Regiocontrolled aerobic oxidative coupling of indoles and benzene using Pd catalysts with 4,5-diazafluorene ligands

Article abstract of DOI:10.1039/c1cc13632a

Palladium-catalyzed aerobic oxidative cross-couplings of indoles and benzene have been achieved by using 4,5-diazafluorene derivatives as ancillary ligands. Proper choice of the neutral and anionic ligands enables control over the reaction regioselectivit

Full text of DOI:10.1039/c1cc13632a

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Regiocontrolled aerobic oxidative coupling of indoles and benzene using
Pd catalysts with 4,5-diazafluorene ligandswz
Alison N. Campbell, Eric B. Meyer and Shannon S. Stahl*
Received 18th June 2011, Accepted 25th July 2011
DOI: 10.1039/c1cc13632a
Palladium-catalyzed aerobic oxidative cross-couplings of indoles and
benzene have been achieved by using 4,5-diazafluorene derivatives as
ancillary ligands. Proper choice of the neutral and anionic ligands
enables control over the reaction regioselectivity.
suggest that the role of the oxidant in these reactions is not limited
to reoxidation of Pd0.7 For example, oxidants have been shown to
promote C–C reductive elimination from PdII 8 and to control the
regioselectivity of oxidative cross-coupling reactions.3a–d,9 In
2007, Fagnou and co-workers reported Pd-catalyzed oxidative
cross-coupling of indoles with benzene in which they demon-
strated selective functionalization of the indole C3 position when
Cu(OAc)2 was used as the oxidant,3a but C2 selectivity with
AgOAc as the oxidant (Scheme 1A).3b These observations
provide the foundation for the present investigation.
Biaryls are an important structural motif in diverse classes of
organic molecules, including pharmaceuticals, organic dyes,
agrochemicals and conducting polymers.1 In recent years,
considerable attention has focused on the development of
methods for arylation of arene C–H bonds.2 The direct
oxidative coupling of two arenes (eqn (1)) is among the most
attractive synthetic routes to biaryls,2h,3 but such methods face
numerous intrinsic challenges, including controlling the regio-
selectivity in the functionalization of substituted (hetero)arenes,
achieving selective cross- vs. homocoupling of the substrates,
and identification of an atom-economical oxidant for the
reaction. Here, we show that use of the diazafluorene derivatives,
4,5-diazafluoren-9-one (1) and 9,9-dimethyl-4,5-diazafluorene (2),
as ancillary ligands for a PdII catalyst enables aerobic oxidative
cross-coupling of indoles with benzene, with selectivity for C2 and
C3 indole-arylation products.
We demonstrated recently that the diazafluorenone ligand 1
promotes acetoxylation of p-allyl-PdII species, enabling benzo-
quinone to be replaced by O2 as the oxidant in Pd-catalyzed
allylic C–H acetoxylation reactions.10 This result prompted us
to consider whether analogous ligand-based strategies could
be used to achieve oxidative cross-coupling of (hetero)arenes
with O2 as the oxidant, preferably with control over the
reaction regioselectivity (Scheme 1B).
In the present study, we focused our attention on the oxidative
coupling of indoles and benzene.y A number of different nitrogen
ligands, including pyridine, phenanthroline and related derivatives
were evaluated in reaction of N-pivalyl indole with benzene. The
reactions were carried out with 5 mol% of a PdII source at 120 1C
under 1 atm of O2. Benzene served as the substrate and as a
cosolvent with pivalic acid (Table 1). Reactions with pyridine and
2-fluoropyridine11 exhibited modest yields (B20–30%), and a
ð1Þ
The majority of Pd-catalyzed methods for oxidative cross-
coupling of (hetero)arenes employ stoichiometric organic or
transition-metal oxidants, such as benzoquinone (BQ), AgI, or
CuII.3 Replacement of these oxidants with O2 represents a
significant fundamental challenge that has important implications
for practical applications of these methods;4,5 however, only
limited success has been achieved thus far.6 Several observations
Department of Chemistry, University of Wisconsin—Madison,
1101 University Avenue, Madison, Wisconsin 53706, U.S.A.
E-mail: stahl@chem.wisc.edu; Fax: 1 608 262 6143;
Tel: 1 608 265 6288
w This article is part of the ChemComm ‘Advances in catalytic C–C
bond formation via late transition metals’ web themed issue.
z Electronic supplementary information (ESI) available: Reaction
optimization details, characterization data and NMR spectra of
characterized compounds. See DOI: 10.1039/c1cc13632a
Scheme 1 Regioselective oxidative coupling.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 10257–10259 10257

Table 1 Identification of a ligand for palladium-catalyzed aerobic
oxidative cross-couplinga
Table
2
Identification of optimized conditions for palladium-
catalyzed oxidative coupling of indoles with benzenea
C2 : C3
C2 : C3
Yieldb Selectivityc
Ligand
Yieldb
Selectivityc
Entry Z
Acid
Catalyst Ligand Yieldb C2 : C3 Selectivityc
Ligand
1
2
3
4
5
6
7
8
9
Piv
Ac
PivOH Pd(TFA)2
PivOH Pd(TFA)2
2
2
2
2
2
2
1
1
1
66% 1 : 3.8
67% 1 : 1.2
77% 1 : 5
89% 1 : 5.8
63% 1 : 2.2
68% 1 : 1.5
64% 1 : 4.8
85% 1.4 : 1
80% 2 : 1
None
15% 1 : 1
10% 1 : 1
SO2Ph PivOH Pd(TFA)2
SO2Ph EtCO2H Pd(TFA)2
SO2Ph EtCO2H Pd(OAc)2
SO2Ph EtCO2H Pd(OPiv)2
SO2Ph EtCO2H Pd(TFA)2
SO2Ph EtCO2H Pd(OAc)2
SO2Ph EtCO2H Pd(Opiv)2
22% 1 : 1
18%d 1.6 : 1d
—
0%
24% 1 : 1.4
29%d 1.9 : 1d
14% 1 : 2.5
14% 1 : 1.3
a
Conditions: 5% Pd (7.5 mmol), 5% ligand (7.5 mmol), indole
(0.15 mmol), acid (0.9 mmol), benzene (9.9 mmol), 1 atm O2,
31% 2.4 : 1
47%d 2.9 : 1d
120 1C, 18 h. By 1H NMR (internal standard = tetrachloroethane).
Determined by H NMR analysis.
b
9% 1 : 2
c
1
—
0%
9%e 1 : 1e
—
These observations demonstrate that regioselective aerobic
0%
oxidative arylation of indoles can be achieved by proper selection
of the anionic and neutral ligands for the Pd catalyst. Catalyst
system A, with Pd(TFA)2 and ligand 2, favors the C3-function-
alized product; and catalyst system B, with Pd(OPiv)2 and 1,
favors the C2-functionalized product. These insights were then
applied to a small series of other indole substrates (Table 3).
The N-pivalyl indole gave superior selectivity under the
conditions optimized for the C2 product (entry 1) while the
N-benzenesulfonyl indole showed higher regioselectivity under
the C3 optimized conditions (entry 2). The 5- and 6-substituted
chloro and methoxy derivatives were used to probe the influence of
electron-withdrawing and electron-donating groups on the reaction
outcome. Neither substituent had a significant impact on the yields,
but the regioselectivity varied (Table 3, entries 3–6). With the
Pd(TFA)2/2 catalyst system (A) the presence of an electron-
donating or -withdrawing group in either position led to a deterio-
ration of the regioselectivity. However, with the Pd(OPiv)2/1
catalyst system (B), the regioselectivity was improved by the
presence of an electron-withdrawing group in the 5- or 6-positions.
Overall, these observations establish that diazafluorene-
derived ancillary ligands enable the replacement of stoichio-
metric transition metals with O2 as the oxidant in Pd-catalyzed
oxidative cross-coupling of (hetero)arenes. Moreover, optimi-
zation of the neutral and anionic ligands permits control over
the regioselectivity of the reactions.
45% 1 : 1.7
34%e 1 : 1.3e
0% —
15% 1 : 2
32%e 1 : 1.7e
a
Conditions: 5% Pd(TFA)2 (7.5 mmol), 5% ligand (7.5 mmol), indole
(0.15 mmol), PivOH (0.90 mmol), benzene (9.9 mmol), 1 atm O2,
120 1C, 18 h. By 1H NMR (internal standard = tetrachloroethane).
b
Determined by 1H NMR. 10% ligand. 2.5% ligand.
c
d
e
better yield was obtained with 3-nitropyridine (47%). Reactions
with bipyridine, phenanthroline and related bidentate ligands
showed little product formation. Use of diazafluorene derivative
2 gave the best result, with a 66% product yield."
The reaction was further optimized by examining the effect
of indole N-substituent and the acid additive on the yield and
regioselectivity (Table 2). The highest product yields and
regioselectivities were obtained with the N-benzenesulfonyl
(SO2Ph) group and propionic acid (Table 2, entry 4). More
extensive screening data is provided in the ESI.z
Several different PdII sources were examined in the course of
these studies, and the identity of the anionic ligand was found
to have a strong effect on the reaction regioselectivity. These
observations resemble results noted recently by Sanford et al.
in BQ-promoted oxidative coupling reactions.8d Tri-fluoro-
acetate favors the formation of the C3-functionalized product,
while pivalate in combination with 2 led to almost no regio-
selectivity (Table 2, entry 6). When Pd(OPiv)2 was used with
the diazafluorenone ligand 1, a switch in regioselectivity was
observed, favoring the C2-functionalized product (Table 2,
entry 9). The addition of CsOPiv (20 mol%) to the standard
reaction mixture led to a similar increase in the formation
of C2-arylated products.12 The yield of biphenyl was not
rigorously quantified in each case, but it was generally r 20%.
The mechanistic basis for these results is not yet understood,
but at least two general mechanisms can be considered.13 One
involves sequential activation of the indole and benzene at a
single PdII center, followed by reductive elimination of the
product and reoxidation of Pd0 by O2. An alternative pathway
involves activation of indole and benzene at independent PdII
centers, followed by transmetalation to afford the PdII(phenyl)
(indolyl) intermediate that undergoes reductive elimination of
the product. Distinguishing between these possibilities and
exploring the basis for the reaction regioselectivity will be an
important focus of future work.
c
10258 Chem. Commun., 2011, 47, 10257–10259
This journal is The Royal Society of Chemistry 2011

Table 3 Oxidative cross-coupling of indoles with simple arenesa
(0.030 mmol), indole (0.60 mmol), EtCO2H (270 mL, 3.6 mmol) and
arene (39.6 mmol). The tube was evacuated and backfilled with O2
(3x), sealed and heated to 120 1C for 24 h with vigorous stirring. The
reaction mixture was then cooled to room temperature, diluted with
EtOAc and washed with sat’d. NaHCO3. The organic layer was
separated and the aqueous layer washed with EtOAc (2x). The
combined organics were dried over MgSO4, filtered and concentrated
by rotatory evaporation. The crude product was purified by silica gel
column chromatography (Et2O in hexanes) to yield the cross-coupled
product as a mixture of two isomers.
Entry
1
Indole
Catalyst
Yieldb
C2 : C3 Selectivityc
A
B
52%
66%
1 : 4.4
4.8 : 1
1 I. Cepanec, Synthesis of Biaryls, Elsevier, New York, 2004.
2 For relevant reviews, see: (a) F. Kakiuchi and T. Kochi, Synthesis,
2008, 2008, 3013; (b) B.-J. Li, S.-D. Yang and Z.-J. Shi, Synlett.,
2008, 949; (c) X. Chen, K. M. Engle, D. H. Wang and J. Q. Yu,
Angew. Chem., Int. Ed., 2009, 48, 5094; (d) T. W. Lyons and
M. S. Sanford, Chem. Rev., 2010, 110, 1147; (e) A. Lei, W. Liu,
C. Liu and M. Chen, Dalton Trans., 2010, 39, 10352; (f) S. L. You
and J. B. Xia, Top. Curr. Chem., 2010, 292, 165; (g) C. Liu,
H. Zhang, W. Shi and A. Lei, Chem. Rev., 2011, 111, 1780;
(h) C. S. Yeung and V. M. Dong, Chem. Rev., 2011, 111, 1215.
3 For examples of Pd-catalyzed oxidative cross-coupling, see
ref. 2h and references therein, and: (a) D. R. Stuart and
K. Fagnou, Science, 2007, 316, 1172; (b) D. R. Stuart, E. Villemure
and K. Fagnou, J. Am. Chem. Soc., 2007, 129, 12072;
(c) S. Potavathri, A. S. Dumas, T. A. Dwight, G. R. Naumiec,
J. M. Hammann and B. DeBoef, Tetrahedron Lett., 2008, 49, 4050;
(d) S. Potavathri, K. C. Pereira, S. I. Gorelsky, A. Pike, A. P. LeBris
and B. DeBoef, J. Am. Chem. Soc., 2010, 132, 14676; (e) X. Gong,
G. Song, H. Zhang and X. Li, Org. Lett., 2011, 13, 1766; (f) Z. Wang,
K. Li, D. Zhao, J. Lan and J. You, Angew. Chem., Int. Ed., 2011,
50, 5365.
A
B
66%
76%
1 : 5.8
2 : 1
2
A
B
71%
68%
1 : 1.3
5 : 1
A
B
71%
66%
1.4 : 1
3.7 : 1
4
5
A
B
54%
71%
1 : 3.9
2.3 : 1
A
B
70%
65%
1 : 1.3
2.6 : 1
6
a
Condition A: 5% Pd(TFA)2 (30 mmol), 5% 2 (30 mmol), indole
(0.60 mmol), EtCO2H (3.6 mmol), benzene (39.6 mmol), 1 atm O2,
120 1C, 24 h. Condition B: 5% Pd(OPiv)2 (30 mmol), 5% 1 (30 mmol),
indole (0.60 mmol, EtCO2H (3.6 mmol), benzene (39.6 mmol), 1 atm
4 For reviews of Pd-catalyzed oxidation reactions that employ O2 as
the sole oxidant, see: (a) S. S. Stahl, Angew. Chem., Int. Ed., 2004,
43, 3400; (b) K. M. Gligorich and M. S. Sigman, Chem. Commun.,
2009, 3854 and references therein.
b
O2, 120 1C, 24 h. Isolated as a mixture of C2 and C3 regioisomers.
Determined by 1H NMR analysis of the reaction mixture.
c
5 Prospects for safe and scalable Pd-catalyzed aerobic oxidation
methods were considered in the recent development of a continuous-
flow process: X. Ye, M. D. Johnson, T. Diao, M. H. Yates and
S. S. Stahl, Green Chem., 2010, 12, 1180.
6 Pd-catalyzed oxidative cross-coupling that use O2 as the terminal
oxidant: (a) T. A. Dwight, N. R. Rue, D. Charyk, R. Josselyn and
B. DeBoef, Org. Lett., 2007, 9, 3137; (b) B. H. Li, S. L. Tian,
Z. Fang and Z. H. Shi, Angew. Chem., Int. Ed., 2008, 47, 1115;
(c) G. Brasche, J. Garcia-Fortanet and S. L. Buchwald, Org. Lett.,
2008, 10, 2207.
7 For studies of Pd(0) oxidation by O2, see: (a) J. Muzart,
Chem.–Asian J., 2006, 1, 508; (b) S. S. Stahl, J. L. Thorman,
R. C. Nelson and M. A. Kozee, J. Am. Chem. Soc., 2001,
123, 7188; (c) M. M. Konnick, I. A. Guzei and S. S. Stahl,
J. Am. Chem. Soc., 2004, 126, 10212; (d) M. M. Konnick and
S. S. Stahl, J. Am. Chem. Soc., 2008, 130, 5753; (e) B. V. Popp and
S. S. Stahl, Chem.–Eur.J., 2009, 15, 2915.
A few preliminary mechanistic observations can be noted.
When reactions with catalysts A and B were carried out with a
1 :1 mixture of C6H6 and C6D6, deuterium kinetic isotope effects
varied from 2.8–3.8, depending upon the specific reaction.12
This primary KIE is consistent with a concerted metalation-
deprotonation pathway for C–H activation that has been charac-
terized previously in related reactions.14 When the reaction was
carried out with CD3CO2D as the acid additive, extensive
deuterium incorporation was observed into the benzene and
the indole substrates. Deuteration of the indole ring occurred
primarily at the C3-position, irrespective of the catalyst system,
even though catalyst B leads to predominant C2-functionaliza-
tion. Negligible deuteration occurs in the absence of PdII under
these conditions.12 These results, which indicate that C–H
activation is reversible for both substrates under the reaction
conditions, potentially provide circumstantial support for a
transmetalation mechanism, but more work is required before
a conclusion can be reached. The relative simplicity of the
catalyst systems should facilitate such mechanistic investigations.
We thank Paul White (UW-Madison) for experimental
assistance, and we are grateful to the NIH (R01-GM67163/
SSS; F32-GM087890/ANC) and the Camille and Henry
Dreyfus Postdoctoral Program in Environmental Chemistry
for financial support of this work. High-pressure instrumenta-
tion was supported by the NSF (CHE-0946901).
8 Oxidatively-induced reductive elimination from PdII has extensive
precedent. For recent examples relevant to catalytic oxidative
coupling reactions, see the following and references cited therein:
(a) X. Chen, C. E. Goodhue and J. Q. Yu, J. Am. Chem. Soc., 2006,
128, 12634; (b) M. P. Lanci, M. S. Remy, W. Kaminsky,
J. M. Mayer and M. S. Sanford, J. Am. Chem. Soc., 2009,
131, 15618; (c) J. R. Khusnutdinova, N. P. Rath and L. M. Mirica,
J. Am. Chem. Soc., 2010, 132, 7303–7305; (d) T. W. Lyons, K. L. Hull
and M. S. Sanford, J. Am. Chem. Soc., 2011, 133, 4455.
9 N. P. Grimster, C. Gauntlett, C. R. A. Godfrey and M. J. Gaunt,
Angew. Chem., Int. Ed., 2005, 44, 3125.
10 A. N. Campbell, P. B. White, I. A. Guzei and S. S. Stahl, J. Am.
Chem. Soc., 2010, 132, 15116.
11 Y. Izawa and S. S. Stahl, Adv. Synth. Catal., 2010, 352, 3223.
12 See the ESI for additional detailsz.
13 The mechanism of these reactions has received relatively
little attention. For a recent computational study, see: R. Meir,
S. Kozuch, A. Uhe and S. Shaik, Chem.–Eur. J., 2011, 17,
7623.
Notes and references
14 (a) S. I. Gorelsky, D. Lapointe and K. Fagnou, J. Am. Chem. Soc.,
2008, 130, 10848–10849; (b) L. Ackermann, Chem. Rev., 2011,
111, 1315.
y General procedure for catalytic reactions: A pressure tube fitted
with a plunger valve was charged with Pd (0.030 mmol), ligand
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 10257–10259 10259