Gold-Catalyzed [4+2] Annulation/Cyclization Cascades of Benzisoxazoles with Propiolate Derivatives to Access Highly Oxygenated Tetrahydroquinolines

Article abstract of DOI:10.1002/anie.201707423

This work describes gold-catalyzed annulations of electron-deficient alkynes with benzisoxazoles to yield quinoline oxides chemoselectively. Chemical functionalizations of these resulting azacyclic compounds afforded various oxygenated tetrahydroquinolines which are present as the cores of many bioactive molecules. With the same reactants, a new relay catalysis using gold and zinc(II) catalysts affords highly oxygenated tetrahydroquinoline derivatives stereoselectively.

Full text of DOI:10.1002/anie.201707423

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Accepted Article
Title: Gold-catalyzed [4+2]-Annulation/Cyclization Cascades of
Benzisoxazoles with Propiolate Derivatives to Access Highly
Oxygenated Tetrahydroquinolines
Authors: Rajkumar Lalji Sahani and Rai-Shung Liu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201707423
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10.1002/anie.201707423
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Gold-catalyzed [4+2]-Annulation/Cyclization Cascades of
Benzisoxazoles with Propiolate Derivatives to Access Highly
Oxygenated Tetrahydroquinolines
Rajkumar Lalji Sahani and Rai-Shung Liu*
Abstract: This work describes gold-catalyzed annulations of
electron-deficient alkynes with benzisoxazoles to yield quinoline
oxides chemoselectively. Chemical functionalizations of these
resulting azacyclic compounds afforded various oxygenated
tetrahydroquinolines that are present as the cores of many bioactive
molecules. With the same reactants, a new relay catalysis using gold
and Zn(II) catalysts affords highly oxygenated tetrahydroquinoline
derivatives stereoselectively.
alkynes with poor nucleophiles.[6] The use of N-O containing
nucleophiles is a viable route to access valuable azacyclic
frameworks. Ye[7] and Hashmi[8] reported interesting [3+2]-
annulations of isoxazoles and benzisoxazoles with electron-rich
ynamides,
yielding
substituted
pyrrole
derivatives
chemoselectively (eq 1). These annulations are expanded to
other N-O heterocycles including 1,2,4-oxadiazoles,[9a] 1,4,2-
dioxazoles[9b] and 4,5-dihydro-1,2,4-oxadiazoles;[9c] but typical
[3+2]-annulations occurred to yield five-membered azacycles (eq
2). We reported distinct [4+1]-annulations of electron-deficient
propiolates with isoxazoles to give pyrrole derivatives (eq 3),[10]
but the C-C triple bonds of propiolate derivatives were cleaved
to reflect the distinct reactivity of propiolates. In gold catalysis,
the use of N-O heterocycles as the nucleophiles afforded five-
membered azacycles nearly exclusively.[11] Here, we describe
gold-catalyzed [4+2] annulation/cyclization cascades between
benzisoxazoles and propiolate derivatives, yielding quinoline
oxides 3 efficiently (eq 4). With the same reactants, we
developed also a new relayed catalysis using Au(I)/Zn(II)
sequentially, enabling one-pot productions of highly oxygenated
tetrahydroquinolines 7 (eq 5). Compounds 3 are accessible to
the cores of endochin (I), WR-109,878 (II) and ELQ series (III-
IV) whereas derivatives 7 enabled a rapid construction of the
frameworks of natural products VII-VIII bearing cis-diols.
Quinoline cores exist in numerous bioactive molecule.[1] The
historical antimalarial drug endochin (I) comprises a quinolin-
4(1H)-one core, which serves a structural lead,[2] leading to more
active molecules such as WR-109,878 (II) and several ELQ
derivatives (III-IV).[2] Natural products V-VIII comprise
a
dihydroquinoline core bearing one or two hydroxyls, as shown in
Figure 1.[3] Species V and VI showed MDR modulating activity[3a]
and inhibitory activity against glutamate toxicity, respectively.
Compound VII[3c-3e] was a nematicidal alkaloid and species VIII
exhibited insecticidal antibiotic activitiy.[3f-3g] Site-selective
epoxidations at the quinoline moieties (path a) are envisaged to
be a concise route to access their structural cores,[4] but this
epoxidation is troubled with other undesired epoxidations (paths
b and c), rendering this route infeasible.[4] The current syntheses
of these bioactive molecules rely on diverse and long
procedures.[2-3,5]
Figure 1. Representative molecules and a postulated concise route.
The advent of gold catalysis has inspired new annulations of
[a]
R. L. Sahani, Prof. Dr. R.-S. Liu
Department of Chemistry, National Tsing-Hua University
Hsinchu (Taiwan, ROC)
E-mail: rsliu@mx.nthu.edu.tw
We tested the reactions of propiolate 1a with benzisoxazole
2a in hot dichloroethane (DCE, 80 0C) with commonly used gold
catalysts, L’AuCl/AgNTf2 (L’ = IPr, P(t-Bu)2(o-biphenyl), PPh3),
yielding a mixture of quinoline oxide 3a and indole derivative 3a’,
each in significant proportions (entries 1-3); compound 3a’ arose
Supporting information for this article is given via a link at the end of
the document.
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from a reported [3+2] annulation (see eq 1).[8a] A rapid and
efficient construction of structurally complicated epoxides 3a
inspired us to improve the chemoselectivity; the use of
(PhO)3AuCl/AgNTf2 produced only desired epoxide 3a with
unreacted 1a in a 30% recovery (entry 4). A complete
conversion was achieved with (PhO)3AuCl/AgSbF6 to afford
quinoline oxide 3a with the yield up to 85%; the yield became
70% when MS 4Å was absent. A change of silver salts as in
(PhO)3AuCl/AgX (X= OTf and BF4) showed no activity at all.
(PhO)3AuCl/AgSbF6 in hot acetonitrile and MeNO2 were
catalytically inactive at all. AgSbF6 and PtCl2 in hot DCE led to a
high recovery of starting 1a. Structural elucidation of compound
3a relied on X-ray diffraction[12] whereas the structure of its
indole 3a’ was determined by 1H NOE.
phenyl derivatives 1b-1c being more efficient. To our pleasure,
these annulations are successfully applicable to various alkyl-
substituted propiolates 1f-1h (R = cyclopropyl, isopropyl and n-
butyl), affording desired products 3f-3h in high yields (> 76%).
Propiolates 1i and 1j bearing different esters (R’ = OEt, OBn)
maintained a high annulation efficiency; desired quinoline oxides
3i and 3j were obtained in 80-82% yields (entries 8-9). For
alkynone 1k, its corresponding reaction produced desired 3k in
70% yield together with quinolin-3-ol 4k’ in minor proportion; the
structure of byproduct 4k’ was confirmed with X-ray diffraction
(entry 10).[12] Notably, propiolates 1l and 1m bearing R = 4-
MeOC6H4 and styryl would afford quinolin-4(1H)-ones 4l and 4m
through a facile epoxide rearrangement.[13] The molecular
structure of compound 4l was characterized with X-ray
diffraction.[12]
Table 1. Reaction chemoselectivity over various catalysts.
Table 2. Annulations with various alkynoates and alkynones.
Entry
Catalyst
Conditions
Yield%[b]
1a
-
3a
3a’
1.
2.
IPrAuCl/AgNTf2
DCE, 12 h
DCE, 12 h
DCE, 12 h
DCE, 7 h
55
45
60
62
-
[c]
LAuCl/AgNTf2
-
35
3.
PPh3AuCl/AgNTf2
(PhO)3PAuCl/AgNTf2
(PhO)3PAuCl/AgSbF6
(PhO)3PAuCl/AgOTf
(PhO)3PAuCl/AgBF4
(PhO)3PAuCl/AgSbF6
(PhO)3PAuCl/AgSbF6
AgSbF6
-
30
4.
30
traces
85
95
92
88
90
94
60
5.
DCE, 7 h
85(70)[d]
-
6.
DCE, 24 h
DCE, 24 h
ACN, 24 h
MeNO2, 24 h
DCE, 24 h
DCE, 12 h
traces
-
7.
-
-
-
-
-
-
8.
-
9.
-
[a] [1] = 0.15 M, 2 (1.2 equiv). [b] Product yields are reported after purification
from a silica column. [c] Minor product 4k' is obtained along with 3k. [d]
rearranged product 4l and 4m were obtained
10.
11.
-
PtCl2
-
[a] [1a] = 0.15 M, 2a (1.2 equiv). [b] Product yields are reported after purification
from a silica column. [c] L = P(t-Bu)2(o-biphenyl). DCE = 1,2-dichloroethane, IPr =
As depicted in Table 3, the scope of these annulations is
significantly expanded with various benzisoxazoles 2b-2j as
applicable substrates. For substrates 2b-2f bearing various 4-
phenyl substituents (R1 = Cl, Br, Me, OMe and OCO2Et), their
annulations with propiolate 1a delivered quinoline oxides 5b-5f
with yields exceeding 74% (entries 1-5). In the case of
benzisoxazoles 2g and 2h bearing R2 = Cl and Br, similar oxides
5g and 5h were obtained in satisfactory yields (75-85%, entries
6-7). We tested the reactions with benzisoxazole 2i bearing R2 =
Me, the expected quinoline oxide seemed to be highly reducible
to form quinoline 5i-H in 45% yield (entry 8). We prepared
additional benzisoxazole 2j bearing R3 = Me to form quinolin-
1,3-bis(diisopropylphenyl)imidazole-2-ylidene), Tf
= trifluoromethanesulfonyl. [d]
The yield in this parentheses refer to the absence of MS 4Å .
These new annulations were tested with various alkynoates
and alkynones to assess the reaction generality; the results are
summarized in Table 2. In most cases, quinoline oxides 3 were
generated smoothly, but two instances afforded quinolin-4(1H)-
ones 4 because of a facile epoxide rearrangement.[13] For
various phenyl-substituted propiolates 1b-1e (R = 4-XC6H4, X =
Cl, Br, Me, t-Bu), their annulations with benzisoxazole 2a
proceeded smoothly, yielding quinoline oxides 3b-3e in
satisfactory yields (60-78%, entries 1-4), with electron-deficient
1
4(1H)-ones 6i in 80% yield; its structure was determined by H
NOE (entry 9).
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Table 3. Annulations with various benzisoxazoles.
propiolates bearing aryl (4-XC6H4, X = Cl and Br) and alkyl
substituents (R = cyclopropyl and isopropyl), yielding desired
products 7b-7e in 62-90% yields respectively (Table 4, entries 1-
4). The reactions were compatible also with various
benzisoxazoles substituted with X = Cl, Br and OCO2Et; Y = Cl;
the corresponding products 7f-7i were obtained efficiently
(entries 5-8).
Table 4. Relay catalysis with Au(I) and Zn(II) catalysts.
[a] [1] = 0.15 M, 2 (1.2 equiv). [b] Product yields are reported after purification
from
a silica column. [c] Deoxygenated product 5i-H is obtained. [d]
Rearranged product 6i is obtained
Quinoline oxides 3 are versatile intermediates to deliver
oxygenated quinoline derivatives because of their epoxide
functionality. As shown in Scheme 1, LiAlH4-reductions of
species 3a afforded alcohol 8a as a single diastereomer; the
structure of this diol derivative was determined by 1H NOE.
Removal of the epoxide of the species 3a was achieved with
Pd/C/H2 in MeOH, yielding quinoline derivative 3a-H in 75%
yield. An epoxide opening with DBU (1.5 equiv) in hot DCE led
to the production of benzo[d][1,3]-oxazepine 9a in 92% yield.
Particularly notable is Zn(OTf)2-catalyzed hydrative cyclizations
of epoxide 3a in DCE; this process is unprecedented in
literatures. Structural elucidation of the complex framework of
compound 7a were performed by X-ray diffraction of its isopropyl
analogue 7e.[12]
[a] [1] = 0.15 M, 2 (1.2 equiv). [b] Product yields are reported after purification
from a silica column. [c] Minor product 4f is obtained along with 7d.
Scheme 2 shows a proposed mechanism of this relay catalysis.
The formation of quinoline oxides 3 arises from an O-attack of
benzisoxazoles 2 at propiolates 1 to form species B, further
yielding gold carbene C through a cleavage of its N-O bond. The
electron-deficient phosphite group L accelerates the attack of
the imido anion at gold carbene C to form seven-membered
heterocycles D, in which the oxoninum center induces a
dissociation of LAu+ to generate species E. A subsequent 6-
electrocyclization to form compound 3 is expected to be very
feasible because of the nature of aromatization. Zn(II)-catalyzed
hydrative lactonizations of compounds
3
can also be
mechanistically elucidated upon considering the Payne
rearrangement.[14] To implement this process, water attacks the
iminium center of species F opposite its epoxide moiety,
resulting in species G in which the basic amine center abstract a
proton from the hydroxyl group to facilitate the Payne
rearrangement.[14] In such epoxy migrations,[14] more substituted
epoxides H are more thermodynamically favorable than less
substituted analogues F; a subsequent hydrolysis[15] of epoxy
esters H generates triols I stereoselectively, further affording
observed products 7 with excellent diastereoselectivity.
Scheme 1. Chemical functionalizations of quinoline oxides.
We aimed at a one-pot synthesis of highly oxygenated
tetrahydroquionolines
7
using gold and Zn(II) catalysts
sequentially. In a typical operation, a mixture of propiolates 1
and benzisoxazoles 2 was heated with (PhO)3AuCl/AgSbF6 in
hot DCE until a complete consumption of initial propiolates; to
this solution was added Zn(OTf)2 (20 mol%) with further heating
until a complete disappearance of quinoline oxides 3. We
selected those substrates that could generate quinoline oxides 3
efficiently. These cascade reactions were applicable to various
The N-attack regioselectivity of benzisoxazoles 2 is also likely
to occur for electron-rich phosphine gold catalysts (see Table 1,
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Dogget, K. L. White, D. J. Hinrichs, R. W. Winter, S. A. Charman, L. N.
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entries 1-3). The N- and O-regioselectivity is postulated to be
reversible,[10] and electron-deficient phosphite ligands increases
the elctrophilicity of gold carbene C to form intermediate D very
preferably, thus controlling the entire O-attack regioselectivity.
[3]
[4]
[5]
B. Akagah, A. T. Lormier, A. Fournet, B. Figadére, Org. Biomol. Chem.,
2008, 6, 4494-4497.
See selected examples: a) F. Salvaggio, J. T. Hodgkinson, L. Carro, S.
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Chem. 2016, 434-437; b) J. P. Schmidt, C. Li, B. Breit, Chem. Eur. J.
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9939-9953; d) Y. Wang, H. Liang, C. Chen, D. Wang, J. Peng,
Synthesis 2015, 47, 1851-1860.
Scheme 2. A plausible mechanism for this relay catalysis.
In summary, gold-catalyzed one-pot annulations of
propiolates with benzisoxazoles to yield quinoline oxides are
described. These annulations were compatible with substrates
over a wide scope. Chemical functionalizations of these resulting
products afforded various oxygenated tetrahydroquinolines that
are present as the cores of bioactive molecules. We developed
also a new relay catalysis using gold and Zn(II) catalysts to
produce highly oxygenated tetrahydroquinoline derivatives
stereoselectively.
[6] a) A. S. K. Hashmi, Chem. Rev., 2007, 107, 3180-3211; b) N. T. Patil, Y.
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[8]
Experimental Section.
[9]
A two-neck flask was charged with (PhO)3PAuCl (26.8 mg, 0.049 mmol)
and AgSbF6 (17.0 mg, 0.049 mmol), MS 4Å (50 mg), and to this mixture
was added dry DCE (1.0 mL). The resulting mixture was stirred at room
temperature for 10 min, and to this mixture was added a dry DCE
solution (2 mL) of tert-butyl 3-phenylpropiolate (1a) (100.0 mg, 0.495
mmol) and benzo[c]isoxazole (2a) (70.8 mg, 0.594 mmol). After stirring at
80 °C for 7 h, the reaction mixture was filtered over a short celite bed,
washed with dry acetone, concentrated, and eluted through a silica
column (EA/hexane = 1/50) to give quinoline oxide (3a) (135.0 mg, 0.42
mmol, 85%) as colorless solid.
[10]
R. L. Sahani, R.-S. Liu, Angew. Chem. Int. Ed. 2017, 56, 1026-1030;
Angew. Chem. 2017, 129, 1046-1050.
[11] Non-pyrrole products were produced with the use of PtCl2/CO catalyst
or propargylic silyl ethers, see W.-B. Shen, X.-Y. Xiao, Q. Sun, B. Zhou,
X.-Q. Zhu, J.-Z. Yan, X. Lu, L.-W. Ye, Angew. Chem. Int. Ed. 2017, 56,
605-609; Angew. Chem. 2017, 129, 620-624.
[12] Crystallographic data of compounds 3a, 4k’, 4l and 7e were deposited
at Cambridge Crystallographic Centers; 3a, CCDC 1561351; 4k’,
CCDC 1561352; 4l, CCDC 1561354 and 7e, CCDC 1561350.
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Murase, R. Bureau, T. Ooi, H. Yamamoto, Tetrahedron 1994, 50, 3663-
3672.
Keywords: propiolates • benzisoxazoles • gold catalyzed
annulation/cyclization cascades • quinoline oxides • oxygenated
tetrahydroquinolines
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[14] R. M. Hanson, Organic Reactions, 50, 1-35.
[15] For regioselective hydrolysis of epoxy esters, see selected examples: a)
P. Risch, T. Pfeifer, J. Segrestaa, H. Fretz, J. Pothier, J. Med. Chem.
2015, 58, 8011-8035; b) D. E. White, P. M. Tadross, Z. Lu, E. N.
[2]
a) A. Nilsen, G. P. Miley, I. P. Forquer, M. W. Mather, K. Katneni, Y. Li,
S. Pou, A. M. Pershing, A. M. Stickles, E. Ryan, J. X. Kelly, J. S.
Jacobsen,
Tetrahedron,
2014,
70,
4165-4180.
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Entry for the Table of Contents (Please choose one layout)
COMMUNICATION
Rajkumar Lalji Sahani, Rai-Shung Liu*
Page No. – Page No.
Gold-catalyzed [4+2]-
Annulations/Cyclization Cascades of
Benzisoxazoles with Propiolate
Derivatives to Access Highly
Oxygenated Tetrahydroquinolines
This work describes gold-catalyzed [4+2]-annulation/cyclization cascades of
electron-deficient alkynes with benzisoxazoles to yield quinoline oxides
chemoselectively. With the same reactants, a new relay catalysis using gold and
Zn(II) catalysts afford highly oxygenated tetrahydroquinoline derivatives
stereoselectively.
This article is protected by copyright. All rights reserved.