Palladium-catalyzed regioselective C-2 arylation of 7-azaindoles, indoles, and pyrroles with arenes

Article abstract of DOI:10.1039/c6cc00133e

A palladium-catalyzed regioselective C-2 arylation of 7-azaindoles, indoles, and pyrroles with arenes has been developed. This study unveils that a critical substrate dependent acid concentration is essential for achieving exclusive C-2 selectivity as wel

Full text of DOI:10.1039/c6cc00133e

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DOI: 10.1039/C6CC00133E
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COMMUNICATION
Palladium-Catalyzed Regioselective C-2 Arylation of 7-Azaindoles,
Indoles, and Pyrroles with Arenes
Received 00th January 20xx,
Accepted 00th January 20xx
Joydev K. Laha,* Rohan A. Bhimpuria, Dilip Prajapati, Neetu Dayal, and Shubhra Sharma
DOI: 10.1039/x0xx00000x
www.rsc.org/
Fagnou Protocol
Abstract. A palladium-catalyzed regioselective C-2 arylation of 7-
azaindoles, indoles, and pyrroles with arenes has been developed.
The study unveils that a critical substrate dependent acid
concentration is essential for achieving exclusive C-2 selectivity as
well as mono-arylation in pyrroles. Incongruent to the literature,
the protocol uses a reduced volume (at least 5 times) of arenes for
a workable access to C-2 arylated heterocycles.
Pd-Catalyst6c,d
Ar-H
Ar
- Low acid concentration
N
- Issue of C-2/C-3 regioselectivity
- Issue of C-2/C-3 diarylation
N
R = Ac, Piv
R
R
Pd-catalyst6c
Ar-H
- High acidity of the medium
- C-2/C-5 diarylation when R2 = H
- Limited substrtate scope
R2
N
R2
Ar
N
R1
R1 = CH3 and methoxymethyl
R1
Deboef Protocol
Conditon A7a
25 mol% Pd(OAc)2
4 equiv AgOAc
7-Azaindoles, indoles, and pyrroles containing a 2-aryl group
are privileged molecular scaffolds in therapeutic discovery
with a proven track record of drugabililty, while each requiring
a 2-aryl group for demonstrated pharmacophoric activities.1 C-
2 arylation of these nitrogen heterocycles have traditionally
been effected using transition-metal-catalyzed cross-
couplings2 or direct arylations3 utilizing either one or both
prefunctionalized substrate(s). However, the dependence on
these cross-couplings reactions has gradually been reduced
since the evolution of oxidative couplings involving double
C(sp2)-H bonds. Unlike traditional cross-couplings, transition-
metal-catalyzed oxidative couplings involving double C(sp2)-H
bonds4 obviate the requirement of prefunctionalized
substrates and alleviate the generation of salt-waste
substantially, thereby empowering superior sustainability and
environmental compatibility. Remarkably, transition-metal-
catalyzed oxidative couplings have been proven a powerful
variant of traditional couplings enabling rapid C-H arylation on
heteroarenes.5 However, a fundamental challenge intrinsic to
these oxidative functionalizations lies in achieving
regioselective C-H arylations of nitrogen heterocycles.5a,c,e,f
Condition B7b
Condition A7a
350 equiv AcOH/
350 equiv Arene
- R =SEM
- R =Ts, only C-2 product
- High acid concentration
- High catalyst loading
- only moderate (30%) yield
Ar
- Issue of C-2/C-3 regioselectivity
- Basic Buffered condition
- C-2 selectivity only in case of
indoles with an EWG group
N
Conditon B7b
10 mol% Pd(OAc)2
3 equiv AgOAc
2.5 equiv PivOH/
350 equiv Arene
N
R
R
Condition 7b
Ph
Pd catalyst
- Only one example with azaindole
- Issue of C-2/C-3 regioselectivity
- Basic Buffered condition
- Use of microwave
H
Ph-
N
N
N
N
SEM
SEM
C2:C3 (8:1)
Our protocol
Pd-catalyst
- Complete C-2 selectivity
- Acidiity of the medium depends upon substrate
- 2,5-Diarylation minimized with pyrroles
Ar
H
Ar-
N
N
X
X
R
R
X = C,N
Scheme 1. Regioselective C-2-Arylation of 7-azaindoles, indoles and pyrroles with
Arenes.
achieved enabling C-2 arylated indoles/pyrroles in good to
excellent yields.6,7 While a complete C-2 selectivity utilizing N-
Ts indoles was achieved under a high acid concentration albeit
in low yield (30%),7a only a mixture of C-2/C-3 arylated
products could be obtained when N-SEM indoles was used
under low acid concentration.7b In contrast, C-2 arylation of N-
Towards this endeavor,
a
few reports, contributed
protected pyrroles required
a
strong acidic medium.6c
independently by Fagnou and DeBoef, of regioselective C-2
arylation of indoles and pyrroles with arenes via transition-
metal-catalyzed oxidative coupling has successfully been
Although the current literature is quite resourceful warranting
applications of oxidative couplings to the preparation of 2-aryl
indoles or pyrroles, they still suffer from C-2/C-3 site-
selectivities within indoles and mono/2,5-diarylation in
pyrroles. Moreover, the application is largely impeded to the
preparation of 2-aryl-7-azaindoles. Remarkably, DeBoef et al.
included an exotic example of oxidative coupling to the
preparation of 2-phenyl-1-SEM-7-azaindole in a report.7b
However, the limitations may include a) formation of both C-2
a.Department of Pharmaceutical Technology (Process Chemistry)
National Institute of Pharmaceutical Education and Research
S. A. S. Nagar, Punjab 160062, India; E-mail: jlaha@niper.ac.in
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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and C-3 regioisomers in a 8:1 ratio, b) use of 350 equivalent of overall concentration in the reaction (entries 3-9). Increasing
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benzene, and c) requirement of microwave use (Scheme 1). To the acid concentration in the reaction iDmOpI:r1o0v.1e0d39t/hCe6CyCi0e0ld133oEf
the best of our knowledge, no other report of C-2 arylation on the product (entries 3-5). Further increase of acid
7-azaindoles using arene as the coupling partner is currently concentration was detrimental (entries 6-7). Beside acid
available, despite significant relevance of 2-aryl-7-azindoles as concentration, the concentration of arenes also plays an
pharmacophores. A defined objective of C-2 arylation of 7- important role delivering the product (entry 8). Reducing the
azaindoles that considers a) achieving complete C-2 selectivity, total volume of solvent by half is also detrimental (entry 9).
b) avoids usage of a large excess of arenes, c) beneficial effect The best conditions obtained for C-2 arylation of
of acid concentration, and d) conventional heating would be a heating a mixture of and benzene in the presence of
daunting challenge. Based on our previous experiences on Pd(TFA)2 (10 mol%), AgOAc (3 equiv), CsOPiv (40 mol%), and
double C(sp2)-H oxidative couplings in the synthesis of biaryl PivOH at 130 °C for 12 h affording
in 65% yield (entry 5). A
1 entailed
1
2
sultams8 and heterobiaryl sultams,9 and regioselective C-3 different palladium catalyst or oxidant was not beneficial
alkenylation on indoles as well as 7-azaindoles,10 we embarked (entries 10-13). It is important to mention here that C-3
on this ambitious objective. Herein, we describe a palladium- arylated product was not isolated under the optimized
catalyzed intermolecular oxidative coupling of 7-azaindoles condition (entry 5).
and arenes under high acid concentration yielding 2-aryl-7-
With the optimized conditions in hand, we next investigated
azaindoles in good to excellent yields. Moreover, our protocol the scope of substrates that could participate in the reaction.
is not only useful for 7-azaindoles, but also for indoles and The 7-azaindole substrates 3-8 were either commercially
pyrroles, warranting a wide substrates scope. Distinct from the available or prepared using
a known procedure (see
current literature, our protocol uses a high acid concentration supporting information). Our protocol worked with different
for C-2 arylation of 7-azaindoles and indoles, while a low arenes to give C-2 arylated 7-azaindoles 9-19 in good to
acidity of the reaction medium is essential for successful C-2 excellent yields. For example, N-Me or N-Bn 7-azaindoles 3 and
mono-arylation of pyrroles.
4 worked eventfully affording 9 and 10 in 71-86% yields.
While N-methyl azaindole is largely used as a successful
coupling partner in the C-2-arylation,3c,e we considered using
7-azaindoles with a N-protecting group that could be easily
installed and subsequently removed, if desired. Reaction of N-
R2
R2
10 mol% Pd(TFA)2
40 mol% CsOPiv
ArH
(40-55
equiv)
Ar
3 equiv AgOAc
PivOH (2 mL/0.5 mmol)
130 oC, 12 h
N
R1
N
N
R1
N
Ts 7-azaindole 1 and benzene under the conditions described
previously to prepare 2-phenyl-1-SEM-7-azaindole7b was
ineffective (Table 1, entry 1).
3-8
9-19
Br
Ph
Ph
Ph
Ph
Ph
N
N
N
N
Table 1. Optimization studya
N
N
N
N
Me
Me
Me
Bn
10 (71%)
9 (86%)
12
(75%)
11 (71%)
Pd-catalyst
Oxidant, CsOPiv
H
Ph
Ph-H
CHO
N
Solvent
130 0C, 12 h
N
N
Cl
Cl
N
Br
Ts
Ts
2
1
Ph
N
N
N
N
N
N
Entry
Pd-
Oxidant
PhH
PivOH
Yield of
2 (%)b
Me
Ts
R =Ts (45%)
R = Me (87%)
Me
16
(32%)
catalyst
14
15
13 (66%)
1c
2d
3
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(OAc)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
AgOAc
O2
13 mL
2.5 equiv
<10
n.r.
Trace
29
NO2
OMe
Br
NO2
5 equiv
2.5 mL
2.5 mL
2.5 mL
1 mL
N
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
Cu(OAc)2.5H2O
K2S2O8
K2S2O8
2.5 equiv
5.0 equiv
2 .0 mL
3.5 mL
4.5 mL
2 .0 mL
1 mL
N
N
N
N
N
Me
Me
17a (31%)
4
Bn
18a (21%)
17b (14%)
5
65
6
51
Br
Br
3
Me
4
1
7
8e
10 equiv
10 equiv
1.25 mL
2.5 mL
2.5 mL
2.5 mL
2.5 mL
44
OMe
N
N
N
N
22
Bn
18b (42%)
Me
19 3-Me:4-Me (76%)
9
35
10
11f
12
13g
2 .0 mL
2 .0 mL
2 .0 mL
2 .0 mL
53
n.r.
n.r.
n.r.
Scheme 2. C-2 Arylation of 7-azaindoles with arenes.
5-Bromo-7-azaindole
5 is especially an attractive substrate for
a N-Ts azaindole 1 (0.5 mmol), Pd-catalyst (10 mol%), oxidant (3.0 equiv), CsOPiv (40
C-2 arylation yielding 11 in 71% yield. The bromo-substituent
mol%), benzene, PivOH, 130 °C, 12 h; b Isolated yield; c Referred to conditions in ref
d
e
could serve as a synthetic handle for further functionalizations.
7b; PPh3 (20 mol%), Cu(OTf)2 (50 mol%), dioxane (4 mL), DMSO (1 mL); 2.5 mL
DMF; f rt-80 °C; g AgOAc (50 mol%); n.r.= No reaction.
Interestingly, 7-azaindole
also a viable substrate furnishing 13 in 66% yield. 7-Azaindoles
or reacted with disubstituted arenes, for example, 1,2-
7 containing a C-3 formyl group was
1
3
Similarly, a neutral condition largely used for alkenylation of
indoles11 was futile (entry 2). We next investigated the effect
of acid concentration, usage of reduced volume of arenes, and
dichlorobenzene yielding C-2 arylated 7-azaindoles 14 and 15
in varying yields. However, p-xylene reacted sluggishly yielding
2 | J. Name., 2012, 00, 1-3
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16 albeit in low (32%) yield. 7-Azaindoles
3
or
8
also reacted arenes to give mono-arylated products 44-46 in vVairewyiAnrgticlyeiOenldlinse.
rare report ofDOmI: 1o0n.1o0-3a9r/yCl6aCtiCo0n0133oEf
with mono-substituted arenes such as, nitrobenzene, anisole, This constitutes
a
and toluene resulting in two regioisomeric products, which unsubstituted pyrroles via double C-H functionalizations.
required extensive chromatography for isolation of the pure Pyrroles containing an electron -withdrawing or -donating
products. The two regioisomers were originated from C-2 group reacted smoothly with different arenes to give 2-
arylation of 7-azaindoles at the meta and para-positions of arylpyrroles 47-52 in good yields.
arenes, irrespective of the nature of substituent.12 Thus, when
3
reacted with nitrobenzene, two regioisomers 17a
&
17b
10 mol% Pd(TFA)2
were isolated with a 2:1 ratio. Similarly, the reaction of
8
and
R2
ArH
(40-55
equiv)
R2
H
Ar
N
R1
N
3 equiv AgOAc,
5 equiv PivOH,
80 oC, 12 h
anisole formed 18a and 18b in a 1:2 ratio. On the other hand,
R1
toluene gave an inseparable mixture of C-2 arylated 7-
42-53
35-41
azaindole 19 in
a combined 76% yield. Perhaps most
importantly, our protocol offers exclusive C-2 arylation on 7-
azaindoles, overcoming the difficulties encountered
previously.7b
MeO2C
OHC
N
N
N
Ms
Ms
44
Ms
43 (69%)
42 (75%)
(70%)
N-tosyl indole 20 reacted with benzene under a slightly
modified condition affording 27 in 70% yield (Scheme 3).
However, N-Ms indole 21 reacted more efficiently with
benzene to give 28 in 88% yield.
OHC
N
N
N
Ms
Ms
Ts
45 (68%)
46
47 (72%)
(35%)
Cl
10 mol% Pd(OAc)2
20 mol% CsOPiv
R1
MeO2C
MeO2C
R1
H3COC
ArH
N
N
N
+
Cl
(40-55
equiv)
Ms
48 (54%)
Ms
49 (76%)
Me
3 equiv AgOAc,
PivOH (2 mL/0.5 mmol),
130 oC, 12 h
N
R
Ar
N
R
50 (65%)
20-26
27-34
H3COC
MeO
MeO2C
Ph
N
N
Ts
52 (65%)
Me
51 (55%)
Ph
Ph
N
Ts
Ph
N
N
Ms
Ms
29 (86%)
27 (70%)
28 (88%)
Scheme 4. C-2 Arylation of pyrroles with arenes.
Me
3
Me
1
A 3-substituted pyrrole underwent arylation at the less
sterically hindered 5-position. It is also important to mention
that 2,5-diarylated pyrroles were not obtained in any of these
cases.
Me
4
N
N
N
Me
Ms
Ms
Ms
Me
32 (73%)
30 3-Me: 4-Me (80%)
31 (66%)
Finally, fluoride ion assisted deprotection of sulfonyl group
Cl
Cl
R
from
1 and 43 under a mild condition further demonstrates
N
N
R = 2-Me or
3-COCH3, 3-CO2Et,
and 3-CHO
Ms
Ms
the synthetic utility of the protocol. (Scheme 5)
34
(0%)
33 (75%)
Scheme 3. C-2 Arylation of indoles with arenes.
TBAF.3H2O
(4 equiv)
Ph
Ph
N
N
N
N
MeCN, reflux
6 h
Generally, mono- or di-substituted indoles or arenes are good
coupling partners irrespective of the nature of substituents
affording various substituted 2-arylindoles 29-33 in 66-86%
yields. Similar to the reaction of 7-azaindole and toluene,
reaction of indole 21 and toluene gave an inseparable mixture
of 2-arylated indole 30 resulting from functionalization at the
meta- or para-position of the methyl group. Notably, the
formation of 3-arylated indoles was not observed in any of
H
Ts
1
53 (82%)
TBAF.3H2O
(4 equiv)
MeO2C
Ph
MeO2C
Ph
N
N
MeCN, reflux
6 h
Ms
H
54 (91%)
43
Scheme 5. Deprotection of sulfonyl group
In conclusion, we have developed, for the first time, an
these oxidative coupling reactions. Unlike 7-azaindole 7, a 3-
efficient protocol for exclusive C-2 arylation of N-protected 7-
substituted indole did not give any C-2 arylated product. More
interestingly, a substitution at the 2-position of indole also did
not give any 3-arylated product 34.
azaindoles. Incongruent to the literature,
a high acid
concentration in the reaction medium is essential for complete
C-2 selectivity in 7-azaindoles and indoles. A low acidity of the
reaction medium largely impedes the formation of 2,5-
diarylpyrroles yielding 2-arylpyrroles in good to excellent
Reaction of 2-formyl-N-mesylpyrrole (35) and benzene under
a slightly acidic condition gave 42 in 75% yield (Scheme 4).
More importantly, C-2 unsubstituted pyrroles reacted with
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Chem. Front., 2014,
Wang and Z. Li, Org. Lett., 2014, 16, 5156.
12 For arylation trend with mono-substituted arenes see; (a) Z.
Yang, F. C. Qiu, J. Gao, Z. W. Li and B. T. Guan, Org. Lett.,
2015, 17, 4316; (b) Y. Wei and W. Su, J. Am. Chem. Soc.,
2010, 132, 16377.
1, 707; (c) X. Zheng, L. Lv, S. Lu, W.
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yields. Further applications of this protocol to the
intramolecular cyclizations is currently under investigation.
DOI: 10.1039/C6CC00133E
Acknowledgements
The financial support from the SERB, Department of Science
and Technology is greatly appreciated. RAB, ND and SS thank
to the UGC, New Delhi and NIPER S.A.S. Nagar for the award of
Senior Research Fellowships, respectively.
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