Tandem oxidation processes for the preparation of nitrogen-containing heteroaromatic and heterocyclic compounds

Abstract

α-Hydroxy ketones undergo manganese dioxide-mediated oxidation followed by in situ trapping with aromatic or aliphatic 1,2-diamines to give quinoxalines or dihydropyrazines, respectively, in a one-pot procedure which avoids the need to isolate the highly reactive dicarbonyl intermediates. The scope and limitations of these procedures are outlined and modifications to this procedure are discussed in which reduction is carried out in the same reaction vessel, generating piperazines, or oxidation, leading to pyrazines.

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Introduction

Nitrogen-containing heteroaromatic and heterocyclic compounds are indispensable structural units for both the chemist and the biochemist. Quinoxalines constitute the basis of many insecticides, fungicides, herbicides and anthelmintics, as well as being important in human health and as receptor antagonists.^1,2 There are numerous methods of preparing quinoxalines but the double condensation of a 1,2-dicarbonyl compound and a 1,2-diaminoaromatic is commonly employed.^1–3 Similarly, dihydropyrazines, piperazines and pyrazines are of great importance in natural products and as chemotherapeutic agents^2b,4 and can be prepared from the corresponding 1,2-dicarbonyl compound and an aliphatic 1,2-diamine,^3a,4,5 followed by reduction or oxidation of the resulting dihydropyrazines, if required.

We have recently developed a number of manganese dioxide-mediated tandem oxidation processes (TOPs) for the elaboration of alcohols.^6–8 As part of this programme, we established that α-hydroxyketones undergo in situ oxidation-trapping when treated with manganese dioxide in the presence of stabilised Wittig reagents, giving γ-ketocrotonates (Scheme 1a).⁷ In addition, we have also developed a TOP-amine trapping sequence leading to imines (Scheme 1b).⁸ We therefore decided to extend these procedures and investigate the conversion of α-hydroxyketones 1 into diamino heterocycles.⁹

Scheme 1 TOP approaches to γ-ketocrotonates and imines.

Results and discussion

We first studied the preparation of quinoxalines 4 and related heterocycles employing a manganese dioxide-mediated TOP with suitable 1,2-diaminoaromatics 2 avoiding the need to isolate the “hyper-reactive”¹⁰ 1,2-dicarbonyl intermediate 3 (Scheme 2).

Scheme 2 Proposed TOP synthesis of quinoxalines.

Preliminary studies were carried out using hydroxyacetone 1a (R=Me) and o-phenylenediamine 2a (R′=H), and are summarised in Table 1. On the first attempt we were delighted to observe the formation of 2-methylquinoxaline 4a^11a but the yield of 43% was disappointing (Table 1, entry i). Addition of acid or base (entries ii and iii), or changing the solvents (entries iv and v) gave no improvement. The major by-product was isolated and identified as the known¹² diazobenzene 5a resulting from oxidative coupling of 2a. We therefore investigated batchwise addition of the reagents and the use of different stoichiometries (entries vi and vii). The optimum conditions involved the use of a two fold excess of diamine 2a (entry vii); in this case the reaction was complete in just one hour and 2-methylquinoxaline 4a was isolated in 79% yield (after chromatography to remove 5a and polymeric by-products). The operational simplicity of this process is noteworthy: after the reaction is complete the remaining oxidant and its by-products are removed by filtration and concentration in vacuo followed by chromatography gives the pure product.

Table 1 Optimisation of MnO₂-mediated TOP leading to quinoxaline 4a^a

Entry	Reagents	Conditions	Time/h	Yield (%)
a Based on 1 eq. alcohol 1a unless otherwise stated; the diazo compound 5a was also formed (up to 15%). b Yield based on diamine 2a. c The isolated yield of diazo compound in this case was 6% based on 2a.
i	15 eq. MnO2, 1.1 eq. 2a	CH2Cl2, Δ	20	43
ii	15 eq. MnO2, 1.1 eq. 2a, 1% AcOH	CH2Cl2, Δ	20	10
iii	15 eq. MnO2, 1.1 eq. 2a, 1% K2CO3	CH2Cl2, Δ	20	10
iv	15 eq. MnO2, 1.1 eq. 2a	Et2O, Δ	20	12
v	15 eq. MnO2, 1.1 eq. 2a	THF, Δ	20	15
vi	15 eq. MnO2, 3.0 eq. 1a, 1.0 eq. 2a	CH2Cl2, Δ	20	51^b
vii	10 eq. MnO2, 2.0 eq. 2a, 4 Å mol. sieves	CH2Cl2, Δ	1	79^c

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With the successful optimisation results in hand, we moved on to investigate the scope of the process (Table 2), first in terms of α-hydroxyketone substrate (entries i–v). As can be seen, in addition to α-hydroxyacetone 1a, the related 1-cyclohexyl-2-hydroxyethanone 1b¹³ also gave an excellent yield of the corresponding quinoxaline 4b on treatment with manganese dioxide and 1,2-diaminobenzene. Substrates 1a and 1b were of particular interest as the intermediate α-keto aldehydes are often problematic in terms of the “hyper-reactivity” of the aldehyde function.¹⁰ We next moved on to examine aryl substituted α-hydroxyketones (entries iii and iv), both hydroxyacetophenone 1c and the related furyl system 1d¹³ giving the expected adducts 4c and 4d, respectively. The secondary alcohol benzoin 1e was also shown to react well under these oxidative-trapping conditions with 1,2-diaminobenzene 2a giving 2,3-diphenylquinoxaline 4e in 75% yield (entry v).

Table 2 MnO₂-mediated TOP quinoxaline formation^a

Entry	α-Hydroxy ketone 1	Amine 2	Product 4	Yield (%)
a Using 10 eq. MnO2 and 2 eq. diamine in CH2Cl2 at reflux; diazo and polymeric byproducts were removed during chromatography. Yield refers to isolated, chromatographically and spectroscopically pure product. b Isolated as a mixture of regioisomers, ∼7 : 1 in favour of the 3-methylpyrido[2,3-b]pyrazine as determined by ^1H NMR spectroscopy c Isolated as a mixture of regioisomers, ∼2 : 1 in favour of the 3-phenylpyrido[2,3-b]pyrazine as determined by ^1H NMR spectroscopy.
i	1a	2a	4a ^11a	79
ii	1b	2a	4b ^11b	78
iii	1c	2a	4c ^11c	79
iv	1d	2a	4d ^11c	89
v	1e	2a	4e ^11d	75
vi	1c	2b	4f ^2c	66
vii	1b	2b	4g	89
viii	1f	2b	4h	62
ix	1a	2c	4i ^11e	66^b
x	1c	2c	4j ^2c ^11f	69^c

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We next studied the use of other diamines (entries vi–x). Thus, 1,2-diamino-4,5-dimethylbenzene 2b was also shown to work well in these reactions giving the desired 2,6,7-trisubstituted quinoxalines 4f, 4g and 4h in good to excellent yields with α-hydroxyketones 1c, 1b and 1f, respectively (entries vi–viii). Finally, 2,3-diaminopyridine 2c was investigated as a coupling partner with 1a and 1c, giving the corresponding 2/3-substituted pyrido[2,3-b]pyrazines 4i and 4j as mixtures of regioisomers (entries ix and x).

Finally in this section of the research, we attempted to apply this methodology to the synthesis of quinoxalin-2-ones. Hence, methyl glycolate (1.20 equivalents) and 1,2-phenylene diamine 2a were reacted under the standard conditions. Unfortunately, oxidation of the glycolate is much slower than for the α-hydroxyketones and therefore, production of diazobenzene is much faster than formation of the quinoxalinone 4k, which was isolated in a disappointing yield of 36% (Scheme 3). Even when the glycolate was used in two-fold excess with respect to phenylene diamine 2a, ¹H NMR spectroscopy of the crude product, after complete consumption of 2a, showed the molar ratio of diazobenzene 5a to quinoxaline 4k to be ∼1.1 : 1.

Scheme 3 Synthesis of quinoxalin-2-ones.

With a facile and technically straightforward synthesis of quinoxalines and related heteroaromatic compounds from the corresponding α-hydroxyketones to hand, our attention turned to the development of related procedures for the preparation of pyrazines, dihydropyrazines and piperazines.

Initial studies concentrated on the preparation of dihydropyrazines, using α-hydroxyacetophenone 1c as the model α-hydroxyketone with ethylenediamine 5a (Scheme 4). We quickly established that the process was viable under the optimum conditions as used for quinoxaline synthesis. The expected 2-phenyl-5,6-dihydropyrazine 6a was produced in 28% yield without contamination by diazo byproducts. However, somewhat surprisingly, the major product from this reaction was N-benzoyl-N′-formyl 1,2-diaminoethane 7a, obtained in a yield of 50%.

Scheme 4 TOP approach to dihydropyrazines.

We assume that a bis-hemi-aminal intermediate, such as 8,^5a which would give adduct 6a after dehydration, can also undergo oxidative cleavage in the presence of manganese dioxide giving bis-amide 7a. The oxidative cleavage of 1,2-diols using MnO₂ is well known¹⁴ but, to our knowledge, it has not been reported with hemi-aminals before. An isolated example of the oxidative cleavage of a bis-hemiaminal using sodium perbromate has however been reported.¹⁵ By varying the reaction conditions and solvent (Scheme 4), we found that it was possible to minimise formation of bis-amide 7a by the addition of 2.0 M HCl in Et₂O (1 equivalent with respect to the diamine) to the reaction mixture. Using this optimised procedure, dihydropyrazine 6a was obtained in 53% yield. The dihydropyrazines produced in this manner are fairly sensitive, particularly in unpurified form, and were therefore chromatographed immediately after work up using deactivated, neutral alumina.

We then went on to determine the scope of this procedure, particularly in terms of the α-hydroxyketone substrate (Table 3). When using a more hindered diamine, exemplified by (±)-trans-1,2-diaminocyclohexane 5b (entries ii–iv), the dihydropyrazines 6b–6d were obtained in fair to excellent yields, reflecting their greater hydrolytic stability. It should be noted that when using cyclohexanediamine 5b, the bis-amide by-products (corresponding to 9a) were formed in relatively low yields (<15%), and the addition of HCl in Et₂O was not required.

Table 3 MnO₂-mediated TOP dihydropyrazine formation^a,b

Entry	R	R′	Dihydropyrazine	Yield (%)
				6	7
a Using MnO2 (10 eq.), diamine (1.2 eq.) and powdered 4 Å mol. sieves in CH2Cl2 at reflux; when using diamine 5a, 2.0 eq. of diamine were employed along with 2.0 M HCl in Et2O (1 eq. with respect to diamine). Yield refers to isolated, chromatographically and spectroscopically pure product. b The products were purified immediately after work up (chromatography on deactivated neutral alumina) in order to prevent degradation.
i	Phenyl 1c	H5a	6a	53	26
ii	Phenyl 1c	(CH2)45b	6b	64	14
iii	2-Furyl 1d	(CH2)45b	6c	64	15
iv	Cyclohexyl 1b	(CH2)45b	6d	53	0

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Having shown that it was possible to produce dihydropyrazines 6a–din situ using TOP methodology, attention moved to the extended one-pot procedures. We recently reported the production of secondary and tertiary amines from activated alcohols using a MnO₂ mediated one-pot oxidation imine-formation reduction sequence.⁸ We envisaged a similar sequence leading from α-hydroxyketones 1 to piperazines 9 (Table 4). Thus, the dihydropyrazine-forming reactions described above were repeated using MnO₂–NaBH₄. No piperazine formation was observed under these conditions, but the addition of excess methanol to the reaction mixture after dihydropyrazine formation gave the corresponding piperazines 9a–d in good yields (Table 4). As can be seen, the procedure gave good to excellent yields with aromatic (entries i–iii) and aliphatic α-hydroxyketones (entry iv). In the reactions using (±)-trans-1,2-diaminocyclohexane 5b (entries ii–iv), only one diastereomeric product was isolated and we have tentatively assigned these as the all-equatorial adducts shown. There is literature precendence for this selectivity¹⁶ and, furthermore, pertinent coupling constants in the ¹H NMR spectra were in the region expected for trans-diaxial protons, e.g. for H-2 to H-3_axial in compound 9b, the J value is 10.4 Hz.

Table 4 MnO₂–NaBH₄-mediated TOP piperazine formation^a

Entry	R	R′	Piperazine	Yield (%)
a Using MnO2 (10 eq.), diamine (1.2 eq.), NaBH4 (4.0 eq.) and powdered 4 Å mol. sieves in CH2Cl2 at reflux; when using diamine 5a, 2.0 eq. of diamine were employed along with 2.0 M HCl in Et2O (1 eq. with respect to diamine. Yield refers to isolated, spectroscopically pure product.
i	Phenyl 1c	H 5a	9a	52
ii	Phenyl 1c	(CH2)45b	9b	75
iii	2-Furyl 1d	(CH2)45b	9c	60^b
iv	Cyclohexyl 1b	(CH2)45b	9d	84

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Finally, we investigated the TOP-dihydropyrazine formation-aromatisation sequence leading to pyrazines 10 (Table 5). To this end, the original dihydropyrazine formation was repeated in THF and toluene at reflux for extended periods of time in the presence of excess MnO₂ to effect the aromatisation. However, under these conditions, only trace amounts of pyrazines 8 were observed in the toluene reaction. The use of co-oxidants, such as DDQ and CAN, in these reactions resulted in complete degradation of the dihydropyrazines 6. We eventually established that the addition of ∼0.4 M KOH in methanol^3a,5b to the refluxing reaction mixture after the formation of dihydropyrazines 6, resulted in production of the corresponding pyrazines 10. It should be noted that the addition of methanol alone did not achieve the desired transformation. The results are summarised in Table 5. As is apparent, the presence of an aromatic substituent facilitates aromatisation (e.g. entries i and iv versus vi and vii).

Table 5 MnO₂-mediated TOP-aromatisation pyrazine formation^a

Entry	R	R′	Pyrazine	Yield (%)
a Using MnO2 (10 eq.), diamine (1.2 eq.) and powdered 4 Å mol. sieves in CH2Cl2 at reflux; when using diamine 5a, 2.0 eq. of diamine were employed along with 2.0 M HCl in Et2O (1 eq. with respect to diamine). After consumption of the hydroxy ketone, KOH in MeOH was added to complete aromatisation. Yield refers to isolated, chromatographically and spectroscopically pure product.
i	Phenyl 1c	H 5a	10a ^17a	45
ii	4-BrC6H41h	H 5a	10b	57
iii	2-Furyl 1d	H 5a	10c	60
iv	Phenyl 1c	(CH2)45b	10d	66
v	2-Furyl 1d	(CH2)45b	10e	64
vi	Cyclohexyl 1b	H 5a	10f ^17b	33
vii	Cyclohexyl 1b	(CH2)45b	10g	0

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Finally, we examined the value of these methodologies with the complex, multifunctional substrate, hydrocortisone 11. Exposure of 11 to the standard conditions for the formation of quinoxalines, dihydropyrazines, piperazines or pyrazines gave the novel derivatives 12–17 in moderate to excellent unoptimised yields (Scheme 5).

Scheme 5 Hydrocortisone as a viable substrate for MnO₂-mediated TOP formation of heterocyclic and heteroaromatic functionality.

Conclusion

In conclusion, we have developed a novel methodology for the conversion of α-hydroxy ketones 1 into the corresponding quinoxalines 4 and dihydropyrazines 6via MnO₂-mediated tandem oxidation processes with in situ trapping using 1,2-diamines. This methodology has been extended to allow the direct synthesis of piperazines 9 and pyrazines 10 in related TOP sequences from the corresponding α-hydroxy ketones 1 in fair to good yields. These MnO₂-TOPs offer the synthetic chemist significant time-cost benefits and, hence, we expect them to find applications in both academic and industrial environments. Further work is continuing to optimise and apply this new chemistry to more complex targets and compound-library synthesis.

Experimental

General details: NMR spectra were recorded on Jeol EX-270 and EX-400 instruments using CDCl₃ as solvent unless otherwise stated. Tetramethylsilane was used as an internal standard in all cases. IR spectra were recorded on an ATI Mattson Genisis FT-IR or a ThermoNicolet IR100 spectrometer. Low resolution electron impact (EI) mass spectra were recorded on a Kratos MS 25 spectrometer. Chemical ionisation (CI) and high resolution mass spectra were recorded on a Micromass Autospec spectrometer. Flash column chromatography was carried out using Matrex silica gel 60 (70–200) or Brockmann grade 1 neutral alumina, deactivated by the addition of 6 wt% H₂O. The α-hydroxy ketones 1b, 1d and 1f were synthesised from the corresponding methyl ketones using the method reported by Moriarty et al.¹³ All other reagents were purchased from commercial sources and used without further purification. Activated MnO₂ was purchased from Aldrich chemical company, catalogue number 21,764–6. PE refers to petroleum ether (boiling point 40–60 °C).

Representative procedure for quinoxalines 4

2-Methylquinoxaline 4a. To a solution of α-hydroxyacetone 1a (0.50 mmol, 0.037 g) in dry CH₂Cl₂ (25 mL) was added sequentially o-phenylenediamine 2a (1.00 mmol, 0.108 g), powdered 4 Å molecular sieves (0.50 g) and activated MnO₂ (5.00 mmol, 0.435 g) and the mixture heated to reflux. After 45 min, TLC showed the reaction to be complete. The reaction mixture was cooled to RT, filtered through Celite^® and the solid residues washed well with CH₂Cl₂. The solvent was removed in vacuo and the product purified by column chromatography (2 : 1 PE : EtOAc) to give the title compound 4a (0.056 g, 79%) as an orange oil: R_f 0.23 (2 : 1 PE : EtOAc); ν_max (film) 1560, 1492, 1435, 1409, 1369 cm⁻¹; δ_H (270 MHz) 2.78 (3 H, s, CH₃), 7.65–7.75 (2 H, m, H-6,7), 7.98–8.03 (2 H, m, H-5,8), 8.72 (1 H, s, H-3); m/z (EI) 144 (M⁺). Data consistent with literature values.^11a

2-Cyclohexylquinoxaline 4b. Prepared by the procedure given for 4a using 1-cyclohexyl-2-hydroxyethanone 1b¹³ (0.50 mmol, 0.106 g) and o-phenylenediamine 2a (1.00 mmol, 0.108 g). Purified by column chromatography (2 : 1 PE : EtOAc) to give the title compound 4b (0.083 g, 78%) as a brown solid: R_f 0.63 (2 : 1 PE : EtOAc); mp 46 °C (lit.¹⁷ 48 °C); ν_max (film) 1559, 1490, 1445, 1364 cm⁻¹; δ_H (270 MHz) 1.32–1.94 (10 H, m, H-2′,3′,4′,5′,6′), 2.84 (1 H, tt, J 11.8 Hz, J 3.1 Hz, H-1′), 7.62 (2 H, m, H-6,7), 7.97 (2 H, m, H-5,8), 8.67 (1 H, s, H-3); m/z (CI) 213 (MH⁺). Data consistent with literature values.^11b

2-Phenylquinoxaline 4c. Prepared by the procedure given for 4a using α-hydroxyacetophenone 1c (0.50 mmol, 0.068 g) and o-phenylenediamine 2a (1.00 mmol, 0.108 g). Purified by column chromatography (3 : 1 PE : EtOAc) to give the title compound 4c (0.081 g, 79%) as an orange solid: R_f 0.32 (3 : 1 PE : EtOAc); mp 81 °C (lit.^11c 79–80 °C); ν_max (film) 1619, 1577, 1560, 1531, 1492, 1436, 1410, 1374 cm⁻¹; δ_H (270 MHz) 7.49–7.75 (3 H, m, H-3′,4′,5′), 7.77–7.81 (2 H, m, H-1′,6′), 8.10 (2 H, m, H-6,7), 8.19 (2 H, m, H-5,8), 9.45 (1 H, s, H-3); m/z (EI) 206 (M⁺). Data consistent with literature values.^11c

2-(2-Furanyl)quinoxaline 4d. Prepared by the procedure given for 4a using 1-(2-furanyl)-2-hydroxyethanone 1d¹³ (0.50 mmol, 0.063 g) and o-phenylenediamine 2a (1.00 mmol, 0.108 g). Purified by column chromatography (2 : 1 PE : EtOAc) to give the title compound 4d (0.041 g, 89%) as an orange solid: R_f 0.55 (2 : 1 PE : EtOAc); mp 101 °C (lit.¹⁸ 103 °C); ν_max (film) 1612, 1586, 1560, 1552, 1496, 1459 cm⁻¹; δ_H (270 MHz) 6.58 (1 H, dd, J 3.2 Hz, J 1.9 Hz, H-4′), 7.31 (1 H, d, J 3.2 Hz, H-3′), 7.64 (2 H, m, H-6,7), 7.68 (1 H, d, J 1.9 Hz, H-5′), 8.03 (2 H, m, H-5,8), 8.03 (1 H, s, H-3); m/z (EI) 196 (M⁺). Data consistent with literature values.^11c

2,3-Diphenylquinoxaline 4e. Prepared by the procedure given for 4a using benzoin 1e (0.50 mmol, 0.106 g) and o-phenylenediamine 2a (1.00 mmol, 0.108 g). Purified by column chromatography (9 : 1 PE : EtOAc) to give the title compound 4e (0.106 g, 75%) as a white solid: R_f 0.25 (9 : 1 PE : EtOAc); mp 128 °C (lit.¹⁹ 125 °C); ν_max (film) 1558, 1477, 1441, 1395 cm⁻¹; δ_H (270 MHz) 7.33–7.39 (6 H, m, H-3′,4′,5′,3″,4″,5″), 7.50–7.54 (4 H, m, H-2′,6′,2″,6″), 7.72 (2 H, m, H-6,7), 8.08 (2 H, m, H-5,8); m/z (EI) 282 (M⁺). Data consistent with literature values.^11d

2-Phenyl-6,7-dimethylquinoxaline 4f. Prepared by the procedure given for 4a using α-hydroxyacetophenone 1c (0.50 mmol, 0.068 g) and 4,5-dimethyl-1,2-phenylenediamine 2b (1.00 mmol, 0.136 g). Purified by column chromatography (3 : 1 PE : EtOAc) to give the title compound 4f (0.077 g, 66%) as an orange solid: R_f 0.48 (3 : 1 PE : EtOAc); mp 120 °C (lit.^2c 124 °C); ν_max (film) 1538, 1485, 1449 cm⁻¹; δ_H (270 MHz) 2.51 (6 H, s, 2 × CH₃), 7.50–7.56 (3 H, m, H-3′,4′,5′), 7.88 (2 H, m, H-1′,6′), 8.16 (2 H, m, H-5,8), 9.22 (1 H, s, H-3); m/z (EI) 234 (M⁺). Data consistent with literature values.^2c

2-Cyclohexyl-6,7-dimethylquinoxaline 4g. Prepared by the procedure given for 4a using 1-cyclohexyl-2-hydroxyethanone 1b¹³ (0.50 mmol, 0.106 g) and 4,5-dimethyl-1,2-phenylenediamine 2b (1.00 mmol, 0.136 g). Purified by column chromatography (4 : 1 PE : EtOAc) to give the title compound4g (0.107 g, 89%) as an orange solid: R_f 0.40 (4 : 1 PE : EtOAc); mp 66 °C; ν_max (film) 1542, 1485, 1454, 1369 cm⁻¹; δ_H (270 MHz) 1.32–1.94 (10 H, m, H-2′,3′,4′,5′,6′), 2.90 (1 H, tt, J 11.9 Hz, J 3.3 Hz, H-1′), 2.40 (6 H, s), 7.72 (2 H, m, H-5,8), 8.59 (1 H, s, H-3); δ_C (68 MHz) 20.2, 20.3, 25.8, 26.4, 32.3, 45.0, 128.1 (×2), 139.1, 140.2, 140.3, 141.0, 143.9, 160.1; m/z (CI) 241 (MH⁺) [HRMS (CI) calcd. for C₁₆H₂₁N₂ 241.1705. Found 241.1703 (0.9 ppm error)].

2-Pentyl-6,7-dimethylquinoxaline 4h. Prepared by the procedure given for 4a using 1- hydroxypentan-2-one 1f¹³ (0.50 mmol, 0.065 g) and 4,5-dimethyl-1,2-phenylenediamine 2b (1.00 mmol, 0.136 g). Purified by column chromatography (2 : 1 PE : EtOAc) to give the title compound4h (0.071 g, 62%) as an orange oil: R_f 0.58 (2 : 1 PE : EtOAc); ν_max (film) 1628, 1552, 1488, 1464, 1362 cm⁻¹; δ_H (270 MHz) 0.82 (3 H, t, J 6.8 Hz, H-5′), 1.32–1.37 (6 H, m, H-2′,3′,4′), 2.40 (6 H, s, 2 × CH₃), 2.90 (2 H, m, H-1′), 7.72 (2 H, m, H-5,8), 8.57 (1 H, s, H-3); δ_C (68 MHz) 14.6, 20.9, 23.1, 30.0, 30.3, 32.2, 37.0, 128.5, 128.8, 139.9, 140.7, 141.0, 141.7, 145.5, 157.3; m/z (CI) 229 (MH⁺) [HRMS (CI) calcd. for C₁₅H₂₁N₂ 229.1705. Found 229.1699 (2.6 ppm error)].

2-/3-Methylpyrido[2,3-b]pyrazine 4i. Prepared by the procedure given for 4a using α-hydroxyacetone 1a (0.50 mmol, 0.034 mL) and 2,3-diaminopyridine 2c (1.00 mmol, 0.109 g). Purified by column chromatography (19 : 1 CH₂Cl₂ : MeOH) to give the title compound 4i (0.048 g, 66%), a white solid, as a mixture of regioisomers (∼7 : 1 3-methyl : 2-methyl as determined by ¹H NMR spectroscopy): R_f 0.27 (19 : 1 CH₂Cl₂ : MeOH); δ_H (270 MHz) 3-methylpyrido[2,3-b]pyrazine 2.80 (3 H, s, CH₃), 7.61 (1 H, dd, J 8.2 Hz, J 3.4 Hz, H-7), 8.37 (1 H, dd, J 8.2 Hz, J 1.7 Hz, H-8), 8.77 (1 H, s, H-2), 9.07 (1 H, dd, J 3.4 Hz, J 1.7 Hz, H-6); 2-methylpyrido[2,3-b]pyrazine 2.76 (3 H, s, CH₃), 7.64 (1 H, m, H-7), 8.31 (1 H, dd, J 8.5 Hz, J 1.7 Hz, H-8), 8.90 (1 H, s, H-3), 9.07 (1 H, m, H-6); δ_C (68 MHz) 3-methylpyrido[2,3-b]pyrazine 22.9, 124.5, 136.0, 138.2, 147.2, 150.7, 154.0, 157.7; m/z (EI) 145 (M⁺) [HRMS (EI) calcd. for C₈H₇N₃ 145.0640. Found 145.0639 (0.5 ppm error)]. The data for 2-methylpyrido[2,3-b]pyrazine were consistent with those reported in the literature.^11e

2-/3-Phenylpyrido[2,3-b]pyrazine 4j. Prepared by the procedure given for 4a using α-hydroxyacetophenone 1c (0.50 mmol, 0.068 g) and 2,3-diaminopyridine 2c (1.00 mmol, 0.109 g). Purified by column chromatography (EtOAc) to give the title compound 4j (0.072 g, 69%), a yellow solid, as a mixture of regioisomers (∼2 : 1 3-phenyl : 2-phenyl as determined by ¹H NMR spectroscopy): R_f 0.34 (EtOAc); δ_H (270 MHz) 3-phenylpyrido[2,3-b]pyrazine 7.48–7.57 (3 H, m, H-3′,4′,5′), 7.65 (1 H, dd, J 8.3 Hz, J 4.1 Hz, H-7), 8.26–8.31 (2 H, m, H-1′,6′), 8.43 (1 H, dd, J 8.3 Hz, J 1.5 Hz, H-8), 9.14 (1 H, dd, J 4.1 Hz, J 1.5 Hz, H-6), 9.41 (1 H, s, H-2); 2-phenylpyrido[2,3-b]pyrazine 7.48–7.57 (3 H, m, H-3′,4′,5′), 7.69 (1 H, dd, J 8.7 Hz, J 3.9 Hz, H-7), 8.15–8.19 (2 H, m, H-1′,6′), 8.46 (1 H, dd, J 8.7 Hz, J 1.5 Hz, H-8), 9.11 (1 H, dd, J 3.9 Hz, J 1.5 Hz, H-6), 9.50 (1 H, s, H-3); δ_C (68 MHz) 3-phenylpyrido[2,3-b]pyrazine 124.8, 128.1, 129.3, 131.9, 135.7, 136.8, 138.2, 144.4, 150.8, 154.5, 154.7; 2-phenylpyrido[2,3-b]pyrazine 125.7, 127.7, 129.3, 130.8, 135.9, 137.6, 138.6, 146.3, 150.4, 153.5, 158.7; m/z (EI) 207 (M⁺) [HRMS (EI) calcd. for C₁₃H₉N₃ 207.0796. Found 207.0796 (0.2 ppm error)]. Data consistent with literature values.^2c,11f

Quinoxalin-2-one 4k. Prepared by the procedure given for 4a using methyl glycolate 1g (1.20 mmol, 0.093 mL), 1,2-phenylenediamine 2a (1.00 mmol, 0.108 g) and manganese dioxide (10.0 mmol, 1.043 g). Purified by column chromatography (EtOAc) to give the title compound 4k (0.052 g, 36%) as a white solid: R_f 0.38 (EtOAc); mp 267–268 °C (lit.²⁰ 266–267 °C); δ_H (DMSO-d₆, 270 MHz) 7.25–7.34 (2 H, m), 7.54 (1 H, m), 7.77 (1 H, m), 8.16 (1 H, s, H-3); δ_C (DMSO-d₆, 68 MHz) 115.6, 123.1, 128.7, 130.6, 131.7, 132.0, 151.5, 154.8; m/z (CI) 147 (MH⁺). Data consistent with literature values.²⁰

Representative procedure for dihydropyrazines 6

2-Phenyl-5,6-dihydropyrazine 6a. To a solution of α-hydroxyacetophenone 1c (0.50 mmol, 0.068 g) in dry CH₂Cl₂ (25 mL) was added sequentially ethylenediamine 5a (1.00 mmol, 0.07 mL), powdered 4 Å molecular sieves (0.50 g), 2.0 M HCl in Et₂O (1.00 mmol, 0.50 mL) and activated MnO₂ (5.00 mmol, 0.435 g) and the mixture heated to reflux. After 90 min, TLC showed the reaction to be complete. The reaction mixture was cooled to RT, filtered through Celite^® and the solid residues washed well with CH₂Cl₂. The solvent was removed in vacuo and the product purified by column chromatography on neutral alumina deactivated with H₂O (6% w/w) (EtOAc to 19 : 1 EtOAc : MeOH) to give first the title compound6a (0.042 g, 53%) as a pale yellow oil: R_f 0.50 (EtOAc); ν_max (film) 3057, 2939, 2845, 1627, 1569, 1449, 929, 766, 694 cm⁻¹; δ_H (400 MHz) 3.55–3.62 (2 H, m), 3.65–3.71 (2 H, m), 7.42–7.49 (3 H, m, H-3′,4′,5′), 7.79–7.86 (2 H, m, H-1′,6′), 8.37 (1 H, t, J 1.4 Hz, H-3); δ_C (100 MHz) 44.8, 44.9, 126.6, 128.8, 130.7, 135.8, 152.4, 156.2; m/z (CI) 159 (MH⁺) [HRMS (CI) calcd. for C₁₀H₁₁N₂ 159.0922. Found 159.0920 (1.3 ppm error)]. This was followed by N-benzoyl-N′-formylethylenediamine7a (0.026 g, 26%): R_f 0.12 (EtOAc); ν_max (film) 3064, 1651, 1539, 909, 733 cm⁻¹; δ_H (400 MHz) 3.46–3.52 (2 H, m), 3.53–3.60 (2 H, m), 7.31 (1 H, t, J 6.9 Hz, NH, exchanged in a D₂O shake), 7.34–7.42 (2 H, m, H-3′,5′), 7.44–7.51 (1 H, m, H-4′), 7.71 (1 H, t, J 4.4 Hz, NH, exchanged in a D₂O shake), 7.77–7.82 (2 H, m, H-1′,6′), 8.15 (1 H, s, NCHO); δ_C (100 MHz) 38.5, 40.5, 127.1, 128.6, 131.7, 133.9, 162.8, 168.7; m/z (CI) 193 (MH⁺), 210 (MNH₄⁺) [HRMS (CI) calcd. for C₁₀H₁₃N₂O₂ 193.0977. Found 193.0976 (0.5 ppm error)].

2-Phenyl-4a,5,6,7,8,8a-hexahydoquinoxaline 6b. Prepared by the procedure given for 6a using α-hydroxyacetophenone 1c (0.50 mmol, 0.068 g) and trans-1,2-diaminocyclohexane 5b (0.60 mmol, 0.07 mL). With trans-1,2-diaminocyclohexane 5b no HCl is necessary as the amount of bis-amide formed is much lower than for ethylenediamine 5a. The first eluting product was the title compound6b (0.068 g, 64%) as a pale yellow oil: R_f 0.50 (EtOAc); ν_max (film) 2931, 2856, 1681, 1565, 1447, 904, 762, 690 cm⁻¹; δ_H (400 MHz) 1.22–1.55 (4 H, m), 1.68–1.88 (2 H, m), 2.29–2.41 (2 H, m), 2.56–2.83 (2 H, m, H-4a,8a), 7.28–7.44 (3 H, m, H-3′,4′,5′), 7.70–7.81 (2 H, m, H-1′,6′), 8.23 (1 H, d, J 3.0 Hz, H-3); δ_C (100 MHz) 25.6, 33.4, 33.8, 59.0, 59.2, 126.8, 128.9, 130.7, 135.9, 151.9, 156.0; m/z (CI) 213 (MH⁺) [HRMS (CI) calcd. for C₁₄H₁₇N₂ 213.1392. Found 213.1384 (3.4 ppm error)]. This was followed by N-benzoyl-N′-formyl-trans-1,2-diaminocyclohexane7b (0.017 g, 14%): R_f 0.24 (EtOAc); ν_max (film) 3304, 1665, 1636, 1554, 1536, 1291, 721, 667 cm⁻¹; δ_H (400 MHz) 1.08–1.39 (4 H, m), 1.72–1.81 (2 H, m), 1.91–2.14 (2 H, m), 3.81 (2 H, br s, H-1,2), 6.36 (1 H, d, J 3.2 Hz, NH, exchanged in a D₂O shake), 6.80 (1 H, d, J 3.8 Hz, NH, exchanged in a D₂O shake), 7.28–7.45 (3 H, m, H-3′,4′,5′), 7.66–7.75 (2 H, m, H-1′,6′), 8.05 (1 H, s, NCHO); δ_C (100 MHz) 24.7, 24.8, 32.3, 32.4, 52.4, 54.5, 127.2, 128.7, 131.7, 134.1, 162.1, 168.0; m/z (CI) 247 (MH⁺) [HRMS (CI) calcd. for C₁₄H₁₉N₂O₂ 247.1447. Found 247.1446 (0.3 ppm error)].

2-(2-Furanyl)-4a,5,6,7,8,8a-hexahydoquinoxaline 6c. Prepared by the procedure given for 6a using 1-(2-furanyl)-2-hydroxyethanone 1d¹³ (0.22 mmol, 0.028 g) and trans-1,2-diaminocyclohexane 5b (0.30 mmol, 0.036 mL). With trans-1,2-diaminocyclohexane 5b no HCl is necessary as the amount of bis-amide formed is much lower than for ethylenediamine 5a. The first eluting product was the title compound6c (0.028 g, 64%) as a pale yellow solid: R_f 0.38 (EtOAc); mp 124–126 °C; ν_max (nujol) 1584, 1408, 1297 cm⁻¹; δ_H (400 MHz) 1.19–1.60 (4 H, m), 1.80–1.92 (2 H, m), 2.34–2.49 (2 H, m), 2.67–2.89 (2 H, m, H-4a,8a), 6.51 (1 H, m, H-4′), 6.99 (1 H, m, H-3′), 7.56 (1 H, s, H-5′), 8.19 (1 H, d, J 2.4 Hz, H-3); δ_C (100 MHz) 25.6, 25.7, 33.5, 33.8, 58.6, 59.3, 111.9, 113.1, 145.4, 147.5, 150.5; m/z (CI) 203 (MH⁺) [HRMS (CI) calcd. for C₁₂H₁₅N₂O 203.1184. Found 203.1183 (0.5 ppm error)]. This was followed by N-furoyl-N′-formyl-trans-1,2-diaminocyclohexane7c (0.009 g, 15%): R_f 0.18 (EtOAc); ν_max (film) 3246, 3048, 1650, 1640, 1575, 1538, 1332 cm⁻¹; δ_H (400 MHz) 1.18–1.45 (4 H, m), 1.70–1.88 (2 H, m), 2.01–2.18 (2 H, m), 3.75–3.94 (2 H, m, H-1,2), 6.30 (1 H, d, J 5.8 Hz, NH, exchanged in a D₂O shake), 6.48 (1 H, m, H-4′), 6.64 (1 H, d, J 6.7 Hz, NH, exchanged in a D₂O shake), 7.07 (1 H, m, H-3′), 7.45 (1 H, s, H-5′), 8.10 (1 H, s, NCHO); δ_C (100 MHz) 24.7, 24.9, 32.4, 32.5, 52.9, 53.2, 112.2, 114.6, 144.5, 147.6, 159.2, 161.7; m/z (CI) 237 (MH⁺) [HRMS (CI) calcd. for C₁₂H₁₇N₂O₃ 237.1239. Found 237.1240 (0.5 ppm error)].

2-Cyclohexyl-4a,5,6,7,8,8a-hexahydoquinoxaline 6d. Prepared by the procedure given for 6a using 1-cyclohexyl-2-hydroxyethanone 1b¹³ (0.25 mmol, 0.036 g) and trans-1,2-diaminocyclohexane 5b (0.30 mmol, 0.036 mL). With trans-1,2-diaminocyclohexane 5b no HCl is necessary as the amount of bis-amide formed is much lower than for ethylenediamine 5a. The only product isolated was the title compound6d (0.029 g, 53%) as a pale yellow oil: R_f 0.43 (EtOAc); ν_max (film) 2930, 2856, 1587, 1449, 921, 733 cm⁻¹; δ_H (400 MHz) 1.09–1.51 (9 H, m), 1.51–1.68 (1 H, m), 1.70–1.81 (6 H, m), 2.22–2.36 (3 H, m), 2.45–2.64 (2 H, m, H-4a,8a), 7.75 (1 H, d, J 2.7 Hz, H-3); δ_C (100 MHz) 25.6, 25.7, 25.9, 25.9, 26.1, 29.3, 30.0, 33.4, 33.8, 44.7, 58.5, 59.3, 153.2, 163.9; m/z (CI) 219 (MH⁺) [HRMS (CI) calcd. for C₁₄H₂₃N₂ 219.1861. Found 219.1854 (3.2 ppm error)].

Representative procedure for piperazines 9

2-Phenylpiperazine 9a. To a solution of α-hydroxyacetophenone 1c (0.50 mmol, 0.068 g) in dry CH₂Cl₂ (25 mL) was added sequentially ethylenediamine 5a (1.00 mmol, 0.07 mL), powdered 4 Å molecular sieves (0.50 g), 2.0 M HCl in Et₂O (1.00 mmol, 0.50 mL), NaBH₄ (2.00 mmol, 0.076 g) and activated MnO₂ (5.00 mmol, 0.435 g) and the mixture heated to reflux. After 75 min, TLC showed complete conversion to the dihydropyrazine. The reaction mixture was cooled to RT and MeOH (6 mL) was added. After a further 20 h at RT, the mixture was filtered through Celite^® and the solid residues washed well with CH₂Cl₂. The solvent was removed in vacuo and the product purified by acid/base extraction to give the title compound6a (0.042 g, 52%) as a colourless oil: ν_max (film) 3198, 2930, 2828, 1650, 1539, 1454, 1326, 1137, 877, 754, 699 cm⁻¹; δ_H (400 MHz) 1.95 (2 H, br s, 2 × NH), 2.55–3.16 (6 H, m, H-3,5,6), 3.67 (1 H, dd, J 15.7 Hz, J 4.0 Hz, H-2), 7.12–7.39 (5 H, m, H-2′,3′,4′,5′,6′); δ_C (100 MHz) 46.1, 47.8, 54.3, 62.0, 127.0, 127.5, 128.5, 142.7; m/z (CI) 163 (MH⁺) [HRMS (CI) calcd. for C₁₀H₁₅N₂ 163.1235. Found 163.1234 (0.7 ppm error)].

2-Phenyl-1,2,3,4,4a,5,6,7,8,8a-decahydoquinoxaline 9b. Prepared by the procedure given for 9a using α-hydroxyacetophenone 1c (0.50 mmol, 0.068 g) and trans-1,2-diaminocyclohexane 5b (0.60 mmol, 0.07 mL). With trans-1,2-diaminocyclohexane 5b no HCl was used. Acid/base extraction gave the title compound9b (0.081 g, 75%) as a colourless solid: mp 82–83 °C; ν_max (film) 3225, 3209, 2855, 2820, 1454, 1333, 1136, 755, 699, 652 cm⁻¹; δ_H (400 MHz) 1.15–1.40 (4 H, m), 1.55–1.85 (6 H, m), 2.26–2.48 (2 H, m, H-4a,8a), 2.78 (1 H, dd, J 11.8 Hz, J 10.4 Hz, H-3_axial), 3.06 (1 H, dd, J 11.8 Hz, J 2.9 Hz, H-3_equatorial), 3.85 (1 H, dd, J 10.4 Hz, J 2.9 Hz, H-2_axial), 7.17–7.40 (5 H, m, H-2′,3′,4′,5′,6′); δ_C (100 MHz) 25.0, 25.2, 32.0, 32.2, 54.5, 60.4, 62.4, 62.4, 127.0, 127.4, 128.5, 142.7; m/z (CI) 217 (MH⁺) [HRMS (CI) calcd. for C₁₄H₂₁N₂ 217.1705. Found 217.1698 (3.2 ppm error)].

1,4-Diacetyl-2-(2-furanyl)-1,2,3,4,4a,5,6,7,8,8a-decahydoquin-oxaline 9c. Prepared by the procedure given for 9a using 1-(2-furanyl)-2-hydroxyethanone 1d¹³ (0.25 mmol, 0.032 g) and trans-1,2-diaminocyclohexane 5b (0.30 mmol, 0.036 mL). With trans-1,2-diaminocyclohexane 5b no HCl was used. After filtration, the solvents were removed in vacuo and the crude mixture taken up in CH₂Cl₂ (5 mL). To this was added Et₃N (1 mL) and acetyl chloride (1.00 mmol, 0.07 mL) and the mixture stirred at RT for 3 h. It was then poured into sat. NaHCO₃ (15 mL) and extracted with CH₂Cl₂ (3 × 5 mL). The combined organics were dried (MgSO₄), filtered and concentrated in vacuo. Purification by column chromatography (EtOAc) gave the title compound9c (0.044 g, 60%) as a colourless oil: R_f 0.14 (EtOAc); ν_max (nujol) 1662, 1629, 1411, 1324, 1307, 1183, 1144, 751 cm⁻¹; δ_H (270 MHz) 0.94–1.18 (1 H, m), 1.25–1.54 (3 H, m), 1.57–1.78 (2 H, m), 1.94 (3 H, s, CH₃), 2.07 (3 H, s, CH₃), 2.44–2.83 (1 H, m), 2.85 (1 H, br d, J 11.9 Hz), 3.43 (1 H, dt, J 2.2 Hz, J 10.8 Hz), 3.72 (1 H, dt, J 2.6 Hz, J 10.8 Hz), 3.99 (1 H, m), 5.15 (1 H, br s, H-2), 6.28 (1 H, m, H-3′), 6.33 (1 H, m, H-4′), 7.35 (1 H, s, H-5′); δ_C (68 MHz, toluene-d₈, 80 °C) 22.1, 22.3, 25.6, 25.8, 32.2, 32.6, 47.7, 52.5, 58.0, 58.9, 108.1, 111.0, 142.2, 154.7, 170.5, 171.7; m/z (CI) 291 (MH⁺) [HRMS (CI) calcd. for C₁₆H₂₃N₂O₃ 291.1710. Found 291.1713 (1.5 ppm error)].

2-Cyclohexyl-1,2,3,4,4a,5,6,7,8,8a-decahydoquinoxaline 9d. Prepared by the procedure given for 9a using 1-cyclohexyl-2-hydroxyethanone 1b¹³ (0.25 mmol, 0.036 g) and trans-1,2-diaminocyclohexane 5b (0.30 mmol, 0.036 mL). With trans-1,2-diaminocyclohexane 5b no HCl was used. Acid/base extraction gave the title compound9d (0.047 g, 84%) as a colourless solid: mp 78–80 °C; ν_max (film) 3362, 3290, 3226, 1341, 833 cm⁻¹; δ_H (400 MHz) 0.85–1.00 (2 H, m), 1.02–1.36 (8 H, m), 1.54–1.82 (9 H, m), 2.09–2.41 (4 H, m), 2.41–2.51 (2 H, m), 2.99–3.11 (1 H, m); δ_C (100 MHz) 24.9, 25.1, 26.2, 26.3, 26.5, 29.2, 29.4, 31.7, 32.2, 41.3, 50.1, 60.8, 61.4, 61.6; m/z (CI) 223 (MH⁺) [HRMS (CI) calcd. for C₁₄H₂₇N₂ 223.2174. Found 223.2167 (3.2 ppm error)].

Representative procedure for pyrazines 10

2-Phenylpyrazine 10a. To a solution of α-hydroxyacetophenone 1c (0.50 mmol, 0.068 g) in dry CH₂Cl₂ (25 mL) was added sequentially ethylenediamine 5a (1.00 mmol, 0.07 mL), powdered 4 Å molecular sieves (0.50 g), 2.0 M HCl in Et₂O (1.00 mmol, 0.50 mL) and activated MnO₂ (5.00 mmol, 0.435 g) and the mixture heated to reflux. After 2.5 h, TLC showed complete conversion to the dihydropyrazine. The reaction mixture was cooled to RT and ∼0.4 M KOH in MeOH (5 mL) was added. The mixture was returned to reflux for a further 20 h, then was filtered through Celite^® and the solid residues washed well with CH₂Cl₂. The solvent was removed in vacuo and the product purified by column chromatography on neutral alumina deactivated with H₂O (6% w/w) (3 : 1 PE : EtOAc) to give the title compound 10a (0.035 g, 45%) as a colourless solid: mp 74 °C (lit.^16a 72 °C); ν_max (film) 2904, 2854, 1728, 1464, 1379, 1271 cm⁻¹; δ_H (270 MHz) 7.49–7.52 (3 H, m, H-3′,4′,5′), 7.98–8.04 (2 H, m, H-2′,6′), 8.50 (1 H, d, J 2.4 Hz, H-6), 8.63 (1 H, dd, J 2.4 Hz, ⁴J 1.5 Hz, H-5), 9.03 (1 H, d, ⁴J 1.5 Hz, H-3); δ_C (100 MHz) 127.0, 129.2, 130.0, 136.4, 142.3, 143.0, 144.3, 152.9; m/z (CI) 157 (MH⁺). Data consistent with literature values.^17a

2-(4-Bromophenyl)pyrazine 10b. Prepared by the procedure given for 6a using 1-(4-bromophenyl)-2-hydroxyethanone 1h (0.50 mmol, 0.108 g) and ethylenediamine 5a (1.00 mmol, 0.07 mL). Column chromatography (3 : 1 PE : EtOAc) gave the title compound10b (0.067 g, 57%) as a yellow oil: R_f 0.29 (3 : 1 PE : EtOAc); ν_max (film) 1555, 1470, 1412, 1385 cm⁻¹; δ_H (400 MHz) 7.64 (2 H, d, J 8.9 Hz, H-3′,5′), 7.90 (2 H, d, J 8.9 Hz, H-2′,6′), 8.53 (1 H, s, H-6), 8.63 (1 H, s, H-5), 9.04 (1 H, s, H-3); δ_C (100 MHz) 125.2, 129.2, 132.9, 135.8, 142.5, 143.7, 144.8, 152.3; m/z (CI) 232/234 (MH⁺) [HRMS (CI) calcd. for C₁₀H₇N₂⁸¹Br 233.9792. Found 233.9795 (1.1 ppm error)].

2-(2-Furanyl)pyrazine 10c. Prepared by the procedure given for 6a using 1-(2-furanyl)-2-hydroxyethanone 1d¹² (0.50 mmol, 0.064 g) and ethylenediamine 5a (1.00 mmol, 0.07 mL). Column chromatography (2 : 1 PE : EtOAc) gave the title compound10c (0.044 g, 60%) as a yellow oil: R_f 0.67 (2 : 1 PE : EtOAc); ν_max (film) 1590, 1470, 1411, 1384 cm⁻¹; δ_H (270 MHz) 6.57 (1 H, m, H-4′), 7.15 (1 H, m, H-3′), 7.60 (1 H, m, H-5′), 8.42 (1 H, d, J 2.7 Hz, H-6), 8.53 (1 H, d, J 2.7 Hz, H-5), 8.97 (1 H, s, H-3); δ_C (100 MHz) 111.3, 112.9, 138.3, 141.2, 143.1, 144.7, 145.0, 147.9; m/z (CI) 147 (MH⁺) [HRMS (CI) calcd. for C₈H₇N₂O 147.0558. Found 147.0558 (0.0 ppm error)].

2-Phenyl-5,6,7,8-tetrahydoquinoxaline 10d. Prepared by the procedure given for 6a using α-hydroxyacetophenone 1c (0.50 mmol, 0.068 g) and trans-1,2-diaminocyclohexane 5b (0.60 mmol, 0.07 mL). With trans-1,2-diaminocyclohexane 5b no HCl was used. Column chromatography (3 : 1 PE : EtOAc) gave the title compound10d (0.069 g, 66%) as a colourless oil: R_f 0.31 (2 : 1 PE : EtOAc); ν_max (film) 2937, 2861, 1457, 1444, 1380, 1142, 775, 694 cm⁻¹; δ_H (270 MHz) 1.78–1.94 (4 H, m, H-6,7), 2.83–2.98 (4 H, m, H-5,8), 7.29–7.43 (3 H, m, H-3′,4′,5′), 7.82–7.91 (2 H, m, H-1′,6′), 8.64 (1 H, s, H-3); δ_C (68 MHz) 22.7, 22.7, 31.8, 32.8, 126.8, 129.0, 129.3, 137.0, 138.9, 149.8, 151.3, 152.4; m/z (CI) 211 (MH⁺) [HRMS (CI) calcd. for C₁₄H₁₅N₂ 211.1235. Found 211.1234 (0.7 ppm error)].

2-(2-Furanyl)-5,6,7,8-tetrahydoquinoxaline 10e. Prepared by the procedure given for 6a using α-hydroxyacetophenone 1c (0.50 mmol, 0.068 g) and trans-1,2-diaminocyclohexane 5b (0.60 mmol, 0.07 mL). With trans-1,2-diaminocyclohexane 5b no HCl was used. Column chromatography (3 : 1 PE : EtOAc) gave the title compound10e (0.069 g, 66%) as a colourless oil: R_f 0.31 (2 : 1 PE : EtOAc); ν_max (film) 2937, 2861, 1457, 1444, 1380, 1142, 775, 694 cm⁻¹; δ_H (270 MHz) 1.78–1.94 (4 H, m, H-6,7), 2.83–2.98 (4 H, m, H-5,8), 7.29–7.43 (3 H, m, H-3′,4′,5′), 7.82–7.91 (2 H, m, H-1′,6′), 8.64 (1 H, s, H-3); δ_C (68 MHz) 22.7, 22.7, 31.8, 32.8, 126.8, 129.0, 129.3, 137.0, 138.9, 149.8, 151.3, 152.4; m/z (CI) 211 (MH⁺) [HRMS (CI) calcd. for C₁₄H₁₅N₂ 211.1235. Found 211.1234 (0.7 ppm error)].

2-Cyclohexylpyrazine 10f. Prepared by the procedure given for 6a using 1-cyclohexyl-2-hydroxyethanone 1b¹³ (0.50 mmol, 0.106 g) and ethylenediamine 5a (1.00 mmol, 0.07 mL). Column chromatography (3 : 1 PE : EtOAc) gave the title compound10f (0.027 g, 33%) as a yellow oil: R_f 0.38 (3 : 1 PE : EtOAc); ν_max (film) 1558, 1441, 1381 cm⁻¹; δ_H (400 MHz) 1.32–1.94 (10 H, m, H-2′,3′,4′,5′,6′), 2.75 (1 H, dd, J 11.9 Hz, J 2.4 Hz, H-1′), 8.37 (1 H, s, H-3), 8.39 (2 H, m, H-5,6); δ_C (100 MHz) 25.8, 26.3, 32.4, 44.0, 142.2, 143.6, 143.9, 161.0; m/z (EI) 162 (M⁺) [HRMS (EI) calcd. for C₁₀H₁₄N₂ 162.1157. Found 162.1156 (0.8 ppm error)].

11,17-Dihydroxy-10,13-dimethyl-17-quinoxalin-2-yl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydocyclopenta[a]phenanthren-3-one 12

Prepared by the procedure given for 4a using hydrocortisone 1i (0.20 mmol, 0.072 g) and o-phenylenediamine 2a (0.40 mmol, 0.043 g). Purified by column chromatography (EtOAc) to give the title compound12 (0.058 g, 67%) as an orange solid: R_f 0.50 (EtOAc); mp 266–268 °C; ν_max (nujol) 3392, 1638, 1276, 1231, 1227, 1112, 942, 865, 775 cm⁻¹; δ_H (400 MHz) 0.86 (3 H, s, CH₃), 1.01 (1 H, dd, J 10.7 Hz, J 3.1 Hz), 1.08–1.18 (1 H, m), 1.31 (1 H, dd, J 14.0 Hz, J 2.1 Hz), 1.37 (3 H, s, CH₃), 1.50–1.64 (1 H, m), 1.77 (1 H, dt, J 4.6 Hz, J 13.4 Hz), 1.86–2.51 (12 H, m), 3.04 (1 H, dd, J 12.5 Hz, J 11.9 Hz), 4.41 (1 H, s, OH), 4.61 (1 H, s, OH), 5.61 (1 H, s, C=CH), 7.67–7.76 (2 H, m, H-6,7), 7.96–8.07 (2 H, m, H-5,8), 9.01 (1 H, s, H-3); δ_C (100 MHz) 18.5, 21.0, 24.3, 31.9, 32.2, 32.8, 33.8, 34.9, 35.0, 39.3, 39.4, 49.1, 51.9, 56.1, 68.4, 84.8, 122.3, 129.0, 129.1, 129.8, 130.3, 140.5, 141.2, 143.9, 157.0, 172.7, 199.8; m/z (CI) 433 (MH⁺), 415 (MH⁺ − H₂O) [HRMS (CI) calcd. for C₂₇H₃₃N₂O₃ 433.2491. Found 433.2497 (1.3 ppm error)].

17-(5,6-Dihydropyrazin-2-yl)-11,17-dihydroxy-10,13-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-3-one 13

Prepared by the procedure given for 6a using hydrocortisone 1i (0.20 mmol, 0.072 g) and ethylenediamine 5a (0.40 mmol, 0.027 mL). Purified by column chromatography (25 : 1 to 15 : 1 CH₂Cl₂ : MeOH) to give the title compound13 (0.030 g, 40%) as the only isolated product, a pale yellow solid: R_f 0.24 (9 : 1 CH₂Cl₂ : MeOH); mp 130–132 °C; ν_max (nujol) 3404, 1659, 1615, 1590, 1276, 1233, 1189, 1119, 950, 926, 868 cm⁻¹; δ_H (400 MHz) 0.96 (3 H, s, CH₃), 1.01–1.04 (1 H, m), 1.06–1.21 (1 H, m), 1.42 (3 H, s, CH₃), 1.34–1.52 (3 H, m), 1.54–1.65 (1 H, m), 1.71–1.95 (3 H, m), 1.96–2.09 (3 H, m), 2.12–2.28 (2 H, m), 2.33 (1 H, m), 2.39–2.53 (2 H, m), 2.73 (1 H, m), 3.34–3.55 (4 H, m, DHP), 3.87 (1 H, br s, OH), 4.43 (1 H, br s, OH), 5.66 (1 H, s, C=CH), 8.11 (1 H, d, J 1.5 Hz, imine); δ_C (100 MHz) 18.5, 21.1, 24.2, 31.5, 32.2, 32.8, 33.5, 33.9, 35.1, 39.3, 39.9, 43.9, 44.5, 48.5, 51.7, 56.1, 68.5, 84.7, 122.4, 152.6, 162.2, 172.4, 199.7; m/z (CI) 385 (MH⁺) [HRMS (CI) calcd. for C₂₃H₃₃N₂O₃ 385.2491. Found 385.2489 (0.5 ppm error)].

17-(4a,5,6,7,8,8a-Hexahydroquinoxalin-2-yl)-11,17-dihydroxy-10,13-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-3-one 14

Prepared by the procedure given for 6a using hydrocortisone 1i (0.20 mmol, 0.072 g) and trans-1,2-diaminocyclohexane 5b (0.24 mmol, 0.028 mL). Purified by column chromatography (EtOAc to 19 : 1 EtOAc : MeOH) to give the title compound14 (0.072 g, 82%) as an inseparable mixture of diastereomers (∼1 : 1 A : B), a colourless solid: R_f 0.19 (EtOAc); mp 123–125 °C; ν_max (nujol) 3393, 1658, 1615, 1584, 1233, 1118, 915, 730 cm⁻¹; δ_H (400 MHz) 0.88 (3 H, s, CH₃A), 0.93 (3 H, s, CH₃B), 0.94–1.00 (1 H, m, A + B), 1.02–1.18 (1 H, m, A + B), 1.24–1.57 (6 H, m, A + B), 1.39 (3 H, s, CH₃A + B), 1.60–2.06 (11 H, m, A + B), 2.08–2.82 (10 H, m, A + B), 3.68 (1 H, br s, OH, A), 4.39 (1 H, br s, OH, A + B), 4.52 (1 H, br s, OH, B), 5.62 (1 H, s, C=CH A + B), 7.98 (1 H, d, J 2.8 Hz, imine A), 8.04 (1 H, d, J 2.7 Hz, imine B); δ_C (100 MHz) 18.4/18.5 (CH₃), 21.0/21.1 (CH₃), 24.0/24.3 (CH₂), 25.4/25.5 (CH₂), 25.5/25.5 (CH₂), 31.4/31.5 (CH), 32.2 (CH₂), 32.7/32.8 (CH₂), 32.9/33.7 (CH₂), 33.0/33.1 (CH₂), 33.5/33.5 (CH₂), 33.8 (CH₂), 34.9 (CH₂), 39.2/39.3 (C), 39.5/40.0 (CH₂), 48.0/48.9 (C), 51.5/51.6 (CH), 56.1/56.1 (CH), 58.1/58.3 (CH), 58.8/59.1 (CH), 68.2/68.3 (CH), 84.1/84.5 (C), 122.2/122.3 (CH), 151.5/152.4 (CH), 161.7/161.8 (C), 172.6/172.7 (C), 199.7/199.7 (C) [The pairs of signals were tentatively assigned due to their similar chemical shift and type; however, this is by no means a definitive assignation]; m/z (CI) 439 (MH⁺) [HRMS (CI) calcd. for C₂₇H₃₉N₂O₃ 439.2961. Found 439.2967 (1.4 ppm error)].

11,17-Dihydroxy-10,13-dimethyl-17-piperazin-2-yl-1,2,6,7,8,9,-10,11,12,13,14,15,16,17-tetradecahydocyclopenta[a]phenanthren-3-one 15

Prepared by the procedure given for 9a using hydrocortisone 1g (0.20 mmol, 0.072 g) and ethylenediamine 5a (0.40 mmol, 0.027 mL). Acid/base extraction gave the title compound15 (0.054 g, 69%) as a colourless solid: mp 104–106 °C; ν_max (CH₂Cl₂) 3445, 3053, 2934, 1661, 1451, 1266, 1133, 909, 738, 704 cm⁻¹; δ_H (400 MHz) 0.73–3.16 (28 H, m), 1.02 (3 H, s, CH₃), 1.40 (3 H, s, CH₃), 4.33 (1 H, br s, OH), 5.63 (1 H, s, C=CH); δ_C (100 MHz) 16.9, 21.1, 23.4, 31.3, 32.3, 32.7, 33.9, 35.0, 37.3, 39.3, 41.5, 45.5, 45.8, 46.6, 46.9, 52.1, 56.0, 61.5, 68.2, 83.6, 122.2, 173.0, 199.9; m/z (CI) 389 (MH⁺) [HRMS (CI) calcd. for C₂₃H₃₇N₂O₃ 389.2804. Found 389.2807 (0.8 ppm error)].

17-(Decahydroquinoxalin-2-yl)-11,17-dihydroxy-10,13-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-3-one 16

Prepared by the procedure given for 9a using hydrocortisone 1g (0.20 mmol, 0.072 g) and trans-1,2-diaminocyclohexane 5b (0.24 mmol, 0.028 mL). With trans-1,2-diaminocyclohexane 5b no HCl was used. Acid/base extraction gave the title compound 16 (0.077 g, 89%) as a mixture of several diastereomers (as shown by ¹H and ¹³C NMR spectroscopy), a colourless solid: mp 112–113 °C; ν_max (nujol) 3429, 2870, 2727, 1657, 1461, 1377, 749 cm⁻¹; m/z (CI) 443 (MH⁺) [HRMS (CI) calcd. for C₂₇H₄₃N₂O₃ 443.3274. Found 443.3275 (0.4 ppm error)].

11,17-Dihydroxy-10,13-dimethyl-17-pyrazin-2-yl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydocyclopenta[a]phenanthren-3-one 17

Prepared by the procedure given for 10a using hydrocortisone 1g (0.20 mmol, 0.072 g) and ethylenediamine 5a (0.40 mmol, 0.027 mL). Column chromatography (EtOAc to 4 : 1 EtOAc : MeOH) gave the title compound17 (0.008 g, 10%) as a colourless solid: R_f 0.34 (9 : 1 CH₂Cl₂ : EtOAc); mp 185–190 °C (decomp.); ν_max (nujol) 3455, 2953, 1642, 1614, 1234, 1157, 1116, 1915, 859 cm⁻¹; δ_H (400 MHz) 0.84 (3 H, s, CH₃), 1.08 (1 H, m), 1.13–1.34 (3 H, m), 1.43 (3 H, s, CH₃), 1.50–1.64 (2 H, m), 1.81–2.12 (6 H, m), 2.12–2.21 (1 H, m), 2.23–2.30 (1 H, m), 2.32–2.40 (1 H, m), 2.42–2.57 (2 H, m), 2.82 (1 H, m), 4.18 (1 H, br s, OH), 4.49 (1 H, br d, J 2.8 Hz, OH), 5.70 (1 H, s, C=CH), 8.53 (2 H, br s, H-pyraz.), 8.82 (1 H, s, H-pyraz.); δ_C (100 MHz) 18.6, 21.2, 24.3, 32.2, 32.4, 33.0, 34.1, 35.0, 35.2, 39.5, 39.6, 48.7, 51.8, 56.3, 68.8, 84.4, 122.6, 142.6, 143.1, 143.3, 157.2, 172.4, 199.8; m/z (CI) 383 (MH⁺) [HRMS (CI) calcd. for C₂₃H₃₁N₂O₃ 383.2321. Found 383.2331 (2.6 ppm error)].

Acknowledgements

We are grateful to the EPSRC for postdoctoral support (ROPA fellowship, S.A.R.) and to Universiti Teknologi, Petronas, Malaysia for a Ph. D. Scholarship (C.D.W.).

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