Introduction

In recent years, multicomponent reactions (MCRs) have extensively been developed as efficient synthetic strategies for the construction of biologically interesting compounds [1,2,3]. The need of modern methods in organic synthesis as well as medicinal chemistry has led chemists to design processes in which reactions occur not through a single-step procedure, but rather via several sequential steps involving cascades or domino reactions [4]. The advantages of MCRs include one-pot reaction, time saving, greater efficiency, and atom economy with the generation of simultaneous several bond formations leading to complex structures [5, 6].

Isocyanide-based multicomponent reactions (IMCRs), which are a subclass of MCRs, are defined as processes in which an isocyanide is used as one of the starting materials to prepare new compounds [7,8,9,10,11,12]. In this context, the work of Ugi is perhaps the first report of IMCR [13,14,15,16,17]. Thereafter, there have been many reports on the synthesis of more complex structures through tandem Ugi/post-Ugi reactions [18,19,20,21,22,23,24].

Fig. 1
figure 1

a Drugs containing a tetrazole ring, b example of natural products and bioactive molecules containing a pyrrolo[1,2-a]pyrazine scaffold

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In the Ugi-azide reaction, which is another aspect of the Ugi multicomponent process, carboxylic acid is replaced by hydrazoic acid, trimethylsilyl azide \((\hbox {TMSN}_{3})\) or sodium azide in order to achieve the novel biologically important 1,5-disubstituted-1H-tetrazole (1,5-DS-1H-T) [25,26,27,28,29,30,31,32,33,34,35,36]. Particularly significant in this regard is the first use of an internally generated secondary amine in order to obtain fused ketopiperazine-tetrazoles [37]. Other approaches to obtaining tetrazoles through post-condensation modifications on the initially prepared Ugi-azide product often by an internal nucleophilic substitution may not also be overlooked [38, 39].

1,5-DS-1H-Ts are bioisosteres of cis-amide bond [40,41,42,43]. Due to their metabolic stability [44], 1,5-DS-1H-T heterocycles are important in medicinal chemistry. Certain derivatives of 1,5-DS-1H-Ts are active on the central nervous system (CNS) [45]. Pharmaceutically important tetrazoles including losartan, valsartan, pemirolast and cilostazol have been used for the treatment of cardiovascular diseases [46], antihypertension [47], allergies [48] and reducing the symptoms of intermittent claudication [49], respectively (Fig. 1a). Non-biological properties such as primary explosives [50] and ligands [51] have also been reported for some tetrazole derivatives.

1,2,3,4-Tetrahydropyrrolo[1,2-a]pyrazines are important heterocyclic skeletons exhibiting antiarrhythmic [52], psychotropic [53], antiamnesic and antihypersensitive [54], antiamnesic [55], and antihypoxic (Fig. 1b) [56].

Scheme 1
scheme 1

Synthesis of 4a via a two-step Ugi-azide reaction

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Table 1 Optimization of reaction conditions
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Table 2 Synthesis of 4a–r via a two-step Ugi-azide reaction
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Scheme 2
scheme 2

Role of iminium I intermediate in the synthesis of tetrazole 4a

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We became interested in the synthesis of tetrahydropyrrolo[1,2-a]pyrazine and 1,5-DS-1H-T heterocycles due to their biological activities and uses. Based on our contribution to Ugi-azide reactions [57, 58] as well as synthesis of 2-chloropyridinium adducts [59,60,61], herein, we report a new methodology for the synthesis of novel 1-(1H-tetrazol-5-yl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine derivatives via a facile Ugi-azide four-component process using 1-(2-bromoethyl)-1-H-pyrrole-2-carbaldehyde, aromatic or benzyl amines, phenylhydrazine, phenylhydrazide, p-toluenesulfonyl hydrazide and isocyanide or sodium azide.

Scheme 3
scheme 3

Synthesis of 4a–r via a two-step Ugi-azide reaction

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Table 3 Synthesis of 6a–i via a two-step Ugi-azide reaction
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Results and discussion

Initially, 1-(2-haloethyl)-1H-pyrrole-2-carbaldehydes 1a–b were synthesized according to the literature [62]. In order to optimize reaction conditions, 1-(2-bromoethyl)-1H-pyrrole-2-carbaldehyde 1a and aniline 2a were initially condensed within 20 min, followed by addition of solvent, t-butylisocyanide 3a and sodium azide in room temperature (rt) (Scheme 1, Table 1). Although DCM and THF furnished tetrazole 4a in low yields (entries 1 and 2, Table 1), this product was obtained in 63 and 92% yields within 6 and 3 h in EtOH and MeOH, respectively (entries 3 and 4, Table 1). Increasing the temperature to \(40\,^{\circ }\hbox {C}\) lowers the yield of 4a (entry 5, Table 1). Compound 4a was obtained in lower yield either using 1-(2-chloroethyl)-1H-pyrrole-2-carbaldehyde 1b at rt or \(40\,^{\circ }\hbox {C}\), or replacing \(\hbox {NaN}_{3}\) by \(\hbox {TMSN}_{3}\) (entries 6–8, Table 1). Finally, carrying out the reaction in one step in MeOH afforded 4a in 46% (entry 9, Table 1).

Scheme 4
scheme 4

Preparation of 6a–i via a two-step Ugi-azide reaction

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The iminium I was suggested to be generated as an intermediate in order to rationalize the results shown in Table 1. Since Br is a better leaving group than Cl (entries 4 and 6, Table 1), the iminium ion I is generated more efficiently from 1a in comparison with that of Cl analogue 1b (Scheme 2). Therefore, the Ugi-azide reaction of 1-(2-bromoethyl)-1H-pyrrole-2-carbaldehyde 1a to tetrazole 4a proceeds faster accordingly. The utilization of \(\hbox {NaN}_{3}\) as a stronger nucleophile in comparison with that of \(\hbox {TMSN}_{3}\) also affords tetrazole 4a in higher yield (entries 4 and 8, Table 1). Moreover, generation of I apparently occurs faster under solvent-free condition since a decrease in yield is observed when using a solvent (entries 4 and 9, Table 1). On the other hand, obtaining lower yield of 4a at \(40\,^{\circ }\hbox {C}\) can be rationalized by partial instability of 1a since the reaction color turned black under this condition.

Fig. 2
figure 2

ORTEP diagram of compound 4m

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Fig. 3
figure 3

ORTEP diagram of compound 6e

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Scheme 5
scheme 5

Alternate synthetic route to 6g

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With the optimized reaction conditions in hand, the generality of this reaction was studied. The reaction of 1-(2-bromoethyl)-1H-pyrrole-2-carbaldehyde 1a, amines 2a–j and isocyanides 4a–c afforded products 5a–r in moderate to high yields (Scheme 3, Table 2). Whether strong or weak amines such as n-butylamine, cyclohexylamine and 2- or 4-aminopyridine were used, they were found to be inefficient perhaps due to the formation of highly stable iminium intermediates or the inefficiency of weak heteroaromatic amines in forming the corresponding imines, respectively.

To explore the versatility of the reaction, substituted hydrazines 5a–c were used as amine source. Interestingly, the corresponding products 6a–i were obtained in good yields (Scheme 4, Table 3).

Compounds 4a–r and 6a–i were characterized and confirmed by elemental analysis, MS, IR, and \(^{1}\hbox {H}\) and \(^{13}\hbox {C}\) NMR spectroscopy. An unambiguous evidence for the proposed structures of 4m and 6e was obtained by single-crystal X-ray diffractometry, and ORTEP diagrams are shown in Figs. 2 and 3. The CCDC deposition number for compound 4m is 1530979. Formula: \(\hbox {C}_{20}\hbox { H}_{23}\hbox { Cl N}_{6}\). Unit cell parameters: \(a = 16.079\)(5) Å, \(b = 8.3270\)(17) Å, \(c = 29.813\)(6) Å, \(\alpha = 90^{\circ }\), \(\beta = 93.41(4)^{\circ }\), \(\gamma = 90^{\circ }\), space group C2 / c. The CCDC deposition number for compound 6e is 1530978. Formula: \(\hbox {C}_{21}\hbox { H}_{27}\hbox { N}_{7}\hbox { O}_{2}\) S. Unit cell parameters: \(a = 9.4374\)(19) Å, \(b = 11.577\)(2) Å, \(c = 12.175\)(2) Å, \(\alpha = 108.87(3)^{\circ }\), \(\beta = 112.26(3)^{\circ }\), \(\gamma = 93.59(3)^{\circ }\), space group \(P -1\).

Synthesis of 6g was also carried out in 93% yield using a previously reported procedure (Scheme 5) [63, 64]. The initially generated iminium intermediate I \(^{{\prime }}\) from condensation of 1a with benzohydrazide (5c) was converted to azomethine imine 7 [65]. This imine then reacted with chlorotrimethylsilane, \(t\hbox {-BuNC}\) and \(\hbox {NaN}_{3}\), to afford 6g in 82% yield [66] (Scheme 5).

Conclusion

In summary, we have developed a simple and convenient strategy for the synthesis of several bifunctional novel 1-(1H-tetrazol-5-yl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine derivatives 4a–r and 6a–i as biologically interesting derivatives with good to excellent yields. These new structures broaden the scaffolds that are accessible through Ugi-azide reaction, and many of them may represent interesting pharmacophores.

Experimental

General information

The chemicals and reagents used in this work were purchased from Merck Chemical Company and used without further purification. Melting points were obtained with an electrothermal model 9100 apparatus and are uncorrected. IR spectra were recorded using a Shimadzu 4300 spectrophotometer. \(^{1}\hbox {H}\) and \(^{13}\hbox {C}\) NMR spectra were recorded on a Bruker DRX-300-ADVANCE spectrometer at 300 (\(^{1}\hbox {H}\)) and 75 MHz (\(^{13}\hbox {C}\)) using \(\hbox {CDCl}_{3}\) or DMSO as solvent. Chemical shifts (\(\delta \) in ppm) are referenced to the solvent \(\hbox {CDCl}_{3}\) (\(\delta = 7.26\) ppm for \(^{1}\hbox {H}\) and 77.0 ppm for \(^{13}\hbox {C}\) NMR). Multiplicity abbreviations used for the chemical shifts are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet. Mass spectra were recorded on an HP (Agilent technologies) 5937 Mass Selective Detector. Elemental analyses were performed using a CHN-Rapid Heraeus elemental analyzer (Wellesley, MA).

General procedure for the synthesis of compounds 5a–r

1-(2-Bromoethyl)-1H-pyrrole-2-carbaldehyde 1a (202 mg, 1 mmol) and primary amines 2a–i (1 mmol) were taken in a 5-mL round-bottom flask and then stirred for 20 min to form solid iminium intermediates 3a–i. Methanol (4 mL) was then added to dissolve the solid. Sodium azide (65 mg, 1 mmol) and isocyanides 4a–c (1 mmol) were added, and the reaction mixture was stirred at room temperature for 3 h. After completion of the reaction as indicated by TLC, the solvent was removed under reduced pressure and the reaction mixture was extracted with ethyl acetate (\(2 \times 30\) mL). The organic phase was washed with brine (30 mL) and dried over anhydrous \(\hbox {Na}_{2}\hbox {SO}_{4}\). The crude products were purified by column chromatography through a silica gel column using ethyl acetate and hexane (30%) as eluents to afford desired solid products 5a–r.

1-(1-(tert-Butyl)-1H-tetrazol-5-yl)-2-phenyl-1,2,3,4 tetrahydropyrrolo[1,2-a]pyrazine (5a)

White solid (296 mg, 92%); mp 169–171 \(^{\circ }\hbox {C}\); IR (KBr) \(\nu _{\mathrm{max}}\): 2978, 1595, 1494, 1360, 1237, 1208, 1171, 1112, 817, 769, 704 \(\hbox {cm}^{ - 1}\); \(^{1}\)H NMR (300 MHz, \(\hbox {CDCl}_{3})\): \(\delta \) 1.66 (s, 9H), 3.57–3.65 (m, 1H), 3.87–4.07 (m, 3H), 5.93 (d, J = 2.5 Hz, 1H), 6.20 (t, J = 3.3 Hz, 1H), 6.35 (s, 1H), 6.65 (t, J = 2.2 Hz, 1H), 6.97–7.04 (m, 3H), 7.27 (t, J = 7.8 Hz, 2H); \(^{13}\)C NMR (75 MHz, \(\hbox {CDCl}_{3})\) \(\delta \) 29.9, 41.7, 46.3, 51.1, 62.1, 105.2, 108.5, 120.1, 120.6, 122.8, 123.5, 129.6, 148.7, 154.9 ppm; m / z (EI, 70 eV) 322 (19, \(\hbox {M}^{+})\) 266 (13), 197 (100), 119 (55), 104 (32), 77 (58), 57 (44%); Anal. Calcd for \(\hbox {C}_{18}\hbox {H}_{22}\hbox {N}_{6}\): C, 67.06; H, 6.88; N, 26.07. Found: C, 67.09; H, 6.90; N, 26.05%.

2-Benzyl-1-(1-(tert-butyl)-1H-tetrazol-5-yl)-1,2,3,4 -tetrahydropyrrolo[1,2-a]pyrazine (5b)

White solid (272 mg, 81%); mp 124–126 \(^{\circ }\hbox {C}\); IR (KBr) \(\nu _{\mathrm{max}}\): 2986, 2941, 2807, 1485, 1451, 1406, 1305, 1238, 760, \(731\,\hbox {cm}^{- 1}\); \(^{1}\)H NMR (300 MHz, \(\hbox {CDCl}_{3})\): \(\delta \) 1.63 (s, 9H), 2.73 (m, 1H), 3.39 (m, 1H), 3.45 (d, \(J = 13\) Hz, 1H), 3.75 (d, \(J = 13\) Hz, 1H), 3.98–4.11 (m, 2H), 5.52 (t, \(J = 1.7\) Hz, 1H), 5.64 (s, 1H), 6.11 (t, \(J = 3.3\) Hz, 1H), 6.61 (d, \(J = 1.7\) Hz, 1H), 7.24–7.36 (m, 5H); \(^{13}\hbox {C}\) NMR (75 MHz, \(\hbox {CDCl}_{3})\) \(\delta \) 30.2, 43.2, 47.1, 56.7, 58.7, 63.1, 105.0, 108.8, 119.2, 125.2, 127.7, 128.6, 128.9, 136.6, 154.3 ppm; m / z (EI, 70 eV) 336 (11, \(\hbox {M}^{+})\) 280 (9), 210 (53), 119 (47), 91 (100), 57 (31%); Anal. Calcd for \(\hbox {C}_{19}\hbox {H}_{24}\hbox {N}_{6}\): C, 67.83; H, 7.19; N, 24.98. Found: C, 67.87; H, 7.21; N, 25.01%.

1-(1-(tert-Butyl)-1H-tetrazol-5-yl)-2-(o-tolyl)-1,2,3,4 -tetrahydropyrrolo[1,2-a]pyrazine (5c)

White solid (225 mg, 67%); mp 192–194 \(^{\circ }\hbox {C}\); IR (KBr) \(\nu _{\mathrm{max}}\): 2951, 1595, 1489, 1433, 1239, 1078, 818, 757, 707 \(\hbox {cm}^{- 1}\); \(^{1}\)H NMR (300 MHz, \(\hbox {CDCl}_{3})\): \(\delta \) 1.55 (s, 9H), 2.31 (s, 3H), 3.17 (d, \(J = 13.3\) Hz, 1H), 3.97–4.04 (m, 2H), 4.35 (s, 1H), 5.79 (s, 1H), 6.15 (s, 1H), 6.20 (s, 1H), 6.70 (s, 1H), 6.89 (s, 1H), 7.04 (t, \(J = 3.7\) Hz, 2H), 7.19 (t, \(J = 3.7\) Hz, 1H); \(^{13}\)C NMR (75 MHz, \(\hbox {CDCl}_{3})\) \(\delta \) 17.8, 30.1, 42.3, 44.9, 52.3, 61.5, 104.2, 108.5, 119.9, 122.9, 124.5, 125.2, 127.1, 131.3, 133.5, 147.7, 154.9 ppm; m / z (EI, 70 eV) 336 (61, \(\hbox {M}^{+})\) 280 (42), 251 (27), 211 (100), 173 (18), 133 (56), 118 (61), 106 (21), 91 (43), 57 (26%); Anal. Calcd for \(\hbox {C}_{19}\hbox {H}_{24}\hbox {N}_{6}\): C, 67.83; H, 7.19; N, 24.98. Found: C, 67.80; H, 7.23; N, 25.01%.

1-(1-(tert-Butyl)-1H-tetrazol-5-yl)-2-(m-tolyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine (5d)

White solid (300 mg, 89%); mp 155–157 \(^{\circ }\hbox {C}\); IR (KBr) \(\nu _{\mathrm{max}}\): 2971, 1604, 1580, 1492, 1294, 1236, 1115, 933, 773, 708 \(\hbox {cm}^{- 1}\); \(^{1}\)H NMR (300 MHz, \(\hbox {CDCl}_{3})\): \(\delta \) 1.67 (s, 9H), 2.29 (s, 3H), 3.57–3.64 (m, 1H), 3.87–4.05 (m, 3H), 5.91 (d, \(J = 2.3\) Hz, 1H), 6.20 (t, \(J = 3.3\) Hz, 1H), 6.34 (s, 1H), 6.65 (t, \(J = 2.3\) Hz, 1H), 6.80–6.83 (m, 3H), 7.14 (t, \(J = 7.8\) Hz, 1H); \(^{13}\hbox {C}\) NMR (75 MHz, \(\hbox {CDCl}_{3})\) \(\delta \) 21.6, 29.9, 41.8, 46.3, 51.1, 62.1, 105.2, 108.4, 117.4, 120.1, 121.3, 123.5, 123.6, 129.3, 139.3, 148.7, 154.9 ppm; m / z (EI, 70 eV) 336 (18, \(\hbox {M}^{+})\) 280 (9), 251 (10), 211 (100), 167 (14), 149 (38), 133 (52), 91 (48), 69 (83), 57 (78%); Anal. Calcd for \(\hbox {C}_{19}\hbox {H}_{24}\hbox {N}_{6}\): C, 67.83; H, 7.19; N, 24.98. Found: C, 67.80; H, 7.21; N, 24.97%.

1-(1-(tert-Butyl)-1H-tetrazol-5-yl)-2-(p-tolyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine (5e)

White solid (313 mg, 93%); mp 153–155 \(^{\circ }\hbox {C}\); IR (KBr) \(\nu _{\mathrm{max}}\): 2988, 2947, 1510, 1450, 1237, 1204, 1113, 820, 774, 704 \(\hbox {cm }^{- 1}\); \(^{1}\)H NMR (300 MHz, \(\hbox {CDCl}_{3})\): \(\delta \) 1.65 (s, 9H), 2.27 (s, 3H), 3.51–3.54 (m, 1H), 3.94–3.96 (m, 3H), 5.89 (s, 1H), 6.20 (s, 1H), 6.27 (s, 1H), 6.64 (s, 1H), 6.92 (d, \(J = 7.6\) Hz, 2H), 7.06 (d, \(J = 7.6\) Hz, 2H); \(^{13}\)C NMR (75 MHz, \(\hbox {CDCl}_{3})\) \(\delta \) 20.6, 29.9, 41.6, 46.7, 51.5, 62.1, 105.1, 108.4, 120.0, 121.0, 123.7, 130.1, 132.6, 146.3, 154.9 ppm; m / z (EI, 70 eV) 336 (22, \(\hbox {M}^{+})\) 280 (11), 251 (8), 211 (100), 197 (11), 133 (59), 118 (18), 104 (16), 91 (40), 57 (24%); Anal. Calcd for \(\hbox {C}_{19}\hbox {H}_{24}\hbox {N}_{6}\): C, 67.83; H, 7.19; N, 24.98. Found: C, 67.80; H, 7.18; N, 24.95%.

1-(1-(tert-Butyl)-1H-tetrazol-5-yl)-2-(3,4-dimethylphenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine (5f)

White solid (308 mg, 88%); mp 178–180 \(^{\circ }\hbox {C}\); IR (KBr) \(\nu _{\mathrm{max}}\): 2982, 2943, 1609, 1571, 1498, 1450, 1237, 1209, 1156, 819, 705 \(\hbox {cm }^{- 1}\); \(^{1}\)H NMR (300 MHz, \(\hbox {CDCl}_{3})\): \(\delta \) 1.66 (s, 9H), 2.18 (s, 3H), 2.20 (s, 3H), 3.51–3.58 (m, 1H), 3.90–3.99 (m, 3H), 5.88–5.90 (m, 1H), 6.19 (t, \(J = 3.5\) Hz, 1H), 6.29 (s, 1H), 6.63–6.65 (m, 1H), 6.75 (dd, \(J = 8.1\), 2.4 Hz, 1H), 6.82 (s, 1H), 6.99 (d, \(J = 8.1\) Hz, 1H); \(^{13}\)C NMR (75 MHz, \(\hbox {CDCl}_{3})\) \(\delta \) 19.0, 20.1, 29.9, 41.6, 46.7, 51.4, 62.1, 105.1, 108.4, 118.1, 120.0, 122.4, 123.7, 130.5, 131.2, 137.7, 146.6, 155.0 ppm; m / z (EI, 70 eV) 350 (18, \(\hbox {M}^{+}\)) 294 (6), 265 (7), 225 (100), 211 (21), 147 (41), 105 (31), 57 (51%); Anal. Calcd for \(\hbox {C}_{20}\hbox {H}_{26}\hbox {N}_{6}\): C, 68.54; H, 7.48; N, 23.98. Found: C, 68.50; H, 7.51; N, 24.00%.

1-(1-(tert-Butyl)-1H-tetrazol-5-yl)-2 -(4-chlorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine (5g)

White solid (254 mg, 71%); mp 182–184 \(^{\circ }\hbox {C}\); IR (KBr) \(\nu _{\mathrm{max}}\): 3118, 2978, 1593, 1491, 1360, 1297, 1234, 1208, 821, 725 \(\hbox {cm }^{- 1}\); \(^{1}\)H NMR (300 MHz, \(\hbox {CDCl}_{3})\): \(\delta \) 1.66 (s, 9H), 3.53–3.59 (m, 1H), 3.86–4.05 (m, 3H), 5.91 (s, 1H), 6.19 (s, 1H), 6.28 (s, 1H), 6.65 (s, 1H), 6.95(d, \(J = 8.5\) Hz, 2H), 7.21 (d, \(J = 8.5\) Hz, 2H); \(^{13}\)C NMR (75 MHz, \(\hbox {CDCl}_{3})\) \(\delta \) 29.9, 41.6, 46.4, 51.2, 62.2, 77.3, 105.4, 108.6, 120.3, 121.8, 123.0, 127.9, 129.6, 147.3, 154.6 ppm; m / z (EI, 70 eV) 356 (27, \(\hbox {M}^{+})\) 300 (24), 271 (11), 231 (100), 153 (31), 111 (18), 57 (17%); Anal. Calcd for \(\hbox {C}_{18}\hbox {H}_{21}\hbox {ClN}_{6}\): C, 60.58; H, 5.93; Cl, 9.93; N, 23.55. Found: C, 60.55; H, 5.94; N, 23.56%.

1-(1-(tert-Butyl)-1H-tetrazol-5-yl)-2-(4-methoxyphenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine (5h)

White solid (317 mg, 90%); mp 145–147 \(^{\circ }\hbox {C}\); IR (KBr) \(\nu _{\mathrm{max}}\): 3129, 2975, 1582, 1503, 1447, 1297, 1240, 1176, 1028, 829, 726 \(\hbox {cm }^{- 1}\); \(^{1}\)H NMR (300 MHz, \(\hbox {CDCl}_{3})\): \(\delta \) 1.62 (s, 9H), 3.39–3.44 (m, 1H), 3.74 (s, 3H), 3.91–4.02 (m, 3H), 5.83 (d, \(J = 2.3\) Hz, 1H), 6.17–6.19 (m, 2H), 6.65 (s, 1H), 6.78(d, \(J = 8.8\) Hz, 2H), 6.97 (d, \(J = 8.8\) Hz, 2H); \(^{13}\)C NMR (75 MHz, \(\hbox {CDCl}_{3})\) \(\delta \) 29.9, 41.8, 47.5, 52.4, 55.4, 55.5, 62.1, 104.9, 108.5, 114.6, 119.9, 123.3, 123.9, 142.3, 154.8, 155.9 ppm; m / z (EI, 70 eV) 352 (16, \(\hbox {M}^{+})\) 296 (6), 227 (100), 149 (39), 104 (17), 69 (18), 57 (41%); Anal. Calcd for \(\hbox {C}_{19}\hbox {H}_{24}\hbox {N}_{6}\)O: C, 64.75; H, 6.86; N, 23.85; O, 4.54. Found: C, 64.76; H, 6.86; N, 23.88%.

2-Benzyl-1-(1-cyclohexyl-1H-tetrazol-5-yl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine (5i)

White solid (266 mg, 73%); mp 157–159 \(^{\circ }\hbox {C}\); IR (KBr) \(\nu _{\mathrm{max}}\): 2930, 2859, 1494, 1446, 1300, 1059, 898, 749, 723, 698 \(\hbox {cm }^{- 1}\); \(^{1}\)H NMR (300 MHz, \(\hbox {CDCl}_{3})\): \(\delta \) 0.90–1.04 (m, 1H), 1.16–1.37 (m, 3H), 1.58–1.79 (m, 3H), 1.87–2.09 (m, 3H), 2.68–2.77 (m, 1H), 3.24 (dt, \(J = 11.8\), 3.0 Hz, 1H), 3.41 (d, \(J = 13.9\) Hz, 1H), 3.75 (d, \(J = 13.9\) Hz, 1H), 4.02–4.16 (m, 2H), 4.28–4.39 (m, 1H), 5.47 (s, 1H), 5.51–5.52 (m, 1H), 6.10 (t, \(J = 3.0\), Hz, 1H), 6.63 (s, 1H), 7.21–7.35 (m, 5H); \(^{13}\)C NMR (75 MHz, \(\hbox {CDCl}_{3})\) \(\delta \) 24.9, 25.5, 25.6, 31.8, 32.8, 44.8, 48.1, 55.7, 58.6, 58.9, 105.6, 109.2, 119.3, 124.0, 127.6, 128.5, 128.6, 136.4, 153.7 ppm; m / z (EI, 70 eV) 362 (22, \(\hbox {M}^{+})\) 230 (5), 210 (46), 197 (7), 119 (41), 106 (13), 91 (100), 55 (26%); Anal. Calcd for \(\hbox {C}_{21}\hbox {H}_{26}\hbox {N}_{6}\): C, 69.58; H, 7.23; N, 23.19. Found: C, 69.60; H, 7.20; N, 23.20%.

1-(1-Cyclohexyl-1H-tetrazol-5-yl)-2-(m-tolyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine (5j)

White solid (275 mg, 76%); mp 123–125 \(^{\circ }\hbox {C}\); IR (KBr) \(\nu _{\mathrm{max}}\): 2943, 2860, 1602, 1492, 1444, 1384, 1307, 1239, 767, 695 \(\hbox {cm }^{- 1}\); \(^{1}\)H NMR (300 MHz, \(\hbox {CDCl}_{3})\): \(\delta \) 1.00–1.39 (m, 4H), 1.63–1.82 (m, 4H), 1.85–1.93 (m, 2H), 2.27 (s, 3H), 3.53–3.61 (m, 1H), 3.85 (dt, \(J = 13.2\), 4.7 Hz, 1H), 4.16 (dt, \(J = 12.1\), 4.1 Hz, 1H), 4.26–4.36 (m, 2H), 5.71 (t, \(J = 1.7\), Hz, 1H), 6.16 (t, \(J = 3.2\), Hz, 1H), 6.27 (s, 1H), 6.68 (s, 1H), 6.79–6.87 (m, 3H), 7.12 (t, \(J = 7.8\), Hz, 1H); \(^{13}\)C NMR (75 MHz, \(\hbox {CDCl}_{3})\) \(\delta \) 21.5, 24.8, 25.5, 25.6, 32.2, 32.7, 44.8, 49.6, 51.9, 58.4, 105.7, 109.1, 117.6, 119.7, 121.2, 123.7, 124.2, 129.2, 139.3, 148.6, 153.6 ppm; m / z (EI, 70 eV) 362 (33, \(\hbox {M}^{+})\) 230 (10), 211 (100), 197 (16), 133 (41), 91 (42), 55 (31%); Anal. Calcd for \(\hbox {C}_{21}\hbox {H}_{26}\hbox {N}_{6}\): C, 69.58; H, 7.23; N, 23.19. Found: C, 69.61; H, 7.22; N, 23.21%.

1-(1-Cyclohexyl-1H-tetrazol-5-yl)-2-(p-tolyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine (5k)

White solid (326 mg, 90%); mp 165–167 \(^{\circ }\hbox {C}\); IR (KBr) \(\nu _{\mathrm{max}}\): 2939, 2852, 1512, 1439, 1308, 1210, 1142, 827, 768, 709 \(\hbox {cm }^{- 1}\); \(^{1}\)H NMR (300 MHz, \(\hbox {CDCl}_{3})\): \(\delta \) 0.98–1.34 (m, 4H), 1.58–1.79 (m, 4H), 1.83–1.91 (m, 2H), 2.24 (s, 3H), 3.47–3.56 (m, 1H), 3.78 (dt, \(J = 13.0\), 4.4 Hz, 1H), 4.15 (dt, \(J = 12.0\), 4.2 Hz, 1H), 4.25–4.38 (m, 2H), 5.66 (m, 1H), 6.14 (t, \(J = 3.4\), Hz, 1H), 6.23 (s, 1H), 6.67 (d, \(J = 1.7\), Hz, 1H), 6.96 (d, \(J = 8.5\), Hz, 2H), 7.03 (d,\( J = 8.5\), Hz, 2H); \(^{13}\)C NMR (75 MHz, \(\hbox {CDCl}_{3})\) \(\delta \) 20.6, 24.9, 25.5, 25.6, 32.1, 32.6, 44.9, 50.6, 52.3, 58.4, 105.7, 109.1, 119.7, 121.2, 123.8, 130.0, 133.4, 146.3, 153.5 ppm; m / z (EI, 70 eV) 362 (24, \(\hbox {M}^{+})\), 211 (100), 197 (20), 149 (31), 133 (41), 119 (29), 91 (78), 55 (81%); Anal. Calcd for \(\hbox {C}_{21}\hbox {H}_{26}\hbox {N}_{6}\): C, 69.58; H, 7.23; N, 23.19. Found: C, 69.60; H, 7.24; N, 23.21%.

1-(1-Cyclohexyl-1H-tetrazol-5-yl)-2-(3,4-dimethylphenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine (5l)

White solid (271 mg, 72%); mp 138–140 \(^{\circ }\hbox {C}\); IR (KBr) \(\nu _{\mathrm{max}}\)t: 2945, 2854, 1608, 1502, 1441, 1339, 1284, 1209, 1137, 1033, 820, 766, 707 \(\hbox {cm }^{- 1}\); \(^{1}\)H NMR (300 MHz, \(\hbox {CDCl}_{3})\): \(\delta \) 0.98–1.33 (m, 4H), 1.59–1.81 (m, 4H), 1.84–1.92 (m, 2H), 2.15 (s, 3H), 2.18 (s, 3H), 3.47–3.56 (m, 1H), 3.78 (dt, \(J = 13.0\), 4.4 Hz, 1H), 4.15 (dt, \(J = 12.1\), 4.1 Hz, 1H), 4.26–4.39 (m, 2H), 5.66 (m, 1H), 6.15 (t,\( J = 3.5\), Hz, 1H), 6.23 (s, 1H), 6.68 (t, \(J = 1.8\), 1H), 6.79 (dd,\( J = 8.1\), 2.4 Hz, 1H), 6.86 (d,\( J = 2.2\), Hz, 1H), 6.98 (d,\( J = 8.1\), Hz, 1H); \(^{13}\)C NMR (75 MHz, \(\hbox {CDCl}_{3})\) \(\delta \) 19.0, 20.0, 24.9, 25.5, 25.6, 32.2, 32.7, 45.0, 50.5, 52.4, 58.4, 105.6, 109.1, 118.6, 119.6, 122.6, 123.9, 130.4, 132.2, 137.7, 146.6, 153.6 ppm; m / z (EI, 70 eV) 376 (56, \(\hbox {M}^{+})\), 225 (100), 211 (23), 147 (38), 121 (21), 105 (24), 55 (16%); Anal. Calcd for \(\hbox {C}_{22}\hbox {H}_{28}\hbox {N}_{6}\): C, 70.18; H, 7.50; N, 22.32. Found: C, 70.21; H, 7.51; N, 22.30%.

2-(4-Chlorophenyl)-1-(1-cyclohexyl-1H-tetrazol-5-yl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine (5m)

White solid (261 mg, 68%); mp 145–147 \(^{\circ }\hbox {C}\); IR (KBr) \(\nu _{\mathrm{max}}\): 2943, 2852, 1488, 1442, 1340, 1308, 1212, 1129, 1010, 949, 836, 771, 714 \(\hbox {cm }^{- 1}\); \(^{1}\)H NMR (300 MHz, \(\hbox {CDCl}_{3})\): \(\delta \) 1.01–1.42 (m, 4H), 1.64–1.79 (m, 4H), 1.85–1.88 (m, 2H), 3.52–3.60 (m, 1H), 3.80 (dt, \(J = 13.0\), 4.5 Hz, 1H), 4.15 (dt, \(J = 12.4\), 4.4 Hz, 1H), 4.20–4.33 (m, 2H), 5.70 (d,\( J = 2.2\), Hz, 1H), 6.14 (t,\( J = 3.0\), Hz, 1H), 6.24 (s, 1H), 6.68 (s, 1H), 6.98 (d,\( J = 8.7\), Hz, 2H), 7.18 (d,\( J = 8.7\), Hz, 2H); \(^{13}\)C NMR (75 MHz, \(\hbox {CDCl}_{3})\) \(\delta \) 24.8, 25.4, 25.6, 32.3, 32.7, 44.6, 49.8, 51.8, 58.5, 105.8, 109.2, 119.9, 121.6, 123.1, 128.3, 129.4, 147.1, 153.4 ppm; m / z (EI, 70 eV) 382 (56, \(\hbox {M}^{+})\), 271 (7), 231 (100), 127 (10), 111 (17), 55 (16%); Anal. Calcd for \(\hbox {C}_{20}\hbox {H}_{23}\hbox {ClN}_{6}\): C, 62.74; H, 6.05; Cl, 9.26; N, 21.95. Found: C, 62.76; H, 6.04; N, 21.92%.

1-(1-Cyclohexyl-1H-tetrazol-5-yl)-2-(4-methoxyphenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine (5n)

White solid (352 mg, 93%); mp 168–170 \(^{\circ }\hbox {C}\); IR (KBr) \(\nu _{\mathrm{max}}\): 2938, 2848, 1510, 1444, 1284, 1242, 1210, 1034, 846, 772, 750, 713 \(\hbox {cm }^{- 1}\); \(^{1}\)H NMR (300 MHz, \(\hbox {CDCl}_{3})\): \(\delta \) 0.95–1.32 (m, 4H), 1.55–1.81 (m, 4H), 1.85–1.88 (m, 2H), 3.42–3.50 (m, 1H), 3.64–3.70 (m, 4H), 4.14 (dt, \(J = 11.9\), 3.6 Hz, 1H), 4.25–4.37 (m, 2H), 5.61 (s, 1H), 6.13 (t,\( J = 2.9\), Hz, 1H), 6.15 (s, 1H), 6.67 (s, 1H), 6.75 (d,\( J = 8.8\), Hz, 2H), 7.01 (d,\( J = 8.8\), Hz, 2H); \(^{13}\)C NMR (75 MHz, \(\hbox {CDCl}_{3})\) \(\delta \) 24.9, 25.5, 25.6, 32.0, 32.6, 45.1, 51.6, 53.1, 55.4, 58.4, 105.6, 119.1, 114.6, 119.6, 123.4, 123.9, 142.0, 153.4, 156.4 ppm; m / z (EI, 70 eV) 378 (11, \(\hbox {M}^{+})\), 362 (6), 227 (48), 211 (26), 149 (25), 81 (55), 69 (100), 57 (58%); Anal. Calcd for \(\hbox {C}_{21}\hbox {H}_{26}\hbox {N}_{6}\)O: C, 66.64; H, 6.92; N, 22.21; O, 4.23. Found: C, 66.66; H, 6.90; N, 22.25%.

1-(1-Cyclohexyl-1H-tetrazol-5-yl)-2-(pyridin-3-yl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine (5o)

White solid (164 mg, 47%); mp 183–185 \(^{\circ }\hbox {C}\); IR (KBr) \(\nu _{\mathrm{max}}\): 2928, 2861, 1579, 1489, 1443, 1349, 1229, 1136, 1078, 948, 768, 713 \(\hbox {cm }^{- 1}\); \(^{1}\)H NMR (300 MHz, \(\hbox {CDCl}_{3})\): \(\delta \) 1.02–1.35 (m, 3H), 1.47–1.50 (m, 1H), 1.65–1.93 (m, 6H), 3.61–3.70 (m, 1H), 3.88 (dt, \(J = 12.8\), 4.8 Hz, 1H), 4.14–4.25 (m, 2H), 4.30–4.38 (m, 1H), 5.75 (d,\( J = 2.7\), Hz, 1H), 6.15 (t,\( J = 2.9\), Hz, 1H), 6.29 (s, 1H), 6.68 (d,\( J = 1.3\), Hz, 1H), 7.14 (dd,\( J = 8.3\), 4.6 Hz, 1H), 7.35 (d,\( J = 8.3\), Hz, 1H), 8.19 (d,\( J = 4.6\), Hz, 1H), 8.35 (d,\( J = 2.7\), Hz, 1H); \(^{13}\)C NMR (75 MHz, \(\hbox {CDCl}_{3})\) \(\delta \) 24.7, 25.4, 25.5, 32.4, 32.7, 44.4, 49.1, 51.1, 58.6, 105.9, 109.2, 120.1, 122.7, 123.7, 125.8, 142.6, 143.8, 144.5, 153.2 ppm; m / z (EI, 70 eV) 349 (27, \(\hbox {M}^{+})\), 227 (100), 198 (95), 149 (28), 119 (38), 105 (34), 78 (44), 55 (46%); Anal. Calcd for \(\hbox {C}_{19}\hbox {H}_{23}\hbox {N}_{7}\): C, 65.31; H, 6.63; N, 28.06. Found: C, 65.30; H, 6.64; N, 27.99%.

2-Phenyl-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazol-5-yl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine (5p)

White solid (318 mg, 84%); mp 166–168 \(^{\circ }\hbox {C}\); IR (KBr) \(\nu _{\mathrm{max}}\): 2956, 1597, 1491, 1361, 1295, 1211, 1175, 1088, 926, 839, 767, 703 \(\hbox {cm }^{- 1}\); \(^{1}\)H NMR (300 MHz, \(\hbox {CDCl}_{3})\): \(\delta \) 0.75 (s, 9H), 1.74 (s, 3H), 1.79 (s, 3H), 1.95 (s, 2H), 3.62 (d, \(J = 13.9\) Hz, 1H), 3.82–3.98 (m, 2H), 4.10–4.19 (m, 1H), 5.93 (m, 1H), 6.20 (t,\( J = 3.4\) Hz, 1H), 6.41 (s, 1H), 6.64 (t,\( J = 2.5\) Hz, 1H), 6.96–7.04 (m, 3H), 7.25–7.30 (m, 2H); \(^{13}\)C NMR (75 MHz, \(\hbox {CDCl}_{3})\) \(\delta \) 30.2, 30.3, 30.7, 31.6, 41.0, 45.8, 50.4, 53.8, 65.6, 105.0, 108.4, 120.2, 120.4, 122.6, 123.2, 129.6, 148.7, 155.0 ppm; m / z (EI, 70 eV) 378 (30, \(\hbox {M}^{+})\), 266 (47), 237 (13), 197 (100), 173 (14), 148 (11), 119 (44), 77 (23%), 57 (31); Anal. Calcd for \(\hbox {C}_{22}\hbox {H}_{30}\hbox {N}_{6}\): C, 69.81; H, 7.99; N, 22.20. Found: C, 69.82; H, 8.03; N, 22.23%.

2-(p-Tolyl)-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazol-5-yl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine (5q)

White solid (341 mg, 87%); mp 170–172 \(^{\circ }\hbox {C}\); IR (KBr) \(\nu _{\mathrm{max}}\): 2946, 1611, 1509, 1477, 1448, 1355, 1202, 1082, 1021, 827, 770, 719 \(\hbox {cm }^{- 1}\); \(^{1}\)H NMR (300 MHz, \(\hbox {CDCl}_{3})\): \(\delta \) 0.76 (s, 9H), 1.73 (s, 3H), 1.78 (s, 3H), 1.95 (s, 2H), 2.27 (s, 3 H), 3.54 (d, \(J = 13.9\) Hz, 1H), 3.81–3.95 (m, 2H), 4.05–4.14 (m, 1H), 5.92 (d,\( J = 2.5\) Hz, 1H), 6.20 (t,\( J = 3.2\) Hz, 1H), 6.34 (s, 1H), 6.64 (s, 1H), 6.93 (d, \(J = 8.4\) Hz, 2H), 7.07 (d, \(J = 8.2\) Hz, 2H); \(^{13}\)C NMR (75 MHz, \(\hbox {CDCl}_{3})\) \(\delta \) 20.6, 30.1, 30.4, 30.7, 31.6, 40.9, 46.0, 50.7, 53.8, 65.6, 104.9, 108.3, 120.1, 120.7, 123.4, 130.1, 132.2, 146.3, 155.0 ppm; m / z (EI, 70 eV) 392 (21, \(\hbox {M}^{+})\), 280 (39), 251 (10), 251 (100), 197 (9), 133 (41), 118 (12), 91 (18), 57 (27%); Anal. Calcd for \(\hbox {C}_{23}\hbox {H}_{32}\hbox {N}_{6}\): C, 70.37; H, 8.22; N, 21.41. Found: C, 70.40; H, 8.18; N, 21.43%.

2-(4-Methoxyphenyl)-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazol-5-yl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine (5r)

White solid (375 mg, 92%); mp 114–116 \(^{\circ }\hbox {C}\); IR (KBr) \(\nu _{\mathrm{max}}\): 2984, 1507, 1447, 1247, 1205, 1109, 1039, 976, 936, 832, 800, 718 \(\hbox {cm }^{- 1}\); \(^{1}\)H NMR (300 MHz, DMSO): \(\delta \) 0.67 (s, 9H), 1.69 (s, 3H), 1.70 (s, 3H), 1.91 (s, 2H), 3.57–3.77 (m, 6H), 3.94 (d,\( J = 8.6\) Hz, 1H), 5.85 (s, 1H), 6.03 (s, 1H), 6.42 (s, 1H), 6.71 (s, 1H), 6.84 (d, \(J = 7.2\) Hz, 2H), 7.01(d, \(J = 7.2\) Hz, 2H); \(^{13}\)C NMR (75 MHz, DMSO) \(\delta \) 28.9, 29.8, 30.2, 31.2, 45.0, 50.1, 53.0, 55.1, 65.5, 104.9, 107.6, 114.5, 119.8, 121.3, 123.6, 141.5, 154.5, 155.0 ppm; m / z (EI, 70 eV) 408 (13, \(\hbox {M}^{+})\), 296 (16), 227 (100), 184 (4), 149 (21), 104 (12), 57 (29%); Anal. Calcd for \(\hbox {C}_{23}\hbox {H}_{32}\hbox {N}_{6}\)O: C, 67.62; H, 7.90; N, 20.57; O, 3.92. Found: C, 67.60; H, 7.89; N, 20.55%.

General procedure for the synthesis of compounds 7a–i

1-(2-Bromoethyl)-1H-pyrrole-2-carbaldehyde 1a (202 mg, 1 mmol) and amines 6a–c (1 mmol) were taken in a 5-mL round-bottom flask and then stirred for 20 min to form the corresponding iminium intermediates. Methanol (4 mL) was then added to dissolve the solid. Sodium azide (65 mg, 1 mmol) and isocyanides 4a–c (1 mmol) were added, and the reaction mixture was stirred at room temperature for 24 h. After completion of the reaction as indicated by TLC, the solvent was removed under reduced pressure and the reaction mixture was extracted with ethyl acetate (\(2 \times 30\) mL). The organic phase was washed with brine (30 mL) and dried over anhydrous \(\hbox {Na}_{2}\hbox {SO}_{4}\). The crude products were purified by column chromatography through a silica gel column using ethyl acetate and hexane (30%) as eluents to afford the desired products 7a–i.

1-(1-(tert-Butyl)-1H-tetrazol-5-yl)-N-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-amine (7a)

White solid (192 mg, 57%); mp 237–239 \(^{\circ }\hbox {C}\) (Decompose); IR (KBr) \(\nu _{\mathrm{max}}\): 3245, 2990, 1601, 1492, 1448, 1253, 1067, 857, 754, 713 \(\hbox {cm }^{- 1}\); \(^{1}\)H NMR (300 MHz, DMSO): \(\delta \) 1.68 (s, 9H), 3.10–3.30 (m, 1H), 3.40–3.60 (m, 1H), 4.10–4.30 (m, 2H), 5.38 (s, 1H), 5.84 (s, 1H), 6.00 (t, \(J = 2.9\) Hz, 1H), 6.65 (t, \(J = 7.1\) Hz, 1H), 6.75 (s, 1H), 6.84–6.89 (m, 3H), 7.08 (t, \(J = 7.8\) Hz, 2H); \(^{13}\)C NMR (75 MHz, DMSO) \(\delta \) 29.9, 44.2, 50.3, 57.7, 61.8, 104.6, 108.4, 113.4, 118.6, 119.4, 126.0, 128.7, 147.6, 155.0 ppm; m / z (EI, 70 eV) 337 (76, \(\hbox {M}^{+})\) 281 (16), 211 (100), 188 (16), 161 (32), 133 (40), 119 (65), 105 (62), 92 (42), 77 (57), 57 (37%); Anal. Calcd for \(\hbox {C}_{18}\hbox {H}_{23}\hbox {N}_{7}\): C, 64.07; H, 6.87; N, 29.06. Found: C, 64.11; H, 6.85; N, 29.10%.

1-(1-Cyclohexyl-1H-tetrazol-5-yl)-N-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-amine (7b)

White solid (185 mg, 51%); mp 235–237 \(^{\circ }\hbox {C}\) (Decompose); IR (KBr) \(\nu _{\mathrm{max}}\): 3212, 2934, 2856, 1602, 1492, 1448, 1312, 1080, 894, 749, 718, 683 \(\hbox {cm }^{- 1}\); \(^{1}\)H NMR (300 MHz, DMSO): \(\delta \) 0.90–1.25 (m, 2H), 1.30–1.50 (m, 3H), 1.55–1.90 (m, 5H), 3.10 (dt,\( J = 11.1\), 3.9 Hz, 1H), 3.43 (d, \(J = 11.1\) Hz, 1H), 4.10–4.40 (m, 2H), 4.63 (t, \(J = 11.1\) Hz, 1H), 5.29 (s, 1H), 5.69 (s, 1H), 6.01 (t, \(J = 3.0\) Hz, 1H), 6.66 (t, \(J = 7.2\) Hz, 1H), 6.70–6.90 (m, 3H), 7.10 (t, \(J = 9.2\) Hz, 3H); \(^{13}\)C NMR (75 MHz, DMSO) \(\delta \) 24.5, 24.6, 24.8, 31.8, 32.3, 44.6, 50.9, 57.2, 57.3, 104.6, 108.5, 112.8, 118.6, 120.0, 124.5, 128.9, 146.9, 153.4 ppm; m / z (EI, 70 eV) 363 (40, \(\hbox {M}^{+})\) 316 (7), 256 (13), 231 (13), 211 (100), 133 (25), 119 (77), 106 (50), 92 (44), 77 (58), 55 (44%); Anal. Calcd for \(\hbox {C}_{20}\hbox {H}_{25}\hbox {N}_{7}\): C, 66.09; H, 6.93; N, 26.98. Found: C, 66.12; H, 6.90; N, 26.99%.

N-Phenyl-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazol-5-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-amine (7c)

White solid (236 mg, 60%); mp 178–180 \(^{\circ }\hbox {C}\); IR (KBr) \(\nu _{\mathrm{max}}\): 3330, 2955, 1602, 1492, 1401, 1255, 1113, 1071, 805, 750, 711, 655 \(\hbox {cm }^{- 1}\); \(^{1}\)H NMR (300 MHz, DMSO): \(\delta \) 0.70 (s, 9H), 1.76 (s, 6H), 1.96 (d,\( J = 14.9\) Hz, 1H), 2.15 (brds, 1H), 3.19 (brds, 1H), 3.48 (d,\( J = 11.3\) Hz, 1H), 4.16 (brds, 2H), 5.38 (s, 1H), 5.86 (s, 1H), 5.99 (s, 1H), 6.64 (t, \(J = 7.1\) Hz, 1H), 6.75 (s, 1H), 6.80–7.00 (m, 3H), 7.07 (t, \(J = 7.4\) Hz, 2H); \(^{13}\)C NMR (75 MHz, DMSO) \(\delta \) 29.5, 30.3, 31.3, 43.8, 49.8, 53.1, 57.0, 65.6, 104.7, 108.2, 113.5, 118.6, 119.4, 125.9, 128.6, 147.4, 155.3 ppm; m / z (EI, 70 eV) 393 (24, \(\hbox {M}^{+})\) 287 (54), 211 (76), 161 (39), 133 (52), 119 (79), 105 (85), 92 (51), 77 (81), 57 (100%); Anal. Calcd for \(\hbox {C}_{22}\hbox {H}_{31}\hbox {N}_{7}\): C, 67.15; H, 7.94; N, 24.91. Found: C, 67.17; H, 7.93; N, 24.95%.

N-(1-(1-(tert-Butyl)-1H-tetrazol-5-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-4-methylbenzenesulfonamide (7d)

White solid (307 mg, 74%); mp 201–203 \(^{\circ }\hbox {C}\) (Decompose); IR (KBr) \(\nu _{\mathrm{max}}\): 3189, 2936, 1598, 1485, 1453, 1418, 1355, 1241, 1162, 1094, 895, 782, 744, 666 \(\hbox {cm }^{- 1}\); \(^{1}\)H NMR (300 MHz, DMSO): \(\delta \) 1.76 (s, 9H), 2.39 (s, 3H), 3.73 (brds, 2H), 3.91 (brds, 2H), 5.59 (s, 1H), 5.98 (t, \(J = 3.2\) Hz, 1H), 6.06 (s, 1H), 6.66 (t, \(J = 1.8\) Hz, 1H), 7.41 (d, \(J = 8.1\) Hz, 2H), 7.70 (d, \(J = 8.0\) Hz, 2H), 9.13 (s, 1H); \(^{13}\)C NMR (75 MHz, DMSO) \(\delta \) 21.1, 30.1, 43.9, 49.4, 52.3, 62.3, 104.8, 108.4, 119.6, 124.4, 127.6, 129.6, 135.8, 143.6, 153.8 ppm; m / z (EI, 70 eV) 415 (6, \(\hbox {M}^{+})\) 287 (78), 176 (76), 148 (18), 106 (100), 91 (33), 57 (28%); Anal. Calcd for \(\hbox {C}_{19}\hbox {H}_{25}\hbox {N}_{7}\hbox {O}_{2}\)S: C, 54.92; H, 6.06; N, 23.60; O, 7.70; S, 7.72. Found: C, 54.95; H, 6.10; N, 23.58; S, 7.76%.

N-(1-(1-Cyclohexyl-1H-tetrazol-5-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-4-methylbenzenesulfonamide (7e)

White solid (300 mg, 68%); mp 205–207 \(^{\circ }\hbox {C}\) (Decompose); IR (KBr) \(\nu _{\mathrm{max}}\): 3040, 2927, 2850, 1598, 1445, 1335, 1303, 1160, 1092, 1027, 925, 810, 743, 660 \(\hbox {cm}^{- 1}\); \(^{1}\)H NMR (300 MHz, \(\hbox {CDCl}_{3})\): \(\delta \) 1.22–1.40 (m, 3H), 1.70–1.96 (m, 7H), 2.44 (s, 3H), 2.93 (brds, 1H), 3.50 (brds, 1H), 3.99 (brds, 2H), 4.10–4.30 (m, 1H), 5.67 (s, 1H), 5.74 (s, 1H), 6.12 (s, 1H), 6.60 (s, 1H), 7.07 (s, 1H), 7.28 (d, \(J = 7.6\) Hz, 2H), 7.71 (d, \(J = 7.5\) Hz, 2H); \(^{13}\)C NMR (75 MHz, \(\hbox {CDCl}_{3})\) \(\delta \) 21.6, 24.9, 25.4, 25.6, 32.5, 43.9, 50.6, 56.6, 58.5, 106.5, 109.5, 119.9, 122.4, 127.9, 129.7, 135.3, 144.4, 152.4 ppm; m / z (EI, 70 eV) 441 (7, \(\hbox {M}^{+})\) 365 (29), 258 (37), 213 (17), 176 (81), 148 (24), 135 (30), 119 (24), 106 (100), 91 (47), 55 (44%); Anal. Calcd for \(\hbox {C}_{21}\hbox {H}_{27}\hbox {N}_{7}\hbox {O}_{2}\)S: C, 57.12; H, 6.16; N, 22.21; O, 7.25; S, 7.26. Found: C, 57.11; H, 6.18; N, 22.19; S, 7.28%.

4-Methyl-N-(1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazol-5-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)benzenesulfonamide (7f)

White solid (353 mg, 75%); mp 117–119 \(^{\circ }\hbox {C}\); IR (KBr) \(\nu _{\mathrm{max}}\): 3073, 2954, 1597, 1452, 1399, 1336, 1298, 1163, 1093, 1029, 814, 776, 719, 659 \(\hbox {cm}^{- 1}\); \(^{1}\)H NMR (300 MHz, \(\hbox {CDCl}_{3})\): \(\delta \) 0.90 (s, 9H), 1.87 (s, 3H), 1.89 (s, 3H), 2.08 (m, 2H), 2.41 (s, 3H), 2.52 (brd, 1H), 3.80–3.88 (m, 1H), 4.01–4.09 (m, 2H), 5.74 (d, \(J = 2.2\) Hz, 1H), 6.08 (t, \(J = 3.1\) Hz, 1H), 6.17 (s, 1H), 6.56 (s, 1H), 6.91 (s, 1H), 7.26 (d, \(J = 7.9\) Hz, 2H), 7.72 (d, \(J = 8.0\) Hz, 2H); \(^{13}\)C NMR (75 MHz, \(\hbox {CDCl}_{3})\) \(\delta \) 21.6, 30.4, 30.6, 30.9, 31.8, 43.4, 48.5, 50.5, 56.0, 106.1, 108.9, 120.1, 123.6, 128.2, 129.6, 135.2, 144.2 153.7 ppm; m / z (EI, 70 eV) 471 (4, \(\hbox {M}^{+})\) 287 (16), 204 (17), 176 (53), 106 (100), 57 (50%); Anal. Calcd for \(\hbox {C}_{23}\hbox {H}_{33}\hbox {N}_{7}\hbox {O}_{2}\)S: C, 58.57; H, 7.05; N, 20.79; O, 6.78; S, 6.80. Found: C, 58.60; H, 7.07; N, 20.80; S, 6.77%.

N-(1-(1-(tert-Butyl)-1H-tetrazol-5-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)benzamide (7g)

White solid (266 mg, 73%); mp 228–230 \(^{\circ }\hbox {C}\) (Decompose); IR (KBr) \(\nu _{\mathrm{max}}\): 3231, 2986, 2940, 2876, 1661, 1512, 1478, 1311, 1232, 1077, 951, 901, 811, 707 \(\hbox {cm }^{- 1}\); \(^{1}\)H NMR (300 MHz, DMSO): \(\delta \) 1.56 (s, 9H), 2.54 (s, 1H), 3.63 (s, 1H), 4.19 (brds, 2H), 5.36 (s, 1H), 6.19 (s, 1H), 6.79 (s, 1H), 7.41 (t, \(J = 7.2\) Hz, 2H), 7.49 (t, \(J = 6.5\) Hz, 1H), 7.58 (d, \(J = 7.1\) Hz, 2H), 9.91 (s, 1H); \(^{13}\)C NMR (75 MHz, DMSO) \(\delta \) 29.5, 43.9, 51.6, 57.3, 63.2, 104.2, 108.6, 119.6, 125.3, 127.2, 128.3, 131.5, 133.3, 153.4, 165.4 ppm; m / z (EI, 70 eV) 365 (2, \(\hbox {M}^{+})\) 308 (4), 262 (6), 244 (87), 215 (13), 188 (30), 161 (48), 146 (16), 119 (34), 105 (100), 77 (55), 57 (20%); Anal. Calcd for \(\hbox {C}_{19}\hbox {H}_{23}\hbox {N}_{7}\)O: C, 62.45; H, 6.34; N, 26.83; O, 4.38. Found: C, 62.44; H, 6.31; N, 26.80; %.

N-(1-(1-Cyclohexyl-1H-tetrazol-5-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)benzamide (7h)

White solid (274 mg, 70%); mp 203–205 \(^{\circ }\hbox {C}\) (Decompose); IR (KBr) \(\nu _{\mathrm{max}}\): 3218, 2932, 2857, 1678, 1515, 1486, 1448, 1270, 1077, 1004, 909, 787, 697, 670 \(\hbox {cm }^{- 1}\); \(^{1}\)H NMR (300 MHz, DMSO): \(\delta \) 0.88–1.84 (m, 9H), 2.33 (d, \(J = 8.9\) Hz, 1H), 3.44–3.57 (m, 2H), 4.26 (s, 2H), 4.49 (s, 1H), 5.40 (s, 1H), 5.99 (s, 1H), 6.04 (s, 1H), 6.84 (s, 1H), 7.41 (t, \(J = 7.1\) Hz, 2H), 7.51 (t, \(J = 6.8\) Hz, 1H), 7.60 (d, \(J = 7.0\) Hz, 2H), 9.92 (s, 1H); \(^{13}\)C NMR (75 MHz, DMSO) \(\delta \) 24.6, 25.0, 25.2, 31.5, 31.7, 44.7, 52.1, 56.1, 57.9, 104.8, 108.8, 120.0, 123.5, 127.2, 128.3, 131.6, 133.3, 152.9, 164.9 ppm; m / z (EI, 70 eV) 391 (2, \(\hbox {M}^{+})\) 368 (3), 321 (5), 287 (93), 270 (86), 241 (15), 213 (18), 189 (22), 161 (100), 146 (64), 119 (36), 105 (92%); Anal. Calcd for \(\hbox {C}_{21}\hbox {H}_{25}\hbox {N}_{7}\)O: C, 64.43; H, 6.44; N, 25.05; O, 4.09. Found: C, 64.40; H, 6.47; N, 25.03; %.

N-(1-(1-(2,4,4-Trimethylpentan-2-yl)-1H-tetrazol-5-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)benzamide (7i)

White solid (274 mg, 65%); mp 179–181 \(^{\circ }\hbox {C}\); IR (KBr) \(\nu _{\mathrm{max}}\): 3194, 2952, 1659, 1524, 1482, 1370, 1313, 1239, 1116, 1077, 951, 809, 770, 709 \(\hbox {cm }^{- 1}\); \(^{1}\)H NMR (300 MHz, DMSO): \(\delta \) 0.68 (s, 9H), 1.66 (s, 6H), 1.90 (d, \(J = 14.8\) Hz, 1H), 2.02 (d, \(J = 14.8\) Hz, 1H), 3.33 (brds, 2H), 4.18 (brds, 2H), 5.41 (s, 1H), 6.03 (t, \(J = 2.9\) Hz, 1H), 6.28 (s, 1H), 6.79 (s, 1H), 7.40 (t, \(J = 7.6\) Hz, 2H), 7.49 (t, \(J = 7.2\) Hz, 1H), 7.61 (d, \(J = 7.2\) Hz, 2H); \(^{13}\)C NMR (75 MHz, \(\hbox {CDCl}_{3})\) \(\delta \) 28.1, 29.9, 30.5, 31.2, 43.2, 51.1, 54.0, 56.7, 66.7, 104.5, 108.2, 119.7, 124.7, 127.3, 128.2, 131.4, 133.3, 153.7 165.3 ppm; m / z (EI, 70 eV) 421 (3, \(\hbox {M}^{+})\) 300 (7), 280 (9), 262 (12), 240 (24), 188 (82), 161 (61), 146 (12), 119 (38), 97 (55), 77 (48), 57 (100%); Anal. Calcd for \(\hbox {C}_{23}\hbox {H}_{31}\hbox {N}_{7}\)O: CC, 65.53; H, 7.41; N, 23.26; O, 3.80. Found: C, 65.55; H, 7.40; N, 23.22; %.

Benzoyl(3,4-dihydropyrrolo[1,2-a]pyrazin-2-ium-2-yl)amide (8)

Yellow solid (220 mg, 92%); mp 172–174 \(^{\circ }\hbox {C}\) (Decompose); IR (KBr) \(\nu _{\mathrm{max}}\): 3074, 3019, 2945, 1727, 1661, 1584, 1546, 1474, 1409, 1317, 1287, 1059, 1018, 884, 698 \(\hbox {cm }^{- 1}\); \(^{1}\)H NMR (300 MHz, DMSO): \(\delta \) 4.27 (t, \(J = 6.7\) Hz, 2H), 4.41 (t, \(J = 6.7\) Hz, 2H), 6.37 (dd,\(J = 3.8\), 2.4 Hz, 1H), 6.87 (dd,\(J = 3.9\), 1.1 Hz, 1H), 7.32–7.38 (m, 4H), 7.96–7.99 (m, 2H),9.48 (s, 1H); \(^{13}\)C NMR (75 MHz, DMSO) \(\delta \) 42.6, 53.4, 112.1, 117.8, 122.4, 127.4, 127.5, 128.9, 129.4, 138.5, 141.2, 168.4 ppm; m / z (EI, 70 eV) 239 (93, \(\hbox {M}^{+})\) 162 (10), 119 (100), 105 (61), 77 (75), 51 (29%); Anal. Calcd for \(\hbox {C}_{14}\hbox {H}_{13}\hbox {N}_{3}\)O: C, 70.28; H, 5.48; N, 17.56; O, 6.69. Found: C, 70.30; H, 5.47; N, 17.55; %.