Highly efficient ruthenium(II) porphyrin catalyzed amidation of aldehydes

Article abstract of DOI:10.1002/anie.200704695

H to N: The first example of a mild, highly efficient C-H bond amidation catalyzed by ruthenium(II) porphyrin complexes uses PhI=NTs as the nitrogen source for installing the amide bond functionality in a wide variety of aldehydes (see scheme). The protocol is chemoselective, with the new C-N bond forming only at the acyl C-H bond, even in aldehyde substrates containing other functional groups.

Full text of DOI:10.1002/anie.200704695

Communications
DOI: 10.1002/anie.200704695
Amide Bond Formation
Highly Efficient Ruthenium(II) Porphyrin Catalyzed Amidation of
Aldehydes**
Joyce Wei Wei Chang and Philip Wai Hong Chan*
The installation of the amide bond functionality is of immense
interest in organic synthesis owing to the prevalence of this
structural motif in a myriad of compounds of biological,
pharmaceutical, and materials interest.[1] Conventional routes
to this ubiquitous class of nitrogen-containing compounds
have relied heavily upon the coupling of activated carboxylic
acid and amine precursors.[2] Although these methodologies
have been shown to be exceptionally efficient for the
synthesis of small peptides, many classes of amides, including
Scheme 1. Ruthenium porphyrin catalyzed amidation ofaldehydes.
Ts =toluene-4-sulfonyl.
those found in many natural products, bioconjugates, and
pharmaceutical targets, along with the lability of the activated
carboxylic acid derivatives, pose significant challenges. In
view of these shortcomings, alternative amide bond formation
strategies have been actively pursued.[3–5] One such strategy is
noteworthy that the acylsulfonamides obtained herein are
themselves a class of biologically active compounds of current
therapeutic interest.[11] Acylsulfonamides 3–5 (Scheme 2), for
example, have been reported to exhibit potent HCV NS5B
polymerase allosteric inhibitor activity,[11a] anti-inflammatory
activity,[11b] and antitumor activity,[11d] respectively.
À
the direct reaction of the acyl C H bond of aldehydes with
amines in the presence of a transition-metal catalyst under
oxidative conditions.[5] According to the seminal reports by
the groups of Li,[5a] Beller,[5b] and others,[5c,d] these catalytic
systems are thought to involve the formation of a carbinol-
amine intermediate that undergoes metal-catalyzed oxidation
to furnish the amide product. However, catalytic systems that
can effect amide bond formation for a wide range of
aldehydes through nitrogen atom insertion have remained
sparse. In this context, and attracted by recent reports by Che
and co-workers showing ruthenium(II) porphyrins to be
À
=
efficient catalysts in C H bond amidation reactions with PhI
NTs as the nitrogen source,[6,7] we envisioned that a “Ru +
=
PhI NTs” strategy could hold promise as the basis for a new
approach to amide-bond synthesis. Herein, we report the first
chemoselective ruthenium(II) porphyrin catalyzed amidation
Scheme 2. Examples ofbioactive compounds containing the acyl-
sulfonamide moiety.
=
of a wide range of aldehydes with PhI NTs as the nitrogen
source; these reactions proceed with product yields up to
99% (Scheme 1). While insertions of a putative reactive
3
À
metal–nitrene/imido species into C(sp ) H bonds of alka-
At the outset of this study, we focused our attention on
developing a catalytic system that would effect amide bond
formation regardless of the aliphatic or aromatic nature of the
aldehyde starting material. With this aim in mind, we
examined the amidation of isovaleraldehyde 1a as a model
substrate to establish the reaction conditions (Table 1). We
nes[6–8] and, more recently, C(sp ) H bonds of benzene[9] and
2
À
heteroarenes[10] have been extensively examined, to our
knowledge the analogous nitrogen-atom transfer reactions
to the acyl C(sp ) H bond of aldehydes is not known. It also
2
À
=
found that treating one equivalent of 1a with PhI NTs
[*] J. W. W. Chang, Prof. Dr. P. W. H. Chan
Division ofChemistry and Biological Chemistry
School ofPhysical and Mathematical Sciences
Nanyang Technological University
Singapore 637371 (Singapore)
(2equiv) and 10 mol% [Ru(TTP)(CO)] [12] as catalyst in
CH2Cl2 at room temperature for 30 minutes gave the best
result, furnishing 3-methyl-N-tosylbutanamide 2a as the sole
product in 94% yield (Table 1, entry 1). Under these con-
ditions, no byproduct that could be attributed to amidation at
the tertiary carbon center of 1a was detected. As shown in
entries 2–5 in Table 1, a comparable yield of 93% was
Fax: (+65)6791-1961
E-mail: waihong@ntu.edu.sg
[**] This work is supported by a University Research Committee Grant
(RG55/06) and Supplementary Equipment Purchase Grant (RG134/
06) from Nanyang Technological University.
=
obtained on increasing the amount of PhI NTs to four
equivalents, but slightly lower product yields (76–82%) were
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
=
afforded on decreasing PhI NTs to one equivalent or catalyst
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Table 1: Optimization ofreaction conditions. [a]
Table 2: [Ru(TTP)(CO)]-catalyzed amidation of 1a–1t.[a]
Entry
Aldehyde
Product
Yield
[%][b]
1
2
3
4
5
2a, R=iBu
2b, R=iPr
2c, R=Et
2d, R=nHex
2e, R=tBu
94
86
97
97
60
=
Entry
Equiv PhI NTs
Catalyst
Yield [%][b]
1a–e
1
2
3
2
4
1
4
4
2
2
[Ru(TTP)(CO)]
[Ru(TTP)(CO)]
[Ru(TTP)(CO)]
[Ru(TTP)(CO)]
[Ru(TTP)(CO)]
[Rh2(OAc)4]
94
93
82
76
80
31
58
24
4[c]
5[d]
6
6
7
8
2 f, n=1
2g, n=3
2h, n=4
91
99
97
1 f–h
1i–k
7
8
[Ru(F20-TPP)(CO)]
[Ru(TTP)(CO)]
[e]
–
9
10
11
2i, n=1, R=Ph
2j, n=2, R=Ph
2k, n=4, R=Br
86
68
96
[a] Unless otherwise stated, all reactions were carried out in CH2Cl2
(2 mL) with molar ratio catalyst/1a=1:10 at room temperature for 0.5 h.
[b] Yield ofisolated product. [c] Reaction conducted with 1 mol%
catalyst. [d] Reaction conducted with 5 mol% catalyst. [e] Reaction
12
13
2l, R1 =nPr, R2 =H 99
1l–m
2m, R1 =R2 =Me
91
=
conducted with PhI(OAc)2 and p-TsNH2 in place ofPhI NTs with
molar ratio 1a/PhI(OAc)2/p-TsNH2 =1:1.25:1.5 at room temperature for
24 h.
14
1n
2n
99
=
15
16
17
2o, X=H
2p, X=Me
2q, X=OMe
93
92
96
loadings to 1 or 5 mol% using four equivalents of PhI NTs.
In contrast, the analogous reactions with [Ru(F20-
TPP)(CO)][12] or [Rh2(OAc)4] as catalyst gave 2a in markedly
lower yields (Table 1, entries 6–7).
1o–q
To define the scope of the [Ru(TTP)(CO)]-catalyzed
amidation reactions, we applied this process to a series of
aliphatic and aromatic aldehydes 1b–t (entries 2–20 in
Table 2). These reactions afforded the corresponding acylsul-
fonamides 2b–t in good to excellent yields (60–99%).
Notably, for reactions of substrates also containing a tertiary
18
1r
2r
68
19
20
2s, X=S
2t, X=O
76
93
1s,t
À
carbon center, C N bond formation was found to occur
chemoselectively at the aldehyde functional group, which is
consistent with our earlier findings for the amidation of 1a
(Table 2, entries 1, 2, and 6–8). Furthermore, in instances
[a] All reactions were carried out at room temperature for 30 min with
molar ratio [Ru(TTP)(CO)]/1/PhI NTs=1:10:20. [b] Yield ofisolated
product.
=
À
where it was envisioned that the presence of a benzylic C H
=
or C C bond or an alkyl bromide functionality would lead to
competitive side reactions, the corresponding adducts were
furnished as the sole products in good to excellent yields
(Table 2, entries 9–14). On the other hand, steric effects of the
aliphatic aldehyde could play a role, since a substrate
containing the bulky tBu group provided amide 2e in
moderate yield (Table 2, entry 5).
The [Ru(TTP)(CO)]-catalyzed amidation of a variety of
aromatic aldehydes 1o–t was also found to proceed well, with
the corresponding aryl-substituted acylsulfonamides 2o–t
afforded in good to excellent yields (entries 15–20 in
Table 2). Interestingly, aldehydes with a pendant heteroarene
functionality (Table 2, entries 19–20) were also efficiently
amidated, which is noteworthy as these are common struc-
tural motifs in a myriad of bioactive natural and pharma-
ceutical compounds.[1]
1H NMR spectroscopy and verified by mass spectrometry of
the crude mixture (see the Supporting Information for
details). This finding led us to speculate tentatively that the
present ruthenium-catalyzed aldehyde amidation reaction
À
proceeds by C H bond functionalization (Scheme 3). In a
manner similar to that proposed by the groups of Che,
Du Bois, Sanford, and others,[13] the high-oxidation-state
metal complex [Ru(TTP)(NTs)2] 6 is thought to initially
[14]
=
form from reaction of [Ru(TTP)(CO)] with PhI NTs. As
shown in Scheme 3, subsequent transfer of the imido/nitrene
group from this newly formed intermediate by either direct
insertion or by H-atom abstraction/radical rebound (route a
or b, respectively) is thought to give the amide product 2.
In summary, we have developed a highly efficient
ruthenium(II)-catalyzed strategy for the direct amidation of
=
To gain insight into the possible mechanism of the present
reaction, we conducted a deuterium-labeling experiment.
Treating a CH2Cl2 solution of a-[D]-benzaldehyde with
aldehydes using PhI NTs as a nitrogen source. The method
was shown to be applicable to a wide range of aldehydes. It is
high-yielding and chemoselective, with amidation only occur-
=
À
10 mol% [Ru(TTP)(CO)] catalyst and PhI NTs as the
ring at the acyl C H bond of the starting aldehyde. Further
nitrogen source at room temperature for 1 h gave N,N-[D]-
tosylbenzamide in 90% yield and with a deuterium content of
76% incorporated at the nitrogen atom, as determined by
investigations are underway to examine the scope, mecha-
nism, and applications of this reaction and will be reported in
due course.
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Communications
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Note: Structures 2o–q, Table 2, corrected since publication in
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À
Keywords: aldehydes · amide bond formation · C H activation ·
homogeneous catalysis · ruthenium
.
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[12] a) H2(TTP) = meso-tetrakis(p-tolyl)porphyrin;
TPP) = meso-tetrakis(pentafluorophenyl)porphyrin.
b) H2(F20-
[13] A similar mechanism has been proposed for the analogous
3
À
metal-mediated amidations of C(sp ) H bonds, see referen-
ces [6–8].
[14] For spectroscopic evidence for the formation of bis-
(imido)ruthenium(VI) complexes, see reference [7].
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