Published:August 10,2011
NOTE
/joc
Organocatalytic Asymmetric Domino Aza-Michael ÀMannich Reaction:Synthesis of Tetrahydroimidazopyrimidine Derivatives
Hong Li,†Junling Zhao,*,†Lili Zeng,†and Wenhui Hu*,†,‡
†
Guangzhou Institute of Biomedicine and Health,Chinese Academy of Sciences,Guangzhou Science Park,Guangdong 510530,People ’s Republic of China ‡
State Key Laboratory of Respiratory Disease,Guangzhou,Guangdong 510120,People ’s Republic of China
b
Supporting Information T
he tetrahydroimidazopyrimidine ring system is found in many naturally occurring products that have attracted attention due to the broad scope of their biological activities.1,2Di fferent classes of tetrahydroimidazopyrimidine compounds have shown antidepressant 2a,b and antihypertonia 2c activities that have been put to pharmaceutical uses.However,syntheses of tetrahydroimidazopyrimidine derivatives are not very well documented in the literature.2b,3The traditional methods for their synthesis often require many synthetic manipulations and puri fications,which result in low overall yields.Thus the devel-opment of novel,concise methodologies that allow the rapid construction of these tetrahydroimidazopyrimidine skeletons,preferably in a single operation,is highly desired.
Organocatalytic domino reactions 4À6allow the sequential formation of several new bonds and chiral centers in just one operation.They have been proven to be powerful tools for the e fficient and stereoselective synthesis of complex molecules 7that are di fficult to access by traditional methods.The aza-Michael addition 8participated domino reaction provides a simple and direct way for the synthesis
of nitrogen-containing heterocycles.For example,the asymmetric syntheses of 1,2-dihydroquin-olines,9pyrrolidines,10tetrahydro-1,2-oxazines,11and iso-indolines 12have been realized.Herein,we report the first asymmetric synthesis of enantioenriched tetrahydroimidazopyr-imidine derivatives through an organocatalytic domino strategy using R ,β-unsaturated aldehydes and N -arylidene-1H -imidazol-2-amines as starting materials (Scheme 1).
The reactions of 2-carbonyl-substituted indoles 13and pyrroles 14with enals have been realized for the syntheses of pyrrolidine-fused heterocycles.However,the asymmetric synth-esis of six-membered ring-fused heterocycles,such as biologically interesting tetrahydroimidazopyrimidines,through aza-Michael reaction of nitrogen heterocycles has not been reported.We would like to focus our research on this challenging task.Unlike tetrazole,triazole,and other nitrogen heterocycles,15the N ÀH
group of imidazole is not acidic enough to participate in N-alkyaltion reactions.The introduction of electron-withdrawing groups,such as carbonyl or cyano,can reduce the p K a value of this N ÀH group,making it possible for N-alkylation reactions 13,14,15b to occur.The iminic group is a weak electron-withdrawing group and enables many further transformations.We envisaged that the N -arylidene-1H -imidazol-2-amines (1)and the R ,β-unsaturated aldehydes (2)might be suitable substrates for the domino aza-Michael ÀMannich reaction and that they would generate the highly sub
stituted tetrahydroimidazopyrimidine derivatives (3).To test our hypothesis,the readily available L -proline-derived secondary amines (I ÀIV ),which are capable of both iminium 16and enamine 17catalysis,were explored as catalysts for this domino reaction.
The reaction of N -benzylidene-1H -imidazol-2-amine (1a )and cinnamaldehyde (2a )was selected as a model reaction.We first studied catalysis of the domino reaction with diphenyl prolinol silyl ether (I )in dichloromethane.The reaction pro-ceeded with high stereoselectivity (97%ee,>20:1dr)but in low yield (30%,Table 1,entry 1).There was no signi ficant improve-ment in yield when using a variety of di fferent solvents,most
Scheme 1.Domino Aza-Michael ÀMannich Reaction of r ,β-Unsaturated Aldehyde and N -Arylidene-1H -imidazol-2-
amine
Received:June 22,2011ABSTRACT:Highly substituted tetrahydroimidazopyrimidine derivatives with three chiral centers have been synthesized for the first time using an organocatalytic asymmetric domino aza-Michael ÀMannich reaction of R ,β-unsaturated aldehydes and N -arylidene-1H -imidazol-2-amines.This e fficient approach fur-nishes the products in good yields (42À87%)with excellent stereoselectivities (>20:1dr,up to >99%
ee).
likely due to the poor solubility of 1a in these solvents.However,high stereoselectivities were retained (
Table 1,entries 2À5).When methanol was used as solvent,the starting material 1a was completely consumed in just 6h to provide the product 3a in 55%yield and 96%ee (Table 1,entry 6).The arylaldehyde and 2-aminoimidazole derived from the decomposition of 1a also were detected.Those results suggested that 1a was more active in methanol and that the use of a mixture of dichloromethane and methanol might improve the e fficiency of the reaction.Experi-ments indicated that this was the case.After extensive screening,the best results in terms of yield (73%)and enantioselectivity (99%)were obtained using a 9:1ratio of dichloromethane and methanol (Table 1,entry 7).The yield was improved to 80%by the addition of benzoic acid while retaining high enantioselec-tivity (>99%ee,Table 1,entry 9).In contrast,the addition of sodium acetate had almost no in fluence on the reaction (Table 1,entry 11).Other secondary amine catalysts also were examined as catalysts:the reaction proceeded in 42%yield and 99%ee when catalyst II (Table 1,entry 12)was used,and there were no domino reaction product detected in 24h when catalysts III and IV were employed (Table 1,entries 13and 14).
With the optimal reaction conditions in hand,the substrate scope of this domino aza-Michael ÀMannich reaction was ex-plored,and the results are summarized in Table 2.Various substituted aromatic enals were examined.Both electron-with-drawing and electron-donating groups on the aromatic ring were
tolerated,yielding the expected products in moderate to high yields (54À80%)and excellent stereoselectivities (>97%ee,>20:1dr,Table 2,entries 1À12).The reaction of 2-furyl and 2-thiophene enal led to the formation of 3m and 3n in 49and 42%yields,respectively,both in 99%ee (Table 2,entries 13and 14).The electronic nature of the substituent on the aromatic ring of 1had little in fluence on the reaction.Extensions of this strategy to use the less reactive aliphatic enals were unsuccessful;no reaction occurred when crotonaldehyde was used.
The absolute con figuration of the three new chiral centers of 3n was assigned as 5S ,6S ,and 7R by X-ray crystallographic analysis of 4n (the alcohol corresponding to 3n ,Figure 1).On the basis of this observation,a plausible catalytic cycle for the reaction is proposed in Scheme 2.The reaction starts with the iminium activation of 2by I ,followed by aza-Michael addition of 1to the iminium ion to give intermediate A .The enamine of A undergoes an intramolecular Mannich reaction to give B .The catalyst is regenerated for the next catalytic cycle through hydrolysis of B :B then hydrolyzes to give tetrahydroimidazo-pyrimidine 3.
In summary,we have developed a novel organocatalytic domino aza-Michael ÀMannich reaction of N -arylidene-1H -imi-dazol-2-amines and R ,β-unsaturated aldehydes for use in the synthesis of highly substituted tetrahydroimidazopyrimidine
Table 2.Substrate Scope
of the Domino Aza-Michael ÀMannich Reaction a
entry R 1
R 2
yield b (%)dr c ee d (%)1Ph (1a )Ph (2a )803a >20:1>992
Ph (1a )3-MeC 6H 4(2b )713b >20:1993Ph (1a )3-OMeC 6H 4(2c )503c >20:1>994Ph (1a )3-ClC 6H 4(2d )603d >20:1995Ph (1a )3-BrC 6H 4(2e )683e >20:1>996Ph (1a )3-NO 2C 6H 4(2f )703f >20:1997e
Ph (1a )4-MeC 6H 4(2g )583g >20:1998
Ph (1a )4-MeOC 6H 4(2h )543h >20:1>999
e
Ph (1a )4-ClC 6H 4(2i )763i >20:19810e Ph (1a )4-BrC 6H 4(2j )723j >20:19811e
Ph (1a )4-NO 2C 6H 4(2k )763k >20:1>9912Ph (1a )piperonyl (2l )663l >20:19913Ph (1a )2-furyl (2m )493m >20:19914Ph (1a )
2-thiophene (2n )
423n >20:199154-OMeC 6H 4(1b )4-ClC 6H 4(2i )603o >20:198164-OMeC 6H 4(1b )4-NO 2C 6H 4(2k )623p >20:19717e 4-CF 3C 6H 4(1c )Ph (2a )853q >20:19918
4-CF 3C 6H 4(1c )4-ClC 6H 4(2i )873r >20:19919
e
4-CF 3C 6H 4(1c )
4-NO 2C 6H 4(2k )
753s
>20:1
99
a
Reactions was performed with N -arylidene-1H -imidazol-2-amine (0.13mmol),R ,β-unsaturated aldehyde (0.1mmol),I (0.02mmol),and PhCOOH (20mol %)in DCM/MeOH (9:1,0.3mL)at room temperature.b Isolated yield.c Determined by 1H NMR of the products.d
Determined by HPLC analysis with the corresponding alcohol.e
DCM/MeOH (1:1)as solvent.
Table 1.Optimizing of the Reaction Conditions a
entry catalyst solvent time (h)yield b (%)dr c ee d (%)1I DCM 2430>20:1972I THF 2430>20:1953I toluene 24trace ND ND 4I ether 24trace ND ND 5I CHCl 32420>20:1986I MeOH
655>20:1967I DCM/MeOH (9:1)1673>20:1998I DCM/MeOH (1:1)1277>20:1989e I DCM/MeOH (9:1)1
680>20:1>9910f I DCM/MeOH (9:1)1273>20:19811e II DCM/MeOH (9:1)2442>20:19912e III DCM/MeOH (9:1)24NR 13e
IV
DCM/MeOH (9:1)
24
trace
ND
ND
a
Reactions was performed with N -benzylidene-1H -imidazol-2-amine (0.13mmol),cinnamaldehyde (0.1mmol),and secondary amine (0.02mmol)in solvent (0.5mL)at room temperature.b Isolated yield.c
Determined by 1H NMR of the products.d Determined by HPLC analysis with the corresponding alcoh
ol.e With 20%PhCOOH as additive.f With 20%NaOAc as additive.
derivatives bearing three chiral centers.The reaction is catalyzed e fficiently by readily available diphenylprolinol silyl ethers with moderate to good yield (42À87%)and high stereoselectivities (>97%ee,>20:1dr).This strategy described could be extended to the asymmetric synthesis of biologically important tetrahy-dropyrazolopyrimidine derivatives 18and other tetrahydropyri-midine-fused heterocycles.
’EXPERIMENTAL SECTION
General Procedure for the Preparation of 1a À1c.To a
solution of benzaldehyde (1.92mL,18.8mmol)in dichloromethane (15mL)were added sequentially 2-aminoimidazole sulfate (3.7g,14.3mmol),tetraisopropyl orthotitanate (6.83mL,23.3mmol),and triethylamine (3.9mL,28.1mmol).The reaction mixture was stirred at room temperature for 24h and then concentrated in vacuo.The residue was taken up in ethyl acetate and water and filtered.The filtrate was separated,and the organic phase was dried over anhydrous sodium sulfate and concentrated.The crude product was recrystallized from ethyl acetate/hexane to afford 1a 19in 60%yield:1H NMR (400MHz,DMSO-d 6,ppm)δ12.23(s,1H),9.15(s,1H),7.95(m,2H),7.58À7.50(m,3H),7.
15(br s,1H),6.93(br s,1H).
N -(4-Methoxybenzylidene)-1H -imidazol-2-amine (1b).The title compound was obtained according to general procedure described above in 50%yield:1H NMR (400MHz,DMSO-d 6,ppm)δ12.17(s,1H),9.08(s,1H),7.89(d,J =8.8Hz,2H),7.07(d,J =8.8Hz,2H),7.0
(br s,2H),3.83(s,3H);13C NMR (125MHz,DMSO-d 6,ppm)δ162.6,159.2,151.4,130.9,128.9,114.9,55.9;HR-MS (ESI)m /z 202.0979[M +H]+,calcd for C 11H 12N 3O,202.0980.
N -(4-(Trifluoromethyl)benzylidene)-1H -imidazol-2-amine (1c).The title compound was obtained according to general procedure
described above in 70%yield:1H NMR (400MHz,DMSO-d 6,ppm)δ12.49(s,1H),9.24(s,1H),8.14(d,J =8.0Hz,2H),7.85(d,J =8.0Hz,2H),7.19(br s,1H),6.99(br s,1H);13C NMR (125MHz,DMSO-d 6,ppm)δ157.9,150.5,139.7,131.4(q,J C ÀF =31.6Hz),129.5,126.2,126.1,124.4(q,J C ÀF =270.8Hz);HR-MS (ESI)m /z 240.0743[M +H]+,calcd for C 11H 9N 3F 3,240.0749.
General Procedure for Organocatalytic Asymmetric Aza-Michael ÀMannich Reaction.To a solution of catalyst I (0.02
mmol),benzoic acid (0.02mmol),and R ,β-unsaturated aldehyde 2(0.1mmol)in 0.3mL of DCM/MeOH (9/1)was added N -arylidene-1H -imidazol-2-amine 1(0.13mmol)at room temperature.After completion of the reaction as analyzed by TLC,the reaction mixture was directly purified by silica gel column chromatography to give the desired product 3.3was dissolved in 2mL of EtOH,and NaBH 4(1.0equiv)in EtOH (0.1M)was added.The mixture was stirred under room temperature for 30min.The volatile was evaporated under vacuum,and the residue was purified by silica gel column chromatography to give the corresponding alcohol 4in almost quantitative yield.
(5S ,6S ,7R )-5,7-Diphenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidine-6-carbaldehyde (3a).The title compound was ob-tained using the general procedure described above,in 80%yield and >99%ee:[R ]20D =+34.9(c =1.00in CH 2Cl 2);1H NMR (400MHz,CDCl 3,ppm)δ9.22(s,1H),7.49À7.46(m,2H),7.38À7.26(m,6H),7.20À7.15(m,2H),6.26(s,1H),6.01(s,1H),5.41(d,J =10.0Hz,1H),4.62(d,J =10.0Hz,1H),3.54À3.49(m,1H);13C NMR (125MHz,CDCl 3,ppm)δ200.1,148.3,138.0,137.4,129.0,128.9,128.85,128.7,127.7,127.5,123.6,112.6,60.4,57.9,57.3;HR-MS (ESI)m /z 336.1708[M +MeOH +H]+,calcd for C 20H 22N 3O 2,336.1712.The enantio-meric excess was determined by HPLC analysis of the corresponding alcohol (after treatment with NaBH 4)using a Daicel Chiralpak OD-H column,hexane (0.1%TEA)/i -PrOH =9:1,flow rate =1.0mL/min:t r =10.6min (major)and t r =32.5min (minor).
(5S,6S,7R)-7-phenyl-5-m-tolyl-5,6,7,8-tetrahydroimidazo-[1,2-a]pyrimidine-6-carbaldehyde (3b).The title compound was
obtained using the general procedure described above,in 71%yield and 99%ee:[R ]20D =+38.3(c =1.00in CH 2Cl 2);1H NMR (400MHz,CDCl 3,ppm)δ9.24(d,J =1.2Hz,1H),7.50À7.48(m,2H),7.40À7.26(m,3H),7.22(dd,J =7.6,J =8.0Hz 1H),7.11(d,J =7.6Hz,1H),7.05À6.95(m,2H),6.35(s,1H),6.06(s,1H),5.38(d,J =10.4Hz,1H),4.62(d,J =10.4Hz,1H),3.54(ddd,J =1.2Hz,J =10.4Hz,J =10.4Hz,1H),2.31(s,3H);13C NMR (125MHz,CDCl 3,ppm)δ200.3,148.4,138.7,138.1,137.6,129.5,129.1,129.0,128.8,128.3,127.6,124.9,124.6,112.8,60.6,58.1,57.6,21.4;HR-MS (ESI)m /z 350.1866[M +MeOH +H]+,calcd for C 21H 24N 3O 2,350.1869.The enantio-meric excess was determined by HPLC analysis of the corresponding alcohol (after treatment with NaBH 4)using a Daicel Chiralpak OD-H column,hexane (0.1%TEA)/i -PrOH =9:1,flow rate =1.0mL/min:t r =8.5min (major)and t r =19.8min (minor).
(5S ,6S ,7R )-5-(3-Methoxyphenyl)-7-phenyl-5,6,7,8-tetra-hydroimidazo[1,2-a]pyrimidine-6-carbaldehyde (3c).The ti-tle compound was obtained using the general procedure described above,in 50%yield and >99%ee:[R ]20D =+35.6(c =1.00in CH 2Cl 2);1
H NMR (400MHz,CDCl 3,ppm)δ9.22(d,J =1.6Hz,1H),7.55À7.48(m,2H),7.46À7.30(m,3H),7.26À7.20(m,2H),6.85À6.78(m,2H),6.72(s,1H),6.29(s,1H),6.07(d,J =0.8Hz,1H),5.39(d,J =10.0Hz,1H),4.61(d,J =10.0Hz,1H),3.76(s,3H),3.52(ddd,J =1.6Hz,J =10.0Hz,J =10.0Hz,1H);13C NMR (125MHz,CDCl 3,ppm)δ200.2,159.9,148.4,139.7,137.6,129.9,129.03,129.0,127.5,124.6,120.0,114.1,113.2,112.7,60.5,58.0,57.6,55.3;HR-MS (ESI)m /z 366.1816
Scheme 2.Proposed Catalytic Cycle
of
the Domino Aza-Michael ÀMannich Reaction
Figure 1.X-ray structure of 4n .
[M+MeOH+H]+,calcd for C21H24N3O3,366.1818.The enantio-meric excess was determined by HPLC analysis of the corresponding alcohol(after treatment with NaBH4)using a Daicel Chiralpak OD-H column,hexane(0.1%TEA)/i-PrOH=9:1,flow rate=1.0mL/min:t r= 12.3min(major)and t r=28.3min(minor).
(5S,6S,7R)-5-(3-Chlorophenyl)-7-phenyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidine-6-carbaldehyde(3d).The title com-pound was obtained using the general procedure described above,in60% yield and99%ee:[R]20D=+36.3(c=1.00in CH2Cl2);1H NMR(400 MHz,CDCl3,ppm)δ9.23(d,J=1.6Hz,1H),7.50À7.47(m,2H), 7.46À7.30(m,3H),7.30À7.20(m,2H),7.19(s,1H),7.12À7.08(m,1H), 6.50(d,J=1.6Hz,1H),6.10(d,J=1.6Hz,1H),5.89(br s,1H),5.46(d, J=10.0Hz,1H),4.61(d,J=10.0Hz,1H),3.50(ddd,J=1.6Hz,J=10.0 Hz,J=10.0Hz,1H);13C NMR(125MHz,CDCl3,ppm)δ199.6,148.2, 140.2,137.1,134.8,130.1,129.09,129.07,129.0,127.7,127.4,125.0,124.0, 112.6,60.1,57.2,57.0;HR-MS(
ESI)m/z370.1323[M+MeOH+H]+, calcd for C20H21N3O2Cl,370.1322.The enantiomeric excess was deter-mined by HPLC analysis of the corresponding alcohol(after treatment with NaBH4)using a Daicel Chiralpak OD-H column,hexane(0.1%TEA)/ i-PrOH=9:1,flow rate=1.0mL/min:t r=9.6min(major)and t r=37.8 min(minor).
(5S,6S,7R)-5-(3-Bromophenyl)-7-phenyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidine-6-carbaldehyde(3e).The title com-pound was obtained using the general procedure described above,in 68%yield and>99%ee:[R]20D=+36.2(c=1.00in CH2Cl2);1H NMR (400MHz,CDCl3,ppm)δ9.23(d,J=1.2Hz,1H),7.50À7.45(m,2H), 7.42À7.26(m,5H),7.20À7.10(m,2H),6.21(s,1H),6.01(d,J=1.6Hz, 1H),5.42(d,J=9.6Hz,1H),4.58(d,J=10.0Hz,1H),3.48(ddd,J=1.2 Hz,J=9.6Hz,J=10.0Hz,1H);13C NMR(125MHz,CDCl3,ppm)δ199.8,148.6,140.9,137.4,131.8,130.6,130.4,129.1,129.0,127.5,126.4, 124.9,122.9,112.4,60.5,57.4,57.0;HR-MS(ESI)m/z414.0822[M+ MeOH+H]+,calcd for C20H21N3O2Br,414.0817.The enantiomeric excess was determined by HPLC analysis of the corresponding alcohol (after treatment with NaBH4)using a Daicel Chiralpak OD-H column, hexane(0.1%TEA)/i-PrOH=9:1,flow rate=1.0mL/min:t r=10.2min (major)and t r=37.5min(minor).
(5S,6S,7R)-5-(3-Nitrophenyl)-7-phenyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidine-6-carbaldehyde(3f).
The title com-pound was obtained using the general procedure described above, in70%yield and99%ee:[R]20D=+9(c=1.00in CH2Cl2);1H NMR(400MHz,CDCl3,ppm)δ9.27(d,J=0.8Hz,1H),8.13À8.11 (m,1H),8.01(s,1H),7.52À7.38(m,4H),7.38À7.26(m,3H),6.28 (d,J=1.2Hz,1H),6.00(d,J=1.6Hz,1H),5.64(d,J=8.8Hz,1H),4.68 (d,J=8.8Hz,1H),3.53À3.48(m,1H);13C NMR(125MHz,CDCl3, ppm)δ199.2,148.6,148.4,141.1,137.2,133.6,129.2,129.0,127.3, 125.3,123.5,122.5,112.2,60.1,57.0,56.4;HR-MS(ESI)m/z381.1559 [M+MeOH+H]+,calcd for C20H21N4O4,381.1563.The enantio-meric excess was determined by HPLC analysis of the corresponding alcohol(after treatment with NaBH4)using a Daicel Chiralpak OD-H column,hexane(0.1%TEA)/i-PrOH=85:15,flow rate=0.8mL/min: t r=15.8min(major)and t r=44.7min(minor).
(5S,6S,7R)-7-Phenyl-5-p-tolyl-5,6,7,8-tetrahydroimidazo-[1,2-a]pyrimidine-6-carbaldehyde(3g).The title compound was obtained according to general procedure described above,in58%yield and99%ee:[R]20D=+44.8(c=1.00in CH2Cl2);1H NMR(400MHz, CDCl3,ppm)δ9.22(d,J=1.6Hz,1H),7.50À7.49(m,2H),7.48À7.26 (m,3H),7.20À7.05(m,4H),6.35(d,J=0.8Hz,1H),6.05(d,J=1.6 Hz,1H),5.38(d,J=10.0Hz,1H),4.61(d,J=10.4
Hz,1H),3.52(ddd, J=1.6Hz,J=10.0Hz,J=10.4Hz,1H),2.32(s,3H);13C NMR(125 MHz,CDCl3,ppm)δ200.3,148.3,138.7,137.7,135.1,129.6,129.1, 129.0,127.7,127.6,124.6,112.7,60.7,57.9,57.7,21.1;HR-MS(ESI) m/z350.1869[M+MeOH+H]+,calcd for C21H24N3O2,350.1869. The enantiomeric excess was determined by HPLC analysis of the corresponding alcohol(after treatment with NaBH4)using a Daicel Chiralpak OD-H column,hexane(0.1%TEA)/i-PrOH=9:1,flow rate= 1.0mL/min:t r=9.7min(major)and t r=20.3min(minor).
reactive carbonyl species(5S,6S,7R)-5-(4-Methoxyphenyl)-7-phenyl-5,6,7,8-tetra-hydroimidazo[1,2-a]pyrimidine-6-carbaldehyde(3h).The title compound was obtained using the general procedure described above,in54%yield and>99%ee:[R]20D=+50.0(c=1.00in CH2Cl2); 1H NMR(400MHz,CDCl
3
,ppm)δ9.23(d,J=1.2Hz,1H), 7.51À7.48(m,2H),7.40À7.30(m,3H),7.13(d,J=8.4,Hz,2H), 6.84(d,J=8.4,Hz,2H),6.24(s,1H),6.02(s,1H),5.35(d,J=10.4Hz, 1H),4.60(d,J=10.0Hz,1H),3.78(s,3H),3.49(ddd,J=1.2Hz,J= 10.0Hz,J=10.4Hz,1H);13C NMR(125MHz,CDCl3,ppm)δ200.4, 159.7,148.5,137.7,130.0,129.0,128.9,127.6,124.4,114.2,112.4,60.7, 57.6,55.2;HR-MS(ESI)m/z366.180
6[M+MeOH+H]+,calcd for C21H24N3O3,366.1818.The enantiomeric excess was determined by HPLC analysis of the corresponding alcohol(after treatment with NaBH4)using a Daicel Chiralpak OD-H column,hexane(0.1% TEA)/i-PrOH=9:1,flow rate=1.0mL/min:t r=16.6min(major) and t r=33.5min(minor).
(5S,6S,7R)-5-(4-Chlorophenyl)-7-phenyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidine-6-carbaldehyde(3i).The title com-pound was obtained according to general procedure described above,in 76%yield and98%ee:[R]20D=+47.8(c=1.00in CH2Cl2);1H NMR (400MHz,CDCl3,ppm)δ9.21(d,J=0.8Hz,1H),7.48À7.45(m,2H), 7.40À7.33(m,3H),7.29(d,J=8.4Hz,2H),7.13(d,J=8.4Hz,2H),6.38 (s,1H),6.04(s,1H),5.44(d,J=10.0Hz,1H),4.62(d,J=10.0Hz,1H), 3.49À3.44(m,1H);NMR(125MHz,CDCl3,ppm)δ199.7,148.1,137.0, 136.5,134.7,129.18,129.15,129.1,128.7,127.4,123.9,112.6,60.3,57.4, 57.1;HR-MS(ESI)m/z370.1316[M+MeOH+H]+,calcd for C20H21N3O2Cl,370.1322.The enantiomeric excess was determined by HPLC analysis of the corresponding alcohol(after treatment with NaBH4) using a Daicel Chiralpak OD-H column,hexane(0.1%TEA)/i-PrOH= 9:1,flow rate=1.0mL/min:t r=11.0min(major)and t r=31.3min (minor).
(5S,6S,7R)-5-(4-Bromophenyl)-7-phenyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidine-6-carbaldehyde(3j).The title com-pound was obtained using the general procedure described above,in 72%yield and98%ee:[R]20D=+64.4(c=1.00in CH2Cl2);1H NMR (400MHz,CDCl3,ppm)δ9.21(d,J=1.6Hz,1H),7.49À7.30(m,7H), 7.08(d,J=8.4Hz,2H),6.36(d,J=1.2Hz,1H),6.04(d,J=1.6Hz,1H), 5.43(d,J=10.0Hz,1H),4.59(d,J=10.0Hz,1H),3.47(ddd,J=1.6Hz, J=10.0Hz,J=10.0Hz,1H);13C NMR(125MHz,CDCl3,ppm)δ199.8,148.4,137.5,137.2,132.1,129.4,129.2,127.4,125.0,122.8,112.6, 60.7,57.6,57.2;HR-MS(ESI)m/z414.0809[M+MeOH+H]+,calcd for C20H21N3O2Br,414.0817.The enantiomeric excess was determined by HPLC analysis of the corresponding alcohol(after treatment with NaBH4) using a Daicel Chiralpak OD-H column,hexane(0.1%TEA)/i-PrOH= 9:1,flow rate=1.0mL/min:t r=12.1min(major)and t r=35.2min (minor).
(5S,6S,7R)-5-(4-Nitrophenyl)-7-phenyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidine-6-carbaldehyde(3k).The title com-pound was obtained using the general procedure described above,in 76%yield and>99%ee:[R]20D=+58.0(c=1.00in CH2Cl2);1H NMR(400MHz,CDCl3,ppm)δ9.25(d,J=0.8Hz,1H),8.11(d,J= 8.8Hz,1H),7.48À7.45(m,2H),7.39À7.26(m,5H),6.24(d,J= 1.6Hz,1H),5.99(d,J=1.6Hz,1H),5.63(d,J=9.2H
z,1H),4.63(d, J=9.2Hz,1H),3.45(ddd,J=0.8Hz,J=9.2Hz,J=9.2Hz,1H);13C NMR(125MHz,CDCl3,ppm)δ199.2,148.7,147.8,146.1,137.1, 129.2,129.1,128.6,127.3,125.3,124.0,112.3,60.3,57.4,56.5;HR-MS(ESI)m/z381.1554[M+MeOH+H]+,calcd for C20H21N4O4, 381.1563.The enantiomeric excess was determined by HPLC analysis of the corresponding alcohol(after treatment with NaBH4) using a Daicel Chiralpak OD-H column,hexane(0.1%TEA)/i-PrOH= 80:20,flow rate=0.8mL/min:t r=14.3min(major)and t r=33.7min (minor).
(5S ,6S ,7R )-5-(Benzo[d ][1,3]dioxol-5-yl)-7-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidine-6-carbaldehyde (3l).The
title compound was obtained using the general procedure described above,in 66%yield and 99%ee:[R ]20D =+66.8(c =1.00in CH 2Cl 2);1
H NMR (400MHz,CDCl 3,ppm)δ9.24(d,J =1.6Hz,1H),7.50À7.48(m,2H),7.42À7.28(m,3H),6.75À6.70(m,2H),6.65(s,1H),6.28(d,J =1.2Hz,1H),6.07(d,J =1.6Hz,1H),5.94(d,J =1.2Hz,2H),5.32(d,J =10.0Hz,1H),4.59(d,J =10.4Hz,1H),3.48(ddd,J =1.6Hz,J =10.0Hz,J =10.4Hz,1H);13C NMR (125MHz,CDCl 3,ppm)δ200.2,14
8.4,148.2,147.9,137.6,131.89,129.1,129.0,127.6,124.7,112.5,108.3,107.6,101.3,60.7,57.9,57.6;HR-MS (ESI)m /z 380.1597[M +MeOH +H]+,calcd for C 21H 22N 3O 4,380.1610.The enantiomeric excess was determined by HPLC analysis of the corresponding alcohol (after treatment with NaBH 4)using a Daicel Chiralpak OD-H column,hexane (0.1%TEA)/i -PrOH =9:1,flow rate =1.0mL/min:t r =19.8min (major)and t r =33.9min (minor).
(5S ,6S ,7R )-5-(Furan-2-yl)-7-phenyl-5,6,7,8-tetrahydroimi-dazo[1,2-a]pyrimidine-6-carbaldehyde (3m).The title com-pound was obtained using the general procedure described above,in 49%yield and 99%ee:[R ]20D =+52.3(c =1.00in CH 2Cl 2);1H NMR (400MHz,CDCl 3,ppm)δ9.34(d,J =1.2Hz,1H),7.49À7.45(m,2H),7.40À7.26(m,4H),6.33À6.28(m,3H),6.24(d,J =1.6Hz,1H),5.51(d,J =10.0Hz,1H),4.64(d,J =9.6Hz,1H),3.77(ddd,J =1.2Hz,J =9.6Hz,J =10.0Hz,1H);13C NMR (125MHz,CDCl 3,ppm)δ199.5,149.2,147.5,143.2,137.6,129.0,128.9,127.4,124.7,112.1,110.5,110.0,57.2,55.9,51.0;HR-MS (ESI)m /z 326.1499[M +MeOH +H]+,calcd for C 18H 20N 3O 3,326.1505.The enantiomeric excess was determined by HPLC analysis of the corresponding alcohol (after treatment with NaBH 4)using a Daicel Chiralpak OD-H column,hexane (0.1%TEA)/i -PrOH =9:1,flow rate =1.0mL/min:t r =13.1min (major)and t r =40.5min (minor).
(5S ,6S ,7R )-7-Phenyl-5-(thiophen-2-yl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidine-6-carbaldehyde (3n).The title com-
pound was obtained using the general procedure described above,in 42%yield and 99%ee:[R ]20D =+41.9(c =1.00in CH 2Cl 2);1H NMR (400MHz,CDCl 3,ppm)δ9.29(d,J =1.6Hz,1H),7.52À7.45(m,2H),7.42À7.32(m,3H),7.32À7.26(m,1H),7.05À7.04(m,1H),6.95À6.92(m,1H),6.30(d,J =1.6Hz,1H),6.20(d,J =1.6Hz,1H),5.72(d,J =10.4Hz,1H),4.60(d,J =10.0Hz,1H),3.61(ddd,J =1.2Hz,J =10.0Hz,J =10.4Hz,1H);13C NMR (125MHz,CDCl 3,ppm)δ199.8,147.8,140.6,137.4,129.1,127.9,127.6,126.8,126.5,124.7,112.4,60.7,57.8,53.6;HR-MS (ESI)m /z 342.1263[M +MeOH +H]+,calcd for C 18H 20N 3O 2S,342.1276.The enantiomeric excess was determined by HPLC analysis of the corresponding alcohol (after treatment with NaBH 4)using a Daicel Chiralpak OD-H column,hexane (0.1%TEA)/i -PrOH =9:1,flow rate =1.0mL/min:t r =12.7min (major)and t r =27.0min (minor).
(5S ,6S ,7R )-5-(4-Chlorophenyl)-7-(4-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidine-6-carbaldehyde (3o).
The title compound was obtained using the general procedure de-scribed above,in 60%yield and 98%
ee:[R ]20D =+28.6(c =1.00in CH 2Cl 2);1H NMR (400MHz,CDCl 3,ppm)δ9.22(d,J =1.6Hz,1H),7.39(d,J =8.8Hz,2H),7.30(d,J =8.4Hz,2H),7.15(d,J =8.8Hz,2H),6.91(d,J =8.8Hz,2H),6.38(d,J =1.6Hz,1H),6.03(d,J =1.2Hz,1H),5.43(d,J =10Hz,1H),4.54(d,J =10.0Hz,1H),3.80(s,3H),3.43(ddd,J =1.6Hz,J =10.0Hz,J =10.0Hz,1H);13C NMR (125MHz,CDCl 3,ppm)δ200.0,160.1,148.5,137.0,134.6,129.1,128.6,125.1,114.5,112.6,60.9,57.2,57.1,55.3;HR-MS (ESI)m /z 400.1422[M +MeOH +H]+,calcd for C 21H 23N 3O 3Cl,400.1428.The enantiomeric excess was determined by HPLC analysis of the corresponding alcohol (after treatment with NaBH 4)using a Daicel Chiralpak OD-H column,hexane (0.1%TEA)/i -PrOH =9:1,flow rate =1.0mL/min:t r =20.3min (major)and t r =47.0min (minor).
(5S ,6S ,7R )-7-(4-Methoxyphenyl)-5-(4-nitrophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidine-6-carbaldehyde (3p).
The title compound was obtained using the general procedure described above,in 62%yield and 97%ee:[R ]20D =+57.4(c =1.00in CH 2Cl 2);1H NMR (400MHz,CDCl 3,ppm)δ9.23(d,J =0.8Hz,1H),8.15(d,J =8.8Hz,2H),7.39(d,J =8.8Hz,2H),7.34(d,J =8.8Hz,2H),6.89(d,J =8.8Hz,2H),6.31(d,J =1.6Hz,1H),5.99(d,J =1.2Hz,1H),5.62(d,J =9.6Hz,1H),4.57(d,J =9.6Hz,1H),3.79(s,3H),3.44(ddd,J =0.8Hz,J =9.6Hz,J =9.6Hz,1H);13C NMR (125MHz,CDCl 3,ppm)δ1
99.4,160.2,148.8,146.1,128.8,128.7,128.5,125.4,124.0,114.5,112.3,60.7,56.8,56.6,55.3;HR-MS (ESI)m /z 411.1656[M +MeOH +H]+,calcd for C 21H 23N 4O 5,411.1668.The enantiomeric excess was determined by HPLC analysis of the corresponding alcohol (after treatment with NaBH 4)using a Daicel Chiralpak OD-H column,hexane (0.1%TEA)/i -PrOH =80:20,flow rate =0.8mL/min:t r =19.7min (major)and t r =40.0min (minor).
(5S ,6S ,7R )-5-Phenyl-7-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidine-6-carbaldehyde (3q).
The title compound was obtained using the general procedure described above,in 85%yield and 99%ee:[R ]20D =+13.7(c =1.00in CH 2Cl 2);1H NMR (400MHz,CDCl 3,ppm)δ9.29(d,J =1.6Hz,1H),7.62À7.60(m,4H),7.32À7.26(m,3H),7.17À7.14(m,2H),6.19(d,J =1.6Hz,1H),6.05(d,J =1.2Hz,1H),5.41(d,J =9.6Hz,1H),4.77(d,J =9.6Hz,1H),3.53(ddd,J =1.2Hz,J =9.6Hz,J =9.6Hz,1H);13C NMR (125MHz,CDCl 3,ppm)δ199.7,148.2,142.0,137.7,131.0(q,J C ÀF =32.5Hz),129.0,128.9,128.0,127.5,127.0,125.9,125.8,124.4,123.8(q,J C ÀF =271.0Hz),112.7,60.2,58.0,56.7;HR-MS (ESI)m /z 404.1569[M +MeOH +H]+,calcd for C 21H 21F 3N 3O 2,404.1586.The enantiomeric excess was determined by HPLC analysis of the corresponding alcohol (after treatment with NaBH 4)using a Daicel Chiralpak OD-H column,hexane (0.1%TEA)/i -PrO
H =9:1,flow rate =1.0mL/min:t r =8.00min (major)and t r =33.2min (minor).
(5S ,6S ,7R )-5-Phenyl-7-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidine-6-carbaldehyde (3r).
The title compound was obtained using the general procedure described above,in 87%yield and 99%ee:[R ]20D =+21.1(c =1.00in CH 2Cl 2);1
H NMR (400MHz,CDCl 3,ppm)δ9.28(d,J =1.6Hz,1H),7.62(dd,J =8.4Hz,J =8.4Hz,4H),7.28(d,J =8.4Hz,2H),7.10(d,J =8.4Hz,2H),6.25(d,J =1.6Hz,1H),6.05(d,J =1.6Hz,1H),5.44(d,J =9.6Hz,1H),4.74(d,J =9.6Hz,1H),3.47(ddd,J =1.6Hz,J =9.6Hz,J =9.6Hz,1H);13C NMR (125MHz,CDCl 3,ppm)δ199.3,148.1,141.7,136.3,134.8,131.2(q,J C ÀF =36.3Hz),129.0,128.9,128.9,127.9,127.0,124.8,123.7(q,J C ÀF =276.0Hz),112.6,60.2,57.2,56.7;HR-MS (ESI)m /z 438.1192[M +MeOH +H]+,calcd for C 21H 20ClF 3N 3O 2,438.1196.The enantiomeric excess was determined by HPLC analysis of the corresponding alcohol (after treatment with NaBH 4)using a Daicel Chiralpak OD-H column,hexane (0.1%TEA)/i -PrOH =9:1,flow rate =1.0mL/min:t r =9.00min (major)and t r =30.7min (minor).
(5S ,6S ,7R )-5-Phenyl-7-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidine-6-carb
aldehyde (3s).
The title compound was obtained using the general procedure described above,in 75%yield and 99%ee:[R ]20D =+33.0(c =1.00in CH 2Cl 2);1H NMR (400MHz,CDCl 3,ppm)δ9.29(d,J =1.2Hz,1H),8.16(d,J =8.4Hz,2H),7.62(dd,J =8.4Hz,J =8.4Hz,4H),7.33(d,J =8.8Hz,2H),6.53(d,J =1.6Hz,1H),6.11(d,J =1.6Hz,1H),5.68(d,J =9.2Hz,1H),4.79(d,J =9.2Hz,1H),3.50(ddd,J =1.2Hz,J =9.2Hz,J =9.2Hz,1H);13C NMR (125MHz,CDCl 3,ppm)δ198.5,148.2,147.9,145.4,141.4,131.3(q,J C ÀF =32.5Hz),128.4,127.8,126.1,126.0,125.1,124.7,123.3(q,J C ÀF =270.0Hz),112.5,59.8,56.4,56.3;HR-MS (ESI)m /z 449.1422[M +MeOH +H]+,calcd for C 21H 20F 3N 4O 4,449.1437.The enantiomeric excess was determined by HPLC analysis of the corresponding alcohol (after treatment with NaBH 4)using a Daicel Chiralpak OD-H column,hexane (0.1%TEA)/i -PrOH =80:20,flow rate =0.8mL/min:t r =12.7min (major)and t r =26.1min (minor).
’ASSOCIATED CONTENT
b Supporting Information.Copies of CSP-HPLC chro-matograms,and1H and13C NMR spectra of the products,and X-ray crystallographi
c data of4n.This material is available free of charge via the Internet at
’AUTHOR INFORMATION
Corresponding Authors
*E-mail:zhao_junling@gibh.ac,hu_wenhui@gibh.ac.
’ACKNOWLEDGMENT
This work was supported by the Guangdong Natural Science Foundation(10251066302000000).Prof.Jinsong Liu is grate-fully acknowledged for X-ray structure determination.The authors also wish to thank Prof.Ke Ding for his assistance with HPLC analysis.
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