Efficient nickel-mediated intramolecular amination of aryl chlorides

Article abstract of DOI:10.1021/ol034659w

(Matrix presented) The use of an in situ generated Ni(0) catalyst associated with 2,2′-bipyridine or N,N′ -bis(2,6-diisopropylphenyl)dihydroimidazol-2-ylidene (SIPr) as a ligand and NaO-t-Bu as the base for the intramolecular coupling of aryl chlorides with amines is described. The procedure has been applied to the formation of five-, six-, and seven-membered rings.

Full text of DOI:10.1021/ol034659w

ORGANIC
LETTERS
2003
Vol. 5, No. 13
2311-2314
Efficient Nickel-Mediated Intramolecular
Amination of Aryl Chlorides
Rafik Omar-Amrani, Antoine Thomas, Eric Brenner, Raphae1l Schneider,* and
Yves Fort*
Synthe`se Organome´tallique et Re´actiVite´, UMR CNRS UHP 7565,
UniVersite´ Henri Poincare´, Nancy I, BP 239,
54506 VandoeuVre les Nancy Cedex, France
yVes.fort@sor.uhp-nancy.fr
Received April 18, 2003
ABSTRACT
The use of an in situ generated Ni(0) catalyst associated with 2,2′-bipyridine or N,N′-bis(2,6-diisopropylphenyl)dihydroimidazol-2-ylidene (SIPr)
as a ligand and NaO-t-Bu as the base for the intramolecular coupling of aryl chlorides with amines is described. The procedure has been
applied to the formation of five-, six-, and seven-membered rings.
As a result of the important pharmacological activity of
nitrogen heterocycles, general and efficient methods for their
preparation are continually being developed. Among them,
transition-metal-promoted processes have gained in popular-
ity in recent years.1
One significant area of improvement is that of metal-
catalyzed cross-coupling methods. Palladium-catalyzed ami-
nation, first introduced by Buchwald and Hartwig, has proven
to be a valuable synthetic method for aryl carbon-nitrogen
bond formation and has been intensively examined for the
preparation of a wide range of arylamines.2 This method has
gained popularity as a mild alternative for the synthesis of
amino derivatives, inaccessible through other routes.
extensions for the synthesis of N-aryl-indazoles12 and benz-
imidazoles13 have also been reported.
Despite significant improvements in the cyclization of aryl
bromides with secondary amines and carbamates with bis-
phosphines such as DPEphos (bis(2-diphenylphosphino-
phenyl)ether) or Xantphos (9,9-dimethyl-4,5-bis(diphenyl-
phosphino)xanthene) or with the monophosphine MOP
ligand (2-(diphenylphosphino)-2′-methoxy-1,1′-binaphthyl),8
no optimization study has been undertaken with aryl
(3) Wolfe, J. P.; Rennels, R. A.; Buchwald, S. L. Tetrahedron 1996, 52,
7525-7546.
(4) Peat, A. J.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 1028-
1030.
(5) Wagaw, S.; Rennels, R. A.; Buchwald, S. L. J. Am. Chem. Soc. 1997,
119, 8451-8458.
An intramolecular variant of this reaction has first been
utilized to construct indoline, tetrahydroquinoline, benz-
azepine, oxindole, and carboline derivatives.3-11 A few
(6) He, F.; Foxman, B. M.; Snider, B. B. J. Am. Chem. Soc. 1998, 120,
6417-6418.
(7) Abouabdellah, A.; Dodd, R. H. Tetrahedron Lett. 1998, 39, 2119-
2122.
(1) Li, J. J.; Gribble, G. W. Palladium in Heterocyclic Chemistry: A
Guide for the Synthetic Chemist; Pergamon: Amsterdam, 2000.
(8) Yang, B. H.; Buchwald, S. L. Org. Lett. 1999, 1, 35-37.
(9) Watanabe, M.; Yamamoto, T.; Nishiyama, M. Angew. Chem., Int.
Ed. 2000, 39, 2501-2504.
(2) Reviews: (a) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald,
S. L. Acc. Chem. Res. 1998, 31, 805-818. (b) Hartwig, J. F. Angew. Chem.,
Int. Ed. 1998, 37, 2046-2067. (c) Yang, B. H.; Buchwald, S. L. J.
Organomet. Chem. 1999, 576, 125-146. (d) Muci, A. R.; Buchwald, S. L.
Practical Palladium Catalysts for C-N and C-O Bond Formation. In Cross-
Coupling Reaction: A Practical Guide: Miyaura, N., Ed.; Topics in Current
Chemistry Ser. 219; Springer-Verlag: New York, 2002; pp 131-209.
(10) Brown, J. A. Tetrahedron Lett. 2000, 41, 1623-1626.
(11) Margolis, B. J.; Swidorski, J. J.; Rogers, B. N. J. Org. Chem. 2003,
68, 644-647.
(12) (a) Song, J. J.; Yee, N. K. Org. Lett. 2000, 2, 519-521. (b) Song,
J. J.; Yee, N. K. Tetrahedron Lett. 2001, 42, 2937-2940.
(13) Evindar, G.; Batey, R. A. Org. Lett. 2003, 5, 133-136.
10.1021/ol034659w CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/31/2003

chlorides with pendant simple amines. Moreover, the high
cost of palladium invites less expensive alternatives.
We initially reported the use of 2,2′-bipyridine (bpy)-bound
Ni(0) clusters, generated in situ by reduction of a nickel(II)
salt with alkoxide-activated sodium hydride, to mediate the
coupling of aryl chlorides with secondary cyclic and acyclic
amines.14 The use of a Pd(0)/N-heterocyclic carbene15 (NHC)
catalyst system for the amination of aryl chlorides was first
described by Hartwig16 and Nolan.17 Following up on this
work, we have recently reported the use of a Ni(0) catalyst
associated with a strong electron-donating and sterically
hindered NHC (N,N′-bis(2,6-diisopropylphenyl)dihydro-
imidazol-2-ylidene, SIPr) to allow mild amination of aryl
chlorides with several classes of amines.18 Motivated by the
extension of this method and by increased understanding of
Ni-catalyzed amination reactions, we report herein an
alternative synthesis of nitrogen heterocycles from aryl
chlorides with pendant amino groups by intramolecular
Ni(0)-catalyzed N-arylation reactions.
Figure 1. NHC precursors used for the nickel-catalyzed amination
reaction.
% Ni in dioxane, whereas with bpy as ligand, reactions
required 5 mol % Ni and better results were obtained in THF
compared to dioxane. During our optimization efforts, the
influence of the nickel/ligand ratio was also investigated. We
have found that with SIPr as supporting ligand, a 1:1 nickel-
ligand ratio afforded optimum reaction rates, whereas with
bpy, a 1:3 nickel-ligand ratio was found to be the most
effective. We have subsequently verified in control experi-
ments containing all of the reagents, except Ni(0) and ligand,
that without catalyst, only traces amounts of indoline were
obtained (entries 13 and 14).
Using SIMes or SITol as ligand gave poor results. Even
with 10 mol % Ni, the reaction reached only 13% and 9%
yield, respectively (Table 1, entries 9 and 10), showing that
SIPr is a much better ligand for this Ni-catalyzed C-N bond-
forming reaction and that the steric hindrance of the ligand
is responsible for the improved catalytic performances. The
use of phen (Table 1, entry 11) led to complex mixtures
where 53% of the starting material, 43% dechlorinated
N-benzyl-N-(2-chlorophenethyl)amine, and only 4% N-
benzylindoline were observed. A catalyst based on the dppf
ligand also possesses lower activity than Ni/SIPr or Ni/bpy
for intramolecular Ni-catalyzed C-N bond forming reactions
(Table 1, entry 12).
The cyclization of N-benzyl-N-(2-chlorophenethyl)amine
into N-benzylindoline was first studied to establish the most
effective conditions (Table 1).
Table 1. Optimization of Conditionsa
entry mol % Ni conditions ligand
solvent
yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
10
10
5
2
10
5
B
B
B
B
A
A
A
A
B
B
B
B
A
B
SIPr
SIPr
SIPr
SIPr
bpy
bpy
bpy
bpy
THF
77
97
94
95
84
84
52
47
13
9
dioxane
dioxane
dioxane
THF
THF
THF
The intramolecular aryl amination was applied to various
aryl chlorides using the two sets of optimized conditions,
method A for Ni/bpy (Table 1, entry 6) and method B for
Ni/SIPr (Table 1, entry 4) catalysis. Note that method A is
not effective for the arylation of primary amines.18b
Treatment of amino aryl chlorides with a nickel catalyst
and a base in THF for Ni/bpy catalyst or 1,4-dioxane for
2
2
dioxane
10
10
10
10
-
SIMes dioxane
SITol
phen
dppf
bpy
dioxane
dioxane
dioxane
THF
4
55
8
(14) (a) Brenner, E.; Fort, Y. Tetrahedron Lett. 1998, 39, 5359-5362.
(b) Brenner, E.; Schneider, R.; Fort, Y. Tetrahedron 1999, 55, 12829-
12842. (c) Desmarets, C.; Schneider, R.; Fort, Y. Tetrahedron Lett. 2000,
41, 2875-2879. (d) Brenner, E.; Schneider, R.; Fort, Y. Tetrahedron Lett.
2000, 41, 2881-2884. (e) Desmarets, C.; Schneider, R.; Fort, Y. Tetra-
hedron Lett. 2001, 42, 247-250. (f) Desmarets, C.; Schneider, R.; Fort, Y.
Tetrahedron 2001, 57, 7657-7664. (g) Brenner, E.; Schneider, R.; Fort,
Y. Tetrahedron 2002, 58, 6913-6924. (h) Desmarets, C.; Schneider, R.;
Fort, Y.; Walcarius, A. J. Chem. Soc., Perkin Trans. 2 2002, 1844-1849.
(15) Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1290-1309.
(16) Stauffer, S. R.; Lee, S.; Stambuli, J. P.; Hauck, S. I.; Hartwig, J.
F. Org. Lett. 2000, 2, 1423-1426.
-
SIPr
dioxane
9
a Reaction conditions A: 10.0 mmol of N-benzyl-N-(2-chlorophenetyl)-
amine, L/Ni ) 3/1, 1.0 mmol of NaO-t-Bu, 9.5 mmol of NaH, 0.5 mmol
of styrene, 15 mL of solvent, reflux, 5 h. Reaction conditions B: 10 mmol
of N-benzyl-N-(2-chlorophenethyl)amine, L/Ni ) 1/1, 15 mmol of NaO-
t-Bu, 15 mL of solvent, reflux, 5 h. b Isolated yield; average of two runs.
(17) For recent reports, see: (a) Viciu, M. S.; Kelly, R. A., III; Stevens,
E. D.; Naud, F.; Studer, M.; Nolan, S. P. Org. Lett. 2003, 5, 1479-1482.
(b) Viciu, M. S.; Kissling, R. M.; Stevens, E. D.; Nolan, S. P. Org. Lett.
2002, 4, 2229-2231. (c) Grasa, G. A.; Viciu, M. S.; Huang, J.; Nolan, S.
P. J. Org. Chem. 2001, 66, 7729-7737.
Besides SIPr and bpy (which were typically used in our
previous reports of intermolecular arylation of amines), other
NHCs, 1,10-phenanthroline (phen), and dppf (1,1′-bis-
(diphenylphosphino)ferrocene) used by Buchwald19 and
Lipshutz20 in aryl aminations catalyzed by Ni(cod)2 were
tested as ligands. With SIPr or bpy as ligand, the reaction
went smoothly to completion without any formation of
undesired byproducts (Table 1, entries 4 and 6). With the
Ni/SIPr catalyst, reactions were best performed with 2 mol
(18) (a) Gradel, B.; Brenner, E.; Schneider, R.; Fort, Y. Tetrahedron
Lett. 2001, 42, 5689-5692. (b) Desmarets, C.; Schneider, R.; Fort, Y. J.
Org. Chem. 2002, 67, 3029-3036.
(19) Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 6054-
6058.
(20) (a) Lipshutz, B. H.; Ueda, H. Angew. Chem., Int. Ed. 2000, 39,
4492-4494. (b) Lipshutz, B. H.; Tasler, S.; Chrisman, W.; Spliethoff, B.;
Tesche, B. J. Org. Chem. 2003, 68, 1177-1189. (c) Tasler, S.; Lipshutz,
B. H. J. Org. Chem. 2003, 68, 1190-1199.
2312
Org. Lett., Vol. 5, No. 13, 2003

Ni/SIPr catalyst promoted the cyclization into the corre-
sponding heterocycles (Table 2). At reflux temperature, the
(11-17 h) (the conversion being incomplete even after
heating for 24 h) and gave slightly lower yields (entries 11-
15).
A series of ether-linked substrates, shown in Table 3, were
next subjected to these cross-coupling conditions to explore
the reaction scope further.
Table 2. Ni(0)-Catalyzed Intramolecular N-Arylationa
Table 3. Ni(0)-Catalyzed Synthesis of Benzoxazines and
Benzoxazepinesa
a Reactions conditions A: 10.0 mmol of amino aryl chloride, 5 mol %
Ni(0), 15 mol % bpy, 1 mmol of NaO-t-Bu, 9.5 mmol of NaH, 5 mol %
styrene, THF (15 mL), 65 °C. Reactions conditions B: 10 mmol of amino
aryl chloride, 2 mol % Ni(0), 2 mol % SIPr, 15.0 mmol of NaO-t-Bu,
dioxane (15 mL), 100 °C. b Isolated yields of pure material. c No conversion
of the starting material.
a
Reactions conditions A: 10.0 mmol of amino aryl chloride, 5 mol %
Ni(0), 15 mol % bpy, 1 mmol of NaO-t-Bu, 9.5 mmol of NaH, 5 mol %
styrene, THF (15 mL), 65 °C. Reactions conditions B: 10 mmol of amino
aryl chloride, 2 mol % Ni(0), 2 mol % SIPr, 15.0 mmol of NaO-t-Bu,
dioxane (15 mL), 100 °C. b Isolated yields. d Isolated as a 9:1 mixture with
the corresponding indole.
Examples 1-4 of Table 3 clearly indicate that the
cyclization into benzoxazines worked under conditions A and
B but provided the oxygenated heterocycles in decreased
yields compared to their carbon analogues. These results are
not surprising and follow the electronic trends expected for
these electron-rich aryl chlorides. Finally, the synthesis of
benzoxazepines (entries 5-10, Table 3) could be achieved
with the Ni/bpy catalyst, but the presence of an ortho oxygen
completely inhibited the Ni/SIPr-catalyzed cyclizations. The
superiority of bpy relative to SIPr for the preparation of
seven-membered benzoxazine rings might result from a
coordination of the SIPr-bound nickel center at the oxygen
atom of the starting 3-(2-chlorophenoxy)-1-propanamine, as
previously observed with o-chloro- or fluoroanisoles in
synthesis of indolines (entries 1-5) and tetrahydroquinolines
(entries 6-10) proceeded quickly (3-9 h) and in excellent
yields. It is worth noting that indolines (entries 1-5) were
isolated as 90:10 mixtures with side products identified as
the corresponding indoles, arising from a classical oxidation,
which were separable by column chromatography. Dehalo-
genation of the starting aryl chloride was only a minor side
reaction (<1%) and no side products were isolated from any
of the other intramolecular aryl amination.
The reaction gave better results in the formation of five-
and six-membered rings. The cyclization into 2,3,4,5-
tetrahydro-1H-1-benzazepines required longer reaction times
amination18b
and defluorination21 reactions mediated by our
Ni(0)/NHC complexes. This coordination seems not to take
Org. Lett., Vol. 5, No. 13, 2003
2313

place in the putative Ni(II) oxidative addition complex
yielding benzoxazines (entries 2 and 4, Table 3).
The application of our Ni-catalyzed cyclization protocols
to couplings involving secondary cyclic amines was also
briefly explored. The synthesis of benzo[e]indolizidine
(Scheme 1) under Pd-catalysis was first explored by Buch-
Scheme 2. Ni-Catalyzed Synthesis of
5,6-Dihydroindolo[2,1-a]isoquinoline
Scheme 1. Ni-Catalyzed Synthesis of Benzo[e]indolizidine
wald, and the reported conditions did not efficiently provide
access to the desired ring system (Pd(PPh3)4 (10 mol %),
NaO-t-Bu, toluene, 100 °C, 55%).3
We applied the conditions described in Table 2 to this
intramolecular cycloamination and were pleased to find out
that both Ni catalysts were quite equally effective and
allowed the transformation in good yields and short reaction
times.
We finally evaluated the efficiency of our Ni(0) catalysts
for the synthesis of indolo[2,1-a]isoquinoline. Recent studies
have demonstrated that nucleophilic addition of the iso-
quinoline nitrogen to an aryl bromide is the more general
route to the desired tetracyclic structure, but the reaction
required rather harsh conditions and long reaction times
(K2CO3, DMF, reflux, 2-3 days).22
ficiently within 7 h (Scheme 2). The 5,6,12,12a-tetrahy-
droindolo[2,1-a]isoquinoline could, however, not be char-
acterized because of its instability and was converted to the
corresponding 5,6-dihydro[2,1-a]isoquinoline by treatment
with HCO2NH4 in the presence of Pd/C.23
In summary, we report alternative methods for intra-
molecular coupling of aryl chlorides with amines using Ni/
bpy or Ni/SIPr catalysts. The complexes show good catalytic
activity for the synthesis of indoles, quinolines, benzazepines,
benzoxazines, and benzoxazepines. We have also disclosed
promising results in the Ni-catalyzed intramolecular arylation
of cyclic amines. Work is currently underway to optimize
and extend the scope of these Ni-catalyzed aminations.
Supporting Information Available: Experimental details
and characterization of all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
Under Ni catalysis, the cyclization of the readily accessible
1-(2-chlorobenzyl)tetrahydroisoquinoline22a proceeded ef-
(21) Kuhl, S.; Schneider, R.; Fort, Y. AdV. Synth. Catal. 2003, 345,
341-344.
(22) (a) Orito, K.; Miyazawa, M.; Kanbayashi, R.; Tokuda, M.;
Sugimone, H. J. Org. Chem. 1999, 64, 6583-6596. (b) Orito, K.; Harada,
R.; Uchiito, S.; Tokuda, M. Org. Lett. 2000, 2, 1799-1801.
OL034659W
(23) Kiguchi, T.; Kuninobu, N.; Yukiyo, Y.; Naito, T.; Ninomiya, I.
Synthesis 1989, 778-781.
2314
Org. Lett., Vol. 5, No. 13, 2003