Copper-catalyzed synthesis of five-membered heterocycles via double C-N bond formation: an efficient synthesis of pyrroles, dihydropyrroles, and carbazoles

Article abstract of DOI:10.1016/j.tet.2009.08.075

An efficient copper-catalyzed double C-N bond forming reaction using diiodides and nitrogen-centered nucleophiles including amides and carbamates is reported. The reactions proceed to afford di- or tri-substituted N-acylpyrroles, dihydropyrroles, and carbazoles in good to excellent yields when different diiodides such as 1,4-diiodo-1,3-butadienes, 1,4-dihalobut-1-enes, and 2,2′-diiodobiphenyls were employed, respectively. It is crucial to use CuI as the catalyst with the assistance of proper base and diamine ligand.

Full text of DOI:10.1016/j.tet.2009.08.075

Tetrahedron 65 (2009) 8961–8968
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Tetrahedron
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Copper-catalyzed synthesis of five-membered heterocycles via double C–N
bond formation: an efficient synthesis of pyrroles, dihydropyrroles,
and carbazoles
*
Ende Li, Xiaobing Xu, Hongfeng Li, Huimin Zhang, Xiaolei Xu, Xiyuan Yuan, Yanzhong Li
Institute of Medicinal Chemistry, Department of Chemistry, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 May 2009
Received in revised form 17 August 2009
Accepted 27 August 2009
Available online 2 September 2009
An efficient copper-catalyzed double C–N bond forming reaction using diiodides and nitrogen-centered
nucleophiles including amides and carbamates is reported. The reactions proceed to afford di- or tri-
substituted N-acylpyrroles, dihydropyrroles, and carbazoles in good to excellent yields when different
diiodides such as 1,4-diiodo-1,3-butadienes, 1,4-dihalobut-1-enes, and 2,20-diiodobiphenyls were em-
ployed, respectively. It is crucial to use CuI as the catalyst with the assistance of proper base and diamine
ligand.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
course of our ongoing study on the development of transition metal
catalyzed new selective heterocycle forming protocols,11 we found
The nitrogen-containing five-membered rings are an important
class of heterocyclic compounds1 because they represent useful
building blocks in the synthesis of natural products or key struc-
tural unit in compounds that exhibit remarkable pharmacological
activities.2,3 They have also found broad applications in the field of
material science.4 As a consequence, much attention has been paid
to the development of efficient methodologies for their preparation.
The known methods for the construction of these five-membered
rings proceed either by traditional methods or by transition-metal-
catalyzed reactions. Among the transition-metal-catalyzed re-
actions, palladium was demonstrated to be highly efficient for the
construction of C–N bonds toward five-membered rings. For ex-
amples, palladium-catalyzed tandem alkenyl and aryl–C–N bond
formation to indoles was reported by Willis et al.,5 double N-ary-
lation of amines to carbazoles by Nozaki et al.6 Buchwald reported
the direct N-arylation of amides to carbazoles.7 Larock showed the
synthetic route to carbazoles through hydroamination and cycli-
zation.8 In the past few years, copper-catalyzed aryl C–X bond
(X¼N, O, S, etc.) formation reactions through coupling between aryl
halides and heterocentered nucleophiles have drawn considerable
attention,9 which provide an excellent complement to the Pd-cat-
alyzed reactions. More recently, this methodology was successfully
extended to the synthesis of allenamides,9g enamides,10 and lac-
tams9h by coupling of amides with allenyl halides, vinyl halides, and
iodoenamides via intramolecular vinylation, respectively. In the
that a variety of five-membered ring compounds such as pyrroles11a
and dihydropyrroles11c could be efficiently prepared by the reaction
of dihalides and nitrogen-centered nucleophiles.12,13 Here we’d like
to report the full detail of nitrogen-containing five-membered ring
formation reactions.
2. Results and discussion
2.1. Synthesis of pyrrole derivatives through double
alkenylation reactions
We began our investigation with (1Z,3Z)-2,3-dibutyl-1,4-diiodo-
1,3-butadiene 1a, which was synthesized according to the reported
method.14 The reaction of 1a with valeramide 2a was selected as the
prototypical case to screen the experimental conditions (Table 1). It
was demonstrated that certain copper ligands play important roles
for rate accelerations in the coupling reactions. These ligands are
thought to increase catalyst solubility, stability and to prevent
aggregation of the metal. We thus first carried out ligand screen
using CuI (20 mol %) as the catalyst and Cs2CO3 (2 equiv) as the base
in dioxane at refluxing temperature. The results are summarized in
Table 1. Five commercially available ligands were evaluated for the
coupling reaction, among them, the ligand of trans-N,N0-dimethyl-
cyclohexane-1,2-diamine (L1) gave the most promising results. Thus,
heating a mixture of diiodide 1a and amide 2a together with CuI
catalyst in the presence of 20 mol % L1 in dioxane at 100 ꢀC afforded
the expected pyrrole 3a in 98% yield (Table 1, entry 5). The yield was
rather low under ligandless condition (Table 1, entry 6). Switching
* Corresponding author.
E-mail address: yzli@chem.ecnu.edu.cn (Y. Li).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.08.075

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E. Li et al. / Tetrahedron 65 (2009) 8961–8968
Table 1
89% yield (entry 9). Interestingly, this method is also effective for
Optimization of reaction conditions for the formation of 3a
trisubstituted dienyl diiodide compounds. The reaction of (1Z,3Z)-
2-butyl-1,4-diiodo-3-propylhepta-1,3-diene (1d) and amide 2d led
to the formation of 3i in 70% isolated yield (entry 10). The substrate
of 1d also reacted with benzamide to give the tri-substituted acyl
pyrrole 3j in moderated yield (entry 11). However, the diiodide 1e
bearing a phenyl group at C1 reacted with 2e gave the pyrrole 4b in
only 32% isolated yield after 20 h (entry 12). When tetrasubstituted
dienyl diiodide such as (3Z,5Z)-4,5-diethyl-3,6-diiodoocta-3,5-di-
ene was treated with 2e under the optimized reaction condition, no
coupling product was observed.
O
Bu
Bu
Bu
O
cat. CuI, ligand
I
I
N
+
H2N
base, solvent, reflux
Bu
1a
2a
3a
Entry Ligand (20 mol %)
Base (2 equiv) Solvent
Temp (ꢀC) Yielda (%)
1
2
3
2,20-Bipyridine
Ethane-1,2-diol
Cs2CO3
Cs2CO3
Cs2CO3
1,4-Dioxane 100 20
1,4-Dioxane 100
1,4-Dioxane 100
54
27
L
-Proline
The scope of this reaction was further examined by applying the
optimized conditions to carbamate. Treatment of dienyl diiodide 1a
with ethyl carbamate using a catalytic amount (20%) of CuI resulted
in the formation of 3k only in 20% yield. Reasonable yield (68%) was
obtained when 1.0 equiv of ligand and 1.0 equiv of CuI was
employed (Eq 1).
4
Cs2CO3
1,4-Dioxane 100
43
N
N
(L1)
NHMe
5
Cs2CO3
1,4-Dioxane 100
98
MeHN
R3
6
7
8
9
None
L1
L1
L1
L1
Cs2CO3
K2CO3
K3PO4
KOH
1,4-Dioxane 100
1,4-Dioxane 100
1,4-Dioxane 100
1,4-Dioxane 100
15
28
25
45
95
O
R3
O
O
I
I
100 mol% CuI,100 mol% L1
+
N
H2N
O
Cs2CO3, dioxane, reflux
R2
R2
R1
R1
10
Cs2CO3
Toluene
110
3k:R1=H, R2 = R3 = Bu, 68%
3l:R1=H, R2 = R3 = Ph, 80%
a
Yields were determined by GC after hydrolysis. All the reactions were carried
out with 20 mol % of CuI and kept for 24 h.
ð1Þ
to other bases such as K2CO3, K3PO4, and KOH afforded lower yields
of the product (entries 7–9). When the solvent was changed to
toluene, the product yield was similar to that of dioxane (entry 10).
It was cleared that the optimized reaction condition was to use
20 mol % of CuI in combination of 20 mol % of rac-trans-N,N0-
dimethylcyclohexane-1,2-diamine (L1) as the ligand, Cs2CO3 as the
base, and dioxane as the solvent.
2.2. Synthesis of dihydropyrrole derivatives through
N-alkenylation and N-alkylation reactions
We envisaged that the dihydropyrrole derivatives could be ac-
cessible by the combination of N-alkylation and N-alkenylation
starting from amides and 1,4-dihalobut-1-ene derivatives under the
similar conditions as for pyrroles. Initial studies were performed in
toluene using (Z)-3-propyl-1,4-diiodohept-3-ene (6a) and valer-
amide (2a) as model substrates under the optimized reaction
conditions for pyrrole formation. Interestingly, the desired dihy-
dropyrrole 8a was obtained in 53% yield with 38% of (Z)-4-idodo-5-
vinyloct-4-ene (9) (Table 3, entry 2). These results indicated the
formation of 9 through elimination of HI presumably due to the
strong basicity of Cs2CO3. As expected, 80% yield of 8a was gener-
ated when a mild base such as K2CO3 was used in the reaction, and
no formation of 9 was observed (Table 3, entry 3). When the
amount of CuI and L1 was lowered to 10 mol % using K2CO3 as the
base, the yield of 8a dropped substantially to 55% with 29% of 6a
remained (Table 3, entry 4). Changing the solvent to 1,4-dioxane,
only 35% of 8a was observed (Table 3, entry 5). Switching to
a weaker base such as NaHCO3, or organic base like triethylamine
resulted in no coupling reaction or very low yield of the product
(Table 3, entries 7 and 8). Other copper salts such as CuCN, CuCl,
CuBr gave the desired compound 8a in 68%, 57%, and 48% yields,
respectively (Table 3, entries 9–11). Three commercially available
Having established an effective catalytic system for the cou-
pling reactions, we next synthesized a variety of diiodo dienes to
explore the scope of double alkenylation under the optimized
conditions. The representative results are shown in Table 2. The
reaction was applicable to various amides and dienyl diiodo
compounds. Coupling of 1a with 2-phenylacetamide 2b gave the
corresponding pyrrole derivative 3b in 95% yield (Table 2, entry
2). The aryl amide of 4-methylbenzamide 2c reacted with 1a to
produce 3c in 80% yield (Table 2, entry 3). Likewise, the coupling
of 1a with 4-aminobenzamide 2d furnished the expected pyrrole
3d in 92% yield, in which –NH2 group was well tolerated during
the reaction (entry 4). When 2,3-diphenyl-substituted dienyl
diiodide 1b was employed, the reaction with benzyl amide was
completed within 4 h to give the desired product 3f in 48% iso-
lated yield, along with 24% deacylation product of 3,4-diphenyl-
1H-pyrrole15 (4a) (entry 6). To our delight, the crystal of 3f was
suitable for single crystal analysis, and its structure was fully
characterized by X-ray diffraction analysis16 (Fig. 1). Interestingly,
when 1b reacted with 2 equiv of benzamide 2e for 20 h, the
product of 4a was obtained in 95% yield as the only pyrrole
product, at the meantime, N-benzoylbenzamide17 was isolated in
51% yield (entry 7). This result indicated that the acyl C–N bond
of the initially formed pyrrole was cleaved during the reaction. It
might be due to the delocalization of the nitrogen lone pair into
the pyrrole ring of the pyrrole amide. The reduced electrodensity
on the N-acylpyrrole carbonyl favors nucleophilic attack.
ligands, namely, L
-proline (L2), N,N0-dimethylethane-1,2-diamine
(L3), and 1,10-phenanthroline (L4) were also evaluated for the
coupling reaction, and the yields of the corresponding product were
0%, 63%, and 61%, respectively (Table 3, entries 12–14). It was clear
that the optimized reaction condition for dihydropyrrole formation
was to use 20 mol % CuI in combination of 20 mol % rac-trans-N,N0-
dimethylcyclohexane-1,2-diamine (L1), K2CO3 as the base in
toluene.
This CuI catalyzed one-pot N-heterocyclization reaction was ap-
plicabletoavarietyofamidesanddiiodidestofurnishdihydropyrroles
in good to high yields. The representative results are depicted in Table
4. Coupling of 6a with benzamide 2e gave the corresponding dihy-
dropyrroles 8b in 64% yield (Table 4, entry 2). Diphenyl substituted
diiodide 6b reacted with 2e to produce 8c in 83% yield (Table 4, entry
3). The coupling of 6b with 4-methylbenzamide (2c) furnished the
In order to make an insight into this reaction, we stopped the
reaction in 3 h, the corresponding acyl pyrrole 3g was obtained in
54% yield along with 4a (22%) and N-benzoylbenzamide (30%) (entry
8). This reaction provides a useful method for synthesis of pyrroles
with two aryl groupson adjacent positions, which frequently display
interesting biological and pharmacological properties.2d
When a diiodide fused with a six-membered ring of 1c was
used, the reaction smoothly occurred to afford bicyclic pyrrole 3h in

E. Li et al. / Tetrahedron 65 (2009) 8961–8968
8963
Table 2
Preparation of pyrroles from amides and dienyl diiodides
Entry
1
Dienyl diiodide
Amide
Time (h)
24
Product
Yielda (%)
O
Bu
Bu
O
Bu
3a
3b
98(95)
95(73)
N
NH2
(2a)
Bu
O
Bu
O
2
3
18
24
N
Ph
NH2
(2b)
Ph
Bu
Bu
O
O
N
Me
Bu
Bu
I
3c
80(68)
92(71)
NH2
I
(2c)
Bu
Me
(1a)
Bu
Bu
O
O
N
H2N
4
18
3d
NH2
(2d)
NH2
O
Bu
O
5
6
24
4
3e
3f
63(54)
(48)b
N
NH2
Ph
Bu
Ph
(2e)
O
2b
N
Ph
Ph
I
Ph
I
Ph
Ph
Ph
7
2e
20
4a
(95)c
NH
(1b)
Ph
O
8
9
2e
2e
3
3g
3h
(54)d
(89)
N
Ph
O
Ph
I
I
20
N
Ph
(1c)
Bu
Pr
O
N
10
2d
24
3i
(70)
Pr
Bu
I
NH2
I
Pr
Pr
Bu
Pr
O
(1d)
N
11
2e
2e
24
20
3j
(54)
(32)
Ph
Pr
Bu
I
Bu
Ph
I
NH
Ph
Ph
12
4b
Ph
(1e)
a
GC yields. Isolated yields are given in parentheses.
3,4-Diphenyl-1H-pyrrole 4a was obtained in 24% yield.
Compound 2e (2 equiv) was used. N-Benzoylbenzamide was isolated in 51% yield.
Compound 4a and N-benzoylbenzamide were isolated in 22% and 30% yields, respectively.
b
c
d
expected dihydropyrroles in 59% yield (Table 4, entry 4). Reaction of
diethyl substituted diiodide 6cwith 2a afforded 8e in highyield (Table
4, entry 5). Likewise, the coupling of 6c with 2c gave the desired
product in 75% yield (Table 4, entry 6).
When a diiodide 6d fused with a six-membered ring was used,
the reaction with 2a or 4-methoxybenzamide (2g) occurred
smoothly to produce the desired bicyclic dihydropyrroles in 69% or
59% yield, respectively (Table 4, entries 7 and 8). The coupling of
(E)-(1,4-diiodo-3,4-diphenylbut-3-enyl)trimethylsilane (6e) with
2a furnished the expected dihydropyrroles in 59% yield, in which
the trimethylsilyl group was well tolerated during the reaction
(Table 4, entry 9).

8964
E. Li et al. / Tetrahedron 65 (2009) 8961–8968
Table 4
Preparation of dihydropyrroles from amides and diiodobutenes
Entry Diiodide
Amide
Product
Yielda
(%)
Pr
Pr
Pr
O
Pr
1
2
2a
2e
8a 80(69)
8b 64(46)
N
Pr
Bu
O
I
I
Pr
(6a)
N
Ph
Ph
N
Ph
O
3
4
2e
2c
8c 83(65)
8d 59(47)
Ph
Ph
Ph
I
I
Ph
N
Ph
Figure 1. The X-ray crystal structure of 3f.
O
(6b)
Table 3
Optimization of reaction conditions for the formation of 8a
Pr
Pr
N
Me
O
Pr
Pr
O
cat. CuI, ligand
I
I
Et
N
+
H2N
Bu
Et
base, solvent, reflux
O
Bu
5
6
2a
2c
8e 84(70)
8f 75(64)
Et
Bu
6a
2a
8a
Et
I
I
Et
N
Yielda (%)
27b
Et
Entry
1
Ligand/mol %
(L1) / 10
CuX/mol %
CuI/10
Base (2 equiv)
Cs2CO3
O
(6c)
MeHN
NHMe
(L1)/20
(L1)/20
(L1)/10
(L1)/10
None
(L1)/20
(L1)/20
(L1)/20
(L1)/20
(L1)/20
Me
2
3
4
5
6
7
8
9
CuI/20
CuI/20
CuI/10
CuI/10
CuI/20
CuI/20
CuI/20
CuCN/20
CuCl/20
CuBr/20
CuI/20
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
NaHCO3
Triethylamine
K2CO3
K2CO3
K2CO3
53c
80
55
35d
49
0
Bu
O
7
8
2a
8g 69(57)
8h 59(32)
N
Bu
Bu
I
I
Bu
4
O
68
57
48
0
O
(6d)
N
10
11
12
MeO
NH2
L-Proline (L2)/20
K2CO3
(2g)
( L 3 ) / 20
(L 4) / 20
13
CuI/20
K2CO3
K2CO3
63
O
NH HN
Ph
Ph
N
Ph
Ph
O
14
CuI/20
61
I
I
9
2a
8i 59(41)
N
N
Bu
a
Yields were determined by GC after hydrolysis. All the reactions were done for
48 h. Unless noted, all the reactions were carried out in toluene.
TMS
(6e)
TMS
b
a
(Z)-4-Iodo-5-vinyloct-4-ene(9) was obtained in 53% yield.
Compound 9 was obtained in 38% yield.
1,4-Dioxane was used as solvent.
GC yields. Isolated yields are given in parentheses.
c
d
2.3. Synthesis of carbazole derivatives through double
arylation reactions
The scope of the copper-catalyzed N-alkenylation and N-alkyl-
ation reaction could also be extended to carbamates under the
optimized conditions. Treatment of 6a with ethylcarbamate led to
63% yield of 8j (Eq. 2). The reaction of 6b with benzyl carbamate
resulted in the formation of 8k in 38% yield.
Carbazoles are very important in material science. The
Pd-catalyzed synthesis of carbazoles is known.6,7,17 However,
Cu-catalyzed carbazole formation through double arylation of
amides is rare.12 We reasoned that this Cu-catalyzed N–C cou-
pling system could be effective for their synthesis. Thus, the
coupling reaction of 2,20-diiodobiphenyl (10a) and valeramide 2a
was carried out under the same reaction conditions as for dihy-
dropyrrole formation. As expected the desired carbazole 12a was
obtained in 47% yield (Table 5, entry 4), along with ca. 30% of 10a
recovered.
R1
R1
N
O
R1
R1
O
I
I
20 mol% CuI, 20 mol% L1
K2CO3, toluene, reflux
R2
+
H2N
O
O R2
8j: R1 = Pr, R2 = Et, 63%
8k: R1 = Ph, R2 = Benzyl, 38%
Double amount of 2a resulted in the formation of 10a in 73%
yield (Table 5, entry 5). Changing the ligand to N,N0-dimethyl-
ethane-1,2-diamine (L3) furnished 10a in 98% yield (Table 5, entry
8). All results of the reaction condition screening were depicted in
Table 5. Thus, the optimized reaction condition for carbazole
ð2Þ
When alkyl 1,4-diidodide like 1-iodo-3-(iodomethyl)nonane
was treated with benzamide 2e under the same reaction condi-
tions, no desired product was observed.

E. Li et al. / Tetrahedron 65 (2009) 8961–8968
8965
Table 5
4. Experimental
Optimization of reaction conditions for the formation of 12a
4.1. General
O
cat. CuI, ligand
+
H2N
Bu
base, solvent, reflux
N
All reactions were carried out in 1 mmol scale unless noted using
standard Schlenk techniques under nitrogen. 1,4-Dioxane and tol-
uenewere distilled from sodium and benzophenone. All commercial
reagents such as rac-trans-N,N0-dimethylcyclohexane-1,2-diamine,
cesium carbonate, and alkynes were used without further purifica-
tion. (1Z,3Z)-1,4-Diiodo-1,3-dienes were prepared according to the
published methods.14 1H and 13C NMR spectra were recorded at 300
and 75.4 MHz, or 400 and 100 MHz, respectively, in CDCl3 (con-
taining 1% TMS) solutions. GC yields were determined using suitable
hydrocarbons as internal standards. The product characterization
data, and 1H and 13C NMR spectra for compounds 3a–3l and 4b can
be found in Supplementary data of our previous communication.11a
I
I
Bu
12a
O
10a
2a
Entry Ligand/mol % CuX/mol % 2a (equiv) Base (2 equiv) Yielda (%)
1
2
3
4
5
6
7
8
L1/10
L1/10
L1/10
L1/20
L1/20
L3/10
L3/10
L3/20
L3/20
L3/20
L3/20
CuI/10
CuI/10
CuBr/10
CuI/20
CuI/20
CuI/10
CuI/10
CuI/20
CuI/20
CuI/20
CuI/20
1.0
1.0
1.0
1.0
2.0
1.0
1.5
2.0
2.0
2.0
2.0
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
KOH
60
58
55
47
73(56)
63
68
98(85)
d
9
10
11
Cs2CO3
Na2CO3
d
4.2. General procedure for products synthesis
d
a
GC yields, isolated yields were given in parentheses. All the reactions were done
for 48 h. Unless noted, all the reactions were carried out in toluene.
4.2.1. A typical procedure for the formation of pyrroles. A 20 mL
Schlenk tube was charged with valeramide (101 mg, 1.0 mmol), CuI
(38 mg, 0.2 mmol), and Cs2CO3 (652 mg, 2 mmol). After that
1,4-dioxane (8 mL) was added followed by trans-N,N0-dimethylcy-
clohexane-1,2-diamine (0.032 mL, 0.2 mmol) and (1Z,3Z)-2,3-
dibutyl-1,4-diiodo-1,3-butadiene 1a (418 mg, 1.0 mmol). The
reaction mixture was heated to 100 ꢀC for 24 h and then cooled
down to room temperature. The mixture was quenched with
aqueous NaHCO3 and extracted with ethyl acetate (3ꢁ10 mL). The
extract was washed with brine and dried over magnesium sulfate.
The solvent was evaporated in vacuo and the residue was purified by
chromatography on silica gel to afford 250 mg (95%) pyrrole de-
rivative 3a as a light-yellow oil. GC yield: 98%.
forming was to use 20 mol % of CuI in combination of 20 mol % of
N,N0-dimethylethane-1,2-diamine (L3) as the ligand, K2CO3 as the
base, and toluene as the solvent.
A variety of 2,20-diiodobiphenyl and amide analogs were sub-
jected to the modified reaction conditions to define the reaction
scope. As shown in Table 6, not only amides but also carbamates
were applicable to the coupling reaction to afford the corre-
sponding carbazoles in good to high yields. When 2,20-diiodobi-
phenyl (10a) was employed, it coupled with carbamate 2f and
amides (2g, 2d) to give the desired compounds in 69–89% yields
(Table 6, entries 3–5), in which –NH2 and –OMe groups were well
tolerated during the reaction. It is worthy to note that the reaction
of 10a with benzyl amide furnished the deacylation product 12b in
78% yield (Table 6, entry 2). Substituted diiodobiphenyles, for
example, 2,20-diiodo-4,40,5,50-tetramethylbiphenyl (10b) reacted
with benzamide (2e) gave the corresponding carbazole 12g in 61%
yield (Table 6, entry 7). Compound 10b also coupled with ethyl
carbamate (2f) to produce 12f in 63% yield (Table 6, entry 6).
Likewise, the coupling of 2,20-diiodo-4,40,5,50-tetramethoxy-
biphenyl (10c) with 2a and 2f furnished the expected carbazoles
12h and 12i in 62% and 53% yields, respectively (Table 6, entries 8
and 9). When diaryl dibromide such as 2,20-dibromobiphenyl was
treated with 2a under the optimized reaction condition, no cou-
pling product was observed.
4.2.2. A typical procedure for the formation of dihydropyrroles. A
20 mL Schlenk tube was charged with valeramide (101 mg,
1.0 mmol), CuI(38 mg, 0.2 mmol), and K2CO3(276 mg, 2 mmol).
After that toluene (8 mL) was added, followed by rac-trans-N,N0-
dimethylcyclohexyldiamine (0.032 mL, 0.2 mmol) and (Z)-3-pro-
pyl-1,4-diiodohept-3-ene (1.0 mmol). The reaction mixture was
heated to 110 ꢀC for 48 h. The reaction mixture was cooled and
quenched with aqueous NaHCO3, extracted with ether (3ꢁ10 mL),
washed with brine, dried over sodium sulfate, and concentrated
under vacuum. Column chromatography on silica gel afforded the
corresponding products. An orange oil of dihydropyrrole derivative
8a (164 mg, 69%) was obtained. GC yield: 80%.
4.2.3. A typical procedure for the formation of carbazoles. A 20 mL
Schlenk tube was charged with valeramide (202 mg, 2.0 mmol),
CuI(38 mg, 0.2 mmol), and K2CO3(276 mg, 2 mmol). After that tol-
uene (8 mL) was added, followed by N,N0-dimethylethane-1,2-di-
amine (0.2 mmol) and 2,20-diiodobiphenyl (1.0 mmol). The reaction
mixture was heated to 110 ꢀC for 48 h. The reaction mixture was
cooled and quenched with aqueous NaHCO3, extracted with ether
(3ꢁ10 mL), washed with brine, dried over sodium sulfate, and
concentrated under vacuum. Column chromatography on silica gel
afforded the corresponding products. A white solid of carbazole
derivative 12a (213 mg, 85%) was obtained. GC yield: 98%.
3. Conclusion
We have reported an efficient copper-catalyzed double C–N
bond forming reaction using diiodides and nitrogen-centered
nucleophiles including amides and carbamates. This methodo-
logy provided a facile route for the synthesis of di- or tri-
substituted N-acylpyrroles, dihydropyrroles, tetrahydropyrroles,
and carbazoles in good to excellent yields when different diio-
dides such as 1,4-diiodo-1,3-butadienes, 1,4-dihalobut-1-enes,
and 2,20-diiodobiphenyles were employed, respectively. It is
crucial to use CuI as the catalyst with the assistance of proper
base and diamine ligand in order to achieve reasonable yields,
the optimized reaction conditions are: rac-trans-N,N0-dime-
thylcyclohexane-1,2-diamine (L1) and Cs2CO3 for pyrroles, rac-
trans-N,N0-dimethylcyclohexane-1,2-diamine, and K2CO3 for
dihydropyrroles, and N,N0-dimethylethane-1,2-diamine (L3) and
K2CO3 for carbazoles.
4.2.3.1. 1-(4,5-Dipropyl-2,3-dihydropyrrol-1-yl)pentan-1-one
(8a). Orange liquid. 1H NMR (CDCl3, Me4Si)
d
0.83 (t, J¼5 Hz, 3H),
0.84 (t, J¼7 Hz, 3H), 0.86 (t, J¼8 Hz, 3H), 1.18–1.46 (m, 6H), 1.51–1.61
(m, 2H), 1.98 (t, J¼7 Hz, 2H), 2.19 (t, J¼8 Hz, 2H), 2.38 (t, J¼9 Hz, 2H),
2.52 (t, J¼7 Hz, 2H), 3.66 (t, J¼9 Hz, 2H); 13C NMR (CDCl3, Me4Si)
d
13.67, 13.71, 13.73, 21.03, 22.24, 22.35, 26.83, 28.31, 29.11, 30.41,
35.69, 46.89, 120.87, 138.67, 169.22. HRMS for C15H28NO [MþH]þ:
calcd 238.2171, found 238.2165.

8966
E. Li et al. / Tetrahedron 65 (2009) 8961–8968
Table 6
Preparation of carbazole derivatives
Entry
Diiodide
Amide
Product
Yielda (%)
98(85)
1
2a
12a
12b
12c
N
Bu
O
2
3
2b
78(69)
69(58)
N
N
O
O
NH2
(2f)
Et
I
I
(10a)
O
O
O
O
4
5
12d
12e
89(84)
82(65)
N
NH2
(2g)
4-OMeC6H4
O
O
2d
2f
N
4-NH2C6H4
6
7
8
12f
63(47)
61(41)
62(55)
N
Et
O
O
O
I
I
(10b)
2e
2a
12g
12h
N
Ph
OMe
OMe
MeO
MeO
N
N
Bu
O
O
O
MeO
MeO
OMe
OMe
OMe
OMe
MeO
MeO
I
I
(10c)
9
2f
12i
53(47)
Et
a
GC yields. Isolated yields are given in parentheses.
4.2.3.2. (4,5-Dipropyl-2,3-dihydropyrrol-1-yl)(phenyl)methanone
(8b). Orange liquid. 1H NMR (CDCl3, Me4Si)
4.2.3.4. (4,5-Diphenyl-2,3-dihydropyrrol-1-yl)(p-tolyl)methanone
d
0.84 (t, J¼7 Hz, 6H),
(8d). Pale yellow solid. 1H NMR (CDCl3, Me4Si)
d 2.29 (s, 3H), 3.04 (t,
1.31–1.39 (m, 4H), 2.04 (t, J¼7 Hz, 2H), 2.30 (t, J¼8 Hz, 2H), 2.52 (br
J¼8 Hz, 2H), 4.21 (t, J¼8 Hz, 2H), 7.00–7.39 (m, 14H); 13C NMR
s, 2H), 3.67 (br s, 2H), 7.21–7.46 (m, 5H); 13C NMR (CDCl3, Me4Si)
(CDCl3, Me4Si) d 21.29, 33.64, 51.09, 124.61, 126.41, 127.21, 127.54,
d
13.63, 13.84, 21.12, 21.41, 27.85, 29.34, 31.14, 50.70, 124.57, 127.34,
127.89, 127.99,128.24, 128.40, 128.95, 132.90, 133.39,135.80,138.62,
140.55, 169.07. Mp: 203–205 ꢀC. HRMS calcd for C24H21NO
339.1623, found 339.1621.
128.06, 128.44, 129.89, 137.61, 168.13. HRMS for C17H24NO [MþH]þ:
calcd 258.1858, found 258.1852.
4.2.3.3. (4,5-Diphenyl-2,3-dihydropyrrol-1-yl)(phenyl)methanone
4.2.3.5. 1-(2,3-Diethyl-4,5-dihydropyrrol-1-yl)pentan-1-one
(8c). Light yellow solid. 1H NMR (CDCl3, Me4Si)
d
2.97 (t, J¼8 Hz,
(8e). Light yellow liquid.1H NMR (CDCl3, Me4Si)
d
0.85 (t, J¼8 Hz, 3H),
2H), 4.14 (t, J¼8 Hz, 2H), 6.90–7.35 (m, 15H); 13C NMR (CDCl3,
0.91 (t, J¼8 Hz, 3H), 0.98 (t, J¼8 Hz, 3H), 1.27–1.32 (m, 2H), 1.54–1.58
Me4Si)
d 33.40, 50.86, 124.80, 126.47, 127.20, 127.69, 127.74, 127.90,
(m, 2H), 2.01 (q, J¼8 Hz, 2H), 2.04–2.21 (m, 2H), 2.39–2.42 (m, 2H),
128.03, 128.13, 129.07, 130.17, 132.70, 135.70, 136.32, 138.37, 168.89.
Mp: 155–158 ꢀC. HRMS for C23H20NO [MþH]þ: calcd 326.1545,
found 326.1531.
2.55–2.58(m, 2H), 3.67(t,J¼8 Hz, 2H);13CNMR(CDCl3, Me4Si)
d12.83,
13.74, 14.01, 19.63, 19.99, 22.34, 26.81, 30.00, 35.60, 46.87, 121.67,
139.66, 169.17. HRMS calcd for C13H23NO 209.1780, found 209.1777.

E. Li et al. / Tetrahedron 65 (2009) 8961–8968
8967
4.2.3.6. (2,3-Diethyl-4,5-dihydropyrrol-1-yl)(p-tolyl)methanone
(8f). Light yellow liquid. 1H NMR (CDCl3, Me4Si)
0.93 (t, J¼8 Hz,
4.2.3.14. 9H-Carbazole (12b)8b. White solid. 1H NMR (DMSO,
d
Me4Si)
d
7.18 (t, J¼8 Hz, 2H), 7.41 (t, J¼8 Hz, 2H), 7.54 (d, J¼8 Hz,
6H), 2.06–2.09 (m, 2H), 2.27–2.52 (m, 7H), 3.6 (m, 2H), 7.10 (d,
2H), 8.13 (d, J¼8 Hz, 2H), 11.34 (s, 1H); 13C NMR (CDCl3, Me4Si)
J¼8 Hz, 2H), 7.34 (d, J¼8 Hz, 2H); 13C NMR (CDCl3, Me4Si)
d
12.87,
d 110.89, 118.42, 120.10, 122.34, 125.44, 139.68.
13.24,19.27, 20.30, 21.29, 30.70, 50.81,125.03,127.46,128.67,134.74,
139.37, 140.07, 168.26. HRMS calcd for C16H21NO 243.1623, found
243.1625.
4.2.3.15. Ethyl 9H-carbazole-9-carboxylate (12c)8b. White solid. 1H
NMR (CDCl3, Me4Si)
1.47 (t, J¼7 Hz, 3H), 4.50 (q, J¼7 Hz, 2H), 7.27
d
(t, J¼8 Hz, 2H), 7.40 (t, J¼7 Hz, 2H), 7.85 (d, J¼8 Hz, 2H), 8.13 (d,
4.2.3.7. 1-(1-Butyl-3a,4,5,6-tetrahydro-1H-isoindol-2(4H)-yl)pen-
J¼8 Hz, 2H); 13C NMR (CDCl3, Me4Si)
d 14.28, 62.84, 116.07, 119.37,
tan-1-one (8g). Yellow liquid. 1H NMR (CDCl3, Me4Si)
d
0.80–0.87
122.99, 125.66, 126.91, 138.05, 152.17.
(m, 6H), 0.95–1.03 (m, 2H), 1.24–1.37 (m, 7H), 1.52–1.59 (m, 2H),
1.68–1.89 (m, 4H), 2.18 (br s, 2H), 2.36–2.47 (m, 2H), 2.63 (br s, 2H),
3.14–3.19 (m, 1H), 3.86 (t, J¼8 Hz, 1H); 13C NMR (CDCl3, Me4Si)
4.2.3.16. (9H-Carbazol-9-yl)(4-methoxyphenyl)methanone
(12d)18. White solid. 1H NMR (CDCl3, Me4Si)
3.78 (s, 3H), 6.86–
d
d
13.83, 13.91, 22.15, 22.43, 24.62, 25.28, 25.96, 26.81, 26.90, 31.36,
6.88 (d, J¼8 Hz, 2H), 7.23–7.27 (m, 4H), 7.45–7.47 (m, 2H), 7.59 (d,
34.31, 35.83, 41.21, 53.81, 123.41, 135.80, 169.28. HRMS calcd for
C17H29NO 263.2249, found 263.2255.
J¼8 Hz, 2H), 7.89–7.97 (m, 2H); 13C NMR (CDCl3, Me4Si)
d 55.41,
113.99, 115.43, 119.74, 122.95, 125.67, 126.49, 127.42, 131.67, 139.25,
163.11, 168.98. Mp 110–113 ꢀC. HRMS calcd for C20H15NO2 301.1103,
found 301.1111.
4.2.3.8. (1-Butyl-3a,4,5,6-tetrahydro-1H-isoindol-2(4H)-yl)(4-me-
thoxyphenyl)methanone (8h). Light yellow liquid. 1H NMR (CDCl3,
Me4Si)
d
0.80 (t, J¼8 Hz, 3H), 0.91–1.00 (m, 2H), 1.11–1.33 (m, 6H),
4.2.3.17. (4-Aminophenyl)(9H-carbazol-9-yl)methanone (12e). Light
1.67–1.82 (m, 4H), 2.34–2.7 (m, 3H), 3.28 (t, J¼8 Hz,1H), 3.76 (s, 3H),
yellow solid. 1H NMR (CDCl3, Me4Si)
d
4.11 (s, 2H), 6.61–6.64 (d,
3.70–3.86 (m, 1H), 6.78–6.86 (m, 2H), 7.43–7.48 (m, 2H); 13C NMR
J¼8 Hz, 2H), 7.18–7.27 (m, 4H), 7.52–7.56 (m, 4H), 7.95–7.97 (m, 2H);
(CDCl3, Me4Si)
d
13.90, 22.17, 24.71, 25.07, 25.50, 26.51, 30.28, 33.87,
13C NMR (CDCl3, Me4Si)
d 114.06, 115.38, 119.76, 122.67, 124.31,
41.43, 55.30, 57.75, 113.31, 126.19, 129.55, 129.97, 135.76, 161.00,
168.14. HRMS calcd for C20H27NO2 313.2042, found 313.2039.
125.55, 126.42, 132.27, 139.49, 150.98, 169.22. Mp 220–222 ꢀC.
HRMS calcd for C19H14N2O 286.1106, found 286.1119.
4.2.3.9. 1-(4,5-Diphenyl-2-(trimethylsilyl)-2,3-dihydropyrrol-1-yl)-
4.2.3.18. Ethyl 2,3,6,7-tetramethyl-9H-carbazole-9-carboxylate (12f).
pentan-1-one (8i). Orange red liquid. 1H NMR (CDCl3, Me4Si)
d
0.00
White solid. 1H NMR (CDCl3, Me4Si)
d
1.43 (t, J¼7 Hz, 3H), 2.19 (s,
(s, 9H), 0.55 (t, J¼8 Hz, 3H), 0.80–0.87 (m, 2H), 1.13–1.28 (m, 2H),
1.29–1.58 (m, 2H), 2.39 (d, J¼12 Hz, 1H), 3.46 (t, J¼12 Hz, 1H), 4.38
(br s, 1H), 6.76–6.79 (m, 2H), 6.95–6.99 (m, 3H), 7.13–7.20 (m, 5H);
6H), 2.25 (s, 6H), 4.43 (q, J¼7 Hz, 2H), 7.49 (s, 2H), 7.90 (s, 2H); 13C
NMR (CDCl3, Me4Si)
d 14.42, 19.86, 20.81, 62.63, 116.82, 119.66,
123.93, 131.44, 135.21, 136.76, 152.44. Mp 162 ꢀC. HRMS calcd for
C19H21NO2 295.1572, found 295.1578.
13C NMR (CDCl3, Me4Si)
51.83, 126.04, 126.22, 127.01, 127.88, 128.43, 128.78, 129.01, 133.93,
136.24, 137.12, 171.81. HRMS calcd for C24H31NOSi 377.2175, found
377.2185.
d
ꢂ3.10, 13.53, 22.18, 27.35, 35.02, 35.71,
4.2.3.19. Phenyl(2,3,6,7-tetramethyl-9H-carbazol-9-yl)methanone
(12g). Light yellow solid. 1H NMR (CDCl3, Me4Si)
d
2.13 (s, 6H), 2.24
(s, 6H), 7.13 (s, 2H), 7.39 (s, 2H), 7.45–7.55 (m, 5H); 13C NMR (CDCl3,
4.2.3.10. Ethyl 4,5-dipropyl-2,3-dihydropyrrole-1-carboxylate
Me4Si) d 19.89, 20.68, 116.56, 119.80, 124.19, 128.64, 128.74, 131.80,
(8j). Yellow liquid. 1H NMR (CDCl3, Me4Si)
d
1.01 (t, J¼7 Hz, 3H),
131.86, 134.89, 136.11, 137.64, 169.32. Mp 192–193 ꢀC. HRMS calcd
for C23H21NO 327.1623, found 327.1624.
1.03 (t, J¼7 Hz, 3H), 1.39 (t, J¼7 Hz, 3H), 1.48–1.63 (m, 4H), 2.16 (t,
J¼9 Hz, 2H), 2.52 (t, J¼9 Hz, 2H), 2.60 (t, J¼8 Hz, 2H), 3.85 (t, J¼9 Hz,
2H), 4.26 (q, J¼7 Hz, 2H); 13C NMR (CDCl3, Me4Si)
d
13.82, 13.85,
4.2.3.20. 1-(2,3,6,7-Tetramethoxy-9H-carbazol-9-yl)pentan-1-one
14.64, 21.24, 22.18, 27.67, 29.54, 29.91, 46.35, 60.54, 119.38, 136.41,
152.77. HRMS calcd for C13H23NO2 225.1729, found 225.1721.
(12h). Light yellow solid. 1H NMR (CDCl3, Me4Si)
d
0.95 (t, J¼7 Hz,
3H), 1.43–1.46 (m, 2H), 1.77–1.82 (m, 2H), 2.86 (t, J¼7 Hz, 2H), 3.88
(s, 6H), 3.91 (s, 6H), 7.07 (s, 2H), 7.59 (s, 2H); 13C NMR (CDCl3, Me4Si)
4.2.3.11. Benzyl 4,5-diphenyl-2,3-dihydropyrrole-1-carboxylate
d 13.67, 22.15, 26.29, 38.13, 55.79, 55.91, 100.18, 100.57, 118.75,
131.83, 146.09, 147.51, 172.18. Mp 152–154 ꢀC. HRMS calcd for
C21H25NO5 371.1733, found 371.1729.
(8k). Yellow solid. 1H NMR (CDCl3, Me4Si)
d
3.02 (t, J¼8 Hz, 2H),
4.10 (t, J¼8 Hz, 2H), 4.97 (s, 2H), 6.89–7.29 (m, 15H); 13C NMR
(CDCl3, Me4Si)
d 31.93, 47.36, 66.82, 121.22, 126.02, 126.86, 127.72,
127.77, 127.83, 127.92, 128.10, 128.17, 129.26, 133.62, 135.64, 136.07,
137.57, 152.95. Mp: 90–93 ꢀC. HRMS calcd for C24H21NO2 355.1572,
found 355.1570.
4.2.3.21. Ethyl 2,3,6,7-tetramethoxy-9H-carbazole-9-carboxylate (12i).
White solid. 1H NMR (CDCl3, Me4Si)
d
1.46 (t, J¼7 Hz, 3H), 3.88 (s,
6H), 3.90 (s, 6H), 4.42 (q, J¼7 Hz, 2H), 7.06 (s, 2H), 7.70 (s, 2H); 13C
NMR (CDCl3, Me4Si)
d 14.19, 55.88, 55.99, 62.67, 100.07, 100.33,
118.17, 131.79, 146.08, 147.78, 151.98. Mp 148–150 ꢀC. HRMS calcd
for C19H21NO6 359.1369, found 359.1364.
4.2.3.12. (Z)-4-Iodo-5-vinyloct-4-ene (9)14c. Colorless liquid. 1H
NMR (CDCl3, Me4Si)
d
0.93 (t, J¼8 Hz, 3H), 0.94 (t, J¼8 Hz, 3H), 1.40–
1.46 (m, 2H), 1.58–1.63 (m, 2H), 2.35 (t, J¼8 Hz, 2H), 2.65 (t, J¼8 Hz,
2H), 5.15 (d, J¼12 Hz, 1H), 5.26 (d, J¼20 Hz, 1H), 6.66 (dd, J¼12 Hz,
Acknowledgements
16 Hz, 1H); 13C NMR (CDCl3, Me4Si)
d 13.08, 14.12, 22.44, 23.04,
30.53, 43.93, 114.70, 116.09, 140.31, 143.01.
We are grateful to the National Natural Science Foundation of
China (No. 20572025 and 20872037) for financial support.
4.2.3.13. 1-(9H-Carbazol-9-yl)pentan-1-one (12a). White solid. 1H
NMR (CDCl3, Me4Si)
d
0.92 (t, J¼8 Hz, 3H), 1.40–1.53 (m, 2H), 1.79–
1.83 (m, 2H), 3.00 (t, J¼8 Hz, 2H), 7.26 (t, J¼8 Hz, 2H), 7.36 (t, J¼8 Hz,
References and notes
2H), 7.86 (d, J¼8 Hz, 2H), 8.09 (d, J¼8 Hz, 2H); 13C NMR (CDCl3,
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d 13.94, 22.35, 26.71, 38.83, 116.37, 119.72, 123.43, 126.33,
127.22, 138.52, 173.30. Mp 80–82 ꢀC. HRMS calcd for C17H17NO
251.1310, found 251.1321.

8968
E. Li et al. / Tetrahedron 65 (2009) 8961–8968
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