.32 (s, 6H), 1.95− 1.94 (s, 3H). 13C NMR (CDCl3, 101 MHz): δ 188.6, 137.3, 133.6, 132.1, 131.7, 131.2, 130.6, 129.1, 128.2, 123.7, 120.2, 27.6, 21.4, 12.4. IR (neat) νmax cm−1 1619 (CO); GC-MS: 367.1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H19BrNO 368.0645; found: 368.0653. 1-(4-(4-Fluorophenyl)-5-methyl-3-(p-tolyl)-1H-pyrrol-2-yl)ethanone (3bn). Yellow solid, 44 mg (48% yield), mp: 159−161 °C; 1 H NMR (CDCl3, 400 MHz): δ 9.66 (s, 1H), 7.11−7.07 (m, 4H), 6.99−6.95 (m, 2H), 6.90−6.86 (m, 2H), 2.34 (s, 3H), 2.32 (s, 3H), 1.96 (s, 3H). 13C NMR (CDCl3, 101 MHz): δ 188.6, 137.2, 132.3, 132.0, 131.8, 131.7, 131.6, 130.6, 129.0, 128.1, 124.0, 115.1, 114.9 27.6, 21.4, 12.3. IR (neat) νmax cm−1 1608 (CO); GC-MS: 307.1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H19FNO 308.1451; found: 308.1455. 1-(3-Phenyl-5-propyl-4-(4-(trifluoromethyl)phenyl)-1H-pyrrol-2yl)butan-1-one (3ap). Yellow solid, 44.1 mg (40% yield), mp: 161− 163 °C; 1H NMR (CDCl3, 400 MHz): δ 9.72 (s, 1H), 7.42 (s, 2H), 7.32−7.27 (m, 3H), 7.20 (m, 2H), 7.12 (d, J = 8.1 Hz, 2H), 2.69−2.62 (m, 2H), 2.22−2.15 (m, 2H), 1.67 (m, 2H), 1.50 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H), 0.68 (t, J = 7.4 Hz, 3H). 13C NMR (CDCl3, 101 MHz): δ

191.8, 138.6, 136.3, 135.3, 131.0, 130.8, 130.4, 128.2, 127.6, 124.9, 123.5, 41.1, 28.4, 22.9, 18.6, 13.99 (d, J = 18.4 Hz). IR (neat) νmax cm−1 1608 (CO); GC-MS: 399.2. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C24H25F3NO 400.1883; found: 400.1880. General Procedure for the Synthesis of Product 4. An ovendried sealed tube was charged with the mixture of alkylnitriles 1 (0.3 mmol), MeOTf (0.3 mmol, 34 μL), and aromatic alkyne 3 (0.3 mmol) and then stirred in dichloroethane (0.5 mL) at 130 °C under nitrogen atmosphere for 24 h. After completion, the crude mixture was subjected to 200−300 mesh neutral aluminum oxide column chromatography (petroleum ether/ethyl acetate: 10/1) to provide the desired substance. 4-Benzyl-3-propylisoquinoline (4as). Faint yellow oil, 54.8 mg (70% yield); 1H NMR (CDCl3, 400 MHz): δ 9.17 (s, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.57 (t, J = 7.7 Hz, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.19 (dd, J = 19.1, 7.3 Hz, 3H), 7.06 (d, J = 7.5 Hz, 2H), 4.47 (s, 2H), 3.00−2.93 (m, 2H), 1.76 (dt, J = 14.9, 7.5 Hz, 2H), 0.98 (t, J = 7.4 Hz, 3H). 13C NMR (CDCl3, 101 MHz): δ 154.4, 151.2, 140.1, 136.1, 130.5, 129.6, 129.3, 128.6, 128.5, 128.4, 128.3, 128.2, 128.1, 127.4, 126.2, 126.0, 125.4, 123.7, 37.8, 33.4, 23.5, 14.4. GC-MS: 261.2. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H20N 262.1590; found: 262.1589. 4-Benzyl-3-methylisoquinoline (4bs).12 Faint yellow oil, 47 mg (67% yield); 1H NMR (CDCl3, 400 MHz): δ 9.14 (s, 1H), 7.94 (d, J = 8.1 Hz, 1H), 7.88 (d, J = 8.5 Hz, 1H), 7.60 (ddd, J = 8.3, 6.9, 1.1 Hz, 1H), 7.50 (t, J = 7.4 Hz, 1H), 7.23 (dd, J = 11.6, 4.5 Hz, 2H), 7.17 (d, J = 7.2 Hz, 1H), 7.06 (d, J = 7.3 Hz, 2H), 4.44 (s, 2H), 2.71 (s, 3H). 13 C NMR (CDCl3, 101 MHz): δ 150.9, 150.6, 139.4, 135.9, 130.6, 128.7, 128.3, 128.1, 127.5, 126.3, 126.1, 126.0, 123.3, 33.7, 22.8. GCMS: 233.1. 4-Benzyl-3-phenethylisoquinoline (4ds). Yellow oil, 69 mg (72% yield); 1H NMR (CDCl3, 400 MHz): δ 9.22 (s, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.63−7.56 (m, 1H), 7.52 (d, J = 7.4 Hz, 1H), 7.26−7.12 (m, 8H), 7.02 (d, J = 7.8 Hz, 2H), 4.36 (s, 2H), 3.31−3.23 (m, 2H), 3.07−2.98 (m, 2H). 13C NMR (CDCl3, 101 MHz): δ 151.3, 142.0, 139.9, 136.0, 130.5, 128.8−128.4 (m), 128.1(d, J = 11.3 Hz), 127.4, 126.0 (dd, J = 28.2, 11.8 Hz), 123.6, 37.8, 36.3, 33.2. GC-MS: 323.1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C24H22N 324.1747; found: 324.1750. 4-Benzyl-3-isopropylisoquinoline (4es).13 Faint yellow oil, 31 mg (40% yield); 1H NMR (CDCl3, 400 MHz): δ 9.23 (s, 1H), 7.94 (d, J = 8.1 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.50 (t, J = 7.5 Hz, 1H), 7.24 (dd, J = 11.8, 4.8 Hz, 2H), 7.19−7.15 (m, 1H), 7.06 (d, J = 7.2 Hz, 2H),4.50 (s, 2H), 3.50−3.47 (m, 1H), (d, J = 6.8 Hz, 6H). 13C NMR (CDCl3, 101 MHz): δ 158.7, 151.5, 140.2, 136.1, 129.4, 128.7, 128.2, 128.1, 126.2, 126.0, 124.1, 123.8, 33.0, 31.4, 22.6. GC-MS: 261.2. 4-Benzyl-3-cyclopropylisoquinoline (4fs). Faint yellow oil, 35 mg (45% yield); 1H NMR (CDCl3, 400 MHz): δ 9.08 (s, 1H), 7.91−7.86 (dd, J = 12.0, 8.4 Hz, 2H), 7.58 (t, J = 7.0 Hz, 1H), 7.46 (t, J = 7.1 Hz, 1H), 7.27−7.23 (m, 2H), 7.19−7.15 (m, 3H), 4.61 (s, 2H), 2.29−2.27 (t, J = 4.9 Hz, 1H), 1.20−1.81 (dt, J = 4.8, 3.1 Hz, 2H), 0.98−0.95 (m, 2H). 13C NMR (CDCl3, 101 MHz): δ 153.8, 151.2, 140.1, 135.8, 130.5, 128.7, 128.3, 127.1, 126.2, 125.6 (d, J = 21.8 Hz), 125.4, 123.2, 33.1, 14.1, 9.11. GC-MS: 259.1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H18N 260.1434; found: 260.1441. 7-Methyl-4-(4-methylbenzyl)-3-propylisoquinoline (4at). Faint yellow oil, 65 mg (75% yield); 1H NMR (CDCl3, 400 MHz): δ 9.08 (s, 1H), 7.76−7.69 (m, 2H), 7.41 (dd, J = 8.7, 1.7 Hz, 1H), 7.03 (d, J = 8.0 Hz, 2H), 6.94 (d, J = 8.0 Hz, 2H), 4.41 (s, 2H), 2.96−2.91 (m, 2H), 2.50 (s, 3H), 2.28 (s, 3H), 1.76 (d, J = 7.8 Hz, 2H), 0.98 (t, J = 7.3 Hz, 3H). 13C NMR (CDCl3, 101 MHz): δ 153.5, 150.5, 137.1, 135.7, 134.4, 132.7, 129.3, 128.0, 127.7, 126.9, 125.6, 123.6, 37.7, 33.0, 23.6, 21.5, 21.1, 14.4. GC-MS: 289.2. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C21H24N 290.1903; found: 290.1907. 3,7-Dimethyl-4-(4-methylbenzyl)isoquinoline (4bt). Faint yellow oil, 56 mg (71% yield); 1H NMR (CDCl3, 400 MHz): δ 9.04 (s, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.70 (s, 1H), 7.47−7.42 (m, 1H), 7.03 (d, J = 7.9 Hz, 2H), 6.94 (d, J = 7.9 Hz, 2H), 4.38 (s, 2H), 2.68 (s, 3H), 2.50 (s, 3H), 2.28 (s, 3H). 13C NMR (CDCl3, 101 MHz): δ 150.2, 149.6, 11396



■

136.5, 135.7 (d, J = 4.8 Hz), 134.3, 132.8, 129.4, 128.0, 127.8, 127.0, 126.2, 123.2, 33.4, 22.6, 21.6, 21.1. GC-MS: 261.2. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H20N 262.1590; found: 262.1595. d-4-Benzyl-3-methylisoquinoline (4ks). Faint yellow oil, 45.6 mg (65% yield); 1H NMR (CDCl3, 400 MHz): δ 9.13 (s, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.88 (d, J = 8.5 Hz, 1H), 7.60 (m, 1H), 7.50 (m, 1H), 7.25−7.20 (m, 2H), 7.16 (t, J = 7.3 Hz, 1H), 7.06 (d, J = 7.3 Hz, 2H), 4.44 (s, 2H). 13C NMR (CDCl3, 101 MHz): δ 150.8, 139.4, 135.9, 130.6, 128.9, 128.22 (d, J = 15.9 Hz), 127.5, 126.52−125.86 (m), 123.3, 33.7. GC-MS: 236.1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H13D3N 237.1466, found: 237.1475. 6-Methyl-4-(3-methylbenzyl)-3-propylisoquinoline(4au). Yellow oil, 42.4 mg (49% yield); 1H NMR (CDCl3, 400 MHz): δ 9.10 (s, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.63 (s, 1H), 7.33 (dd, J = 8.3, 1.2 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H), 6.99 (s, 1H), 6.90 (s, 1H), 6.85 (d, J = 7.6 Hz, 1H), 4.40 (s, 2H), 2.95−2.87 (m, 2H), 2.46 (s, 3H), 2.26 (s, 3H), 1.75 (dd, J = 15.4, 7.6 Hz, 2H), 0.97 (t, J = 7.3 Hz, 3H). 13C NMR (CDCl3, 101 MHz): δ 154.5, 150.7, 140.7, 140.1, 138.2, 136.4, 128.9, 128.5, 128.15 (d, J = 18.5 Hz), 126.9, 125.9, 125.2, 124.9, 122.6, 37.8, 33.2, 23.5, 22.6, 21.5, 14.4. GC-MS: 289.2. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C21H24N [M + H]+ 290.1903; found: 290.1912. 5-Methyl-4-(3-methylbenzyl)-3-propylisoquinoline (4au′). Yellow oil, 25.1 mg (29% yield); 1H NMR (CDCl3, 400 MHz): δ 9.40 (s, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.45 (dd, J = 8.5, 7.0 Hz, 1H), 7.27 (d, J = 7.0 Hz, 1H), 7.10 (t, J = 7.6 Hz, 1H), 6.97 (d, J = 7.4 Hz, 1H), 6.89 (s, 1H), 6.83 (d, J = 7.5 Hz, 1H), 4.43 (s, 2H), 2.78 (s, 3H), 2.25 (s, 3H), 1.77 (d, J = 7.8 Hz, 2H), 0.99 (t, J = 7.3 Hz, 3H). 13C NMR (CDCl3, 101 MHz): δ 154.1, 147.8, 140.2, 138.2, 136.4, 135.8, 130.2, 128.9, 128.5, 126.92 (d, J = 8.5 Hz), 126.4, 125.8, 125.2, 122.1, 37.8, 33.5, 23.5, 21.5, 18.8, 14.4. GC-MS: 289.2. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C21H24N 290.1903; found: 290.1910. A Procedure for the Synthesis of 2,5-Dimethyl-3-(p-tolyl)-4-(4(trifluoromethyl)phenyl)-1H-pyrrole (5). An oven-dried sealed tube was charged with a mixture of acetonitrile 1b (0.3 mmol, 16 μL), CH 3 CH 2 OTf (0.3 mmol, 39 μL), and 1-methyl-4-((4(trifluoromethyl)phenyl)ethynyl)benzene 2o (0.3 mmol, 78 mg) and then stirred in dichloroethane (0.5 mL) at 80 °C under nitrogen for 24 h. After completion, the crude mixture was subjected to 200−300 mesh silica gel column chromatography (petroleum ether/ethyl acetate: 20/1) to provide title compound 5. Yellow oil, 39.5 mg (40% yield); 1H NMR (CDCl3, 400 MHz): δ 7.81 (s, 1H), 7.46 (d, J = 8.2 Hz, 2H), 7.17 (d, J = 8.2 Hz, 2H), 7.06 (d, J = 7.9 Hz, 2H), 6.95 (d, J = 7.9 Hz, 2H), 2.32 (d, J = 4.5 Hz, 6H), 2.29 (s, 3H). 13C NMR (CDCl3, 101 MHz): δ 140.3, 135.1, 132.7, 130.10 (d, J = 3.4 Hz), 128.9, 124.8, 123.7, 123.3, 120.5, 21.3, 12.1, 11.9. GC-MS: 329.1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H19F3N 330.1464; found: 330.1471. d-1-(4,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)ethanone (6). Yellow solid, 39.5 mg (61% yield), mp: 150−152 °C; 1H NMR (CDCl3, 400 MHz): δ 9.59 (s, 1H), 7.45−7.36 (m, 3H), 7.29−7.25 (m, 2H), 1.90 (s, 3H), 1.80 (s, 3H). 13C NMR (CDCl3, 101 MHz): δ 187.8, 136.3, 133.2, 130.2, 128.3, 127.4, 118.1, 27.3, 9.3.IR (neat) νmax cm−1 1619 (CO); GC-MS: 216.1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C14H13D3NO 217.1415; found: 217.1423.

■

Article

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Chanjuan Xi: 0000-0002-9602-7309 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (nos, 21472106 and 91645120) and the National Key Basic Research Program of China (973 program) (2012CB933402).

■

REFERENCES

(1) (a) Walsh, C. T.; Garneau-Tsodikova, S.; Howard-Jones, A. R. Nat. Prod. Rep. 2006, 23, 517. (b) Kuo, W.-J.; Chen, Y.-H.; Jeng, R.-J.; Chan, L.-H.; Lin, W.-P.; Yang, Z.-M. Tetrahedron 2007, 63, 7086. (c) Feng, X.; Tong, B.; Shen, J.; Shi, J.; Han, T.; Chen, L.; Zhi, J.; Lu, P.; Ma, Y.; Dong, Y. J. Phys. Chem. B 2010, 114, 16731. (d) Tamao, K.; Ohno, S.; Yamaguchi, S. Chem. Commun. 1996, 1873. (e) Fürstner, A.; Weintritt, H. J. Am. Chem. Soc. 1998, 120, 2817. (f) Boger, D. L.; Boyce, C. W.; Labroli, M. A.; Sehon, C. A.; Jin, Q. J. Am. Chem. Soc. 1999, 121, 54. (g) Sayah, B.; Pelloux-Léon, N.; Vallée, Y. J. Org. Chem. 2000, 65, 2824. (h) Domingo, V. M.; Alemán, C.; Brillas, E.; Juliá, L. J. Org. Chem. 2001, 66, 4058. (2) (a) Paal, C. Ber. Dtsch. Chem. Ges. 1885, 18, 367. (b) Hantzsch, A. Ber. Dtsch. Chem. Ges. 1890, 23, 1474. (c) Liu, J.-H.; Yang, Q.-C.; Mak, T. C. W.; Wong, H. N. C. J. Org. Chem. 2000, 65, 3587. (d) Minetto, G.; Raveglia, L. F.; Sega, A.; Taddei, M. Eur. J. Org. Chem. 2005, 2005, 5277. (e) Liao, Q.; Zhang, L.; Wang, F.; Li, S.; Xi, C. Eur. J. Org. Chem. 2010, 2010, 5426. (f) Zhou, Y.; Yan, X.; Chen, C.; Xi, C. Organometallics 2013, 32, 6182. (g) Dhinakaran, I.; Padmini, V.; Bhuvanesh, N. ACS Comb. Sci. 2016, 18, 236. (3) For selected reviews, see: (a) Yamamoto, Y. Chem. Rev. 2012, 112, 4736. (b) Ye, J.; Ma, S. Acc. Chem. Res. 2014, 47, 989. (c) Chattopadhyay, B.; Gevorgyan, V. Angew. Chem., Int. Ed. 2012, 51, 862. (d) Estevez, V.; Villacampa, M.; Menendez, J. C. Chem. Soc. Rev. 2014, 43, 4633. (e) Marinetti, A.; Jullien, H.; Voituriez, A. Chem. Soc. Rev. 2012, 41, 4884. (f) Estevez, V.; Villacampa, M.; Menendez, J. C. Chem. Soc. Rev. 2010, 39, 4402. (g) Fan, H.; Peng, J.; Hamann, M. T.; Hu, J.-F. Chem. Rev. 2008, 108, 264. (4) For selected recent examples: (a) Lei, X.; Li, L.; He, Y.-P.; Tang, Y. Org. Lett. 2015, 17, 5224. (b) Reddy, C. R.; Panda, S. A.; Ramaraju, A. J. Org. Chem. 2017, 82, 944. (c) Chen, G.-Q.; Zhang, X.-N.; Wei, Y.; Tang, X.-Y.; Shi, M. Angew. Chem., Int. Ed. 2014, 53, 8492. (d) Xiao, P.; Yuan, H.; Liu, J.; Zheng, Y.; Bi, X.; Zhang, J. ACS Catal. 2015, 5, 6177. (e) Zhu, L.; Yu, Y.; Mao, Z.; Huang, X. Org. Lett. 2015, 17, 30. (f) Li, K.; You, J. J. Org. Chem. 2016, 81, 2327. (g) Dawande, S. G.; Kanchupalli, V.; Lad, B. S.; Rai, J.; Katukojvala, S. Org. Lett. 2014, 16, 3700. (h) Zhang, X.; Xu, X.; Chen, G.; Yi, W. Org. Lett. 2016, 18, 4864. (i) Miura, T.; Tanaka, T.; Hiraga, K.; Stewart, S. G.; Murakami, M. J. Am. Chem. Soc. 2013, 135, 13652. (5) (a) Katsuyama, A.; Matsuda, A.; Ichikawa, S. Org. Lett. 2016, 18, 2552. (b) Wu, X.; Li, K.; Wang, S.; Liu, C.; Lei, A. Org. Lett. 2016, 18, 56. (c) Falvey, D. E. Org. Lett. 2015, 17, 484. (d) Das, B.; Bhunia, N.; Lingaiah, M. Synthesis 2011, 2011, 3471. (e) Banik, B. K.; Samajdar, S.; Banik, I. J. Org. Chem. 2004, 69, 213. (f) Soleimani, E.; Zainali, M. J. Org. Chem. 2011, 76, 10306. (g) Xuan, J.; Xia, X.-D.; Zeng, T.-T.; Feng, Z.-J.; Chen, J.-R.; Lu, L.-Q.; Xiao, W.-J. Angew. Chem., Int. Ed. 2014, 53, 5653. (6) For representative references, see: (a) Flatt, P. M.; Wu, X.; Perry, S.; Mahmud, T. J. Nat. Prod. 2013, 76, 939. (b) Pruss, T. P.; Gardocki, J. F.; Taylor, R. J.; Muschek, L. D. J. Clin. Pharmacol. 1980, 20, 216. (c) Guo, J. L.; Feng, Z. M.; Yang, Y. J.; Zhang, Z. W.; Zhang, P. C. Chem. Pharm. Bull. 2010, 58, 983. (d) Ding, B.; Dai, Y.; Hou, Y. L.;

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b01845. Full NMR spectra for all products. The X-ray structure of compounds 3af and 3bm as well as their crystallographic data (PDF) CIF data for 3af (CIF) CIF data for 3bm (CIF) 11397


Article

The Journal of Organic Chemistry Yao, X. S. J. Asian Nat. Prod. Res. 2015, 17, 559. (e) Wood, J. M.; Furkert, D. P.; Brimble, M. A. Org. Biomol. Chem. 2016, 14, 7659. (f) Li, M.; Xiong, J.; Huang, Y.; Wang, L. J.; Tang, Y.; Yang, G. X.; Liu, X. H.; Wei, B. G.; Fan, H.; Zhao, Y.; Zhai, W. Z.; Hu, J. F. Tetrahedron 2015, 71, 5285. (g) Yuen, T.-Y.; Eaton, S. E.; Woods, T. M.; Furkert, D. P.; Choi, K. W.; Brimble, M. A. Eur. J. Org. Chem. 2014, 2014, 1431. (7) For selected recent examples, see: (a) Schumacher, D. P.; Hall, S. S. J. Org. Chem. 1981, 46, 5060. (b) Tamura, O.; Iyama, N.; Ishibashi, H. J. Org. Chem. 2004, 69, 1475. (c) Leen, V.; Leemans, T.; Boens, N.; Dehaen, W. Eur. J. Org. Chem. 2011, 2011, 4386. (d) Ding, Y.; Li, X.; Li, T.; Zhu, W.; Xie, Y. J. Org. Chem. 2013, 78, 5328. (e) You, H. T.; Grosse, A. C.; Howard, J. K.; Hyland, C. J. T.; Just, J.; Molesworth, P. P.; Smith, J. A. Org. Biomol. Chem. 2011, 9, 3948. (8) For representative references, see: (a) Kamijo, S.; Kanazawa, C.; Yamamoto, Y. J. Am. Chem. Soc. 2005, 127, 9260. (b) Suzuki, D.; Nobe, Y.; Watai, Y.; Tanaka, R.; Takayama, Y.; Sato, F.; Urabe, H. J. Am. Chem. Soc. 2005, 127, 7474. (c) Galliford, C. V.; Scheidt, K. A. J. Org. Chem. 2007, 72, 1811. (d) Lu, Y.; Arndtsen, B. A. Angew. Chem., Int. Ed. 2008, 47, 5430. (e) Lourdusamy, E.; Yao, L.; Park, C.-M. Angew. Chem., Int. Ed. 2010, 49, 7963. (f) Li, X.; Chen, M.; Xie, X.; Sun, N.; Li, S.; Liu, Y. Org. Lett. 2015, 17, 2984. (g) Iida, K.; Miura, T.; Ando, J.; Saito, S. Org. Lett. 2013, 15, 1436. (9) (a) Yan, X.; Zou, S.; Zhao, P.; Xi, C. Chem. Commun. 2014, 50, 2775. (b) Yan, X.; Yi, X.; Xi, C. Org. Chem. Front. 2014, 1, 657. (c) Zhao, P.; Yan, X.; Yin, H.; Xi, C. Org. Lett. 2014, 16, 1120. (d) Zhao, P.; Liu, Y.; Xi, C. Org. Lett. 2015, 17, 4388. (e) Liu, Y.; Zhao, P.; Zhang, B.; Xi, C. Org. Chem. Front. 2016, 3, 1116. (f) Wang, S.; Shao, P.; Du, G.; Xi, C. J. Org. Chem. 2016, 81, 6672. (10) Xu, Y.; Zhao, J.; Chen, H.; Wu, W.; Jiang, H. Chem. Commun. 2014, 50, 2488. (11) Giles, R. G.; et al. Tetrahedron 2015, 71, 7367. (12) Gisby, G. P.; Sammes, P. G.; Watt, R. A. J. Chem. Soc., Perkin Trans. 1 1982, 249. (13) Pilgrim, B. S.; Gatland, A. E.; Esteves, C. H. A.; McTernan, C. T.; Jones, G. R.; Tatton, M. R.; Procopiou, P. A.; Donohoe, T. U. Org. Biomol. Chem. 2016, 14, 1065.

11398


MeOTf-Mediated Annulation of Alkylnitriles and Arylalkynes Leading to

Recommend Documents