Palladium-catalyzed direct C-3 arylations of indoles with an air-stable HASPO

Article abstract of DOI:10.1055/s-0028-1087951

Efficient direct arylations of indoles occurred highly regioselectively at position C-3 with an in situ generated palladium complex derived from an air-stable HASPO, which enabled syntheses of diversely functionalized indoles, also with sterically hindere

Full text of DOI:10.1055/s-0028-1087951

808
LETTER
Palladium-Catalyzed Direct C-3 Arylations of Indoles with an Air-Stable
HASPO
P
alladium-Cata
u
lyze
d
D
irect
t
C
-3
A
r
z
ylations of Indole
A
s
ckermann,* Sebastian Barfüßer
Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen, Tammannstr. 2, 37077 Göttingen, Germany
Fax +49(551)396777; E-mail: Lutz.Ackermann@chemie.uni-goettingen.de
Received 11 December 2008
Table 1 Air-Stable SPO and HASPO Preligands in Palladium-
Abstract: Efficient direct arylations of indoles occurred highly
regioselectively at position C-3 with an in situ generated palladium
complex derived from an air-stable HASPO, which enabled synthe-
ses of diversely functionalized indoles, also with sterically hindered
substrates.
Catalyzed Direct Arylation of Indole 1aa
Me
Br
Key words: C–H bond functionalization, heteroarenes, indoles,
Pd(OAc)2 (5 mol%)
regioselectivity, palladium
preligands 4a–h (10 mol%)
+
K2CO3, 1,4-dioxane, 95 °C
N
N
H
H
Me
Indoles are arguably the most abundant heterocyclic sub-
structures in drug discovery.1,2 Therefore, a continued
strong demand exists for generally applicable syntheses of
this structural motif.3–5 Valuable strategies for the de novo
formation of indole’s N-heterocyclic moiety were devel-
oped.6–8 However, direct functionalization reactions of
unreactive C–H bonds in indoles constitute an attractive
alternative. In this context, particularly, transition-metal
catalysis was found to be highly promising, and set the
stage for the development of novel direct arylation meth-
odologies.9 In considering this approach for intermolecu-
lar transformations, achieving regioselectivity represents
a major challenge. Interestingly, the majority of known
protocols for catalytic direct arylations of 2,3-unsubstitut-
ed indoles provides predominantly the C-2 functionalized
products,10–12 likely occurring via an electrophilic metala-
tion at C-3, along with a subsequent 1,2-migration.12–17 In
a recently communicated exception, however, isolated
palladium complexes derived from secondary phosphine
oxides (SPO)18 were shown to enable highly regioselec-
tive direct C-3 arylations of 2,3-unsubstituted indoles.19
Unfortunately, this remarkable protocol provided often
comparable low yields, and proved not applicable to di-
rect arylations of a 2-substituted20,21 indole.19 Given our
interest in efficient syntheses of highly substituted in-
doles,22–24 as well as in the use of air-stable heteroatom-
substituted secondary phosphine oxides (HASPO) in tran-
sition-metal catalysis,6,25–27 we probed the application of
our preligands to palladium-catalyzed28 direct arylations
of indoles, on which we report herein.
1a
2a
3a
Entry
Preligand
–
Yield (%)
1
2
3
4
5
11
–
Mes2P(O)H
4a
(o-Tol)2P(O)H
(t-Bu)2P(O)H
(1-Ad)2P(O)H
4b
4c
4d
13
15
6
Me
Me
Me
Me
Me
O
H
6
7
4e
4f
10
21
P
N
N
Me
Me
Me
Me
Me
Me
N
Me
Cl
P
N
Me
Me
Me
Me
Ph
Ph
O
O
O
8
9
44
O
H
Me
Me
4g
4h
10b
P
O
Ph
Ph
o-Tol
O
o-Tol
O
O
O
H
At the outset of our studies, we explored the catalytic ac-
tivity of in situ generated palladium complexes derived
from representative SPO and HASPO preligands 4a–h
(Table 1). Preliminary experiments revealed that 1,4-di-
Me
Me
10
94
P
O
o-Tol
o-Tol
a Reaction conditions: 1a (1.0 mmol), 2a (1.2 mmol), Pd(OAc)2 (5
mol%), preligand (10 mol%), K2CO3 (3.0 equiv), 1,4-dioxane (4 mL),
95 °C, 20 h; yields of isolated products.
SYNLETT 2009, No. 5, pp 0808–0812
Advanced online publication: 24.02.2009
x
x.
x
x.
2
0
0
9
b Additive: t-BuCO2H (30 mol%).
DOI: 10.1055/s-0028-1087951; Art ID: G36908ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Palladium-Catalyzed Direct C-3 Arylations of Indoles
809
oxane as solvent and K2CO3 as base provided superior re- of substituted aryl bromides 2b–l (Table 2).31,32 We were
sults, whereas the use of polar aprotic solvents, such as pleased to observe that electrophiles 2 displaying valuable
NMP or DMA, resulted in no cross-coupling between the functional groups could be employed for regioselective
starting materials. Unfortunately, various in situ formed direct arylations of indole 1a (entries 1–6). Further, the
(HA)SPO-based complexes gave rise to unsatisfactory re- catalytic system displayed a notable chemoselectivity, al-
sults (entries 2–7).29 In contrast, more efficient catalysis lowing for the selective coupling of bromochloroarene 2h
was accomplished with the aid of HASPO preligands 4g (entries 7, and 8). Sterically more hindered electrophile 2i
and 4h (entries 8–10).
was converted with comparable efficacy (entry 9), as were
substituted pronucleophilic indoles 1b and 1c (entries 8–
10). Contrary to the previously reported SPO-based meth-
odology,19 this enabled the preparation of more congested
2,3-disubstituted indole 3l (entry 11). However, reactions
with di-ortho or nitro-substituted aryl bromides 2k and 2l
occurred with lower efficacy (entries 12 and 13).
While the addition of pivalic acid30 in substoichiometric
amounts inhibited catalytic activity (entry 9), sterically
hindered TADDOL derivative 4h led to an efficient and
selective formation of desired indole 3a (entry 10).
With an optimized catalytic system in hand, we explored
its scope in direct arylations of indoles 1a–d using a range
Table 2 Palladium-Catalyzed Direct C-3 Arylations of Indoles 1a
R2
Br
Pd(OAc)2 (5 mol%)
4h (10 mol%)
R1
R1
+
K2CO3, 1,4-dioxane
95 °C, 20 h
N
N
R2
H
H
1
2
3
Entry
1
1
R1
2
R2
Product
Yield (%)
81
1a
H
2b
H
3b
3c
3d
3e
N
H
OMe
2
3
4
1a
1a
1a
H
H
H
2c
2d
2e
4-MeO
66
69
53
N
H
CO2Et
3-EtO2C
N
H
C(O)Ph
4-Ph(O)C
N
H
Synlett 2009, No. 5, 808–812 © Thieme Stuttgart · New York

810
L. Ackermann, S. Barfüßer
LETTER
Table 2 Palladium-Catalyzed Direct C-3 Arylations of Indoles 1a (continued)
R2
Br
Pd(OAc)2 (5 mol%)
4h (10 mol%)
R1
R1
+
K2CO3, 1,4-dioxane
N
N
R2
95 °C, 20 h
H
H
1
2
3
Entry
5
1
R1
2
R2
Product
Yield (%)
C(O)Me
1a
H
2f
3-Me(O)C
3f
62
61
N
H
NMe2
6
1a
H
2g
4-Me2N
3g
N
H
Cl
7
8
9
1a
1b
1b
H
2h
2h
2i
3-Cl
3-Cl
2-Me
3h
3i
65
56
81
N
H
Cl
5-MeO
5-MeO
MeO
N
H
3j
Me
MeO
N
H
Me
10
11
1c
7-Me
2-Me
2j
2j
3-Me
3-Me
3k
50
53
N
H
Me
Me
1d
3l
Me
N
H
Synlett 2009, No. 5, 808–812 © Thieme Stuttgart · New York

LETTER
Palladium-Catalyzed Direct C-3 Arylations of Indoles
811
Table 2 Palladium-Catalyzed Direct C-3 Arylations of Indoles 1a (continued)
R2
Br
Pd(OAc)2 (5 mol%)
4h (10 mol%)
R1
R1
+
K2CO3, 1,4-dioxane
N
N
R2
95 °C, 20 h
H
H
1
2
3
Entry
12
1
R1
2
R2
Product
Yield (%)
Me
Me
1b
5-MeO
2k
2,4,6-Me3
3m
23
Me
MeO
N
H
NO2
13
1a
H
2l
4-O2N
3n
4
N
H
a Reaction conditions: 1 (1.0 equiv), 2 (1.2 equiv), Pd(OAc)2 (5 mol%), 4h (10 mol%), K2CO3 (3.0 equiv), 1,4-dioxane (0.5 M), 95 °C, 20 h;
yields of isolated products.
(5) Joule, J. A.; Milles, K. Heterocyclic Chemistry, 4th ed.;
Blackwell Science Ltd: Oxford, 2000.
(6) Ackermann, L. Synlett 2007, 507.
(7) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873.
(8) Krüger, K.; Tillack, A.; Beller, M. Adv. Synth. Catal. 2008,
350, 2153.
(9) Ackermann, L. Modern Arylation Reactions; Wiley-VCH:
Weinheim, 2009.
(10) Palladium-catalyzed cross-dehydrogenative arylations can
proceed regioselectively at indoles. However, they display
limited selectivities with respect to the coupling partner and
rely on the use of (over)stoichiometric amounts of Cu(OAc)2
or AgOAc as terminal oxidants: (a) Potavathri, S.; Dumas,
A. S.; Dwight, T. A.; Naumiec, G. R.; Hammann, J. M.;
DeBoef, B. Tetrahedron Lett. 2008, 49, 4050. (b) Stuart,
D. R.; Villemure, E.; Fagnou, K. J. Am. Chem. Soc. 2007,
129, 12072. (c) Dwight, T. A.; Rue, N. R.; Charyk, D.;
Josselyn, R.; DeBoef, B. Org. Lett. 2007, 9, 3137.
(d) Stuart, D. R.; Fagnou, K. Science 2007, 316, 1172; and
references cited therein.
(11) For rhodium-catalyzed direct arylations of indoles,
occurring largely with C-2 regioselectivity, see:
(a) Yanagisawa, S.; Sudo, T.; Noyori, R.; Itami, K.
Tetrahedron 2008, 64, 6073. (b) Yanagisawa, S.; Sudo, T.;
Noyori, R.; Itami, K. J. Am. Chem. Soc. 2006, 128, 11748.
(c) Wang, X.; Lane, B. S.; Sames, D. J. Am. Chem. Soc.
2005, 127, 4996.
As to the mechanism of this transformation, we propose a
catalytic cycle comprising oxidative addition of the or-
ganic electrophile to a palladium(0) species, followed by
electrophilic functionalization of the indole by the gener-
ated palladium(II) species, and subsequent reductive
elimination. The exact reason as to why these catalytic
reactions proceed with excellent C-3 selectivity is, as yet,
not fully understood, and warrants further mechanistic
studies.
In summary, we have developed a highly efficient catalyt-
ic system for direct C-3 arylations of indoles. Thus, an in
situ generated palladium complex derived from an air-
stable HASPO preligand allowed for regioselective aryla-
tions of various indoles employing diversely
functionalized bromides as electrophiles.
Acknowledgment
Support by the DFG and the German-Israeli-Foundation (GIF) is
gratefully acknowledged.
References and Notes
(1) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev.
2003, 103, 893.
(2) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875.
(3) Eicher, T.; Hauptmann, S. The Chemistry of Heterocycles,
2nd ed.; Wiley-VCH: Weinheim, 2003.
(12) Stoichiometrically magnesiated indoles were shown to give
rise to C-3 arylated indoles: Lane, B. S.; Brown, M. A.;
Sames, D. J. Am. Chem. Soc. 2005, 127, 8050.
(13) de Mendoza, P.; Echavarren, A. M. In Modern Arylation
Methods; Ackermann, L., Ed.; Wiley-VCH: Weinheim,
2009, 363.
(4) Gilchrist, T. L. Heterocyclic Chemistry, 3rd ed.; Addison
Wesley Longman: Harlow, 1997.
Synlett 2009, No. 5, 808–812 © Thieme Stuttgart · New York

812
L. Ackermann, S. Barfüßer
LETTER
(31) Representative Procedure – Synthesis of 3a (Table 1,
(14) (a) Seregin, I. V.; Gevorgyan, V. Chem. Soc. Rev. 2007, 36,
1173. (b) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev.
2007, 107, 174.
Entry 10)
A suspension of Pd(OAc)2 (5.6 mg, 0.025 mmol, 5.0 mol%)
and 4h (28.4 mg, 0.05 mmol, 10 mol%) in dry dioxane (1
mL) was stirred for 30 min under N2 at ambient temperature.
K2CO3 (207.0 mg, 1.50 mmol), indole (1a, 59.0 mg, 0.50
mmol), and 4-bromotoluene (2a, 106.0 mg, 0.62 mmol) were
added, and the suspension was stirred at 95 °C for 20 h. After
the reaction mixture was cooled to ambient temperature,
Et2O (50 mL) and brine (50 mL) were added. The aqueous
phase was extracted with Et2O (2 × 50 mL). The combined
organic layers were dried over Na2SO4 and concentrated in
vacuo. The remaining residue was purified by column
chromatography on SiO2 (n-hexane–EtOAc, 10:1) to yield
3a (97.0 mg, 94%) as a pale yellow solid; mp 107.4–
108.3 °C). 1H NMR (300 MHz, DMSO-d6): d = 11.27 (br s,
1 H), 7.86 (d, J = 7.6 Hz, 1 H), 7.64–7.56 (m, 3 H), 7.47 (d,
J = 7.8 Hz, 1 H), 7.24 (d, J = 8.2 Hz, 2 H), 7.19–7.07 (m, 2
H), 2.34 (s, 3 H). 13C NMR (75 MHz, DMSO-d6): d = 136.8
(Cq), 134.1 (Cq), 132.9 (Cq), 129.2 (CH), 126.3 (CH), 125.0
(Cq), 122.8 (CH), 121.2 (CH), 119.4 (CH), 118.9 (CH),
115.6 (Cq), 111.8 (CH), 20.6 (CH3). IR (KBr): 3387, 2361,
2337, 1653, 1617, 1116, 802, 747 cm–1. MS (EI): m/z (%) =
207 (100) [M+], 206 (37), 117 (12), 90 (8). ESI-HRMS: m/z
calcd for C15H14N 208.1121: found: 208.1121. The spectral
data are in accordance with those reported in the literature.19
(15) Selected recent representative examples of palladium-
catalyzed direct arylations of indoles: (a) Lebrasseur, N.;
Larrosa, I. J. Am. Chem. Soc. 2008, 130, 2926. (b) Zhao, J.;
Zhang, Y.; Cheng, K. J. Org. Chem. 2008, 73, 7428.
(c) Yang, S.-D.; Sun, C.-L.; Fang, Z.; Li, B.-J.; Li, Y.-Z.;
Shi, Z.-J. Angew. Chem. Int. Ed. 2008, 47, 1473.
(d) Bellina, F.; Calandri, C.; Cauteruccio, S.; Rossi, R. Eur.
J. Org. Chem. 2007, 2147. (e) Deprez, N. R.; Kalyani, D.;
Krause, A.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128,
4972; and references cited therein.
(16) For elegant site-selective copper-catalyzed direct C-3
arylations of indoles employing [Ar2I]X as arylating
reagents, see: Phipps, R. J.; Grimster, N. P.; Gaunt, M. J.
J. Am. Chem. Soc. 2008, 130, 8172.
(17) For an early example of regioselective direct arylations of
indoles, see: Akita, Y.; Itagaki, Y.; Takizawa, S.; Ohta, A.
Chem. Pharm. Bull. 1989, 37, 1477.
(18) Ackermann, L. Synthesis 2006, 1557.
(19) Zhang, Z.; Hu, Z.; Yu, Z.; Lei, P.; Chi, H.; Wang, Y.; He, R.
Tetrahedron Lett. 2007, 48, 2415.
(20) For the recent use of a heterogenous palladium catalyst for
direct C-3 arylations of 2-substituted indoles, see:
(a) Cusati, G.; Djakovitch, L. Tetrahedron Lett. 2008, 49,
2499. (b) For a direct C-3 arylation of a 2-substituted indole,
see: Djakovitch, L.; Dufaud, V.; Zaidi, R. Adv. Synth. Catal.
2006, 348, 715.
(21) For a recent report on the application of PCy3 or Bn(n-
Bu)3NCl to palladium-catalyzed direct C-3 arylations of
indoles, including 2-substituted ones, see: Bellina, F.;
Benelli, F.; Rossi, R. J. Org. Chem. 2008, 73, 5529.
(22) (a) Ackermann, L. Org. Lett. 2005, 7, 439. (b) Kaspar,
L. T.; Ackermann, L. Tetrahedron 2005, 61, 11311.
(23) Ackermann, L.; Kaspar, L. T.; Gschrei, C. J. Chem.
Commun. 2004, 2824.
(24) Ackermann, L.; Sandmann, R.; Villar, A.; Kaspar, L. T.
Tetrahedron 2008, 64, 769.
(25) (a) Ackermann, L.; Born, R. Angew. Chem. Int. Ed. 2005,
44, 2444. (b) Ackermann, L.; Gschrei, C. J.; Althammer, A.;
Riederer, M. Chem. Commun. 2006, 1419. (c) Ackermann,
L.; Spatz, J. H.; Gschrei, C. J.; Born, R.; Althammer, A.
Angew. Chem. Int. Ed. 2006, 45, 7627.
(32) Analytical Data
Indole 3i: mp 80.3–82.2 °C. 1H NMR (300 MHz, CDCl3):
d = 8.19 (br s, 1 H), 7.62 (t, J = 1.8 Hz, 1 H), 7.53 (dt,
J = 7.7, 1.6 Hz, 1 H), 7.39–7.23 (m, 5 H), 6.93 (dd, J = 8.8,
2.4 Hz, 1 H), 3.88 (s, 3 H). 13C NMR (126 MHz, CDCl3):
d = 154.9 (Cq), 137.5 (Cq), 134.6 (Cq), 131.7 (Cq), 130.0
(CH), 127.1 (CH), 125.9 (Cq), 125.8 (CH), 125.3 (CH),
123.0 (CH), 116.8 (Cq), 112.7 (CH), 112.2 (CH), 101.5
(CH), 56.0 (CH3). IR (KBr): 3391, 1620, 1594, 1485, 1440,
1271, 1214, 791 cm–1. MS (EI): m/z (%) = 257 (100) [M+],
242 (26), 215 (33), 178 (13), 152 (15) 128 (11). ESI-HRMS:
m/z calcd for C15H13ClNO: 258.0680; found: 258.0682.
Indole 3k: mp 134.1–135.8 °C. 1H NMR (300 MHz, CDCl3):
d = 8.07 (br s, 1 H), 7.84 (d, J = 7.9 Hz, 1 H), 7.53–7.50 (m,
2 H), 7.40–7.32 (m, 2 H), 7.18–7.07 (m, 3 H), 2.52 (s, 3 H),
2.46 (s, 3 H). 13C NMR (126 MHz, CDCl3): d = 138.2 (Cq),
136.1 (Cq), 135.5 (Cq), 128.6 (CH), 128.1 (CH), 126.7 (CH),
125.2 (Cq), 124.5 (CH), 122.8 (CH), 121.4 (CH), 120.4 (Cq),
120.4 (CH), 118.8 (Cq), 117.6 (CH), 21.7 (CH3), 16.6 (CH3).
IR (KBr): 3411, 1653, 1635, 1540, 1457, 1113, 789, 751 cm–1.
MS (EI): m/z (%) = 221 (100) [M+], 204 (10), 178 (10), 110
(6), 102 (7). ESI-HRMS: m/z calcd for C16H16N: 222.1277;
found: 222.1277.
(26) Ackermann, L. Org. Lett. 2005, 7, 3123.
(27) Ackermann, L.; Althammer, A.; Born, R. Angew. Chem. Int.
Ed. 2006, 45, 2619.
(28) For recent examples of palladium-catalyzed direct arylations
from our laboratories, see: (a) Ackermann, L.; Althammer,
A.; Fenner, S. Angew. Chem. Int. Ed. 2009, 48, 201.
(b) Ackermann, L.; Vicente, R.; Born, R. Adv. Synth. Catal.
2008, 350, 741. (c) Ackermann, L.; Althammer, A. Angew.
Chem. Int. Ed. 2007, 46, 1627.
(29) Unfortunately, under otherwise identical reaction conditions
catalytic amounts of Bn(n-Bu)3NCl21 provided product 3a
with lower isolated yields, as did the P-para-tolylated
phosphonate derived from HASPO 4h (63%).
(30) Carboxylic acids were used as additives in palladium- and
ruthenium-catalyzed direct arylation reactions, which are
believed to proceed through a concerted metalation–
deprotonation mechanism: [Pd]: (a) Lafrance, M.; Fagnou,
K. J. Am. Chem. Soc. 2006, 128, 16496. (b) [Ru]: Lafrance,
M.; Gorelsky, S. I.; Fagnou, K. J. Am. Chem. Soc. 2007, 129,
14570. (c) Ackermann, L.; Vicente, R.; Althammer, A. Org.
Lett. 2008, 10, 2299. (d) Ackermann, L.; Mulzer, M. Org.
Lett. 2008, 10, 5043; and references cited therein.
Indole 3l: mp 113.0–115.2 °C. 1H NMR (300 MHz, CDCl3):
d = 7.92 (br s, 1 H), 7.65 (d, J = 7.4 Hz, 1 H), 7.38–7.28 (m,
4 H), 7.18–7.07 (m, 3 H), 2.50 (s, 3 H), 2.42 (s, 3 H). 13
C
NMR (126 MHz, CDCl3): d = 137.9 (Cq), 135.2 (Cq), 135.1
(Cq) 131.2 (Cq), 130.0 (CH), 128.3 (CH), 127.8 (Cq), 126.5
(CH), 126.4 (CH), 121.4 (CH), 119.8 (CH), 118.8 (CH),
114.5 (Cq), 110.2 (CH), 21.7 (CH3), 12.7 (CH3). IR (KBr):
3392, 1682, 1653, 1559, 1457, 1306, 792, 746 cm–1. MS
(EI): m/z (%) = 221 (100) [M+], 204 (20), 178 (9), 130 (15),
102 (15). ESI-HRMS: m/z calcd for C16H16N: 222.1277;
found: 222.1272.
Synlett 2009, No. 5, 808–812 © Thieme Stuttgart · New York

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