English

• 1.   Introduction

  4-(3H)-Quinazolinone and its derivatives have attracted many attentions due to their diverse biological activities, ^[1] such as anti-cancer, ^[2] anti-bacterial, ^[3] anti-virus, ^[4] anti- diabetes, ^[5] and anti-glucosidase activities.^[6] As an important nitrogen-containing pharmacophore, 4-(3H)-quinazolinone has been made many efforts to develop the synthetic strategies and structural diversities to meet the ever-growing requirements for the new drug discovery.^{[7, 8]} So far, a vast number of 4-(3H)-quinazolinone derivatives have been prepared and evaluated for their various biological activities.^[9] Owing to their widespread applications, the development of novel quinazoliniones has been a long-standing interest for chemists.^[10~12]

  There are two main strategies for constructing the skeleton of 4-(3H)-quinazolinone. One is the direct condensation of aldehyde and o-aminobenzamide, ^{[13, 14]} the other is the ammonolysis reaction of aromatic amine and isatoic anhydride derived from anthranilic acid.^{[15, 16]} The former is the most common protocol as its simple and efficient.^{[17, 18]} The condensation reactions were generally catalyzed by Lewis acids, such as FeCl₃, ^[19] CuCl₂, ^[20] and I₂.^[21~23] The starting reactants could be the precursors of aldehyde and o-aminobenzamide, respectively, such as benzyl alcohol, ^[24] benzyl amine, ^[25] and o-aminobenzonitrile.^[26] Although there are several literatures to describe the preparation of 4-(3H)-quinazolinone from the aliphatic aldehydes, ^[27~29] aldoses as reactants weren't studied yet. As a continuation of our researches on novel 4-(3H)-quinazolinone derivatives, ^[30~32] herein, we would like to report the synthesis of the aldo-quinazolinone by a one-pot iodine-induced reaction.

  2.   Results and discussion

  We initiated our experiment by examining the reaction of D-ribose (1a) with o-aminobenzamide (2a) in dimethyl sulfoxide (DMSO) solution at 60 ℃ (Table 1, Entry 1) according to the method for the aromatic aldehydes.^[13] However, the reaction didn't occur. Subsequently, the reaction was carried out in methanol solution at 40 ℃ in the presence of some Lewis acids FeCl₃^[19] or CuCl₂^[20] (Table 1, Entries 2, 3), but the reactions still didn't proceed. When using AcOH as the catalyst, ^[33] the reaction could yield small amount of the intermediate A (Scheme 1, two pairs of inseparable amino glycosides including α/β-furanosides and α/β-pyranosides) (Table 1, Entry 4). Finally, iodine (I₂) was added to promote the reaction (Table 1, Entry 5).^[21] The reaction could succeed in generating the target ribo-quinazolinone 3a with a low yield of 12%, although the iodine-induced reaction was very complicated.

  Table 1

  

  Table 1.  Optimization of the condensation of D-ribose and o-aminobenzamide

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  Entry	Conditiona	I2/equiv.	Product	Yield/%
  1	DMSO, 60 ℃, 24 h		—b
  2	FeCl3 (2 mmol), CH3OH, 40 ℃, 24 h		—
  3	CuCl2 (2 mmol), CH3OH, 40 ℃, 24 h		—
  4	AcOH (0.1 mL), CH3OH, 40 ℃, 24 h		Intermediate A	28
  5	I2, CH3OH, 40 ℃, 24 h	0.15	Intermediate B and 3a	12c
  6	I2, CH3OH, 40 ℃, 8 h	0.02	Intermediate A	62
  7	I2, CH3OH, 40 ℃, 8 h	0.1	Intermediate B and 3a	6c
  8	I2, CH3OH, 40 ℃, 24 h	0.23	3a	46
  a The molar ratio of D-ribose (180 mg, 1 mmol) and o-aminobenzamide is 1.0:1.2, the solvent is 5 mL. b No reaction. c Yield of 3a.

  Scheme 1

  

  Scheme 1.  Synthesis of the ribo-quinazolinone 3a through the condensation of D-ribose and o-aminobenzamide using iodine as catalyst

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  The condensation conditions were further optimized. The results showed that the amount of iodine had an important effect on the reaction. Adjusting the amount of iodine could control the synthesis in its different stages to give the different products. For example, adding the catalytic amount of iodine (0.02 equiv.) would lead to the reaction which only afford the intermediate A (Table 1, Entry 6). When the amount of I₂ increased to 0.1 equiv., intermediate A decreased slowly, another key intermediate B (ribo-dihydroquinazolinones, a pair of inseparable isomers) was greatly produced, and 3a was synthesized a little simultaneously (Table 1, Entry 7). Further improving the amount of I₂ to 0.23 equiv., the intermediate B could be oxidized to 3a completely (Table 1, Entry 8).

  The possible mechanism for the synthesis of 3a was summarized in Scheme 1.^{[21, 34]} It was likely that the Schiff base was firstly formed between D-ribose and o-aminoben-amide. Theoretically, 4-/5-hydroxyl on the ribose could attack the imine to generate the intermediate A, while the amino on the amide could attack the imine to produce the intermediate B, respectively. In the presence of iodine, the synthesis of B was predominant, and A could transform to B at the same time. Finally, the ribo-dihydroquinazolinone B was oxidized to 3a by iodine, which was identified by its X-ray crystallographic structure (Figure 1).^[35] To confirm the rationality of the mechanism, the reaction was carried out using the pure intermediate A, which afforded B and 3a as expected in the presence of I₂. Additionally, the pure intermediate B could greatly convert to 3a (70% yield) by the I₂-catalyzed reaction at 70 ℃.

  Figure 1

  

  Figure 1.  X-ray crystallographic structure of 3a

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  To simplify the synthetic progress, we could directly add 0.23 equiv. of I₂ into the methanol solution of D-ribose and o-aminobenzamide at 40 ℃ for 24 h. After simple workup and silica gel column chromatography, aldo- quinazolinone 3a would precipitate from the eluent in the yield of 46% (Table 2, Entry 1). Under the similar conditions using different equivalents of I₂, the corresponding aldo-quinazolinones 3b~3g (Table 2, Entries 2~7) were successfully obtained from seven saccharides with o-aminobenzamides in the satisfactory yields of 30%~59%. The used saccharides included five monosaccharides, D-xylose (1b), D-arabinose (1c), D-glucose (1d), D- mannose (1e) and D-galactose (1f), and one disaccharide, D-maltose (1g), respectively. To demonstrate the generality of the reaction, the substituted o-aminobenzamides were also used to react with D-arabinose (1c), D-mannose (1e), and D-maltose (1g) to prepare the corresponding aldoquinazolinones 3c-1~3c-3, 3f-1~3f-3, and 3g-1~3g-2 (Table 3, Entries 1~8) in the moderate yields of 38%-80%, respectively. However, the production of 3g-2 was accompanied by a side reaction leading to an inseparable I-substuitued byproduct 3g-2-1 (Table 3, Entry 8), as the same as the literature described.^[36] Its molecular formula was deduced to be C₂₀H₂₇IN₂O₁₁ by using HRESIMS.

  Table 2

  

  Table 2.  Synthesis of the aldo-quinazolinones 3a~3g through the condensation of the unprotected saccharides and o-aminobenzamide

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  Table 3

  

  Table 3.  Synthesis of the aldo-quinazolinones 3c-1~3c-3, 3f-1~3f-3, and 3g-1~3g-2 through the condensation of the unprotected saccharides and the substituted o-aminobenzamides

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  It was worth noting that the fluorescent characteristics of the quinazolinone analogs were interesting. For example, the intermediate A exhibited blue fluorescence, the intermediate B appeared green fluorescence, while the aldo-quinazolinones showed no fluorescence in the fluorescent examination. The significant change of the fluorescence color of the compounds could help us to easily monitor the one-pot multistep transformation in the thin layer chromatography (TLC) detection.

  2.   Conclusions

  In conclusion, a serials of novel aldo-quinazolinones were synthesized by the iodine-induced condensation of the monosaccharides and o-aminobenzamides, providing an effective protocol for the preparation of aldo-quinazo-linones.

  3.   Experimental

  3.1   Materials

  Melting points were measured on an SGW^Ⓡ X-4 micro melting point apparatus and were uncorrected. Optical rotations were determined on an SGW^Ⓡ-1 automatic polarimeter. ¹H NMR, and ¹³C NMR spectra were measured on a RT-NMR Bruker AVANCE 600 (600 MHz) and AVANCE 400 (400 MHz), NMR spectrometer using tetramethylsilane (Me₄Si) as an internal standard. Mass Spectra (MS) and High Resolution Mass Spectra (HRMS) were carried out on a FTICR-MS (Ionspec 7.0T) mass spectrometer with electrospray ionization (ESI). X-Ray crystallographic measurements were made on a Bruker SMART CCD Diffractometer. Thin-layer chromatography (TLC) was performed on precoated plates (Qingdao GF₂₅₄) with detection with phosphomolybdic acid in EtOH/H₂O followed by heating. Column chromatography was performed using SiO₂ (Qingdao 300~400 mesh).

  3.2   Methods

  3.2.1   Synthesis of the intermediate A

  A mixture of D-ribose (1.8 g, 12.0 mmol) and o-aminobenzamide (2.0 g, 1.2 equiv.) in 60 mL methanol was stirred at 40 ℃ under N₂ atmosphere for 10 min, then iodine (0.1 g, 0.02 equiv.) was added into the solution. The mixture was continued to stir at 40 ℃ for 8 h, the reaction finished (monitored by TLC). After the solution cooled down, methanol was evaporated under vacuum to afford the crude product. The residue was purified using flash column chromatography (dichloromethane-methanol V:V＝2:1) to afford the intermediate A (two pairs of inseparable isomers, four compounds). The ¹H and ¹³C NMR spectra of A could be seen in the supporting materials. HR-ESI-MS calcd for C₁₂H₁₆N₂O₅Na ([M+Na]⁺) 291.0957, found 291.0956.

  3.2.2   Synthesis of the intermediate B

  A mixture of D-ribose (1.8 g, 12.0 mmol) and 2-amino- benzamide (2.0 g, 1.2 equiv.) in 60 mL methanol was stirred at 40 ℃ under N₂ atmosphere for 10 min, then iodine (0.5 g, 0.1 equiv.) was added into the solution. The mixture was stirred for 8 h, the reaction completed (the intermediate A disappeared on TLC). After the solution cooled down, methanol was evaporated under vacuum to afford the crude product. The residue was purified using flash column chromatography (dichloromethane-methanol V:V＝6:1) to afford the intermediate B.

  ((2S, 3R)-1, 2, 3, 4-tetrahydroxybutyl)-2, 3-dihydro-quin-azolin-4(1H)-one (intermediate B, a pair of inseparable isomers): White solid, yield 17%; m.p. 165.9~169.6 ℃, ¹H NMR (600 MHz, CD₃OD) δ: 7.69~7.67 (m, 1H), 7.28~7.25 (m, 1H), 6.78 (d, J＝8.4 Hz, 0.6H), 6.74~6.71 (m, 1.4H), 5.03 (d, J＝4.8 Hz, 0.4H), 4.97 (d, J＝5.4 Hz, 1H), 3.88 (t, J＝4.2 Hz, 0.5H), 3.84~3.81 (m, 1H), 3.79~3.76 (m, 1.5H), 3.67 (dd, J＝11.4, 6.0 Hz, 1H); ¹³C NMR (150 MHz, CD₃OD) δ: 167.4, 167.3, 149.9, 149.5, 135.2, 128.7, 128.6, 118.9, 116.1, 115.8, 115.7, 74.7, 74.4, 73.9, 73.8, 73.7, 68.0, 67.9, 64.6, 64.5; HR-ESI-MS calcd for C₁₂H₁₇N₂O₅ ([M+H]⁺) 269.1137, found 269.1132.

  3.2.3   General synthesis of the aldo-quinazolinones 3

  A mixture of D-ribose (1.8 g, 12.0 mmol) and 2-aminobenzamide (2.0 g, 1.2 equiv.) in 60 mL methanol was stirred at 40 ℃ under N₂ atmosphere for 10 min, then iodine (0.9 g, 0.23 equiv.) was added into the solution. The mixture was stirred for 24 h till the reaction completed. After the solution cooled down, methanol was evaporated under vacuum to afford the crude product. The residue was purified using flash column chromatography (dichloromethane-methanol V:V＝6:1). White solid could precipitate from the eluent and was washed with ethyl acetate (5 mL×3) to afford compound 3a.

  Under the similar conditions with different amounts of I₂, the corresponding aldo-quinazolinones 3 were obtained in satisfactory yields.

  2-((1S, 2S, 3R)-1, 2, 3, 4-Ttetrahydroxybutyl)quinazolin-4(3H)-one (3a): White solid, yield 46%. m.p. 183.9~185.6 ℃; [α]_D²⁵－8.0 (c 0.01, H₂O); ¹H NMR (600 MHz, DMSO-d₆) δ: 11.36 (s, 1H), 8.11 (d, J＝7.8 Hz, 1H), 7.79 (t, J＝7.2 Hz, 1H), 7.64 (d, J＝7.8 Hz, 1H), 7.48 (t, J＝7.2 Hz, 1H), 5.92 (s, 1H), 5.08 (s, 1H), 4.71 (s, 1H), 4.64 (s, 1H), 4.40 (t, J＝5.4 Hz, 1H), 3.86 (t, J＝5.4 Hz, 1H), 3.61~3.58 (m, 2H), 3.45~3.41 (m, 1H); ¹³C NMR (150 MHz, DMSO-d₆) δ: 161.1, 157.7, 148.5, 134.3, 126.9, 126.2, 125.8, 121.3, 74.2, 72.7, 72.0, 62.9; HR-ESI-MS calcd for C₁₂H₁₄N₂O₅Na ([M+Na]⁺) 289.0800, found 289.0802.

  2-((1S, 2R, 3R)-1, 2, 3, 4-Tetrahydroxybutyl)quinazolin-4(3H)-one (3b): White solid, yield 43%. m.p. 115.4~117.0 ℃; [α]_D²⁵ +36.8 (c 0.04, H₂O), ¹H NMR (600 MHz, CD₃OD) δ: 8.15 (d, J＝7.8 Hz, 1H), 7.71 (t, J＝7.8 Hz, 1H), 7.63 (d, J＝7.8 Hz, 1H), 7.41 (t, J＝7.8 Hz, 1H), 4.783 (s, 1H), 4.045 (s, 1H), 3.88 (d, J＝4.2 Hz, 1H), 3.75~3.69 (m, 2H); ¹³C NMR (150 MHz, CD₃OD) δ: 167.8, 162.2, 150.3, 135.1, 127.1, 127.1, 127.1, 122.2, 74.4, 74.4, 74.0, 64.2; HR-ESI-MS calcd for C₁₂H₁₄N₂O₅Na ([M+Na]⁺) 289.0800, found 289.0804.

  2-((1R, 2S, 3R)-1, 2, 3, 4-tetrahydroxybutyl)quinazolin-4(3H)-one (3c): White solid, yield 48%, m.p. 206.0~207.7 ℃, [α]_D²⁵ －15.6 (c 0.04, H₂O), ¹H NMR (600 MHz, DMSO-d₆) δ: 11.20 (s, 1H, NH), 8.11 (d, J＝7.8 Hz, 1H), 7.79 (t, J＝7.2 Hz, 1H), 7.63 (d, J＝7.2 Hz, 1H), 7.48 (t, J＝7.8 Hz, 1H), 5.56 (d, J＝6.0 Hz, 1H), 4.81 (d, J＝5.4 Hz, 2H), 4.73 (d, J＝4.8 Hz, 1H), 4.44 (s, 1H), 3.76~3.73(m, 1H), 3.64 (d, J＝10.8 Hz, 1H), 3.57 (s, 1H), 3.48~3.46 (m, 1H); ¹³C NMR (150 MHz, DMSO-d₆) δ: 161.1, 159.1, 148.6, 134.4, 126.8, 126.1, 125.1, 121.1, 73.4, 70.8, 70.5, 63.3; HR-ESI-MS calcd for C₁₂H₁₄N₂O₅Na ([M+ Na]⁺) 289.0800, found 289.0802.

  2-((1S, 2R, 3R, 4R)-1, 2, 3, 4, 5-pentahydroxypentyl)quina-zolin-4(3H)-one (3d): White solid, yield 45%, m.p. 166.9~168.7 ℃, [α]_D²⁵ 16.5 (c 0.04, H₂O), ¹H NMR (600 MHz, DMSO-d₆) δ: 11.50 (s, 1H), 8.11 (d, J＝7.8 Hz, 1H), 7.80 (t, J＝7.2 Hz, 1H), 7.65 (d, J＝7.8 Hz, 1H), 7.49 (t, J＝7.8 Hz, 1H), 4.71~4.37 (m, 5H), 4.09 (d, J＝2.4 Hz, 1H), 3.58 (dd, J＝10.8, 3.0 Hz, 1H), 3.53~3.50 (m, 1H), 3.47 (d, J＝8.4, 1H), 3.39 (q, J＝5.4 Hz, 1H); ¹³C NMR (150 MHz, DMSO-d₆) δ: 161.2, 157.8, 148.4, 134.4, 126.9, 126.3, 125.8, 121.2, 73.3, 71.6, 71.4, 71.3, 63.2; HR-ESI-MS calcd for C₁₃H₁₆N₂O₆Na ([M+Na]⁺) 319.0906, found 319.0908.

  2-((1S, 2R, 3S, 4R)-1, 2, 3, 4, 5-pentahydroxypentyl)quina-zolin-4(3H)-one (3e): White solid, yield 41%, m.p. 211.4~212.3 ℃, [α]_D²⁵ 22.6 (c 0.04, H₂O), ¹H NMR (600 MHz, DMSO-d₆) δ: 11.21 (s, 1H), 8.11 (d, J＝7.8 Hz, 1H), 7.79 (t, J＝7.8 Hz, 1H), 7.64 (d, J＝7.8 Hz, 1H), 7.48 (t, J＝7.2 Hz, 1H), 5.52 (s, 1H), 4.84 (s, 1H), 4.74 (s, 1H), 4.52 (s, 1H), 4.28 (s, 2H), 3.88 (d, J＝9.0 Hz, 1H), 3.74 (t, J＝6.0 Hz, 1H), 3.59 (d, J＝9.0 Hz, 1H) 3.47~3.41 (m, 3H); ¹³C NMR (150 MHz, DMSO-d₆) δ: 161.1, 159.5, 148.5, 134.4, 126.6, 126.0, 125.8, 121.0, 72.6, 70.5, 69.6, 69.0, 63.1; HR-ESI- MS calcd for C₁₃H₁₆N₂O₆Na ([M+Na]⁺) 319.0906, found 319.0903.

  2-((1R, 2R, 3R, 4R)-1, 2, 3, 4, 5-pentahydroxypentyl)quinazolin-4(3H)-one (3f): White solid, yield 59%, m.p. 209.9~211.5 ℃, [α]_D²⁵ －16.6 (c 0.04, H₂O), ¹H NMR (600 MHz, DMSO-d₆) δ: 11.93 (s, 1H), 8.10 (d, J＝7.8 Hz, 1H), 7.79 (t, J＝7.8 Hz, 1H), 7.64 (d, J＝7.8 Hz, 1H), 7.48 (t, J＝7.2 Hz, 1H), 5.60 (d, J＝4.8 Hz, 1H), 4.50 (s, 1H), 4.46 (q, J＝6.0 Hz, 1H), 4.40 (s, 3H), 4.10 (t, J＝6.6 Hz, 1H), 3.67~3.62 (m, 2H), 3.51 (s, 1H), 3.45~3.42 (m, 1H); ¹³C NMR (150 MHz, DMSO-d₆) δ: 161.5, 158.9, 148.6, 134.2, 126.9, 126.1, 125.7, 121.4, 71.9, 71.2, 70.9, 69.5, 63.8; HR-ESI-MS calcd for C₁₃H₁₆N₂O₆Na ([M+Na]⁺) 319.0906, found 319.0907.

  2-((1S, 2R, 3R, 4R)-1, 2, 4, 5-tetrahydroxy-3-(((2S, 3R, 4S, 5S, 6R)-3, 4, 5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)pentyl)quinazolin-4(3H)-one (3g): White solid, yield 30%, m.p. 172.6~173.8 ℃, [α]_D²⁵ 114.3 (c 0.04, H₂O), ¹H NMR (400 MHz, DMSO-d₆) δ: 11.31 (s, 1H), 8.11 (d, J＝7.6 Hz, 1H), 7.81 (t, J＝7.2 Hz, 1H), 7.64 (d, J＝8.0 Hz, 1H), 7.49 (t, J＝7.2 Hz, 1H), 5.75 (s, 1H), 5.56 (d, J＝4.8 Hz, 1H), 5.06 (s, 1H), 4.95~4.92 (m, 3H), 4.69 (s, 1H), 4.60 (d, J＝5.2 Hz, 1H), 4.54 (t, J＝5.2 Hz, 1H), 4.48 (t, J＝5.2 Hz, 1H), 4.14 (s, 1H), 3.72 (s, 2H), 3.65~3.61 (m, 3H), 3.50~3.39 (m, 3H), 3.27 (d, J＝8.8 Hz, 1H), 3.13~3.08 (m, 1H); ¹³C NMR (150 MHz, DMSO-d₆) δ: 161.0, 157.8, 148.4, 134.5, 126.8, 126.3, 125.8, 121.1, 100.8, 82.2, 73.4, 73.2, 73.1, 72.3, 72.2, 71.6, 69.8, 62.6, 60.6; HR-ESI-MS calcd for C₁₉H₂₆N₂-O₁₁Na ([M+Na]⁺) 481.1434, found 481.1437.

  6-Chloro-2-((1R, 2S, 3R)-1, 2, 3, 4-tetrahydroxybutyl)-quinazolin-4(3H)-one (3c-1): White solid, yield 57%, m.p. 201.9~203.1 ℃, [α]_D²⁵ －14.5 (c 0.04, H₂O), ¹H NMR (400 MHz, DMSO-d₆) δ: 11.41~11.36 (m, 1H), 8.02 (d, J＝2.4 Hz, 1H), 7.81 (dd, J＝8.8 Hz, 2.4 Hz, 1H), 7.65 (d, J＝8.4 Hz, 1H), 5.53 (d, J＝0.4 Hz, 1H), 4.77~4.68 (m, 3H), 4.39 (t, J＝4.8 Hz, 1H), 3.72~3.54 (m, 3H), 3.43 (m, 1H); ¹³C NMR (150 MHz, DMSO-d₆) δ: 160.1, 159.8, 147.4, 134.5, 130.3, 129.0, 124.8, 122.4, 73.4, 70.8, 70.6, 63.3; HR-ESI-MS calcd for C₁₂H₁₃ClN₂O₅Na ([M+Na]⁺) 323.0410, found 323.0407.

  7-Chloro-2-((1R, 2S, 3R)-1, 2, 3, 4-tetrahydroxybutyl)-quinazolin-4(3H)-one (3c-2): White solid, yield 50%, m.p. 168.9~169.8 ℃, [α]_D²⁵ －32.2 (c 0.04, H₂O), ¹H NMR (600 MHz, DMSO-d₆) δ: 11.33 (s, 1H), 8.10 (d, J＝8.4 Hz, 1H), 7.68 (s, 1H), 7.50 (d, J＝8.4 Hz, 1H), 5.55 (s, 1H), 4.79 (s, 2H), 4.70 (s, 1H), 4.40 (s, 1H), 3.73 (d, J＝7.2 Hz, 1H), 3.64 (dd, J＝11.4, 2.4 Hz, 1H), 3.56 (s, 1H), 3.45 (dd, J＝11.4, 6.0 Hz, 1H); ¹³C NMR (150 MHz, DMSO-d₆) δ: 160.9, 160.5, 149.8, 139.0, 127.9, 126.3, 125.9, 120.0, 73.4, 70.8, 70.7, 63.3; HR-ESI-MS calcd for C₁₂H₁₃ClN₂O₅Na ([M+Na]⁺) 323.0410, found 323.0415.

  7-Methyl-2-((1R, 2S, 3R)-1, 2, 3, 4-tetrahydroxybutyl)-quinazolin-4(3H)-one (3c-3): Yellow solid, yield 45%, m.p. 211.0~212.0 ℃, [α]_D²⁵ －72.5 (c 0.04, H₂O), ¹H NMR (400 MHz, DMSO-d₆) δ: 11.05~11.03 (m, 1H), 7.98 (d, J＝8.0 Hz, 1H), 7.43 (s, 1H), 7.30 (d, J＝8.0 Hz, 1H), 5.54 (d, J＝1.2 Hz, 1H), 4.77~4.69 (m, 3H), 4.41 (t, J＝5.2 Hz, 2H), 3.70~3.55 (m, 3H), 3.47~3.40 (m, 1H), 2.44 (s, 3H); ¹³C NMR (150 MHz, DMSO-d₆) δ: 160.9, 159.1, 148.8, 144.8, 127.5, 126.4, 125.7, 118.7, 73.4, 70.8, 70.5, 63.3, 21.3; HR-ESI-MS calcd for C₁₃H₁₆N₂O₅Na ([M+Na]⁺) 303.0957, found 303.0962.

  6-Chloro-2-((1R, 2R, 3R, 4R)-1, 2, 3, 4, 5-pentahydroxypent-yl)quinazolin-4(3H)-one (3f-1): White solid, yield 78%, m.p. 232.6~233.4 ℃, [α]_D²⁵ －13.5 (c 0.04, H₂O), ¹H NMR (400 MHz, DMSO-d₆) δ: 8.03 (d, J＝2.4 Hz, 1H), 7.79 (d, J＝2.4 Hz, 1H), 7.66 (d, J＝8.8 Hz, 1H), 4.50~4.33 (m, 3H), 4.06 (d, J＝8.8 Hz, 1H), 3.65~3.60 (m, 2H), 3.51~3.42 (m, 2H); ¹³C NMR (150 MHz, DMSO-d₆) δ: 160.8, 159.9, 147.2, 134.3, 130.3, 129.1, 124.7, 122.6, 71.9, 71.1, 70.9, 69.5, 63.7; HR-ESI-MS calcd for C₁₃H₁₅Cl-N₂O₆Na ([M+Na]⁺) 353.0516, found 353.0515.

  7-Chloro-2-((1R, 2R, 3R, 4R)-1, 2, 3, 4, 5-pentahydroxypentyl)quinazolin-4(3H)-one (3f-2): White solid, yield 57%, m.p. 182.9~183.8 ℃, [α]_D²⁵ －33.5 (c 0.04, H₂O), ¹H NMR (400 MHz, DMSO-d₆) δ: 8.09 (d, J＝8.4 Hz, 1H), 7.68 (d, J＝2.0 Hz, 1H), 7.51 (dd, J＝8.4 Hz, 2.0 Hz, 1H), 4.53~4.41 (m, 4H), 4.07 (d, J＝8.8 Hz, 1H), 3.65~3.60 (m, 2H), 3.49 (d, J＝5.2 Hz, 1H); ¹³C NMR (150 MHz, DMSO-d₆) δ: 161.0, 160.7, 149.7, 138.8, 127.9, 126.4, 126.1, 120.2, 71.9, 71.1, 70.8, 69.4, 63.7; HR-ESI-MS calcd for C₁₃H₁₅ClN₂O₆Na ([M+Na]⁺) 353.0516, found 353.0518.

  7-Methyl-2-((1R, 2R, 3R, 4R)-1, 2, 3, 4, 5-pentahydroxypentyl)quinazolin-4(3H)-one (3f-3): Yellow solid, yield 80%, m.p. 191.8~192.7 ℃, [α]_D²⁵ －66.0 (c 0.04, H₂O), ¹H NMR (400 MHz, DMSO-d₆) δ: 7.98 (d, J＝8.0 Hz, 1H), 7.43 (s, 1H), 7.30 (d, J＝8.0 Hz, 1H), 4.48~4.37 (m, 4H), 4.07 (d, J＝8.8 Hz, 1H), 3.65~3.60 (m, 2H), 3.48 (d, J＝6.0 Hz, 1H), 3.44~3.35 (m, 1H), 2.45 (s, 3H); ¹³C NMR (150 MHz, DMSO-d₆) δ: 161.4, 158.9, 148.7, 144.6, 127.6, 126.6, 125.6, 119.0, 71.9, 71.1, 70.9, 69.5, 63.7, 21.3; HR-ESI-MS calcd for C₁₄H₁₈N₂O₆Na ([M+Na]⁺) 333.1062, found 333.1064.

  6-Chloro-2-((1S, 2R, 3R, 4R)-1, 2, 4, 5-tetrahydroxy-3-(((2R, 3R, 4S, 5S, 6R)-3, 4, 5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)pentyl)quinazolin-4(3H)-one (3g-1): White solid, yield 38%, m.p. 198.4~198.8 ℃, [α]_D²⁵ 97.6 (c 0.04, H₂O), ¹H NMR (600 MHz, DMSO-d₆) δ: 11.55 (d, J＝0.8 Hz, 1H), 8.04 (s, 1H), 7.83 (dd, J＝8.8, 2.0 Hz, 1H), 7.67 (d, J＝8.4 Hz, 1H), 5.77 (d, J＝0.8 Hz, 1H), 5.55 (s, 1H), 5.06 (s, 1H), 4.92 (d, J＝2.8 Hz, 3H), 4.69 (s, 1H), 4.60~4.46 (m, 3H), 4.13 (s, 1H), 3.72 (s, 2H), 3.63~3.61 (m, 3H), 3.49~3.38 (m, 3H), 3.28 (s, 1H), 3.13~3.07 (m, 1H); ¹³C NMR (150 MHz, DMSO-d₆) δ: 160.1, 158.6, 147.1, 134.6, 130.5, 129.1, 124.8, 122.4, 100.8, 82.2, 73.3, 73.2, 73.0, 72.3, 72.2, 71.7, 69.8, 62.6, 60.6; HR-ESI-MS calcd for C₁₉H₂₅ClN₂O₁₁Na ([M+Na]⁺) 515.1044, found 515.1049.

  7-Methyl-2-((1S, 2R, 3R, 4R)-1, 2, 4, 5-tetrahydroxy-3-(((2R, 3R, 4S, 5S, 6R)-3, 4, 5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)pentyl)quinazolin-4(3H)-one (3g-2) and 6-iodo-7-methyl-2-((1S, 2R, 3R, 4R)-1, 2, 4, 5-tetrahydroxy-3-(((2R, 3R, 4S, 5S, 6R)-3, 4, 5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)pentyl)-quinazolin-4(3H)-one (3g-2-1): White solid (mixture), total yields 35%, ¹H NMR (400 MHz, DMSO-d₆) δ: 11.34 (s, 0.5H), 11.14 (s, 0.8H), 8.46 (s, 0.5H), 8.00~7.99 (m, 0.8H), 7.62 (s, 0.5H), 7.45 (s, 0.8H), 7.33~7.31 (m, 0.8H), 5.71 (s, 1.5H), 5.49 (s, 1.5H), 5.03~4.85 (m, 6.0H), 4.68 (s, 1.7H), 4.55~4.42 (m, 4.7H), 4.14 (s, 1.4H), 3.73~3.63 (m, 7.8H), 3.54~3.37 (m, 5.0H), 3.18~3.11 (m, 2.0H), 2.45 (s, 3.0H) ¹³C NMR (100 MHz, DMSO-d₆) δ: 162.5, 162.1, 159.3, 159.2, 149.2, 148.8, 146.6, 145.1, 135.1, 127.9, 127.3, 126.6, 126.2, 121.4, 119.2, 101.3, 97.4, 82.8, 82.7, 73.9, 73.8, 73.7, 73.6, 73.0, 72.9, 72.7, 72.6, 72.3, 70.0, 63.0, 61.0, 28.4, 21.9; HR-ESI-MS calcd for C₂₀H₂₉N₂O₁₁ ([M+H]⁺), 473.1766, found 473.1772; and HR-ESI-MS calcd for C₂₀H₂₈IN₂O₁₁ ([M+H]⁺) 599.0732, found 599.0738.

  Supporting Information  he NMR characterization data for compounds A, B, 3a~3g, 3c-1~3c-3, 3f-1~3f-3, and 3g-1~3g-2 are available. Supplementary data associated with this article can be found, in the online version, at doi:

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• 

  Scheme 1  Synthesis of the ribo-quinazolinone 3a through the condensation of D-ribose and o-aminobenzamide using iodine as catalyst

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  Figure 1  X-ray crystallographic structure of 3a

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  Table 1.  Optimization of the condensation of D-ribose and o-aminobenzamide

  Entry	Conditiona	I2/equiv.	Product	Yield/%
  1	DMSO, 60 ℃, 24 h		—b
  2	FeCl3 (2 mmol), CH3OH, 40 ℃, 24 h		—
  3	CuCl2 (2 mmol), CH3OH, 40 ℃, 24 h		—
  4	AcOH (0.1 mL), CH3OH, 40 ℃, 24 h		Intermediate A	28
  5	I2, CH3OH, 40 ℃, 24 h	0.15	Intermediate B and 3a	12c
  6	I2, CH3OH, 40 ℃, 8 h	0.02	Intermediate A	62
  7	I2, CH3OH, 40 ℃, 8 h	0.1	Intermediate B and 3a	6c
  8	I2, CH3OH, 40 ℃, 24 h	0.23	3a	46
  a The molar ratio of D-ribose (180 mg, 1 mmol) and o-aminobenzamide is 1.0:1.2, the solvent is 5 mL. b No reaction. c Yield of 3a.

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  Table 2.  Synthesis of the aldo-quinazolinones 3a~3g through the condensation of the unprotected saccharides and o-aminobenzamide

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  Table 3.  Synthesis of the aldo-quinazolinones 3c-1~3c-3, 3f-1~3f-3, and 3g-1~3g-2 through the condensation of the unprotected saccharides and the substituted o-aminobenzamides

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•