N-Trialkylsilylimines as Coupling Partners for Pd-Catalyzed C-N Bond-Forming Reactions: One-Step Synthesis of Imines and Azadienes from Aryl and Alkenyl Bromides

Article abstract of DOI:10.1002/anie.200352808

A good substitute: Imines, 1-azadienes, 2-azadienes, and even 2-azatrienes are prepared in one step from aryl and alkenyl bromides by palladium-catalyzed cross-coupling with N-trimethylsilylimines. The reaction introduces N-trimethylsilylimines as a synthetic equivalent for the R-CH=N moiety in C-N bond-forming reactions.

Full text of DOI:10.1002/anie.200352808

Angewandte
Chemie
with aryl and heteroaryl halides and sulfonates,[2] and also
with alkenyl halides.[3] With regard to the nitrogen coupling
partner, most NH functional groups can participate in this
=
coupling reaction, including C N-containing species such as
benzophenone imine,[4] and sulfoximines.[5] However, despite
the intense development of this reaction in the recent years,
the direct preparation of N-substituted aldimines by a cross-
coupling protocol has not been described yet, probably as a
result of the instability of the required NH aldimines.
Nevertheless, the one-step transformation of bromides into
aldimines is a very interesting reaction indeed, as imines are
very versatile starting materials in synthetic organic chemis-
try, and especially in heterocyclic chemistry. Moreover,
aldimines can be hydrolyzed under very mild conditions,
therefore the direct synthesis of imines might be a new
alternative for the introduction of the -NH2 group.[6]
Herein we describe the one-step synthesis of aldimines
and of 1- and 2-azadienes from aryl and alkenyl bromides and
introduce the readily available N-trialkylsilyl imines as
surrogates for the unstable NH-aldimines in palladium-
À
catalyzed C N bond-forming reactions.
The palladium-catalyzed aryl amination involves three
fundamental steps[7] (Scheme 1, left): 1) oxidative addition of
the aryl halide to a Pd0 complex to form aryl–palladium–
halide complex I; 2) transformation of I into amido complex
Cross-Coupling
N-Trialkylsilylimines as Coupling Partners for
À
Pd-Catalyzed C N Bond-Forming Reactions:
One-Step Synthesis of Imines and Azadienes from
Aryl and Alkenyl Bromides**
Scheme 1. Left: Simplified mechanism of the palladium-catalyzed aryl
amination. Right: Proposed mechanism for a cross-coupling reaction
involving an N-trialkylsilyl imine.
JosØ Barluenga,* Fernando Aznar, and Carlos ValdØs
À
II (this step requires the presence of a base to cleave the N H
The palladium-catalyzed amination of aryl halides, known as
the Buchwald–Hartwig reaction, has become a widely
employed method in recent years for the synthesis of aryl
bond); 3) reductive elimination to form the aryl amine III and
to regenerate the Pd0 catalyst. A similar catalytic cycle could
be proposed by replacing the amine with an N-trialkylsilyl
imine IV (Scheme 1, right). In such a case, a proper
amines.[1] The broad scope of this C N bond-forming reaction
À
allows its application with a variety of both reactants, the
halide and the nitrogen source. In fact, very efficient catalytic
combinations have been uncovered for the coupling of amines
nucleophilic additive is required to promote the cleavage of
the N Si bond and to form the imido complex V. We
decided to explore this possibility, which would lead directly
to aldimines VI from aryl or alkenyl bromides.
[8]
À
In an initial set of experiments, we studied the reaction of
m-bromoanisole (1a) with the N-trimethylsilylimine 2a[9]
(Scheme 2) and chose the Pd0–binap catalytic system. The
reactions were carried out in toluene at 908C with Pd
(1 mol%) in the presence of different additives. Only the
formation of the cross-coupling imine 3a was observed,
although with low conversion (35%), in the reaction carried
out in the presence of NaOtBu. Other basic reagents such as
NaOMe and triethylamine furnished unaltered starting
[*] Prof. Dr. J. Barluenga, Prof. Dr. F. Aznar, Dr. C. ValdØs
Inst. Universitario de Química Organometµlica “Enrique Moles”
Universidad de Oviedo, 33071 Oviedo (Spain)
Fax: (+34)985-10345
E-mail: barluenga@sauron.quimica.uniovi.es
[**] This research was supported by the DGI (Grant BQU-2001-3853)
and the FYCYT (Grant PR-01-GE-09).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2004, 43, 343 –345
DOI: 10.1002/anie.200352808
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Scheme 2. Influence of the ligand in the coupling of N-trimethylsilyl-
benzaldimine (2a) with 3-bromoanisole (1a) in the presence of
[Pd2(dba)3]. Reaction conditions: 1a (1 equiv), 2a (1.1 equiv), NaOtBu
(1.4 equiv), [Pd2(dba)3] (1 mol%), ligand (2 mol%), toluene (2 mL/
mmol), 908C, 14 h. dba=dibenzylideneacetone, binap=2,2’-bis(diphe-
nylphosphanyl)-1,1’-binaphthyl, xantphos=9,9-dimethyl-4,5-bis-(diphe-
nylphosphanyl)xanthene, dppf=1,1’-bis(diphenylphosphanyl)ferrocene.
[a] Yield of isolated 3a when 4a and 4b were used are indicated in
parentheses.
Scheme 3. Influence of the ligand on the ratio of reductive elimination
vs b-elimination.
quantitative yields and tolerates electron-donating and
-withdrawing groups and some heterocyclic motifs (Table 1,
entries 7–9) in both coupling partners. Interestingly, the same
reaction allows the synthesis of aldimines 3, 1-azadienes 7, 2-
azadienes 8, and even azatrienes 9, depending on the structure
of the coupling partners.
The reaction with vinyl bromides (Table 1, entries 12–14),
which constitutes a novel synthesis of electronically neutral 2-
azadienes 8 and 2-azatriene 9, which are very versatile
reagents in heterocycloaddition reactions.[15] In this case, the
use of ligand 4a is preferred (method B), as no b-elimination
products were formed. Owing to the higher activity of this
catalytic system, complete conversions are possible in much
shorter times and with lower catalyst loadings.
materials. No reaction was observed either with CsF in
toluene (probably as a result of solubility problems),[10] and
phase-transfer catalysts such as methyltribenzylamonium
chloride and tetrabutylammonium fluoride resulted in the
decomposition of the silylimine with no coupling product
being formed.[11]
The same reaction in the presence of NaOtBu was then
studied with a set of different ligands. Only with biphenyl
ligands 4a and 4b was complete conversion achieved
(Scheme 2).[12] However, the yield of pure distilled material
did not exceed 52%.
In a different series of experiments with the 4-bromobi-
phenyl 1b and silylimine 2b (Scheme 3), it was observed that
the reaction with ligands 4a and 4b provided a mixture of
coupling product 3b, 4-methoxy-
In summary, we have introduced N-trialkylsilylimines 2 as
very efficient synthetic equivalents of the unstable and
benzonitrile 5, and biphenyl 6 in a
nearly 1:1:1 ratio. This result could
Table 1: Coupling of silylimines 2 with aryl and alkenyl halides 1.
be explained by a competing cata-
lytic cycle in which b-elimination in
complex V would release nitrile 5
and generate hydride complex VII.
Finally, reductive elimination would
give rise to the dehalogenated aro-
matic hydrocarbon 6 and regener-
ate the palladium catalyst.[13,14]
Apparently, with biphenyls 4 as
ligands, both reaction pathways
occur to a similar extent. Never-
theless, by using binap and increas-
ing the catalyst loading from 1 to
4 mol%, complete conversions
were possible, and interestingly,
less than 5% b-elimination was
observed.
Entry
R1
R2
Product
Method[a]
t [h][b]
Yield [%][c]
1
2
3
4
5
6
7
8
m-MeOPh
p-ClPh
m-CNPh
o-EtPh
m-CNPh
o-EtPh
3-Py
o-EtPh
p-CF3Ph
p-ClPh
m-MeOPh
Ph-CH CH-
p-MeOPh
p-MeOPh
p-MeOPh
p-MeOPh
p-ClPh
p-ClPh
p-ClPh
2-Furyl
2-Furyl
Ph-CH CH-
Ph-CH CH-
p-ClPh
p-MeOPh
3c
3d
3e
3 f
3g
3h
3i
A
A
A
A
A
A
A
A
A
A
A
B
B
B
14
14
20
14
14
14
20
14
14
14
20
2
97
86
79
95
76
96
86
92
90
95
86
92
90
93
3j
9
3k
7a
7b
8a
8b
9
=
=
10
11
12
13
14
=
=
=
Ph-CH CH-
Ph-CH CH-
3
3
=
Ph-CH CH-
The reaction was generalized to
a range of aryl bromides and silyli-
mines. As represented in Table 1,
[a] Method A: 1 (1 equiv), 2 (1.2 equiv), NaOtBu (1.4 equiv), [Pd2(dba)3] (4 mol%), BINAP (8 mol%),
toluene (2 mL/mmol), 908C. Method B: 1 (1 equiv), 2 (1.2 equiv), NaOtBu (1.4 equiv), [Pd2(dba)3]
(2 mol%), 4a (4 mol%), toluene (2 mL/mmol), 908C. [b] Reaction times were not optimized. [c] Yields
the coupling proceeds with good to of isolated product on a 0.5-mmol scale.
344
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Chemie
considerable amounts of decomposition materials derived from
the imine.
[11]These results indicate that strong nucleophiles tend to promote
unavailable NH aldimines in palladium-catalyzed cross-
coupling reactions. The coupling with aryl bromides allows
the one-step synthesis of aldimines, and the reaction with
vinyl bromides gives rise to neutral 2-azadienes with excellent
yields. Given the easy availability of structurally diverse and
functionalized N-trialkylsilyl imines[9,16] and the good yields of
the coupling reaction, we believe that this transformation may
be very useful in heterocyclic chemistry and diversity-
oriented organic synthesis. Moreover, these results open the
door for the incorporation of N-trialkylsilyl imines in other
types of metal-catalyzed cross-coupling processes.
À
the N Si bond cleavage at a much faster rate than the catalytic
process itself, giving rise to decomposition of the imine instead of
coupling-product formation.
[12]D. W. Old, J. P. Wolfe, S. L. Buchwald, J. Am. Chem. Soc. 1998,
120, 9722.
[13]The inhibition of the b-elimination pathway was a major
challenge in the early work of palladium-catalyzed aryl amina-
tion. In fact, catalysts based on chelating ligands such as binap
and dppf, so-called second-generation catalysts, favor reductive
elimination, thus lowering the amount of b-elimination prod-
ucts: a) J. P. Wolfe, S. Wagaw, S. L. Buchwald, J. Am. Chem. Soc.
1996, 118, 7215 – 7216; b) M. S. Driver, J. F. Hartwig, J. Am.
Chem. Soc. 1996, 118, 7217 – 7218; see also: c) P. W. N. M.
van Leeuwen, P. C. J. Kamer, J. N. H. Reek, P. Dierkes, Chem.
Rev. 2000, 100, 2741 – 2769.
[14]The b-elimination pathway in the presence of a Pd catalyst based
on 4b was recently adapted into a new method for the oxidation
of alcohols: A. S. Guram, X. Bei, H. W. Turner, Org. Lett. 2003,
5, 2485 – 2487.
[15]a) For a review of the synthetic applications of azadienes, see: S.
Jayakumar, M. P. S. Ishar, M. P. Mahajan, Tetrahedron 2002, 58,
379 – 471; see also: b) F. Palacios, C. Alonso, P. Amezua, G.
Rubiales, J. Org. Chem. 2002, 67, 1941 – 1946.
Received: September 8, 2003 [Z52808]
Keywords: amination · azadienes · cross-coupling · imines ·
.
palladium
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[16]G. Cainelli, D. Giacomini, P. Galletti, A. Gaiba, Synlett, 1996,
657.
[2]For representative examples of very efficient catalysts in
À
palladium-catalyzed C N bond forming reactions, see: a) D. W.
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À
[8]The palladium-catalyzed C C bond formation involving organo-
silanes (Hiyama coupling) is a well-known reaction: T. Hiyama
in Metal-catalyzed Cross-coupling Reactions (Eds: F. Diederich,
P. J. Stang), Wiley-VCH, New York, 1998, chap. 10; however, to
À
the best of our knowledge, the analogous C N bond-forming
reaction has not been described previously.
[9]E. W. Colvin, D. McGarry, M. J. Nugent, Tetrahedron 1988, 44,
4157 – 4172.
[10]Reactions carried out in the presence of CsF in dioxane as
solvent gave rise to the cross-coupling product together with
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