Thieme chemistry journal awardees - Where are they now? Palladium-catalyzed N-arylation-hydroamination sequence for the synthesis of indoles with sterically demanding N-substituents

Article abstract of DOI:10.1055/s-0029-1216727

A palladium-catalyzed sequence consisting of an N-arylation and an intramolecular hydroamination sets the stage for a modular synthesis of indoles bearing sterically hindered N-substituents. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1216727

LETTER
1219
Thieme Chemistry Journal Awardees – Where Are They Now?
Palladium-Catalyzed N-Arylation–Hydroamination Sequence for the
Synthesis of Indoles with Sterically Demanding N-Substituents
P
alladium-Cata
u
lyze
d
Synthe
t
sis of
I
z
ndoles
w
ith
S
teric
A
ally
D
emanding N
c
-Substitue
k
nts ermann,* René Sandmann, Mikhail V. Kondrashov
Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Goettingen, Tammannstr. 2, 37077 Goettingen, Germany
Fax +49(551)396777; E-mail: Lutz.Ackermann@chemie.uni-goettingen.de
Received 13 February 2009
Abstract: A palladium-catalyzed sequence consisting of an N-aryl-
ation and an intramolecular hydroamination sets the stage for a
modular synthesis of indoles bearing sterically hindered N-substit-
uents.
Key words: amination, heteroarenes, hydroamination, indoles, pal-
ladium
Due to their remarkable range of biological activities, in-
doles are among the most abundant heterocyclic substruc-
tures in drug discovery. As a consequence, a continuing
demand exists for generally applicable syntheses of this
heteroarene.1–5 Recently, significant progress has been ac-
complished, in particular, through the application of tran-
sition-metal catalysis.6–13 Although these efforts greatly
expanded the generality of catalytic indole syntheses, the
preparation of derivatives bearing sterically demanding
N-substituents continues to represent a significant chal-
lenge. For example, functionalizations of free (NH) in-
doles via substitution reactions at nitrogen are hampered
by their relatively low nucleophilicities. However, a ma-
jor advance was recently achieved by Willis and cowork-
ers with an application of their elegant palladium-
catalyzed N-annulation14 to the preparation of indoles
with sterically demanding N-substituents.15 Furthermore,
Schirok reported on the microwave-assisted preparation
of N-tert-alkylated indoles through the conversion of
ortho-(haloaryl)oxiranes with primary amines at
240 °C.16
Lutz Ackermann was educated at the Christian-Albrechts-Universi-
ty Kiel, and obtained his Ph.D. in 2001 under the supervision of Alois
Fürstner, Max-Planck-Institut für Kohlenforschung in Mülheim/
Ruhr. He was a DAAD postdoctoral fellow in the laboratories of
Robert G. Bergman at the University of California at Berkeley, USA,
and initiated his independent career – supported by the Emmy
Noether program (DFG) – in 2003 at the Ludwig-Maximilians-
Universität Munich. In 2007, he became full professor at the Georg-
August-Universität Göttingen. The unifying theme of his research
program is represented by the development and applications of novel
concepts for efficient catalytic processes. Lutz Ackermann was vi-
siting professor at the Università degli Studi di Milano, Italy, as well
as the University of Wisconsin at Madison, USA, and his recent
awards include a Thieme Journal Award, an ORCHEM-prize, an
ADUC-prize, and a Dozentenstipendium (FCI).
R2
Pd(OAc)2 (5 mol%)
ligand (5 mol%)
H2N R3
R1
R1
R2
+
KOt-Bu, PhMe
N
R3
Cl
1
2
3
Previously, we reported on palladium-17,18 and copper-
catalyzed17 syntheses of diversely substituted indoles19
employing ortho-dihaloarenes or ortho-alkynylhalo-
arenes, such as chlorides 1 (Scheme 1). This reaction se-
quence consisting of an intermolecular N-arylation and an
intramolecular hydroamination laid the foundation for a
modular access to N-substituted indoles. Considering the
valuable biological activities20 of indoles with sterically
hindered N-substituents as well as the limitations associ-
ate with their syntheses,14,16 we became interested in ex-
ploring the use of our protocol in this challenging task, the
results of which we wish to report herein.
Scheme 1 Palladium-catalyzed synthesis of indoles 3
At the outset of our studies, we explored palladium com-
plexes derived from various phosphine or N-heterocyclic
carbene21–23 ligands in the conversion of sterically hin-
dered 1-AdNH2 (2a, Table 1). Unfortunately, diphos-
phines 4 and 5 gave only rise to unsatisfactory results
(entries 2 and 3). On the contrary, electron-rich mono-
phosphines 6 and 7a–d24 (entries 4–8) provided improved
isolated yields of desired indole 3a. Interestingly, most ef-
ficient catalysis was achieved with N-heterocyclic car-
bene precursors (entries 9–11), with sterically demanding
imidazolium salt 10 leading to optimal results (entry 11).
SYNLETT 2009, No. 8, pp 1219–1222
Advanced online publication: 17.04.2009
DOI: 10.1055/s-0029-1216727; Art ID: S02109ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
0
9
With a highly active catalytic system in hand, we probed
its scope in the synthesis of indoles bearing sterically
demanding N-substituents (Table 2).25,26 ortho-Alkynyl-

1220
L. Ackermann et al.
LETTER
Table 1 Evaluation of (Pre)Ligands in the Synthesis of Indole 3aa
Bu
Bu
Pd(OAc)2 (5 mol%)
(pre)ligand (5 mol%)
N
+
H2N
KOt-Bu, PhMe
105 °C, 12 h
Cl
1a
2a
3a
Entry
(Pre)Ligand
–
Yield (%)
1
2
3
4
–
4
5
6
–
dppf
–
BINAP
PCy3
(5)b
38
5
6
7
8
R1 = t-Bu, R2 = R3 = R4 = H
R1 = Cy, R2 = NMe2, R3 = R4 = H
R1 = Cy, R2 = R3 = OMe, R4 = H
R1 = Cy, R2 = R3 = R4 = i-Pr
7a
7b
7c
7d
30
51
59
45
P(R1)2
R3
R2
R4
Me
Me
N
Me
Cl
Me
9
8
9
(9)b
N
Me
Me
Me
Me
Me
Me
Cl
10
39
N
N
Me
Me
Me
Me
Me
Me
Me
Me
Cl
11
10
62
N
N
Me
Me
Me
Me
a Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), Pd(OAc)2 (5.0 mol%), (pre)ligand (5.0 mol%), KOt-Bu (1.5 mmol), PhMe (1.5 mL), 105
12 h; yields of isolated products.
b GC conversion.
chloroarenes 1 with both alkyl (Table 1, entry 11, and N-reverse prenyl group. Therefore, we explored the use of
Table 2, entry 6) or aryl substituents (Table 2, entries 1–5, amine 2d under the optimized reaction conditions for the
7, and 8) at the alkyne were converted regioselectively synthesis of this structural motif, and were pleased to ob-
with bulky (1-Ad)NH2 (2a). Importantly, a comparable serve the regioselective formation of indole 3l
efficacy was observed with sterically demanding amine (Scheme 2).
t-BuNH2 (2b, entry 9). Furthermore, the protocol was not
restricted to the use of more nucleophilic alkyl-substituted
amines, but enabled also the high-yielding synthesis of in-
Bu
Pd(OAc)2 (5 mol%)
10 (5 mol%)
dole 3k displaying a sterically encumbered N-aryl substit-
uent (entry 10).
Bu
+
H2N
Me
Me
KOt-Bu, PhMe
105 °C, 14 h
53%
N
Cl
A variety of naturally occurring indole derivatives feature
reverse prenyl substituents. For example, fungal natural
products asterriquinones20 exhibit valuable biological –
including antitumor – activities, and are decorated with an
Me
Me
1a
2d
3l
Scheme 2 Synthesis of indole 3l bearing an N-reverse prenyl group
Synlett 2009, No. 8, 1219–1222 © Thieme Stuttgart · New York

LETTER
Palladium-Catalyzed Synthesis of Indoles with Sterically Demanding N-Substituents
1221
Table 2 Scope of Palladium-Catalyzed Synthesis of Indoles with Sterically Hindered N-Substituentsa
R2
Pd(OAc)2 (5 mol%)
10 (5 mol%)
R1
R1
R2
H2N R3
+
KOt-Bu, PhMe
105–120 °C, 14 h
N
R3
Cl
1
3
2
Entry
1
R3
Temp (°C)
120
Product
Yield (%)
1-Ad
2a
Ph
3b
3c
3d
3e
3f
83
88
79
94
83
80
94
N
1-Ad
1-Ad
2a
n-Pr
OMe
F
2
3
4
5
6
7
120
120
120
120
105
120
N
1-Ad
1-Ad
2a
N
1-Ad
1-Ad
2a
N
1-Ad
1-Ad
2a
CF3
N
1-Ad
1-Ad
2a
3g
3h
N
1-Ad
1-Ad
2a
Ph
N
Me
1-Ad
MeO
1-Ad
2a
n-Pr
8
9
120
120
3i
3j
55
90
N
1-Ad
t-Bu
2b
Ph
N
Me
t-Bu
Ph
i-Pr
N
10
2,6-(i-Pr)2C6H3 2c
105
3k
94
i-Pr
a Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), Pd(OAc)2 (5.0 mol%), 10 (5.0 mol%), KOt-Bu (1.5 mmol), PhMe (1.5 mL), 14 h; yields of
isolated products.
In summary, we have reported on a modular synthesis of Acknowledgment
indoles bearing sterically hindered N-substituents. Thus, a
palladium-catalyzed sequence consisting of an intermo-
ged.
Support by the DFG, and Sanofi-Aventis is gratefully acknowled-
lecular N-arylation and an intramolecular hydroamination
enabled a regioselective N-annulation, which was found
to be applicable to the preparation of an N-reverse prenyl-
substituted indole as well.
Synlett 2009, No. 8, 1219–1222 © Thieme Stuttgart · New York

1222
L. Ackermann et al.
LETTER
(20) Arai, K.; Yamamoto, Y. Chem. Pharm. Bull. 1990, 38, 2929.
(21) N-Heterocyclic Carbenes in Synthesis; Nolan, S. P., Ed.;
Wiley-VCH: Weinheim, 2006.
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Ed.; Springer: Berlin, Heidelberg, New York, 2007.
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47, 6338.
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.
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2nd ed.; Wiley-VCH: Weinheim, 2003.
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Wesley Longman: Harlow, 1997.
(5) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.;
Blackwell Science: Oxford, 2000.
(25) Representative Procedure – Synthesis of 3a (Table 1,
Entry 11)
To a suspension of 2a (91.0 mg, 0.60 mmol), Pd(OAc)2 (5.6
mg, 0.025 mmol, 5.0 mol%), 10 (10.6 mg, 0.025 mmol, 5.0
mol%), and KOt-Bu (168.0 mg, 1.50 mmol) in dry toluene
(1.5 mL) was added 1a (96.0 mg, 0.50 mmol), and the
mixture was stirred for 12 h at 105 °C. After the reaction
mixture was cooled to ambient temperature, H2O (25 mL)
was added. The aqueous layer was extracted with Et2O
(3 × 30 mL), and the combined organic layers were dried
over Na2SO4 and concentrated in vacuo. The remaining
residue was purified by column chromatography on SiO2
(n-hexane) to yield 3a (95.0 mg, 62%) as a white solid (mp
143–145 °C). 1H NMR (300 MHz, CDCl3): d = 7.77 (d,
J = 8.1 Hz, 1 H), 7.51–7.48 (m, 1 H), 7.08–6.98 (m, 2 H),
6.29 (s, 1 H), 3.01 (t, J = 7.2 Hz, 2 H), 2.59 (d, J = 3.0 Hz,
6 H), 2.27 (s, 3 H), 1.81–1.68 (m, 8 H), 1.49–1.39 (m, 2 H),
0.98 (t, J = 7.2 Hz, 3 H). 13C NMR (125 MHz, APT, CDCl3):
d = 142.8 (Cq), 136.4 (Cq), 129.2 (Cq), 119.8 (CH), 119.3
(CH), 118.4 (CH), 115.2 (CH), 103.0 (CH), 61.0 (Cq), 42.3
(CH2), 36.4 (CH2), 33.2 (CH2), 32.0 (CH2), 30.3 (CH), 22.9
(CH2), 14.2 (CH3). IR (KBr): 3429, 2918, 2855, 2361, 2337,
1653, 1457, 777, 746, 731 cm–1. MS (EI): m/z (%) = 307 (22)
[M+], 265 (6), 135 (100), 107 (5). ESI-HRMS: m/z calcd for
C22H30N: 308.2373; found: 308.2374.
(6) Krüger, K.; Tillack, A.; Beller, M. Adv. Synth. Catal. 2008,
350, 2153.
(7) Ackermann, L. Synlett 2007, 507.
(8) Zeni, G.; Larock, R. C. Chem. Rev. 2004, 104, 2285.
(9) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2004, 104,
3079.
(10) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127.
(11) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873.
(12) Larock, R. C. J. Organomet. Chem. 1999, 576, 111.
(13) For selected recent examples of palladium-catalyzed
syntheses or functionalizations of indoles, see: (a) Verma,
A. K.; Kesharwani, T.; Singh, J.; Tandon, V.; Larock, R. C.
Angew. Chem. Int. Ed. 2009, 48, 1138. (b) Schwarz, N.;
Pews-Davtyan, A.; Michalik, D.; Tillack, A.; Krueger, K.;
Torrens, A.; Diaz, J. L.; Beller, M. Eur. J. Org. Chem. 2008,
5425. (c) Bryan, C. S.; Lautens, M. Org. Lett. 2008, 10,
4633. (d) Xu, Z.; Hu, W.; Zhang, F.; Li, Q.; Lu, Z.; Zhang,
L.; Jia, Y. Synthesis 2008, 3981. (e) Bellina, F.; Benelli, F.;
Rossi, R. J. Org. Chem. 2008, 73, 5529. (f) Liegault, B.;
Lee, D.; Huestis, M. P.; Stuart, D. R.; Fagnou, K. J. Org.
Chem. 2008, 73, 5022. (g) Yang, S.-D.; Sun, C.-L.; Fang,
Z.; Li, B.-J.; Li, Y.-Z.; Shi, Z.-J. Angew. Chem. Int. Ed.
2008, 47, 1473. (h) Maehara, A.; Tsurugi, H.; Satoh, T.;
Miura, M. Org. Lett. 2008, 10, 1159. (i) Stuart, D. R.;
Bertrand-Laperle, M.; Burgess, K. M. N.; Fagnou, K. J. Am.
Chem. Soc. 2008, 130, 16474. (j) Wuertz, S.; Rakshit, S.;
Neumann, J. J.; Droege, T.; Glorius, F. Angew. Chem. Int.
Ed. 2008, 47, 7230. (k) Jensen, T.; Pedersen, H.; Bang-
Andersen, B.; Madsen, R.; Jørgensen, M. Angew. Chem. Int.
Ed. 2008, 47, 888. (l) Ohno, H.; Ohta, Y.; Oishi, S.; Fujii, N.
Angew. Chem. Int. Ed. 2007, 46, 2295. (m) Cacchi, S.;
Fabrizi, G.; Goggiamani, A. Adv. Synth. Catal. 2006, 348,
1301. (n) Shimada, T.; Nakamura, I.; Yamamoto, Y. J. Am.
Chem. Soc. 2004, 126, 10546. (o) Siebeneicher, H.;
Bytschkov, I.; Doye, S. Angew. Chem. Int. Ed. 2003, 42,
3042. (p) Campo, M. A.; Huang, Y.; Yao, T.; Tian, Q.;
Larock, R. C. J. Am. Chem. Soc. 2003, 125, 11506; and
references cited therein.
(14) Willis, M. C.; Brace, G. N.; Holmes, I. P. Angew. Chem. Int.
Ed. 2005, 44, 403.
(15) Fletcher, A. J.; Bax, M. N.; Willis, M. C. Chem. Commun.
2007, 4764.
(16) Schirok, H. Synthesis 2008, 1404.
(17) Ackermann, L. Org. Lett. 2005, 7, 439.
(18) Kaspar, L. T.; Ackermann, L. Tetrahedron 2005, 61, 11311.
(19) For selected further indole syntheses from our laboratories,
see: (a) Ackermann, L.; Kaspar, L. T.; Gschrei, C. J. Chem.
Commun. 2004, 2824. (b) Ackermann, L.; Born, R.
Tetrahedron Lett. 2004, 45, 9541. (c) Ackermann, L.;
Althammer, A. Synlett 2006, 3125. (d) Ackermann, L.;
Sandmann, R.; Villar, A.; Kaspar, L. T. Tetrahedron 2008,
64, 769.
(26) Analytical Data
Indole 3j: mp 136 °C. 1H NMR (300 MHz, CDCl3):
d = 7.54–7.34 (m, 7 H), 6.98–6.95 (m, 1 H), 6.27 (s, 1 H),
2.54 (s, 3 H), 1.61 (s, 9 H). 13C NMR (75 MHz, APT,
CDCl3): d = 141.2 (Cq), 138.3 (Cq), 137.7 (Cq), 130.1
(2 × CH), 127.3 (CH), 126.8 (2 × Cq), 121.0 (CH), 120.1
(CH), 115.1 (CH), 106.0 (CH), 58.7 (Cq), 32.0 (CH3), 22.3
(CH3). IR (KBr): 3421, 3003, 2968, 2918, 2356, 1653, 1540,
1443, 1332, 1206, 1104, 1028, 814, 705, 607 cm–1. MS (EI):
m/z (%) = 263 (22) [M+], 235 (4), 220 (4), 207 (100), 178 (5),
152 (2). ESI-HRMS: m/z calcd for C19H21NNa: 286.1566;
found: 286.1567.
Indole 3l: 1H NMR (300 MHz, CDCl3): d = 7.67–7.61 (m, 1
H), 7.50–7.46 (m, 1 H), 7.04–6.99 (m, 2 H), 6.38–6.28 (m, 2
H), 5.16–5.10 (m, 2 H), 2.90 (t, J = 7.2 Hz, 2 H), 1.87–1.68
(m, 8 H), 1.49–1.39 (m, 2 H), 0.97 (t, J = 7.5 Hz, 3H). 13
C
NMR (75 MHz, APT, CDCl3): d = 147.4 (CH2), 143.2 (Cq),
137.3 (Cq), 128.9 (Cq), 119.8 (CH), 119.5 (CH), 118.8 (CH),
114.5 (CH), 111.4 (CH), 102.4 (CH), 62.0 (Cq), 32.2 (CH2),
30.8 (CH2), 29.5 (CH3), 22.8 (CH2), 14.0 (CH3). IR (KBr):
3048, 2959, 2932, 2872, 1456, 1379, 1291, 1265, 1184, 918,
778, 738, 704 cm–1. MS (EI): m/z (%) = 241 (60) [M+], 190
(9), 173 (29), 131 (100), 115 (2). ESI-HRMS: m/z calcd for
C17H24N: 242.1903; found: 242.1906.
Synlett 2009, No. 8, 1219–1222 © Thieme Stuttgart · New York

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