Copper-catalyzed regioselective intramolecular oxidative α-functionalization of tertiary amines: An efficient synthesis of dihydro-1,3-oxazines

Article abstract of DOI:10.1002/anie.201304654

Traffic control: The hydroxy functional group directs the α-functionalization of tertiary amines, synthesizing 1,3-oxazines by C-O bond formation. Reaction occurs with both benzylic and non-benzylic amines. In the case of naphthoxazine synthesis, 100 % diastereoselectivity was observed. A tentative two-pathway mechanism is proposed for the reaction. Copyright

Full text of DOI:10.1002/anie.201304654

Angewandte
Chemie
DOI: 10.1002/anie.201304654
À
C H Activation
Copper-Catalyzed Regioselective Intramolecular Oxidative a-
Functionalization of Tertiary Amines: An Efficient Synthesis of
Dihydro-1,3-Oxazines**
Mohit L. Deb, Suvendu S. Dey, Isabel Bento, M. Teresa Barros, and Christopher D. Maycock*
Oxidative coupling reactions, especially through cross-dehy-
quinoline. Examples relating to the activation of non-benzylic
[9]
À
À
drogenative coupling (CDC) of C H bonds, which avoids the
methyl/methylene C H, are scarce. Hence, despite signifi-
prefunctionalization of substrates, have recently been in focus
for being more atom economical, directive, and environ-
cant development in recent years, still more research in this
area is required to enhance the selectivity and substrate scope.
mentally benign than other cross-coupling reactions.[1]
Looking for synthetic advances in regiocontrolled C H
À
3
À
Among the CDC reactions, the functionalization of sp C H
functionalization, we became interested in the design of
a synthetic strategy for a copper-catalyzed aerobic oxidative/
bonds adjacent to a nitrogen atom has generally been
achieved utilizing transition metal catalysts with co-oxidants,
such as tert-butylhydroperoxide (TBHP), H2O2, molecular
oxygen, and others, to generate iminium ion species, which in
turn react with various nucleophiles.[2] For this purpose,
metals such as Ru,[3] Fe,[4] Rh,[5] V,[6] and others are often used.
However, copper salts retain many advantages, such as ready
availability, low cost, high efficiency and low toxicity, and
have turned out to be the most efficient catalysts for the
a-functionalization of tertiary amines.[7] More recently,
homogeneous copper catalysis have also been used to achieve
dehydrogenative a-functionalization of tertiary amines with
3
À
subsequent intramolecular sp C O bond formation.
Dihydro-1,3-oxazine derivatives are important heterocy-
clic molecules, which exhibit a wide range of pharmacological
activity, including antibacterial,[10] fungicidal,[11] antitumor,[12]
antituberculosis,[13] and anti-HIV.[14] Naphthoxazine deriva-
tives have therapeutic potential for the treatment of Parkin-
sonꢀs disease, and are also used as potent nonsteroidal
progesterone receptor agonists.[15] They can be used as
intermediates in the synthesis of N-substituted aminoalcohols,
bioactive natural products, or in asymmetric catalysis.[16]
Justifiably, the intrinsic versatility and synthetic utility of
these heterocyclic systems has attracted great interest from
chemists, who have developed several exquisite methods for
their synthesis.[17] However, except for a few examples,[18]
most of the reported strategies are primarily based on
Mannich type condensations, which are restricted to the use
of aliphatic alicyclic primary amines. Hence, regardless of
these advances, investigations in search of more efficient
routes for the synthesis of these compounds are still highly
desirable for drug discovery and medicinal chemistry. Herein,
we disclose an efficient, environmentally friendly, diastereo-
selective copper-catalyzed synthesis of naphtho and benzo-
À
the selective aerobic oxidative functionalization of C H
bonds.[8] However, such copper-catalyzed functionalization,
whether under aerobic or anaerobic conditions, is mainly
confined to the benzylic position of N-phenyltetrahydroiso-
[*] Dr. M. L. Deb,[+] Prof. C. D. Maycock
Organic Synthesis Laboratory, Chemistry Division, Instituto de
Tecnologia Quꢀmica e Biologia, Universidade Nova de Lisboa
2780-157 Oeiras (Portugal)
E-mail: maycock@itqb.unl.pt
Dr. M. L. Deb,[+] Dr. S. S. Dey,[+] Prof. M. T. Barros
REQUIMTE, CQFB, Departamento de Quꢀmica, Faculdade de
CiÞncias e Tecnologia, Universidade Nova de Lisboa
2829-516 Caparica (Portugal)
À
2,3-dihydro-1,3-oxazines through regioselective C H bond
activation and cyclization (Scheme 1).
Dr. I. Bento
Biological Chemistry Division, Strucural Genomics, Macro-
molecular Crystallography Unit, Instituto de Tecnologia Quꢀmica
e Biologia, Universidade Nova de Lisboa (Portugal)
Prof. C. D. Maycock
Departamento de Quꢀmica e Bioquꢀmica, Faculdade de CiÞncias
Universidade de Lisboa, Campo Grande
1749-016 Lisboa (Portugal)
[+] These authors contributed equally to this work.
Scheme 1. Synthesis of 2,3-dihydro-1,3-oxazines.
[**] M.L.D. and S.S.D. are grateful to Fundażo para a CiÞncia
e a Tecnologia, Portugal for grants (SFRH/BPD/79215/2011 and
SFRH/BPD/66763/2009). This work was supported by Fundażo
para a CiÞncia e a Tecnologia (PEst-OE/EQB/LA0004/2011 and
PEst-C/EQB/LA0006/2011). The National NMR Network is sup-
ported by Fundażo para a CiÞncia e a Tecnologia (RECI/BBB-BQB/
0230/2012). The authors acknowledge Maria Teresa Duarte for
support and for the provision of X-ray diffraction facilities.
Because of the importance of naphthoxazine derivatives,
we chose the transformation of 1a into 2a as a model for
optimizing the reaction conditions. Different solvents and
metal catalysts, with or without additives, were screened, and
Cu(OAc)2·H2O (5 mol%) in p-xylene at 1308C were deter-
mined to be the optimized conditions (Supporting Informa-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201304654.
tion, Table SA). Among the two types of sp3 C H bonds
À
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adjacent to the nitrogen atom, a-functionalization occurred
mainly at the non-benzylic position, forming 2,3-dihydro-1,3-
oxazine 2a. We also obtained the corresponding ketone 3a in
up to 15% yield as a by-product, depending upon the
oxidizing agent used (Table SA). After optimization, a variety
of derivatives of aminonaphthol were screened (Table 1). The
procedure proved nonetheless to be sensitive to the nature of
secondary amines used for the preparation of aminonaphthol/
phenol derivatives 1. As expected, compounds derived from
benzylic amines were found to be most reactive and to
produce the corresponding oxazines in better yields (Table 1,
entries 4 and 8). Upon changing the amine moiety from
pyrrolidine to piperidine, the yield of the corresponding
product decreased by a small extent (entries 1 and 2). The
yield of product was further reduced in the presence of
a morpholine group (entry 3) and the inactivity of the
piperazine derivative signified that the extra heteroatom,
having a readily available lone pair, might interact with Cu
ion, resulting in the retardation of a-functionalization. A
À
primary C H bond adjacent to the nitrogen atom was
regioselectively activated relative to the secondary one
À
(entry 6), whereas the benzylic C H reacted more readily
À
than non-benzylic primary and secondary C H bonds
(entries 7 and 8). Most significantly, single diastereomers of
the desired naphtho-1,3-oxazines were obtained.
Secondary amine derivative 4 produced binaphthol 5
instead of the desired 1,3-oxazine (Scheme S2). When sub-
jected to these reaction conditions, indoline derivative 6
exclusively produced the corresponding indole
(Scheme S3).
7
To examine the efficiency and generality of this method,
various substituted tertiary aminonaphthols/phenols were
investigated under the optimized conditions, as summarized
in Scheme 2. The corresponding dihydro-1,3-oxazines, which
contain a wide range of substituents, could be obtained in
moderate to excellent yields. To our delight, functional groups
on the aromatic ring such as OMe, Br, F, Cl, and NO2 were
also compatible. The substrate bearing a thiophene hetero-
cyclic moiety underwent a facile oxidative coupling to furnish
the expected product 2m in good yield. The diastereoselec-
tivity appeared to be particularly sensitive to the substrate
chosen: it decreased drastically when exchanging the naph-
thyl moiety for a phenyl group. Remarkably, the regioselec-
tivity of the a-functionalization of the tertiary amine was not
severely affected by switching the nature of the benzylic
carbon from a methanetriyl group (2a and 2v) to a methane-
diyl group (2p and 2z). Hence, the existence of possible steric
hindrance arising from the presence of a substituent at the
benzylic position was not the only reason for the regioselec-
tivity (cyclization vs. ketone/aldehyde formation). This fact
also highlighted the directing nature of the phenolic
OH group in the reaction.
Table 1: Screening of tertiary amines for the synthesis of 2,3-dihydro-1,3-
naphthoxazines.[a]
Entry
Aminonaphthol
t [h]
2
Product[b]
Yield
[%][c]
1
2
85
67
4
3
7
58
To ascertain the role of copper ions in such a regioselective
4
5
6
2
4
3
91
58
66
À
À
C H functionalization, in hope of an intermolecular C O
bond formation, a reaction was performed with substrate 8
and phenol 9 under the reaction conditions described in
Table 1. Unfortunately, only benzaldehyde 10 and tetrahy-
droisoquinoline 11 were formed, presumably through imi-
nium ion formation by direct activation of the exocyclic
benzylic methylene group (Scheme S4).
The above results indicated that the chelation of copper
ions with the nitrogen and the phenolic OH group in
a conformationally rigid system (1a–z), directed dehydrogen-
ative oxidation to take place at the carbon in close proximity
to the phenolic OH group.
To obtain further information about the mechanism of the
reaction, a cross experiment was performed under the
optimized conditions using a 1:1 mixture of 1b and 1i. The
two expected products (2b and 2i) were isolated along with
two cross products (2a and 2ib) in a ratio of 1.5:1.5:1:1,
respectively (Scheme 3).
7
8
3
3
70
81
[a] Reaction conditions: 1 (0.2 mmol), Cu(OAc)2·H2O (5 mol%),
Under the same conditions, the enantiomerically pure
starting material 1a’[19] gave the partially racemized product
2a’ (Scheme 4).[20] These two experiments implied the detach-
p-xylene (1 mL) at 1308C. [b] Only the trans isomer was obtained, as
determined by NMR spectroscopy. [c] Products were purified by
preparative TLC; yields shown are of isolated products.
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Scheme 3. Cross reaction between two substrates furnishing four
products.
Scheme 4. Reaction using chiral substrate.
Based on the above findings, a tentative dual-pathway
mechanism for the reaction may be proposed (Scheme 5).
Compound 1a may form iminium salt 14 through a single-
electron transfer (SET) to CuII, which would form the
intermediate ammoniumyl radical cation 13, followed by
subsequent loss of an H radical (or a combination of electron
and H+).[8d] Release of the cyclic imine 15, with simultaneous
formation of o-quinone methide 16, would be followed by
endo-[4+2] cycloaddition between the two to afford 2,3-
dihydro-1,3-oxazine 2a (path A). The o-quinone methide 16
has been trapped and characterized (Scheme S5). Partial
retention of enantiomeric purity of the product 2a’
(Scheme 4) indicates the possibility of intramolecular cycli-
Scheme 2. Substrate scope for the synthesis of 1,3-oxazines. Reaction
conditions: 1 (0.2 mmol), Cu(OAc)2·H2O (5 mol%), p-xylene (1 mL) at
1308C. Yields shown are of isolated products. Isomer ratios are not
specified where only the trans isomer was observed by NMR spectros-
copy.
ment of the pyrrolidine moiety from 1 with the formation of
an oxabutadiene intermediate (o-quinone methide) during
the course of the reaction.
When our model reaction was carried out in degassed
p-xylene under a continuous flow of argon, 1a remained
almost intact; even after 4 h, only traces of product 2a were
obtained, thus indicating that only molecular oxygen is
required to complete the catalytic cycle.
Scheme 5. Proposed mechanism.
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Communications
À
zation of iminium salt 14 to afford product 2a through C O
bond formation without disturbing the chiral center (path B).
CuI would presumably be reoxidized to CuII by atmospheric
oxygen. The reaction of ketone 3a with pyrrolidine to form
17, and eventually to produce 2a by iminium rearrangment,
was not observed under the reaction conditions
(Scheme 5).[21]
To gain more insight into the SET mechanism, the model
reaction was performed in the presence of radical scavengers
such as 2,6-di-tert-butyl-4-methyl phenol (BHT) and thiophe-
nol (1 equiv of each). A significant drop in yield was observed
and only a trace of product 2a was isolated, thus suggesting
that this reaction includes a radical process. A full under-
standing of the mechanism will require further investigation.
The trans diastereoselectivity in the naphtho analogues
can be explained by considering the more stable pseudo (Z)-
o-naphthoquinone methide[22] as the reacting species (Fig-
ure 1a) and the less sterically hindered endo transition state
In conclusion, we have developed a copper-mediated
intramolecular a-functionalization of tertiary amines through
À
C H bond oxidative activation (benzylic and non-benzylic) to
À
synthesize diverse dihydro-1,3-oxazines through C O bond
formation. The method is very simple and uses inexpensive
Cu(OAc)2·H2O as the catalyst. This conversion can be
efficiently performed in an open vessel without the addition
of external co-oxidants or additives. Neither dry solvent nor
precautions for an inert atmosphere are required. Most
importantly, naphthoxazines can be produced with 100%
diastereoselectivity. The present convenient method for the
synthesis of benzo- or naphtho-2,3-dihydro-1,3-oxazines
should be of great utility in medicinal chemistry. Further
mechanistic studies and applications of the reaction and the
biological activities of the above compounds and analogues
will be disclosed in due course.
Received: May 29, 2013
Revised: June 28, 2013
Published online: July 24, 2013
Keywords: C-H activation · C-O bond formation ·
.
copper catalysis · diastereoselectivity · regioselectivity
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,
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Angew. Chem. Int. Ed. 2013, 52, 9791 –9795
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