TEMPO-mediated allylic C-H amination with hydrazones

Article abstract of DOI:10.1039/c4ob00839a

TEMPO-mediated reactions of alkenyl hydrazones afforded azaheterocycles via sp³ C-H allylic amination. The transformation is featured by a sequence of remote allylic H-radical shift and allylic homolytic substitution with hydrazone radicals. This journal is

Full text of DOI:10.1039/c4ob00839a

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TEMPO-mediated allylic C–H amination
with hydrazones†
Cite this: Org. Biomol. Chem., 2014,
12, 4567
Xu Zhu and Shunsuke Chiba*
Received 23rd April 2014,
Accepted 10th May 2014
DOI: 10.1039/c4ob00839a
www.rsc.org/obc
TEMPO-mediated reactions of alkenyl hydrazones afforded aza-
heterocycles via sp3 C–H allylic amination. The transformation is
featured by a sequence of remote allylic H-radical shift and allylic
homolytic substitution with hydrazone radicals.
Development of methods for oxidative functionalization of sp3
C–H bonds that provide direct and step-economical
approaches to construct functionalized organic structures has
been one of the hottest trends in the area of synthetic organic
chemistry.1 To realize this goal in a regio- and chemo-selective
manner, the use of organometallic intermediates as well as
metal-carbene and -nitrene species with various transition-
metal-catalysts has prevailed. On the other hand, free-radical
Scheme 1 TEMPO-mediated β-C–H oxidation of oximes and
hydrazones.
mediated sp3 C–H bond functionalization by
a remote
H-radical shift2 has been recognized for a long time as rep-
resented by the Hofmann–Löffler–Freytag reaction,3 while the
inherent violent chemical reactivity of the free radical species
often renders these processes of dyscontrol along with unde-
sired side reactions such as fragmentation and intermolecular
H-radical abstraction.
logous mechanism could be proposed for β-sp3-C–H amination
with hydrazones (X = N). Therefore, the presence of at least
one α-hydrogen atom is indispensable to realize this β-sp3-C–H
oxidation via α,β-unsaturated oximes or hydrazone intermedi-
ates IV.
Our group has been interested in the use of stabilized
O- and N-radicals derived from oximes and hydrazones,
respectively, for remote sp3 C–H bond oxidation, and recently
reported β-sp3-C–H oxygenation and amination with oximes
and hydrazones mediated by 2,2,6,6-tetramethylpiperidin-1-
oxyl (TEMPO) (Scheme 1).4–6 In β-sp3-C–H oxygenation with
oximes (X = O), the process is initiated by a 1,5-H-radical shift
of the putative oxime O-radicals I, giving β-C-radicals II that
are subsequently trapped with TEMPO. The resulting β-ami-
noxyl oximes III undergo elimination of 1-hydroxy-2,2,6,6-tetra-
methylpiperidine (TEMPO-H) to form α,β-unsaturated oximes
IV that finally cyclize to deliver dihydroisoxazoles. The ana-
It is therefore inherent that the β-C–H oxygenation of α-qua-
ternary oximes such as 1a and 1b with TEMPO did not proceed
at all (Scheme 2a). In sharp contrast, treatment of these
oximes with TEMPO and diisopropyl azodicarboxylate (DIAD)
(3 equiv. each) delivered β-keto oximes, which were isolated as
the hemiacetal forms 2a and 2b, respectively (Scheme 2b).
Although we are not certain as to the reaction mechanism of
this β-oxygenation reaction, tentative speculation of the reac-
tion course is described in Scheme 2c. In the presence of only
TEMPO, the resulting carbon radical B might be trapped by
TEMPO to give β-aminoxyl oxime C. However, the C–O bond of
oxime C undergoes thermal homolysis to revert to the carbon
radical B,7 which is further converted into more stable
iminoxyl radical A. On the other hand, in the presence of both
TEMPO and DIAD, the carbon-radical B could be trapped by
DIAD8 to give an aminyl radical D and this process is
not reversible under the present reaction conditions. The
resulting aminyl radical re-generates an iminoxyl radical E,
Division of Chemistry and Biological Chemistry, School of Physical and
Mathematical Sciences, Nanyang Technological University, Singapore 637371,
Singapore. E-mail: shunsuke@ntu.edu.sg; Fax: +65-67911961
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, characterization data of products, and copies of 1H and 13C NMR
spectra. CCDC 926979, 996573 and 995494. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c4ob00839a
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These results stimulated us to develop a remote sp3-C–H
amination process with hydrazones that could be realized
regardless of the degree of the α-substitution. We wondered
whether γ,δ-unsaturated hydrazone 3b can be used for allylic
C–H amination,12 in which the resulting allylic radical II by a
1,5-H shift of the corresponding hydrazone radical I might
trap TEMPO to give β,γ-unsaturated-δ-aminoxyl oxime III that
undergoes further intramolecular radical allylic substitution
reaction13,14 with hydrazone radical IV to afford the allylic C–H
amination products 5b (Scheme 4).
Based on the hypothesis outlined in Scheme 4, we began
our investigation with hydrazone 3b (Table 1). Recently, Han
et al. have reported that the reactions of γ,δ-unsaturated hydra-
zones such as 3b with 4 equiv. of TEMPO and 1 equiv. of DIAD
in toluene at 100 °C provided dihydropyrazole 5b′ as a sole
product that was formed via 5-exo radical cyclization of the
putative intermediate IV followed by trapping of the resulting
C-radical with TEMPO.5b On the other hand, the reaction of 3b
with 2.5 equiv. of TEMPO in DMF at 130 °C delivered dihydro-
pyrazole 5b in 77% yield as a sole product (entry 1). In the
presence of the inorganic base such as K2CO3 or K3PO4, the
Scheme 2 β-C–H oxygenation of α-quaternary oximes 1a and 1b.
which undergoes a 1,5-H radical shift to give carbon-radical F.
Further radical fragmentation of F with N–N bond cleavage
generates N-acylimine G and further hydrolysis of the imine
moiety generates β-keto oxime H that cyclizes to form hemi-
acetal 2a or 2b.9
Scheme 4 Allylic C–H amination with γ,δ-unsaturated hydrazone 3b.
Table 1 Allylic C–H amination: optimization of the reaction
conditionsa,b
However, this TEMPO–DIAD system could not be adopted
for the reaction of α-quaternary hydrazones such as 3a
(Scheme 3). In this case, amination proceeded not onto the
β-sp3 C–H bond but onto the sp2 aromatic C–H bond to give
the corresponding indazole 4a in 54% yield.10,11
Yieldsb (%)
Entry
Additive (equiv.)
Temp. (°C)
Time (h)
5b
5b′
1
—
130
130
130
80
24
30
30
45
77
72
0
0
0
11
2c
3
K2CO3 (3)
K3PO4 (3)
—
68
4
24 (56)c
a The reactions were carried out using 0.20 mmol of 3b in DMF (0.1 M)
under an Ar atmosphere. b Isolated yields were recorded. c Recovery
yield of hydrazone 3b.
Scheme 3 The reaction of α-quaternary hydrazone 3a.
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Table 2 Scope on allylic C–H amination with hydrazones 3a
Time
(h)
Yieldsb
(%)
Entry
Hydrazones
Products
1
2
3c: R2 = 4-MeOC6H4
3d: R2 = 4-BrC6H4
12
16
5c
5d
73
74
Scheme 5 Formation of 6-membered rings: the reactions were con-
ducted using 0.30 mmol of 3 in DMF (0.1 M) under an Ar atmosphere.
aThe stereochemistry of the hydrazone moiety of 3n was not
determined.
3
6
62
substituent R2 on the hydrazone nitrogen, 4-methoxy- and
4-bromophenyl groups were introduced to give the desired
dihydropyrazoles 5c and 5d, respectively, in good yields
(entries 1 and 2). The method allowed us to construct spirocyc-
lic dihydropyrazole 5e in 62% yield (entry 3). The reactions of
α-mono-substituted-γ,δ-unsaturated hydrazones 3f–h pro-
ceeded in a diastereoselective manner, delivering 4,5-trans-
dihydropyrazoles 5f–h in good to moderate yields (entries 4–6).
It is worth noting that hydrazone 3h having allylic (marked in
red) and benzylic (marked in green) C–H bonds exclusively
selected allylic one (entry 6). The reaction of γ,δ-unsaturated
hydrazone 3i having no substituent at the α-position with 2.5
equiv. of TEMPO resulted in the formation of an inseparable
mixture of aromatized pyrazole 5i and the corresponding dihy-
dropyrazole.15 The use of 4.5 equiv. of TEMPO could complete
aromatization to give pyrazole 5i in 80% yield (entry 7). Instal-
lation of a methyl group onto the alkene (either γ- or δ-posi-
tion) did not retard the allylic C–H amination, affording the
corresponding dihydropyrazoles (entries 8 and 9).
4
5
3f: R3 = Ph
3g: R3 = Me
20
20
5f
5g
80
53
6
20
72
7c
8
20
23
80
86
9
6
56
The present strategy could be extended further for construc-
tion of tetrahydropyridazine skeletons 5l–n from δ,ε-unsatu-
rated hydrazones 3l–n by rendering their β-position quaternary
to prevent the 1,5-H radical shift (Scheme 5-a). Similarly, the
present method enabled to synthesize dihydrophthalazine 5o
from benzene-tethered hydrazone 3o, while the yield was mod-
erate (Scheme 5-b).
a The reactions were carried out using 0.28–0.35 mmol of 3 with
TEMPO (2.5 equiv.) in DMF (0.1 M) at 130 °C under an Ar atmosphere.
b Isolated yields were recorded above. c The reaction was conducted
using 4.5 equiv. of TEMPO.
reactions were performed with slightly lower yield (entries
2 and 3). Lowering the reaction temperature from 130 °C to
80 °C renders the process sluggish, giving a mixture of dihydro-
pyrazoles 5b and 5b′ in 24% and 11% yields, respectively,
along with the recovery of 3b in 56% yield (entry 4). These
results implicated that higher temperature (130 °C) is indis-
pensable to realize the homolytic allylic substitution reaction
selectively to form 5b.
In summary, we have developed TEMPO-mediated radical
sp3-allylic amination with hydrazones for synthesis of aza-
heterocycles such as dihydropyrazoles and tetrahydropyrida-
zines. The process involves a sequence of remote H-radical
shift and allylic homolytic substitution that could be enabled
by the putative hydrazone radical. This method should be
readily adopted for synthesis of various azaheterocycles valu-
able in pharmaceutical and material-based applications.
This work was supported by funding from the Nanyang
Technological University and the Singapore Ministry of Edu-
cation (Academic Research Fund Tier 2: MOE2012-T2-1-014).
Having optimized the reaction conditions, we next examined
the scope and limitation of this allylic C–H amination using a
series of γ,δ-unsaturated hydrazones 3 (Table 2). By varying the
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saturation followed by 5-endo cyclization as shown in
Scheme 1.
4570 | Org. Biomol. Chem., 2014, 12, 4567–4570
This journal is © The Royal Society of Chemistry 2014