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Tandem [4+1+1] Annulation Approach to 4-Acyl-3,4dihydropyrrolo[1,2-a]pyrazines: Diastereoselective Construction of Dihydropyrazine Units from Pyrroles Anuradha Dagar, Gi Hun Bae, Jeong Hwa Lee, and Ikyon Kim J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00724 • Publication Date (Web): 15 May 2019 Downloaded from http://pubs.acs.org on May 15, 2019

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is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

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The Journal of Organic Chemistry

Tandem [4+1+1] Annulation Approach to 4-Acyl-3,4-dihydropyrrolo[1,2a]pyrazines: Diastereoselective Construction of Dihydropyrazine Units from Pyrroles

Anuradha Dagar, Gi Hun Bae, Jeong Hwa Lee, and Ikyon Kim*

College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University 85 Songdogwahak-ro, Yeonsu-gu, Incheon, 21983, Republic of Korea

* Corresponding author. Tel.: +82 32 749 4515; fax: +82 32 749 4105; e-mail: [email protected]

Graphical Abstract OHC N O

G

ArCHO NH4OAc

N Ar

K2CO3 EtOH, rt

3

O

N 4

G

- an atom-economical approach to new 4-acylated 3,4-dihydropyrrolo[1,2-a]pyrazines via a one-pot three-component reaction - one C-C and two C-N bond formation via a cascade reaction sequence - a diastereoselective setup of the two substituents of this heterocyclic ring core in a trans manner

Abstract: Efficient construction of new chemical space by way of strategic use of tandem reactions is highly important in drug discovery. Described herein is an atom-economical 1

ACS Paragon Plus Environment

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[4+1+1] annulation approach to 3-(hetero)aryl-4-acyl-3,4-dihydropyrrolo[1,2-a]pyrazines, a new chemical space, via a one-pot three-component reaction under mild reaction conditions. Formation of multiple bonds (One C-C and two C-N) was achieved by a cascade reaction sequence consisting of generation of a Schiff base, a diastereoselective Mannich reaction, and intramolecular imine formation. This modular and environment-friendly process allowed rapid access to a wide range of 4-acylated 3,4-dihydropyrrolo[1,2-a]pyrazines and their analogues, opening opportunity to explore biological activity associated with this scaffold.

Keywords: Multi-component reaction; 3,4-Dihydropyrrolo[1,2-a]pyrazine; Cascade reaction; Chemical space; Diversity-oriented synthesis; Atom-economy.

Introduction New chemical space1 is often generated by site-selective decoration of new functional groups onto basic chemical skeletons through intermolecular cross-coupling reactions.2 Alternatively, it can be created via installation of substituent(s) at the unique position(s) of the rings formed newly during cyclization of acyclic precursors, leading to the core scaffolds with distinctive substitution patterns, which was difficult to obtain by other synthetic means. As part of our research interest on nitrogen-fused heterocycles,3 the first principle was applied to some pyrrolo[1,2-a]pyrazines: intermolecular Pd-catalyzed direct arylation4

and

regiodivergent electrophilic acetylation/formylation5 allowed us to get access to pyrrolo[1,2a]pyrazine-based new chemical scaffolds with unprecedented substitution styles, respectively (Scheme 1(a) and (b)). As a means to introduce new functional moieties to a pyrrolo[1,2a]pyrazine nucleus by way of the second principle, we initially envisioned that three2


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component assembly of 4 with aldehyde and ammonium acetate in the presence of base would afford 4-acylated pyrrolo[1,2-a]pyrazine (5) (Scheme 1(c)). Previously, compound 4 has been utilized to make several heterocyclic systems having an acyl group at C4 position through ring annulation methods.6 However, no report on construction of 4-acylpyrrolo[1,2-a]pyrazines from 4 has been disclosed yet. It should be mentioned that it seems difficult to achieve installation of an acyl unit to the pyrazine site of this bicyclic heteroaromatic ring by intermolecular electrophilic acylation of pyrrolo[1,2-a]pyrazine as it typically occurs at the pyrrole ring.7 Scheme 1. Generation of New Chemical Space: Pyrrolo[1,2-a]pyrazines R1

Pd-catalyzed direct arylation

R1 1

N

N N

R2 3

R

1 Electrophilic acylation

1

8

N N

R2 3

three-component one-pot synthesis N

Mannich

O N

R O

RCHO NH4OAc base

G

H 2N

B

(b)

6

3

OHC

NH

O G

N

R2

1

A R

Ar

R1

N

4

6

2

R1

O

(a)

N

2

G

N R

N

3

(c)

4

G

O 5

aromatization

intramolecular imine formation

N N

R O

G

6 (this work)

3



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Despite a wide range of intriguing biological activities associated with pyrrolo[1,2-a]pyrazine derivatives as can be seen in Figure 1,8 synthetic methods to make this ring system have been relatively less explored. Thus, we decided to investigate the feasibility of our idea, thereby generating a novel pyrrolo[1,2-a]pyrazine chemical library for biological evaluation.9 As illustrated in Scheme 1(c), mechanistically, we expected that intermolecular Mannich reaction of 4 with imine A formed from aldehyde and ammonium acetate would furnish B which would be converted to 3,4-dihydropyrrolo[1,2-a]pyrazine (6)10

by way of

intramolecular imine formation. Final aromatization via oxidation11 would occur to give rise to 5. It turned out, however, that the major product from this three-component reaction was 4acyl 3,4,-dihydropyrrolo[1,2-a]pyrazine (6): subsequent oxidation did not take place rapidly. Here we wish to report our results on [4+1+1] annulation route to 4-acylated 3,4dihydropyrrolo[1,2-a]pyrazine scaffold, which has not been reported yet in the literature. Figure 1. Some Bioactive Pyrrolo[1,2-a]pyrazines

4


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NH2

N

N

N

O N

N

N Me

N

SMe

HCl

N N

SMe

O

O

antianxiolytic agent

PI3K inhibitor NH2

HIF-1 inhibitor

Me O

O Br

OMe

N

N N

F Eis inhibitor (antitubercular agent)

MeO

N

anticancer agent

Results and discussion Reaction optimization was carried out with 4a12 and 2-methoxybenzaldehyde (Table 1). To a premixing solution of aldehyde and NH4OAc13 in solvent, 4a and base (0.5 equiv) were added at room temperature. While DABCO, DBU, or L-proline was employed as a base to give the desired product 6a in the range of 60-70% yields, use of Et3N (0.5 equiv) as a base resulted in 90% yield (entries 1-4). The relative stereochemistry of C3 and C4 positions of 6 was unambiguously confirmed by X-ray crystallographic analysis of 6e.14 Screening of inorganic bases such as NaHCO3, NaOH, and K2CO3 indicated that K2CO3 provided the best isolated yield (entries 5-7). Other reaction solvents gave inferior results (entries 8-15). A mixed solvent (EtOH/H2O, 1:1) did not improve the yield of 6a (entry 16). Only a small amount of the product was obtained in H2O (entry 17). Thus, the reaction scope of this reaction was examined with 5



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K2CO3 (0.5 equiv) in EtOH. When the reaction was carried out without K2CO3, it gave a cistrans mixture product after a longer reaction time.15 Treatment of this mixture with K2CO3 in EtOH resulted in only the trans product, indicating the base plays a key role in isomerization as well. The diastereomeric ratio of the product seemed to be more than 20:1 based on the NMR spectra. Notably, this assembly is a highly atom-economical16 and green process as almost all three starting materials are embedded in the final product with loss of water (2 equiv) and the reaction is conducted with a catalytic amount of base (0.5 equiv) in a green reaction medium such as EtOH at ambient temperature. Table 1. Reaction Optimizationa OHC N Ph

O

2-MeOC6H4CHO NH4OAc

N

3

base, solvent rt

4a

entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

OMe N 4

Ph

O 6a

base (0.5 equiv) DABCO DBU L-Proline Et3N NaHCO3 NaOH K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3

solvent EtOH EtOH EtOH EtOH EtOH EtOH EtOH MeOH THF DMSO DMF CH3CN toluene CH2Cl2 1,4-dioxane EtOH:H2O (1:1) 6


time (h) 30 30 30 24 24 24 14 24 24 24 24 24 24 24 24 14

yield (%)b 65 60 70 90 65 60 94 80 85 70 65 80 40 40 85 94

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17 K2CO3 H2O 30 15 After a mixture of 2-methoxybenzaldehyde (1.2 equiv) and NH4OAc (1.2 equiv) in solvent (1 mL) was stirred at rt for 10 min, 4a (1 equiv) and base (0.5 equiv) were added at rt. The reaction mixture was stirred at rt for 16 h. b Isolated yield (%). a

As shown in Table 2, reactions of 4a with various aldehydes were carried out under optimized conditions to afford the corresponding 4-acyl-3,4-dihydropyrrolo[1,2-a]pyrazines in good to excellent yields. Aldehydes bearing an electron-donating group as well as an electronwithdrawing group exhibited similar efficiency. Indole- and furan-containing 3,4dihydropyrrolo[1,2-a]pyrazines (6i and 6j) were prepared in 70 and 75% yields, respectively. Reactions with aliphatic aldehydes did not work under these conditions. Table 2. Synthesis of 6b-6ja,b RCHO NH4OAc

OHC N O

N R

K2CO3 EtOH

Ph

N

3

4

Ph

O

4a

6b-6j

N

N

N N

O

MeO

N Me

Ph

6b (94)

O

N O

Ph

OMe

6c (95)

6d (87) N

N

N

N Cl

O

Br

Ph

O

6e (89) N N

N O

6g (80)

Ph

Ph

6f (86)

N

NC

Ph

O 2N

O

Ph

6h (73) 7


H N

N N O

6i (70)

Ph


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N N

O O

Ph

6j (75) After a mixture of aldehyde (1.2 equiv) and NH4OAc (1.2 equiv) in EtOH (1 mL) was stirred at rt for 10 min, 4a (1 equiv) and K2CO3 (0.5 equiv) were added at rt. The reaction mixture was stirred at rt for 16 h. b Isolated yield (%). a

More

diverse

4-acyl-3,4-dihydropyrrolo[1,2-a]pyrazine

compounds

(6k-6ak)

were

synthesized with 4b-4i.17 The results are shown in Table 3, indicating a wide range of functional group tolerance under these reaction conditions. Table 3. Synthesis of 6k-6aka RCHO NH4OAc

OHC N O

N R

K2CO3 EtOH

G 4b-4i

3

O

N 4

G

6k-6ak

4

aldehyde (RCHO)

yield (%)b

6 N N

4b (G = 3-MeOC6H4)

R = C6H5

OMe

O

6k

90

6l

88

6m

85

N

4b

R = 4MeOC6H4

N MeO

OMe

O

N N

4b

R = 4-ClC6H4 Cl

O

8


OMe

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N N

4b

R = 4-pyridine

N

OMe

O

6n

72

6o

92

6p

86

6q

85

6r

75

6s

87

6t

86

N N

4c (G = 4-MeOC6H4)

R = 4-MeC6H4 Me

O OMe N

4c

R = 3,4(MeO)2C6H3

N

MeO MeO

O OMe N N

4c

R = 4-BrC6H4

Br

O OMe N N

O

4c

R = 2-furan O OMe N N

4d (G = 4-FC6H4)

R = C6H5 O F N N

4d

R = 4-MeC6H4 Me

O F

9



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OMe N

4d

N

R = 2MeOC6H4

6u

83

6v

81

6w

80

6x

75

6y

72

6z

86

6aa

88

O F N

4d

R = 3,4(MeO)2C6H3

N

MeO MeO

O F N N

4d

R = 4-BrC6H4 Br

O F N N

O

4d

R = 2-furan O F N N

4d

R = 4-pyridine

N

O F N N

4e (G = 4-ClC6H4)

R = C6H5 O Cl N N

4e

R = 4-MeC6H4 Me

O Cl

10


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OMe N

4e

N

R = 2MeOC6H4

6ab

84

6ac

73

6ad

85

6ae

87

6af

80

6ag

80

6ah

73

O Cl H N

4e

N N

R = 2-pyrrole O Cl N N

4f (G = 4-BrC6H4)

R = C6H5

O Br N N

4f

R = 4-MeC6H4 Me

O Br N

4f

R = 4MeOC6H4

N MeO

O Br N N

O

4f

R = 2-furan O Br N N

4f

N

R = 2-pyridine O Br

11



Page 12 of 39

N

4g (G = 2naphthalene)

N

R = 4-ClC6H4 Cl

6ai

88c

6aj

89

6ak

83

O

N N

4h (G = 4-PhC6H4)

R = 4-ClC6H4

Cl

O

N

4i (G = 2-furan)

N

R = 4MeOC6H4

MeO

O

O

a

After a mixture of aldehyde (1.2 equiv) and NH4OAc (1.2 equiv) in EtOH (1 mL) was stirred at rt for 10 min, 4 (1 equiv) and K2CO3 (0.5 equiv) were added at rt. The reaction mixture was stirred at rt for 16 h. b Isolated yield (%). c reaction in DMSO at rt.

When this three-component reaction was applied to 7 derived from indole-2-carbaldehyde, the corresponding 3-aryl-4-acyl-3,4-dihydropyrazino[1,2-a]indole (8) was obtained in 72% yield (Scheme 2). Furthermore, trans-cinnamaldehyde was successfully employed as an aldehyde partner of this multicomponent reaction with 4a to afford 9 in good yield. A scale-up reaction was conducted with 4f (1 mmol) and benzaldehyde to afford 6ad without compromising the isolated yield (Scheme 3). In addition, further elaboration of the resulting 6ad was demonstrated. Aromatization of 6ad in refluxing EtOH proceeded well to give pyrrolo[1,2-a]pyrazine product 5. N-alkylation of 6ad with ethyl bromoacetate and phenacyl bromide delivered 3,4-dihydropyrrolo[1,2-a]pyrazinium salts 10a and 10b in excellent yields, respectively.18 Scheme 2. Synthesis of 8 and 9 12


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OHC

N

PhCHO NH4OAc

N

N O

K2CO3 EtOH OMe (72%)

O 7 OHC

OMe 8

Ph

N

CHO NH4OAc

N

N

Ph

K2CO3 EtOH (70%)

O 4a

O 9

Scheme 3. Scale-up and Further Functionalization of 6ad OHC N O 4f (1 mmol)

Br

PhCHO NH4OAc

N

K2CO3 EtOH

O

N

6ad (325 mg, 86%)

Br

N

N N O 6ad

N

K2CO3

Br

reflux EtOH

O Br 5 (90%)

RCH2Br Br R

N N O

10a (R = CO2Et): 95% 10b (R = COPh): 97% Br

Conclusion In conclusion, in the course of our efforts to expand pyrrolo[1,2-a]pyrazine-based chemical territory, we have developed a highly efficient one-pot three-component synthetic route to 413



acylated 3,4-dihydropyrrolo[1,2-a]pyrazine skeleton via a cascade reaction where one C-C and two C-N bonds were formed. A number of derivatives were readily prepared with high atom economy in this modular approach and further elaborations of the resulting products were demonstrated as well. High functional group tolerance, ease of operation, environmentfriendliness, and high chemical yields of this atom-economical protocol would be useful for further biological exploration of the resulting new chemical scaffold. Work is in progress to extend the use of pyrrole-2-carboxaldehydes for the synthesis of other nitrogen-fused heterocycles.

Experimental Section General Methods Unless specified, all reagents and starting materials were purchased from commercial sources and used as received without purification. “Concentrated” refers to the removal of volatile solvents via distillation using a rotary evaporator. “Dried” refers to pouring onto, or passing through, anhydrous magnesium sulfate followed by filtration. Flash chromatography was performed using silica gel (230−400 mesh) with hexanes, ethyl acetate, and dichloromethane as the eluents. All reactions were monitored by thin-layer chromatography on 0.25 mm silica plates (F-254) visualized with UV light. Melting points were measured using a capillary melting point apparatus. 1H and

13C

NMR spectra were recorded on a 400 MHz NMR

spectrometer and were described as chemical shifts, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), coupling constant in hertz (Hz), and number of protons. HRMS was measured with an electrospray ionization (ESI) and Q-TOF mass analyzer.

14


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General Procedure for the Synthesis of 6: Although the reactions are not air-sensitive, they were conducted in sealed vials to prevent solvent evaporation. To a stirred solution of 2-methoxybenzaldehyde (16.3 mg, 0.12 mmol, 1.2 equiv) and NH4OAc (9.2 mg, 0.12 mmol, 1.2 equiv) in ethanol (1.0 mL) were added 4a (21.3 mg, 0.1 mmol, 1 equiv) and base (6.9 mg, 0.05 mmol, 0.5 equiv) at room temperature. Then, the reaction mixture was stirred at room temperature for 14 h (monitored by TLC). Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure, extracted with dichloromethane (3 × 10 mL), and washed with water and brine respectively. The organic layer was dried over MgSO4 and concentrated in vacuo to afford the crude product, which was purified by silica gel column chromatography (EtOAc/dichloromethane/hexane = 1:1:8) to give 6a (31 mg, 94%). ((3R*,4S*)-3-(2-Methoxyphenyl)-3,4-dihydropyrrolo[1,2OMe N

O

N

a]pyrazin-4-yl)(phenyl)methanone (6a). White solid, mp: 216.5-

Ph

218.7 °C (30.6 mg, 94%); 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H),

6a

8.07 (d, J = 7.7 Hz, 2H), 7.61 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.7 Hz,

2H), 7.21 (t, J = 7.7 Hz, 1H), 6.95 (d, J = 7.4 Hz, 1H), 6.82-6.88 (m, 2H), 6.60 (d, J = 3.4 Hz, 1H), 6.53 (s, 1H), 6.27-6.29 (m, 1H), 5.83 (s, 1H), 5.76 (d, J = 3.2 Hz, 1H), 3.90 (s, 3H); 13C{1H}

NMR (100 MHz, CDCl3) δ 195.4, 156.4, 153.1, 134.7, 133.9, 129.1, 129.0, 128.7,

128.4, 126.3, 126.2, 124.3, 121.1, 111.7, 110.7, 110.5, 62.4, 57.7, 55.3; HRMS (ESI-QTOF) m/z [M+Na]+ calcd for C21H18N2O2Na 353.1260, found 353.1268.

((3R*,4S*)-3-Phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-4-yl)methanone (6b). White solid, mp: 171.4-172.2 °C (28.0 mg, 94%); 1H NMR (400 MHz, CDCl3) δ 15

N N O 6b

Ph



8.42 (s, 1H), 7.87 (d, J = 7.7 Hz, 2H), 7.63 (t, J = 7.3 Hz, 1H), 7.49 (t, J = 7.5 Hz, 2H), 7.287.29 (m, 3H), 7.21-7.23 (d, J = 6.8 Hz, 2H), 6.66 (d, J = 3.3 Hz, 1H), 6.61 (s, 1H), 6.36 (s, 1H), 5.71 (d, J = 4.6 Hz, 1H), 5.32 (d, J = 2.9 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 195.6 151.7, 139.8, 134.8, 134.1, 129.1, 129.0, 128.6, 128.2, 127.4, 125.8, 124.1, 112.0, 110.9, 64.2, 62.9; HRMS (ESI-QTOF) m/z [M+Na]+ calcd for C20H16N2ONa 323.1155, found 323.1164.

Phenyl((3R*,4S*)-3-(p-tolyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-4-yl)methanone (6c). Pale yellow solid, mp: 179.5-180.2 °C (29.5 mg, 95%); 1H NMR (400 N

Me

O

N

MHz, CDCl3) δ 8.38 (s, 1H), 7.87 (d, J = 7.5 Hz, 2H), 7.59-7.63

Ph

(m, 1H), 7.46-7.50 (m, 2H), 7.08 (s, 4H), 6.62 (d, J = 3.4 Hz, 1H),

6c

6.57 (s, 1H), 6.32-6.34 (m, 1H), 5.68 (d, J = 4.2 Hz, 1H), 5.29 (d,

J = 3.6 Hz, 1H), 2.29 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 195.4, 151.5, 137.9, 136.9, 134.6, 134.1, 129.7, 129.1, 128.6, 127.2, 125.8, 124.1, 111.9, 110.8, 63.7, 63.1, 21.2; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C21H19N2O 315.1492, found 315.1498.

((3R*,4S*)-3-(3,5-Dimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-4-yl)(phenyl) methanone (6d). Pale yellow solid, mp: 139.4-140.5 °C (32.8 mg, N MeO O OMe 6d

N

87%); 1H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 7.84 (d, J = 7.1

Ph

Hz, 2H), 7.57-7.60 (m, 1H), 7.43-7.47 (m, 2H), 6.57-6.60 (m, 2H), 6.31-6.32 (m, 4H), 5.67 (s, 1H), 5.18 (s, 1H), 3.67 (s, 6H); 13C{1H}

NMR (100 MHz, CDCl3) δ 195.5, 161.2, 151.7, 142.0, 134.8, 134.2, 129.1, 128.6, 125.6, 124.1, 112.1, 110.9, 105.5, 100.0, 64.2, 62.6, 55.4; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C22H21N2O3 361.1547, found 361.1556. 16


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((3R*,4S*)-3-(4-Chlorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-4yl)(phenyl)methanone N

Cl

O

(6e). White solid, mp: 208.4-209.5 °C

N

(29.5 mg, 89%); 1H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 7.83

Ph

(d, J = 7.6 Hz, 2H), 7.60-7.63 (m, 1H), 7.45-7.49 (m, 2H), 7.23 (d,

6e

J = 8.0 Hz, 2H), 7.13 (d, J = 7.7 Hz, 2H), 6.63 (s, 1H), 6.57 (s, 1H),

6.33 (s, 1H), 5.62 (d, J = 4.8 Hz, 1H), 5.25 (d, J = 4.2 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 195.4, 152.0, 138.3, 134.8, 134.3, 134.0, 129.2, 129.1, 128.9, 128.5, 125.7, 124.2, 112.3, 111.0, 63.6, 62.7; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C20H16ClN2O 335.0946, found 335.0952.

((3R*,4S*)-3-(4-Bromophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-4yl)(phenyl)methanone (6f). White solid, mp: 196.0-197.1 °C N

Br

O

N

(32.5 mg, 86%); 1H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 7.83

Ph

(d, J = 7.9 Hz, 2H), 7.60-7.64 (m, 1H), 7.46-7.49 (m, 2H), 7.38 (d,

6f

J = 8.3 Hz, 2H), 7.08 (d, J = 8.2 Hz, 2H), 6.64 (d, J = 2.7 Hz, 1H),

6.58 (s, 1H), 6.32-6.34 (m, 1H), 5.62 (d, J = 5.2 Hz, 1H), 5.24 (d, J = 4.9 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 195.3, 152.0, 138.8, 134.8, 134.3, 132.1, 129.2, 129.2, 128.5, 125.7, 124.2, 122.2, 112.4, 111.0, 63.7, 62.6; HRMS (ESI-QTOF) m/z [M+Na]+calcd for C20H15BrN2ONa 401.0260, found 401.0268.

4-((3R*,4S*)-4-Benzoyl-3,4-dihydropyrrolo[1,2-a]pyrazin-3-yl)benzonitrile (6g). White 17

N N NC

O 6g

Ph



solid, mp: 192.7-193.6 °C (26 mg, 80%); 1H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 7.80 (d, J= 7.4 Hz, 2H), 7.60-7.64 (m, 1H), 7.55 (d, J = 7.7 Hz, 2H), 7.45-7.48 (m, 2H), 7.34 (d, J = 7.9 Hz, 2H), 6.67 (s, 1H), 6.58 (s, 1H), 6.34 (s, 1H), 5.60 (d, J = 5.7 Hz, 1H), 5.29 (d, J = 5.3 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 195.2, 152.5, 144.9, 134.9, 134.6, 133.9, 132.8, 132.2, 129.3, 128.5, 125.7, 124.4, 118.6, 112.9, 112.1, 111.3, 64.1, 62.3; HRMS (ESI-QTOF) m/z [M+Na]+calcd fo C21H15N3ONa 348.1107, found 348.1118.

((3R*,4S*)-3-(4-Nitrophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-4-yl)(phenyl)methanone (6h). White solid, mp: 191.7-192.6 °C (25.3 mg, 73%); 1H NMR N

O 2N

O

N

(400 MHz, acetone-d6) δ 8.40 (s, 1H), 8.03 (d, J = 5.8 Hz, 2H),

Ph

7.66-7.70 (m, 3H), 7.56-7.60 (m, 2H), 7.46-7.50 (m, 2H), 6.84 (s,

6h

1H), 6.62 (s, 1H), 6.25 (d, J = 5.2 Hz, 2H), 5.40 (d, J = 3.8 Hz,

1H); 13C{1H} NMR (100 MHz, acetone-d6) δ 194.9, 151.8, 148.0, 134.9, 132.8, 130.3, 129.3, 129.2, 128.9, 128.7, 125.8, 124.2, 112.2, 110.8, 63.7, 62.5; HRMS (ESI-QTOF) m/z [M+Na]+ calcd for C20H15N3O3Na 368.1006, found 368.1016.

((3S*,4S*)-3-(1H-Indol-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-4-yl)(phenyl)methanone (6i). White solid, mp: 167.7-168.6 °C (23.5 mg, 70%); 1H NMR H N

N

O 6i 13C{1H}

N

(400 MHz, CDCl3) δ 8.67 (s, 1H), 8.30 (s, 1H), 7.94 (d, J = 4.9 Hz,

Ph

2H), 7.60-7.64 (m, 1H), 7.43-7.50 (m, 4H), 7.13 (s, 1H), 7.06 (s, 1H), 6.64-6.72 (m, 2H), 6.36 (s, 2H), 5.97 (s, 1H), 5.60 (s, 1H);

NMR (100 MHz, CDCl3) δ 194.4, 152.4, 136.5, 136.1, 134.5, 131.5, 129.4, 128.7,

126.6, 125.2, 124.6, 122.3, 120.5, 120.1, 113.1, 111.2, 111.2, 99.8, 61.1, 57.5; HRMS (ESI18


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QTOF) m/z [M+Na]+ calcd for C22H17N3ONa 362.1264, found 362.1272.

((3S*,4S*)-3-(Furan-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-4-yl)(phenyl)methanone(6j). White solid, mp: 169.7-170.6 °C (22.0 mg, 75%); 1H NMR (400 MHz, N O O

N

CDCl3) δ 8.35 (s, 1H), 8.00 (d, J = 8.2 Hz, 2H), 7.62-7.66 (m, 1H),

Ph

7.50-7.54 (m, 2H), 7.36 (s, 1H), 6.60-6.62 (m, 2H), 6.30-6.32 (m, 1H),

6j

6.24-6.25 (m, 1H), 6.09 (d, J = 3.0 Hz, 1H), 5.98 (d, J = 4.0 Hz, 1H),

5.49 (d, J = 3.2 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 194.7, 152.9, 151.7, 142.5, 134.3, 134.2, 129.2, 128.7, 125.3, 124.4, 112.5, 110.8, 110.7, 107.8, 60.7, 58.3; HRMS (ESI-QTOF) m/z [M+Na]+ calcd for C18H14N2O2Na 313.0947, found 313.0956.

(3-Methoxyphenyl)((3R*,4S*)-3-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-4yl)methanone (6k). White solid, mp: 147.7-148.6 °C (30.0 mg, N

90%); 1H NMR (400

N OMe

O 6k

MHz, CDCl3) δ 8.36 (s, 1H), 7.33-7.39

(m, 3H), 7.21-7.24 (m, 3H), 7.16 (d, J = 6.8 Hz, 2H), 7.11 (d, J = 7.9 Hz, 1H), 6.59 (d, J = 3.1 Hz, 1H), 6.54 (s, 1H), 6.29-6.30

(m, 1H), 5.63 (d, J = 4.7 Hz, 1H), 5.27 (d, J = 3.1 Hz, 1H), 3.79 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 195.4, 160.2, 151.7, 139.8, 136.1, 130.0, 129.0, 128.2, 127.4, 125.8, 124.1, 120.9, 120.8, 112.9, 112.0, 110.8, 64.2, 63.0, 55.6; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C21H19N2O2 331.1441, found 331.1448.

(3-Methoxyphenyl)((3R*,4S*)-3-(4-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin19 N N MeO

O 6l

OMe



4-yl)methanone (6l). Pale yellow solid, mp: 179.7-180.9 °C (31.8 mg, 88%); 1H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 7.35-7.43 (m, 3H), 7.10-7.15 (m, 3H), 6.80 (d, J = 8.2 Hz, 2H), 6.61 (d, J = 3.2 Hz, 1H), 6.57 (s, 1H), 6.33 (s, 1H), 5.63 (d, J = 4.3 Hz, 1H), 5.26 (d, J = 3.6 Hz, 1H), 3.83 (s, 3H), 3.75 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 195.4, 160.2, 159.5, 151.4, 136.1, 132.0, 130.0, 128.5, 125.7, 124.0, 120.9, 120.7, 114.4, 112.9, 111.8, 110.8, 63.6, 63.2, 55.6, 55.4; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C22H21N2O3 361.1547, found 361.1555.

((3R*,4S*)-3-(4-Chlorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-4-yl)(3methoxyphenyl) methanone (6m). White solid, mp: 172.7N

173.6 °C (31.0 mg, 85%); 1H NMR (400 MHz, CDCl3) δ

N Cl

OMe

O 6m

8.38 (s, 1H), 7.35-7.38 (m, 3H), 7.25 (s, 1H), 7.23 (s, 1H), 7.14 (d, J = 8.2 Hz, 3H), 6.63 (d, J = 3.8 Hz, 1H), 6.57 (s,

1H), 6.33 (t, J = 3.1 Hz, 1H), 5.59 (d, J = 5.2 Hz, 1H), 5.26 (d, J = 5.0 Hz, 1H), 3.83 (s, 3H); 13C{1H}

NMR (100 MHz, CDCl3) δ 195.2, 160.3, 152.0, 138.3, 136.1, 134.1, 130.1, 129.1,

128.8, 125.7, 124.2, 120.8, 113.0, 112.3, 111.0, 63.6, 62.8, 55.6; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C21H18ClN2O2 365.1051, found 365.1062.

(3-Methoxyphenyl)((3R*,4S*)-3-(pyridin-4-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-4yl)methanone (6n). Yellow solid, mp: 167.7-168.6 °C (24.0 N

mg, 72%); 1H NMR (400 MHz, acetone-d6) δ 8.56 (s, 1H),

N N

OMe

O 6n

8.37 (d, J = 7.7 Hz, 2H), 7.60 (d, J = 7.6 Hz, 1H), 7.48 – 7.52 (m, 2H), 7.33 (s, 1H), 7.29 (d, J = 3.3 Hz, 1H), 7.20-7.22 (m, 20


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1H), 6.69 (d, J = 3.8 Hz, 1H), 6.65 (s, 1H), 6.45 – 6.47 (m, 1H), 5.66 (d, J = 4.8 Hz, 1H), 5.36 (d, J = 4.1 Hz, 1H), 3.86 (s, 3H); 13C{1H} NMR (100 MHz, acetone-d6) δ 196.5, 160.4, 151.2, 140.6, 135.5, 134.8, 132.6, 130.3, 129.9, 126.2, 124.0, 121.0, 115.4, 113.2, 112.7, 66.0, 64.5, 55.8; HRMS (ESI-QTOF) m/z [M+H]+calcd for C20H18N3O2 332.1394, found 332.1401.

(4-Methoxyphenyl)((3R*,4S*)-3-(p-tolyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-4yl)methanone (6o). White solid, mp: 179.7-180.6 °C (31.8 N

mg, 92%); 1H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 7.84

N Me

(d, J = 8.9 Hz, 2H), 7.08 (s, 4H), 6.93 (d, J = 8.8 Hz, 2H),

O OMe

6o

6.60 (d, J = 3.6 Hz, 1H), 6.55 (s, 1H), 6.30-6.32 (m, 1H),

5.62 (d, J = 4.8 Hz, 1H), 5.26 (d, J = 3.0 Hz, 1H), 3.88 (s, 3H), 2.29 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.8, 164.3, 151.4, 137.8, 137.0, 131.0, 129.6, 127.6, 127.2, 125.8, 124.0, 114.3, 111.7, 110.7, 64.1, 62.6, 55.7, 21.2; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C22H21N2O2 345.1598, found 345.1605.

((3R*,4S*)-3-(3,4-Dimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-4-yl)(4methoxyphenyl) methanone (6p). White solid, mp: 187.7N

MeO

188.6 °C (34.0 mg, 86%); 1H NMR (400 MHz, CDCl3) δ

N

MeO

8.37 (s, 1H), 7.81 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.5 Hz,

O 6p

OMe

2H), 6.79 (d, J = 8.3 Hz, 1H), 6.74 (d, J = 8.2 Hz, 1H), 6.66

(s, 1H), 6.61 (d, J = 3.3 Hz, 1H), 6.56 (s, 1H), 6.31 (s, 1H), 5.60 (d, J = 6.0 Hz, 1H), 5.17 (d, J = 5.2 Hz, 1H), 3.87 (s, 3H), 3.82 (s, 3H), 3.74 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 194.1, 164.4, 151.4, 149.2, 148.8, 132.6, 131.0, 128.1, 125.7, 123.8, 119.9, 114.3, 111.8, 111.3, 21



110.8, 110.5, 64.4, 62.3, 56.0, 55.9, 55.7; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C23H23N2O4 391.1652, found 391.1660.

((3R*,4S*)-3-(4-Bromophenyl)-3,4-dihydropyrrolo[1,2N

a]pyrazin-4-yl)(4-methoxyphenyl)methanone (6q). White

N Br

solid, mp: 172.7-173.6 °C (35.0 mg, 85%); 1H NMR (400

O 6q

OMe

MHz, CDCl3) δ 8.38 (s, 1H), 7.79 (d, J = 8.3 Hz, 2H), 7.38 (d,

J = 7.8 Hz, 2H), 7.09 (d, J = 7.8 Hz, 2H), 6.91 (d, J = 8.4 Hz, 2H), 6.62 (d, J = 3.3 Hz, 1H), 6.55 (s, 1H), 6.31 (s, 1H), 5.55 (d, J = 5.8 Hz, 1H), 5.20 (d, J = 4.7 Hz, 1H), 3.88 (s, 3H); 13C{1H}

NMR (100 MHz, CDCl3) δ 193.7, 164.5, 151.9, 139.0, 132.0, 131.0, 129.3, 127.9,

125.7, 124.0, 122.1, 114.4, 112.2, 110.9, 64.0, 62.1, 55.8; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C21H18BrN2O2 409.0546, found 409.0552.

((3S*,4S*)-3-(Furan-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-4-yl)(4-methoxyphenyl) methanone (6r). White solid, mp: 167.7-168.9 °C (24.1 mg, N

75%); 1H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 7.99 (d, J

N

O

= 8.6 Hz, 2H), 7.36 (s, 1H), 6.98 (d, J = 8.6 Hz, 2H), 6.59 (d,

O 6r

OMe

J = 4.8 Hz, 2H), 6.29 (s, 1H), 6.24 (s, 1H), 6.10 (d, J = 3.2 Hz,

1H), 5.93 (d, J = 4.2 Hz, 1H), 5.46 (d, J = 2.6 Hz, 1H), 3.89 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.0, 164.4, 152.8, 151.9, 142.4, 131.1, 127.2, 125.4, 124.3, 114.4, 112.3, 110.7, 110.7, 107.8, 60.3, 58.5, 55.7; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C19H17N2O3 321.1234, found 321.1242.

22


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(4-Fluorophenyl)((3R*,4S*)-3-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-4-yl)methanone (6s). White solid, mp: 162.2-163.8 °C (27.8 mg, 87 %); 1H NMR N

(400 MHz, CDCl3) δ 8.38 (s, 1H), 7.84 (dd, J = 8.6, 5.4 Hz, 2H),

N

7.22-7.27 (m, 3H), 7.18 (d, J = 7.6 Hz, 2H) 7.10 (t, J = 8.5, 2H),

O 6s

F

6.62 (d, J = 2.8 Hz, 1H), 6.55 (s, 1H), 6.30-6.34 (m, 1H), 5.62 (d,

J = 5.4 Hz, 1H), 5.22 (d, J = 3.8 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 194.2, 166.1 (d, JC-F = 255.6 Hz), 165.0, 151.7, 139.6, 131.3 (d, JC-F = 9.5 Hz), 129.1, 128.3, 127.4, 125.7, 124.0, 116.3 (d, JC-F = 21.9 Hz), 112.2, 111.0, 64.5, 62.8; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C20H16FN2O 319.1241, found 319.1254.

(4-Fluorophenyl)((3R*,4S*)-3-(p-tolyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-4yl)methanone (6t). White solid, mp: 178.8-180.6 °C (28.5 mg,

N N Me

86 %); 1H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 7.87 (dd, J = 8.4, 5.4 Hz, 2H), 7.13 (t, J = 8.5 Hz, 2H), 7.07 (s, 4H), 6.62

O 6t

F

(d, J = 3.2 Hz, 1H), 6.56 (s, 1H), 6.31-6.34 (m, 1H), 5.62 (d, J

= 4.7 Hz, 1H), 5.23 (d, J = 3.1 Hz, 1H), 2.29 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 194.1, 166.3 (d, JC-F = 255.6 Hz), 165.0, 151.5, 138.1, 136.7, 131.3 (d, JC-F = 9.4 Hz), 129.7, 127.2, 125.7, 124.0, 116.3 (d, JC-F = 21.9 Hz), 112.1, 110.9, 64.0, 63.0, 21.2; HRMS (ESIQTOF) m/z [M+H]+ calcd for C21H18FN2O 333.1398, found 333.1404.

(4-Fluorophenyl)((3R*,4S*)-3-(2-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-4-yl) 23

OMe N N O 6u

F



Page 24 of 39

methanone (6u). White solid, mp: 166.7-168.3 °C (28.7 mg, 83 %); 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 8.11 (dd, J = 8.7, 5.4 Hz, 2H), 7.20-7.25 (m, 1H), 7.15 (t, J = 8.5 Hz, 2H), 6.95 (d, J = 8.5 Hz, 1H), 6.84-6.89 (m, 2H), 6.60-6.63 (m, 1H), 6.52 (s, 1H), 6.27-6.31 (m, 1H), 5.80 (s, 1H), 5.70 (d, J = 3.3 Hz, 1H), 3.91 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.8, 166.3 (d, JC-F = 255.6 Hz), 164.9, 156.3, 153.2, 131.7 (d, JC-F =

9.3 Hz), 130.5 (d,

JC-F = 9.3 Hz), 129.2, 128.4, 126.2, 124.3, 121.2, 115.8 (d, JC-F = 21.9 Hz), 111.7, 110.7, 110.6, 62.4, 57.8, 55.4; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C21H18FN2O2 349.1347, found 349.1356.

((3R*,4S*)-3-(3,4-Dimethoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-4-yl)(4fluorophenyl) methanone (6v). White solid, mp: 156.4-

N N

MeO MeO

158.9 °C (29.8 mg, 81%); 1H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 7.84 (dd, J = 8.7, 5.3 Hz, 2H), 7.12 (t, J = 8.5 Hz, 2H),

O 6v

F

6.72-6.78 (m, 2H), 6.61-6.63 (m, 2H), 6.57 (m, 1H), 6.32-6.34

(m, 1H), 5.61 (d, J = 5.8 Hz, 1H), 5.15 (d, J = 5.7 Hz, 1H), 3.82 (s, 3H), 3.74 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 194.4, 166.3 (d, JC-F = 255.6 Hz), 165.0, 151.5, 149.3, 132.3, 131.2 (d, JC-F = 9.5 Hz), 130.6, 125.6, 123.9, 119.8, 116.3 (d, JC-F = 21.9 Hz), 112.1, 111.4, 111.0, 110.4, 64.2, 62.7, 56.0, 55.9; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C22H20FN2O3 379.1452, found 379.1450.

((3R*,4S*)-3-(4-Bromophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-4-yl)(4-fluorophenyl) methanone (6w). White solid, mp: 164.2-166.1 °C (31.8 mg, N

80%); 1H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 7.84 (dd, J

N Br

24

O 6w

F


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= 8.7, 5.3 Hz, 2H), 7.39 (d, J = 8.3 Hz, 2H), 7.14 (t, J = 8.5 Hz, 2H), 7.07 (d, J = 8.3 Hz, 2H), 6.64 (d, J = 3.7 Hz, 1H), 6.56 (s, 1H), 6.31 – 6.35 (m, 1H), 5.56 (d, J = 5.7 Hz, 1H), 5.19 (d, J = 5.5 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.9, 166.4 (d, JC-F = 256.4Hz), 165.1, 152.0, 138.7, 132.1, 131.2 (d, JC-F = 9.2 Hz), 129.2, 125.6, 124.1, 122.3, 116.5 (d, JC-F = 22.0 Hz), 112.5, 111.2, 63.9, 62.6; HRMS (ESI-QTOF) m/z [M+Na]+ calcd for C20H14NaBrFN2O 419.0166, found 419.0156.

(4-Fluorophenyl)((3S*,4S*)-3-(furan-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-4yl)methanone (6x). White solid, mp: 148.2-150.5 °C (23.2 mg,

N N

O

75%);1H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 8.03 (dd, J = 8.7,

O

5.3 Hz, 2H), 7.36 (s, 1H), 7.19 (t, J = 8.5 Hz, 2H), 6.61 (d, J = 3.4 6x

F

Hz, 2H), 6.30 – 6.33 (m, 1H), 6.23-6.25 (m, 1H), 6.10 (d, J = 3.0

Hz, 1H), 5.93 (d, J = 4.3 Hz, 1H), 5.44 (d, J = 3.3 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.3, 166.4 (d, JC-F = 255.0 Hz), 165.1, 152.9, 151.5, 142.5, 131.4 (d, JC-F = 9.3 Hz), 125.3, 124.4, 116.5 (d, JC-F = 22.0 Hz), 112.6, 110.9 (d, JC-F = 9.1 Hz), 110.8, 108.0, 60.7, 58.4; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C18H14FN2O2 309.1034, found 309.1047.

(4-Fluorophenyl)((3R*,4S*)-3-(pyridin-4-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-4yl)methanone (6y). White solid, mp: 144.7-146.8 °C (22.9 mg,

N N N

72%); 1H NMR (400 MHz, acetone-d6) δ 9.27 (s, 1H), 8.36 (d, J =

O

6.0 Hz, 2H), 8.23 (dd, J = 8.8, 5.5 Hz, 2H), 7.59 (s, 1H), 7.30 – 7.33 6y

F

(m, 2H), 7.18 (d, J = 5.8 Hz, 1H), 6.82-6.84 (m, 1H), 6.24 – 6.27

(m, 1H), 5.70 (d, J = 4.2 Hz, 1H), 5.51 (d, J = 4.3 Hz, 1H), 5.43 (d, J = 3.6 Hz, 1H). 13C{1H} 25



Page 26 of 39

NMR (100 MHz, acetone-d6) δ 194.9, 180.7, 168.3 (d, JC-F = 252.5 Hz), 165.8, 150.2, 133.9, 132.8 (d, JC-F = 9.8 Hz), 130.8, 126.6, 122.5, 116.8 (d, JC-F = 24.9 Hz), 111.9, 110.7, 74.6, 65.6; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C19H15FN3O 320.1194, found 320.1206.

(4-Chlorophenyl)((3R*,4S*)-3-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-4yl)methanone(6z). White solid, mp: 155.1-155.3°C (28.8 mg, 86%);

N N

1H

NMR(400 MHz, CDCl3) δ 8.37 (s, 1H), 7.82 (dd, J = 7.5, 5.6

Hz, 2H), 7.21-7.24 (m, 3H), 7.16 (d, J = 6.4 Hz, 2H), 7.09 (t, J = 8.2

O 6z

Cl

Hz, 2H), 6.61 (d, J = 3.4 Hz, 1H), 6.54 (s, 1H), 6.31 (s, 1H), 5.60 (d,

J = 5.2 Hz, 1H), 5.20 (d, J = 4.3 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 194.2, 151.7, 139.6, 131.3, 131.3, 129.1, 128.3, 127.4, 125.7, 124.0, 116.4, 116.2, 112.2, 111.0, 64.5, 62.8; HRMS (ESI-QTOF) m/z [M+Na]+ calcd for C20H15ClN2ONa 357.0765, found 357.0775.

(4-Chlorophenyl)((3R*,4S*)-3-(p-tolyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-4yl)methanone (6aa). White solid, mp: 154.7-155.8°C (30.5 mg, N

88%); 1H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 7.86 (s, 2H),

N Me

7.07-7.13 (m, 6H), 6.62 (s, 1H), 6.56 (s, 1H), 6.33 (s, 1H), 5.62

O 6aa

Cl

(s, 1H), 5.23 (s, 1H), 2.29 (s, 3H);

13C{1H}

NMR (100 MHz,

CDCl3) δ 194.1, 151.5, 138.1, 136.7, 131.4, 131.3, 129.7, 127.2, 125.7, 124.0, 116.4, 116.2, 112.0, 110.9, 64.0, 63.0, 21.2; HRMS (ESI-QTOF) m/z [M+Na]+ calcd for C21H17ClN2ONa 371.0922, found 371.0931.

26


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(4-Chlorophenyl)((3R*,4S*)-3-(2-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-4yl) methanone (6ab). White solid, mp: 150.6-151.8°C (30.6 mg, OMe N

84%); 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 8.11 (dd, J

N

= 7.5, 5.9 Hz, 2H), 7.21-7.25 (m, 1H), 7.15 (t, J = 8.4 Hz, 2H),

O 6ab

Cl

6.95 (d, J = 7.4 Hz, 1H), 6.83-6.89 (m, 2H), 6.60 (d, J = 2.4 Hz,

1H), 6.52 (s, 1H), 6.28 (s, 1H), 5.80 (s, 1H), 5.70 (d, J = 2.6 Hz, 1H), 3.91 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.8, 156.3, 153.2, 131.8, 131.7, 129.2, 128.4, 128.4, 126.2, 124.3, 121.2, 116.0, 115.8, 111.7, 110.7, 110.6, 62.4, 57.8, 55.4; HRMS (ESI-QTOF) m/z [M+Na]+ calcd for C21H17ClN2O2Na 387.0871, found 387.0881.

((3S*,4S)-3-(1H-Pyrrol-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-4-yl)(4-chlorophenyl) methanone (6ac). White solid, mp: 152.7-153.6 °C (23.8 mg, H N

N

73%); 1H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 8.25 (s, 1H),

N

7.93 (dd, J = 8.6, 5.4 Hz, 2H), 7.17 (t, J = 8.5 Hz, 2H), 6.67 (s,

O 6ac

Cl

2H), 6.61 (d, J = 3.6 Hz, 1H), 6.33-6.35 (m, 1H), 6.07 (d, J = 2.8

Hz, 1H), 6.00 (s, 1H), 5.79 (d, J = 4.2 Hz, 1H), 5.40 (d, J = 2.8 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.9, 151.4, 131.3, 131.3, 129.1, 128.3, 127.4, 125.7, 124.0, 116.4, 116.2, 112.1, 110.8, 107.1, 102.8, 62.6, 59.1; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C18H15ClN3O 324.0898, found 324.0910.

(4-Bromophenyl)((3R*,4S*)-3-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-4-yl)methanone (6ad). White solid, mp: 167.5-168.6 °C (32.3 mg, 85%); 1H NMR N

(400 MHz, CDCl3) δ 8.37 (s, 1H), 7.64 (d, J = 8.6 Hz, 2H), 7.56

N

27

O 6ad

Br



(d, J = 8.6 Hz, 2H), 7.22-7.25 (m, 3H), 7.15-7.19 (m, 2H), 6.61 (d, J = 3.6 Hz, 1H), 6.53 (s, 1H), 6.30-6.32 (m, 1H), 5.59 (d, J = 5.3 Hz, 1H), 5.20 (d, J = 3.3 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 194.9, 151.7, 139.6, 132.4, 130.0, 129.6, 129.1, 128.4, 128.2, 127.4, 125.7, 124.0, 112.2, 111.0, 64.4, 62.9; HRMS (ESI-QTOF) m/z [M+Na]+ calcd for C20H15BrN2ONa 401.0260, found 401.0269.

(4-Bromophenyl)((3R*,4S*)-3-(p-tolyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-4yl)methanone (6ae). White solid, mp: 171.7-172.9 °C (34.2 mg, N

87%); 1H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 7.68 (d, J =

N Me

8.6 Hz, 2H), 7.60 (d, J = 8.6 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H),

O 6ae

Br

7.05 (d, J = 8.4 Hz, 2H), 6.62 (d, J = 2.7 Hz, 1H), 6.56 (s, 1H),

6.32-6.34 (m, 1H), 5.60 (d, J = 4.8 Hz, 1H), 5.21 (d, J = 4.6 Hz, 1H), 2.29 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 194.8, 151.5, 138.1, 136.6, 133.5, 132.4, 130.0, 129.7, 129.5, 127.2, 125.7, 124.0, 112.1, 110.9, 63.9, 63.0, 21.2; HRMS (ESI-QTOF) m/z [M+Na]+ calcd for C21H17BrN2ONa 415.0416, found 415.0427.

(4-Bromophenyl)((3R*,4S*)-3-(4-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-4yl)methanone (6af). White solid, mp: 165.2-166.5°C (32.7 N


N MeO

(d, J = 8.5 Hz, 2H), 7.59 (d, J = 8.5 Hz, 2H), 7.08 (d, J = 8.6

O 6af

Br

Hz, 2H), 6.78 (d, J = 8.6 Hz, 2H), 6.62 (d, J = 3.8 Hz, 1H),

6.56 (s, 1H), 6.32-6.34 (m, 1H), 5.59 (d, J = 5.1 Hz, 1H), 5.18 (d, J = 3.4 Hz, 1H), 3.75 (s, 3H); 13C{1H}

NMR (100 MHz, CDCl3) δ 194.9, 159.5, 151.4, 133.6, 132.4, 131.7, 130.0, 129.5, 28


Page 28 of 39

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128.5, 125.6, 124.0, 114.4, 112.0, 110.9, 63.7, 63.0, 55.4; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C21H18BrN2O2 409.0546, found 409.0555.

(4-Bromophenyl)((3S*,4S*)-3-(furan-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-4yl)methanone (6ag). Yellow solid, mp: 153.1-154.4°C (29.5 mg, N

80%); 1H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 7.83 (d, J = 8.4

N

O

Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.35 (s, 1H), 6.60 (s, 2H), 6.28-

O 6ag

Br

6.31 (m, 1H), 6.24 (s, 1H), 6.09 (s, 1H), 5.91 (d, J = 4.3 Hz, 1H),

5.42 (d, J = 3.9 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 194.0, 152.9, 151.4, 142.5, 133.0, 132.6, 130.1, 129.7, 125.3, 124.4, 112.6, 110.9, 110.8, 108.0, 60.7, 58.3; HRMS (ESI-QTOF) m/z [M+Na]+ calcd for C18H13BrN2O2Na 391.0053, found 391.0061.

(4-Bromophenyl)((3S*,4S*)-3-(pyridin-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-4-yl) methanone (6ah). Yellow solid, mp: 151.4-152.6 °C (20.5 mg, N N

73%); 1H NMR (400 MHz, CDCl3) δ 8.58 (d, J = 4.6 Hz, 1H),

N

8.48 (s, 1H), 8.14 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H),

O 6ah

Br

7.59-7.62 (m, 1H), 7.31 (d, J = 7.9 Hz, 1H), 7.18 (t, J = 6.2 Hz,

1H), 6.58 (d, J = 3.0 Hz, 2H), 6.51 (d, J = 2.9 Hz, 1H), 6.25-6.27 (m, 1H), 5.65 (s, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 194.5, 158.4, 154.5, 149.9, 148.3, 137.1, 136.5, 132.5, 130.7, 124.2, 122.1, 121.8, 118.0, 112.3, 110.7, 64.2, 61.8; HRMS (ESI-QTOF) m/z [M+Na]+ calcd for C19H14BrN3ONa 402.0213, found 402.0225.

29



Page 30 of 39

((3R*,4S*)-3-(4-Chlorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-4-yl)(naphthalen-2-yl) methanone (6ai). Yellow solid, mp: 140.4-142.2 °C (33.8 N


N Cl

(s, 1H), 7.89-7.90 (m, 4H), 7.65 (t, J = 7.5 Hz, 1H), 7.59 (t, J

O 6ai

= 7.5 Hz, 1H), 7.23 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.4 Hz,

2H), 6.65 – 6.66 (m, 1H), 6.61 (s, 1H), 6.34-6.35 (m, 1H), 5.77 (d, J = 5.7 Hz, 1H), 5.31 (d, J = 5.4 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 195.4, 151.9, 138.5, 136.1, 134.1, 132.5, 132.3, 130.6, 129.8, 129.4, 129.3, 129.2, 129.0, 128.0, 127.4, 125.7, 124.1, 123.8, 112.3, 111.1, 63.9, 62.7; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C24H18ClN2O 385.1102, found 385.1116.

[1,1'-Biphenyl]-4-yl((3R*,4S*)-3-(4-chlorophenyl)-3,4N

dihydropyrrolo[1,2-a]pyrazin-4-yl)methanone

N Cl

(6aj).

White solid, mp: 129.5-131.0 °C (36.5 mg, 89%); 1H

O

NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 7.89 (d, J = 8.3

6aj

Hz, 2H), 7.69 (d, J = 8.3 Hz, 2H), 7.63 (d, J = 7.6 Hz, 2H), 7.49 (t, J = 7.4 Hz, 2H), 7.44 (d, t = 7.3 Hz, 1H), 7.24 (s, 2H), 7.17 (d, J = 8.4 Hz, 2H), 6.65 (d, J = 3.7 Hz, 1H), 6.60 (s, 1H), 6.34 – 6.35 (m, 1H), 5.65 (d, J = 5.6 Hz, 1H), 5.28 (d, J = 5.5 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 194.9, 152.0, 147.1, 139.5, 138.3, 134.1, 133.5, 132.8, 129.2, 129.2, 128.9, 128.8, 127.8, 127.4, 125.7, 124.2, 112.5, 111.1, 63.7, 62.7; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C26H20ClN2O 411.1259, found 411.1266.

Furan-2-yl((3R*,4S*)-3-(4-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-4yl)methanone (6ak). Yellow solid, mp: 165.2-167.4 °C (26.5 mg, N

30

N MeO

O 6ak

O


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83%); 1H NMR(400 MHz, CDCl3) δ 8.40 (s, 1H), 7.62 (s, 1H), 7.15 (d, J = 8.3 Hz, 2H), 7.06 (d, J = 3.0 Hz, 1H), 6.81 (d, J = 8.4 Hz, 2H), 6.57–6.60 (m, 2H), 6.54 (s, 1H), 6.31 (s, 1H), 5.43 (d, J = 4.6 Hz, 1H), 5.32 (d, J = 3.8 Hz, 1H), 3.75 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 184.3, 159.4, 151.7, 151.2, 147.4, 131.8, 128.5, 125.7, 124.0, 119.2, 114.2, 113.1, 111.8, 110.8, 63.9, 63.5, 55.4; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C19H17N2O3 321.1234, found 321.1247.

(4-Methoxyphenyl)((3R*,4S*)-3-phenyl-3,4-dihydropyrazino[1,2-a]indol-4yl)methanone (8). Yellow solid, mp: 169.6-170.8 °C (27.5 mg, N

72%); 1H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 7.72 (d, J =

N

8.2 Hz, 2H), 7.30 (d, J = 8.3 Hz, 2H), 7.21-7.23 (m, 2H), 7.14-

O 8

OMe

7.17 (m, 2H), 7.05-7.07 (m, 2H), 6.98 (d, J = 7.0 Hz, 1H), 6.91

(d, J = 8.3 Hz, 2H), 6.30 (s, 1H), 5.69 (s, 1H), 5.51 (s, 1H), 3.83 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 195.5, 163.2, 151.4, 145.1, 143.5, 134.4, 130.4, 130.1, 129.4, 128.6, 127.4, 127.1, 124.0, 122.5, 121.5, 114.3, 112.0, 108.9, 64.3, 62.8, 55.9; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C25H21N2O2 381.1598, found 381.1608.

Phenyl((3R*,4S*)-3-((E)-styryl)-3,4-dihydropyrrolo[1,2-a]pyrazin-4-yl)methanone (9). Yellow solid, mp: 161.4-162.5 °C (22.8 mg, 70%); 1H NMR (400 N N

Ph O 9

MHz, CDCl3) δ 8.27 (s, 1H), 7.83 (d, J = 7.8 Hz, 2H), 7.57-7.60 (m, 1H), 7.43-7.47 (m, 2H), 7.22-7.24 (m, 3H), 7.18 (d, J = 7.1 Hz, 2H), 6.62(s, 1H), 6.56 (s, 1H), 6.32(s, 1H), 5.80 (s, 1H), 5.67 (d, J 31



Page 32 of 39

= 4.6 Hz, 1H), 5.28 (s, 1H), 4.69 (s, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 194.7, 151.7, 136.3, 134.2, 133.3, 129.3, 128.6, 128.6, 128.4, 128.1, 126.7, 126.5, 125.7, 124.4, 112.2, 110.8, 62.2, 62.2; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C22H19N2O 327.1492, found 327.1499.

Synthesis of 5: A mixture of 6ad (37.9 mg, 0.1 mmol) and K2CO3 (20.7 mg, 1.5 equiv) in ethanol (1.0 mL) was refluxed at 80 °C for 7 h (monitored by TLC). Upon completion of the reaction, the reaction mixture was concentrated in vacuo, extracted with ethyl acetate (3 × 10 mL), and washed with water and brine respectively. The organic layer was dried over MgSO4 and concentrated in vacuo to afford the crude product, which was purified by silica gel column chromatography (EtOAc/hexane = 1:8) to give 5 (33.9 mg, 90%). (4-Bromophenyl)(3-phenylpyrrolo[1,2-a]pyrazin-4-yl)methanone (5). Yellow fluorescent solid, mp: 177.7-178.9 °C (33.9 mg, 90%); 1H NMR(400 MHz, N

CDCl3) δ 8.99 (s, 1H), 7.65-7.67 (m, 1H), 7.54 (d, J = 8.4 Hz, 2H),

N

7.46 (dd, J = 7.2, 2.0 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.21-7.23

O 5

Br

(m, 3H), 6.98 (d, J = 4.2 Hz, 1H), 6.94-6.96 (m, 1H);

13C{1H}

NMR (100 MHz, CDCl3) δ 191.7, 145.8, 139.8, 137.7, 135.3, 132.0, 130.9, 129.8, 129.3, 128.9, 128.5, 128.3, 116.5, 116.2, 105.5; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C20H14BrN2O 377.0284, found 377.0292.

General Procedure for the Synthesis of 10: A mixture of 6ad (37.9 mg, 0.1 mmol) and ethyl bromoacetate (33.4 mg, 0.2 mmol) in CH3CN (5.0 mL) was refluxed for 1 h (monitored by TLC). Upon completion of the reaction, the reaction mixture was cooled down to rt. The precipitate was filtered off to afford 10a (51.6 mg, 32


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95%). (3R*,4S*)-4-(4-Bromobenzoyl)-2-(2-ethoxy-2-oxoethyl)-3-phenyl-3,4dihydropyrrolo[1,2-a]pyrazin-2-ium bromide (10a). Yellow Br EtO2C

solid, mp: 224.5-226.6 °C (51.6 mg, 95%); 1H NMR(400 MHz,

N N

acetone-d6) δ 9.93 (s, 1H), 8.26 (d, J = 8.5 Hz, 2H), 8.24 (s,

O

1H), 7.83 (d, J = 8.3 Hz, 2H), 7.70 (d, J = 4.3 Hz, 1H), 7.68 (s,

10a

Br

1H), 7.46-7.52 (m, 2H), 7.38-7.44 (m, 3H), 6.71 (dd, J = 4.2,

2.3 Hz, 1H), 5.87 (s, 1H), 5.56 (d, J = 17.3 Hz, 1H), 4.49 (d, J = 17.3 Hz, 1H), 3.99-4.09 (m, 2H), 1.11 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, acetone-d6) δ 192.7, 167.3, 155.6, 139.3, 134.1, 133.4, 133.0, 132.4, 130.5, 130.4, 129.5, 129.3, 127.7, 125.1, 117.3, 65.8, 63.7, 62.8, 57.4, 14.2; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C24H23BrN2O3 466.0881, found 466.0872.

(3R*,4S*)-4-(4-Bromobenzoyl)-2-(2-oxo-2-phenylethyl)-3-phenyl-3,4dihydropyrrolo[1,2-a]pyrazin-2-ium bromide(10b). Yellow Ph

O

Br

solid, mp: 247.7-248.6 °C (56 mg, 97%); 1H NMR (400 MHz,

N

acetone-d6) δ 9.90 (s, 1H), 8.31 (d, J = 8.2 Hz, 2H), 8.25 (s,

N

1H), 7.79 (d, J = 7.7 Hz, 2H), 7.72-7.75 (m, 3H), 7.55-7.58(m,

O 10b

Br

2H), 7.47-7.52 (m, 2H), 7.39 (t, J = 7.5 Hz, 2H), 7.35 (s, 3H),

6.61 (d, J = 17.6 Hz, 2H), 5.83 (s, 1H), 5.19 (d, J = 17.6 Hz, 1H); 13C{1H} NMR (100 MHz, acetone-d6) δ 193.2, 191.9, 155.3, 138.9, 134.9, 134.9, 134.4, 133.8, 132.8, 132.5, 130.3, 130.3, 129.6, 129.6, 128.9, 128.7, 127.7, 125.0, 116.8, 66.2, 63.7, 63.0; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C28H23BrN2O2 500.0912, found 500.0899. 33



Supporting Information The Supporting Information is available free of charge on the ACS Publication website at DOI: 1H

and 13C NMR spectra of the synthesized compounds and a CIF file for 6e.

Notes The authors declare no competing financial interest.

Acknowledgements We thank the National Research Foundation of Korea (NRF-2017R1A2A2A05069364 and NRF-2018R1A6A1A03023718) for generous financial support.

References

34


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Compound 4 was synthesized by following the literature procedures. See ref 6c.

13

Use of other ammonium salts were screened as well. While use of ammonium formate gave

a comparable yield of 6a, other salts such as ammonium carbonate, ammonium bicarbonate, ammonium sulfate, and ammonium chloride provided inferior results. 14

For crystal structure data of 6e, see the SI. CCDC 1894586 contains the supplementary

crystallographic data for compound 6e. These data can be obtained free of charge from The 38


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Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. 15

We thank the reviewer who suggested the reaction in the absence of K2CO3.

16

(a) Trost, B. M. The Atom Economy--a Search for Synthetic Efficiency. Science 1991, 254,

1471-1477. (b) Trost, B. M. Atom Economy—A Challenge for Organic Synthesis: Homogeneous Catalysis Leads the Way. Angew. Chem., Int. Ed. 1995, 34, 259-281. (c) Sheldon, R. A. Atom Efficiency and Catalysis in Organic Synthesis. Pure Appl. Chem. 2000, 72, 1233-1246. 17

These reactions can be carried out in DMSO if the starting materials are not much soluble in

EtOH. DMSO was used for the synthesis of 6ai due to poor solubility of 4g in EtOH. 18

Sypchenko, V. V.; Potikha, L. M.; Kovtunenko, V. A.; Baumer, V. N.; Shishkin, O. V.

Preparation

of

Isoindolo[2,1-a]quinoxalines

Based

on

Derivatives. Chem. Heterocycl. Compd. 2012, 48, 1033-1042.

39


N-(2-Aminophenyl)isoindole

pyrazines - ACS Publications

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