Sp3 C-H bond activation with ruthenium(II) catalysts and C(3)-alkylation of cyclic amines

Article abstract of DOI:10.1021/ja203875d

A selective C(3)-alkylation via activation/functionalization of sp ³ C-H bond of saturated cyclic amines was promoted by (arene)ruthenium(II) complexes featuring a bidentate phosphino-sulfonate ligand upon reaction with aldehydes. This highly regioselective sustainable transformation takes place via initial dehydrogenation of cyclic amines and hydrogen autotransfer processes.

Full text of DOI:10.1021/ja203875d

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sp3 CÀH Bond Activation with Ruthenium(II) Catalysts and C(3)-
Alkylation of Cyclic Amines
Basker Sundararaju,† Mathieu Achard,† Gangavaram V. M. Sharma,‡ and Christian Bruneau*,†
†UMR6226 CNRS - Universitꢀe de Rennes, Sciences chimiques de Rennes, Catalyse et Organomꢀetalliques, Campus de Beaulieu,
35042 Rennes Cedex, France
‡Organic Chemistry Division III, D 211, Discovery Laboratory, Indian Institute of Chemical Technology (CSIR), Hyderabad 500 007, India
S Supporting Information
b
Scheme 1. Functionalization of Cyclic Amines Involving
Hydrogen Transfer Processes
ABSTRACT: A selective C(3)-alkylation via activation/
functionalization of sp3 CÀH bond of saturated cyclic
amines was promoted by (arene)ruthenium(II) complexes
featuring a bidentate phosphino-sulfonate ligand upon
reaction with aldehydes. This highly regioselective sustain-
able transformation takes place via initial dehydrogenation
of cyclic amines and hydrogen autotransfer processes.
C(3)-Alkylation of N-benzylpyrrolidine 1a with benzaldehyde
2a to give the corresponding alkylated product 3a was first
attempted as a model reaction with various ruthenium precata-
lysts (Table 1).
Two equivalents of 1a and one equivalent of 2a were heated at
140 °C in the presence of 2 mol % of various ruthenium pre-
catalysts. Ruthenium(II) and ruthenium(0) complexes such as
[RuCl2(p-cymene)]2, [RuCl2(COD)]n, [Ru3(CO)12], were found
to be rather ineffective affording low yields in 3a (entries 1À4).
However, these results showed that amine 3a was produced as
major compound along with small amount of enamine and
pyrrole as side products 4a, demonstrating that hydrogen
transfer occurred.
As already observed in alkylation with alcohols involving
ruthenium-catalyzed hydrogen transfer,13,14 addition of a catalytic
amount of acid (camphor sulfonic acid (CSA)) improved the
conversion (entry 2). We further evaluated well-known efficient
transfer hydrogenation ruthenium catalysts. Whereas Shvo
catalyst15 and [RuCl2(p-cymene)]2 associated to dppf16 revealed
poor activity (entries 5, 6), neutral arene ruthenium(II) pre-
catalysts (A, B)14 exhibited interesting reactivities (entries 7À8).
Dicationic C17 afforded good results only in the presence of tert-
butylphenylphosphinosulfonate ligand (entry 9). Especially,
complexes A and B containing a phosphinesulfonate ligand
(Figure 1) afforded the best conversions (entries 7, 8) with a
3a/4a ratio highly in favor of the saturated amine 3a. Comparing
entries 8 and 11, the positive effect of CSA as additive was
confirmed. Under the conditions of entry 11, other acids such as
acetic acid and PTSA afforded lower yields of 72 and 66%,
respectively. In the absence of ruthenium, CSA alone did not
catalyze the transformation. Comparing entries 12 and 13
demonstrated that 1a was also acting as hydrogen source, and
the best result in terms of selectivity was obtained with 2 mol % of
the ruthenium(II) complex B in the presence of 6 mol % of CSA
onsidering the importance of cyclic amines and alkaloids in
C
industry as dyes and as pharmaceutical and agrochemical
drugs, straightforward and eco-friendly preparation of these
compounds still represents a challenging task for chemists.1,2
The functionalization of cyclic amines with direct formation of
carbonÀcarbon bond requires an assisted sp3 CÀH bond
activation that is still a real challenge.3 Several functionalization
at the C(2) position of cyclic aliphatic amines have been reported
involving either activation of the HÀC(2) bond via formal
oxidative addition to a transition metal,4 or oxidation by various
types of oxidant into iminium intermediates followed by reaction
with a nucleophile.5,6 C(3)-functionalized cyclic amines repre-
sent an important class of biologically active compounds,7 but as
the HÀC(3) bond of unfunctionalized cyclic amines is inert,
their preparation requires multistep syntheses.8 Indeed, functio-
nalization of cyclic aliphatic amines at C(3) is scarce, and to
the best of our knowledge only one example of C(3)-alkylation
based on platinum-catalyzed oxidation of cyclic amines in the
presence of oxygen followed by Michael addition and leading to
C(3)-substituted enamines has been reported.9 One approach
to perform HÀC(3) functionalization involves as the first
step the in situ generation of reactive enamines via sp3 CÀH
activation and dehydrogenation as already shown in the presence
of iridium10 and cobalt catalysts.11 Whereas ruthenium catalysts
are well-known for hydrogen transfer from alcohols,12 they have
not been used for dehydrogenation of cyclic amines except for
alkylation of anilines.13 We have thus investigated the possibility
of performing a sequence of catalytic reactions from cyclic
amines with ruthenium catalysts based on hydrogen transfers
according to Scheme 1.
We now report that ruthenium catalysts are able to perform
regioselective alkylation at the C(3) position of N-protected
cyclic aliphatic amines via sequential dehydrogenation under
nonoxidative conditions, CÀC bond formation, and final transfer
hydrogenation to produce C(3)-alkylated cyclic amines.
Received: February 4, 2011
Published: June 14, 2011
r
2011 American Chemical Society
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Table 1. C(3)-Functionalization of Pyrrolidine with
Benzaldehydea
Scheme 2. Regioselective Alkylation of N-Substituted
Morpholine
entry
precatalyst
CSAb 3a/4ac conv.d yielde, f
1
[RuCl2(p-cymene)]2
À
10
10
10
10
10
À
À
À
10
10
6
67/32
71/29
70/30
94/6
53
86
81
53
82
90
97
98
99
99
99
99
99
22
28
2
[RuCl2(p-cymene)]2
3
[RuCl2(COD)]n
27
result also demonstrated that the presence of the N-protecting
benzyl group is not essential to achieve this process. On the other
hand, no alkylation product was formed when N-phenylmorpho-
line was reacted with benzaldehyde 2a. This observed reactivity is
in favor of a mechanism involving initial formation of an exocyclic
iminium ion.19
4
Ru3(CO)12
23
5
6g
Shvo’s cat.
78/21
75/25
90/10
85/15
89/11
89/11
88/12
86/13
91/9
10
[Ru(p-cymene)Cl2]2 + dppf
39
7
A
69
8
B
62
Ch
A
B
84(70)
58
The scope of the C(3)-alkylation reaction, starting from
various aldehydes and tertiary cyclic amines has been examined
(Table 2). N-Benzylpyrrolidine 1a was smoothly converted to
the desired products with various aromatic aldehydes with up to
81% isolated yield (entries 1À3). No direct electronic effects of
the substituents on the aromatic aldehydes were observed, as
indifferently aldehydes bearing electron-withdrawing or electron-
releasing groups were successfully engaged in this reaction.
Similar results were obtained with N-benzylpiperidine 1c, afford-
ing alkylated products in 72À82% yield (entries 4À9). Interest-
ingly, a large azacycle such as azepane 1d was found to be suitable
for this methodology, and amine 3l was obtained in 70% yield
(entry 10). Then, the reaction was performed with N-alkylated
tetrahydroisoquinoline (THIQ) derivatives 1e and 1f. In both
cases, aromatic aldehydes reacted smoothly in favor of the C(3)-
alkylated product (entry 11).
9
10
11
12i
13j
77
B
85(70)
B
6
89(82)
a Reactions were carried out at 0.125 M concentration with 1a/2a/
precatalyst in 2.0/1/0.02 molar ratio under an inert atmosphere using a
thermostatted oil bath at 140 °C. b Amount of acid (mol %). c Ratio of
3a/4a determined by GC analysis. d Conversion based on GC analysis
with respect to 2a (tetradecane as internal standard). e Yield of 3a deter-
f
mined by GC analysis with respect to 2a. Number in parentheses is
isolated yield of 3a. g Reaction performed with [Ru(p-cymene)Cl2]2 and
dppf in a 0.01/0.02 molar ratio. h C = [Ru(p-cymene)(CH3CN)2-
(PPh3)][BF4]2 and tert-butylphenylphosphino sulfonic acid in a 0.05/
0.07 molar ratio at 0.5 M concentration. i 36 h reaction time. j Reaction
performed with 1a/2a in a 4/1 molar ratio.
The structure of 3m was unequivocally elucidated by single-
crystal X-ray diffraction study (Figure 2). More importantly, the
reaction was not limited to aromatic aldehydes, and aliphatic alde-
hydes such as hexanal and butanal provided good yields (entries
13, 14, and 16). Noteworthy, the heterocyclic aldehyde 2g con-
taining a furan moiety was compatible with the catalytic system
affording amine 3n and 3q in 78 and 88% yield, respectively
(entries 12 and 15). It is notable that under these alkylation con-
ditions, halogen functionalities remained intact, thus offering opp-
ortunities for further valuable functionalization (entries 2, 7, 8).
Since cyclic amines contain two possible sites for C(3)-alkyla-
tion, we undertook the challenging dialkylation starting from N-
methylpiperidine 1g. Notably, in the presence of 2.5 equiv of
benzaldehyde 2a, the N,C,C-trialkylated amine 3s was isolated in
55% yield after purification (Scheme 3). It should be noted that
employing aliphatic aldehydes with N-substituted piperidine led
to the competitive formation of mono- and dialkylated products
even starting from an equimolar amine/aldehyde ratio.
The formation of compounds 3 can be rationalized according
to Figure 3. In the presence of ruthenium catalyst amine can be
converted to the corresponding iminium I via hydrogen transfer
that affords, after hydrogen abstraction, ruthenium hydride
species along with azomethine ylides II.19 The geminal dehy-
drogenation of amine by ruthenium(II) species leading to a cyclic
carbene,20 potential precursor of enamine, cannot be excluded.
The presence of acid might then facilitate the isomerization of
this intermediate to enamine III.19 Further condensation of the
Figure 1. Arene ruthenium(II) containing phosphino sulfonate.
and a 4-fold excess of amine 1a, which afforded 82% of 3a after
purification (entry 13). With these conditions in hands, we
further evaluated the regioselectivity of this transformation.
Substrate 1b contains three competitive sites for C(3)-alkylation,
two on the morpholine ring and one exocyclic site. Interestingly,
during the reaction of 1b with benzaldehyde, C(3)-alkylation
only occurred at the ring position, and 3b was formed in 80% GC
yield. However, during the reaction, a substantial amount of
unsaturated intermediates (about 15%) was detected. To com-
pletely eliminate the presence of these intermediates without
using a large excess of amine, additional stirring in the presence of
formic acid as hydrogen donor allowed complete reduction of
enamine via a concomitant hydrogen autotransfer/transfer18 and
led to the formation of 3b in 70% isolated yield (Scheme 2). This
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COMMUNICATION
Table 2. C(3)-Alkylation of Tertiary Amines with Aldehydesa
Figure 2. Structure of compound 3m.
Scheme 3. C(3)-Dialkylation of N-Methylpiperidine
a Reactions were carried out at 0.125 M concentration with 1/2/B/CSA
in 1.2/1.0/0.02/0.1 molar ratio under an inert atmosphere using a
thermostatted oil bath at 140 °C; after 16 h, 1.5 molar ratio of formic acid
was added and stirred for an additional hour. b Isolated yield. c Average
isolated yield based on two runs.
Figure 3. Proposed mechanism.
aldehyde 2 and acid-promoted dehydration would afford the
unsaturated iminium V, which could be readily reduced by
ruthenium hydride species arising from amine or formic acid as
hydrogen donor.21
In conclusion, selective C(3)-alkylation of tertiary cyclic
amines involving activation of sp3 CÀH bond via hydrogen
transfer was efficiently catalyzed by ruthenium complex B. The
reaction described here appears general and efficient. From a
synthetic point of view, it complements the other catalytic
methods used for C(2)-functionalization of cyclic amines. This
new catalytic reaction makes possible the selective introduction
of a variety of substituents arising from aldehydes at the C(3)
position. Further studies to extend this methodology and effort
to establish the detailed mechanism are in progress.
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’ AUTHOR INFORMATION
Corresponding Author
christian.bruneau@univ-rennes1.fr
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for a grant to B.S.
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