Cu(I)-catalyzed intramolecular cyclization of ene-carbamates: Synthesis of indoles and pyrrolo[2,3-c]pyridines

Article abstract of DOI:10.1016/j.tetlet.2005.10.077

Over the past few years, the use of palladium-catalyzed aromatic carbon-nitrogen bond forming reactions by the cross-coupling of aryl halides or triflates and amines has become a useful synthetic tool. Herein, we describe a copper(I) catalyst system that allows efficient synthesis of functionalized indoles and pyrrolo[2,3-c]pyridines. This method takes advantage of amino acid promoted copper coupling of amines with aryl halides, in particular, the use of the CuI/l-proline catalyst system.

Full text of DOI:10.1016/j.tetlet.2005.10.077

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8877–8880
Cu(I)-catalyzed intramolecular cyclization of ene-carbamates:
synthesis of indoles and pyrrolo[2,3-c]pyridines
Claude Barberis, Thomas D. Gordon, Christine Thomas,
Xiaolei Zhang and Kevin P. Cusack*
Abbott Bioresearch Center, 100 Research Drive, Worcester 01605, USA
Received 22 August 2005; revised 18 October 2005; accepted 18 October 2005
Available online 2November 2005
Abstract—Over the past few years, the use of palladium-catalyzed aromatic carbon–nitrogen bond forming reactions by the cross-
coupling of aryl halides or triflates and amines has become a useful synthetic tool. Herein, we describe a copper(I) catalyst system
that allows efficient synthesis of functionalized indoles and pyrrolo[2,3-c]pyridines. This method takes advantage of amino acid pro-
moted copper coupling of amines with aryl halides, in particular, the use of the CuI/L-proline catalyst system.
Ó 2005 Elsevier Ltd. All rights reserved.
Nitrogen heterocycles are among the most important
classes of pharmacologically active compounds. The
biological significance of indole derivatives in particular
has made this heterocyclic system one of the most fre-
quent subunits encountered in pharmacologically active
compounds. Examples of pharmaceutically relevant
indole containing drugs include vincristine, indomethi-
can, sumatriptan and pindolol.1
a wide range of substrates.5 Recently, it has been
observed that amino acids not only accelerate Cu-media-
ted self-coupling with aryl halides6 but also promote
the coupling reaction of amines and phenols with aryl
halides.7
Herein, we describe the use of a CuI/L-proline catalyst
system in the intramolecular cyclization of ene-carba-
mates leading to either indoles8 or pyrrolo[2,3-c]pyr-
idines (Scheme 1).
A significant number of methods to synthesize nitrogen
containing heterocyclic targets such as indoles have been
developed using intramolecular or intermolecular
approaches.2 Over the past few years, these efforts have
been aided by progress in the transition metal-catalyzed
formation of carbon–nitrogen bonds. Mainly, the use of
palladium- and copper-catalyzed aromatic carbon–
nitrogen bond forming reactions by the cross-coupling
of aryl halides or triflates with amines or amides have
become increasingly useful synthetic tools.3 The use of
palladium and copper catalysis has also overcome some
of the hurdles encountered in the synthesis of indoles
such as substitution pattern tolerance.4
An initial probe into the reaction conditions (Table 1)
led us away from nucleophilic bases such as t-BuONa
in order to reduce exchange of the ester group and cleav-
age of the Cbz protecting group. Though acceptable for
Horner–Wadsworth–Emmons condensation, DBU did
not appear to be optimal for cyclization. In fact, only
30% of deprotected cyclized product was observed
(Table 1, entry 1) along with multiple by-products.
O
R
R
(a)
O
O
The copper-mediated N-arylation reaction is an impor-
tant transformation and has been developed to include
O
O
HN
A
A
N
Y
X
O
Keywords: Copper catalysis; Indole; Pyrrolo[2,3-c]pyridine; L-Proline.
Y = Cbz, R = H, A = CH; 1a
Y = H, R = H, A = CH; 1b
X = Cl, B
*
Corresponding author. Tel.: +1 508 688 8006; fax: +1 508 688
8100; e-mail: kevin.cusack@abbott.com
Scheme 1. Reagents and conditions: (a) CuI (10 mol %), (L)-proline
(20 mol %), K2CO3 (3 equiv), 1,4-dioxane, 100 °C, 24 h.
Present address: Sanofi-Aventis, 13 Quai Jules Guesde 94403, Vitry
sur Siene, France.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.077

8878
C. Barberis et al. / Tetrahedron Letters 46 (2005) 8877–8880
Table 1. Investigation of copper salt and base via Scheme 1
The results indicate a preference for electron rich over
electron-poor systems. For electron rich systems, yields
of cyclized products were found to be in the 66–99%
range with the exception of ene-carbamate 7 (Table
2). This analog is unique, however, in that it is the only
ortho-substituted analog. Electron-poor systems such as
those substituted with fluorine or nitro were somewhat
less reactive overall with total yields of cyclized prod-
ucts in the 64–88% range (Table 2). Combination of
an electron deficient ring with the less reactive chlorine
as in the case of substrates 6 resulted in a 10% yield of
the Cbz protected indole and only a 44% yield of cyc-
lized products. In many of the electron deficient ana-
logs, a significant amount of N-1 deprotected product
was isolated. It should be noted, however, that exam-
ples of both electron-poor systems and electron-rich
systems are shown to produce N-1 protected indole
products in moderate to high yield (Table 2, entries 3
and 8).
Entry
Base
(3.0 equiv)
Cu(I) salta
(0.1 equiv)
Yield (%)b
1a
Yield (%)b
1b
1
2
3
4
5
6
DBU
CuI
CuI
CuI
CuI
CuBr
CuCl
0
95
8
0
95
95
30
0
74
0
3
3
K2CO3
Cs2CO3
t-BuONa
K2CO3
K2CO3
a All reactions were run under an inert atmosphere of nitrogen utilizing
L-proline (0.2equiv) in 1,4-dioxane at 100 °C, 24 h.
b Based on HPLC conversion.
The carbonate bases, K2CO3 and Cs2CO3, were essen-
tially equivalent in their ability to accomplish cyclization
to indole. However, the use of Cs2CO3 resulted in nearly
complete loss of the Cbz protecting group (Table 1,
entry 3). For this reason, we chose to proceed with
K2CO3 as base.
As electron-poor analogs can be considered activated
for simple intramolecular aromatic nucleophilic substi-
tution, there was a concern that the cyclization could
proceed via a SNAr-type mechanism. However, results
in our hands indicate the reaction does not proceed
uncatalyzed.10
Review of various copper halide sources demonstrated
that Cu(I) salts were essentially equivalent when used
in combination with L-proline. For further studies, we
chose the inexpensive CuI (99.999% purity, Aldrich) as
the preferred copper source among copper halides evalu-
ated. Catalyst loading could be varied from 5–20% and
10 mol for reactions herein.
An extension of this process toward pyrrolo[2,3-c]pyri-
dines is shown in Table 2 (entry 11). The yield is lower
presumably due to the more electron-deficient hetero-
cyclic ring, and is consistent with observations in the
case of electron-poor indoles. Similar to electron-defi-
cient indole examples, a significant amount of deprotec-
ted product was observed during cyclization of the
electron-deficient pyridine 11 to give pyrrolo[2,3-c]pyri-
dine system 11b.
To investigate the scope of our synthetic strategy, we
synthesized a number of ene-carbamates by Horner–
Wadsworth–Emmons condensation9 with a correspond-
ing phenyl or pyridyl carboxaldehyde (Scheme 2). The
ene-carbamates could be isolated in moderate to high
yield. Once isolated, the carbamates were subjected to
cyclization conditions as described in Scheme 2.
R'
X
O
O
R
R
R
4
3
(a)
2
O
O
(b)
5
O
O
O
HN
A
A
A
N
X
1
7
Y
Scheme 2. Reagents and conditions: (a) DBU (1.5 equiv), N-benzyloxycarbonyl-a-phosphonoglycine trimethyl ester (1.3 equiv) and aldehyde
(1 equiv) in DCM at rt for 2h. (b) 1,4-Dioxane, K 2CO3 (3 equiv), L-proline (0.2equiv) and CuI (99.999%, 0.1 equiv), 100 °C, 24 h.
Table 2. Investigation of reaction scope: effect of aryl substitution via Scheme 2
Entry
A
R
H
R0
X
Yield %a (ene-carbamate)
Yield %a (a)
Yield %a (b)
1
CH
3,4 (C
CH
CH
CH
CH
CH
CH
CH
CH
N
H
H
H
H
Me
H
H
H
H
H
H
Br
Br
Br
Br
Br
Cl
Cl
Br
Br
Br
Br
87 (1)
91 (2)
54 (3)
91 (4)
0b (5)
97 (6)
68 (7)
92( 8)
88 (9)
79 (10)
77 (11)
91 (1a)
73 (2a)
62 3a)
61 (4a)
0 (5a)
10 (6a)
0 (7a)
95 (8a)
66 (9a)
99 (10a)
0 (11a)
0 (1b)
0 (2b)
2CH
3
4
5
6
7
8
9
10
11
@CAC@C)
5-F
6-F
H
2
3b)
(
6 (
16 (4b)
0 (5b)
34 (6b)
0 (7b)
0 (8b)
0 (9b)
5-NO2
6,7-(dimethoxy)
5,6-(dimethoxy)
5,6-(O–CH2–O)
5-OMe
0 (10b)
85 (11b)
4-Br
aAll reported yields are based on isolated products. Yield is given for individual isolated yields of Y = Cbz (a) and Y = H (b).
b Failed to form ene-carbamate under standard conditions, further optimization was not attempted.

C. Barberis et al. / Tetrahedron Letters 46 (2005) 8877–8880
8879
A comparison of the Cu/L
-proline system with palla-
H
H
Br
Br
(a)
dium catalysis confirms that both reactions proceed in
comparable yields (Scheme 4). Starting from the com-
mercially available bromo or chloro substituted benzal-
dehyde, yields are in line with both solution phase8a and
solid supported8b,c Pd methods. It is noteworthy in the
copper catalyzed reactions described herein that both
bromo and chloro substituted aromatic systems are
effective precursors allowing the use of a broader range
of commercially available starting materials. The cost,
ease of synthesis and the simple purification make the
CuI/L-proline catalyst system an attractive entry into
these and other nitrogen-containing heterocycles.
HO
Br
O
O
O
95%
Br
Br
Br
12
13
H
N
(b)
65%, 2 steps
O
Br
O
O
O
O
O
N
N
H
O
Br
H
In summary, we have shown a new mild and efficient
method to produce 2-substituted indole and pyr-
rolo[2,3-c]pyridines via a key C–N bond forming reac-
tion. This method utilizes commercially available
aldehydes as starting materials and is complementary
to existing methods.
14
U86192A
Scheme 3. Reagents and conditions: (a) K2CO3, MeI. (b) DBU, N-
benzyloxycarbonyl-a-phosphonoglycine trimethyl ester, DCM; CuI,
L-proline, Cs2CO3, 1,4-dioxane, 100 °C, 24 h.
The general utility of this technique was evaluated by
preparing a key indole described in the synthesis of the
antihypertensive agent, U86192A (Scheme 3). Starting
from the commercially available symmetric tribromo-
phenol 12, the target indole 14 was prepared in overall
yield comparable to published results in one less step.11
Our initial approach via a one-pot conversion of alde-
hyde precursor 13 directly to indole 14 was unsuccessful.
Though complete consumption of starting aldehyde was
noted, considerable by-product was observed during
cyclization consistent with model studies employing
DBU (Table 1). Isolation of the ene-carbamate followed
by cyclization proved superior. When K2CO3 was used as
base, a 75% conversion was observed for the cyclization.
However, isolation of products confirmed the presence of
both N-1-Cbz protected (40%) and N-1-deprotected
(35%) indoles. As noted above, the use of Cs2CO3 (Table
1, entry 3), results in primarily deprotected indole. By
taking advantage of this fact, complete conversion to
deprotected indole 14 with an isolated yield of 71% was
achieved. This rapid entry into highly substituted indoles
such as 14 demonstrates the utility of this method.
Acknowledgements
Special thanks to Lisa Schaffter for help in characteriza-
tion of all final products.
Supplementary data
Synthetic procedures including analytical data are in-
cluded. Supplementary data associated with this article
can be found, in the online version, at doi:10.1016/
j.tetlet.2005.10.077.
References and notes
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Pdroute
Solution phase
H
H
O
O
O
O
O
(a)
(b)
O
O
N
Cbz
10a
79%
Br
80%
I
Solid support
H
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O
O
(a)
79%
(c)
62%
O
O
NHCbz
N
Cbz
O
Br
Br
1a
Scheme 4. Reagents and conditions: (a) 1. DBU, glycine phosphonate ester, DCM; 2. CuI, L-proline, K2CO3, 1,4-dioxane, 100 °C, 24 h. (b) 1. DBU,
glycine phosphonate ester, DCM; 2. PdCl2(dppf), KOAc, DMF, 90 °C (c) 1. Pd2(dba)3, Cy2NMe, t-Bu3P, toluene, 80 °C; 2. MeONa, THF/MeOH,
rt, 12h.

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