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Current Organic Chemistry, 2009, 13, 1766-1776

Copper-Catalyzed Multicomponent Reactions: Securing a Catalytic Route to Ketenimine Intermediates and their Reactivities

Eun Jeong Yoo and Sukbok Chang*

Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Korea

Abstract: A new type of Cu-catalyzed multicomponent reaction has been developed relying on the in situ generation of N-sulfonyl- or N-phosphorylketenimine intermediates, which are obtained from the cycloaddition of 1-alkynes and sulfonyl- or phosphoryl azides followed by ring-opening rearrangement of the initially formed copper triazole species. This facile and versatile route to ketenimines has led to develop a range of highly efficient multicomponent reactions by employing diverse nucleophiles such as amines, alcohols, water, pyrroles, and thiolates. Additionally, intramolecular version and cycloadditions of the ketenimines with imines or their derivatives have also been developed on the basis of the same strategy. (This article is dedicated to Professor Bong Rae Cho of Korea University on the occasion of his 60th birthday).

1. INTRODUCTION Ketenimines, a structural cousin of ketene species, are a reactive synthetic intermediate that reacts readily with a diverse range of nucleophiles, electrophiles, or radicals to afford the corresponding nitrogen-containing heterocycles or imine compounds [1]. Ketenimine derivatives have been conventionally prepared via imidation of ketene precursors by the reaction with iminophosphoranes that can be obtained from azides (Scheme 1, Eq. 1) [2], dehydrohalogenation of imidoyl halides under basic conditions (Eq. 2) [3], or treatment of nitriles with a Brønsted base followed by substitution reaction (Eq. 3) [4]. The scope of such preparative approaches for the generation of ketenimines is rather limited only allowing certain

types of substituents being accessible, and, therefore, those procedures have not been much utilized in organic synthesis. Considering the potential utility of ketenimines in the synthesis of biologically interesting compounds [5], a reliable protocol with a broad substrate scope, preferably catalytic in inexpensive metal species, has been strongly desired. Herein, we describe the recent progresses with regard to the above aspects for the practical in situ preparation of various ketenimine species and their amazingly diverse reactivities. 2. IN SITU GENERATION OF KETENIMINE INTERMEDIATE Recently, the Cu-catalyzed cycloaddition of 1-alkynes and aryl- or alkyl azides has been the focus of great interest

R1 R2 R1 O R2 R3 N (1)

R3 N3





R1 R2 O NHR3 PPh3, Br2 R2

R1 NR3 Br -HBr base R2

R1 R3 N (2)

R1 base R2 C N R2

R1 C R2


R3 X N R2

R1 R3 N (3)


Scheme 1.

*Address correspondence to this author at the Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Korea; Tel: (+82)-42-350-2841; Fax: (+82)-42-350-2810; E-mail: [email protected] 1385-2728/09 $55.00+.00

in such diverse areas as organic synthesis, materials and biosciences, and medicinal chemistry [6]. The so called "click reaction" is featured to be operationally simple, regio- and stereoselective, broad in the substrate scope, highly tolerant with most common functional groups, eco-friendly, and high

© 2009 Bentham Science Publishers Ltd.

Copper-Catalyzed Multicomponent Reactions

Current Organic Chemistry, 2009, Vol. 13, No. 18 1767

R1 cat. Cu(I) + R1 N N N R2 N



N2 R1



Cu(H) -N2 25 oC R1 N B R2

Cu A H+




N N R1 C (R2 N


R1 N


D (R2 = sulfonyl)

= alkyl, aryl)

Scheme 2.








Cu(H) SO2Me

Me N









Cu(H) Me





Fig. (1). Computational comparison on the ring-opening process of two types of copper triazole species E and G.

yielding [7]. The transformation was proposed to proceed via a series of stepwise pathways: formation of copper acetylide, cycloaddition of which with azide to form a metallacycle followed by ring-contraction to a copper triazole (A), and then protonation to afford the 1,4-disubstituted triazole (C, Scheme 2) [8]. While the reaction of aryl- or alkyl azides with 1-alkynes affords 1,4-disubstituted triazole adducts (C), the employment of sulfonyl azides resulted in apparently different outcomes. For instance, when the reaction was carried out in the presence of primary or secondary amines, amidine compounds (D, X = NR3R4) were isolated as a main species at room temperature [9]. Subsequent mechanistic studies revealed that amidines are produced by the addition of the employed amines into the in situ generated ketenimine interme-

diate (B) which is driven from the ring-opening rearrangement of the initially formed N-sulfonyl copper triazole species (A, R2 = sulfonyl groups) [10]. Computational studies provided a theoretical basis for the dichotomous behavior of the key copper triazole intermediates (A). It showed that the choice of a main path between the protonation step and ring-opening process of the species A is decisively dependent on the nature of N-substituents (R2) of A (Fig. (1)). An activation barrier for the conversion of N-sulfonyl group-substituted triazole speies E to a ringopened tautomer F was calculated to be dramatically lower than that of N-methyl analogue G [10a]. In fact, the ringopening process of N-sulfonyl copper triazole species is highly facile and readily takes place even at room temperature.

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NSO2R2 R+ N R2 NSO2R2 R1 N H R2 R1 OH R+ + O R2 S O N1 H N R1 NSO2R2 R+ NH R1 IV H2O O R+ III NHSO2R2 [Cu(I)] cat. R+ Cu(H) O N S O R2 R+ O R1 II R1 I

Scheme 3.

3. NUCLEOPHILIC ADDITION REACTIONS WITH KETENIMINE 3.1. Reactions of the Ketenimine Intermediate with Various Nucleophiles Having a facile and reliable procedure for the in situ generation of N-sulfonylketenimines under ambient conditions, reactivity of those species was next extensively investigated. As summarized in Scheme 3, a range of copper-catalyzed three-component reactions could be developed relying on the nucleophilic addition of different types of nucleophiles onto the N-sulfonylketenimine intermediate. All reactions produce the corresponding three-component coupling adducts in high yields under very mild conditions. Amidines (I) were readily obtained from the Cucatalyzed reaction of sulfonyl azides with 1-alkynes in the presence of amines [9]. This reaction has an extremely broad substrate scope with respect to all three components, and no external base additive was required to achieve satisfactory yields. Remarkably, various types of amines including primary, secondary, aliphatic, aryl, cyclic moieties, or even ammonium salts are all highly reactive to afford excellent product yields. In addition, the reaction with an optically active amine proceeds without racemization. When alcohols were used as the third reacting component instead of amines, the corresponding imidates (II) could be obtained in high yields [11]. Unlike the amidine case, an external tertiary amine additive, representatively Et3N, was necessary with prolonged reaction time to attain satisfactory yields at ambient conditions. A subsequent conversion of isolated allylic N-sulfonylimidates to N-allylic sulfonamides

was achieved by the Pd-catalyzed [3,3]-sigmatropic rearrangement under mild conditions. It was particularly noteworthy to observe that water can readily participate in the Cu-catalyzed three-component reaction to afford N-sulfonamides (III), which are presumed to form via tautomerization of the initially produced imidates [12]. This type of hydrative amidation reaction is highly selective in that it proceeds with an anti-Markovnikov manner, leading to a nonconventional synthetic route to amides without relying on the conventional interconversion between carbonyl compounds. One notable application of the hydrative amidation was demonstrated using propargyl alcohols as a substrate to afford -hydroxy amides (Scheme 4) [12c]. Because those products can be accessed alternatively through the aldol reaction of acetamides with aldehydes albeit with poor efficiency, the present hydrative amidation of propargyl alcohols represents a practical aldol surrogate. In addition, the synthetic utility of the amide formation from terminal alkynes was elegantly utilized by Fukuyama et al. in the total synthesis of Manzamine A [13]. The reaction with pyrrole or its derivatives provided 2functionalized pyrroles (IV) under otherwise similar conditions [14]. Accordingly, it demonstrates that the Cucatalyzed three-component reaction can be employed even for the regioselective C-C bond formation on heterocycles. Since N-protected pyrroles participate in the reaction with much slower rates when compared to parent pyrrole, it was proposed that the nitrogen atom of pyrrole coordinates to the copper metal center during the attack of heterocycles onto the ketenimine intermediate.

Copper-Catalyzed Multicomponent Reactions

Current Organic Chemistry, 2009, Vol. 13, No. 18 1769

O + Ph H



OH + Ph (97% ee) TsN3

CuI (2 mol %) t3N (1.1 equ% v) t-BuOH/H2O (2:1) 25 oC, 1 h Ph


O N H Ts

97% (97% ee)

% CuI (2 mol %) % ) OH Ph 79% (3 steps) OH O N H Ts %) 1N HCl % % THF 25 oC, 3 h v) TsN3 (1.1 equ% t3N (1.1 equ% v) H2O 25 oC, 1 h

%CuSO4 ) PPTS Acetone Ph 25 oC, 1 h OH OH

Scheme 4.

Ph CuI 10 ) ol %% + Ar SO2N3 + NH4Cl CH2Cl2 25 oC, 1 h 90% Ph NH2 Et3N 1.5 equiv% CuI 10 ) ol %% O N S O Br 1,10-phenanthroline 20 ) ol %% C+2CO3 2.0 equiv% DMF 80 oC, 16 h 75% Ph N H O N S O

OneP Operation 77%% Pot

Scheme 5.

It was found that ammonium salts or aqueous ammonia can also be readily employed as an "ammonia equivalent" in the Cu-catalyzed three-component reaction giving unsubstituted amidines (Scheme 5) [15]. When the obtained amidines bear an aryl halide moiety at the proper position, a subsequent Cu-catalyzed intramolecular N-arylation was efficiently achieved leading to benzothiadiazine dioxides, an important pharmacophore. The two copper-catalyzed sequential procedures can be performed in one-pot with similar efficiency. 3.2. Product Selectivity in the Three-Component Reactions During the course of the mechanistic investigations, it was found that N-sulfonyltriazoles could also be isolated along with the three-component coupling adducts, and the ratio of two species was dependent on the employed reaction conditions including base additives and temperatures (Table

1). Whereas imidate 1 was almost exclusively obtained in the presence of a Et3N additive at room temperature, the corresponding N-sulfonyltriazole (2) was produced as a major species when 2,6-lutidine was used instead of Et3N at lower temperatures [10b]. This result strongly implies the intermediacy of N-sulfonyl copper triazole species (A, R2 = sulfonyl groups, Scheme 2) in the copper-catalyzed three-component reactions, and that the path favoring the protonation process of those intermediates A can be selectively controlled simply by modifying the reaction conditions. Indeed, on the basis of the above observation, a new experimental procedure was optimized for the preparative synthesis of 1-(N-sulfonyl)-1,2,3-triazoles. Excellent product yields were obtained by performing the Cu-catalyzed cycloaddition between 1-alkynes and sulfonyl azides at 0 oC in the presence of 2,6-lutidine additive in chloroform solvent (Scheme 6) [10a].

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Table 1. Dependence of Product Distribution on the Reaction Conditions [10b]

CuI () ( mol %) additive () % equiv) 2 Ph + TsN+ + BnOH CHCl+ Conversion >99%

Entry 1 2 3 4



OBn + NTs 1 Ph


N N Ts


Ratio (1/2) >99:1 3.2:1 1:9.3 1:>99a

Additive Et3N 2,6-lutidine 2,6-lutidine 2,6-lutidine

Temp (oC) 25 25 0 -25

At 32% conversion.

CuI (10 mol %) S + p-Tol-SO2N3 2,e lutidine (1.2 +quiv) CHCl3 - oC, 12 . S


N N SO2(p-Tol)


Scheme 6.

CuI (10 mol %) Ph + TsN3 Et3N (1.5 equiv) + X H CH2Cl2, 25 oC X N Ts

Fig. (2). Reaction profile in the Cu-catalyzed three-component couplings with various nucleophiles (X­H) [15].

3.3. Comparison of Reaction Rates The relative initial rates were compared among various nucleophiles in the Cu-catalyzed three-component reactions (Fig. (2)) [15]. Quite interestingly, aqueous ammonia exhibited the highest initial rate followed by benzylamine, and NH4Cl. On the other hand, reactions with water or benzyl alcohol proceeded with much slower initial rates. In fact, the Cu-catalyzed three-component reaction of sulfonyl azides, 1alkynes, and amines can be carried out even in aqueous medium to provide amidines with excellent chemoselectivity [9]. The Cu-catalyzed hydrative amidation of 1-alkynes, on the other hand, was found to be significantly accelerated in

water (Table 2), and the reaction could be scaled up to multi grams in aqueous medium, thereby making the process an eco-friendly and practical route as a nonconventional amide synthesis [12d]. 3.4. Additional Substrate Types The developed copper-catalyzed three-component reactions offered efficient preparative route to various nitrogencontaining compounds, particularly, of biological interest from a range of interesting substrates. For instance, when a sugar-bearing alkyne was reacted with sulfonyl azides and amines in the presence of a copper catalyst, the corresponding glycosylated N-sulfonylamidines were obtained in high

Copper-Catalyzed Multicomponent Reactions

Current Organic Chemistry, 2009, Vol. 13, No. 18 1771

Table 2. Rate Acceleration of the Hydrative Amide Synthesis in Water [12d]

CuI (2 mol %) t-Bu + TsN+ + H2O solvent 2- oC, ) h

Entry 1 2 3 Solvent CHCl3 CHCl3/H2O (2:1) H2O Conversion (%) 38 65 >99

) Et+N () % equiv)

t Bu

O N H Ts

Yield (%) 35 55 87

OH HO HO O OH CuI () ( mol %) O + TsN+ + BnNH2 THF/H2O (, :) ) 2/ oC, , / min HO HO

OH O OH 89% O NHBn NTs

Scheme 7.

Boc N Ph + Me SO2N3 + NH i-Pr% 2 CHCl3 25


CuI 10 ) ol %%

Boc N Ph N 90%

N i-Pr% 2



Scheme 8.

O CuI () ( mol %) Ph + (R2O)2 P N+ + HN(i Pr)2 THF 2- oC, ) 2 h Ph N N(i-Pr)2 P(OR2)2 O O EtO P N+ O O P O 20% N+ PhO O P N+

EtO ) +%

PhO 9( %

Scheme 9.

yield (Scheme 7) [16]. Since no protection of the four hydroxyl groups was required, this example nicely demonstrates the excellent compatibility of labile functional groups to the reaction conditions. -Amino amidines, which are regarded as a -amino acid isostere, were also obtained with high efficiency when the Cu-catalyzed amidine coupling reactions were applied to ynamide derivatives under the developed ambient condition (Scheme 8) [17]. Because of the ubiquitous presence of the -amino amidines in both natural and synthetic bioactive compounds, this approach is of great interest for further applications. Not only sulfonyl azides but also phosphoryl azides could be enlisted as a facile reacting partner in the Cucatalyzed three-component reactions [18]. Notably, unlike the case of sulfonyl azides, electronic environment of the phosphoryl azide reactants turned out to affect the reaction

efficiency significantly (Scheme 9). While reactions with phosphoryl azides derived from aliphatic alcohols were sluggish irrespective of their steric variations, diarylphosphoryl azides participated in the reaction with excellent efficiency to afford the corresponding N-phophorylamidine adducts in high yields. It was interesting to observe that an optically active phosphoryl azide derived from chiral BINOL readily underwent the Cu-catalyzed three-component reaction without racemization (Scheme 10) [18]. Furthermore, a subsequent alkylation at the -position to the amidine moiety proceeded with moderate to high diastereoselectivity. 3.5. Synthesis of Heterocyclic Compounds An efficient method for the synthesis of medium- and large-sized heterocycles via the Cu-catalyzed multicompo-

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Yoo and Chang

R Ph N Ph O + O O P N3 + HN iPr% 2 THF 25 oC, 12 h CuI 30 ) ol %% O P N iPr% 2 O O

R = H 92%% 80% d.r, 9:1% Me

Scheme 10.

O H N N O H 2.4 eq% CuI 20 ) ol %% + T+N3 + H2N CH2%NH2 6 CHCl3 25



T+N H N N H NH T+N 63% NH



Scheme 11.

Ts CuI (2( mol %) 2,. lutidine () % equiv) 2 N H Me + TsN+ CHCl+ 2- oC, ) 2 h NHMe 9) % CuCl () ( mol %) ( Et+N () % equiv) + TsN+ CHCl+ 2- oC, + h N Ts 87% NHTs N Me N N Ts (+)



N (, )

Scheme 12.

nent reactions was revealed. For example, the reaction of a bisaminoalkyne with sulfonyl azide and 1,6-diaminohexane gave a 20-membered macrocycle in 63% yield without the need of an extra additive (Scheme 11) [19]. This reaction exemplifies the synthetic utility of the present ring-closure approach as a new entry for the construction of various complex molecules, which are potentially suitable skeletons for the combinatorial and medicinal chemistry. In addition, an intramolecular version of the coppercatalyzed three-component reactions was recently reported using properly organized substrates. For example, 2ethynylanilines readily reacted with sulfonyl azides in the presence of CuI catalyst and an amine additive to afford 2iminoindoline derivatives in high yields at ambient conditions (Scheme 12, Eq. 3) [20]. In addition, when N-(2-

ethynylphenyl)pyrrole was allowed to react with sulfonyl azides, the corresponding pyrrolo[1,2-a]quinoline derivatives were obtained in good yields under the similar conditions (Eq. 4) [14]. In each case, the reaction was proposed to proceed via the intramolecular nucleophilic attack of the orthoamino or pyrrolyl group onto the in situ generated ketenimine intermediate to form a new C-N and C-C bond, respectively. When the Cu-catalyzed three-component reaction conditions were applied to 1,n-aminoalkynes as a substrate for a perspective intramolecular cyclization, the outcome was quite unexpected. Treatment of 1-(N-benzyl)amino-4pentyne with p-toluenesulfonyl azide resulted in 5membered amidines as a mixture of 3 and 4, instead of leading to 6-membered amidine 5 that is an expected product on the basis of the ketenimine pathway (Scheme 13) [21]. It is

Copper-Catalyzed Multicomponent Reactions

Current Organic Chemistry, 2009, Vol. 13, No. 18 1773

CuI % mol %( 3 H N + Bn CuI TsN1 THF / 3 oC, 8 h

N NTs 3

Bn + Me

N NTs 4


51% % = 1+ :. ( 3/4 .



NTs Bn 5

Bn Ru+(CO)) 2 (. mol %) N NTs Me 6 + NTs 7

Scheme 13.

TsN+ THF 2. oC, ) 2 h N Bn



8) % (6/7 = 8%:) ) )

N n H


Bn cat [M] n=2 N TsN3

Bn N H2 C N N N Ts CH2N2 N



cat [M] n=2 N Bn TsN3 Bn N N Ts N N

Bn N NTs N2 Me N2 N

Bn NTs

Scheme 14.

CuI %, mol %( Ph Ph + TsN0 + Ph N pyridine %+ equiv( . , CH0CN . 2 oC, - 3 h Ph Ph N Ph 9, % % >92:2( Ph CuI %, mol %( Ph + TsN0 + N C N CH0CN . 2 oC, - 3 h c)C3H- - N 91% N c)C3H- % 3( NTs NTs % 2(

Scheme 15.

noteworthy that the main product 3 contains a 2pyrrolinylidine skeleton that is missing one carbon compared to the starting material. More surprisingly, the cyclization of 1,n-aminoalkynes with azides could also be catalyzed by a range of metal species including Pd(II), Pt(II), Au(III), and Ru(0 or III) in addition to Cu(I) although the catalytic activity and selectivity were dependent on the metals employed, thus implying that the intramolecular reaction path is different from the intermolecular reactions. Among the above metal catalysts, Ru3(CO)12 displayed notably high efficiency in THF. Whereas sulfonyl- and phosphoryl azides were facile sub-

strate types in the intermolecular reactions, a range of electron-deficient counterparts including acyl-, and alkoxycarbonyl azides also participated in the cyclic amidine synthesis with high efficiency. When 1-(N-benzyl)amino-5-hexyne was allowed to react with p-toluenesulfonyl azide, a derivative of 3-methyl-(2-piperidinylidene) 6 was obtained as a major product along with 7 that is missing one carbon. On the basis of the product distribution and subsequent mechanistic studies, a plausible pathway was proposed (Scheme 14) [21]. Instead of proceeding via the ketenimine route, the intramolecular transformation is assumed to be initiated by the reversible hydroamination with the assistance

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CuI 20 ) ol %% Et3N 2.0 equiv% Ph + T+N3 + PhN PPh3 CH2Cl2 25 oC, 16 h

Ph N T+N PPh3 Ph H Ph

PPh3 NHPh NT+ 93%

Scheme 16.

O O R) + R+ S O + N, XH (XH = NH+, OH, or S K+) R, R, CuI () ( mol %) ( Et, N (+% +quiv) solv+nt +. oC, ) + 0 X . 9 90% R)


Propoced Mechanica R) + R+ SO+N, [Cu] N+

R, R) H+O X L NSO+R+

Cu(H) R)





X K R)


O O R, XH I H+ [Cu] J X N SO+R+ H+ R,

Scheme 17.

of a metal catalyst. Resultant cyclic enamine intermediate is proposed to react with azides leading to triazoline species, which are subsequently rearranged to cyclic amidines upon release of nitrogen or diazomethane depending on the ring size. The equilibrium shift in the hydroamination step was typically facilitated by elevating reaction temperature. Accordingly, this result demonstrates, as the proof-of-principle, that equilibria tandem sequence can be favorably driven by an irreversible step, thereby enabling a facile one-pot synthetic route to deliver molecular complexity under unprecedented mild conditions. 4. [2+2] CYCLOADDITION OF KETENIMINE Fokin and co-workers reported a direct and stereoselective route for the synthesis of N-sulfonylazetidin-2-imines upon the formal [2+2] cycloaddition of the in situ generated

N-sulfonylketenimine intermediates with a range of imines (Scheme 15, Eq. 5) [22]. It was found that the use of a pyridine ligand increased not only the reaction rate, but also resulted in significantly improved diastereoselectivity (trans/cis, >95:5) in the produced azetidinimines, which can be viewed as a -lactam analogue being remarkably stable to a wide range of reaction conditions. Using the same strategy, 2-(sulfonylimino)-4-(alkylimino)azetidine derivatives could also be obtained in excellent yield by employing carbodiimides (Eq. 6) [23]. This approach was appreciated as an efficient and unique route for the preparation of 2,4diiminoazetidine ring which cannot be easily obtained with the conventional methods. Wang and co-workers successfully utilized the formal cycloaddition strategy for the one-pot synthesis of -

Copper-Catalyzed Multicomponent Reactions

Current Organic Chemistry, 2009, Vol. 13, No. 18 1775

CuI () ( mol %) O Ph + TsN+ + MeOH + EtO2C H THF 2%oC, 2, h 8( % (dr, ) :) ) ( Et+N (+% equiv) EtO2C Ph OH NTs OMe

Scheme 18.

phosphoryl amidines upon the reaction with iminophosphoranes (Scheme 16) [24]. The reaction is presumed to proceed via the [2+2] cycloaddition between the in situ generated Nsulfonylketenimine intermediate and iminophosphorane initially leading to 1,2-phosphazetidine species, which then undergoes an intriguing ring-opening rearrangement upon the shift of the phosphino and hydride group at the same time. 5. CASCADE REACTION VIA KETENIMINE One of the notable advances in the Cu-catalyzed multicomponent reactions was reported by Wang and co-workers in the synthesis of iminocoumarins, dihydroquinolines, and thiochromene derivatives, which potentially possess a broad spectrum of biological activities [25]. As shown in Scheme 17, the reaction involves a domino process of the initial nucleophilic addition of anilines, phenols, or thiophenolates on the N-sulfonylketenimine followed by an intramolecular cyclization. For example, the reaction of salicylaldehyde (I, R3 = H, XH = OH) with the in situ generated ketenimine moiety introduces an aza enolate intermediate (J), and subsequent intramolecular condensation of which followed by dehydration offers the construction of iminocoumarin (L) presumably through an intermediate K. These one-pot reactions for the synthesis of 2-imino heterocyclic compounds turned out to be efficient to give high overall yields, and versatile to enable various heteroatoms (O, N, and S) to be incorporated in the cyclic skeletons [26]. While the example in Scheme 17 is a catalytic threecomponent reaction involving four reacting functional groups, a new entry of the copper-catalyzed intermolecular four-component reaction has been reported most recently (Scheme 18) [27]. While simple aldehydes or anhydrides were not effective as the fourth component, ethyl glyoxylates participated in the catalytic coupling reaction with arylalkynes, sulfonyl azides, and alcohols to give -aryl hydroxy imidates in good yields, but with moderate to poor diastereoselectivity. 6. CONCLUSION In the Cu-catalyzed reactions with 1-alkynes, an apparently different outcome between sulfonyl- or phosphoryl azides and alkyl- or aryl azides is postulated to be originated from the relative fragility of the in situ generated copper triazole adducts. In the former case, the ring-opening rearrangement of the electron-deficient N-sulfonyl- or Nphosphoryl copper triazole intermediates readily takes place even at ambient temperatures to afford ketenimine species, with which a range of nucleophiles can react leading to the multicomponent coupling products. In particular, among those nucleophiles, amines, alcohols, water, pyrroles, and

thiolates are especially efficient as the reacting components to afford the corresponding coupling products in high yields. However, the ring-opening process of the N-sulfonyl copper triaozle intermediates can be effectively suppressed simply by employing certain base additives at lower temperatures. As a result, 1,4-disusbtituted N-sulfonyltriazoles can be selectively isolated in synthetically acceptable yields to support the mechanistic proposal of the present catalytic multicomponent reactions. The new route to the N-sulfonyl- or N-phosphorylketenimine species is highly convenient and versatile to allow various subsequent reactions to be developed even including [2+2] cycloaddition with alkyl- or arylimines or iminophosphoranes in addition to the catalytic multicomponent reactions. All reactions relying on the in situ generation of ketenimines appear to offer mild conditions, high selectivity, a wide substrate scope, an excellent functional group tolerance. It is anticipated that additional advances based on the present strategy will be witnessed in the near future in various areas such as organic synthesis, medicinal and combinatorial chemistry, and catalytic methodologies. ACKNOWLEDGEMENT This research was supported by the KOSEF grant (No. R01-2007-000-10618-0). REFERENCES

[1] For recent reports, see: (a) Mass, H.; Bensimon, C.; Alper, H. Ringopening cycloaddition of aziridines to ketenimines. J. Org. Chem., 1998, 63, 17. (b) Fromont, C.; Masson, S. Reactivity of N-phenyl silylated ketenimines with electrophilic reagents. Tetrahedron, 1999, 55, 5405. (c) Cossío, F. P.; Arrieta, A.; Lecea, B.; Alajarín, M; Vidal, A.; Tovar, F. Highly efficient induction of chirality in intramolecular [2 + 2] cycloadditions between ketenimines and imines. J. Org. Chem., 2000, 65, 3633. (d) Alajarín, M.; Vidal, A.; Ortin, M.-M. First radical addition onto ketenimines: A novel synthesis of indoles. Tetrahedron Lett., 2003, 44, 3027. (e) Alajarín, M.; Bonillo, B.; Sánchez-Andrada, P.; Vidal, A.; Bautista, D. Intramolecular ketenimine ketenimine [2 + 2] and [4 + 2] cycloadditions. J. Org. Chem., 2007, 72, 5863. Staudinger, H.; Hause, E. Über Ketene, XXXVII. Mitteilung. Keteniminderivate. Helv. Chim. Acta., 1921, 4, 887. (a) Stevens, C. L.; French, J. C. Nitrogen analogs of ketenes. II. Dehydrochlorination of imino chlorides. J. Am. Chem. Soc., 1954, 76, 4398. (b) Bestmann, H. J.; Lienert, J.; Mott, L. Reaktionen zwischen triphenylphosphin-dibromid und substituierten säureamiden. Liebigs Ann. Chem., 1968, 718, 24. (a) Newman, M. S.; Fukunaga, T.; Miwa, T. Alkylation of nitriles: Ketenimine formation. J. Am. Chem. Soc., 1960, 82, 873. (b) Parker, C. O.; Emmons, W. D.; Pagano, A. S.; Rolewicz, H. A.; McCallum, K. S. Chemistry of dinitroacetonitrile-II: Derivatives of dinitroacetonitrile from Michael, Mannich and alkylation reactions, 2,2-dinitro-2-cyanoethanol and its derivatives. Tetrahedron, 1962, 17, 89. For reviews on the chemistry of ketenimines, see: (a) Krow, G. R. Synthesis and reactions of ketenimines. Angew. Chem., Int. Ed.,

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1776 Current Organic Chemistry, 2009, Vol. 13, No. 18 1971, 10, 435. (b) Dondoni, A. Four- and six-membered heterocycles from 1,2- and 1,4-cycloadditions to ketenimines. Heterocycles, 1980, 14, 1547. (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. A stepwise Huisgen cycloaddition process: Copper(I)-catalyzed regioselective ligation of azides and terminal alkynes. Angew. Chem., Int. Ed., 2002, 41, 2596. (b) Tornøe, C. W.; Christensen, C.; Meldal, M. Peptidotriazoles on solid phase: [1,2,3]-Triazoles by regiospecific copper(I)-catalyzed 1,3-dipolar cycloadditions of terminal alkynes to azides. J. Org. Chem., 2002, 67, 3057. Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Click chemistry: Diverse chemical function from a few good reactions. Angew. Chem., Int. Ed., 2001, 40, 2004. (a) Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.; Noodleman, L.; Sharpless, K. B.; Fokin, V. V. Copper(I)-catalyzed synthesis of azoles. DFT study predicts unprecedented reactivity and intermediates. J. Am. Chem. Soc., 2005, 127, 210. (b) Rodionov, V. O.; Fokin, V. V.; Finn, M. G. Mechanism of the ligand-free CuIcatalyzed azide-alkyne cycloaddition reaction. Angew. Chem., Int. Ed., 2005, 44, 2210. (a) Bae, I.; Han, H.; Chang, S. Highly efficient one-pot synthesis of N-sulfonylamidines by Cu-catalyzed three-component coupling of sulfonyl azide, alkyne, and amine. J. Am. Chem. Soc., 2005, 127, 2038. (a) Yoo, E. J.; Ahlquist, M.; Kim, S. H.; Bae, I.; Fokin, V. V.; Sharpless, K. B.; Chang, S. Copper-catalyzed synthesis of Nsulfonyl-1,2,3-triazoles: Controlling selectivity. Angew. Chem., Int. Ed., 2007, 46, 1730. (b) Yoo, E. J.; Ahlquist, M.; Bae, I.; Sharpless, K. B.; Fokin, V. V.; Chang, S. Mechanistic studies on the Cucatalyzed three-component reactions of sulfonyl azides, 1-alkynes, and amines, alcohols, or water: Dichotomy via a common pathway. J. Org. Chem., 2008, 73, 5520. (a) Yoo, E. J.; Bae, I.; Cho, S. H.; Han, H.; Chang, S. A facile access to N-sulfonylimidates and their synthetic utility for the transformation to amidines and amides. Org. Lett., 2006, 8, 1347. (b) Hwang, S. J.; Cho, S. H.; Chang, S. Evaluation of catalytic activity of copper salts and their removal processes in the threecomponent coupling reactions. Pure Appl. Chem., 2008, 80, 873. (a) Cho, S. H.; Yoo, E. J.; Bae, I.; Chang, S. Copper-catalyzed hydrative amide synthesis with terminal alkyne, sulfonyl azide, and water. J. Am. Chem. Soc., 2005, 127, 16046. (b) Cassidy, M. P.; Raushel, J.; Fokin, V. V. Practical synthesis of amides from in situ generated copper(I) acetylides and sulfonyl azides. Angew. Chem., Int. Ed., 2006, 45, 3154. (c) Cho, S. H.; Chang, S. Rate-accelerated nonconventional amide synthesis in water: A practical catalytic aldol-surrogate reaction. Angew. Chem., Int. Ed., 2007, 46, 1897. (d) Cho, S. H.; Hwang, S. J.; Chang, S. Copper-catalyzed threecomponent reaction of 1-alkynes, sulfonyl azides, and water: N-(4acetamidophenylsulfonyl)-2-phenylacetamide. Org. Synth., 2008, 85, 131. Kita, Y.; Toma, T.; Kan, T.; Fukuyama, T. Synthetic studies on (+)-Manzamine A: Stereoselective synthesis of the tetracyclic core framework. Org. Lett., 2008, 10, 3251. [14]

Yoo and Chang Cho, S. H.; Chang, S. Room temperature copper-catalyzed 2functionalization of pyrrole rings by a three-component coupling reaction. Angew. Chem., Int. Ed., 2008, 47, 2836. Kim, J. H.; Lee, S. Y.; Lee, J.; Do, Y.; Chang, S. Synthetic utility of ammonium salts in a Cu-catalyzed three-component reaction as a facile coupling partner. J. Org. Chem., 2008, 73, 9454. Mandal, S.; Gauniyal, H. M.; Pramanik, K.; Mukhopadhyay, B. Glycosylated N-sulfonylamidines: Highly efficient coppercatalyzed multicomponent reaction with sugar alkynes, sulfonyl azides, and amines. J. Org. Chem., 2007, 72, 9753. Kim, J. Y.; Kim, S. H.; Chang, S. Highly efficient synthesis of amino amidines from ynamides by the Cu-catalyzed threecomponent coupling reactions. Tetrahedron Lett., 2008, 49, 1745. Kim, S. H.; Jung, D. Y.; Chang, S. Phosphoryl azides as versatile new reaction partners in the Cu-catalyzed three-component couplings. J. Org. Chem., 2007, 72, 9769. Jin, Y.; Fu, H.; Yin, Y.; Jiang, Y.; Zhao, Y. Efficient ring-closure approach via copper-catalyzed reactions of sulfonyl azide, terminal alkynes, and alcohols/amines. Synlett, 2007, 901. Yoo, E. J.; Chang, S. A new route to indolines by the Cu-catalyzed cyclization reaction of 2-ethynylanilines with sulfonyl azides. Org. Lett., 2008, 10, 1163. Chang, S.; Lee, M.; Jung, D. Y.; Yoo, E. J.; Cho, S. H.; Han, S. K. Catalytic one-pot synthesis of cyclic amidines by virtue of tandem reactions involving intramolecular hydroamination under mild conditions. J. Am. Chem. Soc., 2006, 128, 12366. Whiting, M.; Fokin, V. V. Copper-catalyzed reaction cascade: Direct conversion of alkynes into N-sulfonylazetidin-2-imines. Angew. Chem., Int. Ed., 2006, 45, 3157. Xu, X.; Cheng, D.; Li, J.; Guo, H.; Yan, J. Copper-catalyzed highly efficient multicomponent reactions: Synthesis of 2-(sulfonylimino)4-(alkylimino)azetidine derivatives. Org. Lett., 2007, 9, 1585. Cui, S.-L.; Wang, J.; Wang, Y.-G. Copper-catalyzed multicomponent reaction: Facile access to novel phosphorus amidines. Org. Lett., 2008, 10, 1267. (a) Cui, S.-L.; Lin, X.-F.; Wang, Y.-G. Novel and efficient synthesis of iminocoumarins via copper-catalyzed multicomponent reaction. Org. Lett., 2006, 8, 4517. (b) Cui, S.-L.; Wang, J.; Wang, Y.G. Efficient synthesis of 2-imino-1,2-dihydroquinolines and 2imino-thiochromenes via copper-catalyzed domino reaction. Tetrahedron, 2008, 64, 487. The synthesis of a novel class of 2-imino-5-arylidene-3-pyrrolines via a Cu-catalyzed three-component reaction of sulfonyl azide s with alkynes and aziridines was also reported: Cui, S.-L.; Wang, J.; Wang, Y.-G. Copper-catalyzed multicomponent reaction: Facile access to functionalized 5-arylidene-2-imino-3-pyrrolines. Org. Lett., 2007, 24, 5023. Yoo, E. J.; Park, S. H.; Lee, S. H.; Chang, S. A new entry of copper-catalyzed four-component reaction: Facile access to -aryl hydroxy imidates. Org. Lett., 2009, 11, 1155.


[15] [16]




[18] [19]

[20] [21]




[23] [24]







Received: 04 April, 2009

Revised: 06 July, 2009

Accepted: 10 July, 2009


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