DOI: 10.1002/adsc.201000199

Gold(I)-Catalyzed Cascade for Synthesis of Pyrrolo[1,2-a :2’,1’-c]-/PyridoACHTUNGTRENNUNG[2,1-c]pyrrolo ACHTUNGTRENNUNG[1,2-a]quinoxalinones

Yu Zhou,a,c Xun Ji,a,b,c Guannan Liu,a Dengyou Zhang,a Linxiang Zhao,b

Hualiang Jiang,a and Hong Liua,*a State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555

Zuchongzhi Road, Shanghai 201203, People�s Republic of ChinaFax: (+86) 21-5080-7042; phone: (+86) 21-5080-7042; e-mail : hliu@mail.shcnc.ac.cn

b School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, People�sRepublic of China

c These authors contributed equally to this work.

Received: March 15, 2010; Revised: April 26, 2010; Published online: July 7, 2010

Supporting information for this article is available on the WWW underhttp://dx.doi.org/10.1002/adsc.201000199.

Abstract: An efficient and convenient method wasdeveloped for the one-pot construction of the com-plex polycyclic heterocycles pyrrolo[1,2-a :2’,1’-c]-/pyrido ACHTUNGTRENNUNG[2,1-c]pyrrolo ACHTUNGTRENNUNG[1,2-a]quinoxalinones from twosimple starting materials via a gold(I)-catalyzeddomino reaction. This strategy presents an atom eco-nomical and environmentally friendly transforma-

tion, in which two new C�N bonds and one new C�C bond are formed in a one-pot reaction process.

Keywords: alkynes; aromatic amines; cascade reac-tions; gold catalysts; pyrrolo[1,2-a :2’,1’-c]-/pyrido-ACHTUNGTRENNUNG[2,1-c]pyrrolo ACHTUNGTRENNUNG[1,2-a]quinoxalinones

Introduction

Transition metal-catalyzed cascade reactions involvingthe one-pot formation or cleavage of multiple carbon-carbon and carbon-heteroatom bonds are useful forthe construction of polycyclic heterocycles owing tothe high synthetic efficiency, intriguing selectivity, andatom economy of these reactions.[1] In particular,gold-catalyzed cascade reactions have attracted con-siderable attention because of their ability to activatealkyne, alkene, and allene functionalities under mildconditions and at low catalyst loadings.[2] In recentyears, significant improvements have been made inthe cascade reactions catalyzed by gold complexes;however, most of the reported cascade sequences em-ployed an intramolecular ring-closing reaction with asingle starting material involving multiple functionalgroups strategically positioned along the chain and aterminal alkyne functionality.[2a,3c] The one-pot synthe-sis of complex fused polycyclic heterocycles via an in-termolecular union from multiple simple starting ma-terials remains a synthetic challenge.

Since polycyclic heterocycles are widely used in me-dicinal chemistry and are considered to be “privilegedstructures” in the pharmaceutical and agrochemical

industries, the development of new and effective tran-sition metal-catalyzed reactions for the synthesis offused heterocycles is being actively researched for ob-taining novel bioactive lead compounds.[4] To the bestof our knowledge, there is no report involving thesynthesis of the molecular scaffolds of pyrrolo[1,2-a :2’,1’-c]-/pyrido ACHTUNGTRENNUNG[2,1-c]pyrrolo ACHTUNGTRENNUNG[1,2-a]quinoxalinonesystems. Water, an environmentally friendly reactionmedium, has often an unprecedented effect on therate and selectivity of organic reactions through hy-drophobic interactions and the enrichment of organicsubstrates in the local hydrophobic environment.[1b,5]

As a part of our ongoing efforts to develop new con-venient and efficient strategies for the preparation ofpotential bioactive heterocycles with transition metalcatalysts,[3] we here present our findings on the syn-thesis of pyrrolo[1,2-a :2’,1’-c]-/pyrido ACHTUNGTRENNUNG[2,1-c]pyrrolo-ACHTUNGTRENNUNG[1,2-a]quinoxalinones via a gold-catalyzed one-potdomino process in aqueous medium (Scheme 1). Theadvantage of this chemical transformation is the for-mation of one new carbon-carbon bond and two newcarbon-nitrogen bonds to build the polycyclic hetero-cycles in a one-pot cascade reaction using aromaticprimary amines with low reactive potency as the start-ing materials.

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Results and Discussion

Initially, 2-(1H-pyrrol-1-yl)aniline (1A) and 4-pentyn-ACHTUNGTRENNUNGoic acid (2a) were chosen as model substrates for in-vestigating the optimum reaction conditions. As de-picted in Table 1, different gold catalysts such asAuBr3, AuCl ACHTUNGTRENNUNG(PPh3) and [Au{P ACHTUNGTRENNUNG(t-Bu)2(o-biphenyl)}-

ACHTUNGTRENNUNG{CH3CN}]SbF6 (Au1 catalyst) were tested at 100 8C for2 h in a sealed tube using H2O as the solvent. Amongthe catalysts tested, the Au1 catalyst was found to bethe most effective (Table 1, entries 1–3). However, thedesired product was not formed in the absence of agold catalyst, and only the starting materials were re-covered (Table 1, entry 4). Some Ag salts and proton-ic acids are usually used as co-catalysts along with thegold catalysts. Thus, to further increase the yield ofproducts, AgSbF6, AgBF4, AgNO3, AgO2CCF3,AgOAc, TFA and TsOH were investigated as co-cata-lyst, respectively. Better results were obtained in themost cases (Table 1, entries 5–11); in particular, withTFA as a co-catalyst, the product was formed in 96%yield after 2 h. The product yield could be further im-proved by lowering the reaction temperature to 80 8C(Table 1, entry 12).

However, when the reaction temperature was re-duced to 50 8C, a dramatic decrease in the yield of3Aa was observed (Table 1, entry 13), which indicatedthat the reaction temperature is an important factorfor this tandem transformation. Subsequently, wescreened different organic solvents at 80 8C, and theresults showed that H2O was the most effective sol-vent for this tandem transformation (Table 1, en-tries 12, and 14–17). Toluene also appeared to be aneffective solvent (Table 1, entry 17) for this reaction.In addition, we found that the reaction time alsoplayed an important role in this domino transforma-tion, the yield decreased slightly when the reactiontime was prolonged to 10 h (Table 1, entry 18). Whenthe reaction time was decreased to 1 h, the yield of3Aa decreased dramatically (Table 1, entry 19). Al-though this transformation was also performed underargon protection, no further improvement of the yieldof 3Aa was obtained (Table 1, entry 20). Therefore,the optimum results were obtained when 2-(1H-pyrrol-1-yl)aniline (0.1 mmol, 1A) and 4-pentynoicacid (0.2 mmol, 2a) in H2O were treated with 2 mol%of Au1 catalyst and 10 mol% of TFA in a sealed tubeat 80 8C for 2 h.

Under the aforementioned optimized reaction con-ditions, we examined the substrate scope of this cas-cade transformation by investigating the changes oc-curring in substituted 2-(1H-pyrrol-1-yl)anilines[6] andalkynoic acids (Table 2, entries 1–20). We found thatthis reaction could be carried out using a variety ofsubstituted 2-(1H-pyrrol-1-yl)anilines to afford prod-ucts 3Aa–3Mb in moderate to excellent yields (54–98%). The different substituted position and type ofsubstituents on the 2-(1H-pyrrol-1-yl)aniline werefound to be important factors for influencing theyields of the products (Table 2, entries 1–9). Highyields were obtained when there were o-, m- and/orp-substituents on the benzene ring, such as CH3,CH3O, CN, CF3, F (Table 2, entries 2–7), or no sub-stituent (Table 2, entry 1), respectively. The introduc-

Scheme 1. Synthesis of pyrrolo[1,2-a :2’,1’-c]-/pyrido ACHTUNGTRENNUNG[2,1-c]pyrrolo ACHTUNGTRENNUNG[1,2-a]quinoxalinones.

Table 1. Optimization of the reaction conditions of synthesisof 3Aa.[a]

Entry Gold catalyst/additive[b] Solvent Yield [%]

1 AuBr3 H2O 852 AuCl ACHTUNGTRENNUNG(PPh3) H2O 703 Au1 catalyst H2O 884 – H2O 05 Au1 catalyst/AgSbF6 H2O 906 Au1 catalyst/AgBF4 H2O 957 Au1 catalyst/AgNO3 H2O 938 Au1 catalyst/AgO2CCF3 H2O 889 Au1 catalyst/AgOAc H2O 8510 Au1 catalyst/TFA H2O 9611 Au1 catalyst/TsOH H2O 9312 Au1 catalyst/TFA H2O 98[c]

13 Au1 catalyst/TFA H2O 70[d]

14 Au1 catalyst/TFA CH3CN 80[c]

15 Au1 catalyst/TFA THF 65[c]

16 Au1 catalyst/TFA CH2Cl2 89[c]

17 Au1 catalyst/TFA Toluene 95[c]

18 Au1 catalyst/TFA H2O 97[c,e]

19 Au1 catalyst/TFA H2O 88[c,f]

20 Au1 catalyst/TFA H2O 97[c,g]

[a] Reaction conditions: 1A (0.1 mmol), 2a (0.2 mmol), Aucatalyst (2 mol%), additive (10 mol%), 100 8C, 2 h.

[b] Au1 catalyst = [Au{P ACHTUNGTRENNUNG(t-Bu)2(o-biphenyl)} ACHTUNGTRENNUNG{CH3CN}]SbF6;TFA = trifluoroacetic acid.

[c] The reaction temperature was 80 8C.[d] The reaction temperature was 50 8C.[e] The reaction time was prolonged to 10 h.[f] The reaction time was shortened to 1 h.[g] The reaction was performed under an argon atmosphere.

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Table 2. Gold-catalyzed one-pot tandem synthesis of 3.[a]

Entry Product Yield Entry Product Yield

1 3Aa 98% 11 3Ka trace[b]

2 3Ba 81% 12 3La 74%[c]

3 3Ca 86% 13 3Ma 75%[c]

4 3Da 85% 14 3Na 70%[c]

5 3Ea 92% 15 3Oa 89%[d]

6 3Fa 85% 16 3Ab 91% (1.5:1 dr)

7 3Ga 81% 17 3Bb 98% (1.1:1 dr)

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Gold(I)-Catalyzed Cascade for Synthesis of Pyrrolo[1,2-a :2’,1’-c]-/Pyrido ACHTUNGTRENNUNG[2,1-c]pyrrolo ACHTUNGTRENNUNG[1,2-a]quinoxalinones

tion of an ethyl group at the 2-position or two methylgroups at the 2,4-positions of the pyrrole ring moietyalso led to the formation of products in good yields(Table 2, entries 8 and 9). However, introduction of astrong electron-withdrawing group (such as the �CNmoiety) at the 2-position of the pyrrole moiety de-creased the yield of the target compound dramatically(Table 2, entry 10), presumably due to charge effects.Similarly, the replacement of the pyrrole ring moietyin 1Aa with an imidazole ring also resulted in a dras-tic decrease in the product yield, even after elevatingthe reaction temperature to 120 8C and prolonging thereaction time to 36 h (Table 2, entry 11). Althoughgood yields were observed in the abovementionedcases under optimal conditions, we did not obtain sim-ilar good results when we replaced the pyrrole ringmoiety in 1Aa with an indole ring (data not shown).However, when these cascade reactions were carriedout in toluene with the same gold catalytic system,moderate to good yields were obtained, and a rela-tively long time and a high reaction temperature wererequired to ensure complete conversion of the sub-strates (Table 2, entries 12–15). Furthermore, substitu-tion of an alkyl group (n-hexyl group) into the alkyn-ACHTUNGTRENNUNGoic acid chain was tolerated and excellent yields wereobserved (Table 2, entries 16–20). The product 3Lawas recrystallized from dichloromethane, and itsstructure was characterized using X-ray crystallogra-phy (Figure 1, see the Supporting Information for de-tails).[7]

The results of more experiments carried out underthe aforementioned optimal reaction conditions indi-cated that the proposed reaction could be extendedfor the synthesis of pyrido ACHTUNGTRENNUNG[2,1-c]pyrrolo ACHTUNGTRENNUNG[1,2-a]quinox-alin-10-ones (5Aa–Oa) and 13b-methyl-1,13b-dihydro-ACHTUNGTRENNUNG[1,4]oxazino ACHTUNGTRENNUNG[3,4-c]pyrrolo ACHTUNGTRENNUNG[1,2-a]quinoxalin-4(3H)-one(5Ab) by the reaction of 2-(1H-pyrrol-1-yl)anilines(1A–O) with 5-hexynoic acid (4a) or 2-(prop-2-ynyl-

Table 2. (Continued)

Entry Product Yield Entry Product Yield

8 3Ha 90% 18 3Cb 95% (1:1 dr)

9 3Ia 84% 19 3Hb 92% (1:1.2 dr)

10 3Ja trace 20 3Mb 85%[e] (1:1.5 dr)

[a] Reaction conditions: 1 (0.1 mmol), 2 (0.2 mmol), Au1 catalyst (2 mol%), TFA (10 mol%), H2O (2–3 mL).[b] The reaction was performed at 120 8C for 36 h.[c] The reaction was performed in toluene at 80 8C for 2 h, then at 100 8C for 8 h.[d] The reaction was performed in toluene at 100 8C for 8 h.[e] The reaction was performed in toluene at 110 8C for 10 h.

Figure 1. X-ray crystallographic structure of 3La.

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Table 3. Scope of the gold-catalyzed tandem synthesis of 5.[a]

Entry Product Yield Entry Product Yield

1 5Aa 80% 8 5Ia 72%

2 5Ba 78% 9 5La 76%[b]

3 5Ca 73% 10 5Ma 78%[b]

4 5Da 76% 11 5Na 81%[b]

5 5Ea 74% 12 5Oa 91%[b]

6 5Ga 72% 13 5Ab 80%[c]

7 5Ha 73%

[a] Reaction conditions: 1 (0.1 mmol), 2 (0.2 mmol), Au1catalyst (2 mol%), TFA (10 mol%), H2O (2–3 mL).[b] The reaction was performed in toluene at 100 8C for 8 h.[c] The reaction was performed in water at 100 8C for 3 h.

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Gold(I)-Catalyzed Cascade for Synthesis of Pyrrolo[1,2-a :2’,1’-c]-/Pyrido ACHTUNGTRENNUNG[2,1-c]pyrrolo ACHTUNGTRENNUNG[1,2-a]quinoxalinones

ACHTUNGTRENNUNGoxy)acetic acid (4b), respectively. As shown inTable 3, diversely substituted 2-(1H-pyrrol-1-yl)ani-lines were tolerated in this reaction, and good yieldswere obtained (Table 3, entries 1–8). Subsequently, wereplaced the pyrrole group in substrate 1A withindole moieties, such as indole, 5-fluoroindole, 5-methylindole, and 5-methoxyindole moieties. We didnot obtain good results under the optimized reactionconditions (data not shown). However, moderate toexcellent yields were obtained when this cascadetransformation was carried out in toluene at 100 8Cfor 8 h in the presence of the same catalyst (Table 3,entries 9–12). Moreover, 2-(prop-2-ynyloxy)aceticacid was selected to investigate the scope of thisdomino reaction. The treatment of 2-(1H-pyrrol-1-yl)aniline 1A with 2-(prop-2-ynyloxy)acetic acid 4b inaqueous medium at 100 8C for 3 h afforded the ex-pected product 5Ab in good yield (Table 2, entry 13).

On the basis of previous knowledge[8] and the re-sults of our present studies, we postulate a plausiblemechanism for the construction of the novel polycy-ACHTUNGTRENNUNGclic molecular scaffolds of the pyrrolo[1,2-a :2’,1’-c]-/pyrido ACHTUNGTRENNUNG[2,1-c]pyrrolo ACHTUNGTRENNUNG[1,2-a]quinoxalinones. As shownin Scheme 2, the unactivated alkynoic acid 2 was firstactivated by gold(I) catalyst to generate the activatedenol-lactone intermediate A,[9] which was then attract-ed by an aromatic primary amino group of 2-(1H-pyrrol-1-yl)aniline 1 to afford an ammonolysis prod-uct (B). The resulting keto amide B underwent agold-catalyzed or protonic acid-catalyzed N-acylimini-um ion formation and this was further converted intothe transition state complex C. Finally, nucleophilicaddition by the alkene yielded the target product 3.In order to obtain some proof for the proposed mech-

anism, we have treated 2-(1H-pyrrol-1-yl)aniline (1A)with intermediate A under the optimized reactionconditions, the results are positive and give a good ex-perimental support to the proposed mechanism.[10]

Conclusions

In summary, we have developed an efficient and con-venient method for the one-pot construction of the in-triguing polycyclic heterocycles the pyrrolo[1,2-a :2’,1’-c]-/pyrido ACHTUNGTRENNUNG[2,1-c]pyrrolo ACHTUNGTRENNUNG[1,2-a]quinoxalinones fromtwo simple starting materials via a gold(I)-catalyzeddomino coupling/cyclization reaction. This strategypresents an atom economical and environmentallyfriendly transformation, and has a good functionalgroup tolerance. Significantly, the strategy presents astraightforward and efficient approach to constructnovel polycyclic molecular architectures by the forma-tion of several C�C and C�N bonds in a one-pot re-action using simple and readily available starting ma-terials.

Experimental Section

Typical Procedure for Synthesis of Pyrrolo[1,2-a :2’,1’-c]-/Pyrido ACHTUNGTRENNUNG[2,1-c]pyrrolo ACHTUNGTRENNUNG[1,2-a]quinoxalinones (3Aa asan Example)

To a solution of 4-pentynoic acid (1.0 mmol) in H2O (3 mL)was added Au1 catalyst (2 mol%). After stirring for 10 minat room temperature, 2-(1H-pyrrol-1-yl)aniline (0.5 mmol)and TFA (10 mol%) were added. Subsequently, the reactionvial was sealed and the mixture was heated to 80 8C for 2 h.

Scheme 2. A plausible mechanism.

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And then, the cold mixture was concentrated under reducedpressure, the resulting reside was purified by flash columnchromatography (petroleum ether/ethyl acetate=5/1, v/v, asan eluent) to afford the desired product 3Aa ; yield: 98%.1H NMR (CDCl3, 300 MHz): d=8.18 (m, 1 H), 7.45 (m,1 H), 7.22 (m, 2 H), 7.15 (m, 1 H), 6.33 (m, 1 H), 6.05 (m,1 H), 2.81 (m, 1 H), 2.56 (m, 2 H), 2.45 (m, 1 H), 1.40 (s, 3 H);13C NMR (CDCl3, 100 MHz): d=172.3, 134.6, 128.2, 125.4,125.1, 124.6, 122.8, 114.9, 114.5, 110.6, 102.7, 59.9, 31.7, 30.6,27.2; LR-MS (ESI): m/z= 239 [M+H]+; HR-MS (ESI):m/z= 261.1004, calcd. for C15H14N2ONa [M +Na]+: 261.1016.

Acknowledgements

We gratefully acknowledge financial support from the Na-tional Natural Science Foundation of China (Grants20721003 and 20872153), International Collaboration Proj-ects (Grant 20720102040), the 863 Hi-Tech Program ofChina (Grants 2006AA020602 and 2006AA10 A201), Nation-al S&T Major Projects (2009ZX09301-001, 2009ZX09501-001, and 2009ZX09501-010) and the Shanghai PostdoctoralScience Foundation (Grant 09R21418000).

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[10] To further explore the proposed mechanism, we havetreated 2-(1H-pyrrol-1-yl)aniline (1A) with the tauto-mer of intermediate A (alpha-angelica lactone, asshown below) under the above optimal reaction condi-tions, and the desirable product 3Aa has been obtainedin 97% yield. Synthetic procedure: To a solution ofalpha-angelica lactone (1.0 mmol) in H2O (3 mL) wasadded Au1 catalyst (2 mol%). After stirring for 10 minat room temperature, 2-(1H-pyrrol-1-yl)aniline(0.5 mmol) and TFA (10 mol%) were added. Subse-quently, the reaction vial was sealed and the mixturewas heated to 80 8C for 2 h. And then, the cold mixturewas concentrated under reduced pressure, the resultingreside was purified by flash column chromatography(petroleum ether/ethyl acetate= 5/1, v/v, as an eluent)to afford 3Aa ; yield: 97%.

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Gold(I)-Catalyzed Cascade for Synthesis of Pyrrolo[1,2-a :2’,1’-c]-/Pyrido ACHTUNGTRENNUNG[2,1-c]pyrrolo ACHTUNGTRENNUNG[1,2-a]quinoxalinones