Unusual Lewis-acid catalyzed formal (3+3)-cycloaddition of azomethine imines and nitrones to N-vinylpyrroles

Tetrahedron 73 (2017) 671e680

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Unusual Lewis-acid catalyzed formal (3þ3)-cycloaddition of azomethine imines and nitrones to N-vinylpyrroles Mariia M. Efremova a, Rafael R. Kostikov a, Alexander V. Stepakov a, Taras L. Panikorovsky a, Victoriya S. Shcherbakova b, Andrey V. Ivanov b, Alexander P. Molchanov a, * a b

Saint-Petersburg State University, Universitetskaya nab. 7/9, St-Petersburg, 199034, Russian Federation A.E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences, 1 Favorsky Str., 664033, Irkutsk, Russian Federation

a r t i c l e i n f o

a b s t r a c t

Article history: Received 29 September 2016 Received in revised form 2 December 2016 Accepted 16 December 2016 Available online 19 December 2016

The addition of Lewis acids change the reaction mechanism of the cycloaddition of N-vinylpyrroles with azomethine imine and C,N-diarylnitrones. The formal (3þ3)-cycloaddition is observed instead of (3þ2)dipolar cycloaddition, which take place in the absence of catalysts. This unusual (3þ3)-cycloaddition leads to heterocyclic compounds with pyrazolo[1,2-a]pyrrolo[1,2-d][1,2,4]triazine- and pyrrolo[2,1-d] [1,2,5]oxadiazine cores, which are difficultly achievable by other methods. © 2016 Elsevier Ltd. All rights reserved.

Keywords: Pyrroles (3þ3)-cycloadditiones Nitrones Azomethine imines Catalysis

1. Introduction 1,3-Dipoles, in particular, azomethine imines and nitrones are widely used as building blocks in the synthesis of heterocyclic compounds. (3þ2)-Cycloaddition reactions with unsaturated compounds are the most investigated for this types of 1,3-dipoles. Azomethine imines and nitrones are capable to react with the formation of (3þ2)-cycloadducts with both electron-deficient and electron-rich olefins, acetylenes, allenes.1 One of the most studied and widely used in organic synthesis are cyclic azomethine imines derived from pyrazolidin-3-ones due to their high reactivity and synthetic accessibility.2 Bicyclic derivatives of pyrazolidinone which are of interest to study due to their antimicrobial activity are formed by reaction with their participation.3 Today, the search for new ways of using synthetic 1,3-dipoles is an actual problem. One of the most promising directions in this area is (nþ3)-cycloaddition reactions, which include, in particular, (3þ3)-cycloaddition.4 Although, (3þ3)-cycloaddition is much more difficult to occur than (3þ2)-cycloaddition, in recent years

* Corresponding author. E-mail address: [email protected] (A.P. Molchanov). http://dx.doi.org/10.1016/j.tet.2016.12.034 0040-4020/© 2016 Elsevier Ltd. All rights reserved.

significant progress has been made in this area. So the latest advances showed that this reaction is an important method to construct six-membered nitrogenous heterocycles.5 Simultaneously, pyrroles and its derivatives are amongst the most important fundamental structural units of biologically and physiologically active molecules such as chlorophyll, porphyrin, hemoglobin, Vitamin B12 and others.6 The development of synthetic strategies for the preparation of pyrrolyl- or indolyl-triazoles, also pyrrolyl-imidazole ensembles remains the subject of a steadily growing number of investigations (see Scheme 1).7 2. Results and discussion The 1,3-dipolar cycloadditions reactions of available, highly reactive N-vinylpyrroles 1a-d8 with stable cyclic azomethine imines and nitrones have been investigated earlier.7b-d It was shown that in absence of catalysts, the reaction occured regioselectively on exo cyclic double bond with the formation of (3þ2)-cycloaddition products as a mixture of two diastereomeric pyrazolidines or isoxazolidines in good yields. In some cases this reaction demanded prolonged heating, therefore we have undertaken the attempt of the use of Lewis acids as catalysts to decrease the temperature and a time of the reaction.9 However, instead of expected products in

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Scheme 1. Reactions of N-vinylpyrroles with nitrones and azomethine imines.

the reaction of vinylpyrrole 1a and azomethine imine 2a in the presence of Ni(ClO4)2$6H2O we have received the products of the formal (3þ3) cycloaddition 3a and 4a with the core of pyrazolo[1,2а]pyrrolo[1,2-d][1,2,4]triazin-7(11H)-one. It is the first example of the reaction of N-vinylpyrroles and azomethine imines or nitrones with change of the reaction path depending on conditions. N-Vinylpyrrole 1a and azomethine imine 2a were chosen as model substrates to optimize the reaction conditions as shown in Table 1. Initially, the reaction was carried out in PhCl or CH2Cl2 at different temperatures in the presence of catalytic Ni(ClO4)2$6H2O (10%, entries 1, 2). The formation of the proposed products 3a and 4a was not observed in CH2Cl2 at room temperature (entry 2). When Co(acac)2 was employed only the decomposition of the reactants was observed (entry 3). ZrCl4 can also catalyze the reaction, generating the products 3a and 4a in 18 and 8% yields, respectively (entry 4). The (3þ3) reaction can also be catalyzed by In(SO3Me)3 in PhCl at 120 С, affording only product 3a in 16% yield (entry 5). We

then found that with NiCl2(Ph2PCH2)2 the products 3a and 4a were formed in 52 and 41% overall yields (entries 6 and 7). Finally, AgOС(O)CF3 was used as catalyst for the (3þ3) cycloaddition reaction. We found that AgOС(O)CF3 gave a relatively higher yield than other Lewis acids (entries 9e12). The best results were observed using AgOC(O)CF3 as catalyst in chlorobenzene at 120  C (entry 9), therefore these conditions have been used further. As can be seen from Table 1, the reaction proceeds to form a mixture of diastereomeric tetracyclic adducts 3a and 4a with the cis-isomer predominant. An isomer ratio was slightly different depending on the reaction conditions. Signals of the other products were not observed in appreciable amounts in 1H NMR spectra of the crude reaction mixture. It was found that the cycloaddition of N-vinylpyrroles 1a-d and azomethine imines 2a-c in the presence of AgOC(O)CF3 proceeds regioselectively with formation a mixture of diastereomeric pyrazolo[1,2-a]pyrrolo[1,2-d][1,2,4]triazin-7(11H)-ones 3a-j and 4a-j with cis-isomer predominant in all cases. The separation of the crude mixtures on silica gel gave pure samples of products 3a-j and 4a, d, e g-j. The nature of the substituents on the pyrrole ring had only a slight effect on the yields of the produced tetracyclic adducts 3 and 4. For example, increased yields of the adducts 3 were obtained by using bicyclic pyrrole 1a (Table 2, entries 1e3). However, when the substituent was the thienyl group (pyrrole 1d), products 3j and 4j were obtained with low yields (6 and 2%, respectively) possibly because of the poor stability of 2-(2-thienyl)pyrrole 1d under the reaction conditions (Table 2, entry 11). Spectroscopic methods and HRMS analysis were used to determine the structure of obtained compounds. To answer the question about the possibility of mutual transformation of diastereomers we heated the product 3a in chlorobenzene at 120  C, at first without catalyst for 9 h (the appearance of the second isomer was not observed by TLC), then with 25 mol percent of AgOC(O)CF3. After 14 h of heating the ratio of isomers 3a:4a was 10:1. Therefore, it is possible to believe that the product 4 only in part formed by isomerization of product

Table 1 Optimization of reactions conditions for Lewis acid-induced reaction of vinylpyrrole 1a and azomethine imine 2a.

No

LA

mol %

Solvent

T,  C

time, h

Yield [%]a 3a

4a

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

Ni(ClO4)2$6H2O Ni(ClO4)2$6H2O Co(acac)2 ZrCl4 In(SO3Me)3 NiCl2(Ph2PCH2)2 NiCl2(Ph2PCH2)2 NiCl2(Ph2PCH2)2 AgOС(O)CF3 AgOС(O)CF3 AgOС(O)CF3 AgOС(O)CF3

10 10 10 10 10 20 20 20 10 20 10 10

PhCl CH2Cl2 PhCl PhCl PhCl PhCl dioxane DMF PhCl PhCl dioxane PhMe

120 r.t. 120 120 120 120 100 100 120 120 100 100

5 24 4 3 1 5 11 5 3 2 5 4

26 e e 18 16 30 22 e 40 37 29 28

5 e e 8 e 22 19 e 12 2 15 15

a

from 1H NMR spectra of the crude reaction mixture using CH2I2 as the internal standard.

M.M. Efremova et al. / Tetrahedron 73 (2017) 671e680

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Table 2 Catalytic (3þ3) cycloaddition of N-vinylpyrroles 1a-d and azomethine imines 2a-c.

No

R1

1

R3

2

Time, h

Ratio 3:4a

Yield [%]b

1 2 3 4 5 6 7

-(CH2)4-(CH2)4-(CH2)4Ph Ph Ph

3

4

1a 1a 1a 1b 1b 1b 1c

Cl H OMe Cl H OMe Cl

2a 2b 2c 2a 2b 2c 2a

3 3 2 12 10 9 4

4:1 7:1 22:1 5:1 5:1 7:1 5:1

3a, 35 3b, 43 3c, 47 3d, 25 3e, 27 3f, 16 3g, 23

4a, 8 e e 4d, 2 4e, 5 e 4g, 4

8

1c

H

2b

5

5:1

3h, 22

4h, 5

9

1c

OMe

2c

5

6:1

3i, 23

4i, 3

1d

OMe

2c

7

3:1

3j, 6

4j, 2

10 a b

R2

2-thienyl

H H H

H

From 1H NMR spectra of the crude reaction mixture. Isolated yield.

3. The structure of compound 3a was unambiguously confirmed by X-ray diffraction analysis (Fig. 1).10 In the reaction of N-vinylpyrrole 1a with azomethine imine 2d, containing two methyl groups in 5-position of pyrazolidinone ring, an unexpected product 6 was isolated besides cycloadduct 5 (Scheme 2). The structure of the compound 6 was confirmed by Xray diffraction analysis (Fig. 2).11 Increasing the steric strain due to methyl groups leads to increasing the time of reaction and lowering the yield. Presumably, compound 6 may be a product of a

rearrangement of the adduct 5. The monitoring of the reaction using 1H NMR spectroscopy reveal the increasing of the quantity of

Scheme 2. Reaction of pyrrole 1a and azomethine imine 2d.

Fig. 1. X-ray crystal structure of 3a.

Fig. 2. X-ray crystal structure of 6.

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Table 3 Catalytic (3þ3) cycloaddition of N-vinylpyrroles 1a, b and nitrones 7a-f.

No

R1

1 2 3 4 5 6 7 8 9 10

-(CH2)4-(CH2)4-(CH2)4-(CH2)4-(CH2)4-(CH2)4Ph Ph Ph Ph

a b

R2

R3

R4

Time, h

Products

Ratio cis/transa

Yield, %b

H H H H

H OMe Cl H OMe Cl OMe H OMe Cl

Ph Ph Ph Me Me Me Ph Ме Ме Me

3 3 3 2 2 2 8 11 11 12

8a, 9a 8b, 9b 8c, 9c 8d, 9d 8e, 9e 8f, 9f 8g, 9g 8h, 9h 8i, 9i 8j, 9j

1.2:1 1.1:1 1.2:1 1.4:1 1.5:1 2.5:1 1.7:1 1.3:1 1.3:1 1.3:1

58 (8aþ9a) 74 (8bþ9b) 57 (8cþ9c) 37(8d); 38 (9d) 46 (8eþ9e) 60 (8f); 26 (9f) 45 (8gþ9g) 35 (8h); 29 (9h) 24(8i); 22 (9i) 30 (8j); 25 (9j)

From 1H NMR spectra of the crude reaction mixture. Isolated yield.

Fig. 3. X-ray crystal structure of 9d.

the product 6 relatively to the quantity of product 5 during the reaction. Unfortunately, our attempts to increase the yield adding of N-vinylpyrrole or catalyst did not give result. Then we attempted to involve in the reaction of catalytic (3þ3)cycloaddition another stable 1,3-dipole e nitrones. In the case of C,N-diarylnitrones and C-aryl-N-methylnitrones the addition of Lewis acids also results in change of the reaction path, and formal (3þ3)-cycloaddition is observed instead of the (3þ2)-dipolar cycloaddition. We have started with an establishment of optimal parameters for the reaction of N-vinylpyrrole 1a and nitrone 7a (see Supporting Information). The best results were observed with using of nickel (II) perchlorate hexahydrate (20 mol %) in toluene at 80  C. A range of nitrones 7a-f was tested in the (3þ3) cycloaddition with N-vinylpyrroles 1a, b (Table 3). Good reactivity, high regioselectivity and low stereoselectivity were observed for all nitrones. In particular, the reaction of the nitrone 7f with 4-chlorophenyl and methyl groups produced the bicyclic products 8f and 9f with the highest overall yield (86%) and with the highest stereoselectivity (2.5:1 ratio) (Table 3, entry 6). It has been established that (3þ3)-

cycloaddition of pyrroles 1a, b and nitrones 9а-f proceeds regioselectively giving mixtures of diastereomeric pyrrolo[2,1-d][1,2,5] oxadiazines, also with the cis-isomer predominant in all cases (Table 3). Signals of other products were not observed in appreciable amounts in 1H NMR spectra of the crude reaction mixture. The isomers were separated by column chromatography on silica. The relative configuration of the adducts was determined on the basis of X-ray diffraction analysis data for compound 9d (Fig. 3).12 Attempts to involve in catalytic reactions nitrones of other types: C,C-bis(methoxycarbonyl)- and N-aryl-C-carbamoylnitrones have not led to obtaining the products of (3þ3)-cycloaddition. The formation of products of (3þ2)-dipolar cycloaddition was observed analogous to the reactions without catalysts. A considerable amount of theoretical works devoted to the study of the mechanism and selectivity of (3þ2)-cycloaddition reactions of nitrones or azomethine imines with alkenes can be found in the literature.13 Depending on the type of the compounds it can be observed concerted (synchronous or asynchronous) and stepwise processes. Usually, the nitrone reacts as the nucleophile and the double bond of the N-vinylpyrrole as the electrophile as it was shown earlier. In catalytic reactions, the catalyst (Lewis acid)

Scheme 3. Proposed mechanism for the formation of the products.

M.M. Efremova et al. / Tetrahedron 73 (2017) 671e680

coordinates with the most nucleophilic oxygen atom of the nitrone (or N-atom of azomethine imine) blocking the approach of these atoms and increasing the electrophilicity of conjugated carbon atom. Thus it is possible to believe, that the change of electronic interaction is observed at the presence of the catalyst: pyrrole acts as nucleophile and the dipole as electrophile. Subsequent electrophilic attack on C2-atom of the pyrrole ring, 1,7-migration of the protone, and intramolecular cyclization leads to the final products (Scheme 3). It is necessary to note, that compounds with pyrrolo[1,2-d] [1,2,4]triazine- and pyrrolo[2,1-d][1,2,5]oxadiazine cores were previously prepared only by the reaction azafulvenium methides with diazene-1,2-dicarboxylates,14 and [6pþ4p] cycloaddition of N-Mannich bases of pyrrole and N,C-diphenylnitrone or azomethine imine, generated from N-phenylhydrazone of benzaldehyde.15 3. Conclusions In summary, we have found that the addition of Lewis acids to systems N-vinylpyrrole - azomethine imine and N-vinylpyrrole nitrone results in change of the reaction path. Formation of products of the formal (3þ3)-cycloaddition is observed instead of adducts of (3þ2)-dipolar cycloaddition, which form in the absence of the catalysts. (3þ3)-Cycloaddition occurs giving a mixtures of diastereomeric pyrazolo[1,2-a]pyrrolo[1,2-d][1,2,4]triazin-7(11H)ones in reactions of pyrroles and azomethine imines or pyrrolo[2,1d][1,2,5]oxadiazines in the reaction with nitrones, cis-isomer predominance in all cases. This methodology can be used as a convenient method of the synthesis of corresponding bi- and polyheterocyclic systems containing pyrrole fragment. 4. Experimental section

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CH2), 4.77 s (1H, CH), 5.17 s (1H, pyrrole), 6.13 q (1H, CH, J 6.0 Hz), 7.35e7.41 m (4H, Ph); 13C, (100 MHz, CDCl3): d ¼ 21.3 (CH3), 21.7 (CH2), 22.8 (CH2), 23.2 (CH2), 23.5 (CH2), 29.6 (CH2), 47.0 (CH2), 59.7 (CH), 66.9 (CH), 105.1 (CH), 118.4 (C), 125.0 (C), 126.7 (C), 128.8 (2CH), 130.4 (2CH), 134.3 (C), 137.3 (C), 170.1 (CО). HRMS (ESI): calculated for (MþNa)þ С20Н22ClN3NaO: 378.1344; found: 378.1349. Isomer 4a, yield 8% (30 mg), beige solid. Rf (33% EtOAc/hexane) 0.17. 1H, (400 MHz, CDCl3): d ¼ 1.66e1.83 m (4H, CH2), 1.67 d (3H, CH3, J 6.0 Hz), 1.88e1.96 m (1H, CH2), 2.04e2.08 m (1H, CH2), 2.35e2.56 m (4H, CH2), 2.52e2.66 m (1H, CH2), 3.19e3.25 m (1H, CH2), 4.95 s (1H, CH), 5.46 s (1H, pyrrole), 6.17 q (1H, CH, J 6.0 Hz), 7.08 d (2H, Ph, J 8 Hz), 7.29 d (2H, Ph, J 8 Hz); 13C, (100 MHz, CDCl3): d ¼ 21.7 (CH3), 22.0 (CH2), 22.9 (CH2), 23.2 (CH2), 23.5 (CH2), 30.6 (CH2), 46.9 (CH2), 60.6 (CH), 64.8 (CH), 104.2 (CH), 118.6 (C), 124.4 (C), 125.7 (C), 128.9 (2CH), 130.3 (2CH), 134.5 (C), 137.4 (C), 169.6 (CО). HRMS (ESI): calculated for (MþNa)þ С20Н22ClN3NaO: 378.1344; found: 378.1341. 4.1.3. rac-(5S,12R)-5-methyl-12-phenyl-5,7,8,9,10,12-hexahydro1H-pyrazolo[10,20 :1,2][1,2,4]triazino[4,5-a]indol-3(2H)-one (3b) Yield 43% (139 mg), white solid. M.p. 155e158  C. Rf (33% EtOAc/ hexane) 0.36. IR (KBr), n ¼ 2928, 2851, 1694 s, 1375, 1319, 1286, 1169, 754, 706 cm1; 1H, (400 MHz, CDCl3): d ¼ 1.61e1.80 m (3H, CH2), 1.70 d (3H, CH3, J 6.0 Hz), 1.86e1.94 m (1H, CH2), 2.36e2.41 m (2H, CH2), 2.41e2.53 m (2H, CH2), 2.58e2.65 m (1H, CH2), 2.80e2.89 m (1H, CH2), 3.05e3.12 m (1H, CH2), 3.34e3.42 m (1H, CH2), 4.80 s (1H, CH), 5.18 s (1Н, pyrrole), 6.15 q (1H, CH, J 6.0 Hz), 7.36e7.41 m (3H, Ph), 7.45e7.47 m (2H, Ph); 13C, (100 MHz, CDCl3): d ¼ 21.0 (CH3), 21.7 (CH2), 22.8 (CH2), 23.2 (CH2), 23.5 (CH2), 29.7 (CH2), 47.0 (CH2), 59.7 (CH), 67.6 (CH), 105.0 (CH), 118.3 (C), 124.8 (C), 127.3 (C), 128.5 (C), 128.6 (2CH), 129.1 (2CH), 138.7 (CH), 170.1 (CO). HRMS (ESI): calculated for (MþH)þ С20Н24N3Oþ: 322.1914; found: 322.1914.

4.1. General information All reactions were performed in anhydrous solvents. Reaction progress was monitored using thin layer chromatography (TLC) on precoated Silufol UVe254 plates. The IR spectra were measured on a Bruker Tensor 27 spectrophotometer. 1H and 13C NMR spectra were recorded in CDCl3 using a Bruker Avance 400 spectrometer. HRMS spectra were obtained with a Bruker-maXis (QTOF). Nitrones and azomethine imines were prepared using known procedures.16 4.1.1. General procedure for the synthesis of 8,9-dihydro-5Hpyrazolo[1,2-a]pyrrolo[1,2-d][1,2,4]triazin-7(11H)-ones A mixture of 1 mmol of the corresponding azomethine imine, 1.3 mmol of N-vinylpyrrole and 0.1 mmol (22 mg) of AgOC(O)CF3 in 10 mL of chlorobenzene was stirred at 120  C under argon until disappearance of the starting azomethine imine (TLC control). The reaction mixture was filtered through a layer of silica gel to separate the catalyst. The solvent was evaporated under reduced pressure and products were obtained by column chromatography on silica gel using gradient elution with hexane/ethyl acetate followed by crystallization from hexane/diethyl ether. 4.1.2. rac-(5S,12R)- and rac-(5R,12R)-12-(4-chlorophenyl)-5methyl-5,7,8,9,10,12-hexahydro-1H-pyrazolo[10,20 :1,2][1,2,4]triazino [4,5-a]indol-3(2H)-ones (3a) and (4a) Isomer 3a, yield 35% (124 mg), white solid. M.p. 143e145  C. Rf (33% EtOAc/hexane) 0.33. IR (KBr), n ¼ 2933, 2847, 1705 s, 1703 s, 1485, 1389, 1366, 1284, 1081, 808 cm1; 1H, (400 MHz, CDCl3): d ¼ 1.61e1.76 m (3H, CH2), 1.71 d (3H, CH3, J 6.0 Hz), 1.84e1.93 m (1H, CH2), 2.35e2.52 m (4H, CH2), 2.57e2.63 m (1H, CH2), 2.78e2.87 m (1H, CH2), 3.00e3.07 m (1H, CH2), 3.34e3.41 m (1H,

4.1.4. rac-(5S,12R)-12-(4-methoxyphenyl)-5-methyl-5,7,8,9,10,12hexahydro-1H-pyrazolo[10,20 :1,2][1,2,4]triazino[4,5-a]indol-3(2H)one (3c) Yield 47% (164 mg), white solid. M.p. 134e135  C. Rf (33% EtOAc/ hexane) 0.23. IR (KBr), n ¼ 2929, 2917, 2850, 1704 s, 1513, 1391, 1287, 1253, 1030, 560, 530 cm1; 1H, (400 MHz, CDCl3): d ¼ 1.64e1.79 m (3H, CH2), 1.68 d (3H, CH3, J 6.0 Hz), 1.86e1.93 m (1H, CH2), 2.37e2.52 m (4H, CH2), 2.57e2.63 m (1H, CH2), 2.78e2.83 m (1H, CH2), 3.05e3.12 m (1H, CH2), 3.31e3.38 m (1H, CH2), 3.83 s (3H, OCH3), 4.73 s (1H, CH), 5.19 s (1H, pyrrole), 6.13 q (1H, CH, J 6.0 Hz), 6.90 d (2H, Ph, J 8.6 Hz), 7.36 d (2H, Ph, J 8.6 Hz); 13C, (100 MHz, CDCl3): d ¼ 21.0 (CH3), 21.7 (CH2), 22.8 (CH2), 23.2 (CH2), 23.5 (CH2), 29.7 (CH2), 46.8 (CH2), 55.7 (CH3), 59.7 (CH), 67.1 (CH), 105.0 (CH), 113.9 (2CH). 118.3 (C), 124.8 (C), 127.7 (C), 130.3 (2CH), 130.7 (C), 159.8 (C), 170.2 (CO). HRMS (ESI): calculated for (MþH)þ C21H26N3Oþ 2 : 352.2020; found: 352.2013. 4.1.5. rac-(5S,11R)- and rac-(5R,12R)-11-(4-chlorophenyl)-5methyl-3-phenyl-8,9-dihydro-5H-pyrazolo[1,2-a]pyrrolo[1,2-d] [1,2,4]triazin-7(11H)-ones 3d and 4d Isomer 3d, yield 25% (95 mg), white solid. M.p. 204e205  C. Rf (33% EtOAc/hexane) 0.38. IR (KBr), n ¼ 2974, 1702, 1488, 1391, 1372, 1306, 1086, 1015, 763, 702 cm1; 1H, (400 MHz, CDCl3): d ¼ 1.32 d (3H, CH3, J 6.1 Hz), 2.46e2.52 m (1H, CH2), 2.84e2.93 m (1H, CH2), 3.10e3.13 m (1H, CH2), 3.33e3.39 m (1H, CH2), 4.85 s (1H, CH), 5.41 d (1H, pyrrole, J 3.3 Hz), 6.13 d (1H, pyrrole, J 3.3 Hz), 6.59 q (1H, CH, J 6.1 Hz), 7.26e7.35 m (2H, Ph), 7.39e7.47 m (8H, Ph); 13C, (100 MHz, CDCl3): d ¼ 20.7 (CH3), 29.5 (CH2), 46.7 (CH2), 60.9 (CH), 66.6 (CH), 108.0 (CH), 109.9 (CH), 127.4 (CH), 128.1 (2CH), 128.9 (2CH), 129.0 (2CH), 130.5 (C), 130.6 (2CH), 132.5 (C), 132.9 (C), 134.6

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(C), 136.8 (C), 170.6 (CO). HRMS (ESI): calculated for (MþNa)þ С22Н20ClN3NaOþ: 400.1187; found: 400.1196. Isomer 4d, yield 2% (9 mg), brown solid. Rf (33% EtOAc/hexane) 0.30. 1H, (400 MHz, CDCl3): d ¼ 1.29 d (3H, CH3, J 6.0 Hz), 1.42e1.51 m (1H, CH2), 2.01e2.07 m (1H, CH2), 3.24e3.30 m (1H, CH2), 3.42e3.51 (1H, CH2), 5.07 s (1H, CH), 5.86 d (1H, pyrrole, J 3.4 Hz), 6.13 d (1H, pyrrole, J 3.4 Hz), 6.65 q (1H, CH, J 6.0 Hz), 7.20e7.18 m (2H, Ph), 7.34e7.36 m (3H, Ph), 7.43e7.47 m (2H, Ph), 7.50e7.53 (2H, Ph); HRMS (ESI): calculated for (MþNa)þ С22Н20ClN3NaOþ: 400.1187; found: 400.1202. 4.1.6. rac-(5S,12R)- and rac-(5R,12R)-5-methyl-3,11-diphenyl-8,9dihydro-5H-pyrazolo[1,2-a]pyrrolo[1,2-d][1,2,4]triazin-7(11H)-ones 3e and 4e Isomer 3e, yield 27% (93 mg), white solid. M.p. 145e147  C. Rf (33% EtOAc/hexane) 0.38. IR (KBr), n ¼ 2981, 1703 s, 1396, 1376, 1310, 755, 744, 701 cm1; 1H, (400 MHz, CDCl3): d ¼ 1.34 d (3H, CH3, J 6.1 Hz), 2.46e2.53 m (1H, CH2), 2.88e2.95 m (1H, CH2), 3.10e3.16 m (1H, CH2), 3.33e3.39 m (1H, CH2), 4.87 s (1H, CH), 5.42 d (1H, pyrrole, J 3.4 Hz), 6.13 d (1H, pyrrole, J 3.4 Hz), 6.61 q (1H, CH, J 6.1 Hz), 7.33 t (1H, Ph, J 7.1 Hz), 7.41e7.50 m (9H, Ph); 13C, (100 MHz, CDCl3): d ¼ 20.7 (CH3), 29.6 (CH2), 46.7 (CH2), 60.9 (CH), 67.3 (CH), 107.9 (CH), 109.9 (CH), 127.3 (CH), 128.1 (2CH), 128.6 (2CH), 128.7 (CH), 129.0 (2CH), 129.3 (2CH), 131.1 (C), 132.7 (C), 132.7 (C), 138.2 (C), 170.7 (CО). HRMS (ESI): calculated for (MþH)þ С22Н22N3Oþ: 344.1757; found: 344.1763. Isomer 4e, yield 5% (17 mg), beige solid. Rf (33% EtOAc/hexane) 0.17. 1H, (400 MHz, CDCl3): d ¼ 1.26e1.34 m (1H, CH2) 1.30 d (3H, CH3, J 6.0 Hz), 1.93e1.99 m (1H, CH2), 3.29e3.35 m (1H, CH2), 3.42e3.51 m (1H, CH2), 5.10 s (1H, CH), 5.88 d (1H, pyrrole, CH2, J 3.4 Hz), 6.23 d (1H, pyrrole, CH2, J 3.4 Hz), 6.68 q (1H, CH, J 6.0 Hz), 7.23e7.25 m (1H, Ph), 7.32e7.39 m (5H, Ph), 7.45 d (2H, Ph, J 7.5 Hz), 7.53 m (2H, Ph); 13C, (100 MHz, CDCl3): d ¼ 21.0 (CH3), 30.4 (CH2), 46.8 (CH2), 61.3 (CH), 65.0 (CH), 106.4 (CH), 110.4 (CH), 127.2 (CH), 128.1 (2CH), 128.6 (2CH), 128.8 (CH), 129.0 (2CH), 129.2 (2CH), 132.0 (C), 132.9 (C), 132.7 (C), 138.1 (C), 170.2 (CO). HRMS (ESI): calculated for (MþNa)þ С22Н21N3NaOþ: 366.1577; found: 366.1578. 4.1.7. rac-(5S,12R)-11-(4-methoxyphenyl)-5-methyl-3-phenyl-8,9dihydro-5H-pyrazolo[1,2-a]pyrrolo[1,2-d][1,2,4]triazin-7(11H)-one 3f Yield 16% (59 mg), white solid. M.p. 174e175  C. Rf (33% EtOAc/ hexane) 0.28. IR (KBr), n ¼ 2977, 2933, 2838, 1696 s, 1512, 1276, 1304, 1235, 1172, 754 cm1; 1H, (400 MHz, CDCl3): d ¼ 1.33 d (3H, CH3, J 6.1 Hz), 2.44e2.51 m (1H, CH2), 2.87e2.91 m (1H, CH2), 3.11e3.17 m (1H, CH2), 3.33e3.36 m (1H, CH2), 3.85 s (3H, CH3), 4.81 s (1H, CH), 5.44 d (1H, pyrrole, J 3.4 Hz), 6.13 d (1H, pyrrole, J 3.4 Hz), 6.59 q (1H, CH, J 6.1 Hz), 6.94 d (2H, Ph, J 8.6 Hz), 7.31e7.34 m (1H, Ph), 7.39e7.48 m (6H, Ph); 13C, (100 MHz, CDCl3): d ¼ 20.7 (CH3), 29.6 (CH2), 46.5 (CH2), 55.3 (CH3), 60.9 (CH), 66.7 (CH), 107.9 (CH), 109.9 (CH), 114.0 (2CH), 127.3 (CH), 128.1 (2CH), 129.0 (2CH), 130.3 (C), 130.5 (2CH), 131.5 (C), 132.7 (C), 132.7 (C), 159.9 (C), 170.7 (CO). HRMS (ESI): calculated for (MþNa)þ С23Н23N3NaOþ 2 : 396.1682; found: 396.1689. 4.1.8. rac-(5S,12R)- and rac-(5R,12R)-8-(4-chlorophenyl)-14methyl-8,10,11,14-tetrahydro-5H-benzo[g]pyrazolo[10,20 :1,2][1,2,4] triazino[4,5-a]indol-12(6H)-ones 3g and 4g Isomer 3g, yield 23% (93 mg), beige solid. M.p. 194e196  C. Rf (33% EtOAc/hexane) 0.34. IR (KBr), n ¼ 2984, 2936, 1708 s, 1491, 1335, 1298, 1269, 1235, 759 cm1; 1H, (400 MHz, CDCl3): d ¼ 1.66 d (3H, CH3, J 6.0 Hz), 2.48e2.55 m (3H, CH2), 2.73e2.79 m (1H, CH2), 2.83e2.93 m (2H, CH2), 3.04e3.10 m (1H, CH2), 3.36e3.44 m (1H, CH2), 4.84 s (1H, CH), 5.24 s (1H, pyrrole), 6.84 q (1H, CH, J 6.0 Hz), 7.05e7.09 m (1H, Ph), 7.20e7.27 m (2H, Ph), 7.39e7.44 m (2H, Ph),

7.48 d (1H, Ph, J 7.7 Hz); 13C, (100 MHz, CDCl3): d ¼ 21.0 (CH3), 22.0 (CH2), 29.5 (CH2), 30.7 (CH2), 46.8 (CH2), 61.6 (CH), 66.9 (CH), 106.8 (CH), 120.0 (2CH), 123.7 (C), 125.1 (CH), 126.6 (C), 126.8 (CH), 128.6 (CH), 128.9 (2CH), 129.3 (C), 130.6 (2CH), 130.8 (C), 134.6 (C), 135.9 (C), 136.7 (C), 170.5 (CO). HRMS (ESI): calculated for (MþH)þ С24Н23ClN3Oþ: 404.1524; found: 404.1519. Isomer 4g, yield 4% (18 mg), brown solid. Rf (33% EtOAc/hexane) 0.25. 1H, (400 MHz, CDCl3): d ¼ 1.39e1.47 m (1H, CH2), 1.64 d (3H, CH3, J 6.0 Hz), 2.01e2.09 m (1H, CH2), 2.51e2.65 m (2H, CH2), 2.78e2.84 m (1H, CH2), 2.87e1.96 m (1H, CH2), 3.25e3.31 m (1H, CH2), 3.46e3.55 m (1H, CH2), 5.05 s (1H, CH), 5.72 s (1H, pyrrole), 6.91 q (1H, CH, J 6.0 Hz), 7.07e7.11 m (1H, Ph), 7.19 d (2H, Ph, J 8.4 Hz), 7.22e7.29 m (2H, Ph), 7.32 d (1H, Ph, J 8.4 Hz), 7.54 d (1H, Ph J 7.7 Hz). HRMS (ESI): calculated for (MþNa)þ С24Н22ClN3NaOþ: 426.1344; found: 426.1339. 4.1.9. rac-(5S,12R)- and rac-(5R,12R)-14-methyl-8-phenyl8,10,11,14-tetrahydro-5H-benzo[g]pyrazolo[10,20 :1,2][1,2,4]triazino [4,5-a]indol-12(6H)-ones 3h and 4h Isomer 3h, yield 22% (83 mg), beige solid. M.p. 191e193  C. Rf (33% EtOAc/hexane) 0.36. IR (KBr), n ¼ 2929, 1706 s, 1602, 1496, 1414, 1368, 1304, 1234, 1097, 767, 697 cm1; 1H, (400 MHz, CDCl3): d ¼ 1.67 d (3H, CH3, J 6.1 Hz), 2.47e2.55 m (3H, CH2), 2.75 m (1H, CH2), 2.84e2.95 m (2H, CH2), 3.09e3.15 m (1H, CH2), 3.40 m (1H, CH2), 4.86 s (1H, CH), 5.25 s (1H, pyrrole), 6.84 q (1H, CH, J 6.0 Hz), 7.05e7.08 m (1H, Ph J 7.3 Hz), 7.19e7.25 m (2H, Ph), 7.41e7.45 m (3H, Ph), 7.48e7.50 m (3H, Ph); 13C, (100 MHz, CDCl3): d ¼ 21.0 (CH3), 22.0 (CH2), 29.6 (CH2), 30.8 (CH2), 46.8 (CH2), 61.6 (CH), 67.6 (CH), 106.7 (CH), 120.0 (CH), 123.7 (C), 125.0 (CH), 126.5 (C), 126.9 (CH), 128.6 (CH), 128.6 (2CH), 128.7 (CH), 129.2 (2CH), 129.5 (C), 131.4 (C), 135.9 (C), 138.2 (C), 170.6 (CO). HRMS (ESI): calculated for (MþNa)þ С24Н23N3NaOþ: 392.1733; found: 392.1744. Isomer 4h, yield 5% (20 mg), beige solid. Rf (33% EtOAc/hexane) 0.23. 1H, (400 MHz, CDCl3): d ¼ 1.19e1.32 m (1H, CH2), 1.65 d (3H, CH3, J 6.0 Hz), 1.93e2.00 m (1H, CH2), 2.51e2.66 m (2H, CH2), 2.78e2.83 m (1H, CH2), 2.88e2.97 m (1H, CH2), 3.30e3.35 m (1H, CH2), 3.49 dt (1H, CH2, J 12.2, 9.7 Hz), 5.08 s (1H, CH), 5.74 s (1H, pyrrole), 6.93 q (1H, CH, J 6.0 Hz), 7.06e7.10 m (1H, Ph), 7.22e7.29 m (4H, Ph), 7.33e7.35 m (3H, Ph), 7.56 d (3H, Ph, J 7.4 Hz); 13C, (100 MHz, CDCl3): d ¼ 21.2 (CH3), 22.2 (CH2), 30.3 (CH2), 30.8 (CH2), 46.6 (CH2), 61.9 (CH), 65.1 (CH), 105.3 (CH), 120.0 (CH), 124.3 (C), 124.9 (CH), 125.7 (C), 126.9 (CH), 128.5 (CH), 128.6 (CH), 128.8 (2CH), 129.2 (2CHþC), 129.6 (C), 135.8 (C), 137.9 (C), 170.3 (CO). HRMS (ESI): calculated for (MþNa)þ С24Н23N3NaOþ: 392.1733; found: 392.1737. 4.1.10. rac-(5S,12R)- and rac-(5R,12R)-8-(4-methoxyphenyl)-14methyl-8,10,11,14-tetrahydro-5H-benzo[g]pyrazolo[10,20 :1,2][1,2,4] triazino[4,5-a]indol-12(6H)-ones 3i and 4i Isomer 3i, yield 23% (91 mg), beige solid. M.p. 183e185  C. Rf (33% EtOAc/hexane) 0.29. IR (KBr), n ¼ 2936, 2831, 1710 s, 1612, 1514, 1334, 1305, 1245, 1176, 1030, 826, 760 cm1; 1H, (400 MHz, CDCl3): d ¼ 1.66 d (3H, CH3, J 6.0 Hz), 2.45e2.56 m (3H, CH2), 2.73e2.76 m (1H, CH2), 2.84e2.93 m (2H, CH2), 3.09e3.15 m (1H, CH2), 3.33e3.41 m (1H, CH2), 3.85 s (3H, CH3), 4.80 s (1H, CH), 5.27 s (1H, pyrrole), 6.83 q (1H, CH, J 6.0 Hz), 9.95 d (2H, Ph J 8.4 Hz), 7.04e7.08 m (1Н, Ph), 7.19e7.25 m (2H, Ph), 7.40 d (2H, Ph J 8.4 Hz), 7.48 d (1H, Ph, J 7.7 Hz); 13C, (100 MHz, CDCl3): d ¼ 21.0 (CH3), 22.0 (CH2), 29.6 (CH2), 30.8 (CH2), 46.5 (CH2), 55.3 (CH3), 61.6 (CH), 67.6 (CH), 106.7 (CH), 114.0 (2CH), 120.0 (CH), 123.7 (C), 124.9 (CH), 126.4 (C), 126.8 (CH), 128.5 (CH), 129.5 (C), 130.2 (C), 130.4 (2CH), 131.8 (C), 135.9 (C), 159.9 (C), 170.6 (CO). HRMS (ESI): calculated for (MþNa)þ С25Н25N3NaOþ: 422.1839; found: 422.1832. Isomer 4i, yield 3% (12 mg), brown solid. Rf (33% EtOAc/hexane) 0.14. 1H, (400 MHz, CDCl3): d ¼ 1.30e1.39 m (1H, CH2), 1.64 d (3H,

M.M. Efremova et al. / Tetrahedron 73 (2017) 671e680

CH3, J 6.0 Hz), 1.95e2.01 m (1H, CH2), 2.51e2.65 m (2H, CH2), 2.77e2.83 m (1H, CH2), 2.88e2.97 m (1H, CH2), 3.27e3.32 m (1H, CH2), 3.45e3.53 m (1H, CH2), 3.78 s (3H, CH3), 5.05 s (1H, CH), 5.73 s (1H, pyrrole), 6.86 d (2H, Ph, J 8.7 Hz), 6.92 q (1H, CH, J 6.0 Hz), 7.08e7.09 m (1H, Ph), 7.15 d (2H, Ph, J 8.7 Hz), 7.22e7.29 m (2H, Ph), 7.55 d (1H, Ph, J 7.7 Hz). HRMS (ESI): calculated for (MþNa)þ С25Н25N3NaOþ: 422.1839; found: 422.1842. 4.1.11. rac-(5S,12R)- and rac-(5R,12R)-11-(4-methoxyphenyl)-5methyl-3-(thiophen-2-yl)-8,9-dihydro-5H-pyrazolo[1,2-a]pyrrolo [1,2-d][1,2,4]triazin-7(11H)-ones 3j and 4j Isomer 3j, yield 6% (22 mg), beige solid. Rf (33% EtOAc/hexane) 0.22. 1H, (400 MHz, CDCl3): d ¼ 1.49 d (3H, CH3, J 6.1 Hz), 2.38e2.43 m (1H, CH2), 2.83e2.92 m (1H, CH2), 3.11e3.16 m (1H, CH2), 3.31e3.39 m (1H, CH2), 4.77 s (1H, CH), 5.42 dd (1H, pyrrole, J 3.5, 0.9 Hz), 6.13 d (1H, pyrrole, J 3.5 Hz), 6.60 q (1H, CH, J 6.1 Hz), 6.94 d (2H, Ph, J 8.6 Hz), 7.08 dd (1H, thienyl, J 5.1, 3.5 Hz), 7.12 dd (1H, thienyl, J 3.5, 0.9 Hz), 7.28 dd (1H, thienyl, J 5.1, 0.9 Hz), 7.38 d (2H, Ph, J 8.6 Hz); 13C, (100 MHz, CDCl3): d ¼ 20.7 (CH3), 29.6 (CH2), 46.6 (CH2), 55.3 (CH3), 61.0 (CH), 66.8 (CH), 107.6 (CH), 111.0 (CH), 114.0 (2CH), 124.4 (C), 125.0 (CH), 125.1 (CH), 127.7 (CH), 130.1 (C), 130.5 (2CH), 131.6 (C), 134.0 (C), 159.9 (C), 170.7 (CO). HRMS (ESI): calculated for (MþNa)þ C21H21N3NaO2S: 402.1247; found: 402.1256. Isomer 4j, yield 2% (8 mg), brown solid. Rf (33% EtOAc/hexane) 0.16. 1H, (400 MHz, CDCl3): d ¼ 1.32e1.41 m (1H, CH2), 1.47 d (3H, CH3, J 5.9 Hz), 1.95e2.04 m (1H, CH2), 3.26e3.31 m (1H, CH2), 3.41e3.51 m (1H, CH2), 3.79 s (3H, CH3), 5.05 s (1H, CH), 5.82 d (1H, pyrrole, J 3.5 Hz), 6.32 d (1H, pyrrole, J 3.6 Hz), 6.68 q (1H, CH, J 5.9 Hz), 6.88 d (2H, Ph, J 8.7 Hz), 7.09e7.11 m (2H Ph, 1H thienyl), 7.17 d (1H, thienyl, J 2.9 Hz), 7.29e7.30 m (1H, thienyl). HRMS (ESI): calculated for (MþNa)þ C21H21N3NaO2S: 402.1247; found: 402.1238. 4.1.12. rac-(5S,12R)-1,1,5-trimethyl-12-phenyl-5,7,8,9,10,12hexahydro-1H-pyrazolo[10,20 :1,2][1,2,4]triazino[4,5-a]indol-3(2H)one 5 Yield 12% (43 mg), brown solid. Rf (33% EtOAc/hexane) 0.42. IR (KBr), n ¼ 2931, 2850, 1703, 1452,1372, 1298, 1245, 730, 705 cm1; 1 H, (400 MHz, CDCl3): d ¼ 0.69 s (3H, CH3), 1.26 s (3H, CH3), 1.58e1.65 m (2H, CH2), 1.68e1.77 m (3H, CH2), 1.71 d (3H, CH3, J 6.1 Hz), 1.82e1.87 m (2H, CH2), 2.22 d (1H, CH2, J 16.6 Hz), 2.31e2.34 m (1H, CH2), 2.43e2.48 m (1H, CH2), 2.57e2.63 m (1H, CH2), 2.75 d (1H, CH2, J 16.6 Hz), 5.10 s (1H, CH), 5.21 s (1H, pyrrole), 6.18 q (1H, CH J 6.1 Hz), 7.27e7.30 m (1H, Ph), 7.32e7.36 m (2H, Ph), 7.43e7.46 m (2H, Ph); 13C, (100 MHz, CDCl3): d ¼ 20.6 (CH3), 21.4 (CH2), 22.8 (CH2), 23.2 (CH2), 23.5 (CH2), 25.0 (CH3), 29.3 (CH3), 43.0 (CH2), 58.1 (CH), 61.4 (C), 62.6 (CH), 105.2 (CH), 118.3 (C), 124.0 (C), 127.5 (CH), 127.6 (C), 127.8 (2CH), 128.5 (2CH), 142.4 (C), 169.2 (CO). HRMS (ESI): calculated for (MþAg)þ C22H27N3AgOþ: 456.1200; found: 456.1185. 4.1.13. rac-(7S,12aR)-5-benzyl-7,11,11-trimethyl-1,2,3,10,11,12ahexahydropyrazolo[10,20 :1,2][1,2,4]triazino[6,5,4-hi]indol-9(7H)-one 6 Yield 5% (19 mg), beige solid. M.p. 153e155  C. Rf (33% EtOAc/ hexane) 0.35. IR (KBr), n ¼ 2930, 2844, 1693, 1416, 1368, 1290, 1210, 708 cm1; 1H, (400 MHz, CDCl3): d ¼ 1.31 (3H, CH3), 1.45 d (3H, CH3, J 6.1 Hz), 1.46 s (3H, CH3), 1.53e1.62 m (1H, CH2), 1.66e1.76 m (1H, CH2), 1.94e2.01 m (1H, CH2), 2.24 d (1H, CH2, J 16.6 Hz), 2.23e2.28 m (1H, CH2), 2.44e2.48 m (2H, CH2), 2.69 d (1H, CH2, J 16.6 Hz), 3.87 s (2H, CH2), 4.05e4.08 m (1H, CH), 5.57 s (1H, pyrrole), 6.14 q (1H, CH, J 6.1 Hz), 7.20e7.24 m (3H, Ph), 7.28e7.32 m (2H, Ph); 13C, (100 MHz, CDCl3): d ¼ 20.0 (CH3), 21.7 (CH2), 22.4 (CH2), 24.4 (CH3), 29.2 (CH2), 29.5 (CH3), 32.7 (CH2), 43.7 (CH2), 57.3

677

(CH), 60.0 (CH), 60.7 (C), 108.4 (CH), 116.1 (C), 124.9 (C), 126.4 (CH), 128.5 (2CH), 128.8 (2CH), 129.3 (C), 138.9 (C), 170.0 (CO). HRMS (ESI): calculated for (MþNa)þ C22H27N3NaOþ: 372.2046; found: 372.2054. 4.1.14. General procedure for the synthesis of 2,4-dihydro-1Hpyrrolo[2,1-d][1,2,5]oxadiazines A mixture of 1 mmol of the corresponding nitrone, 1.3 mmol of N-vinylpyrrole and 0.2 mmol (73 mg) of Ni(ClO4)2$6H2O in 10 mL of toluene was stirred under argon atmosphere at 80  C until nitrone disappeared (TLC-control). The reaction mixture was filtered through silica gel, the solvent was removed under reduced pressure and products were obtained by column chromatography on silica gel, using gradient elution with hexane/methylene chloride followed by crystallization (EtOH or hexane/diethyl ether) to give the pure product. 4.1.15. rac-(1R,4S)- and rac-(1R,4R)-4-methyl-1,2-diphenyl2,4,6,7,8,9-hexahydro-1H-[1,2,5]oxadiazino[5,4-a]indoles 8a and 9a Yield 58% (201 mg), mixture of diastereomers, ratio cis:trans e 1.2:1, white solid. IR (KBr), n ¼ 2925, 2838, 1596, 1493, 1452, 1369, 1320, 1136, 1098, 1029, 766, 754, 692, 597; 1H, (400 MHz, CDCl3): d ¼ 1.69e1.85 m (5H, CH2), 1.81 d (3H, CH3trans, J 5.6 Hz), 1.95 d (3H, CH3cis, J 5.5 Hz), 1.94e1.95 m (3H, CH2), 2.49 br s (4H, CH2), 2.60e2.66 m (4H, CH2), 5.48 s (1H, CHcis), 5.51 s (1H, CHtrans), 5.58 s (1H, pyrrole, trans), 5.68 s (1H, pyrrole, cis), 5.78 q (1H, CHcis, J 5.5 Hz), 6.02 q (1H, CHtrans, J 5.6 Hz), 6.97e7.10 m (7H, Ph), 7.19e7.25 m (13H, Ph); 13C, (100 MHz, CDCl3): d ¼ 20.6 (CH3trans), 21.3 (CH3cis), 22.6 (CH2), 23.0 (CH2), 23.1 (2CH2), 23.5 (4CH2), 66.7 (CH), 67.4 (CH), 84.2 (CH), 84.9 (CH), 103.5 (CH), 103.8 (CH), 118.1 (C), 118.1 (C), 119.5 (2CH), 121.2 (2CH), 123.3 (C), 123.4 (C), 123.8 (CH), 124.8 (CH), 127.6 (CH), 127.7 (CH), 127.8 (C), 127.9 (2CH), 128.0 (2CH), 128.1 (C), 128.4 (4CH), 129.3 (2CH), 129.4 (2CH), 139.2 (C), 139.2 (C), 148.3 (C), 148.4 (C). HRMS (ESI): calculated for (MþH)þ С23Н25N2Oþ: 345.1961; found: 345.1955. 4.1.16. rac-(1R,4S)- and rac-(1R,4R)-1-(4-methoxyphenyl)-4methyl-2-phenyl-2,4,6,7,8,9-hexahydro-1H-[1,2,5]oxadiazino[5,4-a] indoles 8b and 9b Yield 74% (278 mg), mixture of diastereomers, ratio cis:trans e 1.1:1, white solid. IR (KBr), n ¼ 2930, 2837, 1609, 1512 s, 1490, 1370, 1303, 1248 s, 1175, 1033, 761, 694 cm1; 1H, (400 MHz, CDCl3): d ¼ 1.65e1.85 m (6H, CH2), 1.79 d (3H, CH3trans, J 5.7 Hz), 1.92 d (3H, CH3cis, J 5.5 Hz), 1.91e1.97 m (2H, CH2), 2.47e2.48 m (4H, CH2), 2.63e2.67 m (4H, CH2), 3.74 s (3H, CH3), 3.75 s (3H, CH3), 5.46 s (1H, CHcis), 5.48 s (1H, CHtrans), 5.50 s (1H, pyrrole, trans), 5.59 s (1H, pyrrole, cis), 5.85 q (1H, CHcis, J 5.6 Hz), 5.99 q (1H, CHtrans, J 5.6 Hz), 6.70e6.74 m (4H, Ar), 6.97e7.08 m (6H, Ar), 7.12e7.15 m (4H, Ar), 7.17e7.22 m (4H, Ar); 13C, (100 MHz, CDCl3): d ¼ 20.5 (CH3trans), 21.3 (CH3cis), 22.6 (CH2), 23.0 (CH2), 23.1 (CH2), 23.2 (CH2), 23.5 (2CH2), 23.6 (2CH2), 55.1 (CH3), 55.2 (CH3), 66.6 (CH), 67.2 (CH), 84.2 (CH), 84.9 (CH), 103.4 (CH), 103.7 (CH), 113.2 (2CH), 113.3 (2CH), 117.9 (C), 118.0 (C), 119.8 (2CH), 121.4 (2CH), 123.2 (C), 123.3 (C), 123.9 (CH), 124.8 (CH), 128.2 (C), 128.4 (4CH), 128.6 (C), 130.5 (2CH), 130.6 (2CH), 131.3 (C), 131.3 (C), 148.4 (C), 148.5 (C), 159.0 (C), 159.1 (C). HRMS (ESI): calculated for (MþH)þ С24Н27N2Oþ 2 : 375.2067; found: 375.2074. 4.1.17. rac-(1R,4S)- and rac-(1R,4R)-1-(4-chlorophenyl)-4-methyl2-phenyl-2,4,6,7,8,9-hexahydro-1H-[1,2,5]oxadiazino[5,4-a]indoles 8c and 9c Yield 57% (214 mg), mixture of diastereomers, ratio cis:trans e 1.2:1, light pink solid. IR (KBr), n ¼ 2928, 1597, 1490 s, 1436, 1370, 1302, 1089, 1015, 762, 695 cm1; 1H, (400 MHz, CDCl3):

678

M.M. Efremova et al. / Tetrahedron 73 (2017) 671e680

d ¼ 1.66e1.85 m (6H, CH2), 1.78 d (3H, CH3trans, J 5.6 Hz), 1.91 d (3H, CH3cis, J 5.6 Hz), 1.90e1.97 m (2H, CH2), 1.46e1.48 m (4Н, СH2), 1.59e1.63 m (4H, CH2), 5.47 s (1H, CHcis), 5.48 s (1H, CHtrans), 5.54 s (1H, pyrrole, trans), 5.64 s (1H, pyrrole, cis), 5.84 q (1H, CHcis, J 5.6 Hz), 5.98 q (1H, CHtrans, J 5.6 Hz), 6.98e7.07 m (6H, Ph), 7.14e7.23 m (12H, Ph); 13C, (100 MHz, CDCl3): d ¼ 20.5 (CH3trans), 21.2 (CH3cis), 22.7 (CH2), 23.0 (CH2), 23.1 (2CH2), 23.5 (4CH2), 66.0 (CH), 66.7 (CH), 84.3 (CH), 84.9 (CH), 103.7 (CH), 103.8 (CH), 118.1 (C), 118.2 (C), 119.4 (2CH), 121.1 (2CH), 123.5 (C), 123.6 (C), 124.0 (CH), 125.0 (CH), 127.2 (C), 127.4 (C), 128.1 (2CH), 128.2 (2CH), 128.6 (4CH), 130.6 (2CH), 130.7 (2CH), 133.4 (C), 133.5 (C), 137.7 (2C), 148.0 (C), 148.1 (C). HRMS (ESI): calculated for (MþH)þ С23Н24ClN2Oþ: 379.1572; found: 379.1560. 4.1.18. rac-(1R,4S)- and rac-(1R,4R)-2,4-dimethyl-1-phenyl2,4,6,7,8,9-hexahydro-1H-[1,2,5]oxadiazino[5,4-a]indoles 8d and 9d Isomer 8d, yield 37% (103 mg), white solid. M.p. 82e84  C. Rf (50% methylene chloride/hexane) 0.22. IR (KBr), n ¼ 2919, 2830, 1433, 1370, 1303, 1120 s, 756, 700 cm1; 1H, (400 MHz, CDCl3): d ¼ 1.65e1.78 m (3H, CH2), 1.83 dd (3H, CH3, J 5.7, 0.7 Hz), 1.86e1.94 m (1H, CH2), 2.40e2.43 m (2H, CH2), 2.48e2.51 m (2H, CH2), 2.54 s (3H, CH3), 4.65 s (1H, CH), 5.20 s (1H, pyrrole), 5.69 q (1H, CH, J 5.7 Hz), 7.32e7.39 m (5H, Ph); 13C, (100 MHz, CDCl3): d ¼ 21.6 (СН2), 21.8 (СН3), 22.9 (СН2), 23.3 (СН2), 23.6 (СН2), 43.4 (СН3), 70.9 (СН), 82.8 (СН), 103.0 (СН), 117.4 (С), 123.0 (С), 128.1 (СН), 128.2 (С), 128.4 (2СН), 129.2 (2СН), 139.4 (С). HRMS (ESI): calculated for (MþNa)þ С18Н22N2NaOþ: 305.1624; found: 305.1638. Isomer 9d, yield 38% (106 mg), white solid. M.p. 93e94  C. Rf (methylene chloride) 0.58. IR (KBr), n ¼ 2928, 2843, 1455, 1340, 1305, 1159, 1127, 925, 778, 761, 708 cm1; 1H, (400 MHz, CDCl3): d ¼ 1.54e1.62 m (1H, CH2), 1.64e1.75 m (1H, CH2), 1.71 d (3H, CH3, J 5.6 Hz), 1.75e1.83 m (1H, CH2), 1.88e1.96 m (1H, CH2), 2.39e2.42 m (2H, CH2), 2.51e2.57 m (1H, CH2), 2.54 s (3H, CH3), 2.65e2.72 m (1H, CH2), 4.69 s (1H, CH), 5.14 s (1H, pyrrole), 5.83 q (1H, CH, J 5.6 Hz), 7.32e7.36 m (5H, Ph); 13C, (100 MHz, CDCl3): d ¼ 20.4 (СН3), 23.2 (СН2), 23.3 (СН2), 23.7 (СН2), 24.4 (СН2), 43.6 (СН3), 71.3 (СН), 84.8 (СН), 104.2 (СН), 118.1 (С), 123.9 (С), 128.1 (СН), 128.3 (2СН), 129.3 (2СН), 130.3 (С), 139.2 (С). HRMS (ESI): calculated for (MþAg)þ С18Н22AgN2Oþ: 389.0778; found: 389.0784. 4.1.19. rac-(1R,4S)- and rac-(1R,4R)-1-(4-methoxyphenyl)-2,4dimethyl-2,4,6,7,8,9-hexahydro-1H-[1,2,5]oxadiazino[5,4-a]indoles 8e and 9e Yield 46% (142 mg), mixture of diastereomers, ratio cis:trans e 20:1, white solid. IR (KBr), n ¼ 2962, 2840, 1609, 1513, 1303, 1246, 1183, 1029, 829 cm1; 1H, (400 MHz, CDCl3): d ¼ 1.64e1.78 m (3H, CH2), 1.81 d (3H, CH3, J 5.7 Hz), 1.86e1.93 m (1H, CH2), 2.42 t (2H, CH2, J 5.5 Hz), 2.48e2.55 m (2H, CH2), 2.52 s (3H, CH3), 3.82 s (3H, CH3); 4.60 s (1H, CH), 4.64 s (CH, minor isomer); 5.16 s (pyrrole, minor isomer), 5.21 s (1H, pyrrole), 5.68 q (1H, CH, J 5.7 Hz), 6.87 d (2H, Ar, J 8.5 Hz), 7.30 d (2H, Ar, J 8.5 Hz); 13C, (100 MHz, CDCl3): d ¼ 21.6 (CH2), 21.8 (CH3), 22.9 (CH2), 23.3 (CH2), 23.6 (CH2), 43.3 (CH3), 55.3 (CH3), 70.3 (CH), 82.8 (CH), 103.0 (CH), 113.7 (2CH), 117.4 (C), 122.9 (C), 128.5 (C), 130.4 (2CH), 131.7 (C), 159.5 (C). HRMS (ESI): calculated for (MþAg)þ С19Н24AgN2Oþ: 419.0883; found: 419.0893. 4.1.20. rel-(1R,4S)- and rel-(1R,4R)-1-(4-chlorophenyl)-2,4dimethyl-2,4,6,7,8,9-hexahydro-1H-[1,2,5]oxadiazino[5,4-a]indoles 8f and 9f0 Isomer 8f, yield 60% (189 mg), white solid. M.p. 138e141  C. Rf (50% methylene chloride/hexane) 0.33.IR (KBr), n ¼ 2921, 2837, 1488, 1407, 1368, 1318, 1118, 1087, 1014, 806 cm1; 1H, (400 MHz, CDCl3): d ¼ 1.64e1.78 m (3H, CH2), 1.81 d (3H, CH3, J 5.7 Hz), 1.86e1.93 m (1H, CH2), 2.40e2.43 m (2H, CH2), 2.47e2.56 m (2H,

CH2), 2.52 s (3H, CH3), 4.63 s (1H, CH), 5.18 s (1H, pyrrole), 5.68 q (1H, CH, J 5.7 Hz), 7.32 br s (4H, Ar); 13C, (100 MHz, CDCl3): d ¼ 21.6 (CH2), 21.8 (CH3), 22.9 (CH2), 23.3 (СН2), 23.6 (CH2), 43.4 (CH3), 70.1 (CH), 82.8 (CH), 108.2 (CH), 117.5 (C), 123.2 (C), 123.7 (C), 128.6 (2CH), 130.5 (2CH), 133.9 (C), 138.1 (C). HRMS (ESI): calculated for (MþH)þ С18Н22ClN2Oþ: 317.1415; found: 317.1416. Isomer 9f, yield 26% (81 mg), white solid. M.p. 105e107  C. Rf (50% methylene chloride/hexane) 0.20. IR (KBr), n ¼ 2939, 2844, 1488, 1402, 1304, 1132, 1086, 1014, 814 cm1; 1H, (400 MHz, CDCl3): d ¼ 1.53e1.63 m (1H, CH2), 1.67e1.73 m (1H, CH2), 1.70 d (3H, CH3, J 5.6 Hz), 1.73e1.82 m (1H, CH2), 1.89e1.94 m (1H, CH2), 2.35e2.42 m (2H, CH2), 2.52 s (3H, CH3), 2.54e2.56 m (1H, CH2), 2.64e2.71 m (1H, CH2), 4.66 s (1H, CH), 5.12 s (1H, pyrrole), 5.80 q (1H, CH, J 5.6 Hz), 2.27e2.32 m (4H, Ar); 13C, (100 MHz, CDCl3): d ¼ 20.3 (CH3), 23.1 (CH2), 23.2 (CH2), 23.6 (CH2), 24.4 (CH2), 43.6 (CH3), 70.5 (CH), 84.8 (CH), 104.2 (CH), 118.2 (C), 124.0 (C), 128.6 (2CH), 129.7 (C), 130.6 (2CH), 133.9 (C), 137.8 (C). HRMS (ESI): calculated for (MþH)þ С18Н22ClN2Oþ: 317.1415; found: 317.1430.

4.1.21. rel-(1R,4S)- and rel-(1R,4R)-1-(4-methoxyphenyl)-4methyl-2,6-diphenyl-2,4-dihydro-1H-pyrrolo[2,1-d][1,2,5] oxadiazines 8g and 9g Yield 45% (165 mg), mixture of diastereomers, ratio cis:trans e 1.7:1, colorless oil. A mixture with ratio cis:trans e 10:1 was obtained by crystallization from hexane/diethyl ether (30 mg, 10%, light-pink solid). IR (KBr), n ¼ 2948, 2834, 1609, 1512, 1367, 1247, 1111, 1025, 764, 698 cm1; 1H, (400 MHz, CDCl3): d ¼ 1.42 d (3H, CH3trans, J 5.5 Hz), 1.57 d (3H, CH3cis, J 5.6 Hz), 3.75 s (3H, CH3trans), 3.77 s (3H, CH3cis), 5.60 s (1H, CHcis), 5.67 s (1H, CHtrans), 5.70 br d (1H, pyrrole, cis, J 3.4 Hz), 5.58 d (1H, pyrrole, trans, J 3.3 Hz), 6.21 d (1H, pyrrole, cis, J 3.4 Hz, 1H, pyrrole, trans), 6.32 q (1H, CHcis, J 5.6 Hz), 6.46 q (1H, CHtrans, J 5.5 Hz), 6.73e6.77 m (2H, Ph), 7.04e7.10 m (3H, Ar), 7.17e7.24 m (7H, Ar), 7.30e7.34 m (1H, Ar), 7.40e7.46 m (4H, Ar); 13C, (100 MHz, CDCl3): d ¼ 20.5 (СH3, trans), 21.2 (СH3, cis), 55.2 (CH3, cisþtrans), 67.3 (CH, trans), 67.4 (CH, cis), 85.6 (CH, cis), 86.0 (CH, trans), 105.3 (CH, trans), 105.9 (CH, cis), 109.7 (CH, trans), 109.9 (CH, cis), 113.3 (2CH, trans), 113.4 (2CH, cis), 120.0 (CH, trans), 121.4 (CH, cis), 124.2 (CH, trans), 125.0 (CH, cis), 126.9 (CH, trans), 127.0 (CH, cis), 128.2 (4CH, cis), 128.4 (2CH, cis), 128.7 (2CH, trans), 128.7 (2CH, cis), 130.3 (C, trans), 130.5 (C, cis), 130.7 (C, cis), 130.8 (2CH, trans), 130.8 (2CH, cis), 130.9 (C, trans), 131.6 (C, cis), 131.7 (C, trans), 133.8 (C, cis), 134.1 (C, trans), 148.2 (C, cis), 148.3 (C, trans), 159.2 (C, trans), 159.3 (C, cis). HRMS (ESI): calculated for (MþAg)þ С26Н24AgN2Oþ 2 : 503.0883; found: 503.0887.

4.1.22. rel-(1R,4S)- and rel-(1R,4R)-2,4-dimethyl-1,6-diphenyl-2,4dihydro-1H-pyrrolo[2,1-d][1,2,5]oxadiazine 8h and 9h Isomer 8h, yield 35% (105 mg), white solid. M.p. 87e89  C. Rf (50% methylene chloride/hexane) 0.33. IR (KBr), n ¼ 2966, 1600, 1511, 1448, 1367, 1314, 1272, 1128, 1089, 757, 746 cm1; 1H, (400 MHz, CDCl3): d ¼ 1.50 d (3H, CH3, J 5.7 Hz), 2.56 s (3H, CH3), 4.74 s (1H, CH), 5.44 br s (1H, pyrrole), 6.13 d (1H, pyrrole, J 3.5 Hz), 6.16 q (1H, CH, J 5.7 Hz), 7.29e7.33 m (1H, Ar), 7.36e7.42 m (9H, Ar); 13 C, (100 MHz, CDCl3): d ¼ 21.6 (СН3), 43.4 (СН3), 70.8 (СН), 84.6 (СН), 106.0 (СН), 109.2 (СН), 126.9 (СН), 128.2 (2СН), 128.3 (СН), 128.5 (2СН), 128.7 (2СН), 129.4 (2СН), 130.6 (С), 131.6 (С), 133.4 (С), 139.1 (С). HRMS (ESI): calculated for (MþH)þ С20Н21N2Oþ: 305.1648; found: 305.1661. Isomer 9h, yield 29% (88 mg), beige solid. Isolated only as a crude product. 1H, (400 MHz, CDCl3): d ¼ 1.28 d (3H, CH3, J 5.5 Hz), 2.58 s (3H, CH3), 4.82 s (1H, CH), 5.48 d (1H, pyrrole, J 3.3 Hz), 6.10 d (1H, pyrrole, J 3.3 Hz), 6.32 q (1H, CH, J 5.5 Hz), 7.27e7.30 m (1H, Ar), 7.33e7.40 m (9H, Ar).

M.M. Efremova et al. / Tetrahedron 73 (2017) 671e680

4.1.23. rac-(1R,4S)- and rac-(1R,4R)-1-(4-methoxyphenyl)-2,4dimethyl-6-phenyl-2,4-dihydro-1H-pyrrolo[2,1-d][1,2,5]oxadiazines 8i and 9i Isomer 8i, yield 24% (81 mg), white solid. M.p. 63e65  C. Rf (50% methylene chloride/hexane) 0.17. IR (KBr), n ¼ 3002, 1610, 1512, 1370, 1277, 1248, 1173, 1128, 1035, 758 cm1; 1H, (400 MHz, CDCl3): d ¼ 1.48 d (3H, CH3, J 5.7 Hz), 2.54 s (3H, CH3), 3.84 s (3H, CH3), 4.69 s (1H, CH), 5.46 br s (1H, pyrrole), 6.13 d (1H, pyrrole J 3.6 Hz), 6.14 q (1H, CH, J 5.7 Hz), 6.90e6.92 m (2H, Ar), 7.28e7.33 m (3H, Ar), 7.38e7.41 m (4H, Ar); 13C, (100 MHz, CDCl3): d ¼ 21.6 (CH3), 43.3 (CH3), 55.3 (CH3), 70.1 (CH), 84.5 (CH), 105.9 (CH), 109.2 (CH), 113.8 (2CH), 126.9 (CH), 128.2 (2CH), 128.7 (2CH), 130.6 (2CH), 131.1 (2C), 132.0 (C), 133.4 (C), 159.6 (C). HRMS (ESI): calculated for (MþH)þ С21Н23N2Oþ 2 : 335.1754; found: 335.1762. Isomer 9i, yield 22% (74 mg), white solid. M.p. 81e83  C. Rf (methylene chloride) 0.42. IR (KBr), n ¼ 2932, 2840, 1609, 1372, 1306, 1246, 1119, 1029, 829 cm1; 1H, (400 MHz, CDCl3): d ¼ 1.28 d (3H, CH3, J 5.4 Hz), 2.57 s (3H, CH3), 3.83 s (3H, CH3), 4.78 s (1H, CH), 5.51 d (1H, pyrrole, J 3.3 Hz), 6.11 d (1H, pyrrole, J 3.3 Hz), 6.32 q (1H, CH, J 5.4 Hz), 6.87e6.91 m (2H, Ar), 7.27e7.32 m (3H, Ar), 7.35e7.39 m (4H, Ar); 13C, (100 MHz, CDCl3): d ¼ 20.4 (CH3), 43.3 (CH3), 55.3 (CH3), 71.2 (CH), 85.3 (CH), 105.0 (CH), 110.0 (CH), 113.8 (2CH), 126.6 (CH), 128.1 (2CH), 128.5 (2CH), 130.2 (C), 130.6 (2CH), 131.2 (C), 132.4 (C), 134.7 (C), 159.6 (C). HRMS (ESI): calculated for (MþNa)þ С21Н22N2NaOþ 2 : 357.1573; found: 357.1567. 4.1.24. rac-(1R,4S)- and rac-(1R,4R)-1-(4-chlorophenyl)-2,4dimethyl-6-phenyl-2,4-dihydro-1H-pyrrolo[2,1-d][1,2,5]oxadiazines 8j and 9j Isomer 8i, yield 30% (102 mg), white solid. M.p. 92e94  C. Rf (50% methylene chloride/hexane) 0.38. IR (KBr), n ¼ 2969, 1601, 1488, 1369, 1310, 1228, 1128, 1108, 1086, 1228, 1128, 1108, 1086, 1014, 798, 749, 698 cm1; 1H, (400 MHz, CDCl3): d ¼ 1.48 d (3H, CH3, J 5.7 Hz), 2.54 s (3H, CH3), 4.72 s (1H, CH), 5.43 br s (1H, pyrrole), 6.12 d (1H, pyrrole J 3.5 Hz), 6.14 q (1H, CH, J 5.7 Hz), 7.32 tt (1H, Ar J 8.7, 4.1 Hz), 7.36 s (4H, Ar), 7.40e7.41 m (4H, Ar); 13C, (100 MHz, CDCl3): d ¼ 21.5 (CH3), 43.4 (CH3), 70.0 (CH), 84.6 (CH), 106.0 (CH), 109.3 (CH), 127.0 (CH), 128.2 (2CH), 128.7 (2CH), 128.8 (2CH), 130.7 (2CH), 130.8 (C), 131.0 (C), 133.2 (C), 134.2 (C), 137.6 (C). HRMS (ESI): calculated for (MþH)þ С20Н20ClN2Oþ: 339.1259; found: 339.1271. Isomer 9i, yield 25% (86 mg), white solid. M.p. 80e82  C. Rf (50% methylene chloride/hexane) 0.32. IR (KBr), n ¼ 2908, 1601, 1491, 1454, 1380, 1318, 1230, 1128, 1087, 1013, 856, 752, 704 cm1; 1H, (400 MHz, CDCl3): d ¼ 1.28 d (3H, CH3, J 5.5 Hz), 2.57 s (3H, CH3), 4.80 s (1H, CH), 5.48 br d (1H, pyrrole J 3.4 Hz), 6.10 d (1H, pyrrole J 3.4 Hz), 6.30 q (1H, CH, J 5.5 Hz), 7.27e7.32 m (1H, Ph), 7.34 s (4H, Ph), 7.38e7.39 m (4H, Ph); 13C, (100 MHz, CDCl3): d ¼ 20.3 (CH3), 43.4 (CH3), 71.0 (CH), 85.4 (CH), 105.1 (CH), 109.9 (CH), 126.8 (CH), 128.1 (2CH), 128.5 (2CH), 128.7 (2CH), 130.3 (C), 130.7 (2CH), 132.4 (C), 134.1 (C), 134.6 (C), 137.7 (C). HRMS (ESI): calculated for (MþNa)þ С20Н19ClN2NaOþ: 361.1078; found: 361.1090. Acknowledgements We gratefully acknowledge the financial support from the Russian Science Foundation (Project No 14-13-00126). This research made use of resources from the X-ray Diffraction Centre, Centre for Magnetic Resonance, Educational Resource Center of Chemistry and the Centre for Chemical Analysis and Materials of Saint-Petersburg State University. Appendix A. Supplementary data Copies of 1H and 13C NMR spectra for all products. Supplementary data associated with this article can be found in the online

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