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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: zaiqun-liu@jlu.edu.cn
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
nucleophilic addition
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.
Two Neglected Multicomponent Reactions: Asinger and Groebke Reaction Current Organic Synthesis, 2015, Vol. 12, No. 1 23
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.
24 Current Organic Synthesis, 2015, Vol. 12, No. 1 Zai-Qun Liu
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.
Two Neglected Multicomponent Reactions: Asinger and Groebke Reaction Current Organic Synthesis, 2015, Vol. 12, No. 1 25
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
26 Current Organic Synthesis, 2015, Vol. 12, No. 1 Zai-Qun Liu
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.
Two Neglected Multicomponent Reactions: Asinger and Groebke Reaction Current Organic Synthesis, 2015, Vol. 12, No. 1 27
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.
28 Current Organic Synthesis, 2015, Vol. 12, No. 1 Zai-Qun Liu
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
Two Neglected Multicomponent Reactions: Asinger and Groebke Reaction Current Organic Synthesis, 2015, Vol. 12, No. 1 29
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.
30 Current Organic Synthesis, 2015, Vol. 12, No. 1 Zai-Qun Liu
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.
Two Neglected Multicomponent Reactions: Asinger and Groebke Reaction Current Organic Synthesis, 2015, Vol. 12, No. 1 31
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
room temperature, 16 hours
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.
32 Current Organic Synthesis, 2015, Vol. 12, No. 1 Zai-Qun Liu
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.
Two Neglected Multicomponent Reactions: Asinger and Groebke Reaction Current Organic Synthesis, 2015, Vol. 12, No. 1 33
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.
34 Current Organic Synthesis, 2015, Vol. 12, No. 1 Zai-Qun Liu
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.
Two Neglected Multicomponent Reactions: Asinger and Groebke Reaction Current Organic Synthesis, 2015, Vol. 12, No. 1 35
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……
36 Current Organic Synthesis, 2015, Vol. 12, No. 1 Zai-Qun Liu
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.
Two Neglected Multicomponent Reactions: Asinger and Groebke Reaction Current Organic Synthesis, 2015, Vol. 12, No. 1 37
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].
38 Current Organic Synthesis, 2015, Vol. 12, No. 1 Zai-Qun Liu
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
Two Neglected Multicomponent Reactions: Asinger and Groebke Reaction Current Organic Synthesis, 2015, Vol. 12, No. 1 39
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.
40 Current Organic Synthesis, 2015, Vol. 12, No. 1 Zai-Qun Liu
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 +
nucleophilic addition
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.
Two Neglected Multicomponent Reactions: Asinger and Groebke Reaction Current Organic Synthesis, 2015, Vol. 12, No. 1 41
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,
42 Current Organic Synthesis, 2015, Vol. 12, No. 1 Zai-Qun Liu
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
+ +
Scheme 31. Contd……
Two Neglected Multicomponent Reactions: Asinger and Groebke Reaction Current Organic Synthesis, 2015, Vol. 12, No. 1 43
N NH2N
C
Br
HO HCl / O OCH3CN
microwave irradiation
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
microwave irradiation
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
44 Current Organic Synthesis, 2015, Vol. 12, No. 1 Zai-Qun Liu
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.
Two Neglected Multicomponent Reactions: Asinger and Groebke Reaction Current Organic Synthesis, 2015, Vol. 12, No. 1 45
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
46 Current Organic Synthesis, 2015, Vol. 12, No. 1 Zai-Qun Liu
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.
Two Neglected Multicomponent Reactions: Asinger and Groebke Reaction Current Organic Synthesis, 2015, Vol. 12, No. 1 47
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.)
room temperature, 3 hours
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
48 Current Organic Synthesis, 2015, Vol. 12, No. 1 Zai-Qun Liu
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.
Two Neglected Multicomponent Reactions: Asinger and Groebke Reaction Current Organic Synthesis, 2015, Vol. 12, No. 1 49
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
microwave irradiation
(100°C), 10 min
N
NO
O
N
N C
microwave irradiation
(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
Scheme 38. Contd……
50 Current Organic Synthesis, 2015, Vol. 12, No. 1 Zai-Qun Liu
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.
Two Neglected Multicomponent Reactions: Asinger and Groebke Reaction Current Organic Synthesis, 2015, Vol. 12, No. 1 51
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-
52 Current Organic Synthesis, 2015, Vol. 12, No. 1 Zai-Qun Liu
NH HN
HOOH
O O1. SOCl2, reflux, 2 hours
2. RNH2
(HOCH2CH2)3N, (C2H5)2O
room temperature, 4 hours
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
Two Neglected Multicomponent Reactions: Asinger and Groebke Reaction Current Organic Synthesis, 2015, Vol. 12, No. 1 53
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.
54 Current Organic Synthesis, 2015, Vol. 12, No. 1 Zai-Qun Liu
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……
Two Neglected Multicomponent Reactions: Asinger and Groebke Reaction Current Organic Synthesis, 2015, Vol. 12, No. 1 55
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.
56 Current Organic Synthesis, 2015, Vol. 12, No. 1 Zai-Qun Liu
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
microwave irradiation
+
+
2. HBF4 (48%, aq.)
n-C4H9OH
160°C, 20 min
microwave irradiation
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…….
Two Neglected Multicomponent Reactions: Asinger and Groebke Reaction Current Organic Synthesis, 2015, Vol. 12, No. 1 57
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.
58 Current Organic Synthesis, 2015, Vol. 12, No. 1 Zai-Qun Liu
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