Synthesis of benzannulated N-heterocycles by a palladium-catalyzed C-C/C-N coupling of bromoalkylamines

Article abstract of DOI:10.1021/ol702472u

(Chemical Equation Presented) A palladium-catalyzed domino intermolecular alkylation/intramolecular amination of functionalized aryl iodides represents a new strategy for the synthesis of benzannulated N-heterocycles, affording functionalized indolines an

Full text of DOI:10.1021/ol702472u

ORGANIC
LETTERS
2007
Vol. 9, No. 25
5255-5258
Synthesis of Benzannulated
N-Heterocycles by a Palladium-Catalyzed
C−C/C−N Coupling of Bromoalkylamines
Praew Thansandote, Manuel Raemy, Alena Rudolph, and Mark Lautens*
DaVenport Research Laboratories, Department of Chemistry, UniVersity of Toronto,
80 St. George Street, Toronto, Ontario, Canada M5S 3H6
mlautens@chem.utoronto.ca
Received October 10, 2007
ABSTRACT
A palladium-catalyzed domino intermolecular alkylation/intramolecular amination of functionalized aryl iodides represents a new strategy for
the synthesis of benzannulated N-heterocycles, affording functionalized indolines and tetrahydroquinolines from simple precursors.
In our continuing efforts to discover novel approaches to
heterocycles, we have developed a method to synthesize
indolines by palladium-catalyzed sequential C-C and C-N
bond formations between bromoalkylamines and iodoarenes.
Indolines are a biologically active motif found in alkaloids1
and pharmaceuticals.2 Commonly synthesized by cyclization
of 2-substituted or N-substituted anilines through either
metal-catalyzed processes,3 non-metal-catalyzed processes,4
or radical means,5 numerous steps are often required either
to synthesize the starting precursors or the indoline itself.
Furthermore, few methods exist in which the functionality
on the benzenoid ring can be easily varied.6 Typically, either
C-C or C-N bond formation occurs in the key transforma-
tion, but to the best of our knowledge, there are no previously
reported strategies for indoline synthesis that accomplish both
C-C and C-N bond formations in one step.
We have shown that palladium-catalyzed ortho-alkylation-
based methodologies are compatible with a variety of
terminal bond-forming reactions. Each of these sequences
involves the formation of a new C-C7 or C-H8 bond;
however, the introduction of a new carbon-heteroatom bond
(1) For oxaline, see: (a) Steyn, P. S. Tetrahedron 1970, 26, 51. (b)
Sunazuka, T.; Shirahata, T.; Tsuchiya, S.; Hirose, T.; Mori, R.; Harigaya,
Y.; Kuwajima, I.; Ohmura, S. Org. Lett. 2005, 7, 941. For neoxaline, see:
(c) Hirano, A.; Iwai, Y.; Masuma, R.; Tei, K.; Ohmura, S. J. Antibiot. 1979,
32, 781. For mersicarpine, see: (d) Kam, T.-S.; Subramaniam, G.; Lim,
K.-H.; Choo, Y.-M. Tetrahedron Lett. 2004, 45, 5995. For anhydroly-
corinone, see: (e) Ghosal, S.; Rao, P. H.; Jaiswal, D. K.; Kumar, Y.; Frahm,
A. W. Phytochemistry 1981, 20, 2003. For oxoassoanine, see: (f) Llabres,
J. M.; Viladomat, F.; Bastida, J.; Codina, C.; Rubiralta, M. Phytochemistry
1986, 25, 2637.
(2) For 5-hydroxytryptamine receptor antagonists, see: (a) Bermudez,
J.; Dabbs, S.; Joiner, K. A.; King, F. D. J. Med. Chem. 1990, 33, 1929. For
muscarine receptor agonists and antagonists, see: (b) Adachi, S.; Koike,
K.; Takayanagi, I. Pharmacology 1996, 53, 250. For DPP-IV inhibitors,
see: (c) Sakashita, H.; Akahoshi, F.; Yoshida, T.; Kitajima, H.; Hayashi,
Y.; Ishii, S.; Takashina, Y.; Tsutsumiuchi, R.; Ono, S. Bioorg. Med. Chem.
2007, 15, 641.
(3) For examples, see: (a) Lira, R.; Wolfe, J. P. J. Am. Chem. Soc. 2004,
126, 13906. (b) Aoki, K.; Peat, A. J.; Buchwald, S. L. J. Am. Chem. Soc.
1998, 120, 3068. (c) Ganton, M. D.; Kerr, M. A. Org. Lett. 2005, 7, 4777.
(d) Yip, K.-T.; Yang, M.; Law, K.-L.; Zhu, N.-Y.; Yang, D. J. Am. Chem.
Soc. 2006, 128, 3130. (e) Liu, P.; Huang, L.; Lu, Y.; Dilmeghani, M.; Baum,
J.; Xiang, T.; Adams, J.; Tasker, A.; Larsen, R.; Faul, M. M. Tetrahedron
Lett. 2007, 48, 2307.
(4) For examples, see: (a) Bailey, W. F.; Luderer, M. R.; Mealy, M. J.
Tetrahedron Lett. 2003, 44, 5305. (b) Correa, A.; Tellitu, I.; Dom´ınguez,
E.; SanMartin, R. J. Org. Chem. 2006, 71, 8316.
(5) For examples, see: (a) Moutrille, C.; Zard, S. Z. Tetrahedron Lett.
2004, 45, 4631. (b) Leroi, C.; Bertin, D.; Dufils, P.-E.; Gigmes, D.; Marque,
S.; Tordo, P.; Couturier, J.-L.; Guerret, O.; Ciufolini, M. A. Org. Lett. 2003,
5, 4943.
(6) For the synthesis of indoles and indolines that are highly substituted
on the benzenoid ring, see: Dunetz, J. R.; Danheiser, R. L. J. Am. Chem.
Soc. 2005, 127, 5776.
(7) For selected examples with the Heck reaction, see: (a) Piguel, S.;
Lautens, M. Angew. Chem., Int. Ed. 2000, 39, 1045. (b) Pache, S.; Lautens,
M. Org. Lett. 2003, 5, 4827. (c) Rudolph, A.; Rackelmann, N.; Lautens,
M. Angew. Chem., Int. Ed. 2007, 46, 1485. With cyanation, see: (d)
Mariampillai, B.; Alberico, D.; Bidau, V.; Lautens, M. J. Am. Chem. Soc.
2006, 128, 14436. With direct arylation, see: (e) Bressy, C.; Alberico, D.;
Lautens, M. J. Am. Chem. Soc. 2005, 127, 13148. (f) Martins, A.; Alberico,
D.; Lautens, M. Org. Lett. 2006, 8, 4827.
10.1021/ol702472u CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/15/2007

is less studied.9 Herein we report our first example of a
carbon-nitrogen bond-forming reaction in this domino se-
quence.
To realize our goal of making highly substituted indolines,
we required bromoethylamines with a limited tendency to
form aziridines (Scheme 1). The nucleophilicity of the amine
increased the yield to 88% with respect to the limiting reagent
(entry 7), and decreasing the equivalents of base up to half
the original amount had minimal effect (entry 8). The Ph-
protected amine (1e) had similar reactivity under these
conditions (method B, Table 1) compared to method A (entry
9), but the CO2Et-protected substrate (1d) gave a lower yield
of desired product 2d (entry 10). Thus, the conditions used
in entry 8 were chosen as the optimized reaction conditions.
We then examined the scope of this reaction with a variety
of iodoarenes (Table 2). Well-tolerated functional groups at
Scheme 1. Our Strategy for the Synthesis of Substituted
Indolines
Table 2. Scope of Domino Alkylation/Amination Reaction
was suppressed by testing various nitrogen-protecting groups.
These substrates were subjected to ortho-alkylation condi-
tions with 2-iodotoluene (Table 1). Using method A, the Boc,
entry
R1
R2
R3
R4
1
2
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13a
14a
15
16
Me
Me
CF3
Cl
CH2OTBS
2,3-benzo
F
Me
Me
Cl
OMe
NO2
Me
2,3-benzo
Me
2,3-benzo
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
F
H
Cl
H
H
H
H
H
H
1f
1f
1f
1f
1f
1f
1f
1f
1f
1f
1f
1f
1d
1d
1e
1e
2f
86
24
53
54
30
62
40
64
80
50
0
Table 1. Optimization of Domino Alkylation/Amination
Reaction
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2d
2r
2e
2s
H
H
Cl
H
H
H
H
entry
R
methoda
product
yield (%)
1
2
3
4
5
6
7
8c
9
Boc (1a)
Bz (1b)
Ts (1c)
CO2Et (1d)
Ph (1e)
4-NO2C6H4 (1f)
4-NO2C6H4 (1f)
4-NO2C6H4 (1f)
Ph (1e)
A
A
A
A
A
A
B
B
B
B
s
s
s
s
0
s
s
45
43
62
46
2d
2e
2f
2f
2f
2e
2d
45
62
60
88
86
60
12
H
a Using method A in Table 1.
10
CO2Et (1d)
the 2-position of the arene include methyl, trifluoromethyl,
fluoro, chloro, and TBS-protected benzyl alcohol (entries
1-5, 7). In addition, 1-iodonaphthalene gave the benzoin-
doline 2k in 62% yield (entry 6). The reaction also tolerated
arenes containing a C-F bond (entries 7 and 8) or a C-Cl
bond (entries 4, 9, and 10). The latter substrates furnished
indolines with aryl-Cl bonds at the 2-, 3-, or 5-positions of
the benzenoid ring which are useful for post-modification.
Strongly electron-donating groups at the 2-position are not
tolerated under the optimized conditions (entry 11), increas-
ing the importance of these C-Cl bonds which can be
converted into electron-rich alcohols, amines, and thiols in
one step.10 Using bromoethylamines 1d and 1e (entries 13-
16), higher temperatures and larger amounts of base were
required for appreciable product yields. Only iodoarenes
containing ortho-substituents have been investigated thus far,
although we do have precedence for using external alkyl
halides in palladium-catalyzed ortho, ortho′ substitution
reactions.11
a Method A: iodoarene (1 equiv), bromoethylamine (2 equiv), Pd(OAc)2
(10 mol %), tri(2-furyl)phosphine (22 mol %), norbornene (2 equiv), Cs2CO3
(8 equiv), acetonitrile (0.1 M), microwave 180 °C for 5 min. Method B:
iodoarene (2 equiv), bromoethylamine (1 equiv), Pd(OAc)2 (10 mol %),
tri(2-furyl)phosphine (22 mol %), norbornene (2 equiv), Cs2CO3 (8 equiv),
acetonitrile (0.1 M), 135 °C for 20 h. b With 1 equiv of iodoarene and 2
equiv of bromoalkylamine. c With 4 equiv of Cs2CO3.
Bz, and Ts groups led exclusively to decomposition or
aziridination products (entries 1-3). However, moderate
yields of the indoline were obtained with the ethyl carbamate
(CO2Et), phenyl (Ph), and 4-nitrophenyl (4-NO2C6H4) groups
(entries 4-6), and these were explored further. Switching
to method B for the 4-NO2C6H4-protected amine (1f)
(8) (a) Wilhelm, T.; Lautens, M. Org. Lett. 2005, 7, 4053. (b) Mitsudo,
K.; Thansandote, P.; Wilhelm, T.; Mariampillai, B.; Lautens, M. Org. Lett.
2006, 8, 3939.
(9) Catellani has reported a domino ortho-arylation/amidation reaction:
Ferraccioli, R.; Carenzi, D.; Rombola`, O.; Catellani, M. Org. Lett. 2004, 6,
4759.
5256
Org. Lett., Vol. 9, No. 25, 2007

While 2-nitroiodobenzene failed to give product (entry 12),
3-nitro-2-methyliodobenzene produced the indole (3a) in
70% yield (Scheme 2). Though the Pd-catalyzed dehydro-
Scheme 3. Example of the Use of Secondary Alkyl Halides
Scheme 2. Synthesis of Indoles
pylamine (1h) was the optimal substrate for this process,17
reacting with 2-iodotoluene and 1-iodonaphthalene to give
tetrahydroquinolines 5a and 5b in 54 and 66% yields,
respectively (Scheme 4).
genation of indolines to indoles is known,12 we do not
observe indole formation with any of the other iodoarenes
tested. We are currently investigating the possibility that
another mechanism might be operating that is substrate-
dependent. However, we have shown that this process is
protecting-group dependent; phenyl-protected substrate 1e
also gave indole 3b in 53% yield, while CO2Et substrate 1d
gave only indoline in 20% yield.
Scheme 4. Synthesis of Tetrahydroquinolines
We next investigated the use of secondary bromoalky-
lamines to furnish 3-methylindolines. Although secondary
alkyl halides decrease the rate of oxidative addition,13 we
hoped that, more importantly, aziridination would be dis-
couraged. We have reported that secondary alkyl halides
participate in an intramolecular palladium-catalyzed annu-
lation reaction.7c However, there is limited information on
the intermolecular process.14 Compared with the primary
alkyl halides, optimization studies revealed that changing the
solvent to DMF and the ligand to tri(p-tolyl)phosphine
increased the product yield. Thus, N-(2-bromopropyl)-4-
nitrobenzenamine (1g) coupled with 2-iodotoluene in DMF
at 135 °C in the presence of Pd(OAc)2, tri(p-tolyl)phosphine,
norbornene, and Cs2CO3 to give 3-methylindoline 4a in 55%
isolated yield (Scheme 3).15
A proposed mechanism for the synthesis of indoline 2 is
shown in Scheme 5. Pd(0) inserts into the aryl-iodide bond
Scheme 5. Proposed Mechanism
We also extended the methodology to N-protected bro-
mopropylamines to produce tetrahydroquinolines, another
common alkaloid scaffold.16 Previous approaches to this
heterocycle largely focused on insertion reactions, ring
expansions, and ring contractions.15 Phenyl-protected pro-
(10) For the coupling of ammonia and LiNH2 with aryl halides, see: (a)
Shen, Q.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 10028. For the
coupling of aryl halides with KOH, see: (b) Anderson, K. W.; Ikawa, T.;
Tundel, R. E.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 10694. For
the coupling of silyl-protected arenethiols with aryl halides, see: (c) Kreis,
M.; Bra¨se, S. AdV. Synth. Catal. 2005, 47, 313.
(11) For examples, see: (a) Ref 7b. (b) Jafarpour, F.; Lautens, M. Org.
Lett. 2006, 8, 3601. (c) Martins, A.; Marquardt, U.; Kasravi, N.; Alberico,
D.; Lautens, M. J. Org. Chem. 2006, 71, 4837.
(12) For examples, see: (a) Moores, A.; Poyatas, M.; Luo, Y.; Crabtree,
R. H. New J. Chem. 2006, 30, 1675. (b) Beller, M.; Breindl, C.; Riermeier,
T. H.; Tillack, A. J. Org. Chem. 2001, 66, 1403. (c) Hara, T.; Mori, K.;
Mizugaki, T.; Ebitani, K.; Kaneda, K. Tetrahedron Lett. 2003, 44, 6207.
(13) Hills, I. D.; Netherton, M. R.; Fu, G. C. Angew. Chem., Int. Ed.
2003, 42, 5749.
(14) Catellani reported that isopropyl iodide could be used in the ortho-
alkylation/vinylation reaction with 31% conversion using a large excess of
the halide: Catellani, M.; Cugini, F. Tetrahedron 1999, 55, 6595.
(15) Preliminary results show that reaction with 3-nitro-2-methyliodo-
benzene produces the indole in 27% unoptimized yield.
of the iodoarene, followed by carbopalladation of norbornene
to give 6a. C-H activation of the 2-position of the arene
forms palladacycle 6b. Oxidative addition of the bromoet-
hylamine leads to the Pd(IV) species 6c,18 and reductive
elimination generates ortho-alkylated product 6d. Extrusion
Org. Lett., Vol. 9, No. 25, 2007
5257

of norbornene due to steric congestion gives aryl-Pd(II)
complex 6e. Last, an intramolecular Buchwald-Hartwig
reaction with 6e yields product 2.
mopropylamines can be used to yield tetrahydroquinolines.
Broadening of the reaction scope and improving the condi-
tions for bromoalkylamines with removal N-protecting
groups is currently under investigation and will be reported
in due course.
In summary, we have tuned the reactivity of the amine
moiety in various bromoethylamines to allow these substrates
to participate in a novel palladium-catalyzed domino ortho-
alkylation/aromatic amination with substituted iodoarenes or
1-iodonaphthalene. The resulting highly functionalized in-
dolines or benzoindolines are formed in moderate to good
yields. In some cases, in situ formation of the indole was
possible and proceeded in good yields. Using a N-protected
bromoethylamine with a secondary alkyl bromide success-
fully produces 3-methylindoline, while N-protected bro-
Acknowledgment. We gratefully acknowledge the fi-
nancial support of the University of Toronto, the Natural
Sciences and Engineering Research Council of Canada
(NSERC), and Merck Frosst Canada for an IRC. We also
thank Dr. Alan Lough (University of Toronto) for X-ray
structure determination. A.R. and P.T. thank NSERC for
Canada Graduate Scholarships. M.R. thanks the Swiss
National Science Foundation for funding.
(16) For virantmycin, see: (a) Ohmura, S.; Nakagawa, A.; Hashimoto,
H.; Oiwa, R.; Iwai, Y.; Hirano, A.; Shibukawa, N.; Kojima, Y. J. Antibiot.
1980, 33, 1395. For isoschizogaline, see: (b) Kariba, R. M.; Houghton, P.
J.; Yenesew, A. J. Nat. Prod. 2002, 65, 566. (c) Katritzky, A. R.; Rachwal,
S.; Rachwal, B. Tetrahedron 1996, 52, 15031.
(17) Reaction with 4-NO2C6H4-protected amine gave 24 and 35% of a
and b, respectively, and CO2Et-protected amine gave no products.
(18) Based on the mechanistic proposal of Catellani and co-workers, see
ref 13 and references therein.
Supporting Information Available: Experimental pro-
cedures and characterization data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL702472U
5258
Org. Lett., Vol. 9, No. 25, 2007