Nitroxyl-Radical-Catalyzed Oxidative Coupling of Amides with Silylated Nucleophiles through N-Halogenation

Article abstract of DOI:10.1002/anie.201607223

A nitroxyl-radical-catalyzed oxidative coupling reaction between amines with an N-protecting electron-withdrawing group (EWG) and silylated nucleophiles was developed to furnish coupling products in high yields, thus opening up new frontiers in organocatalyzed reactions. This reaction proceeded through the activation of N-halogenated amides by a nitroxyl-radical catalyst, followed by carbon–carbon coupling with silylated nucleophiles. Studies of the reaction mechanism indicated that the nitroxyl radical activates N-halogenated amides, which are generated from N-EWG-protected amides and a halogenation reagent, to give the corresponding imines.

Full text of DOI:10.1002/anie.201607223

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International Edition: DOI: 10.1002/anie.201607223
German Edition: DOI: 10.1002/ange.201607223
Radical Catalysis
Nitroxyl-Radical-Catalyzed Oxidative Coupling of Amides with
Silylated Nucleophiles through N-Halogenation
Katsuhiko Moriyama,* Masako Kuramochi, Kozo Fujii, Tsuyoshi Morita, and Hideo Togo
Abstract: A nitroxyl-radical-catalyzed oxidative coupling
reaction between amines with an N-protecting electron-with-
drawing group (EWG) and silylated nucleophiles was devel-
oped to furnish coupling products in high yields, thus opening
up new frontiers in organocatalyzed reactions. This reaction
proceeded through the activation of N-halogenated amides by
a nitroxyl-radical catalyst, followed by carbon–carbon cou-
pling with silylated nucleophiles. Studies of the reaction
mechanism indicated that the nitroxyl radical activates N-
halogenated amides, which are generated from N-EWG-
protected amides and a halogenation reagent, to give the
corresponding imines.
T
he organocatalytic activation of halogen-containing sub-
strates by the dissociation of a halogen atom has received
much attention. Halide-binding catalysts have emerged,
including hydrogen-bond catalysts, such as thiourea[1] and
oligotriazole catalysts,[2] and halogen-bond catalysts, which
are exemplified by electron-deficient iodine catalysts.[3] These
catalysts recognize an electrically negative halogen atom
through a halogen-bond interaction between the halogen
atom and the halogen-bond-donor groups on the catalyst to
generate highly reactive cationic species (Scheme 1a). Lewis
base organocatalysts that recognize halonium ions (X+) have
also been designed that activate a halogenation reagent to
promote chemoselective halogenation (Scheme 1b).[4] On the
other hand, nitroxyl radicals bearing an unpaired electron,
such as 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO), have
been used to activate some transformations.[5] However,
nitroxyl-radical-catalyzed transformations have narrow
scope in spite of the high activity of the nitroxyl moiety.[6]
Among them, it is noteworthy that nitroxyl radical is oxidized
into oxoammonium cation through one-electron oxidation
with NaOCl for the oxidation of alcohols (Anelli method).[7]
Otherwise, studies of the association between nitroxyl
radicals and halogen compounds have been limited to
physicochemical characterization and crystal engineering,[8]
Scheme 1. Activation of halogen-containing compounds with organo-
catalysts.
and there have been no reports of organoradical-catalyzed
reactions of halogen compounds with a nitroxyl-radical
catalyst.
We anticipated that a nitroxyl radical could be used as an
organocatalyst for the oxidation of amides to imines N-
protected with an electron-withdrawing group (EWG)
through the dissociation of the electropositive halogen atom
on N-halogenated amides (Scheme 1c). The catalytic oxida-
3
À
tive coupling of amines through the oxidation of the C(sp ) H
bond adjacent to the nitrogen atom is an elegant method for
amine functionalization, and some ingenious methods have
been developed.[9] In contrast, the development of catalytic
systems for such an oxidation of amides is challenging,
because the nitrogen atom of an amide has much lower
electron density than that of an amine. Accordingly, to the
best of our knowledge, there are no known examples of the
catalytic oxidation of amides to N-EWG-protected imines,
even though the protected nitrogen units are very useful
because the protecting group can be cleaved readily under
mild conditions. Herein we report a nitroxyl-radical-catalyzed
oxidative coupling reaction of amides with silylated nucleo-
philes that proceeds by the transformation of N-halogenated
amides, which are generated from amides with a halogenation
reagent in situ, into imines.
[*] Prof. Dr. K. Moriyama, M. Kuramochi, Prof. Dr. H. Togo
Department of Chemistry, Graduate School of Science
Chiba University
1–33 Yayoi-cho, Inage-ku, Chiba 263-8522 (Japan)
E-mail: moriyama@faculty.chiba-u.jp
Prof. Dr. K. Moriyama
Molecular Chirality Research Center, Chiba University
1–33 Yayoi-cho, Inage-ku, Chiba 263-8522 (Japan)
Dr. K. Fujii, Dr. T. Morita
Graduate School of Advanced Integration Science, Chiba University
1–33 Yayoi-cho, Inage-ku, Chiba 263-8522 (Japan)
First,
we
chose
the
a-cyanation
of
N-
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201607223.
benzylbenzenesulfonamide (1a) as a model reaction and
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screened for oxidants, bases, and additives in the presence of
TEMPO as the catalyst in MeCN (see Table S1 in the
Supporting Information). The optimum reaction conditions
were found to include 1a, TEMPO (20 mol%), KBr
(50 mol%), tBuOCl (1.2 equiv), and Na2CO3 (1.0 equiv) in
the presence of Na2SO4 (2.0 equiv) as a desiccant in MeCN for
20 h, followed by the addition LiClO4 (10 mol%) as a Lewis
acid catalyst[10] and TMSCN (1.5 equiv). Under these con-
ditions, the a-cyano adduct 2a was obtained in 99% yield
(Scheme 2).
Scheme 2. TEMPO-catalyzed a-cyanation of sulfonamide 1a with
TMSCN. TMS=trimethylsilyl.
To explore the scope of the TEMPO-catalyzed a-cyana-
tion, we examined a range of sulfonamides 1 under the
optimum conditions (Scheme 3). The reaction of substrates
bearing various sulfonamide groups (substrates 1b–d) and
benzyl groups with substituents on the aromatic ring (sub-
strates 1e–p) proceeded successfully, and the corresponding
a-cyano adducts 2b–p were obtained in high yields (78 to
> 99%). The N-heterocycle-containing sulfonamide 1q and
sulfonamide 1r with an N-aliphatic group were also converted
into the desired products 2q and 2r in high yields of 81 and
92%. The oxidative a-cyanation of sulfonamides 1s and 1t
with a secondary N-substituent provided a-cyano adducts 2s
and 2t bearing a quaternary carbon center in 60 and 92%
yield, respectively, when AZADO[11] was used instead of
TEMPO as the catalyst.
We examined the nitroxyl-radical-catalyzed oxidative a-
cyanation of N-benzylphosphinamides 3 and found that the
symmetric phosphinamide 3a and asymmetric phosphina-
mide 3b could be converted into the desired products 4a and
4b (d.r. 64:36) in 97 and 90% yield, respectively, under
modified reaction conditions, whereas under the optimum
conditions for sulfonamides 1, the reaction did not proceed at
all (Scheme 4).[12] Fortunately, the use of tert-butylphenyl-
phosphinamide 3c in the oxidative coupling reaction resulted
in the formation of a-cyano product 4c with good diastereo-
selectivity (d.r. 80:20).
Scheme 3. TEMPO-catalyzed a-cyanation of sulfonamides 1 with
TMSCN. [a] TEMPO (20 mol%) was used. [b] KBr (1.2 equiv) was
used. [c] The reaction was carried out at 08C. [d] TEMPO (30 mol%)
was used. [e] KBr (1.2 equiv) and AZADO (20 mol%) were used.
AZADO=2-azaadamantane-N-oxyl, Ts=p-toluenesulfonyl.
We investigated the nitroxyl-radical-catalyzed oxidative
coupling reaction of sulfonamide 1a with various silylated
nucleophiles (Scheme 5). The oxidative coupling of 1a with
TMSCF3 and allyltrimethylsilane as nucleophiles proceeded
smoothly to give the corresponding adducts 5a and 6a in high
yields; the reactions involved trifluoromethylation with
a catalytic amount of LiOAc[13] and allylation[14] with
TMSOTf. A Mukaiyama-type reaction[15] and a vinylogous
reaction[16] with silyl enol ethers and ketene silyl acetals also
gave coupling products 7a–11a in high yields (93–96%). The
reaction of sterically hindered ethyl tert-butyldimethylsilyl
ketene acetal was also promoted by a Lewis base catalyst to
give the desired product 12a in 92% yield. Whereas the aza-
Scheme 4. TEMPO-catalyzed a-cyanation of N-benzylphosphinamides
3 with TMSCN. [a] The second step was carried out in CH2Cl2 instead
of dimethyl carbonate. DABCO=1,4-diazabicyclo[2.2.2]octane.
2
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Scheme 5. TEMPO-catalyzed a-substitution reaction of sulfonamide 1a
with silylated nucleophiles. Reaction conditions for the second step:
À
Conditions A: LiOAc (20 mol%), Si Nu (1.5 equiv), DMF, À208C, 17 h;
À
conditions B: TMSOTf (1.1 equiv), Si Nu (1.5 equiv), CH2Cl2, À788C,
À
48 h; conditions C: TBAI (20 mol%), Si Nu (3.0 equiv), MeCN, room
temperature, 22 h. [a] The reaction was carried out at room temperature.
DMF=N,N-dimethylformamide, TBAI=tetrabutylammonium iodide,
TBS=tert-butyldimethylsilyl, Tf=trifluoromethanesulfonyl.
Diels–Alder reaction of imines with the Danishefsky diene is
generally used for the formation of dihydropyridones,[17] the
present oxidative coupling reaction with the catalyst TBAI[18]
provided the unprecedented 2-methoxy-4-piperidinone deriv-
ative 13a in 72% yield.
Scheme 6. Mechanistic study of the nitroxyl-radical-catalyzed oxidative
To determine the reaction mechanism of the nitroxyl-
radical-catalyzed oxidative coupling reaction, we conducted
a number of supporting experiments (Scheme 6). The reac-
tion of 1a without a silylated nucleophile under the present
conditions provided the corresponding aldimine 14a in
quantitative yield [Eq. (1)]. Furthermore, the treatment of
1a with KBr and tBuOCl readily furnished N-halogenated
products 15a and 16a [Eq. (2)], and 15a was oxidized to
aldimine 14a with a catalytic amount of TEMPO under basic
conditions [Eq. (3)]. However, the attempted transformation
of 15a into 14a without TEMPO hardly proceeded at all
[Eq. (4)]. The oxidation of 15a with Br2 under basic
conditions provided almost none of the corresponding imine
14a [Eq. (5)]. These results indicate that TEMPO is essential
to promote the transformation of N-halogenated amides into
imines. The use of an oxoammonium chloride in the reaction
of 1a or 15a produced a small amount of 14a, thus indicating
that the TEMPO catalyst promoted the present oxidation via
an active species different from that involved in the TEMPO-
catalyzed oxidation of alcohols[6,7,19] and oxidative trans-
formations with oxoammonium salts[9g,h,20] [Eq. (6)]. The
presence of KBr in the reaction with oxoammonium chloride
coupling reaction.
did not affect the oxidation of 15a [Eq. (7)]. Moreover, the
deuterium kinetic isotope effect on the TEMPO-catalyzed
oxidation was evaluated with substrate [D]1a labeled with
deuterium at the benzylic position. Reactions in the presence
or absence of KBr showed small kH/kD values of 1.54 and 1.44,
respectively, which indicate that the abstraction of a benzylic
hydrogen atom is not the rate-determining step in the
oxidation of amides [Eq. (8)].[19,20]
To confirm the further details of the oxidation of 15a with
the nitroxyl-radical catalyst, we determined the time course of
the reaction of 15a and TEMPO in a 5:1 molar ratio in MeCN
under basic conditions by Raman spectroscopic analysis[21]
(Figure 1). After 1.5 h, peaks assignable to oxoammonium
chloride were observed (553.8 and 695.7 cmÀ1) together with
those of 14a (541.2 and 797.4 cmÀ1), but peaks attributable to
the reduced form of TEMPO (TEMPOH; 669.6 and
782.1 cmÀ1) were not detected at all (see the Supporting
Information).
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Acknowledgements
Financial support from the Ministry of Education, Culture,
Sports, Science and Technology of Japan in the form of
a Grant-in-Aid for Scientific Research (No.20550033; K.M.)
and from the Naito Foundation (K.M.) is gratefully acknowl-
edged.
À
Keywords: amides · C C coupling · nitroxyl radicals ·
organocatalysis · oxidation
Figure 1. Time-course Raman spectroscopy of a solution of 15a and
TEMPO (5:1) in MeCN in the presence of Na2CO3. a) TEMPO in
MeCN; b) oxoammonium chloride in MeCN; c) TEMPOH in MeCN;
d–f) time-course spectra after 1.5 h (d), 3 h (e), 5 h (f), and 22 h (g).
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On the basis of these mechanistic experiments, we
propose a reaction mechanism for the nitroxyl-radical-cata-
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an EWG-protected aldimine 14 with the simultaneous
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À
The final C C bond-forming reaction of 14 with a silylated
nucleophile proceeds under the corresponding optimum
conditions.
In conclusion, we have developed a nitroxyl-radical-
catalyzed oxidative coupling reaction of N-EWG-protected
amines (amides) with silylated nucleophiles by the N-
halogenation of N-EWG-protected amides with a halogena-
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coupling products in high yields. We believe that nitroxyl
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Received: July 26, 2016
Revised: August 19, 2016
Published online: && &&, &&&&
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Communications
Radical Catalysis
K. Moriyama,* M. Kuramochi, K. Fujii,
T. Morita, H. Togo
&&&& — &&&&
Nitroxyl-Radical-Catalyzed Oxidative
Coupling of Amides with Silylated
Nucleophiles through N-Halogenation
A halo to make them shine: A high-
yielding nitroxyl-radical-catalyzed oxida-
tive coupling reaction between amines
protected with an electron-withdrawing
group and silylated nucleophiles pro-
ceeded through the activation of N-halo-
genated amides by the nitroxyl-radical
catalyst to give imines. The N-halogen-
ated amide intermediates were generated
in situ from amides by treatment with
a halogenation reagent (see scheme).
6
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