Highly Diastereoselective NHC-Catalyzed [4+3] Annulation of Enals, Alde­hydes and N-Phenyl Urea/Thiourea for the Synthesis of Monocyclic trans-1,3-Diazepanes

Abstract

N-Heterocyclic carbene catalyzed synthesis of 1,3-diazepanes from α,β-unsaturated aldehydes, N-phenyl urea/thiourea and aromatic aldehydes has been developed. The reactive Breslow intermediate, formed by reaction of the enal with the NHC, attacks as a d³ nucleophile at the 1-arylidene-3-arylurea derivative, which is produced by simple reaction of N-phenyl urea/thiourea with an aromatic aldehyde. The resulting intermediate, on subsequent heterocyclization, forms the product with high yield. The reaction proceeded smoothly with high atom economy, producing a new C–C and a new C–N bond in a one-pot operation.

The 1,3-diazepane system represents an architecture that exhibits a wide range of pharmaceutical activities. Many 1,3-diazepane derivatives have been identified to have inhibitory effects on HIV-1 protease,[1] AMP deaminase,[2] cytotoxic effects on jurkat and glial cells,[3] as well as NK1 receptor-binding properties.[4] 1,3-Diazepanes with a ring-expanded nucleoside act as competitive inhibitors of both adenosine deaminase and guanase.[5] Most recently, benzo-fused 1,3-diazepanes have been screened for their antibacterial activity[6] against Gram positive as well as Gram negative microorganisms, and their application in cancer treatment[7] has also been disclosed (Figure [1]).

Over the past two decades, N-heterocyclic carbenes (NHC) have received substantial interest due to the continuously growing number of successful and novel applications in organic synthesis.[8] NHCs belong to a versatile class of organic compounds with a formally divalent carbon that can form Breslow intermediates with enals, which can offer an unconventional bond-forming tactic. NHCs have been used to catalyze organic transformations such as benzoin and Stetter type reactions,[9] homoenolate formation,[10] and transesterification reactions.[11]

To this point, only a few procedures for the synthesis of monocyclic 1,3-diazepanes have been reported.[12] In a continuation of our program to develop simple, efficient, atom-economical and eco-compatible protocols for the synthesis of biodynamic heterocycles, we report herein a simple and convenient method for direct access to monocyclic 1,3-diazepanes from α,β-unsaturated carbonyl compounds, N-phenyl urea/thiourea and aromatic aldehydes, involving NHC-promoted intermolecular nucleophilic addition (Scheme [1]).[13]

Table 1 Influence of Solvent on NHC-Catalyzed [4+3] Annulation of Aldehyde 1d, Urea 2 and Aromatic Aldehyde 3b

Entry	Solvent	Time (h)	Yield (%)
1	EtOH	8	trace
2	DME	4	78
3	CH2Cl2	3	91
4	toluene	4.5	74
5	DMF	5	49
6	MeCN	5	55
7	THF	3	85
8	MeOH	5	18

Initially, α,β-unsaturated aldehyde 1d, urea 2 and aromatic aldehyde 3b were selected as model substrates to optimize the reaction conditions (Table [1]). The reaction was first carried out in ethanol with 4b (10 mol%) as the catalyst, and Cs₂CO₃ (10 mol%) as the base at room temperature under a nitrogen atmosphere. To our disappointment, we observed very little cyclization. However, when DMF was used as the solvent and DBU was used as the base, formation of 1,3-diazepane was observed in 49% yield. This result encouraged us to optimize the reaction parameters to enhance the yield of 5d in this model system.

Table 2 Influence of NHC and Base on NHC-Catalyzed [4+3] Annulations

Entry	NHC precursor	NHC (mol%)	Base (mol%)	Time (h)	Yield (%)
1	4a	10	DBU (10)	4	85
2	4b	10	DBU (10)	3	91
3	4c	10	DBU (10)	4	81
4	4d	10	DBU (10)	4	79
5	4b	5	DBU (10)	4	69
6	4b	10	DBU (15)	4	65
7	4b	10	DBU (5)	4	62
8	4b	10	KOH (10)	4	54
9	4b	10	Et3N (10)	4	57
10	4b	10	pyrrolidine (10)	4.5	54
11	4b	10	Cs2CO3 (10)	4	78

As shown in Table [1], we initiated our investigations by screening solvents. Whereas the use of CH₂Cl₂ and THF were found to be good for this transformation, resulting in yields of 91 and 85%, respectively (Table [1], entries 3 and 7), ethanol, DME, toluene, DMF, acetonitrile, and methanol led to relatively low yields (Table [1], entries 1, 2, 4–6 and 8).

The optimal NHC catalyst for the synthesis of 1,3-diazepane 5d was 4b (91%; Table [2], entry 2); with 4a, 4c and 4d as NHC catalyst, yields were 85, 81 and 79%, respectively (Table [2], entry 1, 3 and 4). Screening for this transformation with bases such as KOH, Et₃N, pyrrolidine, DBU, and Cs₂CO₃ revealed that the combination of 4b with DBU was more efficient than other catalyst/base combinations (Table [2], entry 2). Consequently 4b/DBU was chosen as the ideal NHC/base combination and this system was employed in all subsequent reactions. When the amount of the catalyst was decreased from 10 to 5 mol%, the yield of 1,3-diazepane was reduced (Table [2], entry 5), but the use of 15 mol% 4b did not enhance the yield.

With the optimized reaction conditions in hand, the scope of the reaction with respect to substrates was then investigated (Table [3]). α,β-Unsaturated aldehydes with an electron-withdrawing group on the aromatic ring worked well (Table [3], entries 4 and 5), giving the corresponding diazepanes in excellent yields with good diastereoselectivities. Furthermore, α,β-unsaturated aldehydes with electron-donating groups also reacted to afford diazepanes in good yields (Table [3], entries 3, 6 and 9). Aromatic aldehydes with electron-withdrawing groups provided the best yields (Table [3], entry 2, 4 and 5).

Table 3 Influence of Substituents on NHC-Catalysed [4+3] Annulations

Entry	Ar1	1	X	Ar2	5	Time (h)	Yield (%)
1	Ph	1a	O	Ph	5a	4	77
2	4-MeOC6H4	1b	O	4-O2NC6H4	5b	4	83
3	4-MeC6H4	1c	O	4-MeOC6H4	5c	4.5	68
4	4-O2NC6H4	1d	O	4-O2NC6H4	5d	3	91
5	4-BrC6H4	1e	O	4-BrC6H4	5e	4	86
6	4-MeC6H4	1c	O	Ph	5f	4.5	65
7	4-O2NC6H4	1d	S	4-O2NC6H4	5g	4	83
8	Ph	1a	S	4-O2NC6H4	5h	4.5	71
9	4-MeC6H4	1c	S	4-MeOC6H4	5i	5	67
10	4-BrC6H4	1e	S	4-O2NC6H4	5j	4	80

A plausible mechanism for the reaction is shown in Scheme [2]. The imidazolium carbene 4b', produced by reaction of imidazolium salt 4b and DBU, adds to the enal 1 to give the Breslow intermediate (I). This generates a more reactive homoenolate (II), which attacks at the electrophilic site of the 1-arylidene-3-aryl urea/thiourea (III), produced by reaction of phenylurea/thiourea 2 with aromatic aldehyde 3, to form intermediate (IV). This intermediate then undergoes intramolecular attack of the distal nitrogen onto the carbonyl group to afford the 1,3-diazepane and regenerate the imidazolium carbene to complete the catalytic cycle (Scheme [2]).

The diastereoselectivity of the reaction leading to 5 was determined by ¹H NMR spectroscopic analysis. The coupling constant of the vicinal methane protons was in the range of J _6,7 = 9.1–9.4 Hz, which is indicative of a trans relationship.

In conclusion, we have developed a novel NHC-catalyzed multicomponent reaction that enables facile access to 1,3-diazepane derivatives of potential pharmaceutical importance in an expedient manner in a one-pot operation. This methodology features atom- and step-economies.

Acknowledgment

The authors gratefully acknowledge financial support by the CSIR, New Delhi and particularly acknowledge the SAIF, Chandigarh for spectroscopic analysis.

• References and Notes

• 1 Lam PY. S, Jahdav PK, Eyermann CJ, Hodge CN, Ru Y, Bacheler LT, Meek JL, Otto MJ, Rayner MM, Wong YN, Chang C.-H, Weber PC, Jackson DA, Sharpe TR, Erickson-Viitanen S. Science 1994; 263: 380
  CrossrefPubMedSearch in Google Scholar
• 2 Bookser BC, Kasibhatla SR, Appleman JR, Erion MD. J. Med. Chem. 2000; 43: 1495
  CrossrefSearch in Google Scholar
• 3 Rotas G, Natchkebia K, Natsvlishvili N, Kekelidze M, Kimbaris A, Varvounis G, Mikeladze D. Bioorg. Med. Chem. Lett. 2005; 15: 3220
  CrossrefSearch in Google Scholar
• 4a Boks GJ, Tollenaere JP, Kroon J. Bioorg. Med. Chem. 1997; 5: 535
  CrossrefSearch in Google Scholar
• 4b Dieltiens N, Claeys DD, Allaert B, Verpoort F, Stevens CV. Chem. Commun. 2005; 35: 4477
  Search in Google Scholar
• 5 Wang L, Hosmane RS. Bioorg. Med. Chem. Lett. 2001; 11: 2893
  CrossrefSearch in Google Scholar
• 6 Kharate RM, Deohate PP, Berad BN. Chem. Sci. Trans. 2013; 2: 65
  Search in Google Scholar
• 7 Kondaskar A, Kondaskar S, Kumar R, Fishbein JC, Muvarak N, Lapidus RG, Sadowska M, Edelman MJ, Bol GM, Vesuna F, Raman V, Hosmane RS. ACS Med. Chem. Lett. 2011; 2: 252
  CrossrefSearch in Google Scholar
• 8a Vora HU, Rovis T. Aldrichimica Acta 2011; 44: 3
  Search in Google Scholar
• 8b Hirano K, Piel I, Glorius F. Chem. Lett. 2011; 40: 786
  CrossrefSearch in Google Scholar
• 8c Chiang PC, Bode JW. TCI Mail 2011; 149: 2
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• 8d Moore JL, Rovis T. Top. Curr. Chem. 2010; 291: 77
  PubMedSearch in Google Scholar
• 8e Nair V, Vellalath S, Babu BP. Chem. Soc. Rev. 2008; 37: 2691
  CrossrefPubMedSearch in Google Scholar
• 8f Enders D, Niemeier O, Henseler A. Chem. Rev. 2007; 107: 5606
  Search in Google Scholar
• 8g Marion N, Díez-González S, Nolan SP. Angew. Chem. Int. Ed. 2007; 46: 2988
  Search in Google Scholar
• 8h Burstein C, Tschan S, Xie X, Glorius F. Synthesis 2006; 2418
  Thieme Connect
• 8i He M, Struble JR, Bode JW. J. Am. Chem. Soc. 2006; 128: 8418
  Search in Google Scholar
• 9a Enders D, Kallfass U. Angew. Chem. Int. Ed. 2002; 41: 1743
  Search in Google Scholar
• 9b Kerr MS, de Alaniz JR, Rovis T. J. Am. Chem. Soc. 2002; 124: 10298
  CrossrefPubMedSearch in Google Scholar
• 9c Chow KY. K, Bode JW. J. Am. Chem. Soc. 2004; 126: 8216
  CrossrefSearch in Google Scholar
• 9d Reynold NT, de Alaniz JR, Rovis T. J. Am. Chem. Soc. 2004; 126: 9518
  CrossrefSearch in Google Scholar
• 9e Myers MC, Bharadwaj AR, Milgram BC, Scheidt KA. J. Am. Chem. Soc. 2005; 127: 14675
  CrossrefSearch in Google Scholar
• 10a Burstein C, Glorius F. Angew. Chem. Int. Ed. 2004; 43: 6205
  Search in Google Scholar
• 10b Sohn SS, Rosen EL, Bode JW. J. Am. Chem. Soc. 2004; 126: 14370
  Search in Google Scholar
• 10c Chan A, Scheidt KA. Org. Lett. 2005; 7: 905
  Search in Google Scholar
• 10d Nair V, Vellalath S, Poonoth M, Suresh E. J. Am. Chem. Soc. 2006; 128: 8736
  Search in Google Scholar
• 10e Chiang PC, Kaeobamrung J, Bode JW. J. Am. Chem. Soc. 2007; 129: 3520
  Search in Google Scholar
• 10f Chan A, Scheidt KA. J. Am. Chem. Soc. 2008; 130: 2740
  CrossrefPubMedSearch in Google Scholar
• 11a Grasa GA, Kissling RM, Nolan SP. Org. Lett. 2002; 4: 3583
  Search in Google Scholar
• 11b Nyce GW, Lamboy JA, Connor EF, Waymouth RM, Hedrick JL. Org. Lett. 2002; 4: 3587
  Search in Google Scholar
• 12a Masurier N, Aruta R, Gaumet V, Denoyelle S, Moreau E, Lisowski V, Martinez J, Maillard LT. J. Org. Chem. 2012; 77: 3679
  CrossrefSearch in Google Scholar
• 12b Liang M, Saiz C, Pizzo C, Wipf P. Tetrahedron Lett. 2009; 50: 6810
  CrossrefSearch in Google Scholar
• 12c Kumar S, Pratap R, Kumar A, Kumar B, Tandon VK, Ram VJ. Tetrahedron 2013; 69: 4857
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• 13 Synthesis of 1,3-Diazepanes 5a–j; General Procedure: A flame-dried round-bottom flask was charged with imidazolium salt 4b (0.034 g, 0.1 mmol, 10 mol%), α,β-unsaturated aldehyde (1 mmol) and CH₂Cl₂ (4 mL) under a positive pressure of nitrogen, followed by addition of DBU (0.0152 g, 0.1 mmol, 10 mol%) by using a syringe, and the resulting orange solution was stirred for 30 min at room temperature. To this solution, aromatic aldehyde (1.0 mmol) and N-phenyl urea/thiourea (1.0 mmol) was added by using a syringe and the reaction mixture was stirred for a further 2.5 h (completion of reaction was confirmed by TLC analysis). Subsequently, water (5 mL) was added and the reaction mixture was extracted with EtOAc. The organic phase was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was then purified by column chromatography (silica gel; Merck, 60–120 mesh; EtOAc–hexane, 3:22) to afford the pure product. 6-(4-Methoxyphenyl)-7-(4-nitrophenyl)-3-phenyl-1,3-diazepane-2,4-dione (5b);Yellow solid; mp 227–229 °C. ¹H NMR (400 MHz, CDCl₃): δ = 2.44 (dd, J _5Ha–5Hb = 14.4, J _5Ha–6H = 10.4 Hz, 1 H), 2.69 (dd, J _5Hb–5Ha = 14.4, J _5Hb–6H = 2.4 Hz, 1 H), 3.73 (s, 3 H), 4.05 (ddd, J _6H-5Ha = 10.4, J _6H-7H = 9.4, J _6H-5Hb = 2.4 Hz, 1 H), 5.30 (dd, J _7H-6H = 9.4, J _7H-NH = 2.1 Hz, 1 H), 6.36 (d, J _NH-7H = 2.1 Hz, 1 H), 6.69–7.02 (m, 4 H), 7.09–7.64 (m, 5 H), 7.38–8.14 (m, 4 H). ¹³C NMR (100 MHz, CDCl₃): δ = 171.8, 157.9, 155.4, 146.4, 145.5, 140.9, 135.7, 129.9, 129.0, 127.2, 124.7, 121.8, 121.3, 114.0, 57.6, 55.9, 40.5, 37.4. MS: m/z = 431.15 [M⁺]. Anal. Calcd for C₂₄H₂₁N₃O₅: C, 66.81; H, 4.91; N, 9.74. Found: C, 66.86; H, 4.87; N, 9.79. 6,7-Bis(4-nitrophenyl)-3-phenyl-1,3-diazepane-2,4-dione (5d): Yellow solid; mp 231–233 °C. ¹H NMR (400 MHz, CDCl₃): δ = 2.78 (dd, J _5Ha-5Hb = 14.4, J _5Ha-6H =10.3 Hz, 1 H), 3.09 (dd, J _5Hb-5Ha = 14.4, J _5Hb-6H =2.3 Hz, 1 H), 4.35 (ddd, J _6H-5Ha = 10.3, J _6H-7H = 9.4, J _6H-5Hb = 2.3 Hz, 1 H), 5.63 (dd, J _7H-6H = 9.4, J _7H-NH = 2.3 Hz, 1 H), 6.76 (d, J _NH-7H = 2.3 Hz, 1 H), 7.09–7.78 (m, 5 H), 7.39–8.12 (m, 4 H), 7.45–8.24 (m, 4 H). ¹³C NMR (100 MHz, CDCl₃): δ = 172.4, 156.7, 154.6, 146.9, 146.2, 145.3, 135.9, 130.2, 129.4, 127.6, 124.6, 122.5, 121.8, 120.3, 58.3, 40.7, 38.5. MS: m/z = 446.12 [M⁺]. Anal. Calcd for C₂₃H₁₈N₄O₆:C, 61.88; H, 4.06; N, 12.55. Found: C, 61.83; H, 4.10; N, 12.49. 6,7-Bis(4-bromophenyl)-3-phenyl-1,3-diazepane-2,4-dione (5e): Yellow solid; mp 246–248 °C. ¹H NMR (400 MHz, CDCl₃): δ = 2.73 (dd, J _5Ha-5Hb = 14.4, J _5Ha-6H = 10.3 Hz, 1 H), 2.85 (dd, J _5Hb-5Ha = 14.4, J _5Hb-6H = 2.3 Hz, 1 H), 4.17 (ddd, J _6H-5Ha = 10.3, J _6H-7H = 9.3, J _6H-5Hb = 2.3 Hz, 1 H), 5.35 (dd, J _7H-6H = 9.3, J _7H-NH = 2.3 Hz, 1 H), 6.12 (d, J _NH-7H = 2.3 Hz, 1 H), 7.02–7.60 (m, 5 H), 7.05–7.40 (m, 4 H), 7.12–7.44 (m, 4 H). ¹³C NMR (100 MHz, CDCl₃): δ = 171.1, 155.3, 147.2, 136.4, 135.8, 135.3, 131.6, 129.9, 129.0, 128.7, 128.1, 124.9, 121.5, 120.6, 57.6, 39.3, 36.5, 24.3. MS: m/z = 511.97 [M⁺]. Anal. Calcd for C₂₃H₁₈Br₂N₂O₂: C, 53.72; H, 3.53; N, 5.45. Found: C, 53.76; H, 3.59; N, 5.50.

• References and Notes

• 1 Lam PY. S, Jahdav PK, Eyermann CJ, Hodge CN, Ru Y, Bacheler LT, Meek JL, Otto MJ, Rayner MM, Wong YN, Chang C.-H, Weber PC, Jackson DA, Sharpe TR, Erickson-Viitanen S. Science 1994; 263: 380
  CrossrefPubMedSearch in Google Scholar
• 2 Bookser BC, Kasibhatla SR, Appleman JR, Erion MD. J. Med. Chem. 2000; 43: 1495
  CrossrefSearch in Google Scholar
• 3 Rotas G, Natchkebia K, Natsvlishvili N, Kekelidze M, Kimbaris A, Varvounis G, Mikeladze D. Bioorg. Med. Chem. Lett. 2005; 15: 3220
  CrossrefSearch in Google Scholar
• 4a Boks GJ, Tollenaere JP, Kroon J. Bioorg. Med. Chem. 1997; 5: 535
  CrossrefSearch in Google Scholar
• 4b Dieltiens N, Claeys DD, Allaert B, Verpoort F, Stevens CV. Chem. Commun. 2005; 35: 4477
  Search in Google Scholar
• 5 Wang L, Hosmane RS. Bioorg. Med. Chem. Lett. 2001; 11: 2893
  CrossrefSearch in Google Scholar
• 6 Kharate RM, Deohate PP, Berad BN. Chem. Sci. Trans. 2013; 2: 65
  Search in Google Scholar
• 7 Kondaskar A, Kondaskar S, Kumar R, Fishbein JC, Muvarak N, Lapidus RG, Sadowska M, Edelman MJ, Bol GM, Vesuna F, Raman V, Hosmane RS. ACS Med. Chem. Lett. 2011; 2: 252
  CrossrefSearch in Google Scholar
• 8a Vora HU, Rovis T. Aldrichimica Acta 2011; 44: 3
  Search in Google Scholar
• 8b Hirano K, Piel I, Glorius F. Chem. Lett. 2011; 40: 786
  CrossrefSearch in Google Scholar
• 8c Chiang PC, Bode JW. TCI Mail 2011; 149: 2
  Search in Google Scholar
• 8d Moore JL, Rovis T. Top. Curr. Chem. 2010; 291: 77
  PubMedSearch in Google Scholar
• 8e Nair V, Vellalath S, Babu BP. Chem. Soc. Rev. 2008; 37: 2691
  CrossrefPubMedSearch in Google Scholar
• 8f Enders D, Niemeier O, Henseler A. Chem. Rev. 2007; 107: 5606
  Search in Google Scholar
• 8g Marion N, Díez-González S, Nolan SP. Angew. Chem. Int. Ed. 2007; 46: 2988
  Search in Google Scholar
• 8h Burstein C, Tschan S, Xie X, Glorius F. Synthesis 2006; 2418
  Thieme Connect
• 8i He M, Struble JR, Bode JW. J. Am. Chem. Soc. 2006; 128: 8418
  Search in Google Scholar
• 9a Enders D, Kallfass U. Angew. Chem. Int. Ed. 2002; 41: 1743
  Search in Google Scholar
• 9b Kerr MS, de Alaniz JR, Rovis T. J. Am. Chem. Soc. 2002; 124: 10298
  CrossrefPubMedSearch in Google Scholar
• 9c Chow KY. K, Bode JW. J. Am. Chem. Soc. 2004; 126: 8216
  CrossrefSearch in Google Scholar
• 9d Reynold NT, de Alaniz JR, Rovis T. J. Am. Chem. Soc. 2004; 126: 9518
  CrossrefSearch in Google Scholar
• 9e Myers MC, Bharadwaj AR, Milgram BC, Scheidt KA. J. Am. Chem. Soc. 2005; 127: 14675
  CrossrefSearch in Google Scholar
• 10a Burstein C, Glorius F. Angew. Chem. Int. Ed. 2004; 43: 6205
  Search in Google Scholar
• 10b Sohn SS, Rosen EL, Bode JW. J. Am. Chem. Soc. 2004; 126: 14370
  Search in Google Scholar
• 10c Chan A, Scheidt KA. Org. Lett. 2005; 7: 905
  Search in Google Scholar
• 10d Nair V, Vellalath S, Poonoth M, Suresh E. J. Am. Chem. Soc. 2006; 128: 8736
  Search in Google Scholar
• 10e Chiang PC, Kaeobamrung J, Bode JW. J. Am. Chem. Soc. 2007; 129: 3520
  Search in Google Scholar
• 10f Chan A, Scheidt KA. J. Am. Chem. Soc. 2008; 130: 2740
  CrossrefPubMedSearch in Google Scholar
• 11a Grasa GA, Kissling RM, Nolan SP. Org. Lett. 2002; 4: 3583
  Search in Google Scholar
• 11b Nyce GW, Lamboy JA, Connor EF, Waymouth RM, Hedrick JL. Org. Lett. 2002; 4: 3587
  Search in Google Scholar
• 12a Masurier N, Aruta R, Gaumet V, Denoyelle S, Moreau E, Lisowski V, Martinez J, Maillard LT. J. Org. Chem. 2012; 77: 3679
  CrossrefSearch in Google Scholar
• 12b Liang M, Saiz C, Pizzo C, Wipf P. Tetrahedron Lett. 2009; 50: 6810
  CrossrefSearch in Google Scholar
• 12c Kumar S, Pratap R, Kumar A, Kumar B, Tandon VK, Ram VJ. Tetrahedron 2013; 69: 4857
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• 13 Synthesis of 1,3-Diazepanes 5a–j; General Procedure: A flame-dried round-bottom flask was charged with imidazolium salt 4b (0.034 g, 0.1 mmol, 10 mol%), α,β-unsaturated aldehyde (1 mmol) and CH₂Cl₂ (4 mL) under a positive pressure of nitrogen, followed by addition of DBU (0.0152 g, 0.1 mmol, 10 mol%) by using a syringe, and the resulting orange solution was stirred for 30 min at room temperature. To this solution, aromatic aldehyde (1.0 mmol) and N-phenyl urea/thiourea (1.0 mmol) was added by using a syringe and the reaction mixture was stirred for a further 2.5 h (completion of reaction was confirmed by TLC analysis). Subsequently, water (5 mL) was added and the reaction mixture was extracted with EtOAc. The organic phase was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was then purified by column chromatography (silica gel; Merck, 60–120 mesh; EtOAc–hexane, 3:22) to afford the pure product. 6-(4-Methoxyphenyl)-7-(4-nitrophenyl)-3-phenyl-1,3-diazepane-2,4-dione (5b);Yellow solid; mp 227–229 °C. ¹H NMR (400 MHz, CDCl₃): δ = 2.44 (dd, J _5Ha–5Hb = 14.4, J _5Ha–6H = 10.4 Hz, 1 H), 2.69 (dd, J _5Hb–5Ha = 14.4, J _5Hb–6H = 2.4 Hz, 1 H), 3.73 (s, 3 H), 4.05 (ddd, J _6H-5Ha = 10.4, J _6H-7H = 9.4, J _6H-5Hb = 2.4 Hz, 1 H), 5.30 (dd, J _7H-6H = 9.4, J _7H-NH = 2.1 Hz, 1 H), 6.36 (d, J _NH-7H = 2.1 Hz, 1 H), 6.69–7.02 (m, 4 H), 7.09–7.64 (m, 5 H), 7.38–8.14 (m, 4 H). ¹³C NMR (100 MHz, CDCl₃): δ = 171.8, 157.9, 155.4, 146.4, 145.5, 140.9, 135.7, 129.9, 129.0, 127.2, 124.7, 121.8, 121.3, 114.0, 57.6, 55.9, 40.5, 37.4. MS: m/z = 431.15 [M⁺]. Anal. Calcd for C₂₄H₂₁N₃O₅: C, 66.81; H, 4.91; N, 9.74. Found: C, 66.86; H, 4.87; N, 9.79. 6,7-Bis(4-nitrophenyl)-3-phenyl-1,3-diazepane-2,4-dione (5d): Yellow solid; mp 231–233 °C. ¹H NMR (400 MHz, CDCl₃): δ = 2.78 (dd, J _5Ha-5Hb = 14.4, J _5Ha-6H =10.3 Hz, 1 H), 3.09 (dd, J _5Hb-5Ha = 14.4, J _5Hb-6H =2.3 Hz, 1 H), 4.35 (ddd, J _6H-5Ha = 10.3, J _6H-7H = 9.4, J _6H-5Hb = 2.3 Hz, 1 H), 5.63 (dd, J _7H-6H = 9.4, J _7H-NH = 2.3 Hz, 1 H), 6.76 (d, J _NH-7H = 2.3 Hz, 1 H), 7.09–7.78 (m, 5 H), 7.39–8.12 (m, 4 H), 7.45–8.24 (m, 4 H). ¹³C NMR (100 MHz, CDCl₃): δ = 172.4, 156.7, 154.6, 146.9, 146.2, 145.3, 135.9, 130.2, 129.4, 127.6, 124.6, 122.5, 121.8, 120.3, 58.3, 40.7, 38.5. MS: m/z = 446.12 [M⁺]. Anal. Calcd for C₂₃H₁₈N₄O₆:C, 61.88; H, 4.06; N, 12.55. Found: C, 61.83; H, 4.10; N, 12.49. 6,7-Bis(4-bromophenyl)-3-phenyl-1,3-diazepane-2,4-dione (5e): Yellow solid; mp 246–248 °C. ¹H NMR (400 MHz, CDCl₃): δ = 2.73 (dd, J _5Ha-5Hb = 14.4, J _5Ha-6H = 10.3 Hz, 1 H), 2.85 (dd, J _5Hb-5Ha = 14.4, J _5Hb-6H = 2.3 Hz, 1 H), 4.17 (ddd, J _6H-5Ha = 10.3, J _6H-7H = 9.3, J _6H-5Hb = 2.3 Hz, 1 H), 5.35 (dd, J _7H-6H = 9.3, J _7H-NH = 2.3 Hz, 1 H), 6.12 (d, J _NH-7H = 2.3 Hz, 1 H), 7.02–7.60 (m, 5 H), 7.05–7.40 (m, 4 H), 7.12–7.44 (m, 4 H). ¹³C NMR (100 MHz, CDCl₃): δ = 171.1, 155.3, 147.2, 136.4, 135.8, 135.3, 131.6, 129.9, 129.0, 128.7, 128.1, 124.9, 121.5, 120.6, 57.6, 39.3, 36.5, 24.3. MS: m/z = 511.97 [M⁺]. Anal. Calcd for C₂₃H₁₈Br₂N₂O₂: C, 53.72; H, 3.53; N, 5.45. Found: C, 53.76; H, 3.59; N, 5.50.

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