Palladium-catalyzed C-N and C-O bond formation of N-substituted 4-bromo-7-azaindoles with amides, amines, amino acid esters and phenols

Article abstract of DOI:10.3762/bjoc.8.227

Simple and efficient procedures for palladium-catalyzed cross-coupling reactions of N-substituted 4-bromo-7-azaindole (1Hpyrrole[2,3-b]pyridine), with amides, amines, amino acid esters and phenols through C-N and C-O bond formation have been developed. Th

Full text of DOI:10.3762/bjoc.8.227

Palladium-catalyzed C–N and C–O bond formation of
N-substituted 4-bromo-7-azaindoles with amides,
amines, amino acid esters and phenols
Rajendra Surasani1,2, Dipak Kalita*1, A. V. Dhanunjaya Rao1
and K. B. Chandrasekhar2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 2004–2018.
1Custom Pharmaceutical Services, Dr. Reddy’s Laboratories Ltd.,
Miyapur, Hyderabad 50049, India and 2Department of Chemistry,
Institute of Science and Technology, JNTU University of Anantapur,
Anantapur 515002, India
doi:10.3762/bjoc.8.227
Received: 10 August 2012
Accepted: 26 October 2012
Published: 19 November 2012
Email:
Dipak Kalita* - dipakk@drreddys.com
#DRL Communication no.: IPDO IPM- 00294
Associate Editor: D. Y.-K. Chen
* Corresponding author
Keywords:
© 2012 Surasani et al; licensee Beilstein-Institut.
License and terms: see end of document.
7-azaindole; C–N bond; C–O bond; ligand; palladium catalyst
Abstract
Simple and efficient procedures for palladium-catalyzed cross-coupling reactions of N-substituted 4-bromo-7-azaindole (1H-
pyrrole[2,3-b]pyridine), with amides, amines, amino acid esters and phenols through C–N and C–O bond formation have been
developed. The C–N cross-coupling reaction of amides, amines and amino acid esters takes place rapidly by using the combination
of Xantphos, Cs2CO3, dioxane and palladium catalyst precursors Pd(OAc)2/Pd2(dba)3. The combination of Pd(OAc)2, Xantphos,
K2CO3 and dioxane was found to be crucial for the C–O cross-coupling reaction. This is the first report on coupling of amides,
amino acid esters and phenols with N-protected 4-bromo-7-azaindole derivatives.
Introduction
Palladium-catalyzed C–N and C–O bond-forming reactions methods for the synthesis of this class of compounds and func-
between 4-substituted 7-azaindoles and amides, amines, amino tionalization of 7-azaindole scaffolds remain limited [9].
acid esters or phenols have recently gained popularity among Although the literature enumerates various methods for the syn-
the scientific community for different drug-discovery and thesis of substituted azaindole motifs, they are limited to N-1,
-development programs. Particularly, several 7-azaindoles (1H- C-2 or C-3 functionalized structures [5-8,10]. Furthermore,
pyrrole[2,3-b]pyridine) [1-4], including 4-substituted com- regioselective C–O-bond-forming reactions are interesting in
pounds [5-8] have found applications in various therapeutic organic synthesis due to the presence of these bonds in
areas. Despite their utility in various drug-development numerous natural products, biological compounds, pharmaceut-
programs in academic research and the pharmaceutical industry, icals, fragrances, cosmetics and polymers [11-17]. Among
2004

Beilstein J. Org. Chem. 2012, 8, 2004–2018.
others Buchwald, Hartwing and co-workers followed by many of microwave irradiation, results in the amino-7-azaindole in
other groups during the past decade reported the metal- moderate to low yield [5,7]. Primary alkylamines or anilines
catalyzed formation of carbon–heteroatom bonds [18-30]. Most under similar reaction conditions provided the displacement
of the literature reports are limited to aryl halides and indoles rearrangement products 4-amino-5-azaindole as the sole prod-
only. Clearly, each of these protocols has its own virtues; uct [7]. Very recently Buchwald et al. [39] reported a palla-
however, limitations still exist with respect to substrate scope, dium-catalyzed amination of unprotected halo-7-azaindoles
reagents and solvents, etc. Thus, palladium-catalyzed intra- and using biarylphosphine ligands (DavePhos), palladium precata-
intermolecular cross-coupling reactions of azaindoles with lyst (RuPhos)-based reagents, and LiHDMS as a base.
amides, amines, amino acid esters or phenols offer an interest- However, inconsistency of the results was observed when the
ing complementary method for the synthesis of C–N and C–O reactions were carried out on a large scale. As part of contin-
bonds under comparably mild conditions. It is important to note uing efforts in our laboratory [42-46] toward the development
that, in contrast to well-established palladium-catalyzed of new and improved methods in organic synthesis, we became
coupling reactions of indole with amines, alcohols and phenols interested in the possibility of developing an efficient
[5,7,31-36], very few studies on the formation of C–N and C–O palladium-mediated coupling of amides, amines, amino acid
bond formation over 7-azaindole have been performed [37-39]. esters and phenols with N-protected 7-azaindole derivatives
On the other hand, the chemistry of 4-bromo-7-azaindole has for one of our medicinally important drug-development
not been explored in depth until today.
programs.
Amino and phenyl-substituted 7-azaindole scaffolds appear in We herein report on Pd-catalyzed coupling reactions of
various pharmaceutically important molecules (Figure 1), which N-protected 4-bromo-7-azaindoles with amides, amines, amino
are very challenging and lengthy to prepare by the traditional acid esters and phenols (Scheme 1), to yield new important
methods [40,41]. In general, nucleophilic aromatic substitution intermediates for one of our medicinal chemistry programs. To
(SNAr) reaction of a halo-precursor of 7-azaindole with a large the best of our knowledge this is the first report on intermolec-
excess of amine counterpart under high reaction temperatures, ular coupling of 4-bromo-7-azaindole with amides, amino acid
preferably under heating to more than 180 °C or through the use esters and phenols.
Figure 1: Representative drug candidates of amino-azaindole and phenyl-azaindole containing motifs.
2005

Beilstein J. Org. Chem. 2012, 8, 2004–2018.
Scheme 1: Cross coupling of 4-bromo-7-azaindole with amides, amines, amino acid esters and phenols.
Results and Discussion
azaindoles 1 as substrates (Table 1). N-Benzyl-4-bromo-7-
4-Bromo-7-azaindole derivative 1 was prepared from 7-azain- azainole (1-benzyl-4-bromo-1H-pyrrolo[2,3-b]pyridine, 1e) and
dole by the literature procedure [47]. In most of the cases we benzamide (2a) were chosen as model substrates to find the
have used the N-protection of 4-bromo-7-azaindole. It is worth suitable palladium-mediated coupling of amides with
mentioning that 7-azaindole (1H-pyrrole[2,3-b]pyridine), has a N-protected 4-bromo-7-azaindole 1. After extensive screening,
[4.3]-bicyclic indene skeleton with a fused electron-rich pyrrole we found that the combination of Pd(OAc)2, Xantphos (L1) as a
ring and an electron-deficient pyridine ring. The pKa value of ligand [51-53], Cs2CO3 as a base and dioxane as a solvent
7-azaindole is ~4.9, and it undergoes self-association through provided the most successful result (Table 1, entry 1). The reac-
hydrogen-bonding to form a dimer in solution and phototau- tion temperature was maintained at ~100 °C in all cases.
tomerizes by an excited-state double-proton-transfer (ESDPT) Switching the Pd source to Pd2(dba)3 resulted in a slight
process [1,48]. In the presence of copper or palladium catalysts decrease in yield (Table 1, entry 2). Other available ligands,
azaindole undergoes arylation of the heterocyclic N–H nitrogen e.g., SPhos (L2) and XPhos (L3) provided lower yields when
[49,50]. To find a suitable condition for amide coupling with Pd2(dba)3 was used as a catalyst, even after longer reaction time
7-azaindole derivatives, various biaryl/alkyl phosphine ligands, (Table 1, entries 3 and 4). By using Pd(OAc)2 as a catalyst and
palladium catalysts, bases and reaction times, etc., were SPhos (L2) and XPhos (L3) as a bidentate ligand, low to
screened by using electron-deficient N-protected 4-bromo-7- moderate yields were obtained (Table 1, entries 6 and 7). When
2006

Beilstein J. Org. Chem. 2012, 8, 2004–2018.
Table 1: Reaction optimization for coupling of 1e with benzamide (2a) under various conditionsa.
Entry
Pd catalyst (5 mol %)
Ln
Base
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
9
Pd(OAc)2c
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
L1
L1
L2
L3
L4
L2
L3
L1
L1
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
2
95d
90
40
40
0
5
24
24
24
24
24
4
45
61
83
88
K3PO4
3
aReactions of 1-benzyl-4-bromo-1H-pyrrolo[2,3-b]-pyridine (1e) (1.0 mmol) with benzamide (2a) (1.2 mmol) were performed in a sealed Schlenk tube
at 100 °C in dioxane (2 mL) by using Pd catalyst (5 mol %), ligand (10 mol %) and base (1.5 mmol). bYields reported are isolated yields. cNo reaction
occurred without palladium catalyst. dNo reaction occurred at room temperature.
tertiary ligand PCy3 (L4) was used as a ligand for the cross- amide and amine coupling by reacting N-ethyl-7-bromoazain-
coupling reaction no product formation was observed (Table, dole (1d) with 2-aminobenzamide (2f) and obtained 2-amino-N-
entry 5). Cross-coupling reaction of N-benzyl-4-bromo-7-azain- (1-ethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)benzamide (3f) in 85%
dole (1e) and benzamide (2a) with other bases, e.g., K2CO3 and yield (Table 2, entry 8). We found that amide is more reactive
K3PO4, by using Pd(OAc)2 and Xantphos (L1) as a ligand than amine under the reaction conditions studied. The use of
provided good yield in 4 to 3 h (Table 1, entries 8 and 9). It is Cs2CO3 as the base is advantageous because the common func-
worth mentioning that Xantphos (L1) as a supporting ligand tional groups such as fluoro, methoxy, etc., are well tolerated.
finds wide popularity in palladium-mediated amidation reac- We found that the N-protection of 4-bromo-7-azaindoles 1 has a
tions by various research groups [54-56], which prompted us to marginal effect on the reaction yield and time. The coupling of
evaluate the process further, with various substrate scopes.
amides with N-protected 4-bromo-7-azaindoles 1 was demon-
strated in multi-gram synthesis in our hands. Next we diverted
With optimized conditions in hand, we embarked on an investi- our attention towards coupling of N-protected 4-bromo-7-azain-
gation of the reaction scope by subjecting various N-protected doles 1 with amines 4.
7-azaindoles 1 to a wide range of amides 2. The experimental
results are summarized in Table 2. The reaction did not proceed Synthesis of 4-amino-7-azaindoles was generally achieved from
at all without N-protection (1a, Table 2, entry 1). When the the corresponding halide by SNAr displacement reactions,
reaction was carried out with N-sulfonyl-protected 4-bromo-7- which typically require very high temperatures, extended reac-
azaindole 1b only the desulfonated product (Table 2, entry 2) tion times, and a large excess of the amine counterpart [5].
was obtained. It is worth mentioning that the N-sulfonyl Other alternative methods employ the amino-substituted azain-
protected 7-azaindole 1b was efficiently deprotected under dole as the key intermediate, which are challenging to prepare
basic conditions in dioxane [57]. The optimized reaction condi- [6]. Initially, coupling of 4-bromo-1-ethyl-1H-pyrrolo[2,3-
tions worked well with benzamide (2a) (Table 2, entry 3) and b]pyridine (1d) with phenylmethanamine (4a) was selected as a
phenylsulfonamide (2b) (Table 2, entry 4) to obtained a good model reaction to optimize the reaction condition of C–N-bond
yield. A cyclic secondary amide (lactam) 2c also reacted effi- formation of amines. The experimental results are summarized
ciently (Table 2, entry 5). The methodology works equally well in Table 3. After the screening of various ligands (Scheme 1),
with 2-methoxybenzamide (2d) (Table 2, entry 6) and 4-fluoro- palladium catalysts, and bases (Table 1), the catalyst combina-
benzamide (2e) (Table 2, entry 7). We checked the selectivity of tion of Pd2(dba)3, Xantphos and Cs2CO3 in dioxane was found
2007

Beilstein J. Org. Chem. 2012, 8, 2004–2018.
Table 2: C–N-bond-formation cross coupling of N-protected 4-bromo-7-azaindoles 1 with amides 2.
Entry
1
7-Azaindole 1
Amide 2
Product 3a
Time (h) Yield (%)b
–
24
NRc
2a
1a
1b
2
3
–
5
0d
2a
2a
2
95
1c
3a
4
3
85
2b
1c
3b
5
2.5
92
2c
1c
3c
6
3
91
2d
1d
3d
2008

Beilstein J. Org. Chem. 2012, 8, 2004–2018.
Table 2: C–N-bond-formation cross coupling of N-protected 4-bromo-7-azaindoles 1 with amides 2. (continued)
7
8
9
3
3
2
89
85
95
2e
1d
3e
2f
1d
3f
2a
1e
3g
aReactions of N-protected 7-azaindoles 1 (1.0 mmol) with amides 2 (1.2 mmol) were performed in a sealed Schlenk tube at 100 °C in dioxane (2 mL)
by using Pd(OAc)2 (5 mol %), Xantphos (10 mol %) and base (1.5 mmol). bYields reported are isolated yields. cNR no reaction. dDesulfonation reac-
tion takes place.
Table 3: Optimization of the coupling reaction of 4-bromo-1-ethyl-1H-pyrrolo[2,3-b]pyridine (1d) with phenylmethanamine (4a).a
Entry
Pd-catalyst (5 mol %)
Ln
Base
Time (h)
Yield (%)b
1
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
L1
L1
L2
L3
L4
L1
L1
L1
L1
L2
L3
L4
Cs2CO3
K2CO3
1
93
85
60
62
0
2
3
3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
6
4
6
5
24
24
24
24
24
24
24
24
6
20
15
23
20
18
17
0
7
8
NaOt-Bu
K3PO4
9
10
11
12
Cs2CO3
Cs2CO3
Cs2CO3
aReactions of 1-ethyl-4-bromo-1H-pyrrolo[2,3-b]-pyridine (1d) (1.0 mmol) with phenylmethanamine (4a) (1.2 mmol) were performed in a sealed
Schlenk tube at 100 °C in dioxane (2 mL) by using Pd catalyst (5 mol %), ligand (10 mol %) and base (1.5 mmol). bYields reported are isolated yield.
2009

Beilstein J. Org. Chem. 2012, 8, 2004–2018.
to be crucial. The cross-coupling reaction of 4-bromo-1-ethyl- With a viable coupling procedure in hand, attention was turned
1H-pyrrolo[2,3-b]pyridine (1d) with phenylmethanamine (4a) to the generality of the process and couplings of structurally
proceeded rapidly by using the combination of Pd2(dba)3, Xant- diverse nucleophilic amines. As seen from Table 4, the cross-
phos and Cs2CO3 in dioxane at 100 °C for 1 h (Table 3, coupling reaction of N-protected 4-bromo-7-azaindoles 1a–1d
entry 1). When K2CO3 was used as base along with Pd2(dba)3 with various amines 4a–4f proved to be general under the opti-
as catalyst and XantPhos (L1) as ligand, slightly lower yield mized conditions to get the coupled products 5a–5f in very
(~85%) was obtained (Table 3, entry 2) in 3 h. Other ligands good yield (88–94%) within a reasonable time of 2.5 to 3 h. The
SPhos (L2) and XPhos (L3) with Pd2(dba)3 as catalyst provided C–N-bond-forming reaction of primary aromatic amines
average yields of 60 and 62%, respectively, in 6 h (Table 3, (Table 4, entries 3, 4 and 6) proceeded smoothly under the opti-
entries 3 and 4). However, the tertiary phosphine ligand PCy3 mized conditions to provide excellent yields of the corres-
(L4) was ineffective in generating any product (Table 3, entries ponding coupling products 5a, 5b and 5d, respectively. The
5 and 12). Interestingly, Pd(OAc)2 results in poor yields of the reaction was also effective for cyclic amine morpholine
product (Table 3, entries 6–12). Given this surprising result, we (Table 4, entry 5) and Boc-protected piperazine (Table 4, entry
hypothesized that the amination product 5 may interfere with 8). The reaction works equally well for aliphatic primary amine
catalyst turnover by promoting the formation of an inactive too (Table 4, entry 7) resulting in 90% isolated yield. There was
Pd-chelate complex.
a feeble change in yield by varying the substitution on the
Table 4: C–N-bond-formation cross coupling of N-protected 4-bromo-7-azaindoles 1 with amines 4.
Entry
1
7-Azaindole 1
Amine 4
Product 5a
Time (h)
Yield (%)b
NRc
–
24
4a
1a
1b
2
3
–
3
0d
4a
4a
2.5
92
1c
5a
4
3
91
4b
1c
5b
2010

Beilstein J. Org. Chem. 2012, 8, 2004–2018.
Table 4: C–N-bond-formation cross coupling of N-protected 4-bromo-7-azaindoles 1 with amines 4. (continued)
5
3
88
4c
1c
5c
5d
6
7
2.5
2.5
93
90
4d
4e
1d
1d
5e
8
3
94
4f
1d
5f
aAll reactions were carried out at 100 °C by using N-substituted 4-bromo-azaindoles 1 (1.0 mmol), amines (1.2 mmol), Cs2CO3 (1.5 mmol), Pd2(dba)3
(5 mol %), Xantphos (10 mol %), and 2 mL of dioxane. bYields reported are isolated yields. cNR: no reaction. dDesulfonation reaction takes place.
7-azaindole nitrogen (N1) from a methyl to an ethyl group amino acids and its derivatives finds popularity in various
(Table 4, entries 6–8). There was no reaction without the coupling protocols [58]. A copper(I) iodide catalyzed coupling
N-protection (Table 4, entry 1). Heating of the reaction mixture reaction of haloindoles with α-amino acids was reported by
of 4-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (1b) Ishikawa et al. [59].
with phenylmethanamine (4a) in the presence of base and palla-
dium catalyst resulted in the desulfonated 4-bromo-7-azaindole Indole and azaindole moieties functionalized with amino acid
as the sole product (Table 4, entry 2).
ester scaffold are believed to be important synthetic intermedi-
ates and structural components of various medicinal and phar-
Our continuous efforts to develop synthetic methods for the for- maceutical candidates. The coupling of N-methyl-4-bromo-7-
mation of C–N bonds by coupling of N-protected 7-azaindoles azaindole (1c) with D-alanine methyl ester 6b was chosen as the
1 with amino acids or esters result in the development of model reaction to test the feasibility of the palladium-assisted
interesting intermediates in our own medicinal chemistry coupling reaction of 7-azaindole and amino acids. The experi-
program based on 7-azaindole. Large molecular architectures mental results are summarized in Table 5. In our initial
designed by cross-coupling strategies with the introduction of endeavor the coupling of N-methyl-4-bromo-7-azaindole (1c)
an amino acid functionality on 7-azaindole, result in new scaf- with D-alanine (6a) resulted in only a trace amount of product
folding. N-aryl-amino acids are reported as important synthetic 7a with Xantphos (L1) as a ligand (Table 5, entry 1). Other
intermediates and structural motifs for various drug-develop- bidentate aryl phosphine ligands L2 and L3 did not result in any
ment programs by various medicinal and process-research product formation (Table 5, entries 2 and 3). The tertiary phos-
chemists. Therefore, transition metal-catalyzed coupling of phine ligand PCy3 (L4) was ineffective in the arylation of
2011

Beilstein J. Org. Chem. 2012, 8, 2004–2018.
Table 5: Optimization of the coupling reaction of 1c with D-alanine methyl ester (6b).a
Entry
Pd catalyst (5 mol %)
Amino acid (ester) 6
Ln
Base
Time (h)
Yield (%)b
1
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
6a
6a
6a
6a
6b
6b
6b
6b
6b
6b
6b
6b
6b
6b
6b
6b
6b
6b
6b
L1
L2
L3
L4
L1
L1
L1
L1
L1
L2
L3
L4
L1
L1
L1
L1
L2
L3
L4
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
24
24
24
24
1
tracesc
0
2
3
0
4
0
5
93
85
44
33
12
14
traces
0
6
3
7
NaOt-Bu
KOH
3
8
3
9
K3PO4
3
10
11
12
13
14
15
16
17
18
19
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
6
6
24
24
24
24
24
24
24
24
20
15
23
20
18
0
NaOt-Bu
K3PO4
Cs2CO3
Cs2CO3
Cs2CO3
0
aReaction conditions: N-methyl-4-bromo-7-azaindole (1c) (1.0 mmol), amino acid (ester) (1.2 mmol), base (3.0 mmol), palladium catalyst (5 mol %),
ligand (10 mol %), and 2 mL of dioxane, 100 °C, 1–24 h. bYields reported are isolated yields. cTrace amount of product obtained by cross coupling of
1c with 6a.
N-methyl-4-bromo-7-azaindole (1c) with D-alanine (6a) used as a ligand, with Pd2(dba)3 as palladium source, and
(Table 5, entry 4). It is believed that the coordination of the Cs2CO3 as base, a trace amount of product was formed after 6 h
central metal of the oxidative addition complex with the (Table 5, entry 11). On conducting the experiment with
carboxyl functionality of the amino acid scaffold retained the Pd(OAc)2 as catalyst and using the same ligand L3, no product
Pd–N bond, making the 7-azaindole–Pd–N complexes too formation was observed even after 24 h (Table 5, entry 18). The
stable for reductive elimination [58]. As can be seen from tertiary phosphine ligand PCy3 (L4) was found to be ineffective
Table 5, the reaction of N-methyl-4-bromo-7-azaindole (1c) when treated with N-methyl-4-bromo-7-azaindole (1c) and
with D-alanine methyl ester (6b) occurred rapidly with D-alanine methyl ester (6b) (Table 5, entry 19). These results
Pd2(dba)3 as a catalyst, Xantphos (L1) as ligand, and Cs2CO3 as indicate that increasing the steric hindrance of the ligands
base in dioxane at 100 °C in a short reaction time of 1 h promoted the reductive elimination step during the C–N-bond-
(Table 5, entry 5). When K2CO3 was used as a base with forming step [58]. All the coupling reactions of amino acid
Pd2(dba)3 as a catalyst, and Xantphos (L1) as a ligand, 85% of esters were performed in dioxane as the solvent. Finally,
the product conversion was observed in 3 h (Table 5, entry 6). Cs2CO3 as base (Table 5, entry 5) was found to be more effec-
The other palladium catalyst Pd(OAc)2 results in poor yields of tive than stronger bases such as NaOt-Bu, KOH and potassium
the product (Table 5, entry 13–19). Coupling of N-methyl-4- phosphates (Table 5, entries 7–9).
bromo-7-azaindole (1c) with D-alanine methyl ester (6b) by
using SPhos (L2) as a ligand results in low product yield ~14% With a viable coupling procedure in hand, attention was turned
(Table 5, entry 10). When the bulkier ligand XPhos (L3) was to the generality of the process and couplings of structurally
2012

Beilstein J. Org. Chem. 2012, 8, 2004–2018.
diverse amino acid building blocks. Results summarized in AD-H column. Amino acids without extra coordinating groups
Table 6 show that the optimized conditions described proved to gave good coupling yields (Table 6, entries 3, 6 and 7).
be general for the coupling with a wide variety of amino acid Coupling of L-serine(O-t-Bu)-OMe (6d) with 1c resulted in
building blocks. As can be seen from Table 6, the catalytic moderate yield of the product in 3 h (Table 6, entry 4). The
system works well with diversified amino acid building blocks. catalytic system developed by us for the coupling of amino acid
Coupling of N-methyl-4-bromo-7-azaindole (1c) with D-alanine esters with N-protected 7-azaindoles was ineffective for
methyl ester (6b) resulted in good yield of the product 7b in a L-proline (6f), L-serine (6g), and L-glutamic acid (6h) (Table 6,
short reaction time (Table 6, entry 2). The chiral purity of the entries 8–10). This may be ascribed to the fact that these amino
product was determined by chiral HPLC using Chiral Pak acids contain more heteroatoms that bind to the central palla-
Table 6: C–N-bond-formation cross coupling of N-protected 4-bromo-7-azaindoles 1 with amino acid (esters) 6.
Entry
7-Azaindole 1
Amino acid (ester) 6
Product 7a
Time (h) Yield (%)b
ee (%)d
1
2
traces
–
6a
1c
7a
2
2
70
98.79
6b
1c
7b
3
2
72
–
6c
1c
7c
4
3
65
95.48
6d
1c
7d
2013

Beilstein J. Org. Chem. 2012, 8, 2004–2018.
Table 6: C–N-bond-formation cross coupling of N-protected 4-bromo-7-azaindoles 1 with amino acid (esters) 6. (continued)
5
2
71
98.91
6b
1d
7e
6
2.1
72
–
6c
1d
7f
7
2
70
–
6e
1d
7g
8
–
5
5
5
0
0
0
–
–
–
6f
6g
6h
1c
1c
1c
9
–
–
10
aAll reactions were carried out at 100 °C. N-substituted 4-bromo-azaindoles 1c or 1d (1.0 mmol), amino acid (esters) (1.2 mmol), Cs2CO3 (3.0 mmol),
Pd2(dba)3 (5 mol %) and Xantphos (10 mol %) were used for all the reactions. bYields reported are isolated yields. cDesulfonation reaction takes
place. dee was determined by chiral HPLC.
dium atom and enhance the stability of the 7-azaindole–Pd–N of the literature reports described on C–O-bond-formation reac-
complexes, making them too stable for reductive elimination.
tions are limited to aryl halides and phenols or alcohols only
[36,60-63]. Functionalization of 4-substituted-7-azaindole scaf-
After successful demonstration of the C–N-bond-formation folds with 4-amino-2-fluorophenol was reported to be ineffec-
reaction of 4-bromo-7-azaindole derivatives with amides, tive upon heating in the presence of a strong base such as
amines and amino acid esters, we wanted to expand the scope of KOt-Bu [35]. In addition, the N-oxide derivative of 4-substi-
the reaction towards C–O-bond formation. Until today no tuted 7-azaindole fails to provide the desired product under
general method has been described for the C–O-bond-forma- similar conditions [48]. Further, on utilizing palladium or
tion reaction of 4-halo-azaindole with phenols or alcohols. Most copper-mediated cross-coupling reactions of N-protected
2014

Beilstein J. Org. Chem. 2012, 8, 2004–2018.
amino-2-fluorophenol with 4-chloro- or 4-bromo-1H- ring of the reaction mixture at 100 °C. The probable reason may
pyrrolo[2,3-b]pyridine, the desired diaryl ether could not be be that Cs2CO3 is much heavier than K2CO3 and tends to settle
isolated in acceptable yield [5,35]. To select the best reaction in the bottom of the reaction vessel or reactor when run on a
conditions for C–O-bond formation, we envisaged the syn- larger scale, causing improper mixing of the heterogeneous
thesis of an activated 7-azaindole building block that could be mixture.
coupled with phenols. To select the best coupling conditions for
C–O bond formation, the coupling of 4-bromo-1-methy-1H- With a viable coupling procedure in hand, attention was turned
pyrrolo[2,3-b]pyridine (1c) with m-cresol (8a) was selected as a to the generality of the process and couplings of structurally
model reaction to find the suitable ligands (Scheme 1), palla- diverse phenols. Results are summarized in Table 8. The C–O-
dium catalysts, bases and organic solvents. The experimental bond formation was established with good yields with phenol
findings are summarized in Table 7. The coupling of 1c with 8a derivatives and 1-naphthol (Table 8, entries 1–3). Moreover, the
by using a combination of Pd(OAc)2, Xantphos (L1) and outcome of the reaction strongly depended on the electronic
K2CO3 in dioxane at 100 °C in 10 h of time provided 70% of character of the appropriate phenol (Table 8). The more-elec-
the desired diaryl ether 9a (Table 7, entry 3). The reaction rate tron-rich nucleophiles 8a, 8b furnished the desired ethers 9a
is slow, i.e., when run for 3 h at 100 °C, only 30% product was and 9b in good yields. Further studies are in progress in our
obtained (Table 7, entry 2). But upon continuous heating for 7 h laboratory to investigate different substrate scope and mecha-
we observed 70% (Table 7, entry 3) of the expected product. nistic aspects of the C–O-bond-forming reaction.
Interestingly, usage of Pd2(dba)3 resulted in poor yields of the
product (Table 7, entries 5 and 6). In most of the cases we Conclusion
observed decomposition of the Pd2(dba)3 reagent. In compari- In conclusion, we have developed the best coupling conditions
son to the conditions described for the amines and amides, a for C–N-bond formation of N-substituted 4-bromo-7-azain-
much longer reaction time was required for the C–O-bond for- doles with amides, amines, and amino acid esters and demon-
mation when treated with phenols. K2CO3 was found to be a strated well for the synthesis of various N-substituted 7-azain-
suitable base for the C–O-bond formation under the experi- dole compounds, which are very difficult to synthesize other-
mental conditions we studied. When Cs2CO3 was used as base, wise. The combination of Xantphos, Cs2CO3 and dioxane was
settling of the base was observed even under heating and stir- found to be crucial for all the C–N cross-coupling reactions.
Table 7: Optimization of the coupling reaction of N-methyl-4-bromo-7-azaindole (1c) with m-cresol (8a).a
Entry
Pd catalyst (5 mol %)
Ln
Base
Solvent
Time (h)
Yield (%)b
1
2
3
4
5
6
7
7
9
10
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
L1
L1
L1
L1
L1
L1
L2
L3
L1
L1
Cs2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
K2CO3
Cs2CO3
Cs2CO3
K2CO3
K2CO3
dioxane
dioxane
dioxane
THF
5
20
30
70
50
10
32
45
61
68
65
3
10
10
3
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
10
24
24
12
24
aReaction conditions: N-methyl-4-bromo-7-azaindole (1c) (1.0 mmol), m-cresol (1.2 mmol), base (3.0 mmol), palladium catalyst (5 mol %), ligand (10
mol %), and 2 mL of dioxane, 100 °C, 3–24 h. bYields reported are isolated yields.
2015

Beilstein J. Org. Chem. 2012, 8, 2004–2018.
Table 8: C–O-bond-formation cross coupling of N-methyl-4-bromo-7-azaindole (1c) with phenols 9a–9c.
Entry
7-Azaindole 1
Phenol 8
Product 9a
Time (h)
Yield (%)b
1
10
70
8a
1c
9a
2
8
85
8b
1c
9b
3
11
72
8c
1c
9c
aAll reactions were carried out at 100 °C in a dried sealed Schlenk tube by using N-methyl-4-bromo-7-azaindole (1c) (1.0 mmol), phenol (1.2 mmol),
K2CO3 (1.5 mmol), Pd(OAc)2 (5 mol %), Xantphos (10 mol %) and 2 mL of dioxane. bYields reported are isolated yields.
However, different Pd-catalyst precursors were used for
Supporting Information
different amines/amides and amino acid esters. We have
enhanced the methodology towards the C–O-bond formation
Supporting information, containing all experimental details
with various phenols, which is very difficult to achieve. K2CO3
and analytical data of all new compounds given in this
was found to be better for C–O cross-coupling reactions. This
article as well as their 1H, 13C NMR spectra and HRMS
protocol provides a nice alternative for the synthesis of
data, is provided.
N-substituted 7-azaindole derivatives, which exist extensively
Supporting Information File 1
in natural products and pharmaceuticals. This is the first report
on coupling of amides, amino acid esters and phenols with
N-substituted 4-bromo-7-azaindole. Hence, we feel that our
methodology will serve as an excellent tool in medicinal chem-
istry, organic synthesis and process research worldwide.
Experimental procedures, analytical data and NMR spectra.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-227-S1.pdf]
2016

Beilstein J. Org. Chem. 2012, 8, 2004–2018.
24.Chen, W.; Li, J.; Fang, D.; Feng, C.; Zhang, C. Org. Lett. 2008, 10,
4565–4568. doi:10.1021/ol801730g
Acknowledgements
The authors thank Dr. Vilas H Dahanukar for his encourage-
ment and the analytical group for spectral data. Mr. Rajendra
Surasani thanks CPS-DRL, Hyderabad, India for allowing him
to pursue this work as a part of his Ph.D. program.
25.Zhang, H.; Cai, Q.; Ma, D. J. Org. Chem. 2005, 70, 5164–5173.
doi:10.1021/jo0504464
26.Fors, B. P.; Dooleweerdt, K.; Zeng, Q.; Buchwald, S. L. Tetrahedron
2009, 65, 6576–6583. doi:10.1016/j.tet.2009.04.096
27.Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534–1544.
doi:10.1021/ar800098p
References
1. Zhao, S.-B.; Wang, S. Chem. Soc. Rev. 2010, 39, 3142–3156.
28.Buchwald, S. L.; Mauger, C.; Mignani, G.; Scholz, U. Adv. Synth. Catal.
2006, 348, 23–39. doi:10.1002/adsc.200505158
doi:10.1039/c001897j
29.Messaoudi, S.; Audisio, D.; Brion, J.-D.; Alami, M. Tetrahedron 2007,
63, 10202–10210. doi:10.1016/j.tet.2007.07.085
2. Popowycz, F.; Routier, S.; Joseph, B.; Mérour, J.-Y. Tetrahedron 2007,
63, 1031–1064. doi:10.1016/j.tet.2006.09.067
30.Vimolratana, M.; Simard, J. L.; Brown, S. P. Tetrahedron Lett. 2011,
52, 1020–1022. doi:10.1016/j.tetlet.2010.12.088
3. Song, J. J.; Reeves, J. T.; Gallou, F.; Tan, Z.; Yee, N. K.;
Senanayake, C. H. Chem. Soc. Rev. 2007, 36, 1120–1132.
doi:10.1039/b607868k
31.Yao, P.-Y.; Zhang, Y.; Hsung, R. P.; Zhao, K. Org. Lett. 2008, 10,
4275–4278. doi:10.1021/ol801711p
4. Schlummer, B.; Scholz, U. Adv. Synth. Catal. 2004, 346, 1599–1626.
doi:10.1002/adsc.200404216
32.Schwarz, N.; Pews-Davtyan, A.; Alex, K.; Tillack, A.; Beller, M.
Synthesis 2007, 3722–3730. doi:10.1055/s-2007-990819
33.Benarous, R.; Barbey-Treve, S.; Paris, J.-M.; Berrut, S.;
Berlioz-Torrent, C.; Emiliani, S. Novel substituted aryl derivatives, their
process of preparation and their therapeutical uses as anti-HIV agents.
WO Patent WO2010066847, June 17, 2010.
5. Caldwell, J. J.; Cheung, K.-W.; Collins, I. Tetrahedron Lett. 2007, 48,
1527–1529. doi:10.1016/j.tetlet.2007.01.003
6. Schneller, S. W.; Luo, J.-K. J. Org. Chem. 1980, 45, 4045–4048.
doi:10.1021/jo01308a021
7. Girgis, N. S.; Larson, S. B.; Robins, R. K.; Cottam, H. B.
J. Heterocycl. Chem. 1989, 26, 317–325. doi:10.1002/jhet.5570260210
8. Guillard, J.; Decrop, M.; Gallay, N.; Espanel, C.; Boissier, E.;
Herault, O.; Viaud-Massuard, M.-C. Bioorg. Med. Chem. Lett. 2007, 17,
1934–1937. doi:10.1016/j.bmcl.2007.01.033
34.Sergeev, A. G.; Artamkina, G. A.; Velezheva, V. S.; Fedorova, I. N.;
Beletskava, I. P. Russ. J. Org. Chem. 2005, 41, 860–874.
doi:10.1007/s11178-005-0257-0
35.Edmondson, S. D.; Mastracchio, A.; Parmee, E. R. Org. Lett. 2000, 2,
1109–1112. doi:10.1021/ol000031z
9. Busacca, C. A.; Fandrick, D. R.; Song, J. J.; Senanayake, C. H.
Adv. Synth. Catal. 2011, 353, 1825–1864.
36.Gowrisankar, S.; Sergeev, A. G.; Anbarasan, P.; Spannenberg, A.;
Neumann, H.; Beller, M. J. Am. Chem. Soc. 2010, 132, 11592–11598.
doi:10.1021/ja103248d
doi:10.1002/adsc.201100488
10.Merour, J.-Y.; Joseph, B. Curr. Org. Chem. 2001, 5, 471–506.
doi:10.2174/1385272013375427
37.Thutewohl, M.; Schirok, H.; Bennabi, S.; Figueroa-Pérez, S. Synthesis
2006, 629–632. doi:10.1055/s-2006-926310
11.Buckingham, J. Dictionary of Natural Products; University Press:
Cambridge, MA, 1994.
38.Figueroa-Pérez, S.; Bennabi, S.; Schirok, H.; Thutewohi, M.
Tetrahedron Lett. 2006, 47, 2069–2072.
12.Czarnik, A. W. Acc. Chem. Res. 1996, 29, 112–113.
doi:10.1021/ar950256n
doi:10.1016/j.tetlet.2006.01.143
39.Henderson, J. L.; McDermott, S. M.; Buchwald, S. L. Org. Lett. 2010,
12, 4438–4441. doi:10.1021/ol101928m
13.Theil, F. Angew. Chem., Int. Ed. 1999, 38, 2345–2347.
doi:10.1002/(SICI)1521-3773(19990816)38:16<2345::AID-ANIE2345>3
.0.CO;2-5
40.Blake, J.; Gunawardana, I. W.; Le Huerou, Y.; Mohr, P. J.;
Wallace, E. M.; Wang, B. Pyrrolopyridines as kinase inhibitors. WO
Patent WO2009089352, July 16, 2009.
14.Sawyer, J. S. Tetrahedron 2000, 56, 5045–5065.
doi:10.1016/S0040-4020(00)00257-X
41.Toshihiro, H.; Hiroko, N.; Jun, T. Novel compounds. U.S. Patent
Application US20100016307A1, Jan 21, 2010.
15.Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42,
5400–5449. doi:10.1002/anie.200300594
42.Surasani, R.; Kalita, D.; Rao, A. V. D.; Yarbagi, Y.;
Chandrasekhar, K. B. J. Fluorine Chem. 2012, 135, 91–96.
doi:10.1016/j.jfluchem.2011.09.005
16.Cristau, P.; Vors, J.-P.; Zhu, J. Tetrahedron 2003, 59, 7859–7870.
doi:10.1016/j.tet.2003.08.031
17.Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131–209.
doi:10.1007/3-540-45313-X_5
43.Layek, M.; Gajare, V.; Kalita, D.; Islam, A.; Mukkanti, K.; Pal, M.
Tetrahedron 2009, 65, 4814–4819. doi:10.1016/j.tet.2009.04.054
44.Layek, M.; Gajare, V.; Kalita, D.; Islam, A.; Mukkanti, K.; Pal, M.
Tetrahedron Lett. 2009, 50, 3867–3871.
18.Yin, J.; Buchwald, S. L. Org. Lett. 2000, 2, 1101–1104.
doi:10.1021/ol005654r
19.Fors, B. P.; Krattiger, P.; Strieter, E.; Buchwald, S. L. Org. Lett. 2008,
10, 3505–3508. doi:10.1021/ol801285g
doi:10.1016/j.tetlet.2009.04.048
45.Layek, M.; Rao, A. V. D.; Gajare, V.; Kalita, D.; Barange, D. K.;
Islam, A.; Mukkanti, K.; Pal, M. Tetrahedron Lett. 2009, 50, 4878–4881.
doi:10.1016/j.tetlet.2009.06.041
20.Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald, S. L.
J. Org. Chem. 2000, 65, 1158–1174. doi:10.1021/jo991699y
21.Sadig, J. E. R.; Willis, M. C. Synthesis 2011, 1–22.
doi:10.1055/s-0030-1258294
46.Layek, M.; Lakshmi, U.; Kalita, D.; Barange, D. K.; Islam, A.;
Mukkanti, K.; Pal, M. Beilstein J. Org. Chem. 2009, 5, No. 46.
doi:10.3762/bjoc.5.46
22.Hooper, M. W.; Utsunomiya, M.; Hartwig, J. F. J. Org. Chem. 2003, 68,
2861–2873. doi:10.1021/jo0266339
47.Thibault, C.; L'Heureux, A.; Bhide, R. S.; Ruel, R. Org. Lett. 2003, 5,
5023–5025. doi:10.1021/ol036030z
23.Peng, Z.-H.; Journet, M.; Humphrey, G. Org. Lett. 2006, 8, 395–398.
doi:10.1021/ol052578p
2017

Beilstein J. Org. Chem. 2012, 8, 2004–2018.
48.Kühler, T. C.; Swanson, M.; Shcherbuchin, V.; Larsson, H.;
Mellgård, B.; Sjöström, J.-E. J. Med. Chem. 1998, 41, 1777–1788.
doi:10.1021/jm970165r
49.Antilla, J. C.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 11684–11688. doi:10.1021/ja027433h
50.Old, D. W.; Harris, M. C.; Buchwald, S. L. Org. Lett. 2000, 2,
1403–1406. doi:10.1021/ol005728z
51.Kranenburg, M.; van der Burgt, Y. E. M.; Kamer, P. C. J.;
van Leeuwen, P. W. N. M.; Goubitz, K.; Fraanje, J. Organometallics
1995, 14, 3081–3089. doi:10.1021/om00006a057
52.Guari, Y.; van Es, D. S.; Reek, J. N. H.; Kamer, P. C. J.;
van Leeuwen, P. W. N. M. Tetrahedron Lett. 1999, 40, 3789–3790.
doi:10.1016/S0040-4039(99)00527-4
53.Wagaw, S.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121,
10251–10263. doi:10.1021/ja992077x
54.Imbriglio, J. E.; DiRocco, D.; Raghavan, S.; Ball, R. G.; Tsou, N.;
Mosley, R. T.; Tata, J. R.; Colletti, S. L. Tetrahedron Lett. 2008, 49,
4897–4900. doi:10.1016/j.tetlet.2008.05.148
55.Vandromme, L.; Legraverend, M.; Kreimerman, S.; Lozach, O.;
Meijer, L.; Grierson, D. S. Bioorg. Med. Chem. 2007, 15, 130–141.
doi:10.1016/j.bmc.2006.10.003
56.Piguel, S.; Legraverend, M. J. Org. Chem. 2007, 72, 7026–7029.
doi:10.1021/jo071196p
57.Chaulet, C.; Croix, C.; Basset, J.; Pujol, M.-D.; Viaud-Massuard, M.-C.
Synlett 2010, 1481–1484. doi:10.1055/s-0029-1219918
58.Ma, F.; Xie, X.; Ding, L.; Gao, J.; Zhang, Z. Tetrahedron 2011, 67,
9405–9410. doi:10.1016/j.tet.2011.09.109
And references cited therein.
59.Kurokawa, M.; Nakanishi, W.; Ishikawa, T. Heterocycles 2007, 71,
847–854. doi:10.3987/COM-06-10985
60.Wolter, M.; Nordmann, G.; Job, G. E.; Buchwald, S. L. Org. Lett. 2002,
4, 973–976. doi:10.1021/ol025548k
61.Kuwabe, S.-i.; Torraca, K. E.; Buchwald, S. L. J. Am. Chem. Soc. 2001,
123, 12202–12206. doi:10.1021/ja012046d
62.Torraca, K. E.; Huang, X.; Parrish, C. A.; Buchwald, S. L.
J. Am. Chem. Soc. 2001, 123, 10770–10771. doi:10.1021/ja016863p
63.Parrish, C. A.; Buchwald, S. L. J. Org. Chem. 2001, 66, 2498–2500.
doi:10.1021/jo001426z
License and Terms
This is an Open Access article under the terms of the
Creative Commons Attribution License
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
(http://www.beilstein-journals.org/bjoc)
The definitive version of this article is the electronic one
which can be found at:
doi:10.3762/bjoc.8.227
2018