Two Neglected Multicomponent Reactions: Asinger and Groebke Reaction for Constructing Thiazolines...

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20 Current Organic Synthesis, 2015, 12, 20-60

Two Neglected Multicomponent Reactions: Asinger and Groebke Reaction for

Constructing Thiazolines and Imidazolines

Zai-Qun Liu*

Department of Organic Chemistry, College of Chemistry, Jilin University, Changchun 130021, China

Abstract: The multicomponent reaction (MCR) is an important research field in the organic synthetic methodology. In

1956, Professor Friedrich Asinger reported a method for synthesizing thiazoline scaffold, in which a ketone was treated

by sulfur and ammonia in one-pot operation. In 1998, Professor Katrin Groebke, Hugues Bienaymé, and Christopher

Blackburn reported a method for preparing imidazo[1,2-a]pyridine, in which an annulation took place among -

aminopyridine, aldehyde, and isocyanide in one-pot operation, and then the reaction was entitled as Groebke reaction.

Comparing with the bloom in the research of other MCRs such as Strecker (found in 1850), Hantzsch (1882), Biginelli

(1891), Mannich (1912), Passerini (1921) and Ugi (1959) MCR, as newcomers in the family of MCR, Asinger and Groe-

bke reactions are not reported as usually as other MCRs. The aim of the present review is to emphasize the importance of these two

MCRs in the synthesis of thiazolines and imidazolines. Although the Asinger protocol is innovated as the reaction of -halogen-

substituted ketone with thioamide, or, the C-S bond in thiazoline is contributed from mercapto or thiocarbonyl groups, as well as -

aminothiol as the synthon reacts with carbonyl compounds to form the thiazoline scaffold, the advantage of Asinger reaction is still wor-

thy to be noted because four bonds in thiazoline are produced simultaneously from the reaction of ketone with the simple reactants, sulfur

and ammonia. On the other hand, the review on the Groebke reaction is herein catalogued as substrates and catalysts. The 2-

aminopyridine-type substrates are the necessary reagents for the Groebke reaction and therefore limit the applicability of the reaction, but

some efforts succeed in applying catalysts for enlarging the suitable substrates or agitating the following reactions based on the Groebke

adducts. To sum up the present achievements on Asinger and Groebke reaction, it can be concluded that the exploration on catalysts will

break the limitation of the substrates and bring them with wide application in the synthesis of thiazolines and imidazolines.

Keywords: Asinger reaction, Groebke reaction, imidazoline, multicomponent reaction, thiazoline.

1. INTRODUCTION

The multicomponent reaction (MCR), in which more than three reagents are contained in one-pot operation for a series of reactions taking place successively, becomes one of the most active fields in the current researches of organic chemistry [1]. As differing from general step-by-step synthesis, MCR possesses high efficiency in constructing molecular library with multifunctional motifs [2], and thus encourages chemists to carefully allocate reagents and pre-cisely adjust reaction conditions in order to agitate the MCR fol-lowing the perspective routine [3]. In addition, the bloom on the research of MCRs activates the explorations of special reagents [4] and catalysts applied for driving MCRs [5], as well as the investiga-tion on the active intermediates possibly resulting from the process of MCRs [6]. As shown in Scheme 1, Professor Alexander Dömling summarized some typical MCRs in his recently published review [1], where MCRs may be fundamentally cataloged as isocyanide-related reaction, Mannich-type, and Hantzsch-type reactions. The aforementioned MCRs have a common characteristic that an active intermediate is produced by nucleophilic addition. Subsequently, a carbanion deriving either from isonitrile or from active methylene attacks the formed C=N in the active intermediate to initiate the following reactions. Taking Ugi four-component reaction (Ugi 4CR) as an example, it can be found in Scheme 2 that the energy for the formation of the imine locates at the zenith, and then the intermedi-ates convert into the final product with the energy sliding down as in a roller coaster [7]. Therefore, to design an MCR is to allocate a series of reactions in a sequence with the energy gradually lowering, and to select an appropriate intermediate for agitating this domino process.

*Address correspondence to this author at the Department of Organic Chemistry, College

of Chemistry, Jilin University, No.2519 Jiefang Road, Changchun 130021, China;

Tel: +86 431 88499174; Fax: +86 431 88499159; E-mail: [email protected]

1.1. General Introduction to MCRs

The Strecker reaction (shown in Scheme 3) taking place among ketone, amine, and KCN to form -cyanoamine via twice nucleo-philic additions may be the first MCR (reported in 1850) [8], fol-lowed by Hantzsch (1882) and Biginelli (1891), in which the cen-tral reaction is still owing to the carbanion resulting from methylene in -keto carbonyl compound adds to the imine produced by amine and aldehyde group in advance [9]. The Mannich reaction found in 1912 can also be regarded to follow the aforementioned mechanism and thus may be a token for the early stage in the history of MCRs.

A compound with unpleasant smell comes into the field of MCR research. The isocyanide with a characteristic group, isoni-trile, which functions as nucleophile, base, and radical easily form-ing at the -position, triggers a large amount of findings on MCR [10] and begins with a novel journey for the research on the proper-ties of isocyanide [11]. The finding of Passerini in 1921 may initi-ate the exploration of isocyanide, while the report by Ugi in 1959 may promote the usage of isocyanide on MCR to the culmination [6], and Professor Ivar K. Ugi was honored for this contribution to MCRs [12]. As shown in Scheme 4, both Passerini and Ugi reac-tions are commonly based on the formation of imine (-C=N), which is generated from the -N C adding to C=O in the first step of the reaction, or from the reaction between ketone and amine [13].

1.2. General Introduction to Asinger and Groebke Reactions

Compared with the bloom of studies on Ugi and Passerini reac-tions, two MCRs, Asinger and Groebke reactions for synthesizing thiazoline and imidazoline scaffolds seem not very hot topics in MCR research. As shown in Scheme 1, Asinger and Gewald reac-tions represent sulfur-involved MCRs to produce related heterocy-cles, in which thiazoline and thiophene are important structural motifs for developing novel drugs [14] because of their special

1875-6271/15 $58.00+.00 © 2015 Bentham Science Publishers

Two Neglected Multicomponent Reactions: Asinger and Groebke Reaction Current Organic Synthesis, 2015, Vol. 12, No. 1 21

N CR5

isocyanide

R1 OH

O

R3 R4

O

R1 NN

R5

O

R2

R3 R4

O

H

R1 ON

R5

O R3 R4

O

H

Passerini

R2

Ugi

NH2

R1 H

O

N C

R3

EWG

NN

R2

R1

R3

EWG

Orru

If the EWG is Ts, Ts can convert into a H atom,

and reaction is called van Leusen reaction.

R1 H

O X

n[Y]

Z

N

NH2

n = 1, 2

X

n[Y]

Z

N

N

R1

HN R5

Groebke-

Bienayme-

Blackburn

Isocyanide-related MCR

EWG = electron-withdrawing group

Mannich-type MCR

R1

R2

O

R3H

O R4

NH

R5

R1

R2

O

R3N

R4

R5Mannich

OHX

R2 NH2

Betti

OHX

HN

R2

R3

R1 B

OH

OH

R1HN

R2

R3

Petasis

Cl

R1

O

N

R2

O R1

R3

Staudinger

Hantzsch-type MCR

R1 H

O

R2 NH2O O

N

O OR1

R2

Hantzsch

H2N NH2

X

X = O, S

OR3

O O

R2

HN NH

X

OR3

R2

O

R1

Biginelli

NH2X

NX R1

R2

OR3O

Doebner

R1 H

O

R2

R3

HNX R1

R2

R3

Povarov

R1 R2

O

R5

R3

R4

Cl

O

NH3S

S N

R5

R4

R3

R1R2

Asinger

R2

O

R1

EWG

N

SNH2

EWG

R1

R2

Gewald

Scheme 1. Some typical MCRs as summarized in the review [1].

22 Current Organic Synthesis, 2015, Vol. 12, No. 1 Zai-Qun Liu

Scheme 2. The variety of the energy in the process of Ugi 4CR [7].

Strecker

in 1850 R1 R2

O R3 NH2

R1 R2

N

R3

nucleophilic addition

between ketone and amine

KCN

R1 CN

HN

R3

R2


between imine and CN-

Scheme 3. The first reported MCR, Strecker reaction, in 1850.

C N R3

R1 H

OO R2

OH

Passerini

in 1921

NR3

R1

H

O

O R2

O

H

NR3

R1

H

O

OH

R2

O

R1N

R3

OR2

O

O

HA nucleophilic addition

takes place between the

carbanion in the isonitrile

and carbonyl in the aldehyde to form an imine.

An acyl transfers from the first oxygen atom

to the fourth oxygen atom,

and the hydrogen atom

at the fourth oxygen atom

transfers to the first oxygenatom to form an enolic style,

called Mumm's rearrangement.

12

3

4

C N R3

R1 H

O

O R2

O

H

R4 NH2

R1 NR4

H

Ugi

in 1959

O R2

O

R1 NR4

H

H

N

R3

O R2

O

R1

N

R4

H

HR2 N

NR3

O

R4

R1 H

O

H

The imine is produced by

the reaction between amine

and ketone, and the carbon

atom in C=N is attacked bycarbanion in -NC. Then,

Mumm's rearrangement leads

to the final product.

Scheme 4. The processes of Passerini and Ugi reactions.


O

NH3

S

O

SH

NH3

O

- H2O

S

N

3-thiazoline

room temperature

Scheme 5. Friedrich Asinger found that pentan-3-one (or cyclohexanone) can form 3-thiazoline in the presence of sulfur and ammonia at room temperature.

O

2

S

NH3 S

N1. HCN

2. HCl/H2OS

NHHO

O

2-isopropyl-5,5-

dimethylthiazolidine-

4-carboxylic acid

Asinger reaction

SH

NH2

HO

O

D,L-penicillamine

S

NHHO

OO

L-lysine, (-)-norephedrine,

or (-)-pseudonorephedrine

SH

NH2

HO

O

D-penicillamine

2,2,5,5-tetramethylthiazolidine-

4-carboxylic acid

racemic resolution

Scheme 6. The synthesis of D-penicillamine by Asinger reaction.

affinities towards biological species and applications for mimicking sulfur-related enzymes [15]. But the finding of the Asinger reaction can be traced back to 1956, when Friedrich Asinger treated elemen-tal sulfur and gaseous ammonia on pentan-3-one or cyclohexanone at room temperature to afford a solid in almost quantitative yield as shown in Scheme 5 [16]. In addition, another isocyanide-related MCR, Groebke-Blackburn-Bienaymé reaction, which is able to construct imidazoline skeleton with amidine, aldehyde, and isocya-nide being reagents, seems not as attractive as other MCRs, perhaps because this so-called Groebke reaction is a freshly reported as later as in 1998 [17]. Of importance for thiazoline [18] and imidazoline [19] in developing novel medicines, and of not being hot topics of these two MCRs, the aim of the present review is to collect repre-sentative results on the applications of these two MCRs and to em-phasize the key roles of them in constructing thiazoline and imida-zoline scaffolds with high efficiency.

2. ASINGER REACTION FOR CONSTRUCTING THIA-ZOLINE

2.1. Background for Asinger Reaction

In an essay for commemorating Professor Friedrich Asinger [20], he was honored for the contribution to the heterocyclic syn-theses and the advocate of the usage of clean energy such as metha-nol instead of raw mineral energy. Nowadays, when applying clean energy to achieve atomic economy becomes a popular idea [21], it is necessary for us to pay our respects to his pioneering work. An-other important contribution of Professor Friedrich Asinger is to

find a method for synthesizing thiazoline scaffold by treating ke-tone with sulfur and ammonia, and so-called Asinger reaction. The most well-known application of Asinger reaction is to prepare D-penicillamine industrially [22]. As shown in Scheme 6, double molecules of isobutyraldehyde react with sulfur and ammonia to afford 3-thiazoline, in which the imine bond is added by hydrogen cyanide for introducing a cyano group to be converted into the car-boxylic acid group by hydrolysis. The formed 2-isopropyl-5,5-dimethylthiazolidine-4-carboxylic acid is further hydrolyzed in water-vapor, leading to the formation of racemic penicillamine, which can react with acetone to provide 2,2,5,5-tetramethylthiazolidine-4-carboxylic acid for racemic resolution by chiral reagents such as L-lysine, (-)-norephedrine, and (-)-pseudonorephedrine to give D-penicillamine. The L-penicillamine can be re-racemized, and the aforementioned racemic resolution is repeated to obtain D-penicillamine. The Asinger reaction as a “green” chemical process exhibits high efficiency in the usage of atoms in the reagents [23].

The Asinger reaction produces a thiazoline scaffold, in which, as shown in Scheme 7, the -hydrogen atom in ketone is substituted by sulfur to form a -mercaptoketone, and meanwhile, the ammo-nia as a nucleophile attacks the carbonyl group in the ketone to form an imine. The formation of the thiazoline scaffold can be as-cribed to two successive nucleophilic reactions, in which the mer-capto group firstly adds to the carbonyl group from another ketone, and then, an intramolecular ring-closure between nitrogen atom (in imine) and the carbon atom (bearing hydroxyl group) affords the thiazoline scaffold by the dehydration.


The most attractive site in Asinger reaction is owing to the reac-tion between S8 and the -carbanion in ketone to generate a sulfur-rich intermediate for providing -SH in the following process. This deduction is elucidated by the reaction of acetophenone and ele-mental sulfur in the presence of amine because a product, 8-alkylamino-8-phenylmethylidene-1,2,3,4,5,6,7-heptathiocane, was identified by X-ray crystal structure analysis [20]. In addition, the reaction among the elemental sulfur, n-butylamine, and acetophe-none also produces 8-(n-butylaminophenylmethyliden)-1,2,3,4,5, 6,7-heptathiocane, in which a CS7 ring is proved by the analysis of vibrational spectroscopy [24].

The study on Asinger reaction in the earlier period focuses on the traditional method that the mercapto group is still generated by the interaction between the elemental sulfur and -carbanion of ketone [25]. But, as shown in Scheme 8, -hydrogen atom of some ketones are not active enough and cannot be converted into -carbanion readily, leading to the difficulty for producing mercapto group at -position. Thus, -halogen substituted ketone (shown in Scheme 1) may be an appropriate reagent to react with NaSH for producing -mercapto-substituted ketone [26]. If a chiral aldehyde, galactose, replaces the acetone (shown in Scheme 9), the galactose

may be a chiral auxiliary reagent to generate enantiomerical 3-thiazoline, which can subsequently take place Ugi three-component reaction (Ugi 3CR) as shown in Scheme 9 [27]. The chiral carbon at

-position of aldehyde is of importance for the chiral auxiliary process in the formation of 3-thiazoline. For example, when R-citronellal is applied in this case, the produced corresponding 3-thiazoline is a diastereomer because the -carbon in R-citronellal is not a chiral center. On the other hand, it can be found that the C=N in 3-thiazoline is also a reactant for Ugi 3CR in the presence of isocyanide and carboxylic acid. Sometimes, ketone treated by NaSH in the presence of Br2 can also afford -mercaptoketone (shown in Scheme 8) [28].

2.2. C-S Bond Produced by Mercapto Group

As shown in Scheme 7, the ring-closure of 3-thiazoline is com-posed of double nucleophilic substitutions with the sulfur atom in mercapto group and the nitrogen atom in imine group being the nucleophiles. The order of the aforementioned nucleophilic proc-esses may be exchanged in the case of an amide as the reagent, in which the C=N in thiazoline can be produced by the tautomerism from C=O in the amide, and the nucleophilic substitution of -OH

R R2

NH

SH

R1R2

O

R1

R

NH3

R R2

O

H

R1

NH3 / S8

R R2

O

S7

R1

SH

R R2

O R1

R R2

O

SH

R1

R R2

O

S6

R1

S

+

R

R2

HN S

R1

R2 OH

R1RS

NR

R1

R2

R

R1

R2

- H2O

-SH as the nucleophile=NH as the nucleophile

intermediate for

providing -SH

Scheme 7. The process of Asinger reaction.

N

O

traditional method for

attaching -SH at

alpha-position of ketone

S

NH3

N

SN

N

current method for

attaching -SH at

alpha-position of ketone

O

Cl

NaSH

NH3O

CH2Cl2

0°C ~ room temperature

over nightS

N

73%

The chloride atom was subsituted by -SH.

Using sulfur to substitute

alpha-H in ketone.

O

NaSH

Br2

O

SH

NH3

OS

NNaBH4

HClNH SH

Scheme 8. The comparison of traditional and current methods for the formation of -mercapto-substituted ketone.


O

Cl

NaSH

NH3

OO

O

O

O

O

H

S

N

H

OO

O

O

O

H

12 hours

71%

dr > 95:5

O

N

O2N

C

HCOOH

CH3OH, 72 hours

galactose

S

N

H

OO

O

O

O

H

O

HN

O2NOO

H

73%

dr = 20:80

S

N

By using R-citronellal as the chiral

aldehyde just leads to diastereomers.

74%

dr=50:50

0°C

Scheme 9. The galactose acts as a chiral auxiliary reagent to generate the enantiomerical 3-thiazoline, followed by Ugi 3CR.

R1 NH

R2

O

R3

S R4

R1 NR2

OH

R3

S R4

PCl5

CH2Cl2

room temperature

S

NR1

R2

R3

R4Cl

+

Example

C5H11

OCH3

COOH 1. SOCl2, one drop of DMF

S O

NH2

O

OHCl

N

C5H11

OCH3

2.

NH

O

COOCH3

S

O

95%

PCl5

CH2Cl2

C5H11

OCH3

COOCH3

S

N

H

86%

Scheme 10. The nucleophilic substitution towards enolic -OH in amide by sulfur atom acts as the key step in the ring-closure of thiazoline.

(also deriving from the tautomerism of C=O in the amide) by mer-capto group becomes the key step in the ring-closure of thiazoline scaffold. As shown in Scheme 10, the usage of phosphorus penta-chloride (PCl5) promotes the amide to convert into enolic style for the sake of dehydration between mercapto group and hydroxyl group [29]. The formation of halogenated hydrocarbon (R

4Cl) sup-

ports the above deduction because R4Cl can only be derived from

R4OH in the presence of PCl5, and R

4- is the protective group of

sulfur atom originally. A deprotective process takes place in R4S-,

leading to sulfur atom as the nucleophile attacks C-OH and forms thiazoline consequently. The moiety of N- -mercapto-substituted group in the amide can be produced by the reaction of carboxylic acid and S- or N-substituted cysteamines. As shown in Scheme 11, TiCl4 can play the same role as PCl5 in the cyclodehydration be-tween -SH and -OH to form thiazoline [30], while a trityl-protected sulfur instead of -SH can also take place the same cyclodehydration [31]. Moreover, trityl-modified -SH in cysteine may lead to the stereoselectivity because the steric hindrance of trityl group (Tr-) at


sulfur atom results in the enantioselectivity in the process of the cyclodehydration [32]. As shown in Scheme 12, Ph3P=O and (CF3COO)2O [33] as well as some organometallic complexes [34] are recently used to be the dehydrants for the ring-closure of thia-zoline.

2.3. C-S Bond Produced by Thiocarbonyl Group

The aforementioned ring-closure of thiazoline is a nucleophilic substitution of the enolic -OH deriving from amide via the tautomerism. The C=O in amide is the receptor for -SH, the nu-cleophile at -position of N atom in amide. Hence, Lewis acids such as TiCl4, PCl5, and (CF3COO)2O are able to promote the eno-lization of C=O in the amide. Contrarily, if the oxygen atom in C=O and the N- -mercapto group in amide are exchanged to form

N- -hydroxyl-substituted thioamide, the C=S in thioamide can also form sulfur anion via the tautomerism, and thus, acts as a nucleo-phile to attack the N- -hydroxyl group for producing thiazoline. As an inert leaving group, the hydroxyl group in the primary alcohol cannot be readily replaced by the sulfur anion. Thus, in order to carry out the cyclodehydration, some dehydrants are applied to promote the reaction of the hydroxyl group with sulfur anion tautomerized from the C=S. But, before the cyclodehydration takes place between C=S and N- -hydroxyl group, the key problem is to generate the corresponding thioamide, viz., to convert C=O in am-ide into C=S. So, as shown in Scheme 13, the Lawesson reagent is employed to treat the amide, in which the -hydroxyl group is pro-tected by tert-butyldiphenylsilyl group in advance because Lawes-son reagent can also convert the hydroxyl group into mercapto

NH

HN

NH

HN

NH

O

HS

O

SH

O

HS

O H

OH

OTiCl4

N

S

N

SN

S

HN

NH

O H

OH

O

51%

NH

O

OS

O

Tr =

trityl

TiCl4

CH2Cl2

S

N

O

O

88%

NH

HN

O

O

S-Tr

O

S-Tr

OTiCl4

CH2Cl2S

N

S

N

O

O

S

N

S

HN

O

O

[O]S

N S

N O

O

38%ee 97%

25°C

Scheme 11. TiCl4 can drive the cyclodehydration between -SH and -OH, and trityl-protected cysteine N-amide leads to the stereoselectivity in the formation of thiazoline.


group. Then, (CH3)3P (2 equiv.) and 1,1’-azodicarbonyldipiperidine (ADDP, 1.3 equiv.) are employed to drive the ring-closure between the C=S and the -hydroxyl group [35]. As shown in Scheme 14, when the amidated glucosamine is refluxed in toluene solution of Lawesson reagent, the acetoxyl group as an efficient leaving group cyclodehydrates with C=S and forms thioamide within one-pot operation [36]. As shown in Scheme 15, the usage of Lawesson reagent converts C=O into C=S, and meanwhile, dehydrates in the

ring-closure of thiazoline [37]. In addition to the preparation of thioamide from amide by using Lawesson reagent, benzotriazole-substituted thioamide is a reagent for producing N- -hydroxyl-substituted thioamide as shown in Scheme 16 [38]. As a leaving group the benzotriazole is superior to react with amino group other than hydroxyl group, generating the target thioamide for the follow-ing ring-closure of thiazoline with Burgess reagent being the dehy-drant.

OHN

NH

O

O

S-Tr

O

O

Ph3P=O, (CF3COO)2O

CH2Cl2, -180C, 2 hours

N

S

OHN

O

O

O

71%

Molybdenum(VI) oxo compound catalysts

for ring-closure in the formation of thiazoline

MoO2

MoO3

(NH4)6Mo7O24 4H2O

(NH4)2MoO4

MoO2(CH3COCH2COCH3)2

CoMoO4

FeMoO4

NH

O

OHO

O

N

O

O

Othe above catalysts

(10 mol %)

CH3

azeotropic reflux

> 95%1~8 hours

OHN

NH

O

OHS

O

O

N

O

MoO2

2

1 mol %

1 hour

azeotropic refluxCH3

N

S

OHN

O

O

O

85%

dr = 98 :2

N

S

OHN

O

O

O+

Scheme 12. Some novel catalysts for the cyclodehydration between -SH and -OH in the formation of thiazoline.


NH

OO

O

Si Si

tert-butyldiphenylsilyl,

TBDPS,

a protective group

for hydroxyl groupO

Lawesson reagent

CH3

90°C, 5 hours

S

P

S

P

S

S

O

O

Lawesson reagent

NH

SOH

O

O

(n-C4H9)4NF

O230C, 2 hours

78%

(CH3)3P (2 equiv.)

1,1'-azodicarbonyldipiperidine

(ADDP, 1.3 equiv.)

N

N

N N

O

OCH3

-45~-20°C, 2 hours

SN

O

O

90%

N

SH OH

O

O

The tautomerism takes place to form -SH,

which attacks -OH for the cyclodehydration.

- H2O

Scheme 13. By using Lawesson reagent to form thioamide and the following cyclodehydration by (CH3)3P and 1,1’-azodicarbonyldipiperidine (ADDP).

As shown in Scheme 17, an electron-withdrawing group attach-ing to benzotriazole, i.e., -NO2, becomes a popular synthon for preparing thioamide by amide exchange reaction, followed by the cyclodehydration in the presence of Burgess reagent [39]. It is nec-essary to apply a base for catalyzing the amide exchange reaction. For example, N,N-diisopropylethylamine (DIPEA, in Scheme 17) and piperidine (in Scheme 18) are used to prepare thioamide in the case of nitro-substituted benzotriazole as the synthon. Moreover, as shown in Scheme 18, diethylaminosulfur trifluoride (DAST) cannot drive the ring-closure of thiazoline when the N- -hydroxyl group is still protected by triisopropylsilyl group (TIPS). Thus, the protec-tive group for secondary alcoholic hydroxyl group, TBS, is re-moved in order to dehydrate by using CuCl2 in the presence of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC), then, the protective group for primary alcoholic hydroxyl

group, TIPS, is also removed in order to use DAST as the dehy-drant for the ring-closure of thiazoline [40].

The N- -hydroxyl-substituted amide can be dehydrated to af-

ford oxazoline with Burgess reagent being the dehydrant as shown

in Scheme 19 [41]. This reaction provides an approach for produc-

ing thioamide because, as shown in Scheme 20, the formed oxa-

zoline can be decomposed by H2S, by which hydrosulfide anion

acts as the nucleophile to attack the carbon atom of C=N in oxa-

zoline, leading to the cleavage of C-O in oxazoline consequently.

Then, Burgess reagent is used once again to cyclodehydrate thio-

amide for giving thiazoline [42]. As shown in Scheme 21, although

three steps are carried out, this protocol avoids the nonselectivity in the sulfuration of C=O and C-OH in amide when Lawesson reagent

is used as the sulfurating reagent. Instead, the reaction between


O

OH

HOHO

NH3 OH

Cl

glucosamine

(CH3)3SiCl

((CH3)3Si)2NH

N

room temperature

O

OTMS

TMSOTMSO

NH2

OTMS

TMS = (CH3)3Si-90%

NClCl

O O

(C2H5)3N, CH2Cl2

00C~room temperature

N

1. CF3COOH/CH3OH (1:9)

room temperature

N(CH3CO)2O

room temperature

2.

O

Ac = CH3CO-OAc

AcO

OAc

OAc

NH

Lawesson reagent

O

OAc

AcO

OAc

OAc

HN

O O

O

N

S

O

S

NOAc

OAcAcO

AcO

AcO OAc

N

CH3reflux

overall yield 44%

Scheme 14. The acetoxyl group as the leaving group in the formation of thioamide by using Lawesson reagent.

Fe

NH2

OH

FeCl

O

Cl

O

O

(C2H5)3N

71%

FeNH

O

Fe

HN

OH

O

Fe

OH

40%

Lawesson reagent

O

reflux

N

SN

S

Fe

Fe

Fe

Scheme 15. The Lawesson reagent as the sulfurating reagent and the dehydrant.


NH

O

NH2P4S10

Na2CO3

NH

S

NH2

58%

NaNO2

CH3COOH / H2O

S

N

N

N

> 90%

OOH

H2N

DMF, 0°C

OOH

NH

S

87%

Burgess reagent

(C2H5)3N S N

O

O

COOCH3

Burgess reagent

O

O

NS

(+)-Curacin A

50%

Scheme 16. The formation of thioamide by using Burgess reagent as the dehydrant.

N

N

N

O2N

S

synthon for preparing thioamide

HN

NH2

O

O

O

O

OH

HCl

N,N-diisopropylethylamine, DIPEA

NDMF or CH2Cl2

0°C ~room temperature

HN

NH

O

O

O

O

OH

S

Burgess reagent

Oreflux

HN

O

O

O

ON

S

overall yield 66%

Scheme 17. The benzotriazole as the synthon for preparing thioamide.


N

N

N

O2N

S

N

O

O

Fmoc

O O

OSiTBSNH

H

O

NH2

O(i-Pr)3Si

TIPS

1. room temperature, 6 hours

O

2. DMF, room temperature, 16 hoursNH

O O

TBSONH

H

O

NH

TIPSO

S

N

H

40%

OH

HNO

O

O

Boc

N N

N

N

O

N

N

PF6

HATU

N N

N

N

OH

HOBt

N

room temperature, 16 hours

DIPEA

O O

TBSONH

H

O

NH

TIPSO

S

N

85%

O

BocHN

1. (n-C4H9)4NFO


remove all the

protective group

for -OH

2. (i-Pr)3SiClO

protect the

primary -OHN

NH

(imid.)

yield

30%

3. CuCl2, 800C, 30 min CH3

1-ethyl-3-(3-dimethylaminopropyl)

carbodiimide hydrochloride (EDC)

(CH3)2N(CH2)3N=C=NC2H5 HCl

dehydration for

the secondary

alcoholic hydroxyl

yield 65%

4. repeat condition 2 for removing TIPS yield 62%

O O

NH

O

NH

HO

S

N

O

BocHN

diethylaminosulfur

trifluoride (DAST)

(C2H5)2NSF3

CH2Cl2, -15°C, 1 hour

O O

NH

O

N

S

N

O

BocHN

75%

Scheme 18. The formation of thioamide by using DAST as the dehydrant.


S

N

N

S

ON

HN O

NH

O

NH

HO

O

NH

O

S

N

N

S

HN O

NH

O

NH

O

Didmolamide A

Burgess reagent

reflux

O

56%

oxazoline

Scheme 19. The cyclodehydration formation of oxazoline with Burgess reagent as the dehydrant.

O OHHN

O

O ON

O

55%

Burgess reagent

O OHHN

S

OBurgess reagent

H2S

CH3OH/(C2H5)3N

(2:1)

25°C, 48 hours

64%

O SN

50%

curacin A

ON

R1

R2

reaction process

H2S-H+

ON

R1

R2

HS

H+

ON

R1

R2

HS

OHN

R1

R2

HS

OHHN

R1

R2

S

OHN

R1

R2

HS

- H2O

20°C

20°C

Scheme 20. The cyclodehydration-H2S decomposition-cyclodehydration for synthesizing thiazoline.


NH

N

O

O

CH3

O

OH

O

BCl3 NH

N

O

OH

O

OH

O

81%

1. Burgess reagent

2. H2S, (C2H5)3N

NH

N

O

OH

S

OH

O

85%

Burgess reagent

OH70%

N

O

O

S

N

H

NOH

O

O

(EDC)

(CH3)2N(CH2)3N=C=NC2H5

N(CH3)2N

(DMAP)

(i-Pr)2NC2H5

CH2Cl2

HO

NH2 HCl

NNH

O

O

OH

92%

Burgess

reagent

70°C

2 hoursO

NN

O

O

65%

H2S, (C2H5)3N

room temperature

12 hours

NNH

O

S

OH

59%

NN

O

S

Burgess reagent

O50°C, 5 hours

14%

DAST

kalkitoxin

CH2Cl2, -20°C, 1 hour

84%

N

NH

OO

HNOH

HN

O

HN

O

OHN

O

O

NH

O

ON

NH

OS

N

HN

O

HN

O

OHN

O

O

NH

O

O

1. DAST, CH2Cl2

- 15°C

2. H2S, (C2H5)3N

CH3OH

room temperature

59%

3. DAST, CH2Cl2

- 15°C

72%

trunkamide A

Scheme 21. A popular protocol for forming C-S bond in the synthesis of thiazoline.


OH

O(C2H5)3Si

O

Si(CH3)2t-Bu

O

HS O

O

NHO

O

diphenylphosphoryl azide (DPPA)

P

O

O

ONNN

(C2H5)3N, DMF, 0°C

S

O(C2H5)3Si

O

Si(CH3)2t-Bu

O

O

O

NHO

O

85%

1. CF3COOH, CH2Cl2, 0°C

2. 80°C

traditional method for

forming C=N

under acidic conditionO

S

N

O

O

84%

An agent for

producingazide, which can

be a leaving group

to promote the

formation

of thioamide.

HS O

O

O

O

RCOOH

DPPA

(C2H5)3N

DMF

0°C

S O

O

O

O

R

O O

O

Cl

Cl

CN

CN

(DDQ)

CH2Cl2pH =7 buffer

S O

OH

O

R

O

N N OO

O

O

diethyl azodicarboxylate

(DEAD)

DPPA

OPh3P

S O

N3

O

R

O

O

O

N

S

R

O

Ph3P

S O

N

O

R O PPh3 - N2

O

O

N

S

RPPh3O

- Ph3P=O

SS

R1R1

O O

N3 N3R2 OH

O

(CH3)2N(CH2)3N=C=NC2H5

(EDC)

Ph3P (i-Pr)2NC2H5 DMF

room temperature to reflux

S

N R2R1

O

yield up to 86%

dialkyl disulfide

50°C

Scheme 22. A protocol for forming C=N by an intramolecular aza-Wittig reaction.


oxazoline and H2S avoids the sulfuration of N- -hydroxyl group, and the phenolic hydroxyl group cannot be affected by the afore-mentioned procedure [43]. In addition, DAST exhibits higher dehy-dration activity than Burgess reagent in the ring-closure of thia-zoline [44]. Therefore, the method, which is composed of the cy-clodehydration for forming oxazoline, the decomposition by H2S for forming thioamide, and then the cyclodehydration once again for forming thiazoline, becomes a popular way to prepare thiazoline with thioamide being the reactant [45].

2.4. Formations of C=N Bond and S-C=N Bond

The aforementioned synthetic routines mainly focus on the formation of the C-S bond with mercapto group either from N- -position in an amide or from the enolization of C=S in a thioamide being nucleophiles. On the other hand, as shown in Scheme 22, an

intramolecular aza-Wittig reaction produces C=N for the ring-closure of thiazoline, by which the Staudinger reduction converts the S- -azido-thiolester into an aza-ylide for the Wittig reaction with C=O and thus avoids the usage of acidic condition for the formation of imine (C=N) [46]. The cystine can be treated by NaN3 to form a -azido cystine as the reagent, in which, as shown in Scheme 22, the S-S bond in the dialkyl disulfide can be decom-posed and then attacks the carboxylic group in another reagent to form a thiocarbonyl group, followed by the Staudinger reduction to afford the aza-ylide for the Wittig reaction to give thiazoline. The benefit of this protocol is to combine the formation of C-S bond with the C=N bond within one-pot operation [47]. This procedure can be actually ascribed to a traditional way for the synthesis of thiazoline as shown in Scheme 23, in which a -aminothiol as the synthon reacts with carbonyl compounds including aldehyde [48],

R2 H

O SH

NH2R1

HCl

+CH3COOK

C2H5OH

or CH3OH

20°C

N

S

H

R1

R2

H

80~95%

R1 = COOCH3(or C2H5)

R2 = n-Pr, i-Pr, n-Bu, CH3

MnO2

CH3CN

N

S

R1

R2

H

N

S

R1

R2

R2 OH

O OH

NH2R1

R1

+

R1 = H, CH3

R2 = Ar, R

R3 = H, Ph

R3

Lawesson reagent

microwave irradiation

150°CN

S

R1R2

R1

R3

40~82%

SH

NH2R1

R1

R3

R2 OH

O

OH

NH2R1

1. (C2H5)3N,

O

S ClCH3

O

O

2. (C2H5)3N, CH2Cl2

SO2Ph

1. S8, t-BuOK

room temperature

14 hours

2. CH3I

room temperature

1 hour SSN

S

R1

71% R1 = C2H5, 59%

+

SH

NH2

HO

O

CS2 +

NaOH

40°C

6 hours

NH

S

SHO

O

RBr, K2CO3

50°C

6 hours

CH3CN

N

S

SRRO

O

S

N

OH

N

O

OS

N

OH

NH

O

LiAlH4

O

-40~-20°C

SH

NH2

HO

O

+

S

N

OH

N

S

H OH

O

H

CH3COOK

C2H5OH

H2O

two steps yield 90%

20°C

Scheme 23. Contd……


N O

NH

O

O

1. NH3 H2O

CH3OH

2. POCl3 (C2H5)3N CH2Cl2

O

O

N O

NH

O

O

Cl

O

SH

NH2

HO

O+

N O

NH

O

O

N

S

OH

O

76%

N S

NH

O

O

N

CH3ONa

CH3OH

N S

NH

O

O

NH

O

SH

NH2 HCl

HO

O+

96%

(C2H5)3N

CH3OH

CH3OH

reflux

N S

NH

O

O

N

S

OH

O

90%

CH3OH 70°C, 2 hours phosphate buffer

(pH = 5.95)

SH

NH2 HCl

HO

O

yield > 90%NaHCO3

Scheme 23. A series of carbonyl compounds can be the synthon for forming S-C=N in thiazoline.

OHN

NH2

OR

S

KHCO3 OHN

NHO

R

S

Br O

O

O

ethyl 2-bromopyruvate

1.

2. (CF3CO)2O, N

CH3

CH3

CH3OCH2CH2OCH3

-40~-20°C

N

S

OHN

OR

O

O

65~85%

28% NH3 (aq)

CH3OH, N2

12 hours

N

S

OHN

OR

NH2

O

(CF3CO)2O

(i-Pr)2NC2H5

CH2Cl20°C, 1 hour

N

S

OHN

OR

N

67~88%

HS

HCl H2NOH

O

phosphate buffer

70°C, 2 hours, CH3OH

N

S

OHN

OR

99%

S

NOH

O

Scheme 24. Synthesis of thiazole by using ethyl 2-bromopyruvate as the reagent.


Cl

N

HN NH2

S

CH3COONa C2H5OH

Cl

N

HN

NH

S

Br

R

O

Cl

N

HN

NH

S

RO

Cl

N

HN

N

S

R

HOH

- H2O

Cl

N

HN

N

S

R

R = CH3, Ph

77%

BrO

O

R

Cl

N

HN

N

S

OOH

R

Cl

N

HN

N

S

O70%

R

- C2H5OH

R = H, COOC2H5

Scheme 25. Synthesis of thiazole or thiazoline by using -bromoketone or -bromoester as the reagent.

carboxylic acid [49], dithioester [50], carbon disulfide [51], amide [52], acyl chloride [53], imidate and cyano group [54] etc., to form S-C=N via the thiocarbonylation and the imidization.

2.5. -Halogen-substituted Ketone and Thioamide as the Rea-gents

In the Asinger reaction, the -halogen-substituted ketone is available for the nucleophilic attack from mercapto group that may be derived from the elemental sulfur, while the carbonyl group acts as the receptor for the amino group. Thus, the usage of -halogen-substituted ketone in the ring-closure of thiazoline is the most close to the original Asinger’s approach. For example, as shown in Scheme 24, the C=S in a thioamide tautomerizes to form sulfuric anion for attacking the C-Br in ethyl 2-bromopyruvate, resulting in the formations of C-S bond and the C=N bond subsequently. So, ethyl 2-bromopyruvate is the key reagent for preparing thiazole, in which the bromide atom at -position of pyruvate acts as the leav-ing group in the process of nucleophilic substitution by the sulfuric anion. In the following reactions, the ester group converts into a cyano group for the synthesis of thiazoline (see the last equation in Schemes 23 and 24).

An aminolysis takes place between the ester group and imine when -halogen-substituted ester is used as the regent to prepare thiazoline, while -halogen-substituted ketone acts as the regent, further dehydrogenation affords thiazole as shown in Scheme 25 [55].

In the case of -chloroacetoacetanilide as the reagent to react with thiourea and isothiocyanate, different pathways will be fol-lowed when the sulfuric anion resulting from the tautomerism of C=S acts as the nucleophile. As shown in Scheme 26, the C-O bond in dihydrofuran is attacked by the sulfuric anion to give 1,3-imidazoline-2-thione [56], while the chloride atom in C-Cl of -chloroacetoacetanilide is replaced by the sulfuric anion to afford 2-phenylimino-1,3-thiazoline [57], in which the latter pathway be-comes a popular protocol for the preparation of the 2-imino-1,3-thiazolines in the case of an -halocarbonyl compound being the reagent [58].

The benzenesulfonylthiourea can be produced by the aminoly-sis of sulfonamide by isothiocyanate, and the electron-withdrawing property of the sulfuryl group does not influence the following reaction between the -halogen-substituted ketone and the ben-zenesulfonylthiourea as shown in Scheme 27 [59], in which a thiosemicarbazide can be formed by the reaction of the hydrazide with the isothiocyanate, and the sulfamide group as an electron-donating group can also promote the ring-closure of the thiazoline [60]. In addition, isothiocyanate as a nucleophile is able to substi-tute -halogen atom in ketone, followed by the annulation for pro-ducing thiazoline. But the sulfuric atom can also be a leaving group when amino group acts as the nucleophile, and thus, the aforemen-tioned procedure can be readily replaced by a simple nucleophilic substitution [61].


ClNH

R1

O O

-chloroacetoacetanilide

R2 NH2

ClNH

R1

N O

R2

ClN

R1

N OH

R2

- HCl

O NR1

NR2

O NR1

HN

R2

R3 NCS

(C2H5)3NO N

R1

N

R2

N

R3

S

1,3-imidazoline-2-thione

H

O N

R1

N

R2

N

R3

HS

O

HN

R1

N

R2

N

R3

S

R3

NH

NH

R2

S

thiourea

O

O

Cl2

ClCl

O O

R1 NH2

ClNH

R1

O O

R3

NH

NR2

SH

SNH

R1

O O

R3

HN

N

R2S

NH

R1

OH

O

R3

N

N

R2

- H2O2-phenylimino-1,3-thiazoline

R2 = Ph

SNH

R1

O

R3

N

N

R2

+

NH

NH

R

SR'

X

O

alcohol

reflux

N

S

R'

R

N

R, R' = CH3, Ph

Scheme 26. The usage of -halocarbonyl compound and thiourea for synthesizing thiazolines.

To sum up the methods for constructing the thiazoline scaffold as shown in Scheme 28, the C

2-S

1 bond can be generated from N- -

SH(R) amide or N- -OH thioamide by intramolecular dehydration, while C

2=N

3 bond can be produced from S- -azido-thiolester via

aza-Wittig reaction. Moreover, S1-C

2=N

3 bond can be simultane-

ously generated from the reaction between a carbonyl compound and -aminothiol, as well as the C

5-S

1 and C

4-N

3 bonds can be pro-

duced by the reaction of thioamide with -halogen-substituted ke-tone. All these protocols cannot cover up the advantage of Asinger reaction, in which all the bonds (except C

4-C

5 bond) can be gener-

ated via one-pot operation in the case of elemental sulfur and am-monia being S and N resources. Therefore, it is worthy enlarging the applicability of Asinger reaction for constructing thiazoline.

3. GROEBKE REACTION FOR CONSTRUCTING IMIDA-

ZOLINE

3.1. Relationship Between the Groebke Reaction and Asinger

Reaction

The structure of imidazoline is similar to that of thiazoline ex-cept that the sulfur atom in thiazoline is replaced by nitrogen atom in imidazoline, while the synthetic method for imidazoline scaffold is also similar to that of thiazoline. For example, as shown in Scheme 29, double amino groups are condensed with carboxylic acid or triethyl orthoformate [62]. Nowadays, this method is still used to construct imidazoline scaffold [63]. On the other hand, the deep exploration of isocyanides in the organic reactions leads to a


NN

Cl

S

H2NO

ONCS

K2CO3

reflux10 hours

NN

Cl

S

HN

O

O

R1

HN

R1

S

BrCH2COOC2H5

CH3COONa

reflux, 2 hours

NN

Cl

S

N

O

O

N

R1

S

O

60~68%

sulfuryl group

electron-

withdrawing

group

Br

O

CH3COONa

reflux, 3 hours

NN

Cl

S

N

O

O

N

R1

S

55~72%

ArS

NHNH2

O

NCS

ArS

N

O

N

H

H

HN

S

Br

O

R

sulfamide

electron-

donating

group

N

S

N

HN

O

S

Ar

R

S

N

NH2

ClCl

O

S

N

NH

Cl

O

NH4SCN

O

O

room temperature

2 hours

O

reflux5 hours

S

N

NH

S

O

NS

N

SN

O

HN

HS

N

O

N

S

N

S

NO

S

O

O

59%

C2H5OH

reflux2 hours

74%

Scheme 27. Either electron-withdrawing or electron-donating group cannot affect the ring-closure of thiazoline in the case of thiourea as the reagent, together

with amino group being a nucleophile for forming C-N bond via nucleophilic substitution.


N

S

R1

R2

R3

The C=N bond can be

produced by the

intramolecular

aza-Wittig reaction.

(see 2.4)

The C-S bond can be produced by the dehydration

between C=S and N-beta-OH

or C=O and N-beta-SH (or -SR).

(see 2.2 and 2.3)

The S-C=N bond can be

produced by the reaction

between carbonyl compounds and beta-aminothiols.

(see 2.4)

The C-S and C-N bonds

can be produced by

the reaction between

the thioamide and alpha-halogen-

substituted ketone.

(see 2.5)

All the bonds are produced

by Asinger reaction with

elemental sulfur and ammonia

as the S and N resources

and ketone as the other parts.

1

2

34

5

Scheme 28. The methods for constructing thiazoline scaffold.

N

SR2

R3

R1

thiazoline

N

HN

R2

R3

R1

imidazoline

replacing S in thiazolineby N to form imidazoline

This part may be derived from the condensation of

carbonyl group and double

amino groups.

Traditional method for

producing imidazoline

Cl

Cl

NH2

NH2

O

O

O

+

Al(CH3)3CH3

reflux(1.0 equiv.)

NH

N

Cl

Cl

O

77%

Groebke-Bienayme-Blackburn reaction

for producing imidazo[1,2-a]pyridine

N

H2N

R2

alpha-aminopyridine

or other N-contained heterocycles

O

R1 H +


between -NH2 and C=O

for producing C=N

H+

N

N

R2

R1

N CR3

H

[4+1]

annulation

N

N

R2

R1

NR3

N

N

R2

R1

NHR3

fused 3-aminoimidazoles

N CR3+

CH3OH

H+

Three reagents are mixed in

CH3OH and produce

the final product.

Scheme 29. The methods for constructing imidazoline scaffold.


N

NN

N

N

N

PPF6

(PyBOP)

The heating mode in this synthesis is microwave irradication.

O

O

F

NO2

R1 NH2

CH2Cl280°C

10 min

O

O

NH

NO2

R1

89%

CH3OH 90°C

5 min O

O

NH

NH2

R1

80%

N NH2

OH

O

PyBOP

(C2H5)3N

DMF

160°C, 10 min

O

O

NH

NH

R1

N

O

H2N

86%

(CF3CO)2O MgSO4

Cl(CH2)2Cl 130°C, 10 min

O

O

N

N

R1

N

OH

H2N

Hdehydration

NN

NO

O

R1 H2N

82%

Traditional method for

constructing imidazoline

R2 H

O

R3 N C

Sc(CF3SO3)3

135°C

5~10 min

N

N

N

N

O

O

R1

R2

NH

R3

81%

Groebke reaction for

constructing imidazoline

benzimdazole-imidazo[1,2-a]pyridines

Zn HCOONH4

Scheme 30. Two methods for constructing benzimdazole-imidazo[1,2-a]pyridines.

large number of discovery for constructing nitrogen-related com-pounds [10, 13], which enlightens a great deal of attempt to taste the synthesis of nitrogen-fused heterocycles deriving from isocya-nides [64], in which reports by Professor Katrin Groebke [65], Hugues Bienaymé [66] and Christopher Blackburn [67] one decade ago introduce a method commonly applied to prepare imidazo[1,2-a]pyridine by the annulation of -aminopyridine, aldehyde, and isocyanide, and the reaction is then entitled by their names (see Scheme 1) and abbreviated as Groebke reaction. Scheme 29 also provides the mechanism for the reaction, in which the carbanion in isocyanide as a nucleophile adds to the C=N (generated by the reaction of aldehyde with -aminopyridine), subsequently, a [4+1] annulation takes place between carbon atom in isonitrile and conju-gated imines to combine imidazoline with pyridine by [1,2-a] style consequently. As a matter of fact, the mechanism of Groebke reaction possesses similar basis with that of Ugi or Passerini reac-tion, in which imine deriving from the reaction between aldehyde and amino group performs a nucleophilic addition by the carbanion in isocyanide and the proton of carboxylic acid, while, in the Groebke reaction, the addition between the carbanion in isocyanide

and conjugated imine plays the key role in the ring-closure of imi-dazoline. On the other hand, the necessity of aromatic nitrogen atom and -amino group in the formation of [1,2-a] structural feature, to some extents, limits the application of Groebke reaction. The following review on the Groebke reaction is cataloged as the expanding of substrates and the screening of catalysts.

3.2. 2-Aminopyridine-type Substrates

Although a nitrogen-involved aromatic ring and an -amino group are inevitable in the Groebke reaction, some efforts still con-tribute to enlarge the applicability of the substrates, in which 2-aminopyridine-type heterocycles play the major in this case. As can be seen in Scheme 30, the traditional method together with the Groebke reaction are applied successively to afford benzimidazole-linked aminopyridine and then to give benzimdazole-imidazo[1,2-a]pyridines [68]. As shown in Scheme 31, ammonium chloride is applied to catalyze the formation of imine resulting from the reac-tion between benzaldehyde and 2-aminopyridine or 2-aminopyrazine. The electron-donating groups, i.e., methoxy group,


at para-position of benzaldehyde lower the yield of the aryl-aminoimidazo[1,2-a]pyridine because they are not beneficial for the C=O of benzaldehyde to accept the nucleophilic attack from amino group of aminopyridine or aminopyrazine [69]. The simplest way to enrich the substrates for the Groebke reaction is to assign the sub-stituents at 2-aminopyridine, but in order not to influence the for-mation of imine and the stability of isonitrile, some inert substitu-ents including -CH3, -OCH3, -CN, -Cl, and -Br are preferred groups [70]. With the similar structure to 2-aminopyridine, 2-aminopyrazine becomes the preference in the study on the Groebke reaction, during which the usage of 1,1,3,3-tetramethylbutyl isocyanide (Walborsky reagent) affords a amino group after the 1,1,3,3-tetramethylbutyl moiety is hydrolyzed [71]. Or, as shown in Scheme 31, 4-bromo-2-aminopyridine and 10-chloroanthracene-9-carbaldehyde as the reagents carry out the Groebke reaction and then perform the Heck reaction for combining the amino group with pyridine or anthracene moieties [72]. Sometimes, researchers divide the one-pot Groebke reaction into two-step operations according to the mechanism, in which, as shown in Scheme 32, 2-aminobenzimidazoles and methyl 2-formylbenzoate are first heated to afford imine for the following annulation with isonitrile, and an intramolecular amidation takes place between the amino group (deriving from the isonitrile) and the ester group (deriving from the methyl 2-formylbenzoate) [73].

Some five-membered heterocycles bearing -amino such as 3-

amino-1,2,4-triazole, 1,3,4-thiadiazol-2-amine, and 5-amino-1H-

pyrazole-4-carbonitrile can also take part in the Groebke reaction.

As can be seen in Scheme 33, two nitrogen atoms located at the

adjacent position of the amino group in 3-amino-1,2,4-triazole, the

nitrogen atom from C=N (as in pyridine) plays a nucleophilic role

in the following annulation, but the nitrogen atom from N-H (as in

pyrrole) cannot drive the ring-closure because no electron pair

being the nucleophile in the nitrogen atom. The oxygen in air is

capable of oxidizing the product to perform the aromatization [74].

However, when the 1,3,4-thiadiazol-2-amine acts as the reagent to

undergo the Groebke reaction, the desired imidazo[2,1-

b][1,3,4]thiadiazole can only be yielded in the case of the same

amount of trimethylsilyl chloride (TMSCl) used in the aprotic

solvent [75]. The TMSCl can promote the Groebke reaction with 2-

aminopyrimidine or 2-aminopyrazine being the reagent [76] and

almost becomes a popular participant in the Groebke reaction [77].

As shown in Scheme 34, after the toluene-4-sulfonylmethyl

isocyanide takes part in the Groebke reaction, the p-toluenesulfonyl

group as a leaving group affords an amino group, which reacts with

benzaldehyde to afford Schiff base [78]. As a result, toluene-4-

sulfonylmethyl isocyanide may be an aminating agent for the

Groebke adducts.

N

X

NH2

Y

X = CH, N

Y = CH3, H, Br

N C

or

N C

+ +

Z

O

H

Z = H, 4-CH3, 4-Cl;

4-CH3O, 3-NO2

NH4Cl

CH3OH

room temperature

3 hours

NX

N

YHN

or C(CH3)3

Z

58~96%

N

N

NH2

H

O

CH3CN

reflux, 2 hours

1.

(CH3)3SiCl

CH3CN

70°C, 18 hours

2. NC

Walborsky reagent

N

N

N

HN

78%

4 N HCl

O O

room temperature

3 hours

N

N

N

NH2

89%

2-aminopyrazine

N NH2

R5

R4

R6

R3

R3, R4, R5, R6 =

-CH3, -OCH3,

-CN, -Cl, -Br

O

R1 H

R1, R2 = alkyl group

R2 N CN

N

R3

R4

R5

R6

R1

HN R2

+ +



N NH2N

C

Br

HO HCl / O OCH3CN


400 W, 30 min

N N

NH

Br

2-dicyclohexyl

phosphino-2'-

(N,N-dimethyl

amino)biphenyl

(DavePhos)

PN

tris(diben

zylidene

acetone)

dipalladium

(Pd2(dba)3)

O

Pd

Pd

3

63%

(CH3)3COK

Pd2(dba)3

DavePhos

OO

H2N(CH2)3N(CH3)2N N

NH

HN

N

40%

N NH2

NC

HO

HCl / O OCH3CN


400 W, 30 min

N N

NH

59%

(CH3)3COK

Pd2(dba)3

DavePhos

OO

H2N(CH2)3N(CH3)2

N N

NH

26%

ClCl

10-chloroanthracene-9-carbaldehyde

4-bromo-2-

aminopyridine

N

NH

80°C

800C

Scheme 31. Some typical -aminopyridine-type substrates employed in the Groebke reaction.

The N-cyclohexyl-2-phenylimidazo[1,2-a]pyridine-3-amine is highly yielded even in the absence of any catalysts and solvents because the applied reagents involving 2-aminopyridine, benzalde-hyde, and cyclohexylisocyanide for the Groebke reaction do not contain any sensitive substituents [79]. But the yields of the Groebke adducts are generally lower than 50% when hydroxyl-substituted benzaldehydes are used as the reagents, however, the Groebke reaction even follows another procedure to afford an iso-mer with 2-aminopyrimidine being the reagent as shown in Scheme 35 [80].

3.3. Other Substrates

Some efforts break the limitation of the substrates applied for the Groebke reaction. As can be seen in Scheme 36, one of the amino group in o-phenylenediamine reacts with the benzaldehyde to form an imine, the following [1+5] annulation takes place among another amino group (instead of the nitrogen atom in pyridine) and the imine, and the produced 2-aminoquinoxaline can be the substrate for the Groebke reaction [81]. As shown in Scheme 37, when the phenacyl bromide (or chloroacetonitrile) and methyl


N

N

NH2

O

O

O

H

O

O

+

NH

CH2Cl2MgSO4

reflux

8 hours

formation of imine

N

N

NO

O

CH3

NC

NHsealed tube

12 hours

O

O

N

N

NO

O

NO

O

H

NH

intramolecular

amidation

The base abstracts the hydrogen atom,

resulting in an anionic nitrogen to attack

carbonyl group of ester.

N

NN

N

O

O

O

95% Scheme 32. Two-step operation following the mechanism of the Groebke reaction.

N

NH

N

NH2

3-amino-1,2,4-triazole

R1

CHO

R1= -OCH3, -N(CH3)2

R2

N C

R2= -H, -F

CH3OH

NH4Cl

reflux

15 hours

N

N

N

HN

HN

R1

R2

air

NH

N

N

NN

R1

R2

~50%

S

NN

NNR1

O

NH

R1 =,

NH2

N-substituted 5-piperazin-1-yl-

1,3,4-thiadiazol-2-amine

CHO

R2

R2 = 3-F-, 4-C2H5-R3 = (CH3)3C- ,

(1.0 equiv.)

CH3CN

reflux

2 hours

1.

2. (CH3)3SiCl

(1.0 equiv.)

CH3CN

CH2Cl230 min

3. R3 N C

N

S

N

NNNR1

R2

HN R3

92%

N

XY

NH2

H

O

(1.0 equiv.)

CH3CN

reflux

(1.0 equiv.)

CH3CN

CH2Cl2

(CH3)3SiCl

N C N

XY

N

NH

2-aminopyrazine, X = CH, Y = N, 67%

2-aminopyrimidine, X = N, Y= CH, 65%

room temperature

30 min

Scheme 33. Other heterocycles bearing -amino take part in the Groebke reaction.


N

NH

CN

NH2

H

O

CH3 SO3H

N

NH

CN

N

CH3

S N

CO O

toluene-4-sulfonylmethyl

isocyanide

H

[4+1]

annulation

N

N NH

CN

NH

S

O O

CH3

1. oxidationN

N NH

CN

NS

O O

CH3 2. H+

H

H2ON

N NH

CN

N

S

O O

CH3

H

HO

H2O

hydrolysis

S

O O

CH3

OH

N

N NH

CN

N

H

HO

H

H

- HCHON

N NH

CN

H2N

H

O

N

N NH

CN

N

65%

formation of Schiff base

Scheme 34. The toluene-4-sulfonylmethyl isocyanide as the precursor of amino group for the Groebke adducts.

thiocyanate are selected to be the reagents, pyridine (without -amino group contained) is able to perform the Groebke reaction [82]. In addition, the usage of 1,2-diaza-1,3-diene can lead to Michael addition with the nitrogen atom in pyridine, quinoline, or isoquinoline being the nucleophile, followed by a nucleophilic addition occurring between pyridine and nitrogen anion [83].

As shown in Scheme 38, the inorganic cyanide such as KCN is also suitable for the Groebke reaction, in which 2-aminopyridine and phthaldehydic acid act as the reactants, and an intramolecular amidation leads to the formation of pyrido[2’,1’:2,3]imidazo[4,5-c]isoquinolin-5(6H)-one [84]. A diamine reacts with cyanogen bromide (BrCN) to give 2-aminobenzimidazole, which can carry

out the Groebke reaction to afford imidazo[1,2-a]benzimidazole eventually [85]. Following the o-phenylenediamine as the reagent in the Groebke reaction, 2-aminophenol reacts with ketone and isocyanide to afford benzo[b][1,4]oxazine, which can be trapped by the adjacent phenolic hydroxyl of 2-aminophenol to yield benzoxazole (shown in Scheme 38) [86]. The hydroxyl group in pyridoxal can also act as the nucleophile in the second step to produce furo[2,3-c]pyridine scaffold [87]. The oxazolone-type scaffold undergoes a cycloaddition to give imidazoline. For example, as shown in Scheme 38, after phenylglycine reacts with acyl chloride to produce oxazolone in the presence of trifluoroacetic anhydride, the oxazolone is treated by an imine in the presence of


N NH2

CHO N C

+ +from 35°C, 48 hours

to 160°C, 2 hours

catalyst-free

solvent-freeN

N

NH

> 90%

N-cyclohexyl-2-phenyl

imidazo[1,2-a]pyridine-3-amine

N

N

NH2

2-aminopyrimidine

N

CH3

C

CHO

OH

OCH3CH3O

+

+

CH3COOH

CH3OH

N

N

N

OCH3

OH

OCH3

NH

CH3

normal product

N

N

N

HN

isomer

CH3

OH

OCH3

CH3O

normal product : isomer

= 1 : 4

< 50%

20°C

Procedure for

the formation

of the isomer

N

N

NH2

CHO

OH

OCH3CH3O

+

N

N

N

N

N

NH

OH

OCH3

OCH3

HO

CH3O

OCH3

normal

isomer

N

C

CH3

N

C

CH3

N

N

N

OH

OCH3

OCH3

NH

CH3

N

N

N

HO

CH3O

OCH3

NH CH3

Scheme 35. Low yield of the Groebke adducts resulting from the reagents with sensitive substituents.


o-phenylenediamine

R1

R1

NH2

NH2

R1 = H, CH3

O

O

Cl

Cl

N

N

(DDQ)

R2 CHO

NC

concentrated HCl

(1.0 equiv.)

CH3OH

room temperature

18 hours, under Ar

R1

R1

N

NH2

R2

N

C

[1+5] annulation

NH

HN

NH

R2

R2 = H, COOCH3

DDQ (1.0 equiv.)


N

N

NH

R2

R1 = R2 = H, 47%, 94%

R1 = CH3; R2 = H, 39%, 99%

R1 = CH3; R2 = COOCH3, 54%, 88%

4N HCl O O

room temperature

3 hoursN

N

NH2

R2

2-aminoquinoxaline

hydrolysisDDQ

oxidation

CHOF

O NC

(CH3)3SiCl

CH3CN / CH3OH

500C, 20 hours

N

N

N

R1

R1

R2

F

NH

O

65%

R1 = R2 = H

R1

R1

R1

R1

R1

R1

Scheme 36. Screening other reagents for the Groebke reaction.

Lewis acid to generate the imidazoline scaffold as a single diastereomer [88].

Some carefully selected reactants avoid using isocyanides in the Groebke reaction. Scheme 39 illustrates an electrophilic aminoalkoxylation reaction occurs among olefin, N-bromosuccinimide (NBS), and amine, and the produced amidine can flexibly convert into imidazoline within one-pot operation. The NBS provides a bromonium ion to promote the electrophilic addition, and the electrophilic addition makes it possible for the cyano group in CH3CN to add to the carbonium ion. The bromoamidine leads to the following intramolecular nucleophilic substitution for constructing the imidazoline scaffold [89].

Moreover, some efforts focus on the reaction of the imine generated by the reaction of aldehyde with amino group. For example, as shown in Scheme 40, the propiolaldehyde reacts with 2-aminopyridine to form alkynylimine, which can be added by alcohol, thiol, or amine to occur Michael addition with nitrogen atom in pyridine [90]. Or, the nitrogen atom in pyridine substitutes the chloride atom in the imine (generated by 2-aminopyridine and ethyl 2-chloroacetoacetate) to produce imidazo[1,2-a]pyridine-3-carboxylic acid [91].

In addition to the classical Groebke reaction applied for combinatorial screening novel molecules with biological activities [92], other protocols are designed for synthesizing imidazoline and


N

Br

O

CH3 SCN ++phenacyl bromide

ClCH2CN

chloroacetonitrile

CH3 K2CO3

reflux

96 hours

CH3

K2CO3

reflux

12 hours

N

N

O

S

N

N

CN

S

78%

methyl thiocyanate

N

R1 NN O

O R2

O

1,2-diaza-1,3-diene

N

N

isoquinoline

quinoline

no solvent

room temperature

+

N

N

N

N

N

N

R2

R1

O

R2

R1

O

R2

R1

OR1 = OCH3, R2 = CH391%

83%

86%

Procedure of the reaction

R1 NN O

O R2

ON

Michael addition

R1 NN O

O R2

ON

H

nitrogen anion as a base

to abstract the proton

R1 N

HN O

O R2

ON

R1 N

HN O

O R2

ON

nucleophilic

addition

N

N

R1

O

H

NH

O

O - H2NCOOC(CH3)3

R2

N

N

R1

O

R2

Scheme 37. Pyridine as the reagent for the Groebke reaction.


N NH2

O

O

H

OH

+

+ KCNNaOH aq.

NaHSO3 aq.

NH

N

N

O

35%

NC+

N

N

N

O

74%

phthaldehydic acid

pyrido[2',1':2,3]imidazo[4,5-c]

isoquinolin-5(6H)-one

NH

NH2O

O

diamine

BrCN

CH2Cl2reflux

12 hours

N

NO

O

NH2

85%

2-aminobenzimidazole

imidazo[1,2-a]benzimidazole

H

O

NH

(0.3 equiv.)

ClCH2CH2Cl


(100°C), 10 min

N

NO

O

N

N C


(130°C), 10 min

N

NNO

O

HN

86%

55°C

NH2

OH

2-aminophenol

N

O

NC

O

+ +

CF3SO3H

CF3CH2OH

(0.1 equiv.)

55°C

1 hour

HN

O

N

N

O

39%

benzo[b][1,4]oxazine

NH2

XHCF3CH2OH

55°C

24 hour

H+

HN

N

NHO

O

NH

HX

N

N

X

HN

HO

X = N, 98%

= O, 87%

= S, 93%

N

N

X

HN

HO

HN

O

H



H2N

OH

O

phenylglycine

Cl

O

OO

H2O

Na2CO3

room temperature

(CF3CO)2O

CH2Cl2

room temperatureN

O

O

oxazolone

(CH3)3SiCl

CH2Cl2

reflux

R1N R2

N

N

R2

R1

HO

O

R1 and R2 = aromatic group

Scheme 38. Other reagents for the Groebke reaction.

R2 R3

R1

N

O

O

Br

N-bromosuccinimide

(NBS)

Br

bromonium ion

R2

R3

R1 Br

CN R4

R2 R3

R1

Br

CN R4

R NH2

R2

R3

R1 Br

C

N R4

RHN

N

NR1

R2

R3

R4

R

Example

N

O

O

Br

SCH3 NH2

O

O

CH3CN

reflux, 2 hours

Br

NH

CH3

N S

O

O

CH3

92%

(TsNH2)

CH3CN

25°C, 4 hours

N

N

H

H

CH3

S

O

O CH3

Possible mechanism for

the formation of imidazoline

95%

Br

NH

CH3

N Ts

H

Br

H

NH

CH3

NTs

Br

H

N

CH3

NTs H

H

N

CH3

NTs

H

H

bromoamidine

conformation conversion and

intramolecular nucleophilic

substitution

Scheme 39. NBS promotes the electrophilic addition for the formation of imidazoline.


R1

H O

N NH2

+ R2 + RXH

CH3COOH

CH3CN or ROH

80°C, 8 hours

X = O, S, NHpropiolaldehyde

N

NR2

RXR1

R1 = ; R2 = H; RXH = C2H5OH, 80°C, in C2H5OH, 8 hours, 89%

R1 = ; R2 = 4-CF3; RXH = n-C12H25SH, 80°C, in CH3CN, 8 hours, 80%

R1 = ; R2 = 4-CF3; RXH = , 80°C, in CH3CN, 8 hours, 88%

N

CF3

NH2

Possible mechanism

R1

H O

N NH2

R2

CH3COOHN N

R2

R1

H

alkynylimine

R XH

nucleophilic

addition

N

N

R2R1

H

XR

Michael

addition

N

N

R1

XR

CH3COOHN

N

R1

XR

H

H- H+N

N

R1XR

N NH2

R1

CH3OCH2CH2OCH3

reflux, 48 hours

R2 O

O O

Cl N NR1

R2 O

O

Cl

nucleophilic

substitution

N

N

OO

R2

R11. LiOH, C2H5OH

2. HCl, 56 hoursN

N

OOH

R2

R1

(ethyl 2-chloroacetoacetate)

Scheme 40. Other reagents instead of isocyanides for the formation of imidazoline.

oxazole. As shown in Scheme 41, in the preparation of imidazoline-oxazoline scaffold, N- -amino and N- -chloro amides take place the dehydration and the dehalogenation under basic condition, respectively, to afford imidazoline and oxazoline scaffold [93]. On the other hand, in the classical Groebke reaction, the carbanion converts into an oxygen anion via the tautomerism, and subsequently, the oxygen anion performs a nucleophilic addition to the alkynyl group to yield oxazole scaffold [94].

3.4. Catalysts

The Groebke reaction is composed of the formation of imine by the reaction of ketone with amino group and the [4+1] cycloaddition between the isonitrile and the conjugated imine. In principle, these two reactions do not need to be catalyzed because of high reactivity of the reactants, but some catalysts are still applied to drive the formation of imine or to activate other reactants (instead of 2-aminopyridine-type substrates) for producing imidazo-


NH HN

HOOH

O O1. SOCl2, reflux, 2 hours

2. RNH2

(HOCH2CH2)3N, (C2H5)2O


NH HN

ClNH

O O

R

10% NaOH aq.

room temperature

6 hours

HN

Cl

O

N

N

N

O

R

1. CH3OH : (1:4)

O

2. NaOH, reflux, 12 hours

N

N

R

imidazoline-oxazoline

R1H

O R2NH2

R1H

NR2

CN

X

R3

O

N

X

R3

OR1

N

R2

H

N

X

R3

OR1

HN

R2

N

X

R3

OR1

HN

R2

N

O

X

R3

NH

R1

R2

oxazole

Scheme 41. Other protocols for synthesizing imidazoline and oxazole.

Table 1. The catalysts used in the Groebke reaction.

Brønsted Acid or Base Examples Shown in Lewis Acid Examples Shown in Oxidative Catalysts Examples Shown in

NH

Scheme 32 ZrCl4 Scheme 43 I2 Scheme 44

N

N

(DBU)

Scheme 42 Sc(CF3SO3)3 Scheme 30, 43 CuI Scheme 44, 45

HCl Scheme 31, 36 SnCl2 • 2H2O Scheme 43 Cu(CH3COO)2 Scheme 44

NH4Cl Scheme 31, 33 InCl3 Scheme 43 Pd(CH3COO)2 Scheme 45

CH3COOH Scheme 35, 40 CeCl3 • 7H2O Scheme 43

(CH3)3SiCl Scheme 31, 33

SO3HCH3

Scheme 34, 44

CF3SO3H Scheme 38

HClO4 Scheme 42

-Fe2O3 @SiO2-OSO3H Scheme 42


N

N

(DBU)

N NH2

Br

NC

O

H

O

HClO4, CH3OH

N

NOO

microwave

irradiation

2200C, 5 min

Br

NH

O

65%

N

N

Br

N

O

N

N

N

Br

O

- H+

H+

N

N

N

Br

O

H

H N

N

N

Br

O

H

H

N

N

N

Br

O

H H

97%

HO

CH3

+

NC

+

gama-Fe2O3@SiO2-OSO3H

(1 mol %)

solvent-free, 35°C, 1 hour

S

N

NH2

S

N

NCH3

HN

87%

Scheme 42. Brønsted acid or base employed to catalyze the Groebke reaction.

lines. Thus, as can be seen in (Table 1), the catalysts are catalogued as Brønsted acid or base, Lewis acid, and the oxidative catalysts. The aim of the usage of acids is to catalyze the formation of imine, while the oxidative catalysts are able to drive the formation of imidazoline skeleton in the case of non-classical reactants employed.

In addition to the aforementioned Brønsted acid or base applied to catalyze the formation of imine (see the Scheme number in Table 1), other catalysts will be discussed in the following statements. It can be found in Scheme 42 that 2-amino-5-chloropyridine, 3-phenylpropiolaldehyde, and 1-isocyano-4-methoxybenzene are

catalyzed by perchloric acid (HClO4) to give 2-(arylethynyl)imidazo[1,2-a]pyridin-3-amine, which takes place a ring-closure with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) being the catalyst. The formation of pyrido[2’,1’:2,3]imidazo[4,5-b]quinoline is owing to the nucleophilic addition of nitrogen anion (deriving from the abstraction of hydrogen atom in N-H by DBU) to the alkynyl group [95]. The proton can be fixed on the surface of a nanoparticle, -Fe2O3@SiO2-OSO3H, for catalyzing the Groebke reaction [96].

As can be seen in Schemes 30 and 43, the usage of Sc(CF3SO3)3

almost becomes a popular way to catalyze the Groebke reaction.


The nucleophilic activity of the -amino group may be decreased

by the electron-withdrawing property of the pyridine. Although some electron-withdrawing groups attaching to the benzaldehyde,

i.e., -F (at para-position of -CHO) [97], -COOH (at meta-position of -CHO) [98], -Cl (at para-position of -CHO) [99], may enhance

the ability of the aldehyde group to accept the nucleophilic attack from amino group, Sc(CF3SO3)3 as a Lewis acid is still needed to

drive the formation of imine. A suitable catalyst and appropriate solvent are able to increase the yield of the Groebke reaction. As

can be seen in Scheme 43, the yield of adenine-involved Groebke

reaction may increase from 23% to 68% with HClO4, Sc(CF3SO3)3, InCl3, CeCl3, or ZrCl4 being catalyst in the mixture of dimethyl

sulfoxide (DMSO) and water or pure DMSO [100]. The selection of catalyst largely depends upon the reactivity between the

benzaldehyde and -aminopyridine. Scheme 43 shows that the reaction of 2-aminopyridine with benzaldehyde can be catalyzed

by SnCl2•2H2O in a solvent-free system under room temperature [101].

N

H

O

18F

NH2

NC N

N

HN

18F+

R

R

Sc(CF3SO3)3

CH3OH

room temperature

24 hours

R = H, 73%

R= Cl, 62%

N

H

O

NH2

+

HO

O

Sc(CF3SO3)3

CH3OH/CH2Cl2

room temperature

45 min

N

OH

ON

R N C8 hours

N

N

RHN

HO

O

R = -C(CH3)3

CH3O

O

H

O

O

NH2

CH3ON

OC Ugi four-

component

reaction

12 hours

R = -C(CH3)3

N N

NH

R

N

OHN

O

O

O O

72%

N NH2

NC

+ (HCHO)n+

Sc(CF3SO3)3 (10% mol)

CH3OH/CH2Cl2 (v:v=1:2)

reflux, 20 hours

N

N

HN

44%

macroporous polystyrene carbonate HOH

O

O

+

replace (HCHO)n byno catalyst

50°C, 20 hours

71%

Scheme 43 Contd……


N

N N

HN

NH2

adenine

H

Cl

O

+ N C+

catalyst

(10 mol%)

solvent

70°C

N N

NHN

N

HN

Cl

catalyst solvent yield

HClO4 DMSO 43%

Sc(CF3SO3)3 DMSO 52%InCl3 DMSO 47%

CeCl3 7H2O DMSO 42%

ZrCl4 DMSO/H2O(1:1) 23%

ZrCl4 DMSO 68%

N NH2

CH3

S

H

O

+

NC

+

SnCl2 2H2O

solvent-free

room temperature15 min

N

N

SCH3

HN

88% Scheme 43. Lewis acids as catalysts for the Groebke reaction.

N NH2R CH3

O

+

1. I2

2. NaOH (45% aq.) N

N

R

R =

OH

57%OH

61%

O OH

39%

HO

More hydroxyl groups decrease the yield.

OH

56%

Br OH

53%

Br

The electron-withdrawing group at para- or meta-position

does not influence the yield markedly.

55%

N55%

NH

S43% 51%

N NH2

O

+

CuI (5 mol %)

additive and solvent

1000C, 24 hours

1 atm O2

N

N

additive = none solvent = DMF yield = 66%

none NMP 69%

In(CF3SO3)3(1%) NMP 81%

BF3 (C2H5)2O(10%) NMP 50%

CuBr2 (5%) NMP 80%

N H

O

DMF =

N

ONMP =

N NH2

H

OBr

N C

CH3

SO3H

CH3OH

room temperature

18 hours

N

N

NH Br

N N

CuI

Cs2CO3

DMF

120°C, 2 hours

N

N

N

72%

Scheme 44. The oxidative catalysts applied for the Groebke reaction.


N

R1

H

R2

H

N

O

O

oxime ester

+

CuI (20 mol%)

Li2CO3 (20 mol%)

air, DMF

95°C, 2 hours

N N

R2R1

yields of

typical products

N N

81%

N N

73%

N N

61%

N N

40%

N N

O

O

32%

Possible mechanism

N

O

O

CuIX

oxime ester-

Cu(I) complex

N

CuIIIOAcX

elemination

of ester group

N N

CuIIIOAcX

N

N N

CuIIIOAcX

formation of C-N

by C-H in pyridine

and N in imine

H

HN N

CuIIIOAcX

elemination

of CH3COOH

HN N

CuIIIX

formation of C-N

by N in pyridine

and C in terminal

vinyl group

HN N air N N

O

O

X

N C

N

1. Pd(CH3COO)2 (2 mol%)

XantPhos (4 mol%)

DMSO, 150°C, 5 min


+

+

2. HBF4 (48%, aq.)

n-C4H9OH

160°C, 20 min


N

N

O

HN

4-aminophthalazin-

1(2H)-one

O

PPh2 PPh2

XantPhos

Fe

PPh2

PPh2

dppf

R2

H

NH2

R2

R2 = H, X = Br, 98%

R2 = H, X = Cl, 29% R2 = H, X = Br,

R2 = H, X = CF3COO, 89% dppf, DMF, 81%

R2 = Ph, X = Br, 63% XantPhos, DMSO, 99%

yield

one-pot

Scheme 45. Contd…….


Possible mechanism

O

O

Br

(Ligands on Pd are omitted.)

Pd(0)O

O

Pd(II)Br

N CO

O

Pd(II)Br

N

- H2NNH2 HBr

O

O

Pd(II)

N

N

H

NH2

- Pd(0)O

O

N

NH

NH2

- CH3OH

N

NH

O

HN

2 H2NNH2

H

NI

+ + CO

PdN

O

2

(2.5 mol%)

P(t-C4H9)3 (7.5 mol%)

CD3CN

55°C, 18 hours

N N

H O

O

83%

Cat. =

Possible mechanism

(L refers to ligand for Pd, P(t-C4H9)3)

R3 ILnPd(0)

LnPd

R3

I

COLnPd

I

R3

O

R2H

NR1

O

Pd

N

R3

R1R2

Ln

I

CO

O

Pd

N

R3

R1R2

Ln

OC

O

Pd N

R3

R1

R2O

Ln

I

- HI

- LnPd(0)

O

N

R3

R1R2

O

Munchnone H

R2H

NR1H

N N

R3

R1R1

R2

H R2O

O

O

Pd

N

R3

R1R2

Ln

I

The product of the first

stage in the reaction produces the catalyst

for the following

process of the reaction.

Scheme 45. The coupling catalysts applied for the Groebke reaction.


The applications of some oxidative catalysts may enlarge the

scale of the substrates for the Groebke reaction and initiate the further reaction based on the imidazoline scaffold. As shown in Scheme 44, the usage of I2 as the catalyst completely changes the reagents, of which isonitrile is not the necessary reactant, while a methylcarbonyl group provides the structural feature of C=C bond for the imidazoline scaffold. A wide applicability of the substituents for the methylcarbonyl group makes this method an important protocol for the synthesis of imidazo[1,2-a]pyridine [102]. Based on this method, CuI may be another catalyst for the reaction of 2-aminopyridine with acetophenone, and other additives such as CuBr2 and In(CF3SO3)3 and suitable solvents can highly yield the target product [103]. After o-bromobenzaldehyde reacts with 2-aminopyridine and isonitrile to afford imidazo[1,2-a]pyridine, the N-H and Br can be coupled by CuI, generating N-fused polycyclic heterocycle eventually [104].

Some catalysts are able to activate C-H bond and lead to the coupling between C-H and N-H, directly generating imidazo[1,2a]pyridine from pyridine and other reagents instead of the traditional reactant for the Groebke reaction, isonitrile and aldehyde. As can be seen in Scheme 45, an oxime ester can react with pyri-dine to afford imidazo[1,2 a]pyridine, during which the complex of Cu(I) and oxime ester may be oxidized to form Cu(III) complex for combining with the nitrogen atom in pyridine, and then, the C-H in the terminal vinyl group is coupled with the nitrogen atom in pyridine [105]. Moreover, the reaction among o-bromobenzoate, isocyanide, and hydrazine can afford 4-aminophthalazin-1(2H)-one in the presence of Pd(0) as the catalyst, by which the C-Br bond in benzoate is activated for reacting with isocyanide to produce imine, while the complex of Pd(II) and imine is capable of combining with hydrazine. Finally, an intramolecular aminolysis of eater group in benzoate leads to the formation of 4-aminophthalazin-1(2H)-one [106]. Nevertheless, palladium salt is able to catalyze imine reacting with iodobenzene and CO to produce the imidazoline scaffold. The formation of imidazoline is ascribed to the Münchnone deriving from the complex of aryl iodide and palladium salt [107].

To sum up the Groebke reaction, the development of catalytic system may be an important direction for enlarging the application scale because an appropriate catalyst may change the substrates for the Groebke reaction. On the other hand, a suitable catalyst may drive the following reaction based on the Groebke adduct.

CONCLUSION

The high efficiency of MCR in the synthesis of a molecule owing to more than two bonds can be produced by more than two reactions within one-pot operation [108]. Comparing the bloom of some old MCRs [109], as the newcomers in the family of MCR, the research on Asinger and Groebke reactions seems unfrequented because only limited substrates are competent for them. Although many methods are designed for constructing thiazoline scaffold, these precise protocols cannot cover up the advantage of Asinger reaction, in which C-S and C=N bonds are produced simultaneously by using sulfur and ammonia as the resource of S and N atom in the final structure. On the other hand, imidazoline, in particular, imidazo[1,2 a]pyridine is generated by the Groebke reaction with

-aminopyridine being the necessary reagent, but the application of some catalysts breaks the limitation of the necessary reactant and thus develops the applicability of the reaction. Since the thiazoline and imidazoline are important scaffolds in the drug design and usu-ally act as the structural feature in natural compounds [110], it is worthy exploring the available catalysts for the Asinger and Groe-bke reactions in order to break the limitation of substrates and therefore to enlarge the applicability of these two MCRs.

CONFLICT OF INTEREST

The author confirms that this article content has no conflict of interest.

ACKNOWLEDGEMENTS

Declared none.

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Received: August 03, 2014 Revised: September 22, 2014 Accepted: October 10, 2014

Two Neglected Multicomponent Reactions: Asinger and Groebke Reaction for Constructing Thiazolines...

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