Gold-catalyzed N, O-functionalizations of 6-allenyl-1-ynes with n-hydroxyanilines to construct benzo[b]-azepin-4-one cores

Article abstract of DOI:10.1021/acs.orglett.7b02629

Gold-catalyzed reactions of 6-allen-1-ynes with N-hydroxyanilines afford thermally stable benzoazepin-4-ones in anti-selectivity; these anti-configured products are easily isomerized to their syn-isomers on a silica column. The mechanism of reactions likely involve initial nitrone/allene cycloadditions, followed by skeletal rearrangement of resulting intermediates.

Full text of DOI:10.1021/acs.orglett.7b02629

Letter
pubs.acs.org/OrgLett
Gold-Catalyzed N,O‑Functionalizations of 6‑Allenyl-1-ynes with
N‑Hydroxyanilines To Construct Benzo[b]‑azepin-4-one Cores
Antony Sekar Kulandai Raj,† Balaji S. Kale,† Bhanudas Dattatray Mokar, and Rai-Shung Liu*
Department of Chemistry, National Tsing-Hua University, Hsinchu, 30013, Taiwan, ROC
S
* Supporting Information
ABSTRACT: Gold-catalyzed reactions of 6-allen-1-ynes with
N-hydroxyanilines afford thermally stable benzoazepin-4-ones
in anti-selectivity; these anti-configured products are easily
isomerized to their syn-isomers on a silica column. The
mechanism of reactions likely involve initial nitrone/allene
cycloadditions, followed by skeletal rearrangement of resulting
intermediates.
itrones are versatile building blocks to construct
isoxazolidine frameworks through diastereo- or enantio-
Scheme 1. Chemoselectivities between Allenes and Nitrones
N
selective [3 + 2]-cycloadditions with alkenes;1 these species are
commonly generated in situ from the reactions of N-
hydroxyamines with aldehydes.2 Ketone-derived nitrones (R,
R′ = alkyl or aryl) are generally kinetically unstable3a unless R′
or R″ is an electron-withdrawing group.3b−e With aldehyde-
derived nitrones, unactivated allenes generally deliver pyrroli-
din-3-ones (II) from a rearrangement of 5-alkylideneisoxazo-
lidines (I),4 whereas electron-deficient allenes typically afford
indole derivatives IV or V through a facile rearrangement of
unstable benzoazepin-4-one intermediates III′.5 [3 + 2]-
Cycloadditions of ketone-derived nitrones (R′, R″ = alkyl or
aryl) with unactivated allenes still remain undocumented.6 In
our recent findings, terminal alkynes react with N-hydroxyani-
lines to generate ketone-derived nitrones that enable [3 + 2]-
cycloadditions with tethered alkenes.7 We report here gold-
catalyzed N,O-functionalizations of 6-allenyl-1-ynes with N-
hydroxyanilines to initially generate these nitrones (VI), further
affording benzoazepin-4-ones efficiently. Notably, the kinetic
control of these new reactions is to form anti-configured
products, which are subsequently isomerized to their syn-
isomers on a silica column (Scheme 1).
The importance of this work is to provide a facile and
stereoselective construction of valuable benzoazepin-4-one
cores that are present in bioactive molecules VII−XII.8
Homocryptolepione (VII) is a natural product isolated from
the Ghanaian plant, gryptolepis sanquinolenta;8a,b oxcarbaze-
pine (VIII) was used to treat epilepsy and bipolar disorder.8c
Dehydrotolvaptan (IX)8d exhibited oxytocin and vasopressin
antagonists whereas benzoazepin-4-ol (X)8e showed in vitro
antiparasitic activity against trypanosome cruzi. Species XI and
XII are mitochondrial benzodiazepine receptor (MBR)
receptors (Figure 1).8f
Table 1 optimizes the reactions with common gold catalysts.
Our initial tests employed IPrAuCl/AgX (5 mol %, X = NTf2
and OTf) to catalyze the reactions of 6-allenyl-1-yne 1a with N-
hydroxyaniline 2a in dichloromethane (DCM, 25 °C, 20 h),
affording benzoazepin-4-one 3a in 40% and 38% yields,
respectively; unreacted 6-allenyl-1-yne 1a was recovered in
27−31% (entries 1−2). A high loading (10 mol %) of IPrAuCl/
AgNTf2 led to a complete consumption of the initial 1a to yield
the desired 3a in 71% (entry 3). Heating this mixture in DCE at
60 °C (2.5 h) further improved the yield of 3a up to 85%
(entry 4). With a small loading (1.2 equiv) of N-hydroxyaniline,
the reaction still gave the desired 3a in 87% yield. A switch of
catalyst to P(t-Bu)2(o-biphenyl)AuCl/AgNTf2 (10 mol %)
maintained the same efficiency in hot DCE (60 °C, 2 h, entry
6). The reactions became less efficient in other solvents such as
THF, toluene and DMF, giving the desired 3a in low yields
(entries 7−9). The proposed structure of compound 3a was
Received: August 24, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02629
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Organic Letters
Letter
a b
,
Table 2. Reactions with Various 6-Allenyl-1-ynes
Figure 1. Representative bioactive molecules.
Table 1. Synthesis of Benzoazepin-4-ones with Various
a
Catalysts
b
yield (%)
3a 4a
40 42
entry
catalyst (mol %)
n
solvent
°C/h
1
2
3
4
5
6
7
8
9
IPrAuCl/AgNTf2 (5)
IPrAuCl/AgOTf (5)
IPrAuCl/AgNTf2 (10)
IPrAuCl/AgNTf2 (10)
IPrAuCl/AgNTf2 (10)
LAuCl/AgNTf2 (10)
IPrAuCl/AgNTf2 (10)
IPrAuCl/AgNTf2 (10)
IPrAuCl/AgNTf2 (10)
2
DCM
DCM
DCM
DCE
25/20
25/20
25/12
60/2.5
60/1.5
60/2
2
38
71
85
87
86
35
40
−
42
20
15
−
a
b
[1a] = 0.3 M. Product yields are obtained after purification from a
2
silica column. IPr = 1,3-bis(diisopropylphenyl)imidazol-2-ylidene.
2
1.2
1.2
1.2
1.2
1.2
DCE
yields (82−90%, entries 14−18). 6-Allenyl-1-ynes (1a′−1c′)
bearing alkynyl esters or ketones were also compatible with
these reactions, yielding desired benzoazepin-4-ones 4a−4c in
high yields (90−92%, entries 19−21).
DCE
−
THF
60/24
60/24
60/5
20
20
−
toluene
DMF
a
The scope of reactions is significantly expanded with their
compatibility with various N-hydroxyanilines (Table 3). We
prepared N-hydroxyanilines 2b−2c bearing p-phenyl substitu-
ents including R = Me and tert-butyl to test the reactions, their
resulting benzoazepin-4-ones 5a−5b were obtained in satisfac-
torily yields (79−82%). Notably, N-hydroxyanilines 2d−2f
bearing R = Br, Cl and CO2Et were also applicable substrates
[1a] = 0.3 M, 6-allenyl-1-yne 1a was recovered in 27% and 31% in
entries 1−2. Product yields are obtained after purification from a
silica column. IPr = 1,3-bis(diisopropylphenyl)imidazol-2-ylidene, L =
b
P(t-Bu)2(o-biphenyl).
inferred from X-ray diffraction9 of its relative 3i (Table 2, entry
8).
Table 2 shows the scope of these catalytic reactions with 6-
allenyl-1-ynes 1 bearing various substituents on alkynes, allenes
and bridging units X. For NTs or NMs-bridged 6-allenyl-1-ynes
1b and 1c, their reactions with N-hydroxyaniline 2a delivered
benzoazepin-4-ones 3b and 3c in reasonable yields (56−65%,
entries 1−2). We prepared O- and N-linked alkyl-substituted
allenes 1d−1f; their resulting benzoazepin-4-ones 3d−3f were
obtained with high yields and good diastereoselectivity (dr
>10:1, entries 3−5); proton NOE confirms the syn-config-
uration of the major isomers. For aryl-substituted allenes 1g−
1k, their corresponding products 3g−3k were produced
efficiently and highly diastereoselectively (dr > 7:1 entries 6−
10); the molecular structure of compound 3i was confirmed by
X-ray diffraction to confirm the syn-configuration.9 We also
prepared 6-allenyl-1-ynes 1l−1n bearing one or two sub-
stituents at the C(5)-carbon, yielding desired benzoazepin-4-
ones 3l−3n as single diastereomers exclusively (entries 11−
13); these C(5)-substituents significantly enhance the product
yields (>90%) because of the Thorpe−Ingold effects.10 We also
examined the reactions on trisubstituted allene substrates 1o-
1s, affording desired benzo azepin-4-ones 3o−3s in satisfactory
a b
,
Table 3. Reactions with Various N-Hydroxyanilines
a
b
[1l] = 0.3 M. Product yields are obtained after purification from a
silica column. IPr = 1,3-bis(diisopropylphenyl)imidazol-2-ylidene.
B
DOI: 10.1021/acs.orglett.7b02629
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Letter
although the mechanisms involve anilinium carbocations. For
2-choro substituted derivative 2g, its corresponding product 5f
was obtained in 77% yield.
Scheme 3. Postulated Mechanisms
Notably, 1H NMR spectra of crude 3g indicates that the anti-
isomer 3g′ is the major species (anti/syn = 1.9:1); purification
of this crude mixture on a silica column allowed a rapid
epimerization, yielding syn-isomer 3g (syn/anti = 17:1)
predominantly. To ascertain this anti-selectivity, we prepared
trisubstituted allene substrates 1t−1u and 1d′, affording desired
products 3t′−3u′ and 4d′ as single isomeric products; the anti-
configurations of compounds 3t′ and 4d′ were established by
1H NOE spectra. The molecular structure of compound 3t′ was
again confirmed by X-ray diffraction.9
This work reports unprecedented nitrone/allene reac-
tions,4−6 affording kinetically stable benzoazepin-4-ones 3′
with anti-selectivity, which subsequently rearrange to their syn-
isomers. Reported heterocycles such as pyrrolidin-3-ones (II)
and indole derivatives IV or V, as depicted in Scheme 1, are
Scheme 2. Data to Confirm the anti-Selectivity
Dipolar [3 + 2]-cycloadditions of ketone-derived nitrones
with unactivated allenes remain unexplored in nitrone
chemistry.6 We report the feasibility of such reactions through
gold-catalyzed N,O-functionalizations11,12 of 6-alllenyl-1-ynes
with N-hydroxyanilines to afford stable benzoazepin-4-ones in
anti-selectivity. These anti-configured products are easily
isomerized to their syn-isomers on a silica column. Such a
chemoselectivity and antiselectivity is rationalized with a
postulated gold-enolate intermediate bearing an anilinium
moiety; its preferable conformation controls the chemo-
selectivity and stereoselection of benzoazepin-4-one products.
completely absent.4−6 In a postulated mechanism, as depicted
in Scheme 3, gold-catalyzed attack of N-hydroxyaniline at
alkynes A forms species B, and eventually nitrones C; this N-
attack regioselectivity as represented by B is operable only in
the presence of an alkene7 or alllene in this system. A
subsequent nitrone/allene cycloaddition yields 5-alkylidenei-
soxazolidine species D, followed by a gold-catalyzed N−O
cleavage to yield a gold enolate E bearing an anilinium moiety.
Two possible conformations, E or E′, are conceivable for this
enolate intermediate to affect their reaction chemoselectivity
toward pyrrolidin-3-ones F versus benzoazepin-4-ones 3′.
Herein, conformation E is difficult to form because of a steric
hindrance between the methyl and anilinium groups. In our
preferable conformation E′, methyl is larger than its adjacent
hydrogen, rendering its anilinium ring lying above the enolate
moiety; accordingly, this intramolecular cyclization is expected
to yield benzoazepin-4- ones 3′ with anti-selectivity. We
envisage that the amino group of species 3′ facilitates its anti/
syn isomerization through a proton transfer.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02629.
■
S
Experimental details and spectral data of all compounds
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: rsliu@mx.nthu.edu.tw.
ORCID
Rai-Shung Liu: 0000-0002-2011-8124
Author Contributions
†A.S.K.R. and B.S.K. contributed equally.
Notes
The authors declare no competing financial interest.
Herein, we do not exclude an alternative process involving a
3,3-sigamatropic rearrangement of intermediate D′ that has a E-
configured alkene. This rearrangement will also provide anti-
configured precursor G before a tautomerization to the final
product 3′.
ACKNOWLEDGMENTS
The authors thank the financial support of this work from
Ministry of Science and Technology, Taiwan.
■
C
DOI: 10.1021/acs.orglett.7b02629
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Letter
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DOI: 10.1021/acs.orglett.7b02629
Org. Lett. XXXX, XXX, XXX−XXX