Copper-Catalyzed Three-Component Annulations of Alkenes, Nitrosoarenes, and N-Hydroxyallylamines To Form Fused Oxazinane/Isoxazolidine Heterocycles

Article abstract of DOI:10.1002/anie.201611388

One-pot cascade annulations among nitrosoarenes, alkenes, and N-hydroxyallylamines have been achieved with CuCl/O₂catalysts, forming fused oxazinane/isoxazolidine heterocycles with excellent diastereoselectivity (d.r. >20:1). To enhance the synthetic utility, we developed a successive cleavage of the two N?O bonds of the resulting heterocycles. A mechanism involving dipolar [3+2] cycloadditions of nitrone intermediates with their tethered alkenes is postulated for formation of these heterocycles.

Full text of DOI:10.1002/anie.201611388

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201611388
German Edition: DOI: 10.1002/ange.201611388
Cycloadditions
Copper-Catalyzed Three-Component Annulations of Alkenes,
Nitrosoarenes, and N-Hydroxyallylamines to Form Fused Oxazinane/
Isoxazolidine Heterocycles
Rahul Kisan Kawade and Rai-Shung Liu*
Abstract: One-pot cascade annulations among nitrosoarenes,
alkenes, and N-hydroxyallylamines have been achieved with
CuCl/O2 catalysts, forming fused oxazinane/isoxazolidine
heterocycles with excellent diastereoselectivity (d.r. > 20:1).
To enhance the synthetic utility, we developed a successive
À
cleavage of the two N O bonds of the resulting heterocycles. A
mechanism involving dipolar [3+2] cycloadditions of nitrone
intermediates with their tethered alkenes is postulated for
formation of these heterocycles.
À
H
eterocycles containing N O bonds, such as derivatives of
isoxazolidines and 1,2-oxazinanes, are important structural
cores in many naturally occurring compounds.[1] Among
numerous methods developed toward the synthesis of these
Figure 1. Representative bioactive molecules.
two N O-containing rings,[2] the dipolar [3+2] cycloadditions
À
of nitrones with alkenes,[3,4] and [4+2] cycloadditions of
dienes with nitroso groups represent the two most prominent
systems.[5,6] Importantly, their stereo- and enantioselective
synthesis of these bioactive molecules is challenging because
several stereogenic centers are present in the structures. We
envisage that one-pot stereoselective construction of a bicyclic
versions have been satisfactorily achieved with suitable
[7]
À
À
catalysts; a facile cleavage of the N O bonds of the
ring bearing two N O bonds is a viable route. This work
resulting products affords useful 1,3- and 1,4-aminoalcohols
efficiently.
describes Cu-catalyzed oxidative annulations among nitroso-
arenes, alkenes, and N-hydroxyallylamines to deliver bicyclic
1,2-oxazinane/isoxazolidine fused rings (Equation (3)). To
À
enhance the utility, a successive cleavage of two N O bonds is
developed to provide two different products, highly function-
alized isoxazolidines and acyclic aminoalcohols [Eq. (3)].
The unique aspect of this work utilizes nitrosoarenes as
diradical precursors to develop the first three-component
annulations.[9a] In nitroso–ene reactions, nitroxyl diradicals
seem to be viable intermediates according to theoretical
studies.[9b–c]
Table 1 optimizes catalytic annulations among N-
hydroxyallylamines 1a (1.0 equiv),[10] styrene 2a (2.0 equiv),
and nitrosobenzene 3a (1–2 equiv) over various catalysts. In
a typical operation, nitrosobenzene 3a was slowly added to
a mixture of 1a/2a/catalyst in hot toluene (608C) over
a period of 2 h to furnish the reactions. With nitrosobenzene
at two-fold excess, two bicyclic heterocyles 4a and 5a were
isolated in 35% and 36% yields, respectively; here, the
undesired 6 arose from a metal-free reaction of nitrosoben-
zene 3a with styrene 2a.[9a] A low loading of nitrosobenzene
(1 equiv) greatly improved the yield of bicyclic species 4a to
68%. Among other Cu catalysts (entries 3–7), only CuCl2 and
CuBr gave the desired heterocyle 4a in satisfactory yields
(58–59%, entries 4 and 7). Under N2, compound 4a was also
produced with 35% yield; this outcome will be rationalized in
the mechanistic discussion. Notably, in the absence of
a catalyst, the reaction still afforded heterocycles 4a and 5a
in 7–8% yields, together with unreacted 1a in a 63%
À
Many bioactive molecules comprise not only one N O
ring, but also amino and alcohol functionalities; selected
examples I–VI are depicted in Figure 1.[8] Stereoselective
[*] Dr. R. K. Kawade, Prof. Dr. R.-S. Liu
Department of Chemistry
National Tsing-Hua University
Hsinchu (Taiwan)
E-mail: rsliu@mx.nthu.edu.tw
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201611388.
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Table 1: Three-component annulation over various catalysts.
under this aerobic oxidation. These annulations were com-
patible not only with electron-rich styrene derivatives 2b–2c
(X = Me, OMe), but also with their electron-deficient ana-
logues 2d–2 f (X = F, Cl, and NO2), affording compounds 4a–
4 f in 51–73% yields. Electron-deficient styrenes seem to be
more efficient than their electron-rich analogues (entries 2–
6). For 3- and 2-thienylethenes 2g and 2h, their corresponding
products were obtained with 61–66% yields (entries 7–8).
The reaction is applicable to 2-pyridinylethene 2i to afford
desired 4i in 41% yield together with side product 5i in 21%
yield (entry 9). Other nitrosobenzenes 3b–3c (X = Me, Cl)
were also suitable for these annulations to afford compounds
4j and 4k in 60% and 52% yields, respectively (entries 10–
11).
Entry 3a (n equiv) Catalyst (10 mol%) t [h]
Yields [%][b]
4a 5a
6
7
1
2
3
4
5
6
7
8
9
2
1
1
1
1
1
1
1
1
CuCl
CuCl
IPrCuCl
CuBr
CuI
6
8
12
9
14
14
7
12
40
35 35 12 10
68
–
–
7
6
4
4
–
6
8
18
15
14
4
30 26
58 12
33 34
(CuOTf)2L
CuCl2
CuCl[c]
24
59
35
7
6
5
4
8
The scope of these reactions is significantly expanded with
variable N-hydroxyallylamines bearing an electron-withdraw-
ing group (Table 3). We did not isolate any competitive
12 14
16
[d]
–
4
IPr=1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene. L=benzene.
[a] [1a]=0.19 M. [b] Product yields are reported after purification from
a silica column. [c] N2 at 1 atm. [d] 1a was recovered in 63%.
Table 3: Reactions of various N-hydroxyallylamines.
recovery. This observation is helpful to the reaction mecha-
nism (entry 9). The molecular structures of two bicyclic
heterocycles 4a and 5a are inferred from X-ray diffractions of
their relatives 4 f and 5d;[11] only one diastereomeric product
was formed for each product (d.r. > 20:1).
We assessed the scope of the reactions using various
styrenes and nitrosoarenes under the same conditions as
depicted in Table 2. In all of the cases, resulting heterocycles
4a–4k were produced as single diastereomeric products (d.r.
> 20:1). In some entries, other heterocycles 5c–5d and 5i
were produced in minor portions. Species 1 bear a dimethyl
À
substituent to avoid ArN(OH) CH to become a nitrone
Table 2: Reactions of various styrene derivative.
[a] [1d]=0.13 M. [b] Product yields are reported after purification from
a silica column.
heterocycle such as species 5. Nitrosoarenes were used with
1.5 equimolar proportion because byproducts 6 were pro-
duced with minor proportions (yields < 20%). Resulting
heterocycles 8a–8n were obtained as single diastereomers
(d.r. > 20:1), despite there being four stereogenic centers. The
structures were elucidated by X-ray diffraction of one
representative 8 f.[11] In the reaction of unsaturated ester 1d
with styrene derivatives (X = Me (2b), Cl (2c), and F (2d))
[a] [1a]=0.19 M. [b] Product yields are reported after purification from
a silica column.
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and nitrosobenzene, their corresponding products were
We noted that heterocyles 4a and 5a were obtained in low
produced with reasonable yields (54–67%, entries 1–4). The
same reactions with 2- and 3-thienylethenes 2e–2 f afforded
desired compounds 8e and 8 f in 64% and 69% yields,
respectively (entries 5–6). For a cyclopentyl-bridged N-
hydroxyallylamine 1g, its corresponding annulation yielded
species 8g in 58% yield (entry 7). Other N-hydoxyaminoallyl
esters 1h and 1i were also applicable substrates to afford
desired 8h and 8i (R = benzyl and tert-butyl) in 62–65%
yields (entries 8–9). We also prepared unsaturated ketones
1j–1l to deliver our targets 8j–8l (R = Ph, Me, n-hexyl) in 31–
65% yields (entries 10–12). Other nitrosobenzenes 3b and 3c
were applicable to these annulations to produce compounds
8m–8n in 54–59% yields (entries 13–14).
yields (7–8%) in the absence of a catalyst (Table 1, entry 9).
We treated these three reactants with DTBP (di-tert-butyl-
peroxide, 1 equiv) under N2 without any catalyst, yielding
compounds 4a and 5a to 33% and 32% yields, respectively
(Scheme 2). Accordingly, CuCl/O2 is an oxidant but affects
The utility of annulation products 4 and 8 is highlighted by
their chemical transformations to various N- and O-function-
À
alized motifs (Scheme 1). In a reductive cleavage of two N O
Scheme 2. Control experiments.
the 4a/5a product ratio. Among styrene, nitrosobenzene, and
N-hydroxyallylamine, only the styrene/nitrosobenzene pair
showed noticeable reactions in the presence of CuCl/O2. At
a standard 5 h, this mixture in toluene yielded isoxazolidine 6
and nitrone 6’ and unreacted 2a/3a in 22%, 22%, and 56/
58%, respectively, consistent with
a literature report
(entry 1).[9] In the presence of CuCl/O2, the product yields
of compounds 6 and 6’ remained nearly unaffected. These
results suggest that N-hydroxyallylamines 1a affects the
chemoselectivity of the nitroso/styrene reaction, in order to
deliver new heterocycles 4a and 5a.
Scheme 3 shows a consistent mechanism for the formation
of desired heterocycles 4 and 5, which strongly indicates the
intermediacy of nitrone species E. The reaction of nitro-
sobenzene with styrene was reported to yield isoxazolidine 6
and nitrone 6’ via a postulated diradical A.[9a] This radical
pathway was supported by theoretical studies of nitroso–ene
reactions.[9b–c] Diradical
A is unaffected by CuCl/O2
(Scheme 2), but its interception with N-hydroxyallylamine is
expected to give two persistent nitroxy radicals A’ and C. This
À
Scheme 1. Single and double cleavages of N O bonds.
rings, model molecule 4a was subjected to Pd/C/H2 in
MeOH,[12a] yielding acyclic 2-methylhydroxy-1,3-diamino-4-
ol 9a as a single diastereomer (d.r. > 20:1). For an ester 8a, its
initial reduction with LiAlH4 afforded the alcohol 8a’ that
was transformed into 3-methylamino-4-amino-1,2,5-triols 9b
efficiently. We also performed a reductive cleavage on
compound 5a to afford a seven-membered heterocycle 9c
stereoselectively; the structure was assigned based on a com-
parison with the 13C NMR data of compounds 9a and 9b. To
À
increase their utility, we developed a selective N O cleavage
of these products using Zn/AcOH in THF,[12b] as manifested
À
by compounds 8c and 4a, which undergo a single N O
cleavage selectively at their isoxazolidine ring to form
products 9d and 9 f stereoselectively. These structures were
confirmed by X-ray diffraction.[11]
Scheme 3. A postulated mechanism for three-component annulations.
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35% yield (entry 8, Table 1). CuCl likely catalyzed the
oxidation of species D with nitrosobenzene to yield nitrone
E (or E’) and N-hydroxyaniline.
In summary, we report new cascade Cu-catalyzed annu-
lations of styrenes, nitrosobenzene, and N-hydroxyallyl-
amines to yield fused 1,2-oxazinane/isoxazolidine hetero-
cycles with excellent stereoselectivity. To highlight the
À
synthetic utility, we have developed single and double N O
cleavages of these bicyclic products, allowing efficient pro-
duction of highly functionalized 1,2-oxazinanes, acyclic 2-
methylhydroxy-1,3-diamino-4-ols, and new bicyclic hetero-
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styrene; the final step involves dipolar [3+2]-cycloaddition of
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We thank Ministry of Science and Technology, Taiwan for
financial support.
Conflict of interest
The authors declare no conflict of interest.
Keywords: amino alcohols · annulations · copper catalysis ·
dipolar [3+2]-cycloadditions · heterocycles
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Manuscript received: November 21, 2016
Revised: December 15, 2016
Final Article published: && &&, &&&&
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Communications
Cycloadditions
R. K. Kawade, R.-S. Liu*
&&& — &&&
Copper-Catalyzed Three-Component
Annulations of Alkenes, Nitrosoarenes,
and N-Hydroxyallylamines to Form Fused
Oxazinane/Isoxazolidine Heterocycles
One-pot cascade annulations among
nitrosoarenes, alkenes and N-hydroxy-
allylamines with CuCl/O2 catalysts are
described, forming fused oxazinane/iso-
xazolidine heterocycles with excellent
diastereoselectivity.
6
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