CHAPTER I I. Introduction to Heterocyclic Chemistry
I.4. Copper Catalyzed Synthesis of Heterocycles
I.4.3. Recent Examples of Cu-Catalyzed Intramolecular Hetero-Arylations
An intramolecular amination of aryl halides was found to be mediated by the combination of copper iodide and cesium acetate. The reaction works well at room temperature with primary or N-benzyl amines and at high temperature with other amines.
The reaction has been applied to the formation of 5-, 6-, and 7-membered rings. In this
experimental condition halogens at the meta-positions are unaffected providing an advantage over palladium-catalyzed systems (Scheme I.4.3.1.).15a
Br ( )n=0,1
NH Ns
CuI (2equiv) CsOAc (5 equiv)
DMSO 90oC, 5h
N Ns
( )n=0,1
Scheme I.4.3.1.
Batey et al. have described an approach for the formation of 2-amino benzimidazoles via an intramolecular C-N bond formation between an aryl halide and a guanidine moiety using either copper or palladium catalysis. Remarkably, inexpensive copper salt CuI is superior to the use of palladium catalysts for this transformation (Scheme I.4.3.2.).15b
CuI (5 mol%) 1,10-Phen (10 mol%) [or Pd(PPh3)4 (10 mol%)]
Cs2CO3 80oC, DME, 16h N
HN N R3 R2 R1
N N
N R3 R2 R1 Br
Scheme I.4.3.2.
An efficient synthesis of indoles from o-alkynylhaloarenes via a palladium- or a copper-catalyzed amination reaction followed by a subsequent cyclization reaction is achieved by Ackermann et al. In addition, a multi-catalytic one-pot indole synthesis starting from o-chloroiodobenzene using a single catalyst consisting of an N-heterocyclic carbene palladium complex and CuI has also been described (Scheme 1.4.3.3.).15c
N R2 R1 X
I
X R1 [Cu], [Pd]
R2NH2 X = Cl; [Pd]
X = Br; [Cu]
Scheme I.4.3.3.
A ligand assisted copper-catalyzed intramolecular vinylation of iodoenamides is disclosed with CuI as the precatalyst and N,N’-dimethylethylenediamine (DMEDA) as the ligand. A wide variety of iodoenamides involved in cyclization leads to the formation of five to seven membered lactams (Scheme I.4.3.4.).15d
NHR O
I
NHR O
N
N O
O R
R I
( )n
CuI, DMEDA Cs2O3 Dioxane, reflux
n = 1, 2, 3 ( )n
( )n
( )n
Scheme I.4.3.4.
A general protocol leading to 2-alkyl- or 2-aryl-substituted benzofurans in water was reported by Carril et al. involving a Cu-TMEDA complex which catalyzes the transformation of readily available ketone derivatives into the corresponding benzofurans (Scheme I.4.3.5.).15e
O R X
R O
8.5 % CuI, 3.5 equiv. TMEDA H2O, 120 oC, 12h
Scheme I.4.3.5.
A copper-catalyzed intramolecular O-arylation of o-haloanilides leading to the benzoxazole core is reported. This reaction is performed using aryl chlorides as arylating agents and water as the reaction media (Scheme I.4.3.6.).15f
O N
R X
HN R O
8.5 % CuCl, 3.5 equiv. TMEDA H2O, 120 oC, Overnight X = Cl, Br
Scheme I.4.3.6.
The synthesis of the benzofuroindole skeleton by Carril et al. using a recyclable copper-catalytic system in water is presented in Scheme I.4.3.7.15g
Conditions: 8.5 % CuCl, 3.5 equiv. DMEDA, H2O, 120 oC, 12 h O
Ts NH
Br Br +
[Pd]
O Ts NH
Br
Ts NH O
[Cu]
NH Ts
O
Br
NBS
N O
Ts
[Cu]
Scheme I.4.3.7.
A simple C-O carboxylic coupling reaction catalyzed by copper(I) salts has been developed to synthesize benzopyranones by Ruchiravat et al. Various benzopyranones were synthesized using microwave irradiation. Furthermore, a new class of pyrroloisoquinoline alkaloid, isolamellarin, was also synthesized using this methodology (Scheme I.4.3.8.).15h
O O
X COOH
Cu(I) or CuTC MW 200oC X = Br, Cl, OTf
Scheme I.4.3.8.
Li et al. have reported an uncommon 4-exo ring closure in the copper-catalyzed intramolecular O-vinylation of bromo homoallylic alcohols leading to the convenient synthesis of 2-methyleneoxetanes. The 4-exo mode of ring closure is preferred over other modes (5-exo, 6-exo, and 6-endo) of cyclization. However, this unique selectivity is different from that of palladium catalyzed processes (Scheme I.4.3.9.).15i
Br Br OH
Bn
O
Br Bn
Br O Bn
4-exo
5-exo Cu(I)
Pd(0)
N N
Me Me
Me Me
L
Cu(I)-conditions:10 mol% CuI, 20 mol% L, 2 equiv. Cs2CO3, MeCN, reflux
Scheme I.4.3.9.
A variety of pyrazoloindole derivatives were synthesized via Cu(I)-catalyzed intramolecular amination reactions. This method provides a general route for the synthesis of indoles fused with pyrazole rings (Scheme I.4.3.10.).15j
HN N Br
5 mol % CuI, Ligand
K2CO3, dioxane, 110 oC N N
Scheme I.4.3.10.
Nishida et al. have demonstrated a facile access to cinnolines, dihydrocinnolines, and 1-aminoindolines by one-pot Cu-catalyzed N-arylation using hydrazines and hydrazones as cyclization precursors derived from 3-haloaryl-3-hydroxy-2- diazopropanoates (Scheme I.4.3.11.).15k
HO CO2t-Bu N I NHAc
N N OH
CO2t-Bu
Ac CuI (10 mol%)
DMEDA (10 mol%) Cs2CO3 (2equiv) DMSO, rt, 10 min
HO CO2t-Bu NH I NHAc
NaBH4
CuI (10 mol%) DMEDA (10 mol%)
Cs2CO3 (2equiv) DMSO, rt, 1 hr
N OTBS
CO2t-Bu NHAc
Cinnolines
1-amino indolines
Scheme I.4.3.11.
A variety of N-alkylated and N-arylated derivatives of methyl-1H-indole-3- carboxylates were synthesized via Ullmann type intramolecular arylamination, using CuI- K3PO4-DMF system. This catalytic amination procedure can be performed under mild conditions in an air atmosphere (Scheme I.4.3.12.).15l
BrO OMe
1.
2.
O O , NaH RNH2, MeOH
rt, 6 hrs 3. 5 mol% CuI, K3PO4,
DMF, 75 oC
N R O OMe H
Scheme I.4.3.12.
Zhu et al. have shown that the Ugi-adduct undergoes two consecutive metal- catalyzed intramolecular reactions, namely copper-catalyzed O-arylation and palladium- catalyzed C-arylation of benzylic carbon to afford benzoxazolylisoindolinones (Scheme I.4.3.13.).15m
S HO
O I
NH O
R1 N R2
O I
Ugi 4CR adduct
1. Cu(I) cat.
2. Pd(O) cat.
N R1
R2 O O
N
[Cu] conditions: CuI (5 mol %), L (5 mol%), K2CO3, DMSO, 120 oC L =
Scheme I.4.3.13.
Pan and coworkers have reported a copper-catalyzed intramolecular cyclization of various substituted 1-acyl-3-(2-bromophenyl) thioureas to yield N-benzothiazol-2-yl- amides using N-(4,5-dihydrooxazol-2-yl) benzamide as the ligand (Scheme I.4.3.14.).15n
Br NH
S NH
CuI (5 mol%) O L =
R
Ligand (10 mol%) Cs2CO3, DMSO, 70 oC
N S
NH O
R
HN O O
N
Scheme I.4.3.14.
Recently, Ma group has developed a CuI/L-proline catalyzed coupling/additive cyclization, a domino process for assembling substituted 3-methyleneisoindolin-1-ones from 2-bromobenzamides and terminal alkynes (Scheme I.4.3.15.).15o
CuI (10 mol%) L-proline (30 mol%) K2CO3, i-PrOH, 85-110 oC
N R O
NH R Br
+ R'
O
R'
Scheme I.4.3.15.
An amino acid promoted copper-catalyzed coupling of amines with aryl halides has been depicted. This method is applicable for the synthesis of functionalized indoles and pyrrolo[2,3-c]pyridines (Scheme I.4.3.16.).15p
CuI (10 mol%) L-proline (20 mol%) K2CO3 (3 equiv), Dioxane,
100 oC, 24 hrs Br N
HN O
OMe
O
OBn OMe
O
O OBn
Scheme I.4.3.16.
Buchwald et al. have reported an efficient method for amination of aryl bromides with primary alkylamines using copper-catalytic system that uses commercially available diethylsalicylamide as the ligand. This amination method was extended further for the synthesis of indole derivatives (Scheme I.4.3.17.).15q.
CuOAc (5 mol%) Ligand (20 mol%) L =
K3PO4, DMF, 40-100 oC
NH Cl
NH2
OH O Et2N
Scheme I.4.3.17.