Synthesis of decahydropyrrolo[1,2-a]tetrazolo[1,5-d]pyrazines via Strecker reaction and intramolecular [3+2] cycloaddition

Abstract

This paper reports an efficient two-step method for synthesizing a series of new (5aS,10R)-10-aryl-5,5a,6,7,8,10-hexahydropyrrolo[1,2-a]tetrazolo[1,5-d]pyrazines by a catalyst-free three-component Strecker reaction followed by an intramolecular [3+2] cycloaddition. The first step involved three-component coupling of aldehydes, (S)-2-(azidomethyl)pyrrolidine and potassium cyanide in presence of water to form (R)-2-((S)-2-(azidomethyl)pyrrolidin-1-yl)-2-phenylacetonitriles (3a–3v). In the next step products (3a–3v) underwent intramolecular [3+2] cycloaddition on heating to form (5aS,10R)-10-aryl-5,5a,6,7,8,10-hexahydropyrrolo[1,2-a]tetrazolo[1,5-d]pyrazines (4a–4v). The present methodology is cost-effective, operationally simple, and applicable for various aromatic, aliphatic and heterocyclic aldehydes, and gives desired products in satisfactory yields and diastereoselectivities. A proposed mechanism for synthesis of 3a and 4a is reported.

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Introduction

Multicomponent Strecker reactions¹ are excellent reactions for the synthesis of α-amino nitriles.^2,3 These α-aminonitriles have gained considerable attention over the past few years, in particular because the α-aminonitrile functionality acts as an intermediate in the synthesis of pharmaceutically crucial chiral amino acids and their derivatives,⁴ ligands, peptides, and natural products.⁵ Developing a simple, efficient, and cost-effective method for synthesizing α-aminonitriles has become increasingly crucial. Numerous efforts have resulted in the development of highly efficient methods for synthesizing α-aminonitriles.^6–8 Dipolar cycloaddition reactions have been the cornerstone of heterocyclic chemistry for the previous decades.⁹ The Huisgen 1,3-dipolar cycloaddition¹⁰ between an azide and a nitrile is the most favourable and powerful mechanism for constructing a tetrazole moiety.^11a Many strategies have been developed for synthesizing tetrazoles; the conventional synthesis of 5-substituted 1H-tetrazoles through the [3+2] cycloaddition of an azide with the corresponding nitrile was first reported by Hantzsch and Vagt.^11b Sharpless et al. later reported the innovative formation of fused tetrazoles and 1H-tetrazoles, created by using Zn^II salt.^11c,d Pizzo et al. reported a TBAF catalyzed [3+2] cycloaddition,^11e and Yamamoto et al. studied a Cu₂O-catalyzed azide–nitrile cycloaddition.^11f A highly efficient iron-catalyzed synthesis of 5-substituted 1H-tetrazole was demonstrated by Bolm et al.^11g Pitchumani et al. studied a CoY zeolite-catalyzed 5-substituted 1H-tetrazole;^11h Stephen et al. reported a facile Lewis acid-mediated synthesis of bicyclic tetrazoles;¹¹ⁱ and Smith et al. investigated a tricyclic fused tetrazole created by thermal cyclization.^11j Mohapatra and co-workers described synthesis of tricyclic fused tetrazoles from α-amino acid derivatives following ‘click’ chemistry.^11k Finally, Frejd et al. developed tricyclic fused tetrazoles from allylic bromides generated by the DiazAll reaction.^11l Tetrazoles have gained considerable attention from organic chemists because they can act as metabolically stable surrogates for the carboxylic acid group¹² and as precursors in various nitrogen-containing heterocycles,¹³ and they are useful synthons in synthetic organic chemistry (Fig. 1).^14a

Fig. 1 Structure of some biologically active compounds containing tetrazole moiety.

Various biologically active compounds incorporating the tetrazole moiety have been developed. For example, compound (A), an angiotensin II antagonist, has been used to treat hypertension;^14b,c compound (B) has been extensively used in models for anxiety;^14d,e and compound (C) has shown affinity toward benzodiazepine receptors.^14f Moreover, tetrazoles have antibacterial¹⁵ and anticancer¹⁶ activities and exert protective effects against heart disease¹⁷ and neurodegenerative disorder.¹⁸

Results and discussion

To design new fused heterocycles,¹⁹ we developed a simple, efficient, and cost-effective two-step strategy. The first step involved a three-component reaction of benzaldehyde, (S)-2-(azidomethyl)pyrrolidine, and KCN in the presence of water to form (R)-2-((S)-2-(azidomethyl)pyrrolidin-1-yl)-2-phenylacetonitrile (3a). The second step involved the catalyst-free intramolecular [3+2] cycloaddition of 3a to form (5aS,10R)-10-phenyl-5,5a,6,7,8,10-hexahydropyrrolo[1,2-a]tetrazolo[1,5-d]pyrazine (4a). The first step involved using a readily available cyanide source²⁰ and water as the solvent to form aminonitrile (3a); this is an alternative method for the catalyst-free Strecker reaction. The second step enabled the fused tetrazole moiety, created through the catalyst-free intramolecular [3+2] cycloaddition. First, we prepared (S)-2-(azidomethyl)pyrrolidine (2a) by using the commercially available L-proline and following a previously reported procedure.²¹

To establish the optimal experimental conditions for the synthesis of 3a, we use benzaldehyde, (S)-2-(azidomethyl)pyrrolidine (2a) and KCN as a model substrate. Table 1 summarizes the results, which indicated that the reaction temperature, solvents, and the loading of potassium cyanide influenced the product yields of the Strecker reaction. The most satisfactory condition was heating the mixture of benzaldehyde (1 eq.), (S)-2-(azidomethyl)pyrrolidine (1.1 eq.), and potassium cyanide (1.2 eq.) at 70 °C in the presence of water for 8 h (Table 1, entry 18). Initially, several organic solvents were screened for the three-component Strecker reaction of a model substrate by using 1.5 eq. of potassium cyanide: toluene at 111 °C afforded 3a and 4a in 28% and 1% yields, respectively; (Table 1, entry 1), dichloromethane at 40 °C afforded 3a and 4a in 24% and 1.5% yields, respectively; (Table 1, entry 2), acetonitrile at 80 °C afforded 3a and 4a in 17% and 1% yields, respectively; (Table 1, entry 3), and methanol at 65 °C afforded only product 3a in 23% yield (Table 1, entry 4). In addition, we screened solvents such as dioxane, dimethylformamide, and dimethylsulfoxide at 101, 140 and 145 °C, respectively; however, no product was formed (Table 1, entries 5–7). We then used water as the solvent at 100 °C, which afforded 3a and 4a in 69% and 1.3% yields, respectively (Table 1, entry 8). Therefore, we heated the reaction mixture at 100, 90, and 80 °C, which produced 3a in 76%, 81%, and 86% yields and 4a in 1.5%, 2%, and 1.5% yields, respectively (Table 1, entries 9–11). According to these results, as the temperature of the reaction decreased, the yields of the corresponding products increased. Therefore, we heated the reaction mixture of benzaldehyde (1 eq.), (S)-2-(azidomethyl)pyrrolidine (1.1 eq.), and potassium cyanide (1.5 eq.) at 70 °C for 8 h, which produced 3a and 4a in 93% and 1.8% yields, respectively (Table 1, entry 12). In addition, we heated the reaction mixture at 60 °C, 50 °C, 40 °C, and room temperature; however, increase in the reaction time and decrease in the product yields were observed (Table 1, entries 13–16). To further investigate the effect of the amount of potassium cyanide during the reaction, we conducted the same reaction by using 1.0 and 1.2 eq. of potassium cyanide, which afford 3a in 89% and 93% yields and 4a in 1.8% and 2.0% yields, respectively (Table 1, entries 17, 18). Therefore, heating 1.0 eq. of benzaldehyde, 1.1 eq. of (S)-2-(azidomethyl)pyrrolidine, and 1.2 eq. of potassium cyanide at 70 °C in the presence of water was the optimal condition for the Strecker reaction.

Table 1 Optimisation studies for synthesis of aminonitrile 3a^a

Entry	Solvent	KCN (eq.)	Temp. (°C)	Time (h)	3a^b (%)	4a^b (%)
a Reaction conditions: benzaldehyde (1.0 eq.), (S)-2-(azidomethyl)pyrrolidine (1.1 eq.) and potassium cyanide was heated in different solvent at different temperature in screw caped vial.b Isolated yields after flash chromatography.c dr: 86 : 14 determined by ^1H NMR spectroscopy of crude reaction mixture.
1	Toluene	1.5	111	30	28	1
2	DCM	1.5	40	36	24	1.5
3	CH3CN	1.5	80	40	17	1
4	CH3OH	1.5	65	22	23	0
5	Dioxane	1.5	101	32	Traces	0
6	DMF	1.5	140	20	Traces	0
7	DMSO	1.5	145	25	Traces	0
8	H2O	1.5	110	10	69	1.3
9	H2O	1.5	100	8	76	1.5
10	H2O	1.5	90	8	81	2
11	H2O	1.5	80	8	86	1.5
12^c	H2O	1.5	70	8	93	1.8
13	H2O	1.5	60	10	87	1
14	H2O	1.5	50	13	76	0
15	H2O	1.5	40	18	69	0
16	H2O	1.5	RT	34	64	0
17	H2O	1.0	70	8	89	1.8
18^c	H2O	1.2	70	8	93	2

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After determining the optimized conditions for the synthesis of 3a, we developed the intramolecular [3+2] azide–nitrile cycloaddition to obtain 4a. The optimization studies for the synthesis of 3a, in some reactions, we obtained some amounts of 4a. Therefore, we screened various solvents for the intramolecular [3+2] azide–nitrile cycloaddition to obtain the tricyclic product. First, we heated 3a in water at 100 °C, which produced 4a in a 20% yield and 88 : 12 diastereoselectivity (Table 2, entry 1). We then screened toluene, acetonitrile, dimethyl sulfoxide, and dimethylformamide at 111, 80, 160, and 150 °C, which afforded 4a in 58%, 63%, 87%, and 94% yields and 86 : 14, 89 : 11, 90 : 10, 91 : 9 diastereoselectivities respectively (Table 2, entries 2–5). Therefore, heating 3a in the presence of dimethylformamide without any catalyst was the optimal condition for the intramolecular [3+2] azide–nitrile cycloaddition.

Table 2 Optimisation studies for synthesis of tricyclic fused heterocycle 4a^a

Entry	Solvent	T (°C)	Time (h)	4a^b (%)	dr^c
a Reaction conditions: (0.2 mmol) of (R)-2-((S)-2-(azidomethyl)pyrrolidin-1-yl)-2-phenylacetonitriles (3a) was heated in various solvent at different temperature in oven dried, argon flushed, screw caped sealed tube.b Isolated yields after flash chromatography.c Diastereomeric ratio determined by ^1H NMR spectroscopy of crude reaction mixture.
1	H2O	100	12	20	88 : 12
2	Toluene	111	24	58	86 : 14
3	CH3CN	80	72	63	89 : 11
4	DMSO	160	16	87	90 : 10
5	DMF	150	14	94	91 : 9

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Under the optimized reaction conditions, the Strecker reaction and the intramolecular [3+2] azide–nitrile cycloaddition was investigated to illustrate the efficiency of this strategy; Table 3 outlines the obtained results. Various aromatic, aliphatic, and heterocyclic aldehydes were explored. Substituted benzaldehydes bearing electron-donating and electron-withdrawing groups at o-, m-, and p-positions, such as methyl, methoxy, fluoro, chloro, bromo, and cyano groups, generated the corresponding products 3a–3p in satisfactory to excellent yields and diastereoselectivities. Products 3a–3p underwent the intramolecular [3+2] cycloaddition to form the corresponding 4a–4p in satisfactory to excellent yields and diastereoselectivities (Table 3, entries 1–16). 2,4,6-Trimethoxybenzaldehyde reacted smoothly and produced an excellent yield and satisfactory diastereoselectivity of 3q; 3q then underwent the intramolecular [3+2] cycloaddition to form tricyclic 4q in an excellent yield and satisfactory distereoselectivity (Table 3, entry 17). Although 1-napthaldehyde is bulky, it reacted well under optimized conditions and produced 3r in an excellent yield and satisfactory diastereoselectivity; 3r then underwent the intramolecular [3+2] cycloaddition to form 4r in an excellent yield and satisfactory diastereoselectivity (Table 3, entry 18). Aliphatic aldehydes such as isovaleraldehyde and dihydrocenamaldehyde exhibited high reactivity under the optimized reaction conditions and generated 3s and 3t in satisfactory yields and diastereoselectivities; 3s and 3t then underwent the intramolecular [3+2] cycloaddition to form 4s and 4t in satisfactory yields and diastereoselectivities (Table 3, entries 19–20). Heterocyclic aldehydes such as 3-thienylcarbaldehyde and bulky 3-thionapthaldehyde showed satisfactory reactivities under the optimized reaction conditions and generated 3u and 3v, in satisfactory diastereoselectivities and excellent yields; 3u and 3v then underwent the intramolecular [3+2] cycloaddition to form 4u and 4v in excellent yields and satisfactory distereoselectivities (Table 3, entry 21–22). The electronic properties of the substituents on the phenyl ring did not affect the yields of the corresponding products. Due to inseparable diastereomeric mixture of products 3a–3v by flash chromatography we carry forward these products to next step [3+2] cycloaddition to form products 4a–4v. The product 3a was confirmed using ¹H NMR, ¹³C NMR, IR, and mass spectrometry. In the ¹H NMR (CDCl₃) spectrum of 3a, a methine proton (N–CH–) at δ 5.31 ppm was observed as a characteristic singlet; the ¹³C NMR spectrum peak at δ 116.4 ppm and the IR spectrum band at 2100 cm⁻¹ corresponded to the nitrile functionality of 3a and the characteristic ion at m/z = 241 was attributed to the [M]⁺ ion peak in the mass spectrum (EI). The product 4a was recrystallized and confirmed using X-ray diffraction analysis of monocrystal, which is clarified that newly formed stereocenter exhibited an (R) configuration. From X-ray study (Fig. 2), we assigned the absolute configuration of major and minor diastereomers as shown in Scheme 1.

Table 3 Synthesis of 3a–3v^a and 4a–4v^b via KCN/H₂O mediated Strecker reaction followed by intramolecular [3+2] cycloaddition

Entry	R	Products^a (dr)^d	Yield^c (%)	Products^b (dr)^d	Yield^c (%)
a Reaction conditions: aldehyde (1.0 eq.), (S)-2-(azidomethyl)pyrrolidine (1.1 eq.), KCN (1.2 eq.) and 0.1 mL water heated at 70 °C in screw caped vial.b Aminonitriles (1 eq.) in 2 mL dimethylformamide were heated at140–150 °C in screw caped sealed tube.c Isolated yields after flash chromatography.d Diastereomeric ratio determined by ^1H NMR spectroscopy of crude reaction mixture.
1	C6H5	3a (86 : 14)	93	4a (91 : 9)	94
2	o-CH3C6H4	3b (72 : 28)	88	4b (96 : 4)	81
3	m-CH3C6H4	3c (70 : 30)	90	4c (91 : 9)	80
4	p-CH3C6H4	3d (79 : 21)	91	4d (89 : 11)	88
5	m-CH3OC6H4	3e (86 : 14)	89	4e (91 : 9)	89
6	p-CH3OC6H4	3f (76 : 24)	87	4f (92 : 8)	86
7	o-FC6H4	3g (72 : 28)	90	4g (77 : 23)	90
8	m-FC6H4	3h (82 : 18)	89	4h (91 : 9)	81
9	p-FC6H4	3i (86 : 14)	90	4i (95 : 5)	90
10	o-ClC6H4	3j (67 : 33)	87	4j (87 : 13)	77
11	m-ClC6H4	3k (92 : 8)	84	4k (90 : 10)	91
12	p-ClC6H4	3l (94 : 6)	89	4l (96 : 4)	93
13	o-BrC6H4	3m (60 : 40)	90	4m (88 : 12)	71
14	m-BrC6H4	3n (93 : 7)	91	4n (94 : 6)	92
15	m-CNC6H4	3o (90 : 10)	91	4o (98 : 2)	91
16	p-CNC6H4	3p (97 : 03)	92	4p (99 : 1)	93
17	2,4,6-(CH3O)3C6H2	3q (70 : 30)	93	4q (71 : 29)	88
18	1-Naphthyl	3r (70 : 30)	90	4r (71 : 29)	91
19	(CH3)2CHCH2	3s (93 : 07)	91	4s (95 : 5)	81
20	C6H5(CH2)2	3t (75 : 25)	88	4t (78 : 22)	87
21	3-Thienyl	3u (82 : 18)	91	4u (82 : 18)	88
22	Benzothiophen-3-yl	3v (74 : 26)	89	4v (80 : 20)	89

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Scheme 1 Separation and identification of diastereomers.

Further structure of major diastereomer characterized using ¹H NMR, ¹³C NMR, IR, and mass spectrometry. In the ¹H NMR (CDCl₃) spectrum of major diastereomer, a methine proton (N–CH–) at δ 4.60 ppm was observed as a characteristic singlet, in the ¹³C NMR spectrum, peak at δ 154.32 ppm corresponded to the carbon atom of the tetrazole ring, and the characteristic ion at m/z = 241 was attributed to the [M]⁺ ion peak in its mass spectrum (EI). Structure of minor diastereomer identified using ¹H NMR, ¹³C NMR and IR. In the ¹H NMR (CDCl₃) spectrum of minor diastereomer a methine proton (N–CH–) at δ 5.00 ppm was observed as a characteristic singlet, and in the ¹³C NMR spectrum, peak at δ 153.06 ppm corresponded to the carbon atom of the tetrazole ring.

A plausible reaction mechanism for the synthesis of 3a and 4a is outlined in Scheme 2. Benzaldehyde (1a) reacted with (S)-2-(azidomethyl)pyrrolidine (2a) to form iminium ion, ‘re-face’ attack of cyanide on electron deficient carbon atom of iminium ion to form 3a, which is underwent intramolecular [3+2] cycloaddition on heating to form 4a.

Scheme 2 Proposed reaction mechanism for synthesis of 3a and 4a.

To check safety, we studied Strecker reaction using 2-azidoethanamine (molecular weight: 86.09). It is safe to work with low molecular weight azide starting material, no any explosion was observed during course of reaction

Fig. 2 Crystal structure of (5aS,10R)-10-phenyl-5,5a,6,7,8,10-hexahydropyrrolo[1,2-a]tetrazolo[1,5-d]pyrazine (CCDC: 1041454) (major diastereomer, as structure shown in Scheme 1).

Conclusion

In summary, we developed a simple, efficient and catalyst-free synthesis of (5aS,10R)-10-phenyl-5,5a,6,7,8,10-hexahydropyrrolo[1,2-a]tetrazolo[1,5-d]pyrazines through a three-component Strecker reaction, followed by an intramolecular [3+2] cycloaddition. The process is applicable for a wide range of aromatic, aliphatic, and heterocyclic aldehydes. Because the methodology does not involve using expensive starting materials, it is attractive for industrial and pharmaceutical applications.

Experimental section

General experimental procedure for KCN/H₂O mediated Strecker reaction

A mixture of aldehyde (1.0 mmol), (S)-2-(azidomethyl)pyrrolidine (1.1 mmol), KCN (1.2 mmol) and H₂O (100 μL) in screw caped vial was stirred for 6–8 h at 70 °C. After completion of the reaction (monitored by TLC), the mixture was diluted with dichloromethane and washed with water, and the aqueous phase was extracted with dichloromethane, the combined organic extracts were dried over MgSO₄, concentrated under reduced pressure and purified by column chromatography using hexane/EtOAc as eluent to give the desired product. (Note: aqueous phase was combined with (aq.) potassium permanganate solution and discarded in ventilated hood!!!). The products were further identified by FT-IR, ¹H and ¹³C NMR spectroscopy, LRMS, HRMS, and all data were all in good agreement with assigned structures the characterization data of aminonitriles (3a–3v) are as follows:

(S)-2-((S)-2-(Azidomethyl)pyrrolidin-1-yl)-2-phenylacetonitrile (3a). R_f = 0.42 (EtOAc–hexane 1 : 9), pale yellow oil, [α]²⁵_D = −51.2° (c 1.0, CHCl₃), ¹H NMR (CDCl₃, 300 MHz, ppm) δ: 7.58–7.53 (m, 3H), 7.40–7.37 (m, 2H), 5.31 (s, 1H), 3.54–3.49 (dd, J₁ = 4.3 Hz, J₂ = 4.2 Hz, 1H), 3.34–3.28 (m, 1H), 3.19–3.16 (m, 1H), 2.69–2.67 (m, 1H), 2.59–2.51 (m, 1H), 2.10–2.01 (m, 1H), 1.81–1.74 (m, 3H); ¹³C NMR (75 MHz, CDCl₃, ppm) δ: 133.9, 128.7, 128.0, 127.4, 116.4, 60.9, 58.6, 55.0, 49.3, 28.7, 33.0; IR (KBr, thin film cm⁻¹): 2100, 1629, 1450, 1271, 1123, 910, 703; LRMS-EI (m/z): 241 (0.3), 219 (1), 199 (3), 185 (82), 174 (6), 149 (6), 116 (100), 105 (14), 89 (10), 77 (7), 55 (2); HRMS-EI (m/z): M⁺ calcd for C₁₃H₁₅N₅, 241.1327; found: 241.1330.

(S)-2-((S)-2-(Azidomethyl)pyrrolidin-1-yl)-2-(o-tolyl)acetonitrile (3b). R_f = 0.43 (EtOAc–hexane 1 : 9); pale yellow oil, [α]²⁵_D = −42.8° (c 1.0, CHCl₃); ¹H NMR (CDCl₃, 300 MHz, ppm) δ: 7.64–7.56 (m, 1H), 7.35–7.25 (m, 1H), 7.22–7.19 (m, 2H), 5.40 (s, 1H), 3.50–3.44 (dd, J₁ = 5.0 Hz, J₂ = 6.0 Hz, 1H), 3.24–3.21 (m 1H), 3.14–3.09 (m, 1H), 2.62–2.51 (m, 2H), 2.42 (s, 3H), 2.08–2.02 (m, 1H), 1.90–1.87 (m, 1H), 1.76–1.73 (m, 2H); ¹³C NMR (75 MHz, CDCl₃, ppm) δ: 136.7, 131.8, 131.0, 128.1, 126.0, 116.6, 60.7, 56.5, 55.2, 49.4, 28.9, 22.6, 18.8; IR (KBr, thin film, cm⁻¹): 2966, 2100, 1461, 1272, 1127, 918, 732; LRMS-EI (m/z): 259 (0.07), 258 (0.1), 255 (0.2), 252 (0.1), 251 (0.7), 249 (0.08), 248 (0.1), 246 (0.07), 213 (0.6), 199 (73), 185 (1), 173 (2), 144 (2), 116 (2), 105 (5), 99 (1), 77 (8), 55 (2); HRMS-EI (m/z): M⁺ calcd for C₁₄H₁₇N₅, 255.1484; found: 255.1480.

(S)-2-((S)-2-(Azidomethyl)pyrrolidin-1-yl)-2-(m-tolyl)acetonitrile (3c). R_f = 0.43 (EtOAc–hexane 1 : 9), pale yellow oil, [α]²⁵_D = −41.6° (c 1.0, CHCl₃), ¹H NMR (CDCl₃, 300 MHz, ppm) δ: 7.64–7.56 (m, 1H), 7.32–7.30 (m, 1H), 7.22–7.19 (m, 2H), 5.40 (s, 1H), 3.50–3.44 (dd, J₁ = 5.0 Hz, J₂ = 6.0 Hz, 1H), 3.23–3.21 (m, 1H), 3.14–3.09 (m, 1H), 2.67–2.51 (m, 2H), 2.42 (s, 3H), 2.07–2.02 (m, 1H), 1.90–1.87 (m, 1H), 1.76–1.64 (m, 2H); ¹³C NMR (75 MHz, CDCl₃, ppm) δ: 138.4, 135.0, 133.7, 129.3, 128.4, 128.9, 116.4, 60.9, 58.4, 54.7, 49.1, 28.6, 22.9, 21.1; IR (KBr, thin film, cm⁻¹): 2967, 2100, 1459, 1259, 1124, 916, 729; LRMS-EI (m/z): 255 (0.1), 229 (0.2), 213 (0.6), 199 (72), 185 (0.8), 172 (2), 130 (100), 103 (27), 91 (4), 77 (9), 70 (15), 55 (2); HRMS-EI (m/z): M⁺ calcd for C₁₄H₁₇N₅, 255.1484; found: 255.1478.

(S)-2-((S)-2-(Azidomethyl)pyrrolidin-1-yl)-2-(p-tolyl)acetonitrile (3d). R_f = 0.21 (EtOAc–hexane 1 : 9), pale yellow oil, [α]²⁵_D = −47.1° (c 1.0, CHCl₃), ¹H NMR (CDCl₃, 300 MHz, ppm) δ: 7.42–7.40 (d, J = 6.0 Hz, 2H), 7.28–7.18 (m, 2H), 5.26 (s, 1H), 3.52–3.47 (dd, J₁ = 4.3 Hz, J₂ = 4.2 Hz, 1H), 3.32–3.26 (m, 1H), 3.18–3.14 (m, 1H), 2.72–2.66 (m, 1H), 2.58–2.46 (m, 1H), 2.44 (s, 3H), 2.09–2.03 (m, 1H), 1.82–1.69 (m, 3H); ¹³C NMR (75 MHz, CDCl₃, ppm) δ: 138.4, 130.9, 129.4, 129.2, 127.6, 127.2, 116.5, 60.8, 58.2, 54.7, 49.1, 28.6, 22.9, 20.9; IR (KBr, thin film, cm⁻¹): 2961, 2100, 1684, 1511, 1448, 1270, 1201, 1122, 908, 839, 768; LRMS-EI (m/z): 255 (0.1), 239 (0.06), 229 (0.2), 199 (57), 173 (0.9), 149 (1), 130 (100), 103 (7), 91 (2), 77 (5), 70 (12), 55 (0.8); HRMS-EI (m/z): M⁺ calcd for C₁₄H₁₇N₅, 255.1484; found 255.1480.

(S)-2-((S)-2-(Azidomethyl)pyrrolidin-1-yl)-2-(3-methoxyphenyl)acetonitrile (3e). R_f = 0.21 (EtOAc–hexane 1 : 9), pale yellow oil, [α]²⁵_D = −51.2° (c 1.0, CHCl₃), ¹H NMR (CDCl₃, 300 MHz, ppm) δ: 7.33–7.28 (m, 1H), 7.15–7.09 (m, 2H), 6.91–6.88 (d, J = 9.0 Hz, 1H), 5.29 (s, 1H), 3.82 (s, 3H), 3.54–3.49 (dd, J₁ = 3.7 Hz, J₂ = 4.2 Hz, 1H), 3.32–3.26 (m, 1H), 3.20–3.17 (m, 1H), 2.74–2.71 (m, 1H), 2.60–2.51 (m, 1H), 2.10–2.01 (m, 1H), 1.80–1.71 (m, 3H); ¹³C NMR (75 MHz, CDCl₃, ppm) δ: 159.8, 135.3, 129.7, 119.5, 116.4, 114.3, 112.8, 61.0, 58.5, 55.2, 54.8, 49.3, 28.6, 23.1; IR (KBr, thin film, cm⁻¹): 2967, 2100, 1445, 1267, 1122, 910, 699; LRMS-EI (m/z): 271 (0.1), 245 (0.2), 229 (0.4), 215 (84), 171 (0.3), 146 (100), 116 (7), 103 (5), 89 (4), 77 (2), 55 (3), 50 (0.04); HRMS-EI (m/z): M⁺ calcd for C₁₄H₁₇N₅O, 271.1433; found: 271.1435.

(S)-2-((S)-2-(Azidomethyl)pyrrolidin-1-yl)-2-(4-methoxyphenyl)acetonitrile (3f). R_f = 0.21 (EtOAc–hexane 1 : 9), pale yellow oil, [α]²⁵_D = −45.2° (c 1.0, CHCl₃), ¹H NMR (CDCl₃, 300 MHz, ppm) δ: 7.45–7.42 (d, J = 9.0 Hz, 2H), 6.94–6.89 (m, 2H), 5.23 (s, 1H), 3.81 (s, 3H), 3.52–3.46 (dd, J₁ = 4.3 Hz, J₂ = 4.2 Hz, 1H), 3.31–3.25 (m, 1H), 3.17–3.13 (m, 1H), 2.71–2.66 (m, 1H), 2.57–2.47 (m, 1H), 2.09–2.00 (m, 1H), 1.81–1.75 (m, 3H); ¹³C NMR (75 MHz, CDCl₃, ppm) δ: 159.6, 131.8, 128.5, 125.6, 116.6, 114.1, 113.9, 60.8, 57.9, 55.4, 55.1, 54.8, 49.8, 28.6, 22.9; IR (KBr, thin film, cm⁻¹): 2967, 2100, 1695, 1506, 1248, 1028, 908, 834; LRMS-EI (m/z): 271 (0.01), 265 (0.02), 245 (0.2), 217 (0.4), 215 (29), 189 (0.4), 146 (100), 135 (11), 103 (4), 91 (3), 77 (5), 65 (2), 51 (1); HRMS-EI (m/z): M⁺ calcd for C₁₄H₁₇N₅O, 271.1433, found: 271.1437.

(R)-2-((S)-2-(Azidomethyl)pyrrolidin-1-yl)-2-(2-fluorophenyl)acetonitrile (3g). R_f = 0.41 (EtOAc–hexane 1 : 9), pale yellow oil, [α]²⁵_D = −42.8° (c 1.0, CHCl₃), ¹H NMR (CDCl₃, 300 MHz, ppm) δ: 7.57–7.54 (m, 1H), 7.39–7.36 (m, 1H), 7.20–7.10 (m, 2H), 5.51 (s, 1H), 3.52–3.46 (dd, J₁ = 4.7 Hz, J₂ = 4.7 Hz, 1H), 3.35–3.29 (m, 1H), 3.13–3.10 (m, 1H), 2.72–2.68 (m, 2H), 2.68–2.02 (m, 1H), 1.87–1.72 (m, 3H); ¹³C NMR (75 MHz, CDCl₃, ppm) δ: 162.8 (d, J = 245.0 Hz), 136.4 (d, J = 7.2 Hz), 130.2 (d, J = 8.1 Hz), 122.1 (d, J = 2.8 Hz), 121.6 (d, J = 13.0 Hz), 116.0, 115.5, 114.6, 114.3, 60.9, 58.1, 55.0, 49.2, 28.6, 23.0; IR (KBr, thin film, cm⁻¹): 2967, 2100, 1492, 1270, 1097, 921, 806, 757; LRMS-EI (m/z): 259 (0.02), 258 (0.02), 233 (0.3), 215 (0.7), 203 (93), 177 (0.6), 163 (0.3), 146 (2), 134 (100), 107 (8), 83 (1), 68 (2), 57 (1); HRMS-EI (m/z): M⁺ calcd for C₁₃H₁₄FN₅, 259.1233; found 259.1237.

(R)-2-((S)-2-(Azidomethyl)pyrrolidin-1-yl)-2-(3-fluorophenyl)acetonitrile (3h). R_f = 0.41 (EtOAc–hexane 1 : 9), pale yellow oil, [α]²⁵_D = −53.3° (c 1.0, CHCl₃), ¹H NMR (CDCl₃, 300 MHz, ppm) δ: 7.35–7.29 (m, 3H), 7.07–7.05 (m, 1H), 5.32 (s, 1H), 3.55–3.49 (dd, J₁ = 3.9 Hz, J₂ = 4.0 Hz, 1H), 3.34–3.29 (m, 1H), 3.20–3.16 (m, 1H), 2.71–2.69 (m, 1H), 2.56–2.50 (m, 1H), 2.10–2.04 (m, 1H), 1.81–1.72 (m, 3H); ¹³C NMR (75 MHz, CDCl₃, ppm) δ: 160.1 (d, J = 249.0 Hz), 131.0 (d, J = 8.3 Hz), 129.2 (d, J = 2.6 Hz), 124.1 (d, J = 3.8 Hz), 121.7 (d, J = 12.9 Hz), 61.1, 54.7, 52.4, 52.3, 49.2, 28.7, 23.0; IR (KBr, thin film, cm⁻¹): 2923, 2100, 1591, 1443, 1267, 1023, 798; LRMS-EI (m/z): 259 (0.03), 257 (0.2), 239 (0.1), 205 (1), 203 (100), 178 (6), 134 (94), 109 (11), 107 (7), 83 (3), 70 (4), 55 (3); HRMS-EI (m/z): M⁺ calcd for C₁₃H₁₄FN₅, 259.1233; found: 259.1231.

(R)-2-((S)-2-(Azidomethyl)pyrrolidin-1-yl)-2-(4-fluorophenyl)acetonitrile (3i). R_f = 0.41 (EtOAc–hexane 1 : 9), pale yellow oil, [α]²⁵_D = −50.1° (c 1.0, CHCl₃), ¹H NMR (CDCl₃, 300 MHz, ppm) δ: 7.50–7.47 (d, J = 9.0 Hz, 2H), 7.42–7.35 (m, 2H), 5.29 (s, 1H), 3.54–3.49 (dd, J = 3.1 Hz, J = 4.0 Hz, 1H), 3.27–3.34 (m, 1H), 3.20–3.08 (m, 1H), 2.70–2.64 (m, 1H), 2.56–2.48 (m, 1H), 2.00–2.01 (m, 1H), 1.97–1.67 (m, 3H); ¹³C NMR (75 MHz, CDCl₃, ppm) δ: 162.7 (d, J = 246.0 Hz), 130.0, 129.2, 129.1, 116.4, 115.8, 115.6, 60.9, 58.0, 55.1, 49.2, 28.7, 23.1; IR (KBr, thin film, cm⁻¹): 2961, 2100, 1604, 1508, 1223, 834, 791; LRMS-EI (m/z): 259 (0.02), 257 (0.02), 241 (0.02), 229 (0.3), 205 (0.5), 203 (52), 177 (0.6), 148 (1), 134 (100), 107 (5), 83 (1), 68 (2), 57 (0.8); HRMS-EI (m/z): M⁺ calcd for C₁₃H₁₄FN₅, 259.1233; found: 259.1239.

(S)-2-((S)-2-(Azidomethyl)pyrrolidin-1-yl)-2-(2-chlorophenyl)acetonitrile (3j). R_f = 0.43 (EtOAc–hexane 1 : 9), pale yellow oil, [α]²⁵_D = −39.8° (c 1.0, CHCl₃), ¹H NMR (CDCl₃, 300 MHz, ppm) δ: 7.79–7.61 (d, J = 5.4 Hz, 1H), 7.64–7.61 (m, 1H), 7.36–7.31 (m, 2H), 5.59 (s, 1H), 3.53–3.47 (dd, J₁ = 7.0 Hz, J₂ = 5.5 Hz, 1H), 3.29–3.21 (m, 1H), 3.14–3.08 (m, 1H), 2.70–2.62 (m, 2H), 2.09–2.01 (m, 1H), 1.98–1.78 (m, 3H); ¹³C NMR (75 MHz, CDCl₃, ppm) δ: 133.7, 131.4, 130.3, 130.2, 129.6, 126.8, 115.8, 61.1, 55.6, 54.3, 49.0, 28.7, 22.7; IR (KBr, thin film, cm⁻¹): 2967, 2100, 1437, 1264, 1127, 924, 754; LRMS-EI (m/z): 278 (0.01), 275 (0.05), 249 (0.3), 219 (97), 192 (0.6), 150 (100), 123 (6), 89 (3), 68 (3), 50 (0.6); HRMS-EI (m/z): M⁺ calcd for C₁₃H₁₄ClN₅, 275.0938; found: 275.0942.

(S)-2-((S)-2-(Azidomethyl)pyrrolidin-1-yl)-2-(3-chlorophenyl)acetonitrile (3k). R_f = 0.43 (EtOAc–hexane 1 : 9), pale yellow oil, [α]²⁵_D = −54.7° (c 1.0, CHCl₃), ¹H NMR (CDCl₃, 300 MHz, ppm) δ: 7.56–7.54 (d, J = 6.0 Hz, 1H), 7.44–7.43 (m, 1H), 7.34–7.32 (m, 2H), 5.31 (s, 1H), 3.55–3.49 (dd, J₁ = 4.0 Hz, J₂ = 4.2 Hz, 1H), 3.35–3.29 (m, 1H), 3.20–3.14 (m, 1H), 2.72–2.67 (m, 1H), 2.60–2.50 (m, 1H), 2.11–2.01 (m, 1H), 1.85–1.76 (m, 3H); ¹³C NMR (75 MHz, CDCl₃, ppm) δ: 136.0, 134.8, 130.0, 129.0, 127.6, 125.5, 116.0, 61.0, 58.3, 55.3, 49.4, 28.8, 23.1; IR (KBr, thin film, cm⁻¹): 2967, 2100, 1596, 1267, 1078, 888, 770; LRMS-EI (m/z): 275 (0.02), 249 (0.2), 233 (1), 219 (100), 184 (1), 150 (82), 123 (4), 89 (2), 70 (3), 55 (1); HRMS-EI (m/z): M⁺ calcd for C₁₃H₁₄ClN₅, 275.0938; found: 275.0930.

(S)-2-((S)-2-(Azidomethyl)pyrrolidin-1-yl)-2-(4-chlorophenyl)acetonitrile (3l). R_f = 0.43 (EtOAc–hexane 1 : 9), pale yellow oil, [α]²⁵_D = −55.9° (c 1.0, CHCl₃), ¹H NMR (CDCl₃, 300 MHz, ppm) δ: 7.50–7.43 (d, J = 9.0 Hz, 2H), 7.38–7.35 (m, 2H), 5.29 (s, 1H), 3.54–3.49 (dd, J₁ = 3.1 Hz, J₂ = 4.0 Hz, 1H), 3.34–3.27 (m, 1H), 3.19–3.15 (m, 1H), 2.69–2.65 (m, 1H), 2.57–2.51 (m, 1H), 2.10–2.04 (m, 1H), 1.84–1.70 (m, 3H); ¹³C NMR (75 MHz, CDCl₃, ppm) δ: 134.5, 132.5, 129.3, 129.0, 128.8, 128.7, 116.0, 60.9, 58.0, 55.0, 49.2, 28.6, 23.0; IR (KBr, thin film, cm⁻¹): 2967, 2100, 1489, 1267, 1091, 1015, 908, 842; LRMS-EI (m/z): 275 (0.07), 249 (0.2), 233 (0.4), 219 (63), 193 (0.7), 152 (36), 150 (100), 114 (4), 89 (2), 68 (2), 55 (1); HRMS-EI (m/z): M⁺ calcd for C₁₃H₁₄ClN₅, 275.0938; found: 275.0932.

(S)-2-((S)-2-(Azidomethyl)pyrrolidin-1-yl)-2-(2-bromophenyl)acetonitrile (3m). R_f = 0.44 (EtOAc–hexane 1 : 9), pale yellow oil, [α]²⁵_D = −35.7° (c 1.0, CHCl₃), ¹H NMR (CDCl₃, 300 MHz, ppm) δ: 7.65–7.40 (m, 2H), 7.39–7.36 (m, 1H), 7.34–7.27 (m, 1H), 5.56 (s, 1H), 3.54–3.52 (d, J = 6.0 Hz, 1H), 3.14–3.11 (m, 1H), 3.09–3.08 (m, 1H), 2.68–2.59 (m, 2H), 2.09–2.01 (m, 1H), 1.99–1.75 (m, 3H); ¹³C NMR (75 MHz, CDCl₃, ppm) δ: 135.0, 133.7, 133.0, 130.5, 129.9, 127.8, 124.0, 116.0, 61.22, 58.0, 54.3, 49.0, 28.8, 22.6; IR (KBr, thin film, cm⁻¹): 2961, 2100, 1692, 1470, 1264, 1198, 924, 754; LRMS-ESI (m/z): 323 (15), 322 (95), 320 (100), 309 (0.4), 295 (4), 289 (0.6); HRMS-ESI (m/z): M⁺ calcd for C₁₃H₁₅BrN₅, 320.0433, found: 320.0507.

(S)-2-((S)-2-(Azidomethyl)pyrrolidin-1-yl)-2-(3-bromophenyl)acetonitrile (3n). R_f = 0.44 (EtOAc–hexane 1 : 9), [α]²⁵_D = −55.3° (c 1.0, CHCl₃), ¹H NMR (CDCl₃, 300 MHz, ppm) δ: 7.69 (m, 1H), 7.50–7.48 (d, J = 6.0 Hz, 2H), 7.29–7.24 (m, 1H), 5.31 (s, 1H), 3.55–3.49 (dd, J₁ = 4.1 Hz, J₂ = 4.2 Hz, 1H), 3.35–3.29 (m, 1H), 3.18–3.13 (m, 1H), 2.72–2.67 (m, 1H), 2.60–2.53 (m, 1H), 2.11–2.04 (m, 1H), 1.85–1.70 (m, 3H); ¹³C NMR (75 MHz, CDCl₃, ppm): δ = 136.2, 131.8, 130.3, 130.2, 125.9, 122.8, 115.9, 60.9, 58.0, 55.1, 49.3, 28.7, 23.1; IR (KBr, thin film, cm⁻¹): 2961, 2100, 1559, 1470, 1270, 1070, 930, 770; LRMS-ESI (m/z): 325 (2), 323 (16), 322 (93), 320 (100), 309 (2), 278 (5), 276 (12); HRMS-ESI (m/z): M⁺ calcd for C₁₃H₁₅BrN₅, 320.0433; found: 320.0508.

3-((R)-((S)-2-(Azidomethyl)pyrrolidin-1-yl)-(cyano)methyl)benzonitrile (3o). R_f = 0.39 (EtOAc–hexane 1 : 9), pale yellow oil, [α]²⁵_D = −53.5° (c 1.0, CHCl₃), ¹H NMR (CDCl₃, 300 MHz, ppm) δ: 7.87–7.79 (m, 2H), 7.68–7.65 (d, J = 9.0 Hz, 1H), 7.56–7.50 (m, 1H), 5.39 (s, 1H), 3.58–3.53 (dd, J₁ = 3.9 Hz, J₂ = 4.0 Hz, 1H), 3.38–3.32 (m, 1H), 3.21–3.17 (m, 1H), 2.67–2.62 (m, 1H), 2.58–2.53 (m, 1H), 2.12–2.06 (m, 1H), 1.87–1.68 (m, 3H); ¹³C NMR (75 MHz, CDCl₃, ppm) δ: 139.1, 132.6, 128.2, 118.1, 115.6, 112.9, 61.0, 58.6, 55.4, 49.4, 28.7, 23.2; IR (KBr, thin film, cm⁻¹): 2967, 2225, 2100, 1602, 1267, 910, 853; LRMS-ESI (m/z): 279 (0.5), 269 (1.5), 268 (16), 267 (100), 240 (4), 224 (0.7), 244 (5), 238 (3), 222 (2.5); HRMS-ESI (m/z): M⁺ calcd for C₁₄H₁₅N₆, 267.1280; found: 267.1349.

4-((R)-((S)-2-(Azidomethyl)pyrrolidin-1-yl)-(cyano)methyl)benzonitrile (3p). R_f = 0.39 (EtOAc–hexane 1 : 9), pale yellow oil, [α]²⁵_D = −57.7° (c 1.0, CHCl₃), ¹H NMR (CDCl₃, 300 MHz, ppm) δ: 7.69 (s, 4H), 5.39 (s, 1H), 3.57–3.52 (dd, J₁ = 3.8 Hz, J₂ = 3.7 Hz, 1H), 3.36–3.29 (m, 1H), 3.22–3.17 (m, 1H), 2.66–2.61 (m, 1H), 2.56–2.48 (m, 1H), 2.11–2.01 (m, 1H), 1.86–1.70 (m, 3H); ¹³C NMR (75 MHz, CDCl₃, ppm) δ: 135.6, 132.2, 131.5, 130.8, 129.5, 117.9, 115.4, 112.8, 60.8, 57.9, 55.0, 49.1, 28.5, 22.9; IR (KBr, thin film, cm⁻¹): 2972, 2225, 2100, 1478, 1275, 1124, 899, 680; LRMS-ESI (m/z): 285 (4), 269 (2), 268 (17), 267 (100), 256 (7); HRMS-ESI (m/z): M⁺ calcd for C₁₄H₁₅N₆; 267.1280, found: 267.1351.

(R)-2-((S)-2-(Azidomethyl)pyrrolidin-1-yl)-2-(2,4,6-trimethoxyphenyl)acetonitrile (3q). R_f = 0.19 (EtOAc–hexane 1 : 9), pale yellow oil, [α]²⁵_D = −41.6° (c 1.0, CHCl₃), ¹H NMR (CDCl₃, 300 MHz, ppm) δ: 6.12 (s, 2H), 5.45 (s, 1H), 3.85 (s, 9H), 3.46–3.40 (m, 2H), 3.25–3.10 (m, 1H), 2.86–3.79 (dd, J = 9.9 Hz, J = 8.1 Hz, 2H), 2.00–1.94 (m, 1H), 1.79–1.74 (m, 3H); ¹³C NMR (75 MHz, CDCl₃, ppm) δ: 161.9, 161.8, 158.96, 158.8, 117.4, 103.5, 90.9, 60.4, 58.6, 55.7, 55.2, 53.8, 50.4, 45.9, 28.4, 23.3; IR (KBr, thin film, cm⁻¹): 2961, 2100, 1459, 1369, 1116, 924; LRMS-ESI (m/z): 334 (2), 333 (17), 332 (100), 330 (3.3), 305 (3), 289 (0.3); HRMS-ESI (m/z): M⁺ calcd for C₁₆H₂₁N₅O₃, 332.1644; found: 332.1712.

(R)-2-((S)-2-(Azidomethyl)pyrrolidin-1-yl)-2-(naphthalen-1-yl)acetonitrile (3r). R_f = 0.43 (EtOAc–hexane 1 : 9), pale yellow oil, [α]²⁵_D = −41.4° (c 1.0, CHCl₃), ¹H NMR (CDCl₃, 300 MHz, ppm) δ: 8.28–8.25 (d, J = 9.0 Hz, 1H), 7.90–7.83 (m, 3H), 7.61–7.45 (m, 3H), 6.01 (s, 1H), 3.67–3.65 (m, 1H), 3.28–3.27 (m, 1H), 2.66–2.64 (m, 1H), 2.43–2.42 (m, 1H), 2.11–2.08 (m, 1H), 1.75–1.71 (m, 1H), 1.71–1.63 (m, 3H); ¹³C NMR (75 MHz, CDCl₃, ppm) δ: 135.2, 133.8, 130.5, 129.9, 129.3, 128.61, 126.7, 126.2, 125.7, 124.8, 123.4, 116.7, 60.6, 57.0, 55.8, 49.6, 28.9, 22.6; IR (KBr, thin film, cm⁻¹): 2956, 2100, 1690, 1448, 1267, 1122, 913, 781; LRMS-EI (m/z): 291 (0.03), 265 (0.2), 237 (0.6), 235 (40), 208 (1), 180 (1), 166 (100), 139 (10), 115 (2), 89 (0.7), 70 (1), 50 (0.1); HRMS-EI (m/z): M⁺ calcd for C₁₇H₁₇N₅, 291.1484, found: 291.1486.

(R)-2-((S)-2-(Azidomethyl)pyrrolidin-1-yl)-4-methylpentanenitrile (3s). R_f = 0.41 (EtOAc–hexane 1 : 9), pale yellow oil, [α]²⁵_D = −54.8° (c 1.0, CHCl₃); ¹H NMR (CDCl₃, 300 MHz, ppm) δ: 3.98–3.93 (t, J = 9.0 Hz, 1H), 3.36–3.31 (dd, J₁ = 4.5 Hz, J₂ = 4.4 Hz, 1H), 3.12–3.18 (m, 1H), 2.95–3.03 (m, 2H), 2.54–2.63 (m, 1H), 1.82–1.87 (m, 4H); 1.82–1.60 (m, 3H), 0.96 (d, J = 1.8 Hz, 3H), 0.94 (d, J = 1.8 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃, ppm) δ: 118.3, 61.3, 54.7, 52.8, 48.7, 41.3, 28.4, 24.5, 23.2, 22.1, 22.0; IR (KBr, thin film, cm⁻¹): 2956, 2100, 1467, 1270, 1141, 1039, 817, 655; LRMS-EI (m/z): 221 (0.7), 206 (0.5), 191 (2), 179 (2), 165 (100), 138 (8), 109 (18), 97 (1), 80 (3), 70 (21), 55 (5), 52 (0.4); HRMS-EI (m/z): M⁺ calcd for C₁₁H₁₉N₅, 221.1640; found: 221.1648.

(S)-2-((S)-2-(Azidomethyl)pyrrolidin-1-yl)-4-phenylbutanenitrile (3t). R_f = 0.41 (EtOAc–hexane 1 : 9), pale yellow oil, [α]²⁵_D = −42.3° (c 1.0, CHCl₃), ¹H NMR (CDCl₃, 300 MHz, ppm) δ: 7.34–7.31 (m, 2H), 7.29–7.19 (m, 3H), 3.85–3.79 (t, J = 7.8 Hz, 1H), 3.28–3.23 (dd, J₁ = 4.6 Hz, J₂ = 4.7 Hz, 1H), 3.12–3.06 (m, 2H), 2.98–2.90 (m, 1H), 2.83–2.78 (t, J = 7.2 Hz, 2H), 2.67–2.58 (m, 1H), 2.13–2.10 (m, 2H), 2.10–1.82 (m, 3H), 1.79–1.70 (m, 1H); ¹³C NMR (75 MHz, CDCl₃, ppm) δ: 139.8, 128.5, 128.3, 126.4, 117.9, 61.4, 54.5, 53.6, 48.7, 33.9, 31.7, 28.4, 23.2; IR (KBr, thin film, cm⁻¹): 2956, 2100, 1451, 1273, 1119, 908, 699; LRMS-EI (m/z): 269 (0.05), 263 (0.2), 241 (3), 213 (100), 172 (13), 145 (1), 109 (15), 91 (29), 70 (5), 54 (2); HRMS-EI (m/z): M⁺ calcd for C₁₅H₁₉N₅, 269.1640; found: 269.1648.

(S)-2-((S)-2-(Azidomethyl)pyrrolidin-1-yl)-2-(thiophen-3-yl)acetonitrile (3u). R_f = 0.39 (EtOAc–hexane 1 : 9), pale yellow oil, [α]²⁵_D = −54.1° (c 1.0, CHCl₃), ¹H NMR (CDCl₃, 300 MHz, ppm) δ: 7.44–7.36 (m, 1H), 7.35–7.33 (m, 1H), 7.18–7.16 (m, 1H), 5.26 (s, 1H), 3.51–3.45 (dd, J₁ = 4.1 Hz, J₂ = 4.0 Hz, 1H), 3.28–3.22 (m, 1H), 3.16–3.13 (m, 1H), 2.76–2.75 (m, 1H), 2.59–2.56 (m, 1H), 2.09–2.03 (m, 1H), 1.88–1.80 (m, 1H), 1.79–1.71 (m, 3H); ¹³C NMR (75 MHz, CDCl₃, ppm) δ: 135.2, 126.9, 126.6, 123.6, 116.7, 61.0, 54.9, 54.6, 49.6, 28.7, 23.1; IR (KBr, thin film, cm⁻¹): 2956, 2100, 1445, 1275, 888, 792; LRMS-ESI (m/z): 253 (1), 250 (6), 249 (15), 248 (100), 237 (3), 221 (2), 211 (1), 206 (3); HRMS-ESI (m/z): M⁺ calcd for C₁₁H₁₄N₅S, 248.0964, found: 248.0966.

(S)-2-((S)-2-(Azidomethyl)pyrrolidin-1-yl)-2-(benzo[b]thiophen-3-yl)acetonitrile (3v). R_f = 0.39 (EtOAc–hexane 1 : 9), pale yellow oil, [α]²⁵_D = −42.1° (c 1.0, CHCl₃), ¹H NMR (CDCl₃, 300 MHz, ppm) δ: 8.06–8.03 (m, 1H), 7.87–7.84 (m, 1H), 7.68–7.43 (m, 1H), 7.42–739 (m, 2H), 5.60 (s, 1H), 3.62–3.53 (dd, J₁ = 4.5 Hz, J₂ = 6.7 Hz, 1H), 3.24–3.19 (m, 1H), 2.65–2.59 (m, 2H), 2.12–2.07 (m, 1H), 1.97–1.93 (m, 1H), 1.78–1.66 (m, 3H); ¹³C NMR (75 MHz, CDCl₃, ppm) δ: 140.7, 136.5, 128.5, 125.8, 125.0, 124.4, 122.7, 122.4, 116.2, 60.6, 55.7, 54.2, 49.6, 29.0, 22.82; IR (KBr, thin film, cm⁻¹): 2961, 2100, 1679, 1426, 1270, 1135, 1045, 883, 757; LRMS-EI (m/z): 297 (0.03), 271 (0.1), 241 (25), 214 (0.5), 172 (100), 145 (5), 101 (0.9), 89 (0.8), 68 (1), 55 (0.3); HRMS-EI (m/z): M⁺ calcd for C₁₅H₁₅N₅S, 297.1048, found: 297.1044.

General experimental procedure for intramolecular [3+2] cycloaddition

A solution of aminonitrile (1 eq.) in DMF (2 mL) was heated at 140–150 °C in screw caped sealed tube for 14–16 h. After completion of the reaction (monitored by TLC), the mixture was diluted with diethyl ether and washed with water, and the aqueous phase was extracted with diethyl ether. The combined organic extracts were dried over MgSO₄ and concentrated under reduced pressure and purified by column chromatography using n-hexane/EtOAc as eluent to give the desired product. The products were identified by FT-IR, ¹H and ¹³C NMR spectroscopy, and LRMS, HRMS, and all data were all in good agreement with assigned structures. The characterization data of tricyclic fused tetrazoles given as below:

(5aS,10R)-10-Phenyl-5,5a,6,7,8,10-hexahydropyrrolo[1,2-a]tetrazolo[1,5-d]pyrazine (major diastereomer). R_f = 0.31 (EtOAc–hexane 3 : 7), pale yellow solid; mp: 189–190. [α]²⁵_D = −45.2° (c 1.0, CHCl₃), ¹H NMR (CDCl₃, 300 MHz, ppm): δ = 7.36 (m, 5H), 4.77–4.72 (dd, J₁ = 3.3 Hz, J₂ = 3.4 Hz, 1H), 4.60 (s, 1H), 4.18–4.11 (t, J = 12.0 Hz, 1H), 3.02–2.98 (m, 2H), 2.34–2.25 (q, J = 9.0 Hz, 1H); 2.23–2.14 (m, 1H), 2.02–1.83 (m, 2H), 1.79–1.70 (m, 1H); ¹³C NMR (75 MHz, CDCl₃, ppm) δ: 154.3, 137.0, 128.7, 128.4, 128.3, 64.0, 59.6, 51.7, 50.8, 27.6, 22.3; IR (KBr, thin film, cm⁻¹): 2950, 2807, 1659, 1454, 1155, 1075, 1012, 751, 699; LRMS-EI (m/z): 241 (9), 229 (1.0), 187 (1.1), 185 (100), 159 (61), 143 (5), 131 (19), 116 (60), 104 (28), 89 (10), 77 (9.1), 55 (9.6); HRMS-EI (m/z): M⁺ calcd for C₁₃H₁₅N₅, 241.1327; found: 241.1333.

(5aS,10S)-10-Phenyl-5,5a,6,7,8,10-hexahydropyrrolo[1,2-a]tetrazolo[1,5-d]pyrazine (minor diastereomer). R_f = 0.31 (EtOAc–hexane 3 : 7); yellow oil; [α]²⁵_D = −26.6° (c 1.0, CHCl₃), ¹H NMR (CDCl₃, 300 MHz, ppm) δ: 7.38–7.30 (m, 3H), 7.17–7.09 (m, 2H), 5.00 (s, 1H), 4.80–4.77 (dd, J₁ = 3.5 Hz, J₂ = 3.3 Hz, 1H), 4.13–4.20 (t, J = 11.7 Hz, 1H), 3.12–3.00 (m, 2H), 2.44–2.35 (q, J = 8.8 Hz, 1H), 2.28–2.17 (m, 1H), 2.02–1.96 (m, 2H), 1.82–1.75 (m, 1H); ¹³C NMR (75 MHz, CDCl₃, ppm) δ: 153.0, 134.0, 127.7, 127.3, 125.5, 57.3, 50.4, 48.3, 29.5, 27.4, 22.1; IR (KBr, thin film, cm⁻¹): 2950, 2805, 1659, 1450, 1155, 1075, 1012, 750.

(5aS,10R)-10-(o-Tolyl)-5,5a,6,7,8,10-hexahydropyrrolo[1,2-a]tetrazolo[1,5-d]pyrazine (4b). R_f = 0.32 (EtOAc–hexane 3 : 7), brown gum, [α]²⁵_D = −47.6° (c 1.0, CHCl₃), ¹NMR (CDCl₃, 300 MHz, ppm) δ: 7.34–7.31 (d, J = 9.0 Hz, 2H), 7.23–7.07 (m, 2H), 4.92 (s, 1H), 4.78–4.73 (dd, J₁ = 2.6 Hz, J₂ = 2.6 Hz, 1H), 4.18–4.10 (t, J = 11.2 Hz, 1H), 3.09–2.97 (m, 2H), 2.58 (s, 3H), 2.26–2.19 (q, J = 7.4 Hz, 1H), 2.17–2.15 (m, 1H), 1.95–1.88 (m, 2H), 1.79–1.77 (m, 1H); ¹³C NMR (75 MHz, CDCl₃, ppm) δ: 154.1, 130.7, 128.9, 128.1, 127.3, 126.4, 125.7, 59.6, 59.1, 51.5, 50.7, 27.6, 22.3, 19.7; IR (KBr, thin film, cm⁻¹): 2923, 2807, 1603, 1464, 1156, 1077, 726, 700; LRMS-EI (m/z): 255 (18), 227 (14), 200 (8), 199 (74), 173 (54), 172 (65), 158 (12), 144 (29), 130 (100), 115 (17), 104 (19), 84 (15), 70 (11), 55 (8); HRMS-EI (m/z): M⁺ calcd for C₁₄H₁₇N₅, 255.1484; found: 255.1480.

(5aS,10R)-10-(m-Tolyl)-5,5a,6,7,8,10-hexahydropyrrolo[1,2-a]tetrazolo[1,5-d]pyrazine (4c). R_f = 0.32 (EtOAc–hexane 3 : 7); brown gum, [α]²⁵_D = −45.2° (c 1.0, CHCl₃), ¹H NMR (CDCl₃, 300 MHz, ppm) δ: 7.15 (s, 4H), 4.77–4.72 (dd, J₁ = 3.4 Hz, J₂ = 3.3 Hz, 1H); 4.55 (s, 1H), 4.19–4.11 (t, J = 11.3 Hz, 1H), 3.04–2.98 (m, 2H), 2.34 (s, 3H), 2.27–2.14 (m, 2H), 2.02–1.80 (m, 2H), 1.78–1.74 (m, 1H); ¹³C NMR (75 MHz, CDCl₃, ppm) δ: 154.4, 138.4, 136.8, 129.5, 128.9, 128.5, 125.4, 64.15, 59.6, 51.7, 50.8, 27.6, 22.3, 21.3; IR (KBr, thin film, cm⁻¹): LRMS-EI (m/z): 255 (25), 238 (4), 221 (9), 199 (100), 173 (65), 158 (12), 144 (13), 130 (0.01), 118 (28), 103 (10), 77 (8), 55 (6); HRMS-EI (m/z): M⁺ calcd for C₁₄H₁₇N₅, 255.1483; found: 255.1478.

(5aS,10R)-10-(p-Tolyl)-5,5a,6,7,8,10-hexahydropyrrolo[1,2-a]tetrazolo[1,5-d]pyrazine (4d). R_f = 0.32 (EtOAc–hexane 3 : 7); brown gum, [α]²⁵_D = −44.4° (c 1.0, CHCl₃), ¹H NMR (CDCl₃, 300 MHz, ppm) δ: 7.24 (s, 1H), 7.16–7.12 (m, 3H), 4.77–4.71 (dd, J₁ = 3.6 Hz, J₂ = 3.7 Hz, 1H), 4.56 (s, 1H), 4.18–4.10 (t, J = 11.3 Hz, 1H), 3.04–2.98 (m, 2H), 2.34 (s, 3H), 2.32–2.14 (m, 2H), 1.99–1.83 (m, 2H), 1.79–1.74 (m, 1H); ¹³C NMR (75 MHz, CDCl₃, ppm) δ: 154.4, 138.4, 133.8, 129.3, 128.1, 63.7, 59.4, 51.6, 50.7, 27.6, 22.2, 21.0; IR (KBr, thin film, cm⁻¹): 2949, 2800, 1604, 1464, 1317, 1156, 1077, 776, 700; LRMS-EI (m/z): 255 (54), 229 (74), 199 (83), 173 (82), 143 (29), 118 (38), 115 (27), 91 (32), 70 (20), 55 (22); HRMS-EI (m/z): M⁺ calcd for C₁₄H₁₇N₅, 255.1484, found: 255.1488.

(5aS,10R)-10-(3-Methoxyphenyl)-5,5a,6,7,8,10-hexahydropyrrolo[1,2-a]tetrazolo[1,5-d]pyrazine (4e). R_f = 0.22 (EtOAc–hexane 3 : 7), brown gum, [α]²⁵_D = −45.2° (c 1.0, CHCl₃), ¹H NMR (CDCl₃, 300 MHz, ppm) δ: = 7.30–7.28 (m, 1H), 6.98–6.96 (d, J = 7.4 Hz, 1H), 6.89–6.86 (m, 2H), 4.75–4.70 (dd, J₁ = 3.3 Hz, J₂ = 3.2 Hz, 1H), 4.56 (s, 1H), 4.17–4.10 (t, J = 11.0 Hz, 1H), 3.77 (s, 3H), 3.02–3.00 (m, 2H), 2.33–2.24 (q, J = 8.7 Hz, 1H), 2.20–2.14 (m, 1H), 2.02–1.94 (m, 2H), 1.82–1.69 (m, 1H); ¹³C NMR (75 MHz, CDCl₃, ppm) δ: = 159.8, 154.2, 138.4, 129.7, 120.7, 114.1, 63.9, 59.5, 55.1, 51.7, 50.8, 27.6, 22.4; IR (KBr, thin film, cm⁻¹): 2945, 2840, 1599, 1485, 1316, 1154, 1042, 737, 693; LRMS-EI (m/z): 271 (83), 229 (29), 215 (95), 189 (73), 146 (100), 130 (25), 91 (20), 77 (15), 55 (16); HRMS-EI (m/z): M⁺ calcd for C₁₄H₁₇N₅O, 271.1433, found: 271.1435.

(5aS,10R)-10-(4-Methoxyphenyl)-5,5a,6,7,8,10-hexahydropyrrolo[1,2-a]tetrazolo[1,5-d]pyrazine (4f). R_f = 0.22 (EtOAc–hexane 3 : 7), brown gum, [α]²⁵_D = −46.2° (c 1.0, CHCl₃), ¹H NMR (CDCl₃, 300 MHz, ppm) δ: = 7.28 (s, 1H), 7.90–7.87 (d, J = 9.0 Hz, 3H), 4.75–4.70 (dd, J₁ = 3.7 Hz, J₂ = 3.8 Hz, 1H), 4.54 (s, 1H), 4.16–4.09 (t, J = 9.0 Hz, 1H), 3.79 (s, 3H), 3.02–2.96 (m, 2H), 2.32–2.26 (q, J = 8.9 Hz, 1H), 2.20–2.13 (m, 1H), 1.98–1.80 (m, 2H), 1.78–1.72 (m, 1H); ¹³C NMR (75 MHz, CDCl₃, ppm) δ: = 159.8, 154.6, 129.4, 129.1, 114.1, 63.5, 59.6, 55.2, 51.7, 50.8, 27.7, 22.3; IR (KBr, thin film, cm⁻¹): 2956, 2791, 1610, 1511, 1465, 1511, 1256, 1163, 1020, 812; LRMS-EI (m/z): 271 (30), 215 (19), 190 (18), 189 (83), 146 (100), 134 (30), 103 (4), 77 (7), 55 (5); HRMS-EI (m/z): M⁺ calcd for C₁₄H₁₇N₅O, 271.1433; found: 271.1438.

(5aS,10R)-10-(2-Fluorophenyl)-5,5a,6,7,8,10-hexahydropyrrolo[1,2-a]tetrazolo[1,5-d]pyrazine (4g). R_f = 0.33 (EtOAc–hexane 3 : 7), brown gum, [α]²⁵_D = −38.4° (c 1.0, CHCl₃), ¹H NMR (CDCl₃, 300 MHz, ppm) δ: 7.36–7.28 (m, 2H), 7.15–7.07 (m, 2H), 4.98 (s, 1H), 4.78–4.73 (dd, J₁ = 3.8 Hz, J₂ = 3.6 Hz, 1H), 4.18–4.11 (t, J = 11.5 Hz, 1H), 2.05–2.98 (m, 2H), 2.42–2.33 (q, J = 9.0 Hz, 1H), 2.24–2.19 (m, 1H), 2.00–1.80 (m, 2H), 1.79–1.76 (m, 1H); ¹³C NMR (75 MHz, CDCl₃, ppm) δ: 160.7 (d, J = 247.0 Hz), 153.6, 130.3 (d, J = 8.4 Hz), 124.3 (d, J = 3.0 Hz), 124.0, 115.6, 59.6, 51.4, 50.6, 27.5, 22.1; IR (KBr, thin film, cm⁻¹): 2950, 2813, 1588, 1486, 1267, 1157, 1078, 883, 776, 691; LRMS-EI (m/z): 259 (5), 229 (2), 203 (100), 177 (34), 149 (18), 134 (43), 122 (16), 107 (7), 75 (1), 55 (4); HRMS-EI (m/z): M⁺ calcd for C₁₃H₁₄FN₅, 259.1233; found: 259.1228.

(5aS,10R)-10-(3-Fluorophenyl)-5,5a,6,7,8,10-hexahydropyrrolo[1,2-a]tetrazolo[1,5-d]pyrazine (4h). R_f = 0.33 (EtOAc–hexane 3 : 7), brown gum, [α]²⁵_D = −48.8° (c 1.0, CHCl₃), ¹H NMR (CDCl₃, 300 MHz, ppm) δ: 7.36–7.31 (m, 1H), 7.21–7.19 (m, 1H), 7.11–7.02 (m, 2H), 4.77–4.72 (dd, J₁ = 3.6 Hz, J₂ = 3.3 Hz, 1H), 4.61 (s, 1H), 4.18–4.10 (t, J = 11.1 Hz, 1H), 3.03 (m, 2H), 2.34–2.25 (q, J = 9.0 Hz, 1H), 2.22–2.15 (m, 1H), 2.04–1.99 (m, 2H), 1.83–1.74 (m, 1H); ¹³C NMR (75 MHz, CDCl₃, ppm) δ: 162.9 (d, J = 123.0 Hz), 153.8, 139.5, 130.3 (d, J = 8.2 Hz), 124.2 (d, J = 2.9 Hz), 115.9, 115.7, 115.3, 115.0, 63.3, 59.5, 51.6, 50.8, 27.6, 22.3; IR (KBr, thin film, cm⁻¹): 2950, 2802, 1580, 1448, 1242, 1155, 790, 688; LRMS-EI (m/z): 259 (7), 229 (2), 203 (100), 177 (46), 149 (18), 134 (47), 122 (23), 107 (9), 81 (3), 55 (9); HRMS-EI (m/z): M⁺ calcd for C₁₃H₁₄FN₅, 259.1233, found: 259.1242.

(5aS,10R)-10-(4-Fluorophenyl)-5,5a,6,7,8,10-hexahydropyrrolo[1,2-a]tetrazolo[1,5-d]pyrazine (4i). R_f = 0.33 (EtOAc–hexane 3 : 7), brown gum, [α]²⁵_D = −46.9° (c 1.0, CHCl₃), ¹H NMR (CDCl₃, 300 MHz, ppm) δ: 7.33 (s, 4H), 4.77–4.71 (dd, J₁ = 4.9 Hz, J₂ = 3.8 Hz, 1H); 4.59 (s, 1H), 4.17–4.10 (t, J = 11.2 Hz, 1H), 3.00 (m, 2H), 2.32–2.23 (q, J = 7.8 Hz, 1H), 2.22–2.19 (m, 1H), 1.97–1.95 (m, 2H), 1.83–1.74 (m, 1H); ¹³C NMR (75 MHz, CDCl₃, ppm) δ: 154.0, 135.1 (d, J = 64.0 Hz), 130.0, 129.7, 129.0, 128.7, 63.3, 59.6, 51.7, 50.8, 27.6, 22.3; IR (KBr, thin film, cm⁻¹): 2950, 2813, 1489, 1160, 1083, 803; LRMS-EI (m/z): 259 (5), 229 (5), 219 (21), 203 (100), 193 (18), 177 (68), 149 (41), 134 (51), 122 (31), 105 (21), 77 (8), 55 (22); HRMS-EI (m/z): M⁺ calcd for C₁₃H₁₄FN₅, 259.1233, found: 259.1236.

(5aS,10R)-10-(2-Chlorophenyl)-5,5a,6,7,8,10-hexahydropyrrolo[1,2-a]tetrazolo[1,5-d]pyrazine (4j). R_f = 0.34 (EtOAc–hexane 3 : 7), brown gum, [α]²⁵_D = −43.2° (c 1.0, CHCl₃), ¹H NMR (CDCl₃, 300 MHz, ppm) δ: 7.64–7.62 (d, J = 6.0 Hz, 1H), 7.28–7.23 (m, 2H), 7.21–7.16 (m, 1H), 5.33 (s, 1H), 4.79–4.73 (dd, J₁ = 3.0 Hz, J₂ = 3.2 Hz, 1H), 4.18–4.10 (t, J = 11.2 Hz, 1H), 3.16–3.06 (m, 1H), (m, 2.99–2.94, 1H), 2.46–2.37 (q, J = 8.9 Hz, 1H), 2.25–2.15 (m, 1H), 1.97–1.82 (m, 2H), 1.79–1.69 (m, 1H); ¹³C NMR (75 MHz, CDCl₃, ppm) δ: 153.7, 136.4, 133.0, 130.1, 129.9, 128.0, 124.4, 61.9, 59.6, 51.2, 50.8, 27.6, 22.3; IR (KBr, thin film, cm⁻¹): 2956, 2813, 1574, 1473, 1075, 883, 781, 691; LRMS-ESI (m/z): 276 (47), 270 (4), 267 (2), 256 (10), 243 (17), 242 (100), 240 (7), 238 (3), 227 (8); HRMS-ESI (m/z): M⁺ calcd for C₁₃H₁₄ClN₅, 276.0938; found: 276.0998.

(5aS,10R)-10-(3-Chlorophenyl)-5,5a,6,7,8,10-hexahydropyrrolo[1,2-a]tetrazolo[1,5-d]pyrazine (4k). R_f = 0.34 (EtOAc–hexane 3 : 7), brown gum, [α]²⁵_D = −44.6° (c 1.0, CHCl₃), ¹H NMR (CDCl₃, 300 MHz, ppm): δ = 7.36 (s, 1H), 7.30 (s, 3H), 4.76–4.71 (dd, J₁ = 2.7 Hz, J₂ = 2.9 Hz, 1H), 4.58 (s, 1H), 4.17–4.10 (t, J = 11.2 Hz, 1H), 3.03–2.98 (m, 2H), 2.33–2.24 (q, J = 9.0 Hz, 1H), 2.20–2.15 (m, 1H), 2.02–1.95 (m, 2H), 1.83–1.73 (m, 1H); ¹³C NMR (75 MHz, CDCl₃, ppm) δ: 153.8, 139.0, 134.5, 130.0, 128.9, 128.2, 126.7, 63.3, 59.4, 51.6, 50.7, 27.5, 22.3; IR (KBr, thin film, cm⁻¹): 2950, 2807, 1596, 1470, 1316, 1078, 779, 691; LRMS-EI (m/z): 275 (7.5), 265 (3.8), 244 (1.2), 221 (33), 219 (100), 193 (48), 150 (46), 13 (30), 89 (13), 55 (14); HRMS-EI (m/z): M⁺ calcd for C₁₃H₁₄ClN₅, 275.0938, found: 275.0930.

(5aS,10R)-10-(4-Chlorophenyl)-5,5a,6,7,8,10-hexahydropyrrolo[1,2-a]tetrazolo[1,5-d]pyrazine (4l). R_f = 0.34 (EtOAc–hexane 3 : 7), brown gum, [α]²⁵_D = −47.4° (c 1.0, CHCl₃), ¹H NMR (CDCl₃, 300 MHz, ppm) δ: = 7.37–7.33 (t, J = 8.0 Hz, 2H), 7.08–7.02 (t, J = 8.4 Hz, 2H), 4.77–4.72 (dd, J₁ = 2.9 Hz, J₂ = 3.3 Hz, 1H), 4.59 (s, 1H), 4.17–4.10 (t, J = 11.0 Hz, 1H), 3.03–2.96 (m, 2H), 2.33–2.24 (q, J = 8.9 Hz, 1H), 2.22–2.12 (m, 1H), 1.97–1.83 (m, 2H), 1.79–1.70 (m, 1H); ¹³C NMR (75 MHz, CDCl₃, ppm) δ: 154.2, 130.1, 123.0, 115.9, 115.6, 63.3, 59.6, 51.7, 50.8, 27.7, 22.3; IR (KBr, thin film, cm⁻¹): 2856, 2813, 1602, 1508, 1219, 1150, 872, 551; LRMS-EI (m/z): 275 (0.1), 259 (3), 255 (5), 227 (5), 203 (39), 177 (35), 149 (17), 134 (37), 119 (20), 93 (26), 85 (100), 79 (27), 55 (31); HRMS-EI (m/z): M⁺ calcd for C₁₃H₁₄ClN₅, 275.0938; found: 275.0931.

(5aS,10R)-10-(2-Bromophenyl)-5,5a,6,7,8,10-hexahydropyrrolo[1,2-a]tetrazolo[1,5-d]pyrazine (4m). R_f = 0.33 (EtOAc–hexane 3 : 7), brown gum, [α]²⁵_D = −43.5° (c 1.0, CHCl₃), ¹H NMR (CDCl₃, 300 MHz, ppm) δ: 7.44–7.41 (d, J = 9.0 Hz, 1H), 7.25–7.22 (m, 3H), 5.30 (s, 1H), 4.76–4.70 (dd, J₁ = 3.2 Hz, J₂ = 3.1 Hz, 1H), 4.15–4.07 (t, J = 11.0 Hz, 1H), 3.09–3.00 (m, 1H), 2.96 (m, 1H), 2.40–2.32 (q, J = 8.7 Hz, 1H), 2.24–2.19 (m, 1H), 1.95–1.90 (m, 2H), 1.79–1.70 (m, 1H); ¹³C NMR (75 MHz, CDCl₃, ppm) δ: 153.6, 134.6, 133.9, 132.6, 129.6, 127.3, 126.7, 59.6, 59.0, 51.2, 50.7, 27.5, 22.2; IR (KBr, thin film, cm⁻¹): 2956, 2813, 1470, 1157, 1048, 757; LRMS-EI (m/z): 319 (0.1), 307 (0.5), 275 (5), 255 (2), 219 (100), 193 (33), 165 (14), 150 (46), 130 (21), 89 (12), 55 (12); HRMS-EI (m/z): M⁺ calcd for C₁₃H₁₄BrN₅, 319.0433; found: 319.0432.

(5aS,10R)-10-(3-Bromophenyl)-5,5a,6,7,8,10-hexahydropyrrolo[1,2-a]tetrazolo[1,5-d]pyrazine (4n). R_f = 0.33 (EtOAc–hexane 3 : 7), brown gum, [α]²⁵_D = −46.4° (c 1.0, CHCl₃), ¹H NMR (CDCl₃, 300 MHz, ppm) δ: 7.52–7.47 (t, J = 7.0 Hz, 2H), 7.35–7.27 (m, 2H), 4.77–4.72 (dd, J₁ = 3.5 Hz, J₂ = 3.4 Hz, 1H), 4.58 (s, 1H), 4.18–4.11 (t, J = 11.1 Hz, 1H), 3.04–3.01 (m, 2H), 2.34–2.28 (q, J = 8.9 Hz, 1H), 2.25 (m, 1H), 2.05–1.98 (m, 2H), 1.84–1.77 (m, 1H); ¹³C NMR (75 MHz, CDCl₃, ppm) δ: 153.8, 139.2, 132.0, 131.2, 130.3, 127.2, 122.8, 63.4, 59.6, 51.7, 50.8, 27.6, 22.3; IR (KBr, thin film, cm⁻¹): 2950, 2818, 1467, 1273, 1160, 1050, 858, 760; LRMS-ESI (m/z): 359 (33), 341 (8), 331 (6), 323 (16), 322 (89), 321 (22), 320 (100), 310 (4), 296 (3), 293 (7); HRMS-ESI (m/z): M⁺ calcd for C₁₃H₁₄BrN₅, 320.0433; found: 320.0507.

3-((5aS,10R)-5,5a,6,7,8,10-Hexahydropyrrolo[1,2-a]tetrazolo[1,5-d]pyrazin-10-yl)benzonitrile (4o). R_f = 0.32 (EtOAc–hexane 3 : 7), brown gum, [α]²⁵_D = −48.4° (c 1.0, CHCl₃), ¹H NMR (CDCl₃, 300 MHz, ppm) δ: 7.71–7.67 (m, 1H), 7.66–7.64 (m, 2H), 7.53–7.48 (m, 1H), 4.80–4.75 (dd, J₁ = 2.0 Hz, J₂ = 3.7 Hz, 1H), 4.68 (s, 1H), 4.20–4.12 (t, J = 11.5 Hz, 1H), 3.05–2.94 (m, 2H), 2.32–2.29 (q, J = 9.0 Hz, 1H), 2.23 (m, 1H), 2.04–1.98 (m, 2H), 185–1.80 (m, 1H); ¹³C NMR (75 MHz, CDCl₃, ppm) δ: 135.4, 138.6, 132.9, 132.5, 131.9, 129.7, 118.2, 113.0, 63.1, 59.6, 51.7, 50.8, 27.5, 22.3; IR (KBr, thin film, cm⁻¹): 2993, 2950, 2230, 1676, 1445, 1163, 792, 688; LRMS-EI (m/z): 266 (5), 237 (0.9), 210 (100), 184 (39), 156 (15), 141 (25), 129 (17), 115 (6), 70 (2), 55 (5); HRMS-EI (m/z): M⁺ calcd for C₁₄H₁₄N₆, 266.1280, found: 266.1279.

4-((5aS,10R)-5,5a,6,7,8,10-Hexahydropyrrolo[1,2-a]tetrazolo[1,5-d]pyrazin-10-yl)benzonitrile (4p). R_f = 0.32 (EtOAc–hexane 3 : 7), brown gum, [α]²⁵_D = −48.9° (c 1.0, CHCl₃), ¹H NMR (CDCl₃, 300 MHz, ppm) δ: 7.71–7.68 (d, J = 11.6 Hz, 1H), 7.67–7.53 (m, 2H), 7.50–7.25 (m, 1H), 4.80–4.79 (dd, J₁ = 3.5 Hz, J₂ = 3.7 Hz, 1H), 4.68 (s, 1H), 4.20–4.12 (t, J = 11.3 Hz, 1H), 3.08–2.95 (m, 2H), 2.35–2.26 (q, J = 8.8 Hz, 1H), 2.23–2.16 (m, 1H), 2.04–1.98 (m, 2H), 1.86–1.79 (1H); ¹³C NMR (75 MHz, CDCl₃, ppm) δ: 154.2, 130.1, 123.0, 115.9, 115.6, 63.3, 59.6, 51.7, 50.8, 27.7, 22.3; IR (KBr, thin film, cm⁻¹): 2917, 2846, 2225, 1607, 1467, 1273, 1157, 809, 556; LRMS-EI (m/z): 266 (2), 237 (0.2), 210 (100), 184 (42), 155 (17), 141 (32), 129 (17), 115 (7), 73 (4), 55 (14); HRMS-EI (m/z): M⁺ calcd for C₁₄H₁₄N₆, 266.1280, found: 266.1277.

(5aS,10R)-10-(2,4,6-Trimethoxyphenyl)-5,5a,6,7,8,10-hexahydropyrrolo[1,2-a]tetrazolo[1,5-d]pyrazine (4q). R_f = 0.19 (EtOAc–hexane 3 : 7), brown gum, [α]²⁵_D = −35.2° (c 1.0, CHCl₃), ¹H NMR (CDCl₃, 300 MHz, ppm) δ: 6.16 (s, 1H), 6.08 (s, 1H), 5.29 (s, 1H), 4.71–4.66 (dd, J₁ = 3.0 Hz, J₂ = 3.1 Hz, 1H), 4.14–4.06 (t, J = 10.8 Hz, 1H), 3.83 (s, 3H), 3.79 (s, 3H), 3.36 (s, 3H), 3.04–2.98 (m, 1H), 2.89–2.86 (m, 1H), 2.54–2.45 (q, J = 9.0 Hz, 1H), 2.11–2.06 (m, 1H), 1.95–1.88 (m, 1H), 1.78–168 (m, 1H), 1.66–1.58 (m, 1H); ¹³C NMR (75 MHz, CDCl₃, ppm) δ: 154.2, 130.1, 130.0, 115.9, 115.6, 63.3, 59.6, 51.7, 50.8, 27.7, 22.3; IR (KBr, thin film, cm⁻¹): 2923, 2851, 1462, 1256, 1031, 809; LRMS-EI (m/z): 331 (18), 272 (36), 234 (20), 210 (53), 206 (100), 179 (37), 155 (10), 141 (17), 121 (7), 83 (5), 69 (8), 55 (9); HRMS-EI (m/z): M⁺ calcd for C₁₆H₂₁N₅O₃, 331.1644, found: 331.1640.

(5aS,10R)-10-(Naphthalen-1-yl)-5,5a,6,7,8,10-hexahydropyrrolo[1,2-a]tetrazolo[1,5-d]pyrazine (4r). R_f = 0.32 (EtOAc–hexane 3 : 7), brown gum, [α]²⁵_D = −34.9° (c 1.0, CHCl₃), ¹H NMR (CDCl₃, 300 MHz, ppm) δ: 7.90–7.82 (m, 3H), 7.66–7.54 (m, 2H), 7.48–7.37 (m, 2H), 4.90 (s, 1H), 4.87–4.78 (dd, J₁ = 3.5 Hz, J₂ = 3.0 Hz, 1H), 4.32–4.40 (t, J = 11.0 Hz, 1H), 3.08–3.02 (m, 2H), 2.37–2.27 (m, 2H), 1.98–1.86 (m, 2H), 1.73–1.68 (m, 1H); ¹³C NMR (75 MHz, CDCl₃, ppm) δ: 154.3, 134.4, 131.7, 130.2, 128.7, 126.5, 125.8, 125.6, 124.9, 124.5, 122.8, 66.0, 60.1, 59.7, 51.5, 51.0, 27.7, 22.3; IR (KBr, thin film, cm⁻¹): 2961, 2807, 1508, 1377, 1155, 979, 795, 617; LRMS-EI (m/z): 291 (53), 281 (0.7), 262 (4), 235 (32), 210 (67), 208 (100), 180 (33), 166 (96), 141 (25), 127 (10), 102 (1), 68 (0.9), 55 (5); HRMS-EI (m/z): M⁺ calcd for C₁₇H₁₇N₅, 291.1484; found: 291.1481.

(5aS,10R)-10-Isobutyl-5,5a,6,7,8,10-hexahydropyrrolo[1,2-a]tetrazolo[1,5-d]pyrazine (4s). R_f = 0.31 (EtOAc–hexane 3 : 7), brown gum, [α]²⁵_D −46.9° (c 1.0, CHCl₃), ¹H NMR (CDCl₃, 300 MHz, ppm) δ: 3.98–3.93 (t, J = 7.9 Hz, 1H), 3.36–3.30 (dd, J₁ = 4.5 Hz, J₂ = 4.4 Hz, 1H), 3.18–3.12 (m, 1H), 2.02–2.95 (m, 2H), 2.63–2.54 (q, J = 9.0 Hz, 1H), 1.87–1.82 (m, 4H), 1.65–1.60 (m, 3H), 0.96 (d, J = 1.6 Hz, 3H), 0.94–0.93 (d, J = 1.7 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃, ppm) δ: 158.8, 60.4, 58.6, 55.8, 55.7, 55.2, 53.8, 50.4, 45.9, 28.4, 23.3; IR (KBr, thin film, cm⁻¹): 2956, 2868, 1467, 1166, 982, 762; LRMS-EI (m/z): 221 (3), 210 (0.7), 190 (0.9), 179 (10), 164 (100), 151 (3), 124 (3), 109 (5), 96 (15), 84 (8), 70 (9), 55 (10); HRMS-EI (m/z): M⁺ calcd for C₁₁H₁₉N₅, 221.1640, found: 221.1643.

(5aS,10R)-10-Phenethyl-5,5a,6,7,8,10-hexahydropyrrolo[1,2-a]tetrazolo[1,5-d]pyrazine (4t). R_f = 0.31 (EtOAc–hexane 3 : 7), brown gum, [α]²⁵_D −36.3° (c 1.0, CHCl₃), ¹H NMR (CDCl₃, 300 MHz, ppm) δ: 7.34–7.29 (m, 2H), 7.22–7.19 (m, 3H), 3.85–3.80 (t, J = 9.0 Hz, 1H), 3.36–3.31 (dd, J₁ = 4.5 Hz, J₂ = 4.4 Hz, 1H), 3.29–3.23 (dd, J₁ = 4.6 Hz, J₂ = 4.7 Hz, 1H), 3.12–3.06 (m, 2H), 2.83–2.78 (t, J = 7.2 Hz, 2H), 2.67–2.64 (q, J = 9.0 Hz, 1H); 2.13–2.06 (m, 2H), 1.92–1.82 (m, 3H), 1.70–1.62 (m, 1H); ¹³C NMR (75 MHz, CDCl₃, ppm) δ: 154.0, 141.5, 128.5, 128.40, 128.3, 125.9, 59.5, 58.5, 52.2, 50.8, 32.6, 30.0, 27.6, 22.5; IR (KBr, thin film, cm⁻¹): 2950, 2858, 1690, 1454, 1155, 1075, 746, 696; LRMS-EI (m/z): 269 (5), 251 (2), 213 (12), 179 (50), 164 (100), 150 (25), 123 (14), 109 (27), 96 (26), 91 (55), 69 (16), 55 (19); HRMS-EI (m/z): M⁺ calcd for C₁₅H₁₉N₅, 269.1640, found: 269.1648.

(5aS,10R)-10-(Thiophen-3-yl)-5,5a,6,7,8,10-hexahydropyrrolo[1,2-a]tetrazolo[1,5-d]pyrazine (4u). R_f = 0.31 (EtOAc–hexane 3 : 7), brown gum, [α]²⁵_D = −40.2° (c 1.0, CHCl₃), ¹H NMR (CDCl₃, 300 MHz, ppm) δ: 7.39 (s, 1H), 7.32 (m, 1H), 7.25 (s, 1H), 7.02–7.01 (d, J = 3.0 Hz, 1H), 4.76 (s, 1H), 4.71 (m, 1H), 4.15–4.09 (t, J = 8.4 Hz, 1H), 3.10–3.06 (m, 1H), 2.98–2.96 (m, 1H), 2.35–2.28 (q, J = 6.9 Hz, 1H), 2.20–2.16 (m, 1H), 1.96–1.94 (m, 2H), 1.78–1.74 (m, 1H); ¹³C NMR (75 MHz, CDCl₃, ppm) δ: 153.8, 137.4, 126.6, 124.4, 59.6, 59.2, 51.9, 50.8, 27.6, 22.2; IR (KBr, thin film, cm⁻¹): 2961, 2807, 1467, 1150, 836, 776, 603; LRMS-EI (m/z): 247 (30), 235 (4), 218 (3), 205 (10), 191 (73), 166 (13), 165 (100), 136 (23), 122 (80), 110 (33), 97 (13), 70 (8), 55 (9); HRMS-EI (m/z): M⁺ calcd for C₁₁H₁₃N₅S, 247.0892; found:247.0899.

(5aS,10R)-10-(Benzo[b]thiophen-3-yl)-5,5a,6,7,8,10-hexahydropyrrolo[1,2-a]tetrazolo[1,5-d]pyrazine (4v). R_f = 0.30 (EtOAc–hexane 3 : 7), brown gum, [α]²⁵_D = −39.4° (c 1.0, CHCl₃), ¹H NMR (CDCl₃, 300 MHz, ppm) δ: 8.03–8.06 (m, 1H), 7.87–7.84 (m, 1H), 7.68–7.43 (m, 1H), 7.42–7.39 (m, 2H), 5.60 (s, 1H), 3.62–3.53 (dd, J₁ = 4.5 Hz, J₂ = 6.7 Hz, 1H), 3.24–3.19 (m, 1H), 2.65–2.59 (m, 2H), 2.12–2.07 (m, 1H), 1.97–1.93 (m, 1H), 1.78–1.66 (m, 3H); ¹³C NMR (75 MHz, CDCl₃, ppm) δ: 140.7, 136.5, 128.5, 125.8, 125.0, 124.4, 122.7, 122.4, 116.2, 60.6, 55.7, 54.2, 49.6, 29.0, 22.8; IR (KBr, thin film, cm⁻¹): 2956, 2850, 1637, 1442, 1155, 1075, 762, 732; LRMS-EI (m/z): 297 (68), 268 (3), 241 (23), 215 (80), 186 (13), 172 (100), 160 (36), 147 (19), 115 (7), 89 (5), 69 (5), 55 (6); HRMS-EI (m/z): M⁺ calcd for C₁₅H₁₅N₅S, 297.1048; found: 297.1044.

Acknowledgements

The author thanks to Ms L. M. Hsu, at the Instruments Center, National Chung Hsing University, for her help in obtaining mass spectral data, and the Ministry of Science and Technology of Taiwan, for financially supporting this research under the contract MOST 103-2113-M-259-009-MY3.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1041454. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra00063k

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