Copper-Catalyzed Aerobic Oxidations of 3-N-Hydoxyaminoprop-1-ynes to Form 3-Substituted 3-Amino-2-en-1-ones: Oxidative Mannich Reactions with a Skeletal Rearrangement

Article abstract of DOI:10.1002/chem.201404201

Cu-catalyzed aerobic oxidations of readily available 3-N-hydroxyaminopro-1-ynes with water, alcohols, or thiols to form diverse 3-substituted 3-amino-2-en-1-ones are described. The utility of this catalysis is manifested by a wide scope of applicable N-hydroxyl propargylamines and nucleophiles, thus enabling the design of one-pot cascade or two-step sequential reactions. Besides synthetic significances, such oxidative Mannich reactions are mechanistically interesting because structurally reorganized products were obtained. Our mechanistic studies reveal that the aerobic oxidations involve initial formation of nitrone intermediates, followed by the attack of nucleophiles. Herein, water and MeOH implement the conversion of nitrone intermediates to reaction products in two distinct pathways. Go Mannich! Cu-catalyzed aerobic oxidations of 3-N-hydroxyaminopro-1-ynes with water, alcohols, or thiols to form diverse 3-substituted 3-amino-2-en-1-ones are reported (see scheme). Such oxidative Mannich reactions are mechanistically interesting, because structurally reorganized products were obtained.

Full text of DOI:10.1002/chem.201404201

DOI: 10.1002/chem.201404201
Communication
&
Organic Synthesis
Copper-Catalyzed Aerobic Oxidations of 3-N-Hydoxyaminoprop-1-
ynes to Form 3-Substituted 3-Amino-2-en-1-ones: Oxidative
Mannich Reactions with a Skeletal Rearrangement
Rahul Kisan Kawade, Chang-Chin Tseng, and Rai-Shung Liu*[a]
pared from uncommon and sophisticated reagents including
b-oxothioxo esters,[14a] a-oxoketene S,S-ketals,[14b] aryl isothio-
Abstract: Cu-catalyzed aerobic oxidations of readily avail-
cyanate,[14c] 3,5-disubstituted isoxazole,[14d] and b-ketothioamid-
able 3-N-hydroxyaminopro-1-ynes with water, alcohols, or
es.[14e] In this oxidative skeletal rearrangement, nitrone inter-
thiols to form diverse 3-substituted 3-amino-2-en-1-ones
are described. The utility of this catalysis is manifested by
a wide scope of applicable N-hydroxyl propargylamines
and nucleophiles, thus enabling the design of one-pot
cascade or two-step sequential reactions. Besides synthet-
ic significances, such oxidative Mannich reactions are
mechanistically interesting because structurally reorgan-
ized products were obtained. Our mechanistic studies
reveal that the aerobic oxidations involve initial formation
of nitrone intermediates, followed by the attack of nucleo-
philes. Herein, water and MeOH implement the conversion
of nitrone intermediates to reaction products in two dis-
tinct pathways.
mediates II were generated initially and attacked by nucleo-
philes before proceeding to the products. When water and
MeOH were utilized as nucleophiles, the routes to reaction
products proceeded through distinct pathways.
Iminium ions (I) are versatile reagents that react with nucleo-
philes to form new CꢀX bonds (X=C, N, O and S), as manifest-
ed by the Mannich reaction [Eq. (1)].[1] The formation of imini-
um ions by chemical oxidations of a NꢀCH functionality is an
appealing surrogate for the Mannich reaction because tertiary
amines are readily available reagents.[2] Numerous examples
were reported for such CꢀH functionalizations with nucleo-
philes using Cu,[3] Fe,[4] Ru,[5] Rh,[6] and V[7a] catalysts, combined
with tert-butyl hydroperoxide, di-tert-butylperoxide, or H2O2 as
oxidants. Dioxygen is free and environmentally benign; aerobic
oxidations of tertiary amines with nucleophiles (oxidative Man-
nich reactions) were achieved with Cu,[8] Ru,[9] Mo[10] V,[7b] and
Fe[11] catalysts or with dual metal/photo-oxidations[12] [Eq. (2)].
We sought new aerobic oxidations of tertiary amines with nu-
cleophiles beyond the present scope.[8f,13] We report here the
Cu-catalyzed oxidations of 3-N-hydoxyaminoprop-1-ynes to
form 3-substituted 3-amino-2-en-1-ones 2–4 that are useful
building blocks in organic syntheses [Eq. (3)]. Among these
products, highly functionalized 2-en-1-ones 3 and 4 were pre-
Table 1 shows the oxidative rearrangement of N-hydoxypro-
pargylamine 1a with various metal catalysts by using O2
(1 atm.) as the oxidant. We tested first CuCl (3 mol%) in hot
THF (408C), which gave b-oxoamide 2a in 88% yield (Table 1,
entry 1); this yield was maintained even for 1 mol% Cu catalyst
1
(entry 2). H NMR spectra in CDCl3 revealed that major species
2a equilibrated with its enol form 2a’ with 2a/2a’=7.0. [CuCl-
(IPr)] (IPr=1,3-bis(diisopropylphenyl)imidazol-2-ylidene) was
nearly as effective as CuCl yielding 2a in 87% yield (entry 3),
whereas CuBr and CuOTf were less effective yielding species
2a in 79 and 69% yields, respectively (entries 4 and 5). The use
of CuII salts, such as CuCl2 and Cu(OTf)2, gave product yields
(58–61%, entries 6 and 7), smaller than their CuI salts. Dioxy-
gen is the required oxidant because no reaction occurred
when starting with 1a under N2 (entry 8). CuCl maintained
good efficiency in 1,4-dioxane and toluene at 408C, giving the
desired product 2a in 77 and 86% yields, respectively (en-
tries 9 and 10). We also examined the oxidations with FeCl3
and RuCl3, which gave poor yields (23–42%) of compound 2a
[a] R. K. Kawade, C.-C. Tseng, Prof. Dr. R.-S. Liu
Department of Chemistry
National Tsing Hua University
Hsinchu, 30013 (Taiwan)
Fax: (+886)3-5711082
E-mail: rsliu@mx.nthu.edu.tw
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201404201.
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species that equilibrated with minor enol forms 2’. Table 2, en-
tries 1–4, show the applicability of this Cu-catalyzed oxidation
to substrates 1b–c and 1d–e bearing varied phenyl (R’=4-
XC6H4, X=OMe, Cl) and heteroaryl substituents (R’=3-thienyl
and 2-thienyl), affording b-oxoamides 2b–e in good yields
(80–88%, entries 1–4). The same oxidations were amenable to
substrates 1 f–g bearing aliphatic substituents (R’=n-pentyl
and tert-butyl), affording desired 2 f–g in 81–83% yields (en-
tries 5 and 6). For substrates 1h–j bearing various N-hydroxa-
mino groups with R=4-XC6H4 (X=Me and Cl) and benzyl, their
corresponding oxidations gave compounds 2h–j in 78–81%
yields (entries 7–9). Although b-oxo amides can be readily pre-
pared from b-oxo carboxylic acids and suitable amines,[16] our
new method is equally convenient using cheap reagents sour-
ces.
Table 1. Catalytic oxidations with various catalysts.
Entry
Cat.[a] ([mol%])
Solvent
Gas
t [h]
Yields [%][b,c]
1a
2a/2a’
1
2
3
4
5
6
7
8
CuCl (3)
CuCl (1)
[CuCl(IPr)] (1)
CuBr (1)
CuOTf (1)
CuCl2 (1)
Cu(OTf)2 (1)
CuCl (1)
CuCl (1)
CuCl (1)
FeCl3 (1)
RuCl3 (1)
–
THF
THF
THF
THF
THF
THF
THF
THF
1,4-dioxane
toluene
THF
THF
THF
O2
O2
O2
O2
O2
O2
O2
N2
O2
O2
O2
O2
O2
O2
7
8
–
–
–
–
–
–
–
88
88
87
79
69
14
5
14
24
8
12
10
8
58
61
78
–
–
trace
77
86
We envisage that the preceding reactions likely occur by an
attack of H2O at the nitrone intermediates II [Eq. (3)]. To verify
this hypothesis, we performed the reactions in hot THF con-
taining various alcohols and thiols (5 equiv, 408C), yielding E-
configured 3-substituted 3-amino-2-en-1-ones 3a–m and 4a–
b (Table 3); these products were isolated as 2-en-1-one forms
as sole (or major) species that equilibrated with minor tauto-
mers 3’–4’. As Table 3, entries 1–5 show, the Cu-catalyzed oxi-
9
10
11
12
13
14
2
7
–
23
–
42
24
24
59
63
18
16
–
toluene
[a] [1a]=0.22m, O2 (1 atm.). [b] Product yields (2a/2a’) are reported after
purification from a silica column. [c] Keto/enol (2a/2a’)=7.
under O2 (entries 11 and 12). In the absence of a metal catalyst,
3-N-hydoxyaminoprop-1-yne 1a still afforded b-oxoamide 2a
in 18 and 16% yields in THF and toluene, respectively, under
O2 (entries 13 and 14). The NMR spectroscopic data of com-
pound 2a are identical to those of an authentic sample.[15]
We assess the scope of such an oxidative rearrangement
with various N-hydoxypropargylamines bearing distinct R and
R1 substituents. b-Oxoamides 2 were formed as major (or sole)
Table 3. Catalytic oxidations with alcohols and thiols.[a]
Table 2. Catalytic oxidations with water.[a]
[a] [1]=0.22m, O2 (1 atm.), The ratio of keto/enol (2/2’) was determined
1
by H NMR spectroscopy by using CDCl3 as the solvent. [b] Product yields
[a] [1]=0.22m, NuH=(5 equiv), O2 (1 atm.), The ratio of 3/3’ was deter-
mined by H NMR spectroscopy by using CDCl3 as the solvent. [b] Product
1
of the keto/enol (2/2’) mixture are reported after purification from a silica
column.
yields are reported after purification from a silica column.
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dations of N-hydroxypropargylamine derivative 1a occurred
with various ROH groups (R=methyl, isobutyl, allyl, benzyl,
phenyl) to afford 3-alkoxy-3-amino-2-en-1-ones 3a–e in good
yields (71–93%). The reactions of species 1a with thiols (RSH,
R=Et and Ph) afforded thio-substituted analogues 4a and 4b
in 81 and 86% yields, respectively, (entries 6 and 7). For varied
N-hydroxypropargylamines bearing R’=4-XC6H4 (X=Cl and
OMe) and R’=2-thienyl, their aerobic oxidations with MeOH
yielded the desired products 3 f–g and 3h in 71–86% yields
(entries 8–10). We tested the reactions also on additional N-hy-
droxypropargylamines bearing R’=H and n-pentyl, delivering
2-en-1-al 3i and 2-en-1-one 3j in 83 and 80% yields, respec-
tively (entries 11–12). These aerobic oxidations were extendible
to substrates bearing various N-hydroxamino groups with R=
4-XC6H4 (X=Me and F) and benzyl, yielding the expected 2-en-
1-ones 3k–m in 78–92% yields, respectively (entries 13–15).
The molecular structures of compounds 3g and 3l were con-
firmed by X-ray diffraction.[17]
Table 4. Oxidations/Claisen rearrangement cascades.[a]
[a] [1]=0.22m, allylic alcohols (5 equiv), O2 (1 atm). [b] Product yields are re-
ported after purification from a silica column.
The facile introduction of alloxy groups into products 2 ena-
bles a cascade Claisen rearrangement,[18] as depicted in Table 4.
The reactions were catalyzed with CuCl (1 mol%) and O2 in hot
p-xylene (908C, 3–10 h), giving 2-allyl-3-oxoamides 5a–f effi-
ciently. Table 4, entries 1 and 2 show the reactions of allylic al-
cohol with N-hydroxypropargylamines 1a and 1j, yielding the
desired products 5a and 5b in 81 and 61% yields, respectively
(entries 1 and 2). The catalytic oxidations of these substrates
with 3,3-dimethyl-2-en-ol gave the corresponding products 5c
and 5d in 83–87% yields (entries 3 and 4). For 1- or 2-methyl-
2-en-1-ol, their reactions with propargylamine 1a afforded the
desired 5e and 5 f in 83 and 81% yields, respectively (entries 5
and 6). Although products like 5a–b, 5e, and 5 f can also be
prepared from the direct allylation of b-oxo-amide 2a/2a’, our
method is also convenient using different cheap reagents.
Table 5 manifests new synthetic utility using alkynols and al-
lenols in two-step reactions. With 2,3-butadien-1-ol and 3-
phenyl-2-propyn-1-ol, their corresponding Cu-catalyzed aerobic
oxidations produced 3-substituted 3-amino-2-en-1-ones 6a
and 6b in 78 and 79% yields, respectively (entries 1 and 2).
Heating compounds 6a and 6b in p-xylene and toluene yield-
ed dienones 7a and 7b by a Claisen-type rearrangement. We
also prepared similar 2-en-1-ones 6c and 6d, respectively,
from 3,4-pentadien-1-ol and 4-phenyl-3-butyn-3-ol; their sub-
sequent treatment with [P(tBu)2(o-biphenyl)AuSbF6] in hot DCE
(50–608C) afforded six- and seven-membered oxacyclic prod-
ucts 7c and 7d in 83 and 68% yields, respectively. The diene
Table 5. Synthetic utility with two-step reactions.[a]
Entry Step 1 6
(t, yields)[b,c]
Reagents Step 2
conditions
7 (yields)[b]
p-xylene,
908C, 5 h
1
2
–
–
toluene,
110 8C, 24 h
5 mol%,
[AuCl(L)]/
AgSbF6
DCE, 608C,
10 h
3[d]
1
5 mol%,
[AuCl(L)]/
AgSbF6
geometry of compound 7b was determined by H NOE spec-
troscopy.
toluene,
508C, 12 h
4[d]
The preceding Cu-catalyzed aerobic oxidations are mecha-
nistically interesting because the resulting products 2–4 in-
volve an oxidative skeletal rearrangement. The treatment of
species 1a with H2O* (2 equiv O*=98% 18O), O2, and CuCl
(1 mol%) in hot toluene (408C), at a 20% conversion level, af-
forded 18O-2a bearing one 18O atom (ca. 86% 18O content) at
the amide oxygen [Eq. (4)]. Notably, there was no 18O content
for the resulting b-oxoamide 2a when 18O2 was the oxidant
[Eq. (4)]. To generate nitrones II in-situ, N-hydroxyaniline and
alkynylaldehyde in equimolar proportions was treated with
[a] [1a]=0.22m, ROH (5 equiv), O2 (1 atm.); the ratio of 6/6’ was determined
by 1H NMR spectroscopy by using CDCl3 as the solvent. [b] Product yields
are reported after purification from a silica column. [c] [6/6’]=0.17m. [d] L=
P(tBu)2(o-biphenyl).
CuCl (1 mol%) and MeOH (2 equiv) in toluene (288C) under N2,
yielding the desired product 3a in 72% yield [Eq. (5)].
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Compound 3a was obtained in the same yield even though
CuCl was absent. In contrast, b-oxoamide 2a was produced in
only 4% yield when water was used as the nucleophile
(Table 6, entry 1) in THF (408C, 2 h) under N2; herein, diazene
Table 6. Effects of oxidants on water as a nucleophile.
Scheme 1. Proposed mechanisms for MeOH versus H2O.
(entries 1 and 3). For H2O, its corresponding intermediate III’ is
expected to have a f larger than that of species III derived
from MeOH (Thorpe–Ingold effect); accordingly species III’
tends to form species V without a cyclization. H2O2 is weaker
than water in nucleophilicity; the reaction of nitrone II with
aqueous H2O2 still generates species V as well. Some N-hy-
droxyamines were reported to undergo metal-free aerobic oxi-
dations to form N-amidoxyl radicals;[21] accordingly, we postu-
late that species V may be oxidized by H2O2 to form new N-
amidoxyl radicals VI that are very active in a cyclization to pro-
ducing species VII. With N-hydroxyamine V as a possible hy-
drogen donor, this alkenyl radical forms the desired intermedi-
ate IV’, ultimately yielding b-oxoamide 2a by a 1,2-hydride
shift. This mechanism rationalizes well the 18O-labeling experi-
ment [Eq. (4)].
Entry
Reagent/gas
Yield [%][a]
2a
8
1
2
3
4
5
H2O/N2
H2O/O2
30% H2O2/O2
30% tBuO2H/N2
30% tBuO2H/N2
4
14
51
11
33
23
20
8
22
14
[a] Product yields are reported after purification from a silica column.
oxide was obtained in 23% from the decomposition of N-hy-
droxyaniline. Under O2, the yield of b-oxoamide 2a was in-
creased to 14% (entry 2). Surprisingly, the use of H2O2 (2 equiv,
30% in water) greatly improved the reactions to afford b-oxoa-
mide 2a in 51% yield (entry 3). As aqueous tert-butyl hydro-
peroxide was used under N2, the yield of 2a was decreased to
11% (entry 4). Di-tert-butylperoxide was active to provide the
desired 2a in 33% yield (entry 5). Accordingly, the mechanisms
of the Cu-catalyzed aerobic oxidations with MeOH and water
evidently differed.
In summary, we report Cu-catalyzed aerobic oxidations of 3-
N-hydoxyaminoprop-1-ynes with water, alcohols, and thiols to
form b-oxo amides and 3-substituted 3-amino-2-en-1-ones.
The utility of this catalysis is manifested by a wide scope of ap-
plicable N-hydroxyl propargylamines and nucleophiles. With al-
lylic alcohols, alkynols, and allenols, we develop cascade or se-
quential reactions to involve a Claisen rearrangement or gold-
catalyzed cyclizations, providing new products with molecular
complexity. Notably, these oxidations involve structural reor-
ganization of products; the mechanisms have been elucidated
with 18O-labeling and control experiments. The aerobic oxida-
tions are postulated to involve initial formation of nitrone spe-
cies followed by attack of nucleophiles before proceeding to
products. Among these nucleophiles, the production of b-ox-
oamides 2 with water is facilitated by H2O2, whereas MeOH
alone implements effectively the conversion of nitrone to anal-
ogous products.
The control experiments in [Eq. (5)] and Table 6 reveal that
Cu-catalyzed oxidation of N-hydroxypropargylamine 1a with
O2 generates nitrone II and H2O2 as an initiate step,[19,20] as de-
picted in Scheme 1. We exclude the involvement of isoxazoli-
um salts (VIII) that could give desired 2a and 3a upon treat-
ment with strongly basic NaOH or NaOMe.[21] In contrast,
a prior attack of MeOH at nitrone species II is expected to
form oxonium species III bearing an acidic proton; this Brønst-
ed acid increases the electrophilicity of the alkyne to react fac-
ilely with the tethered oxygen anion, as depicted by the III!
IV conversion. We postulate a novel 1,2-hydride shift of species
IV to induce a ring cleavage, ultimately yielding the observed
product 3a; this 1,2-hydride shift is facilitated by the methoxy
group as well as by the weak and charge polarity of the NꢀO
bond in species IV. In Table 6, b-oxoamide 2a was produced
from nitrone more efficiently with aqueous H2O2 than with H2O
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Acknowledgements
The authors wish to thank the National Science Council,
Taiwan, and the Ministry of Education for supporting this work.
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Keywords: aminoenones
·
aerobic oxidations
·
copper
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Received: July 1, 2014
Published online on && &&, 0000
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Communication
COMMUNICATION
&
Organic Synthesis
R. K. Kawade, C.-C. Tseng, R.-S. Liu*
&& – &&
Go Mannich! We report Cu-catalyzed
aerobic oxidations of 3-N-hydroxyami-
nopro-1-ynes with water, alcohols, or
thiols to form diverse 3-substituted 3-
amino-2-en-1-ones (see scheme). Such
oxidative Mannich reactions are mecha-
nistically interesting because structurally
reorganized products were obtained.
Copper-Catalyzed Aerobic Oxidations
of 3-N-Hydoxyaminoprop-1-ynes to
Form 3-Substituted 3-Amino-2-en-1-
ones: Oxidative Mannich Reactions
with a Skeletal Rearrangement
&
&
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!