Direct C-2 arylation of 7-azaindoles: Chemoselective access to multiarylated derivatives

Article abstract of DOI:10.1021/ol4027478

Pd-catalyzed direct C-H arylation of N-methyl-7-azaindole at the C-2 position by diverse arylboronic acids was achieved at room temperature. The method is general and was applied in chemoselective synthesis of multiarylated 7-azaindole derivatives bearing three different aryl groups at the 2, 3, and 5 positions.

Full text of DOI:10.1021/ol4027478

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Direct C‑2 Arylation of 7‑Azaindoles:
Chemoselective Access to Multiarylated
Derivatives
Prakash Kannaboina,†,‡ K. Anilkumar,†,‡ S. Aravinda,‡ Ram A. Vishwakarma,‡ and
Parthasarathi Das*,†,‡
Academy of Scientific and Innovative Research (AcSIR) and Medicinal Chemistry
Division, Indian Institute of Integrative Medicine(CSIR), Jammu 180001, India
partha@iiim.ac.in
Received September 23, 2013
ABSTRACT
Pd-catalyzed direct CÀH arylation of N-methyl-7-azaindole at the C-2 position by diverse arylboronic acids was achieved at room temperature.
The method is general and was applied in chemoselective synthesis of multiarylated 7-azaindole derivatives bearing three different aryl groups at
the 2, 3, and 5 positions.
The azaindole ring system is a key structural unit present
in a number of therapeutically important molecules.1,2
Owing to the presence of an additional nitrogen atom in
the 7-azaindole ring system, when compared to indole,
this structural moiety possesses an advantage to act as a
hydrogen-bond donor as well as an acceptor framework,
a property that has been successfully utilized in drug
discovery.3À5 Marketed anticancer drug vemurafenib
(PLX-4032)6 and many other kinase inhibitors (Figure 1)
contain a C-arylated 7-azaindole moiety. A structureÀ
activity relationship (SAR) study reveals that C-arylation
in both the azole and azine ring plays a significant role in
kinase inhibition.7 Therefore, selective C-arylations of the
7-azaindole nucleus in a controlled manner will provide an
† Academy of Scientific and Innovative Research (AcSIR).
‡ Medicinal Chemistry Division.
(1) For reviews on 7-azaindole, see: (a) Song, J. J.; Reeves, J. T.;
Gallou, F.; Tan, Z.; Yee, N. K.; Senanayake, C. H. Chem. Soc. Rev.
ꢀ
(6) For vemurafenib see: 2011 FDA drug approval: Mullard, A.
Nature Rev. Drug Discov. 2012, 11, 91.
2007, 36, 1120. (b) Popowycz, F.; Routier, S.; Joseph, B.; Merour, J.-Y.
ꢀ
Tetrahedron 2007, 63, 1031. (c) Merour, J.-Y.; Routier, S.; Suzenet, F.;
(7) For kinase inhibition, see: (a) B-Rafinhibitor:Tang, J.;Hamajima,
T.; Nakano, M.; Sato, H.; Dickerson, S. H.; Lackey, K. E. Bioorg. Med.
Chem. Lett. 2008, 18, 4610. (b) Aurora kinase inhibitor:Dhanak, D.;
Newlander, K. A. Preparation of azaindoles as aurora kinase inhibitors for
the treatment of cancer. U.S. Patent US20070149561A1, 2007. (c) PI3K
inhibitor: Hong, S.; Lee, S.; Kim, B.; Lee, H.; Hong, S.-S.; Hong, S. Bioorg.
Med. Chem. Lett. 2010, 20, 7212. (d) Focal adhesion kinase inhibitor:
Heinrich, T.; Seenisamy, J.; Emmanuvel, L.; Kulkarni, S. S.; Bomke, J.;
Joseph, B. Tetrahedron 2013, 69, 4767.
(2) (a) Echalier, A.; Bettayeb, K.; Ferandin, Y.; Lozach, O.; Clement,
M.; Valette, A.; Linger, F.; Marquet, B.; Morris, J. C.; Endicott, J. A.;
Joseph, B.; Meijer, L. J. Med. Chem. 2008, 51, 737. (b) Tung, Y.-S.;
Coumar, M. S.; Wu, Y.-S.; Shiao, H.-Y.; Chang, J.-Y.; Liou, J.-P.;
Shukla, P.; Chang, C.-W.; Chang, C.-Y.; Kuo, C.-C.; Yeh, T.-K.; Lin,
C.-Y.; Wu, J.-S.; Wu, S.-Y.; Liao, C.-C.; Hsieh, H.-P. J. Med. Chem.
2011, 54, 3076.
€
Rohdich, F.; Greiner, H.; Esdar, C.; Krier, M.; Gradler, U.; Musil, D.
(3) For antitumor activity, see: Kim, K. S.; Zhang, L.; Schmidt, R.;
Cai, Z.-W.; Wei, D.; Williams, D. K.; Lombardo, L. J.; Trainor, G. L.;
Xie, D.; Zhang, Y.; An, Y.; Sack, J. S.; Tokarski, J. S.; Darienzo, C.;
Kamath, A.; Marathe, P.; Zhang, Y.; Lippy, J.; Jeyaseelam, R., Sr.;
Wautlet, B.; Henley, B.; Gullo-Brown, J.; Manne, V.; Hunt, J. T.;
Fargnoli, J.; Borzilleri, R. M. J. Med. Chem. 2008, 51, 5330.
(4) For antibacterial activity, see: Manchester, J. I.; Dussault, D. D.;
Rose, J. A.; Ann Boriack-Sjodin, P.; Uria-Nickelsen, M.; Ioannidis, G.;
Bist, S.; Fleming, P.; Hull, K. G. Bioorg. Med. Chem. Lett. 2012, 22,
5150.
J. Med. Chem. 2013, 56, 1160. (e) Tropomyosin-related kinases A (TrkA):
Hong, S.; Kim, J.; Seo, J. H.; Jung, K. H.; Hong, S.-S.; Hong, S. J. Med.
Chem. 2012, 55, 5337.
(8) For transition-metal-catalyzed direct arylation of heterocycle
reviews and selected examples, see: (a) Ackermann, L.; Vicente, R.;
Kapdi, A. R. Angew. Chem., Int. Ed. 2009, 48, 9792. (b) Hirano, K.;
Miura, M. Chem. Commun. 2012, 48, 10704. (c) Bellina, F.; Rossi, R.
Tetrahedron 2009, 65, 10269. (d) Hirano, K.; Miura, M. Synlett 2011,
294. (d) Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev.
2011, 40, 5068. (e) Campeau, L.-C.; Fagnou, K. Chem. Soc. Rev. 2007,
36, 1058. (f) Kirchberg, S.; Tani, S.; Ueda, K.; Yamaguchi, J.; Studer, A.;
Itami, K. Angew. Chem., Int. Ed. 2011, 50, 2387. (g) Kim, Y. W.;
Niphakis, M. J.; Georg, G. I. J. Org. Chem. 2012, 77, 9496.
(5) For anti-inflammatory activity, see: Chen, G.; Liu, Z.; Zhang, Y.;
Shan, X.; Jiang, L.; Zhao, Y.; He, W.; Feng, Z.; Yang, S.; Liang, G. ACS
Med. Chem. Lett. 2013, 4, 69.
r
10.1021/ol4027478
XXXX American Chemical Society

efficient synthetic tool to modulate selective or sequential
arylations at various positions of 7-azaindole that could be
interesting from the point of view of medicinal chemistry.
Direct C-arylation of heteroarenes by CÀH bond acti-
vation with the aid of transition metals is a practical
alternative to conventional cross-coupling reactions.8
In this context, direct C-2 arylation of indole has been
studied where aryl halides,9 arylboronic acids,10 aryltri-
fluoroborate salt,11 and [Ph-I-Ph]BF412 were used as cou-
pling partners, but selective C-2 arylation of 7-azaindole
has been less explored.13,14
Scheme 1. Pd-Catalyzed C-2-Selective Arylation
Sames9a and Fagnou13 reported independently the Pd-
catalyzed C-2arylation of7-azaindolebyusing aryliodides
as coupling partners at elevated temperature.
co-workers in the case of indole.10a Weobserved formation
of the desired product in 30% yield when AcOH was used
as a solvent and Pd(OAc)2 (5 mol %) as a catalyst (Table 1,
entry 1). Use of air or Cu(OAc)2 as the oxidant did not
provide any improvement in yield (Table 1, entries 2
and 3). A poor yield (30%) was observed in the case of
tert-butyl hydroperoxide (TBHP) (Table 1 entry 4), while
PhI(OAc)2, 1,4-benzoquinone (BQ), m-CPBA, Ag2O, and
H2O2 (Table 1, entries 5À9) were ineffective. Among the
peroxydisulfate salts, Na2S2O8 showed an obvious effect
on the coupling reaction and 2a was synthesized in good
isolated yield (60%) (Table 1, entry 11). A change of
solvent from AcOH to PivOH or TFA resulted in poor
yield (Table 1, entries 12 and 13). An examination of dif-
ferent Pd sources was also carried out. We found that
Pd(TFA)2, Pd2(dba)3, and PdCl2 failed to promote the
cross-coupling reaction (Table 1, entries 14À16). In order
to optimize the reaction conditions further, we performed
the cross-coupling in the presence of a ligand (see the
Supporting Information). Among several phosphine li-
gands examined with Pd(OAc)2, it was found that a
protocol which employed PPh3 (10 mol %) provided the
coupled product in 75% isolated yield (Table 1, entry 17).
However, the reaction was sluggish under an N2 atmo-
sphere (Table 1, entry 20).
We have also investigated the scope of N-substitution
on the azaindole nucleus using the optimized procedure
as depicted in Table 1. Only N-alkyl-substituted azaindoles
proved to be suitable substrates, N-phenyl, N-sulfonyl or
N-acetyl azaindoles remained inert under these cross-
coupling conditions (see the Supporting Information).
With the optimized reaction conditions in hand, the
scope of the reaction with respect to boronic acids was
investigated and the results are summarized in Scheme 2.
The reaction can be performed with a wide range of
boronic acids. For example, with N-methyl-7-azaindole,
C-2 arylated products were obtained in good yields
(70À85%) in the case of both electron-rich (2bÀd,gÀh)
and electron-deficient (2eÀf) phenylboronic acids. The
efficiency of arylation of N-methyl-7-azaindole was not
affected by steric hindrance, as ortho-substituted phenyl-
boronic acid afforded the desired product (2h) in good
yield (70%). Disubstituted boronic acids were also tested
under these conditions and the desired products were
obtained in good yield (2i,j, 70%). Bicyclic 2-napthylboro-
nic acid also readily participated in direct arylation
to furnish the expected product in 80% isolated yield
(2k). To enhance the substrate scope, we carried out the
Figure 1. C-Arylated 7-azaindoles as biological target.
DeBoef has reported Pd-catalyzed oxidative arylation of
1-SEM-7-azaindole in an excess of benzene under micro-
wave irradiation at 120 °C, which gave a mixture of
2-phenyl-7-azaindole and 3-phenyl-7-azaindole in an 8:1
ratio.14 Therefore, a mild methodology for the direct aryla-
tion at C-2 position is highly desirable (Scheme 1, eq 1).
Herein, we wish to report a Pd-catalyzed direct C-2 arylation
of N-methyl-7-azaindole that uses boronic acids as coupling
partners at room temperature and Na2S2O8 as the terminal
oxidant (Scheme 1, eq 2). Further, we demonstrate its utility
in the synthesis of multiarylated 7-azaindole derivatives.15
Our initial efforts toward direct coupling of the (sp2)
CÀH bond of N-methyl-7-azaindole (1a) at the C-2
position with phenylboronic acid used various terminal
oxidants (Table 1, entries 1À11). We first examined the
oxidant molecular oxygen, as described by Shi and
(9) (a) Lane, B. S.; Sames, D. Org. Lett. 2004, 6, 2897. (b) Wang, X.;
Gribkov, D. V.; Sames, D. J. Org. Chem. 2007, 72, 1476. (c) Lane, B. S.;
Brown, M. A.; Sames, D. J. Am. Chem. Soc. 2005, 127, 8050. (d) Bellina,
F.; Cauteruccio, S.; Rossi, R. Eur. J. Org. Chem. 2006, 1379. (e)
Lebrasseur, N.; Larrosa, I. J. Am. Chem. Soc. 2008, 130, 2926.
(10) (a) Yang, S.-D.; Sun, C.-L.; Fang, Z.; Li, B.-J.; Li, Y.-Z.; Shi,
Z.-J. Angew. Chem., Int. Ed. 2008, 47, 1473. (b) Nimje, R. Y.; Leskinen,
M. V.; Pihko, P. M. Angew. Chem., Int. Ed. 2013, 52, 4818.
(11) Zhao, J.; Zhang, Y.; Cheng, K. J. Org. Chem. 2008, 73, 7428.
(12) (a) Deprez, N. R.; Kalyani, D.; Krause, A.; Sanford, M. S.
J. Am. Chem. Soc. 2006, 128, 4972. (b) Phipps, R. J.; Grimster, N. P.;
Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 8172.
(13) Huestis, M. P.; Fagnou, K. Org. Lett. 2009, 11, 1357.
(14) Potavathri, S.; Preira, K. C.; Gorelsky, S. I.; Pike, A.; Lebris,
A. P.; DeBoef, B. J. Am. Chem. Soc. 2010, 132, 14676.
(15) For fuctionalized 7-azaindole synthesis, see: (a) Schneider, C.;
David, E.; Toutov, A. A.; Snieckus, V. Angew. Chem., Int. Ed. 2012, 51,
2722. (b) Barl, N. M.; Sansiaume-Dagousset, E.; Karaghiosoff, K.;
Knochel, P. Angew. Chem., Int. Ed. 2013, 52, 10093.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 2. C-2 Arylation of N-Methyl 7-Azaindolesa
Table 1. Optimization Studies on C-2 Arylation of
N-Methyl-7-azaindolea
entry catalyst mol (5%) oxidant solvent time (h) yieldb (%)
1
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
Pd2dba3
O2
AcOH
AcOH
12
12
12
12
12
12
12
12
12
8
30
2
air
30
3
Cu(OAc)2 AcOH
TBHP AcOH
PhI(OAc)2 AcOH
BQ AcOH
m-CPBA AcOH
40
4
30
5
10
6
10
a Reaction conditions: N-methyl-7-azaindole (1 equiv), boronic acid
(1.2 equiv), Pd(OAc)2 (5 mol %), PPh3 (10 mol %), Na2S2O8 (1.5 equiv),
AcOH (2 mL), rt, air, 3À5 h.
7
n.r.
15
8
Ag2O
AcOH
AcOH
AcOH
AcOH
PivOH
TFA
9
H2O2
n.r.
40
70 (60)c
10
10
11
12
13
14
15
16
17d
18e
19f
20g
K2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
6
6
Scheme 3. C-3 Iodination of N-Methyl-2-aryl-7-azaindolesa
6
10
AcOH
AcOH
AcOH
12
12
12
4
trace
n.r.
n.r.
85 (75)c
40
PdCl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Na2S2O8 AcOH
Na2S2O8
Na2S2O8
Na2S2O8
AcOH
AcOH
AcOH
6
6
45
24
10
a Reaction conditions: N-methyl-7-azaindole (1.0 equiv), phenyl-
boronic acid (1.0 equiv), Pd(OAc)2 (5 mol %), Na2S2O8 (1.5 equiv),
AcOH (1 mL), rt, air. b GC yield. c isolated yield. d 10 mol % of PPh3 was
used. e 10 mol % of (p-Tol)3P was used. f 10 mol % of X-phos was used.
g Reaction performed under N2 atmosphere. n.r. = no reaction.
a Reaction conditions: N-methyl-2-aryl-7-azaindole (1 equiv), NIS
(1.1 equiv), KOH (3 equiv), CH3CN (1 mL), rt.
combination with dppf (5 mol %) as a ligand, 4a was
isolated in 30% yield (Table 2, entry 2). Several bases were
examined along with variations in time and temperature
(Table 2, entries3À6). AsdepictedinTable2 whenCs2CO3
was used with Pd(OAc)2 at 60 °C in 1,4-dioxane/H2O (3:1)
the isolated yield was 85% (Table 2, entry 5). Further
screening of different ligand systems such as PPh3 (Table 2,
entry 7) and X-phos (Table 2, entry 8) showed these to be
less effective. Use of different Pd-sources (Table 2, entries 9
and 10) resulted in poor yield. Lower yields were obtained
when we changed the solvent system to DMF/H2O
(Table 2, entry 11). No product formation was observed
when 1,4-dioxane was used as the only solvent (Table 2,
entry 12). This indicated that the presence of water as
solvent was crucial for coupling.
cross-coupling process with 5-bromo-substituted N-methyl-
7-azaindole, and to our delight, bromo derivatives were
tolerated under these catalytic conditions (2lÀq). Here
also the electronic nature of the boronic acid did not
affect the course of the reaction, as the C-arylated products
were isolated in high yield (70À85%). Bicyclic boronic acid
benzo[d][1,3]dioxol-5-ylboronic acid also gave the cross-
coupled product (2q) in 75% yield.
Having optimized the C-2 arylations, we focused on
exploring conditions that would enable us to effect multi
arylation of 7-azaindole. Very few reports are available for
cross-coupling reaction at the C-3 postion of 7-azaindole.7c,e
Surprisingly, C-3 arylation has never been explored in
the presence of the C-2 arylated 7-azaindole system. There-
fore, finding generalized cross-coupling conditions for C-3
arylation would be very useful from a synthetic standpoint.
Our initial efforts were unsuccessful. Therefore, we per-
formed the NIS-mediated iodination on N-methyl-2-aryl-7-
azaindoles, and the 3-iodo derivatives were isolated in high
yields (80À85%) (Scheme 3).
With the optimized protocol in hand the scope of the cross-
coupling reaction was explored by using various arylboronic
acids with different 3-iodo-1-methyl-2-aryl-7-azaindoles
(Scheme 4). For example electron-donating and elec-
tronÀwithdrawing boronic acids all afforded 3-arylated
derivatives 4c and 4bÀd, respectively, in good yields
(75À82%).
We used 3-iodo-N-methyl-2-p-tolyl-7-azaindole (3a) as
a test substrate for further work in the presence of Pd-
(OAc)2 (5 mol %), and Na2CO3 as a base in 1,4-dioxane/
H2O (3:1) at 100 °C. No product was observed even after
12 h (Table 2, entry 1). When we performed the reaction in
In addition to substituted phenylboronic acids, benzo-
[d][1,3]dioxol-5-ylboronic acid was also tested under these
conditions (4e). Interestingly, the presence aryl substitu-
tion at C-2 position did not play any significant role in
cross-coupling at the C-3 position. In order to synthesize
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 2. Optimization Studies for C-3 Arylationa
Scheme 4. Pd-Catalyzed C-3 Arylation of 3-Iodo-N-methyl-2-
aryl-7-azaindolesa
entry catalyst
L
base temp (° C) time (h) yieldb (%)
1
2
3
4
5
6
7
8
9
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Na2CO3
Na2CO3
K2CO3
100
100
100
100
60
12
6
n.r.
30
50
75
85
40
10
35
10
20
45
n.r.
dppf
dppf
dppf
6
Cs2CO3
2
Pd(OAc)2 dppf Cs2CO3
2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
dppf
K3PO4
60
6
PPh3 Cs2CO3
X-phos Cs2CO3
60
6
60
6
a Reaction conditions: 3-iodo-N-methyl-2-aryl-7-azaindole (1 equiv),
boronic acid (1.1 equiv), Pd(OAc)2 (5 mol %), dppf (5 mol %), Cs2CO3
(2 equiv), 1,4-dioxane/H2O (1 mL, 3:1 mixture), 60 °C, 2 h.
Pd(PPh3)4 dppf
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
60
12
12
6
10 Pd(dppf)Cl2 dppf
60
11d Pd(OAc)2
12e Pd(OAc)2
dppf
dppf
60
60
6
a Reaction conditions: 3a (1.0 equiv), phenylboronic acid (1.0 equiv)
Pd(OAc)2 (5 mol %), dppf (5 mol %), Cs2CO3 (2 equiv), 1,4-dioxane/
H2O (2 mL; 3:1 mixture), 60 °C, air. b Isolated yields. d Reaction
performed in DMF/H2O (3:1). e Only 1,4-dioxane was used as solvent.
n.r. = no reaction.
Scheme 5. Pd-Catalyzed C-5 Arylation of 5-Bromo-N-methyl-
2,3-diaryl-7-azaindolesa
the precursor for C-5 cross-coupling, we performed C-3
arylation of the 5-bromo derivatives of 3-iodo-N-methyl-
2-aryl-7-azaindole under these optimized conditions, and
to our delight, the reaction was completely chemoselective.
p-Tolylboronic acid gave higher yields (70À80%) (4f,g)
compared to electron-poor phenylboronic acids (65%)
(4h,i).
Having accomplished C-2 and C-3 arylation, we then
focused our attention on optimizing the cross-coupling for
the C-5 position. Experimentation withthe combination of
Pd(OAc)2 and dppf showed that the reaction with 5 mol %
ofPd(OAc)2, 10mol % ofdppf, and 3.0 equiv ofCs2CO3 in
1,4-dioxane and water (3:1) at 80 °C for 6À8 h afforded the
C-5-arylated product in the best yields. Using these con-
ditions, we evaluated the scope of C-5 arylation with
various boronic acids, and the results are summarized in
Scheme 5. Good yields (60À72%) were observed with the
electronic nature of the boronic acids not playing much of
a role in the arylation process (5aÀf). Bicyclicboronic acids
were also investigated, in case of 2-napthylboronic acid the
yield is 63% (5c), whereas benzo[d][1,3]dioxol-5-ylboronic
acid resulted in 60% (5e) yield. In this context, X-ray
crystal structure analysis of 5-(2,4-difluorophenyl)-1-
methyl-2-phenyl-3-p-tolyl-1H-pyrrolo[2,3-b]pyridine (5b)
confirmed its structure (see the Supporting Information).
In summary, we have developed a practical Pd-catalyzed
method for the C-2 arylation of N-methyl-7-azaindole at
room temperature, where PPh3 was used as a ligand and
Na2S2O8 as an oxidant in an acidic medium. Gereral
methods for the chemoselective C-arylation, at C-3 and
C-5 postions have also been discovered. This Pd-catalyzed
a Reaction conditions: 5-bromo-N-methyl-2,3-diaryl-7-azaindole (1
equiv), boronic acid (1.1 equiv), Pd(OAc)2 (5 mol %), dppf (10 mol %),
Cs2CO3 (3 equiv), 1,4-dioxane/H2O (1 mL, 3:1 mixture), 80 °C, 6À8 h.
cross-coupling condition is ligand, base, and solvent spe-
cific. These selective cross-coupling conditions have pro-
vided the first examples of 7-azaindole derivatives bearing
different aryl units at the 2, 3, and 5 positions. These
reaction conditions are generally versatile. Thus they
can be further exploited in the synthesis of library com-
pounds for drug discovery and for materials chemistry
applications.
Acknowledgment. K.P. and K.A. thanks CSIRÀNew
Delhi and UGC for their research fellowship, respectively.
This research work was financially supported by CSIRÀ
NewDelhi (BSC 0108). IIIM communication no. 1594.
Supporting Information Available. Experimental details
and all spectral data. This material is available free of
charge via Internet at http://pubs.acs.org
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX