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耐士科技400-188-0725www.rysstech.comTetrahedron 70 (2014) 2738-2745 耐士科技400-188-0725www.rysstech.com2739 Contents lists available at ScienceDirect Tetrahedron Tetrahedron ELSEVIER journal ho mepage：www.elsevier.com/locate/tet Formyl group activation of a bromopyrrole ester in Suzuki cross-coupling reactions： application to a formal synthesis of PolycitoneA and B and Polycitrin A John T. Gupton*， Nakul Telang， Michael Wormald， Kristin Lescalleet， Jon Patteson，Will Curry， Andrew Harrison， Megan Hoerrner， John Sobieski， Michael Kimmel，Emily Kluball， Thomas Perry Department of Chemistry， University of Richmond， Richmond， VA 23173， USA ARTICLEINFO Article history：Received 20 January 2014Received in revised form 25 February 2014Accepted 27 February 2014Available online 6 March 2014 Keywords：Suzuki cross-couplingPyrrole 1. Introduction For some time now our research group has been interestedusing vinylogous iminium salt derivatives as key building blocksfor the construction of highly functionalized pyrroles. These sub-stances have proven to be important precursors for the synthesis ofa variety of pyrrole-containing natural products such as the Poly-citones (1a and 1b)as indicated in Fig. 1. The interest by a variety ofinternational researchers to prepare such pyrrole-containing nat-ural products is driven by their significant biological activities suchas their inhibition of HIV-1 integrase， their cytotoxic activity againsta variety of cancer cell lines， and their multi-drug resistance re-versal activity. Consequently， a number of important reviewshaveappeared， which discuss the synthesis and specific modes of actionof many of these alkaloids alongwith their structure-activityrelationships.S. A partial example of our previously published approach to thesynthesis of the Polycitones is presented in Scheme 1 and involvesthe formation of a symmetrical vinamidinium salt (4)， followed bythe reaction of this salt with the appropriate a-aminocarbonylcompound (5) such that a 2，4-disubstituted pyrrole (6) is generated ( * C orresponding author. Tel. ： +1804 2 87 6 498； fax： + 1 8 04 287 1 8 97； e-mail address： jgu p ton@richmond.edu ( J.T. Gupton). ) 2， Polycitrin A Fig.1. Polycitone A (1a)， Polycitone B (1b)， and Polycitrin A (2). in good yield. This material (6) can be further functionalized to anintermediate (7) reported by Steglich’ and co-workers in the firstreported synthesis of the Polycitones. Although our approach to such natural products has providedvery effective transformations to the desired targets， the method-ology is limited by not having a single key intermediate， which canbe rapidly transformed into any of the desired pyrrole-containingnatural products. Since the primary difference between many of ( 0040-4020/$ - s e e front matter @ 2 014 Els e vier Ltd. All r i ghts reserved. http：//dx.doi.org/10.1016/ j .tet.20 1 4.02.091 ) J.T. Gupton et al./ Tetrahedron 70 (2014) 2738-2745 these targets involves the variation of the aromatic or hetero-aromatic groups attached to the pyrrole core， an ideal strategywould involve a key pyrrole-containing compound， which could berapidly functionalized with a variety of aromatic andhetero-aromatic groups. We have previously employedttheSuzuki-Miyaura cross-coupling methodology in some of our steps toprepare pyrrole-containing natural products but have not utilizedthis reaction as the core strategy. Reports by Furstner， Alvarez，Banwell， Handy， Langer， and Iwaoolldescribe the use of suchmethodology but usually the pyrrole nitrogen is substituted whengood yields are obtained. When the nitrogen has been unsub-stituted， poor to modest yields are usually the result and the ob-vious implication is thatsuchpyrrole based cross-couplingreactions work much better when nitrogen is substituted. In ourpreviously mentioned Suzuki-Miyaura cross-coupling work， wehave noticed that good yields are also obtained for nitrogenunsubstituted， brominated pyrroles， when the bromine is ortho toan ester group. When a typical substrate contains bromine， which isconjugatedto iaB-electron withdrawing group， the Suzu-ki-Miyaura cross-coupling reaction is normally facilitated. Conse-quently， it appears that the presence of an electron-withdrawinggroup ortho to the halogen is a more significant factor in the successof the cross-coupling reaction than having the pyrrole nitrogenprotected in some manner. This also suggests that a variety of otherelectron-withdrawing groups attached to a pyrrole carbon andortho to a bromine bearing carbon would produce a similar acti-vating effect. On this basis we now describe a general methodologyfor rapid construction of a variety of nitrogen unsubstituted， arylpyrroles from a single pyrrole building block that contains bromineat C-3 and a formyl group at C-2 of the pyrrole core. We also de-scribe the application of this methodology to the formal synthesisof Polycitone A and B and Polycitrin A (Fig.1). 2. Results and discussions Since many of the pyrrole-containing natural products possesscarbonyl substitution at C-2 and/or C-5 of the pyrrole core， we de-cided to examine ethyl 3-bromo-2-formylpyrrole-5-carboxylate(9)as our ‘potential pyrrole core building block. The regiospecificpreparation of ethyl 4-bromopyrrole-2-carboxylate (8) from 2-trichloroacetylpyrrole has been reported2in very good yield (90%) in two synthetic steps. Consequently， we have studied the for-mylation of ethyl 4-bromopyrrole-2-carboxylate (8) using Vils-meier-Haack-Arnold conditionsand our results are summarizedin iTable 1 (Scheme2)The results suggest that the reaction isvery solvent-dependent and very good yields of ethyl 3-bromo-2-formylpyrrole-5-carboxylate (9) are obtained at room temperature，when conducted in chlorinated solvents. Interestingly， we could notdetect any formylated product when the reaction was run in DMF.This three-step synthetic process can be easily scaled up such thatmulti-gram quantities of the ethyl 3-bromo-2-formylpyrrole-5-carboxylate (9) are easily accessed. It should be noted that thecrude formylated product is usually very pure and can be employedin subsequent steps without any detrimental effect. Table1Formylation of ethyl 4-bromopyrrole-2-carboxylate Entry Solvent Ratio of POCls to DMF % Yield via HPLC % Yield isolated 1 CH2Cl2 2.0：2.5 82 81 2 CHCl3 2.0：2.5 79 80 3 CH3CCl3 2.0：2.5 67 56 4 DMF 2.0：2.5 0 NI 5 THF 2.0：2.5 0 NI 6 CH2Cl2 3.0：3.5 87 86 NI-not isolated； HPLC analyses were carried out on a Waters Alliance 2695 in-strument with an Inertsil ODS-2 column using a 1：1 methanol/acetonitrile eluant ata flow rate of 0.25 mL per minute. Scheme 2. Formylation of ethyl 4-bromopyrrole-2-carboxylate. With substantial amounts of ethyl 3-bromo-2-formylpyrrole-5-carboxylate (9) in hand we next examined a variety of Suzu-ki-Miyaura cross-coupling reaction conditions. Potassium 4-methylphenyltrifluoroborate was utilized as the cross-coupling partner in our initial studies and the results are reported in Table 2(Scheme 3). Several different solvents were evaluated (entries 1-4，Table 2) and very little difference in product yield and purity wasnoted. As a result， we decided to stick with the toluene/ethanol mix，which we have utilized previously in other Suzuki-Miyaura cross- Table 2 Evaluation of solvent， base， and catalyst in the Suzuki cross-coupling reaction ofethyl 3-bromo-2-formylpyrrole-5-carboxylate with potassium 4-methylphenyltrifluoroborate Entry Solvent Base Catalyst % Yield via HPLC (isolated) 1 Toluene/EtOH DIPEA Pd(PPh3)4 86 2 THF DIPEA Pd(PPh3)4 86 3 CH3CN DIPEA Pd(PPh3)4 86 4 EtOH DIPEA Pd(PPh3)4 86 5 Toluene/EtOH CS2CO3 Pd(PPh3)4 72 6 Toluene/EtOH K2CO3 Pd(PPh3)4 73 7 Toluene/EtOH Na2CO3 Pd(PPh3)4 83 8 Toluene/EtOH DABCO Pd(PPh3)4 91 9 Toluene/EtOH DABCO Pd(OAc)2 84 10 Toluene/EtOH DABCO PdCl2 98 11 Toluene/EtOH DABCO PdDBA 53(42) 12 Toluene/EtOH DABCO PdCl2(PPh3)2 100 (89) 13 Toluene/EtOH DABCO PdDPPF(Cl)2 95 (99) HPLC analyses were carried out on a Waters Alliance 2695 instrument with anInertsil ODS-2 column using a 1：1 methanol/acetonitrile eluant at a flow rate of0.25 mL per minute. Scheme 3. Suzuki cross-coupling studiesof ethyl 3-bromo-2-formylpyrrole-5-carboxylate with potassium 4-methylphenyltrifluoroborate. coupling reactions. We next examined the use of several differentbases (entries 1 and 5-8， Table 2) and all the examples workedreasonably well but DABCO consistently gave better yields andcleaner cross-coupled products. Subsequently， a variety of palla-dium catalysts were evaluated (entries 8-13， Table 2) with dichloro[1，1'-bis-(diphenylphosphino)-ferrocene]palladium(II) dichloro-methane adduct [PdDPPF(Cl)2] giving the cleanest reaction prod-ucts in very high yield. The dichloro-(bistriphenylphosphine)palladium(II) catalyst also proved quite effective. The rationale forthe success of these particular catalysts is not obvious at this point.The last optimization parameter that we decided to look at wasstoichiometry (Table 3 and Scheme 4). Various concentrations ofcatalysts were evaluated and no discernable differences in productyield or purity were observed. It was decided to utilize a 5 mol %concentration of the PdDPPFCl2 for standard reaction conditions.When the quantities of base and boronic acid derivative wereevaluated， the best yields and product purity were realized(entry 5，Table 3) when a slight excess of each reagent was used. Following the completion of our optimization studies， we nextturned our attention to examine the scope and limitation of our‘formyl group activation methodology' and several boronic acidderivatives were studied and the results are presented in Table 4. Table 3 Optimization of Suzuki cross-coupling reaction stoichiometry of ethyl 3-bromo-2-formylpyrrole-5-carboxylate with potassium 4-methylphenyltrifluoroborate Entry Catalyst DABCO Trifluoroborate % Yield via HPLC equivalents equivalents equivalents (isolated) 1 0.01 2.0 1.3 98 2 0.05 2.0 1.3 95(99) 3 0.10 2.0 1.3 100 4 0.05 1.0 1.3 83 5 0.05 1.4 1.2 99(99) 6 0.05 3.0 1.3 90 7 0.05 2.0 1.0 79 8 0.05 2.0 1.6 72 9 0.05 2.0 2.0 64 HPLC analyses were carried out on a Waters Alliance 2695 instrument with1 anInertsil ODS-2 column using a 1：1 methanol/acetonitrile eluant at a flow rate of0.25 mL per minute. Scheme 4. Optimization of the stoichiometry for the Suzuki cross-coupling reaction ofethyl 3-bromo-2-formylpyrrole-5-carboxylatewithpotassium4-methylphenyltrifluoroborate. Oxygenated phenyl groups were examined (entries 2， 4， 5， 9，11， and12 Table 4)， since this functionality is most often present in thevarious pyrrole-containing marine natural products.These cross-coupling agents gave very good yields and product purities. In anoverallsense， the variously substituted aryl groups produced veryrespectable yields and the lower yields in a couple of instances mayhave been due to physical losses during the purification process. Table 4 Reactions of various aryl and heteroaryl boronic acid derivatives with ethyl 3-bromo-2-formylpyrrole-5-carboxylate under Suzuki cross-coupling conditions Entry Compound Ar % Yield isolated 4-MePh 2 4-MeOPh 3 4-ClPh 3，4-(MeO)2Ph 3，4，5-(MeO)3Ph Ph 4-MeSPh 4-FPh Benzo(3，4)dioxolyl 3，4-(Cl)2Ph 51 (69) 9 4-HOPh 4-CF3OPh 96° N-Phenylsulfonyl-3-indolyl 55 These reactions utilized the corresponding boronic acids. All other reactionsutilized the corresponding trifluoroborate. The N-phenylsulfonyl-3-indolyl group (entry 13， Table 4) waschosen to study as a consequence of its presence 4 in several im-portant， pyrrole-containing natural products (Scheme 5). In addition to the studies that we have described， it was de-cided to demonstrate the flexibility of the methodology by pre-paring isomeric 3，4-diarylpyrroles. Since the actual pyrrolestarting materials (10 and 12， Scheme 6) were derived from ethyl3-bromo-2-formylpyrrole-5-carboxylate (9)， the utility of thepyrrole building block is thereby extended. Bromination of both MeO Scheme 5. Suzuki cross-coupling reactions of ethyl 3-bromo-2-formylpyrrole-5-carboxylate with various aryl and heteroaryl boronic acid derivatives. pyrroles (10 and 12， Scheme 6) generated the corresponding 3-bromopyrroles (24 and 27， Scheme 6) in very good yields (97%and 83%). Subsequently， applying our optimized cross-couplingconditions to these brominated pyrroles produced the corre-sponding 3-aryl cross-coupled analogs (25 and 28， Scheme 6) ingood yields (68% and 77%) as well. The ultimate application of the ‘formyl group activation’is toutilize the methodology for the construction of one of the pyrrole-containing marine natural products as suggested earlier. PolycitoneA， Polycitone B， and Polycitrin A (Fig.1) were chosen as the initialtargets. Steglich5.15 and co-workers have utilized a tetrasubstitutedsymmetrical pyrrole (31) as a key precursor to all three naturalproducts (1a，1b， and 2， Fig.1) and therefore a synthesis (Scheme 7)of this material (31) would constitute a formal synthesis of Polycitone A， Polycitone B， and Polycitrin A. Key Steglich Precursor Scheme 7. Formal synthesis of Polycitone A， Polycitone B， and Polycitrin A. Scheme 6. Selective preparation of isomeric 3，4-diarylpyrroles via formyl group activation. Cross-coupling of pyrrole 277with potassium 4-methoxytrifluoroborate (26) under optimized conditions produced a tetra-substituted pyrrole (29) in 72% yield. Oxidation of the cross-coupled product (29) with sodium chlorite in aqueous DMSO pro-duced the pyrrole monoacid (30) in 90% yield and subsequent hy-drolysis of this material under basic conditions gave the Steglichsynthon5.15 (31) in 75% yield. This sequence represents a five-stepprocess from ethyl 3-bromo-2-formylpyrrole-5-carboxylate (9) inan overall yield of 42%. 3. Conclusions In this article we have described the preparation of a very flexiblepyrrole synthon [ethyl 3-bromo-2-formylpyrrole-5-carboxylate(9)]， which can undergo Suzuki-Miyaura cross-coupling with a variety of boronic acid derivatives in good yield. This methodologyallows for the convenient and efficient construction of various typesof tetrasubstituted-3，4-diarylpyrroles including regioisomers. Thecompletion of a short， formal synthesis of Polycitone A， Polycitone B，and Polycitrin A is also described. This methodology should provevery useful for the synthesis of libraries of highly functionalizedpyrroles as a part of detailed SAR studies. 4. Experimental 4.1. General All chemicals were used as received from the manufacturer(Aldrich Chemicals and Fisher Scientific). All solvents were driedover 4 A molecular sieves prior to their use. NMR spectra were obtained on either a Bruker 300 MHz spectrometer， or a Bruker500 MHz spectrometer in either CDCl3， DMSO-d6， or acetone-d6solutions. IR spectra were recorded on a Nicolet Avatar 320 FT-IRspectrometer with an HATR attachment. High-resolution massspectra were obtained on a Shimadzu IT-TOF mass spectrometer atthe University of Richmond. Low-resolution GC-MS spectra wereobtained on a Shimadzu QP 5050 instrument. Melting points andboiling points are uncorrected.Chromatographic purifications werecarried out on a Biotage SP-1 instrument or a Biotage Isolera in-strument (both equipped with a silica cartridge). Gradient elutionwith ethyl acetate/hexane was accomplished in both instances. Thereaction products were normally eluted within the range of 4-8column volumes of eluant with a gradient mixture of 60：40 ethylacetate/hexane. TLC analyses were conducted on silica plates withhexane/ethyl acetate as the eluant. All purified reaction productsgave TLC results， flash chromatograms， and 13c NMR spectra con-sistent with a sample purity of>95%. 4.1.2. Ethyl 2-formyl-3-(4-methylphenylpyrrole)-5-carboxylate(10). Into a 20 mL microwave reaction tube was placed a mag-neticcstirbar， ethyl3-bromo-2-formylpyrrole-5-carboxylate(0.250 g， 1.02 mmol)， potassium 4-methylphenyltrifluoroborate(0.255 g， 1.32 mmol)，and DABCO (0.229 g，2.04 mmol). A mixtureof 3：1 toluene/ethanol (12 mL) was added to the microwave re-action tube along with 20 drops of water. After stirring for severalminutes， dichloro[1，1'-bis-(diphenylphosphino)ferrocene]palladiu-m(II) dichloromethane adduct (0.037 g， 0.051mmol) was added tothe reaction mixture and the tube was capped and sealed witha crimping tool. The reaction mixture was heated in a Biotage Ini-tiator microwave system for 2 h at 110°C. After cooling to roomtemperature，the reaction mixture was filtered through a short plugof silica gel and the silica was subsequently washed with 2×30 mLof ethyl acetate and the combined organic materials were con-centrated in vacuo to give a dark solid (0.260 g， 99% yield). Thismaterial was quite pure by TLC and HPLC analysis but an analyticalsample was prepared by flash chromatography on a Biotage Isolerasystem in which case a light colored solid was obtained. We havepreviously describedthe synthesis of this substance by a differentsynthetic route and the spectral properties exhibited by this re-action product were identical to those reported earlier： H NMR(CDCl3)8 9.78 (s，1H)， 7.40 (d，J=8.1 Hz， 2H)， 7.29(d，J=8.1 Hz， 2H)，7.02 (d，J=2.4Hz，1H)， 4.41 (q，J=7.2Hz， 2H)， 2.43 (s， 3H)， and 1.42 (t， J=7.2 Hz， 3H). It should be noted that a control experiment was runon 4-bromo-2-carbethoxypyrrole (the compound minus the 2-formyl group) under conditions as described above in which casea gross mixture of products was obtained. 4.1.3. Ethyl 2-formyl-3-(4-methoxyphenylpyrrole)-5-carboxylate(12). This material was prepared in a manner identical to theprevious example with the exceptions that diisopropylethylamine(DIPEA) was used as the base instead of DABCO and tetrakis(-triphenylphosphine)palladium (0) was used as the catalyst andpotassium 4-methoxyphenyltrifluoroborate was used as the cou-pling agent. Work up of the reaction mixture produced a dark solid，which was purified by flash chromatography on a Biotage Isolerasystem in which case a light colored solid was obtained (0.280g72% yield). We have previously described the synthesis of thissubstance by a different synthetic route and the spectral propertiesexhibited by this reaction product were identical to those reportedearlier： H NMR (CDCl3) 9.76 (s， 1H)， 7.43 (d，J=9.0 Hz， 2H)，7.00-7.02 (m， 3H)， 4.41 (q，J=6.9 Hz， 2H)， 3.88 (s， 3H)， and 1.42 (t，J=6.9 Hz， 3H). 4.1.4.Ethyl 2-formyl-3-(4-chlorophenylpyrrole)-5-carboxylate(13). This material was prepared in a manner identical to thepreviousexample with the： exceptionthat potassium 44-chlorophenyltrifluoroboratewas tused assthe coupling agent.Work up of the reaction mixture produced a dark solid， which waspurified by flash chromatography on a Biotage Isolera system inwhich case a light colored solid was obtained (0.116 g， 69% yield).We have previously described3 the synthesis of this substance bya different synthetic route and the spectral properties exhibited bythis reaction product were identical to those reported earlier： 1HNMR (CDCl3)09.76(s，1H)， 7.45 (d，J=8.5 Hz， 2H)， 7.44 (d，J=8.5 Hz，2H)， 7.02(d，J=2.9 Hz，1H)， 4.42 (q，J=7.2 Hz， 2H)， and 1.42 (t，J=7.2 Hz，3H) 4.1.5. Ethyl 2-formyl-3-(3，4-dimethoxyphenylpyrrole)-5-carboxylate(14). This material was prepared in a manner identical to the pre-viousexample withtheeexceptionthatpotassium 3，4-dimethoxyphenyltrifluoroborate was used as the coupling agent.Work up of the reaction mixture produced a dark solid， which waspurified by flash chromatography on a Biotage Isolera system inwhich case a light colored solid was obtained (0.300 g， 70% yield).We have previously described3 the synthesis of this substance bya different synthetic route and the spectral properties exhibited bythis reaction product were identical to those reported earlier： HNMR(CDCl3)；9.79(s，1H)，7.04(dd，J=2.0，8.5 Hz，1H). 7.00-7.02(m，3H)， 4.42 (q，J=7.2 Hz， 2H)， 3.95 (s， 6H)， and 1.42 (t，J=7.2 Hz， 3H). 4.1.6. Ethyl 2-formyl-3-(3，4，5-trimethoxyphenylpyrrole)-5-carboxylate (15). This material was prepared in a manner identi-cal to the previous example with the exception that potassium3，4，5-trimethoxyphenyltrifluoroborate was used as the couplingagent. Work up of the reaction mixture produced a dark solid，which was purified by flash chromatography on a Biotage Isolerasystem in which case a light colored solid was obtained (0.110 g，64%yield). We have previously described the synthesis of thissubstance by a different synthetic route and the spectral propertiesexhibited by this reaction product were identical to those reportedearlier：HNMR(CDCl3)69.82 (s，1H)， 7.28 (d，J=2.4Hz， 1H)， 6.68 (s，2H)， 4.40 (q，J=6.9 Hz， 2H)， 3.91 (s，6H)， 3.90 (s， 3H)， and 1.41 (t，J=6.9 Hz，3H). 4.1.7. Ethyl 2-formyl-3-phenylpyrrole-5-carboxylate (16). This ma-terial was prepared in a manner identical to the previous examplewith the exception that potassium phenyltrifluoroborate was usedas the coupling agent. Work up of the reaction mixture produced a dark solid， which was purified by flash chromatography ona Biotage Isolera system in which case a light colored solid wasobtained (0.256g， 78% yield). We have previously describedthesynthesis of this substance by a different synthetic route and thespectral properties exhibited by this reaction product were iden-tical to those reported earlier： 1H NMR (acetone-d6) 9.83 (s， 1H)，7.63 (d，J=7.5 Hz， 2H)， 7.49 (t，J=7.5 Hz， 2H)， 7.42 (t，J=7.5 Hz，1H)，7.07(s，1H)， 4.38 (q，J=7.5 Hz， 2H)， and 1.38 (t，J=7.5 Hz， 3H). 4.1.8. Ethyl 2-formyl-3-(4-methylthiophenylpyrrole)-5-carboxylate(17). This material was prepared in a manner identical to theprevious example with the exception that DABCO was used as thebase. dichloro[1，1'-bis-(diphenylphosphino)ferrocene]palladiu-m(II) dichloromethane adduct was used as the catalyst， and po-tassium 4-methylthiophenyltrifluoroborate wasused as thecoupling agent. Work up of the reaction mixture produced a darksolid， which was purified by flash chromatography on a BiotageIsolera system in which case a light colored solid was obtained(0.184 g， 63% yield)， which exhibited the following physical prop-erties： mp 123-124 °C；1H NMR (CDCl3) 9.78 (s， 1H)， 7.42 (d，J=8.4 Hz， 2H)， 7.35 (d，J=8.4 Hz，2H)，7.02(d，J=2.7Hz， 1H)， 4.42(q，J=7.2 Hz， 2H)， 2.55 (s， 3H)， and 1.42 (t， J=7.2 Hz， 3H)； 13c NMR(CDCl3) 8 180.7，160.3，139.1，135.5，130.2，129.4，129.2，127.8，126.6，115.2， 61.5， 15.6， and 14.3； IR (neat) 1701 and 1685 cm-1；HRMS (ES，M+H)m/z calcd for C15H16NO3S 290.0851， found 290.0837. 4.1.10. Ethyl 2-formyl-3-[benzo(3，4)dioxolylpyrrole]-5-carboxylate(19). This material was prepared in a manner identical to theprevious example with the exception that potassium benzo[1，3]dioxolyltrifluorofluoroborate was used as the coupling agent. Workup of the reaction mixture produced a dark solid (0.300 g， 99%yield). This material was quite pure by TLC and HPLC and was notpurified further. This material exhibited the following physicalproperties： mp 140-141 °C；HNMR(acetone-d6)09.81 (s，1H)， 7.15(d，J=1.5 Hz， 1H)， 7.10 (dd，J=1.5， 8.0 Hz， 1H)， 7.01 (s， 1H)， 6.95 (d，J=8.0 Hz， 1H)， 6.08 (s， 2H)， 4.36 (q，J=7.0 Hz， 2H)， and 1.37 (t，J=7.0 Hz， 3H)； 13c NMR (acetone-d6) 6 180.1，159.9，148.2，147.7，134.6，130.6，127.7，127.0，123.0，115.0，109.3，108.4，101.4， 60.7， and13.6； IR (neat) 1704 and 1644 cm-1； HRMS (ES，M+H) m/z calcd forC15H14NO5 288.0872， found 288.0873. 4.1.11. Ethyl 2-formyl-3-(3，4-dichlorophenylpyrrole)-5-carboxylate(20). This material was prepared in a manner identical to theprevious example with the exception that 3，4-dichlorophenylboronic acid was used as the coupling agent. Workup of the reaction mixture produced a dark solid， which was pu-rified by flash chromatography on a Biotage Isolera system in whichcase a light colored solid was obtained (0.340 g， 90% yield) and thismaterialexhibitedthefollowing physicalproperties：mp160-161℃； 1H NMR (CDCl3) 9.77 (s， 1H)， 7.60 (d，J=2.1 Hz， 1H)，7.55 (d，J=8.1 Hz， 1H)， 7.33 (dd，J=2.1， 8.1 Hz， 1H)， 7.02 (d，J=2.4 Hz， 1H)， 4.42 (q， J=7.2 Hz， 2H)， and 1.42 (t， J=7.2 Hz， 3H)；13c NMR(CDCl3)； 179.9， 159.9， 133.2， 133.0，132.7，132.6，130.9，130.7，130.1，128.2， 127.9， 115.2， 61.6， and 14.3； IR (neat) 1717 and 1668 cm；HRMS (ES， M+H) m/z calcd for C14H12Cl2NO3 312.0194， found312.0182. 4.1.12. Ethyl 2-formyl-3-(4-hydroxyphenylpyrrole)-5-carboxylate(21). This material was prepared in a manner identical to theprevious examplee withtheieexception that potassium 4-hydroxyphenylboronic acid was used as the coupling agent. Workup of the reaction mixture produced a dark solid， which was pu-rified by flash chromatography on a Biotage Isolera system in whichcase a light colored solid was obtained (0.173 g， 66% yield) and thismaterial exhibited the following physicaltl properties：inmp158-159°C； 1H NMR (CDCl3) 6 9.76 (s，1H)， 7.38 (d，J=8.7 Hz，2H)，6.99 (d，J=2.7 Hz， 1H)， 6.94 (d，J=8.7 Hz， 2H)， 4.41 (q，J=7.2Hz， 2H)，and 1.42 (t， J=7.2 Hz， 3H)； 13C NMR (CDCl3) 6 180.7，160.3，155.9，135.8， 130.5，130.1，127.7，125.3，115.9，115.1，61.5，and 14.3； IR (neat)3254， 1701， and 1634 cm-1； HRMS (ES， M+H) m/z calcd forC14H14NO4 260.0923， found 260.0908. 4.1.13. Ethyl 2-formyl-3-(4-trifluoromethoxyphenylpyrrole)-5-carboxylate (22). This material was prepared in a manner identi-cal to the previous example with the exception that potassium 4-trifluoromethoxyphenylboronic acid wass used as the couplingagent. Work up of the reaction mixture produced a dark solid(0.320 g， 96% yield)， which did not require additional purification.This material exhibited the following physical properties： mp52-54℃；HNMR(CDCl3)89.77(s，1H)， 7.53(d，J=8.0 Hz，2H)， 7.33(d，J=8.0 Hz， 2H)， 7.03 (d，J=2.5 Hz，1H)， 4.42 (q，J=7.0 Hz，2H)， and1.43 (t，J=7.0 Hz，3H)；C NMR (CDCl3) 6 180.3，160.2，149.3，134.3，131.4， 130 4，130.2，127.8，121.4，120.5(q，J=251.6Hz)，115.3， 61.9，and14.3； IR (neat) 1718 and 1661 cm-1； HRMS (ES， M+H) m/z calcd forC15H13F3NO4328.0797， found 328.0796. 4.1.14. Ethyl 3-(1-benzenesulfonyl-1H-indol-3-yl)-2-formylpyrrole-5-carboxylate (23). This material was prepared in a manner iden-tical to the previous example with the exceptions that diisopro-pylethylamine (DIPEA) was used as the base instead of DABCO andpotassium 1-benzenesulfonyl-1H-indol-3-trifluoroborate was usedas the coupling agent. Work up of the reaction mixture produceda dark orange solid， which was purified by flash chromatography ona Biotage Isolera system in which case a bright orange solid wasobtained (0.470 g， 55% yield) and this material exhibited the fol-lowing physical properties： mp 164-166C；H NMR(CDCl3)6 9.94(s，1H)， 8.10(d，J=8.0 Hz，1H)， 7.97(d，J=8.5 Hz， 2H)， 7.70 (s，1H)， 7.65(d，J=8.0Hz， 1H)， 7.60 (t，J=8.5 Hz，1H)， 7.51 (t，J=8.5Hz， 2H)，7.44(t，J=8.5 Hz， 1H)， 7.36 (t，J=8.5 Hz， 1H)， 7.13 (d，J=3.0 Hz， 1H)， 4.43 (q，J=7.0 Hz， 2H)， and 1.43 (t， J=7.0 Hz， 3H)； 13c NMR (acetone-d6)； 179.8，159.8，137.9，135.1，134.5，131.7，130.0，129.7， 128.3，127.0，125.6， 125.3，124.2，124.0，120.3，115.6，115.0，113.7，60.8， and 13.7； IR(neat) 1714 and 1659 cm-1； HRMS (ES， M+H) m/z calcd forC22H18N205S 423.1009， found 423.1003. 4.1.15. Ethyl 4-bromo-2-formyl-3-(4-methoxyphenylpyrrole)-5-carboxylate (27). Into a 100 mL round bottom flask equippedwithmagnetic stirringgwassplaced ethyl 2-formyl-3-(4-methoxyphenylpyrrole)-5-carboxylate (0.140 g， 0.513 mmol)， po-tassium hydroxide (0.0575 g， 1.03 mmol) and 15 mL of DMF. Themixture was stirred for 15 min and N-bromosuccinimide (0.0913 g，0.513 mmol) was added to the reaction flask and the resulting re-action mixture was allowed to stir overnight at room temperature.The reaction mixture was subsequently quenched with 45 mL ofwater and extracted with ethyl acetate (3×20 mL). The combinedorganic phases were washed with a saturated， aqueous solution oflithium chloride and this was followed by drying the organic phase 耐士科技 www.rysstech.com 400-188-0725 over anhydrous sodium sulfate. The drying agent was removed byfiltration and the filtrate was concentrated in vacuo to give a solidproduct. This material was subjected to flash chromatography ona Biotage Isolera system with a hexane/ethyl acetate gradient inwhich case a tan solid (0.150 g， 83% yield) was obtained， whichexhibited the following physical properties： mp 132-134 C； 1HNMR (CDCl3) ； 9.55 (s，1H)， 7.41 (d，J=6.9 Hz， 2H)， 7.03 (d，J=6.9 Hz，2H)， 4.45 (q，J=7.0 Hz， 2H)， 3.89 (s， 3H)， and 1.45 (t， J=7.0 Hz， 3H)；13C NMR (CDCl3)ò 180.6， 160.1，159.3，135.5，131.8，129.8， 124.7，122.2，114.1，104.3，61.8，55.3， and 14.3； IR (neat) 1690 and1664 cm-1； HRMS (ES， M+H) m/z calcd for C15H15BrNO4 352.0184，found 352.0195. 4.1.16. Ethyl 4-bromo-2-formyl-3-(4-methylphenylpyrrole)-5-carboxylate (24). This material was prepared in a manner identi-cal to the previous example with the exception that 2-formyl-3-(4-methylphenylpyrrole)-5-carboxylate was used as the starting ma-terial for the reaction. The solid product (0.441 g， 97% yield) wassufficiently pure to be used in a subsequent reaction but an ana-lytical sample was prepared by flash chromatography on a BiotageIsolera system with a hexane/ethyl acetate gradient. The resultingpurified solid exhibited the following physical properties： mp125-127 °C； 1H NMR (CDCl3) 9.55 (s，1H)， 7.37 (d，J=8.1 Hz， 2H)，7.31 (d，J=8.1Hz，2H)，4.46(q，J=7.2Hz，2H)， 2.45 (s， 3H)， and 1.45 (t，J=7.2 Hz， 3H)； 13C NMR (CDCl3) 6 180.7， 162.6， 159.4， 135.7， 130.5，129.8，129.3，127.1，124.8，104.2，61.8， 21.3， and 14.3： IR (neat) 1690and 1659 cm-1； HRMS (ES， M+Na) m/z calcd for C15H14BrNNaO3358.0055， found 358.0057. 4.1.17. Ethyl 2-formyl-4-(4-methoxyphenyl)-3-(4-methylphenyl)pyrrole-5-carboxylate (25). Into a 20 mL microwave reaction tubeequipped with a magnetic stir bar was placed ethy! 4-bromo-2-formyl-3-(4-methylphenylpyrrole)-5-carboxylate (0.150 g，0.446 mmol)， potassium 4-methoxyphenyltrifluoroborate (0.124 g，0.580 mmol)，and DABCO (0.100 g， 0.892 mmol). A mixture (12 mL)of 3：1 of toluene/ethanol was added to the reaction tube along with20 drops of water followed by dichloro[1，1'-bis-(diphenylphos-phino)ferrocene]palladium(II) (dichloromethane adduct (0.016 g，0.022 mmol). The reaction tube was capped and sealed witha crimping tool and the reaction mixture was heated in a BiotageInitiator microwave system for 2 h at 110°C. After cooling to roomtemperature， the reaction mixture was filtered through a short plugof silica gel and the silica was subsequently washed with 2×30 mLof ethyl acetate and the combined organic materials were con-centrated in vacuo to give a dark solid. This material was subjectedto flash chromatography on a Biotage Isolera system with a hexane/ethyl acetate gradient in which case a tan solid (0.162 g， 68% yield)was obtained and exhibited the following physical properties： mp116-118C；1H NMR(CDCl3)69.62 (s，1H)， 7.12 (br d，J=8.7 Hz，4H)，7.05 (d，J=8.4 Hz， 2H)， 6.82 (d，J=9.0 Hz， 2H)， 4.28 (q，J=7.2 Hz， 2H)，3.81(s，3H)， 2.35 (s， 3H)， and 1.26 (t，J=7.2Hz， 3H)；13CNMR(CDCl3)； 181.4，160.3，158.8，137.5，135.1，131.9，130.5，130.4，129.9，129.1，128.4，124.6.123.8，113.1， 61.2，55.1，21.1，and 14.1： IR (neat) 1690 and1664 cm-1；HRMS(ES，M+Na)m/z calcd for C22H21NNaO4386.1368，found 386.1372. 4.1.18. Ethyl 2-formyl-3-(4-methoxyphenyl)-4-(4-methylphenyl)pyr-role-5-carboxylate (28)..This material was prepared in a manneridentical to the previous example with the exception that ethyl 4-bromo-2-formyl-3-(4-methoxyphenylpyrrole)-5-carboxylatee wasused as the startingImaterial and1potassium4-methylphenyltrifluoroborate was employed as the cross-coupling agent.After the standard work up and purification a tan solid (0.150 g， 77%yield) was obtained， which exhibited the following physical prop-erties： mp 130-131°C；1HNMR(CDCl3)69.62(s，1H)， 7.09-7.11(m，6H)， 6.83 (d，J=9.0 Hz，2H)， 4.27 (q，J=7.2 Hz， 2H)， 3.81 (s，3H)， 2.35 (s， 3H)， and 1.25 (t，J=7.2 Hz， 3H)； 13c NMR (CDCl3) 6 181.3，160.2，159.3，136.9， 134.8，131.8，130.6，129.8，129.3，128.3，123.9， 123.6，113.8， 61.1， 56.2， 21.6， and 14.0； IR (neat) 1704 and 1659 cm；HRMS (ES， M+Na) m/z calcd for C22H21NNa04 386.1368， found386.1382. 4.1.19. Ethyl 2-formyl-3，4-bis-(4-methoxyphenyl)pyrrole-5-carboxylate (29). This material was prepared in a manner identi-cal to the previous example with the exception that potassium 4-methoxyphenyltrifluoroborateewasemployeddastheecross-coupling agent. After the standard work up and purification a tansolid (0.232 g， 72% yield) was obtained， which exhibited the fol-lowing physical properties： mp 130-132°C； HNMR(CDCl3)89.62(s，1H)，7.08-7.14(m，4H)， 6.84(d，J=5.7 Hz， 2H)， 6.82 (d，J=5.7 Hz，2H)， 4.28 (q，J=7.2 Hz，2H)， 3.82 (s， 6H)， and 1.26 (t，J=7.2 Hz，3H)；c NMR (CDCl3) 181.5，160.3，159.3，158.8，134.8，131.9， 131.8，130.4，129.9，124.6，123.8，123.6，113.9，113.1， 61.1，55.2， 55.1， and 14.1；IR (neat) 1704 and 1655 cm-1； HRMS (ES，M+Na) m/z calcd forC22H21NNaO5 402.1317， found 402.1320. 4.1.20. 3，4-Bis-(4-methoxyphenyl)pyrrole-2，5-dicarboxylic acid mon-oethyl ester (30). Into a 20 mL microwave reaction tube equippedwith a magnetic stir bar was placed ethyl 2-formyl-3，4-bis-(4-methoxyphenyl)pyrrole-5-carboxylate (0.100 g， (0.264 mmol).DMSO (10 mL)， 0.050 M aqueous sodium dihydrogen phosphate(3mL)， and sodium chlorite monohydrate (0.143 g， 1.58 mmol). Thereaction tube was capped and sealed with a crimping tool and thereaction mixture was heated in a Biotage Initiator microwave systemfor 2 h at 60°C. The reaction mixture was cooled to room temper-ature， acidified with 6 M hydrochloric acid， diluted with 300 mL ofwater， and extracted with ethyl acetate (3×30 mL). The combinedorganic layers were washed with water， dried over anhydrous so-dium sulfate， filtered， and concentrated in vacuo to leave a tan solid(0.0940 g， 90% yield). This material was sufficiently pure to be usedin the next step and exhibited the following physical properties： mp259-260 ； 1H NMR (DMSO-d6) 6.97 (d，J=8.5 Hz， 2H)， 6.95 (d，y=8.5 Hz， 2H)， 6.74 (d，J=8.5 Hz， 4H)， 4.10 (q，J=7.2 Hz，2H)， 3.71 (s，6H)， and 1.13 (t， J=7.2 Hz， 3H)； 13C NMR (DMSO-d6) ； 162.0， 160.4，158.3，158.2，132.3，132.2，130.6，130.1，126.4，126.3，123.1，121.9，113.1，60.4，55.4，55.3， and 14.3； IR (neat) 1699 and 1659 cm-1；HRMS (ES，M+Na) m/z calcd for C22H21NNa06 418.1267， found 418.1252. 4.1.21. 3，4-Bis-(4-methoxyphenyl)pyrrole-2，5-dicarboxylic acid(31). Into a 100 mL round bottom flask equipped with magneticstirring and a reflux condenser was placed 3，4-bis-(4-methoxyphenyl)-pyrrole-2，5-dicarboxylic acid monoethyl ester (0.100 g，0.253 mmol)， potassium hydroxide (0.142 g， 2.53 mmol)， and 30 mLof a 1：1 mixture of ethanol/water. The reaction mixture wasrefluxed overnight， cooled to room temperature， and acidified topH 2 with 6M hydrochloric acid. The mixture was diluted with100 mL of water， extracted with ethyl acetate (3×30 mL)， and thecombined organic phases were washed with brine and dried overanhydrous sodium sulfate. The drying agent was removed by fil-tration and the filtrate was concentrated in vacuo to yield a solid(0.070g， 75% yield). This material exhibited spectral propertiesidentical to those reported by Steglich15 and co-workers： mp254-256C (lit. 268-270C)； 1H NMR (DMSO-d6) 6 6.96 (d，J=8.5 Hz， 4H)， 6.73 (d， J=8.5 Hz， 4H)， and 3.71 (S， 6H)； 13C NMR(DMSO-d6)6 161.9，158.2，132.2，130.2，126.5，122.6，113.1， and 55.3；IR (neat) 1659 cm-1； HRMS (ES， M+Na) m/z calcd for C20H17NNaO，390.0954， found 390.0947. Acknowledgements We gratefully thank the National Institutes of Health (grant no.R15-CA67236) for support of this research. Thanks also to the Floyd D. and Elisabeth S. Gottwald Endowment and to the University ofRichmond Faculty Research Grant program for support to J.T.G. Weare exceedingly grateful to Mr. Dave Patteson formerly of BiotageInc. for the generous donation of an SP-1 flash chromatographysystem， which was used in the majority of sample purifications. Weare also very appreciative of Advion Inc. for the generous donationof a CMS electrospray mass spectrometer. Previous grants from theMRI program of the National Science Foundation for the purchaseof a 500 MHz NMR spectrometer (CHE-0116492) and a high-reso-lution electrospray mass spectrometer (CHE-0320669) are alsogratefully acknowledged. References and notes 1. For a recent example see Gupton， J； Giglio， B.； Eaton，J； Rieck， L.； Smith， K.；Keough， M.； Barelli， P.； Firich， L.； Hempel， J； Smith， T.； Kanters， R. Tetrahedron2009，65，4283. 2.(a) Rudi， A.； Goldberg， I； Stein， Z.； Frolow， F； Benayahu， Y.； Schleyer， M.；Kashman， Y. J. Org. Chem. 1994， 59，999；(b) Rudi， A.； Evan， T； Aknin， M.；Kashman， Y. J. Nat. Prod. 2000， 63， 832. 3. For appropriate reviews see：(a) Handy，S.； Zhang， Y. Org. Prep. Proced. Int. 2005，37，411； (b) Fernandez， D.； Ahaidar， A.； Danelon， G.； Cironi， P.； Marfil， M.； Perez，O.； Cuevas， C.；Albericio， F.； Joule，J.； Alvarez， M. Monatsh. Chem. 2004，135，615； (c) Bailly， C. Curr. Med. Chem. Anti-Cancer Agents 2004， 363； (d) Gupton， J.Pyrrole Natural Products with Antitumor Properties InLee， M.， Ed.. HeterocyclicAntitumor Antibiotics：Topics in Heterocyclic Chemistry； Springer： Berlin/Hei-delberg， Germany， 2006； Vol. 2， p 53. 4.Gupton， J； Miller R.； Clough， S.； Krumpe， K.； Banner， E.； Kanters， R.； Du， K.；Keertikar， K.； Lauerman，N.； Solano，J；Adams， B.； Callahan， D.； Little， B.； Scharf，A.； Sikorski， J. Tetrahedron 2005， 61，1845. Kreipl， A.； Reid， c.； Steglich， W. Org. Lett. 2002，4，3287. Furstner，A.； Krause， H.； Thiel， O. Tetrahedron 2002， 58，6373. 7. Pla，D.；Marchal， A.； Olsen， C.； Albericio， F； Alavarez， M. J. Org. Chem. 2005， 70，8231. 8.(a) Banwell， M.； Bray， A.； Edwards， A.； Wong， D. J. Chem. Soc.， Perkin Trans. 12002， 1340； (b) Banwell， M.； Goodwin， T.； Ng， S.； Smith， J； Wong， D. Eur.J. Org.Chem. 2006，14，3043. ( 9. Ha ndy， S . ； Z h a ng， Y.； B regm a n， H . J . Org. Chem. 2 004， 69，2362. ) ( 10. S erge-Mit h erand， T.； Fatu n sin， O.； V i lli n ger， A.； L anger， P . T etrahedron Lett. 20 11 ， 52， 3 732. ) 11. Fukuda， T.； Sudo， E.； Shimokawa， K.； Iwao， M. Tetrahedron 2008，64，328. 12. Handy，S.； Bregman，H.； Lewis，J； Zhang，X.； Zhang， Y. Tetrahedron Lett. 2003，44，427. 13. Gupton， J； Banner， E.； Sartin， M.； Coppock， M.； Hempel， J； Kharlamova，A.；Fisher， D.； Giglio， B.； Smith， K.； Keough， M.； Smith， T.0.180； Kanters， R.； Dominey， R.；Sikorski， J. Tetrahedron 2008， 64， 5246. 14.(a) Frode， R.； Hinze， C.； Josten， I.； Schmidt， B.； Steffan， B.； Steglich， W. Tetrahe-dron Lett. 1994， 35，1689； (b)Hashimoto，T.；Yasuda， A.； Akawaza， K.； Takaoka， S.；Tori， M.；Asakawa， Y. Tetrahedron Lett. 1994， 35，2259 ww.rysstech.com耐士科技