Microwave-assisted, one-pot reaction of 7-azaindoles and aldehydes: A facile route to novel di-7-azaindolylmethanes

Article abstract of DOI:10.1016/j.tetlet.2013.10.143

A novel and highly efficient synthetic method leveraging microwave-assisted organic synthesis (MAOS) to yield di-7-azaindolylmethanes (DAIMs) is reported. Under MAOS conditions, reaction of 7-azaindole with aldehydes resulted predominantly in DAIMs, as opposed to the expected 7-azaindole addition products that form at ambient temperature. Based upon studies of different indoles and azaindoles with various aromatic and aliphatic aldehydes, we herein propose a mechanism where rapid and efficient microwave heating promotes nucleophilicity of 7-azaindoles toward the corresponding alkylidene-azaindolene intermediate to form the DAIM. This sequence provides a versatile approach to efficiently synthesize novel DAIMs that may be useful pharmaceuticals.

Full text of DOI:10.1016/j.tetlet.2013.10.143

Tetrahedron Letters xxx (2013) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave-assisted, one-pot reaction of 7-azaindoles and aldehydes:
a facile route to novel di-7-azaindolylmethanes
Md. Imam Uddin a,b, Jason R. Buck a,b, Michael L. Schulte b, Dewei Tang a,b, Samir A. Saleh b,
Yiu-Yin Cheung b, Joel Harp g, H. Charles Manning a,b,c,d,e,f,
⇑
a Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN 37232, USA
b Vanderbilt University Institute of Imaging Science, Vanderbilt University, Nashville, TN 37232, USA
c Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37232, USA
d Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA
e Program in Chemical and Physical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
f Department of Neurosurgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA
g Department of Biochemistry and Center for Structural Biology, Vanderbilt University, Nashville, TN 37232, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel and highly efficient synthetic method leveraging microwave-assisted organic synthesis (MAOS)
to yield di-7-azaindolylmethanes (DAIMs) is reported. Under MAOS conditions, reaction of 7-azaindole
with aldehydes resulted predominantly in DAIMs, as opposed to the expected 7-azaindole addition prod-
ucts that form at ambient temperature. Based upon studies of different indoles and azaindoles with var-
ious aromatic and aliphatic aldehydes, we herein propose a mechanism where rapid and efficient
microwave heating promotes nucleophilicity of 7-azaindoles toward the corresponding alkylidene–
azaindolene intermediate to form the DAIM. This sequence provides a versatile approach to efficiently
synthesize novel DAIMs that may be useful pharmaceuticals.
Received 7 September 2013
Revised 28 October 2013
Accepted 29 October 2013
Available online xxxx
Keywords:
Microwave
7-Azaindoles
Di-7-azaindolylmethanes
One-pot reactions
MAOS
Ó 2013 Elsevier Ltd. All rights reserved.
Bisindolylmethanes, or diindolylmethanes (DIMs), are a unique
class of compounds with select members exhibiting biological
activity in diseased states, including chemopreventive and thera-
peutic properties.1 In nature, DIMs are found in vegetables of the
cruciferae family, particularly those of the brassica genus, such as
broccoli, brussels sprouts, cabbage, and cauliflower, and are report-
edly associated with reduced risk of breast, prostate, and colorectal
cancer.2 In cancer cells, DIMs promote apoptosis and confer protec-
tion against DNA-damage.3 For example, DIMs have been shown to
inhibit estrogen-induced growth of breast cancer cell lines and hu-
man breast-tumors,4 with responses associated with G1 cell-cycle
arrest.5 In leukemia cells, DIMs have been shown to inhibit extra-
cellular signal-regulated kinase activation, which leads to apopto-
sis.6 Similarly, antitumor properties have recently been reported in
pancreatic cancer using DIM-C-pPhOH (1a) (Fig. 1).7 In addition to
use in oncology, DIMs have also conferred neuroprotective proper-
ties in preclinical models of Parkinson’s disease.8 While the impor-
tance of DIMs is relatively well established in medicinal chemistry,
properties (1b) (Fig. 1).9b These studies highlight the attractiveness
of these chemical classes and demonstrate the importance of
developing robust, yet practical, synthetic methods. Herein, we re-
port the development of a novel synthetic method that can be used
to rapidly synthesize candidate DAIMs and DIMs using microwave
irradiation.
Prior syntheses of DIMs have featured a wide variety of reagents
and reaction conditions, including acid-catalyzed condensation
of indoles with aldehydes under ultrasound irradiation,10
condensation of benzyl alcohols and indoles under visible light
irradiation,11a and metal-catalyzed reactions of indole with
select aldehydes11b and aldimines.11c Interestingly, there are only
a
daughter class of this molecular scaffold is the di-7-aza-
indolylmethanes (DAIMs), which may possess unique biological
⇑
Corresponding author. Tel.: +1 615 322 3793; fax: +1 615 322 0734.
E-mail address: henry.c.manning@vanderbilt.edu (H.C. Manning).
Figure 1. Representative DIM, (1a) DIM-C-pPhOH, and DAIM, di-7-azaindolylme-
thane (1b).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.10.143
Please cite this article in press as: Uddin, M. I.; et al. Tetrahedron Lett. (2013), http://dx.doi.org/10.1016/j.tetlet.2013.10.143

2
M. I. Uddin et al. / Tetrahedron Letters xxx (2013) xxx–xxx
Table 1
recently reported an MAOS of Vemurafenib (PLX-4032) and PLX-
Evaluation of additives and reaction conditionsa
4720, wherein we achieved the synthesis of these V600E-BRAF tar-
geted anticancer molecules in reduced total reaction time.13 As
part of an ongoing program to develop technology-assisted synthe-
sis methods for novel azaindoles, we discovered DAIMs as an unex-
pected byproduct under MAOS conditions when azaindole was in
excess (2X) to aldehyde.
To explore this phenomenon more closely and potentially eluci-
date a mechanism, we examined the effects of base, solvent, and
heating upon condensation of our model aldehyde and azaindole,
N-(3-5-difluoro-4-formylphenyl)propane-1-sulfonamide (2) and
5-chloro-7-azaindole (3) (Table 1). This initial series of experi-
ments revealed that an aqueous solvent and inorganic base were
necessary for condensation (Table 1: 5 vs 1, 4, 8) and that micro-
wave heating facilitated DAIM (4a) formation over the alcohol
(4b) (Table 1: 2 vs 5).13,14 In the absence of microwave and water,
the reaction gave the expected addition product (4b) (Table 1, en-
try 3). Conversely, conventional heating provided only trace
amounts of 4a as a mixture with 4b, even after prolonged heating.
Using iodine as a Lewis acid did not promote DAIM formation
regardless of microwave irradiation (Table 1: 6, 7).15,16 In our prior
work with Vemurafenib and PLX-4720, DAIM (4a) formation was
not significant using equivalent amounts of 2 and 3 under MAOS.13
Prompted by these results, we examined the scope of this MAOS
reaction, coupling 5-substituted-7-azaindoles with different aro-
matic and aliphatic aldehydes under MAOS, with K2CO3 as the base
and MeOH/H2O (1:1) as the solvent system (Table 2). Reaction of
various 5-substituted-7-azaindoles with the sulfonamide-func-
tionalized aldehyde 2 yielded the corresponding DAIM in good
yields (Table 2: 4a, 5, 6). In addition to the sulfonamide, other ali-
phatic and aromatic aldehydes reacted with 3 under identical reac-
tion conditions to give the desired DAIM product in good to
excellent yields (Table 2: 5–24). However, some reaction bias
was observed regarding the functional group tolerance within
the aldehyde. While amido-functionalized substrates such as
Entry
Additive
Solvent
Conditions
Resultsb
1
2
KOH
K2CO3
DMSO
MeOH
H2O (1:1)
MeOH
MWc
MWc
NRe
4a: R = 3-(5-Cl-7-azaindole
(72%)
4b: R = OH
(54%)
NRe
3
KOH
Rtd
4
5
KOH
K2CO3
DME
MeOH
H2O (1:1)
MeCN
MeCN
MWc
Rtd
4b: R = OH
(88%)
NRe
6f
7f
8
I2
I2
None
Rtd
MWc
MWc
NRe
MeOH
H2O (1:1)
NRe
a
Reaction conditions: Aldehyde (0.19 mmol), azaindole/indole (0.38 mmol), base
(1.27 mmol), solvent (2.5 mL).
b
Isolated yield after chromatography.
MW heating at 130 °C, 30 min.
Room temperature, 48 h.
NR = no reaction.
c
d
e
f
Iodine (0.04 mmol).
a limited number of reported syntheses of DAIMs, these include
CH3-activation12 and condensation of azaindole with RMgBr9a or
CH2Br2.9b Unfortunately, these methods are limited by variable
yields and exotic reagents. Thus, methods for rapid and efficient
synthesis of DAIMs remain a synthetic challenge.
Our interest in the synthesis of azaindole stems from our
previous studies of inhibiting mutant BRAF in oncology. We
Table 2
DAIMs synthesized using MAOSa,b
I
O
N
HN
S
O
HN
F
I
F
N
H
N
4a
5
6
(72%)
(64%)
(53%)
Cl
Cl
Cl
N
N
N
O
HN
HN
HN
Cl
Cl
O
N
Cl
N
N
N
7 H
8H
N
H
N
(82%)
(76%)
9
(66%)
Cl
Cl
Cl
N
N
N
HN
HN
HN
O
Cl
Cl
Cl
N
N
H
N
N
N
N
12H
10H
11
(76%)
(71%)
(66%)
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M. I. Uddin et al. / Tetrahedron Letters xxx (2013) xxx–xxx
3
Cl
Cl
Cl
N
N
N
HN
HN
HN
N
F
S
S
Cl
Cl
Cl
Cl
Cl
N
H
N
N
N
H
N
N
14H
15
(67%)
13
(87%)
(65%)
Cl
Cl
Cl
N
N
N
HN
HN
HN
N
Cl
Cl
N
N
N
H
N
H 18
N
H
N
16
(57%)
17
(73%)
Cl
(92%)
Cl
N
N
HN
HN
Cl
N
N
H
N
N
H 19
21
(0%)
20
(83%)
(75%)
22
(47%)
23
(54%)
24
(26%)
a
Reaction conditions: Aldehyde (0.19 mmol), azaindole (0.38 mmol), K2CO3 (1.27 mmol), MeOH/H2O (1:1), MW heating at 130 °C, 30 min.
Isolated yield after chromatography.
b
4-acetamidobenzaldehyde successfully gave the corresponding
DAIM (22), maintaining the amide functionality, the ester-func-
tionalized aldehyde methyl 4-formylbenzoate gave compound 24
in modest yield, and only with hydrolysis of the ester functionality
to the carboxylic acid (Table 2). This could suggest a possible one-
pot DAIM synthesis/ester deprotection approach. Functional group
tolerance for the azaindole proved intriguing as well, with the
unsubstituted 7-azaindole proving recalcitrant to DAIM formation
(Table 2: 21), but rather undergoing decomposition (by TLC). This
could suggest potential electronic tolerances for substituents at
the 7-position of the ring, wherein electron-withdrawing groups
appear preferred. Structural assignment of the new DAIMs was car-
ried out with high-field NMR analysis, which confirmed a plane of
symmetry along the central methyl carbon. These results were fur-
ther supported by X-ray crystallographic analysis of compound 18
(Fig. 2).
We next tested our reaction conditions toward synthesis of
DIMs with select indoles and aldehydes. Substituted indoles reacted
in a manner similar to their 7-azaindole counterparts, including
Table 3
DIMs synthesized using MAOSa,b
Cl
O
S
O
HN
F
HN
HN
Cl
F
N
H 25
N
H 26
(62%)
(0%)
OH
NO2
HN
HN
HO
O2N
N
H
N
H
28
(0%)
27
(33%)
a
Reaction conditions: Aldehyde (0.19 mmol), indole (0.38 mmol), K2CO3
(1.27 mmol), MeOH/H2O (1:1), MW heating at 130 °C, 30 min.
b
Isolated yield after chromatography.
Figure 2. X-ray crystal structure (ORTEP drawing) of compound 18.
Please cite this article in press as: Uddin, M. I.; et al. Tetrahedron Lett. (2013), http://dx.doi.org/10.1016/j.tetlet.2013.10.143

4
M. I. Uddin et al. / Tetrahedron Letters xxx (2013) xxx–xxx
Scheme 1. Proposed mechanism yielding DAIMs via nucleophilic addition of A to alkylidene–azaindolene B under microwave irradiation.
5-chloroindole and 2 to give the desired DIM in 62% yield (Table 3:
25), compared to 4a in Table 2. However, as with the 7-azaindole
substrates, there seemed to be similar electronic constraints for
substitutions at the 7-position of the indole ring, as highlighted
by unsubstituted indole and the electron-donating hydroxyl group
of the 5-hydroxyindole, both of which yielded no DIM product
(Table 3: 26, 28), but rather decomposition (by TLC). Moreover,
as with the azaindoles, electron-withdrawing groups seemed to
have a net positive effect overall (Table 3: 25), though not without
an apparent threshold, as with 5-nitroindole (Table 3: 27), which
gave a lower yield of 33%.
cal DAIM-product 23 in 54% yield (Scheme 2). The formation of
unsymmetrical compound 23 strongly supports the effect of
microwave heating on increased nucleophilicity of 7-azaindoles
since no DAIMs were observed at ambient temperature.
To verify in part the effects of microwave heating on dehydra-
tion of A to form intermediate B, we performed an 18O-labeling
experiment, anticipating that rehydration in the presence of 18O–
water would label intermediate B with 18O. Thus, treatment of
alcohol 4b in a mixture of methanol and H218O (1:1), in the pres-
ence of K2CO3, revealed that microwave heating appears to pro-
mote dehydration, followed by 18O-incorporation (>90%), as there
was no 18O incorporation at room temperature (Fig. 3). Mass spec-
trometry analysis of the samples heated under microwave and at
room temperature revealed 18O-incorporation only in the micro-
wave-heated reaction (Fig. 3).
Toward a potential mechanism, we propose that the addition
product (A) that initially forms undergoes dehydration in the pres-
ence of base and microwave irradiation to the corresponding alkyl-
idene–azaindolene intermediate
B (Scheme 1), an excellent
Michael-acceptor for nucleophiles. Itoh and coworkers reported
similar mechanistic observations for their synthesis of DIMs.11
We envision the effects of microwave heating influencing the reac-
tion by increasing nucleophilicity of the 7-azaindole toward B and
promoting dehydration of A (Scheme 1).17
In summary, we have developed an efficient method to provide
functionalized di-7-azaindolylmethanes (DAIMs) and diindolylme-
thanes (DIMs) via a base-promoted reaction of 7-azaindoles and
indoles, respectively, with various aldehydes using microwave
heating. This stepwise reaction sequence, as shown in Scheme 2,
lays the framework for developing larger libraries of asymmetrical
heterodimeric azaindole and indole chemotypes. Biological appli-
cation of these novel compounds is currently under investigation
in our laboratory.
To test this postulated mechanism, we treated addition-product
4b with 5-bromo-7-azaindole (29) and obtained the unsymmetri-
Acknowledgments
This work has been supported by Grants from the National
Institutes of Health (R01 CA140628, K25 CA127349, P50
CA128323, and P30 DK058404), The Kleberg Foundation.
Supplementary data
Scheme 2. Reaction of isolated addition-product intermediate 4b with 5-bromo-7-
azaindole (29) under microwave heating. Reaction conditions: 4b (0.19 mmol), 29
(0.19 mmol), K2CO3 (1.27 mmol), MeOH/H2O (1:1), MW heating at 130 °C for
30 min.
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.
2013.10.143.
4b + H218O/RT (4b)
4b + H218O/MW (4b-18O)
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