Practical Catalytic Cleavage of C(sp3)?C(sp3) Bonds in Amines

Article abstract of DOI:10.1002/anie.201903019

The selective cleavage of thermodynamically stable C(sp³)?C(sp³) single bonds is rare compared to their ubiquitous formation. Herein, we describe a general methodology for such transformations using homogeneous copper-based catalysts in the presence of air. The utility of this novel methodology is demonstrated for C_α?C_β bond scission in >70 amines with excellent functional group tolerance. This transformation establishes tertiary amines as a general synthon for amides and provides valuable possibilities for their scalable functionalization in, for example, natural products and bioactive molecules.

Full text of DOI:10.1002/anie.201903019

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Accepted Article
Title: Practical Catalytic Cleavage of C(sp³)–C(sp³) Bonds in Amines
Authors: Wu Li, Weiping Liu, David Leonard, Jabor Rabeah, Kathrin
Junge, Angelika Brückner, and Matthias Beller
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201903019
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10.1002/anie.201903019
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COMMUNICATION
Practical Catalytic Cleavage of C(sp3)–C(sp3) Bonds in Amines
Wu Li, Weiping Liu, David K. Leonard, Jabor Rabeah, Kathrin Junge, Angelika Brückner, and Matthias
Beller*
herein, we communicate a general copper-catalyzed selective
cleavage of C(sp3)–C(sp3) single bonds within amines using
simply air (Fig. 1e).
Abstract: The selective cleavage of thermodynamically stable
C(sp3)–C(sp3) single bonds is rare compared to their ubiquitous
formation. Herein, we describe a general methodology for such
transformations using homogeneous copper-based catalysts in the
presence of air. The utility of this novel methodology is demonstrated
for Cα-Cβ bond scission in >70 amines with excellent functional
group tolerance. This transformation establishes tertiary amines as a
general synthon for amides and provides valuable possibilities for
their scalable functionalization including natural products and
bioactive molecules.
(1) State-of-the-art oxidative transformations of tertiary amines.
Carbon-carbon single bonds are arguably one of the least
reactive “functional” groups in chemistry and biology.[1] While in
the past decades, the site selective activation of C-H bonds
attracted widespread interest,[2] related transformations of C-C
bonds are rare in the context of synthetic chemistry.[3] Obviously,
nonpolar C-C σ-bonds are both thermodynamically stable and
lesser accessible,[4] which makes the selective cleavage of them
to one of the most challenging reactions in chemistry.[5]
Contrary, in biology several types of such transformations
catalyzed by metalloenzymes are known.[6] Interestingly, in the
active site of most of these enzymes (dioxygenases) iron or
copper metal ions are found,[7] which productively use both
dioxygen atoms in the metabolism of steroids (cholesterol),[8]
amino acids (tryptophan)[9] as well as xenobiotics.[10] Notably, in
synthetic chemistry the oxidative cleavage of C-C σ-bonds is
only achieved using (over)stoichiometric amounts of hazardous
oxidants such as O3,[11] NaIO4, H5IO6, Pb(OAc)4, and KMnO4,
which resulted often in poor functional group tolerance. Very
recently, it has been demonstrated that these latter limitations
can be overcome by so-called deconstructive functionalizations
using AgNO3 and ammonium persulfate as final oxidants.[12]
From a green and practical perspective still there is substantial
need in selective methodologies, which make use of more
benign oxidants. In this respect, air is the ideal reagent in terms
of price and waste generation.[13]
The oxidation of amines plays a vital role in nature from both
transformative and mechanistic aspects.[14] The main currently
known transformations are summarized in Fig. 1. Most
prominent is the preparation of amine oxides using different
oxidants such as hydrogen peroxide (Fig. 1a). In addition, N-
dealkylation processes are known to be catalyzed by oxidases
to yield the corresponding secondary amines (Fig. 1b).[15] Much
less explored is the synthesis of enamines from amines in the
presence of stoichiometric amounts of mercuric(II) acetate as
shown in Figure 1c.[16] Finally, the preparation of amides by α-C-
H oxidation has been reported to some extent (Fig. 1d).[17]
Complementary to all the known transformations vide supra,
(2) This work:
Figure 1. Oxidative transformation of tertiary amines. (a) N-Oxidation to
amine oxides. (b) N-dealkylation (c) Oxidative dehydrogenation. (d) C-H
oxidation. (e) Selective cleavage of C(sp3)–C(sp3) bonds in tertiary amines.
We commenced this work, studying the C-H oxidation of
industrially relevant tri-n-butylamine as a benchmark system
using a broad range of metal salts, ligands, oxidants, and
solvents. Surprisingly, employing copper salts under pressure of
air resulted in the cleavage of C-C bonds leading to
dibutylformamide 3b.[18] After optimization we obtained product
3b in 90% yield with very high selectivity using 5 mol% of CuCl,
2 equiv. pyridine at 30 bar air and 100 °C in acetonitrile (Tables
S1 and S2). It is worth noting that this reaction can be easily
performed on gram-scale even in the presence of water.
Next, we were interested in the evaluation of the reactivity of
other aliphatic amines. As shown in Table 1, 20 different amines
underwent smooth and selective C-C bond cleavage to give the
corresponding formamides 1b-20b in general in high yields.
Using inexpensive triethylamine shows the general possibility to
synthesize N,N-diethylformamide, which is
alternative for the frequently used
a
less-toxic
solvent N,N-
dimethylformamide. However, for practical applications the
procedure still has to be improved. Given the importance of non-
symmetrical amines, we explored the regioselective cleavage of
carbon-carbon bonds in substrates containing different alkyl
substituents or more than one potential site for functionalization.
Gratifyingly,
this
protocol
exhibits
both
excellent
chemoselectivity and regioselectivity (4a-10a). For example,
several substituted butylamines containing C2-C6 branched
alkyl groups and C4-C8 cyclic alkyl groups were converted into
the desired products with ≥93% yields (11b-17b). Notably, N,N-
dibutyl 2-phenylethan-1-amine afforded the butyl cleaved
product in 56% yield along with trace amount of benzaldehyde
and N,N-bis(2-methoxyethyl)formamide which is observed by
GC-MS (18b) (Scheme S2). The more sterically encumbered
N,N-dibutyl (1-phenylpropan-2-yl) amine gave the desired
product quantitatively (19b). Finally, N,N-dibutylaniline afforded
71% of the oxidized product (20b).
[*]
Dr. W. Li, Dr. W. Liu, D. K. Leonard, Dr. J. Rabeah, Dr. K. Junge,
Prof. Dr. A. Brückner, and Prof. Dr. M. Beller
Leibniz-Institut für Katalyse e.V. an der Universität Rostock
Albert−Einstein Straße 29a, 18059 Rostock (Germany)
E-mail: matthias.beller@catalysis.de
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under: http://dx.doi.
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Table 1. C-C Bond cleavage reactions: tertiary amines.[a]
yield of the amide-containing product 33b was isolated under the
standard conditions. In addition, 4-(naphthalen-1-yl)morpholine
(49a) and 4-(6-methoxynaphthalen-2-yl)morpholine (50a)
provided 49b and 50b in 56% and 63% yield, respectively. Even
nitrogen- and oxygen-heteroaryl-substituted morpholines such
as 4-(pyridin-2-yl)morpholine (51a), 4-(9-phenyl-9H-carbazol-3-
yl)morpholine (52a), and 4-(dibenzo[b,d]furan-2-yl)morpholine
(53a) underwent smooth oxidative cleavage in the presence of
the catalytic system. We were pleased to find that the alkyl-
substituted derivatives undergo a similar transformation. Indeed,
N-methylmorpholine, N-ethylmorpholine and N-decylmorpholine
yielded the cleavage products 54b-56b in 34-82% yields. For
comparison,[18a] we used commercially available CuO and Cu2O
as the catalysts for the cleavage of morpholines such as 4-(p-
tolyl)morpholine (22a), 4-morpholinobenzaldehyde (28a), and 1-
(4-morpholinophenyl)ethan-1-one (30a) (Table S5). All these
results (<32% yields) show that the heterogeneous systems
CuO and Cu2O are not comparable to Cu(CF3SO3)2/pyridine
system and are less efficient, especially for functionalized
substrates (Tables S2, S4 and S5).
Table 2. C-C Bond cleavage reactions of morpholines.[a]
Nitrogen heterocycles such as morpholines and piperazines
constitute privileged scaffolds in modern drugs.[19] In fact,
several out of the top 50 pharmaceuticals belong to this class of
compounds. Thus, their preparation and derivatization continues
to attract considerable attention. As shown in Table 2, 33
different N-(hetero)aryl-morpholines provided the desired
products under
a standard set of conditions (3 mol%
Cu(CF3SO3)2, 20 mol% pyridine, MeCN, 100 °C, 24 hours) with
often excellent selectivity (Tables S3 and S4; see Supporting
Information for further experimental details.) The transformations
can be easily run on gram-scale as shown by conversion of N-
phenylmorpholine (21a), which gave 68% isolated yield of 21b
(eq. S2). More sensitive benzylic C-H bonds in 22b, 40b, 44b
and 45b, as well as a methoxy substituent in 23b are well-
tolerated giving the desired products in 48-87% isolated yields.
N-Aryl morpholines bearing –F, –Cl, –Br, –CN and –COOMe are
shown to be compatible with this procedure, too (24b, 25b, 26b,
29b, 35b, 36b, 37b, 42b, 43b, 46b, 47b and 48b). Although
homogeneous aerobic copper catalysis is known to cleave α-C-
C bonds of ketones,[20] the ketone groups were untouched with
our [Cu]/air system (30b, 31b and 38b). Most surprisingly, even
the formyl-substituted starting material gave mainly the C-C
bond cleavage product 28b in 64% yield and no expected acid
was formed. To the best of our knowledge this is a rare example
of oxidative C-C cleavage in the presence of an aldehyde.
Interestingly, along with C-C cleavage also formation of the
amide 28c was obtained. Similar side-products were observed in
case of 29c and 51c. Substrates bearing one or more electron-
withdrawing functional groups such as ketones, nitro, carboxylic
acid, and ester were also active (30b, 31b, 32b, 34b, 38b and
43b). Boron-containing compounds represent important building
blocks for all kinds of life science molecules, which allow for
numerous further valorizations. Gratifyingly, 27a and 39a gave
the preferred products in 62% and 63% yields. Moreover, a 72%
As shown in Table 3, ring-substituted morpholines reacted in a
similar manner and provided the corresponding products (57b-
60b). Notably, a methyl group in C2 position of the morpholine
ring allowed for selective cleavage of the C5-C6 vs C2-C3 bond
(75:25), while alkyl substituents in the 3-position led exclusively
to activation of the non-substituted bond. Apart from
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morpholines, also the oxidative cleavage of piperazines was
investigated. Although somewhat lower yields of the
corresponding products (61b-64b) were observed, these can be
easily isolated due to their different physical properties. In
addition, we have also tried N-phenylpyrrolidine and N-
phenylpiperidine under the standard conditions, but no C-C
cleavage products were observed.
cleavage products, possible intermediates 4-phenylmorpholin-3-
one (75a) and 4-phenylmorpholine-2,3-dione (76a) were
submitted to the regular reaction conditions (eq. S4 and S5).
Both compounds proved to be stable and no formation of 21b
was observed. Thus, these compounds can be excluded as
putative intermediates. On the other hand, trapping experiments
demonstrate the importance of radical intermediates in this
transformation. When
tetramethyl-1-piperidinyloxy)
2
equivalents of TEMPO (2,2,6,6-
or BHT (2,6-di-tert-butyl-4-
Table 3. C-C Bond cleavage reactions: morpholines and
piperazines.[a]
methylphenol) were added, the reaction completely stopped (eq.
S6), along with the dehydrogenated product 4-phenyl-3,4-
dihydro-2H-1,4-oxazine detected by GC-MS analysis (eq. S7,
Scheme S3). A related intermediate was observed by GC-MS in
the oxidation of tri-n-butylamine, too (Fig. S1 and Scheme S1).
Table 4. Late-stage C-C bond cleavage of modified natural products
and bioactive molecules.[a]
To demonstrate the utility of this copper-catalyzed oxidation
reaction, we evaluated late-stage C-C bond cleavage reactions
of functionalized natural products and bioactive molecules
including derivatives of isophorone, terpenoids such as ionone,
citronellal, piperonylacetone, and 5-cholesten-3-one. As shown
in Table 4 the corresponding amides were obtained in high yield
and selectivity (65b, 66b, 67b, 68b, 71b and 72b). Notably, in
case of 72b the cleavage of Cα(sp3)–Cβ(sp3) single bond
proceeded selectively in the presence of a C=C double bond!
Furthermore, the amination product of pentoxifylline, a xanthine
derivative used to treat muscle pain, was evaluated and the
corresponding products were smoothly isolated (69b and 70b).
Finally, to showcase late-stage drug modifications as well as to
prepare putative drug metabolites, we performed the reactions
of Linezolid (73a), which is a morpholine-containing antimicrobial
used for the treatment of infections caused by Gram-positive
bacteria and nitrogen-containing heterocycle Emorfazone (74a),
a non-steroidal anti-inflammatory drug to treat dental pain and
inflammation. Under aerobic conditions in the presence of
homogeneous copper 73b and 74b were formed in good yield
with excellent selectivity.
Notably, in the absence of air N-phenylmorpholine (21a) gave no
desired product, even in the presence stoichiometric amounts of
copper(II) pre-catalyst (eq. S8). In order to gain more details on
this copper/air catalysis, we performed kinetic studies utilizing
21a under the standard conditions. As shown in Fig. S2, no
induction period is required for the in situ generation of the
active catalytic species and 32% of the product 21b formed in
the first 1 hour. However, no intermediates were detected by gas
chromatography during the whole process. Finally, we added
18O-labeled water to the model reaction under standard
conditions; however, no 18O-incorporated product was observed.
This clearly demonstrates that only O2 from air acts as the
oxygen donor in this transformation (eq. S9). Finally, EPR and
UV-Vis investigations were performed to further explore the
reaction steps. The CuII precursor reacts with 21a via single-
electron transfer (SET) to generate the free-radical cation A and
To understand the mechanism of this general oxidative cleavage
reaction, several experiments and in situ spectroscopic
investigations were performed using N-phenylmorpholine (21a).
Firstly, to prove the stability of the co-catalyst/ligand, which
significantly improves the conversion, deuterated pyridine-d5
was employed instead of pyridine. However, a standard catalytic
experiment revealed only pyridine-d5 was detected by GC-MS
after 24 h (eq. S3). To understand the formation of the oxidative
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CuI. This assumption is confirmed by EPR investigations, which
showed that addition of N-phenylmorphline to a CuII solution
under inert atmosphere resulted in a fast disappearance of the
CuII EPR signal and the formation of a temporary signal at g =
2.004 with unresolved hyperfine structure typical for an organic
radical A (Fig. S3).
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formation of radical intermediate A (eq. 1). No further detailed
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In conclusion, we have developed a general protocol for the
aerobic cleavage of Cα(sp3)–Cβ(sp3) single bonds in amines (>70
examples) using a practical and inexpensive copper-catalyst.
This system is effective for conversion of industrial bulk amines
but also for late-stage functionalization of modified natural
products and bioactive molecules. Complementary to other
oxidation reactions of amines, excellent site-selectivity and
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Acknowledgements
[18] For a copper oxide catalyzed similar reaction of tri-n-butyl amine see: a)
M. Wang, X.-K. Gu, H.-Y. Su, J.-M. Lu, J.-P. Ma, M. Yu, Z. Zhang, F.
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We gratefully acknowledge the support from the Federal Ministry
of Education and Research (BMBF) and the State of
Mecklenburg-Vorpommern. We thank Dr. Wolfgang Baumann,
Susann Buchholz and Dr. Christine Fischer for their excellent
analytical support, Dr. Haijun Jiao, Zhihong Wei, Bianca Wendt
and Dr. Basudev Sahoo (all at LIKAT) for valuable discussions.
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518-526.
Keywords: amines • morpholines • copper • air • C-C cleavage
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10.1002/anie.201903019
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COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Wu Li, Weiping Liu, David K. Leonard,
Jabor Rabeah, Kathrin Junge, Angelika
Brückner, and Matthias Beller*
Page No. – Page No.
Cut by air: A general methodology for C(sp3)–C(sp3) single bonds cleavage
reactions using homogeneous copper-based catalysts in the presence of air is
achieved. The utility of this novel methodology is demonstrated for Cα-Cβ bond
scission in >70 amines with excellent functional group tolerance.
Practical Catalytic Cleavage of
C(sp3)–C(sp3) Bonds in Amines
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