Cu-catalyzed aerobic oxidative cyclizations of 3-N-hydroxyamino-1,2-propadienes with alcohols, thiols, and amines to form α-O-, S-, and N-substituted 4-methylquinoline derivatives

Article abstract of DOI:10.1002/chem.201406317

A one-pot, two-step synthesis of α-O-, S-, and Nsubstituted 4-methylquinoline derivatives through Cu-catalyzed aerobic oxidations of N-hydroxyaminoallenes with alcohols, thiols, and amines is described. This reaction sequence involves an initial oxidation of N-hydroxyaminoallenes with NuH (Nu = OH, OR, NHR, and SR) to form 3-substituted 2-en-1-ones, followed by Bronsted acid catalyzed intramolecular cyclizations of the resulting products. Our mechanistic analysis suggests that the reactions proceed through a radical-type mechanism rather than a typical ni-trone-intermediate route. The utility of this new Cu-catalyzed reaction is shown by its applicability to the synthesis of several 2-amino-4-methylquinoline derivatives, which are known to be key precursors to several bioactive molecules.

Full text of DOI:10.1002/chem.201406317

DOI: 10.1002/chem.201406317
Communication
&
Synthetic Methods
Cu-Catalyzed Aerobic Oxidative Cyclizations of 3-N-
Hydroxyamino-1,2-propadienes with Alcohols, Thiols, and Amines
To Form a-O-, S-, and N-Substituted 4-Methylquinoline Derivatives
Pankaj Sharma and Rai-Shung Liu*[a]
Abstract: A one-pot, two-step synthesis of a-O-, S-, and N-
substituted 4-methylquinoline derivatives through Cu-cat-
alyzed aerobic oxidations of N-hydroxyaminoallenes with
alcohols, thiols, and amines is described. This reaction se-
quence involves an initial oxidation of N-hydroxyaminoal-
lenes with NuH (Nu=OH, OR, NHR, and SR) to form 3-sub-
stituted 2-en-1-ones, followed by Brønsted acid catalyzed
intramolecular cyclizations of the resulting products. Our
mechanistic analysis suggests that the reactions proceed
through a radical-type mechanism rather than a typical ni-
trone-intermediate route. The utility of this new Cu-cata-
lyzed reaction is shown by its applicability to the synthesis
of several 2-amino-4-methylquinoline derivatives, which
Figure 1. Representative bioactive molecules.
are known to be key precursors to several bioactive mole-
cules.
tuted 3-amino-2-en-1-ones [Eq. (2)];[9] this catalytic process is
postulated to involve an attack of nucleophiles (NuH) at alky-
nylnitrone intermediate A.
a-O- and N-substituted 4-methylquinoline motifs are found in
many pharmaceutical substances.[1–7] In several bioactive mole-
cules, a 4-methylquinoline fragment is attached to a main
active backbone to enhance its biological activity. Figure 1
shows several representatives (I–VI) to illustrate their specific
functions in various pharmaceutical applications. Compound I
serves as agonist/antagonist for Neuropeptide FF (NPFF) recep-
tors,[2a] whereas compound II possesses antibacterial activity.[2b]
Species III works as a bactericide/fungicide against Piricularia
oryzae.[3] Compounds IV and V serve as agonists for nonsterio-
dal Farnesoid X Receptor (FXR) and Melanin-Concentration
Hormone 1 Receptor (MCH1R), respectively.[4,5] The final com-
pound VI exhibits potent antimicrobial activity.[6] To meet its
widespread occurrence in drug design, 4-methylquinoline is
purchased commercially[7] to offer a three-step synthesis to
their a-O- and N-substituted derivatives [Eq. (1)];[8] however,
this synthetic method becomes inaccessible for those ana-
logues that bear an additional quinoline substituent, because
a commercial source is lacking.
Furthermore, wih anilines and other amine-based nucleo-
philes, these catalytic oxidations gave the 3-amino-2-en-1-one
products VII in poor yields (<20%).[9] In this work, we use dis-
tinct N-hydroxyaminoallenes and suitable nucleophiles RXH
(X=O, S, R’NH) to achieve a one-pot synthesis of a-substituted
4-methylquinolines through Cu-catalyzed aerobic oxidation
[Eq. (3)], which is further applicable to diverse a-O-, S-, and N-
substituted 4-methylquinolines, including those that contain
additional substituents at the quinoline position. Notably, our
mechanistic analysis indicates that the initial aerobic oxidation
of N-hydroxyaminoallenes proceeds through a radical-type
pathway rather than the generation of nitrone intermediates.
Equation (4) shows a synthetic protocol for the starting N-
hydroxyaminoallenes 1; 2,3-butadienols[10a,b] were first trans-
We reported Cu-catalyzed aerobic oxidations of N-hydroxya-
minoprop-1-ynes with alcohols and thiols, affording 3-substi-
[a] P. Sharma, Prof. Dr. R.-S. Liu
Department of Chemistry, National Tsing-Hua University
Hsinchu (30013) (Taiwan)
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.201406317.
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Table 2. Aerobic oxidation with various nucleophiles.
formed into their acetyl derivatives, which were subsequently
treated with [Pd(PPh3)4] (4 mol%) and a N-hydroxyaniline spe-
cies (1 equiv).[10c] Table 1 shows the aerobic oxidation of N-hy-
Table 1. Catalyst screening by using various oxidants.
Entry
Oxidant
Catalyst
([mol%])
Solvent/t [h]
Yield [%][b]
results are summarized in Table 2. In these products, hydrogen
bonding between NꢀH and C=O is assumed to be present
[Eq. (2)].[9] The corresponding oxidations of species 1a with
phenol and methanol gave 4-alkoxy-4-amino-3-en-2-ones 4a
and 4b in satisfactory yields (85–86%). Notably, compound 4b
exists as a mixture of two tautomers, with a ratio of 4b/4b’=
7:3. The reactions with thiols RSH (R=Et and Ph) yielded the
desired products 4c and 4d in 82–84% yield. Aniline and
benzyl amine were also compatible to give products 4e and
4 f in 90–92% yield. Here, species 4 f was present as a mixture
of Z/E isomers (Z/E=5:1); the major Z isomer is favored owing
to its acidic NHPh proton forming a strong hydrogen bond.
Highly functionalized 2-en-1-ones 4a–4 f were previously pre-
pared from uncommon and complex reagents, including b-
oxothio esters,[12] 3,5-disubstitued isoxazoles,[13] a-oxoketene
S,S-ketals,[14] b-ketothioamides,[15] and b-dichlorovinyl ketone-
s.[16a] No examples for the preparation of these reagents direct-
ly from acetyl acetates were documented. Each of these re-
agents is only applicable to one of the three families of com-
pounds 4a–4 f, whereas our method can cover all them exclu-
sively.
2a
3
1
2
3
4
5
6
7
8
9
O2
O2
O2
O2
O2
O2
O2
IPrCuCl (5)
IPrCuCl (1)
CuCl (5)
CuCl2 (5)
Cu(OAc)2 (5)
CuBr2 (5)
IPrCuCl (5)
IPrCuCl (5)
IPrCuCl (5)
IPrCuCl (5)
THF/16
THF/48
THF/16
THF/8
THF/3
THF/16
toluene/15
toluene/2
toluene/12
THF/16
91
90
66
80
76
86
92
70
65
62
–
–
–
–
–
–
–
30
35
–
TBHP[a,c]
DTBP[a]
[a]
10
H2O2
[a] Oxidants (3 equiv) for entries 8–10. [b] Yields are reported after
column purification on silica gel. [c] BHP=tert-butyl hydroperoxide,
DTBP=Di-tert-butyl peroxide. [d] [1a]=0.16m
droxy aminoallene 1a with various copper catalysts and oxi-
dants. Initially, we tested IPrCuCl (IPr=1,3-bis(diisopropylphe-
nyl)imidazol-2-ylidene) in THF (258C, 16 h) by using O2 (1 atm),
giving b-oxoamide 2a in 91% yield (entry 1). Although when
using a small Cu loading (1 mol%) the yield of 2a was main-
tained (90%), the duration of the reaction tripled (48 h,
entry 2). Under similar conditions, CuCl (5 mol%) was less ef-
fective, giving 2a in 66% yield (entry 3). CuII salts, such as
CuCl2, Cu(OAc)2, and CuBr2, were also catalytically active, pro-
viding yields of 80, 76, and 86%, respectively (entries 4–6). The
use of IPrCuCl in toluene resulted in compound 2a in an excel-
lent yield (92%, entry 7). With TBHP (tert-butyl hydroperoxide)
and DTBP (di-tert-butyl peroxide) as oxidants (3 equiv), IPrCuCl
gave b-oxoamide 2a in only 65–70% yield, together with tert-
butoxy-b-oxoamide 3 (30–35%) as a side product (entries 8
and 9).[11] The use of H2O2 and IPrCuCl yielded b-oxoamide 2a
in 62% yield (entry 10).
To approach our target compound 5a, 4-phenoxy-4-amino-
3-en-2-one 4a was treated with polyphosphoric acid (PPA,
300 wt%) in hot toluene (908C, 15 h) to afford a-phenoxy-4-
methyl-quinoline 5a in 89% yield [Eq. (5)].[16] The one-pot syn-
thesis was feasible by an initial treatment of species 1a with
phenol (1.5 equiv) and IPrCuCl (5 mol%) in toluene (258C, 7 h)
under O2 (1 atm). Then, PPA (300 wt%) was added to the re-
sulting solution before heating at 908C under N2 atmosphere;
this procedure gave 5a in 75% yield.
We tested the reaction of substituted N-hydroxyaminoal-
lenes containing various R and X substituents with diverse nu-
cleophiles (Nu-H, 2 equiv) to afford a-substituted-4-methylqui-
noline derivatives; the results are summarized in Table 3. The
one-pot operation follows the same procedure as described in
Equation (5) (1a!5a). The use of N-hydroxyaminoallene 1a
The formation of b-oxoamide 2a likely arose from the aero-
bic oxidation of N-hydroxyaminoallene 1a with H2O. To verify
this hypothesis, the oxidation with alcohols, amines, or thiols
and IPrCuCl as catalyst (5 mol%, 258C) in THF was tested; the
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work with 1,3-disubstituted allene analogues, which gave
a complicated mixture of products.
Table 3. Reaction scope of 4-methylquinoline derivatives.
Scheme 1 includes additional examples to provide a mecha-
nistic insight into the cyclization step. Notably, the same reac-
tion sequence with 4-chloroaniline species 1c yielded the un-
expected compound 5 f in 87% yield; its structure was clearly
identified by 13C NMR analysis. This observation indicates a fast
equilibrium between two geometric isomers B and B’, with
species B’ being more active in the cyclization step. However,
we did not see this reaction pattern when using 4-methoxyani-
line as a nucleophile (Table 3, entry 6); we postulate that the
corresponding intermediate C’ is not readily formed, because
its NꢀH is too weakly acidic to form effective hydrogen bond-
ing (C=O···HN). This sequence was successfully applied to the
synthesis of 4,6-dimethylquinoline species 5r in 81% yield; its
intermediate D’ is obviously more active than D in the cycliza-
tion. The same reaction sequence between substrate 1a and
3-methoxyaniline gave 6-metoxy-4-methylquinoline 5s and its
8-methoxy analogue 5s’ in 72 and 15% isolated yield, respec-
tively. The structures of products 5r, 5s, and 5s’ were carefully
1
determined by their H and 13C NMR spectra.
This Cu-catalyzed reaction was applied to the synthesis of
key precursors 6a–6d of bioactive molecules I, V, and VI, as
depicted in Scheme 2. Cu-catalyzed aerobic oxidation of N-hy-
droxyaminoallene 1a and benzylamine in toluene, followed by
acid-mediated cyclization, afforded 2-amino-4-methylquinoline
6a in 82% yield. We postulated that the initial product 6a’
was oxidatively cleaved by Cu and residual air to give the re-
sulting product 6a. Compound 6a was converted to the bioac-
tive molecule I according to a patent procedure.[2c] With the
same reaction sequence, we synthesized compounds 6b and
6c in 83 and 78% yield, respectively, starting from 1a and pi-
peridine or morpholine. Species 6b and 6c are the precursors
of bioactive molecules V, which are potent MCH1R antagonists
with excellent IC50 values.[5] Another precursor 6d was also pre-
pared with 1a and 4-methoxy-2-nitroaniline; a short synthesis
of bioactive molecule VI with species 6d is documented in a lit-
erature report.[6]
[a] [1]=0.16m, NuH (2 equiv), O2 (1 atm). [b] Product yields are reported
after purification on silica gel. [c] Reaction temperature is 1108C for en-
tries 7 and 8.
and methanol in toluene yielded the desired product 5b in
45% yield (entry 1). The oxidation cyclization sequence of the
same allene 1a with thiols RSH (R=Et and Ph) yielded thio-
substituted analogs 5c and 5d in 82 and 78%, respectively
(entries 2 and 3). In the reaction of N-hydroxyaminoallene 1a
with aniline, N-substituted 4-methylquinoline derivative 5e
was obtained in 87% yield (entry 4). Similarly, compounds 5 f
and 5g were produced in satisfactory yields (86 and 82%)
from 4-substituted anilines 4-XC6H4NH2 (X=Cl and OMe; en-
tries 5 and 6). We also examined the reaction of ethanethiol or
aniline with additional N-hydroxyaminoallenes 1b–1 f bearing
various aryl substituents (aryl=4-XC6H4, X=fluoro, chloro,
methyl, isopropyl, and tert-
butyl); in most cases, the ex-
pected 6-substituted-4-methyl-
quinoline derivatives 5h–5m
were produced in good yields
(75–86%), whereas 5i was ob-
tained in 46% yield (entries 7–
12). For the 3-butyl-substituted
4-N-hydroxyaminoallene
1g
(R=n-C4H9), the reactions pro-
ceeded smoothly to give highly
substituted products 5n and
5o in good yields of 86 and
84%, respectively (entries 13
and 14). X-ray diffraction of
compound 5e was performed
to characterize its structure.[7]
The same reactions failed to
Scheme 1. Reaction schemes showing the cyclization steps.
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composition of nitone A” to give N-hydroxyaniline, which was
subsequently oxidized by CuCl2.[17]
Scheme 2. Synthesis of key precursors to bioactive molecules.
The oxidative rearrangement of N-hydroxyaminoallene 1a
might proceed through a different mechanism than that of N-
hydroxyaminopro-1-ynes [Eq. (2)].[9] As shown in Scheme 3, we
envisaged that nitrone species A“ is expected to undergo
a facile hydration, rather than to react with a nucleophile (see
[Eq. (10)]). The data in Equation (9) suggests that a radical
pathway is operative in this system. As some N-hydroxyamines
are reported to undergo metal-free aerobic oxidations to gen-
erate N-amidoxyl radicals,[18,19] we speculate that substrate 1a
undergoes a Cu/O2 oxidation to generate amidoxy radical G to
induce a radical/allene cyclization,[20] yielding allylic radical H.
This radical subsequently yields a five-membered heterocycle I
after hydrogen abstraction from species 1a. In this radical pro-
cess, the presence of amidoxyl radical G in small proportions
enables completion of the reaction. A subsequent oxidation of
the resulting intermediate I with a nucleophile (NuꢀH) in the
presence of Cu/O2 will form the key intermediate K before pro-
ceeding to product 4. The 1,2-shift of species K is facilitated by
the heteroatom substituent (Nu=OR, SR, NHR), as well as the
charge polarity of the weak NꢀO bond.
Equation (6) shows a control experiment to elucidate the
role of the nitrone species A’. Treatment of allenyl aldehyde 7
and N-hydroxyaniline in THF in the presence of MeOH failed to
give the desired product 4g under O2 or N2 atmosphere. In
contrast, compound 4g could be obtained in 78% yield from
the Cu-catalyzed aerobic oxidation of N-hydroxyaminoallene
[Eq. (7)]. In Equation (6), we obtained a complicated mixture of
products from which nitrone species A’ could not be isolated
in a tractable amount. In the absence of a Cu catalyst, sub-
strate 1a underwent aerobic auto-oxidation in THF (308C,
48 h) to give b-carbonyl amide 2a in 68% yield, together with
unreacted 1a that was recovered in 30% yield [Eq. (8)]; the
role of IPrCuCl (1 mol%) is evident because it enables com-
plete conversion (Table 1, entry 2). Importantly, the reaction of
species 1a with MeOH (2 equiv) and TEMPO (10 mol%) under
N2 atmosphere and in hot toluene (708C, 12 h) afforded the
desired desired 4b and its tautomer 4b’ in a combined yield
of 80% [Eq. (9)], together with compound 8 in 4% yield. This
observation suggests that a radical type mechanism is likely to
occur to form compounds 4b/4b’ and 8. In the absence of
TEMPO, mainly starting material 1a was recovered (45%). Em-
ploying CuCl2 (1.5 equiv) as an oxidant [Eq. (10)] gave 1,2-dia-
zene oxide 9 in 65% yield, together with b-oxo amide 2a in
only 18% yield. This information excludes the intermediacy of
nitone A“, because 1,2-diazene oxide 9 is indicative of the de-
Scheme 3. Proposed radical pathway.
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[11] According to a recent paper by Li, the synthesis of compound 3 can be
postulated by the following mechanism; see: W. T. Wei, R.-J. Song, J.-H.
Li, Adv. Syn. Catal. 2014, 356, 1703–1707.
In summary, this work reports a one pot, two-step synthesis
of 2-O-, S-, and N-substituted 4-methylquinoline derivatives
through Cu-catalyzed aerobic oxidations of N-hydroxyaminoal-
lenes with alcohols, thiols, and amines.[21] This reaction se-
quence comprises an initial oxidation of N-hydroxyaminoal-
lenes with NuH (Nu=OH, OR, NHR, and SR) to form 3-substi-
tuted-2-en-1-ones, followed by their Brønsted acid catalyzed
intramolecular cyclizations. We postulate that the reaction pat-
tern is distinct from that of N-hydroxyaminopro-1-ynes report-
ed in our previous work; the corresponding nitrone intermedi-
ates are expected to very reactive toward hydration. To dem-
onstrate the synthetic value, we have applied this method to
the one-pot synthesis of several 2-amino-4-methylquinoline
derivatives that are known to be key precursors to several re-
ported bioactive molecules.
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Acknowledgements
The authors wish to thank the National Science Council Taiwan
and the Ministry of Education for supporting this work.
Keywords: aerobic oxidation · copper · hydroxyaminoallenes ·
4-methylquinolines · radical reactions
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Received: December 2, 2014
Published online on && &&, 0000
Chem. Eur. J. 2015, 21, 1 – 6
www.chemeurj.org
5
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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&
These are not the final page numbers! ÞÞ

Communication
COMMUNICATION
Two in one! A one-pot, two-step syn-
thesis of a-O-, S-, and N-substituted 4-
methylquinoline derivatives through Cu-
catalyzed aerobic oxidations of N-hy-
droxyaminoallenes with alcohols, thiols,
and amines is described (see scheme).
Our mechanistic analysis suggests a radi-
cal pathway.
&
Synthetic Methods
P. Sharma, R.-S. Liu*
&& – &&
Cu-Catalyzed Aerobic Oxidative
Cyclizations of 3-N-Hydroxyamino-1,2-
propadienes with Alcohols, Thiols, and
Amines To Form a-O-, S-, and N-
Substituted 4-Methylquinoline
Derivatives
&
&
Chem. Eur. J. 2015, 21, 1 – 6
www.chemeurj.org
6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!