Gold-Catalyzed Bicyclic and [3+2]-Annulations of Internal Propargyl Alcohols with Nitrones and Imines To Yield to Two Distinct Heterocycles

Article abstract of DOI:10.1002/adsc.202001119

A gold-catalyzed synthesis of 1,3-dihydrooxazolo[3,4-a]indoles from 1-oxo-3-yn-4-ols and nitrones is described; this new bicyclic annulation presents the first examples that internal alkynes can react with nitrones to undergo an oxoarylation route. DFT calculations indicate a [3,3]-sigmatropic shift of initial alkenylgold intermediates to elude the intermediacy of gold carbenes. We also developed new [3+2]-annulations of the same 1-oxo-3-yn-4-ols with imines, yielding oxazolidin-4-ylidene derivatives efficiently. The tethered alcohols of these 1-oxo-3-ynes allow trapping of their metastable 2-azadienium intermediates to enable a novel annulation. Our mechanistic analysis indicates that the two products, despite their structural relevance, are produced from two independent systems. (Figure presented.).

Full text of DOI:10.1002/adsc.202001119

Title: Gold-catalyzed Bicyclic and [3+2]-Annulations of Internal
Propargyl Alcohols with Nitrones and Imines to Yield to Two
Distinct Heterocycles
Authors: Rai-Shung Liu, Sayaji More, Mu-Jeng Chen, and Tzu-Hsuan
Chao
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202001119
Link to VoR: https://doi.org/10.1002/adsc.202001119

10.1002/adsc.202001119
Advanced Synthesis & Catalysis
VERY IMPORTANT PUBLICATION
FULL PAPER
DOI: 10.1002/adsc.202((will be filled in by the editorial staff))
Gold-Catalyzed Bicyclic and [3+2]-Annulations of Internal
Propargyl Alcohols with Nitrones and Imines To Yield to Two
Distinct Heterocycles
Sayaji Arjun Morea Tzu-Hsuan Chao,b Mu-Jeng Chenb,* and Rai-Shung Liua,*
a
Frontier Research Centers of Matter Science and Technologies, Department of Chemistry, National Tsing Hua
University, Hsinchu, Taiwan, ROC
E-mail: rsliu@mx.nthu.edu.tw
b
Department of Chemistry, National Cheng Kung University, Tainan, 701, Taiwan, ROC
E-mail: mjcheng@mail.ncku.edu.tw
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract.
A
gold-catalyzed
synthesis
of
1,3-
dihydrooxazolo[3,4-a]indoles from 1-oxo-3-yn-4-ols and
nitrones is described; this new bicyclic annulation presents
the first examples that internal alkynes can react with
nitrones to undergo an oxoarylation route. DFT calculations
indicate a [3,3]-sigmatropic shift of initial alkenylgold
intermediates to elude the intermediacy of gold carbenes. We
also developed new [3+2]-annulations of the same 1-oxo-3-
yn-4-ols with imines, yielding oxazolidin-4-ylidene
derivatives efficiently. The tethered alcohols of these 1-oxo-
3-ynes allow trapping of their metastable 2-azadienium
intermediates to enable a novel annulation. Our mechanistic
analysis indicates that the two products, despite their
structural relevance, are produced from two independent
systems.
Keywords: Oxo-yne; Nitrones; Imines; Oxoaryalation;
Indoles; Oxazolidines
carbene intermediates.[4] This [3,3]-rearrangement
mechanism is confirmed with our DFT
calculations.[4c] Such a 3,3-sigmatropic shift occurs
exclusively with terminal alkynes, so as to minimize
steric interactions in the phenyl attack at the Au-CH=
carbon, as shown by species ln-1 and ln-2. In alkyne
oxidations with nitrones, we are aware of no internal
alkyne that can undergo a 3,3-sigmatropic shift to
afford oxoarylation products.
Introduction
Gold catalysis has emerged as a powerful tool to
access useful heterocyclic compounds through the
N,O-functionalization of alkynes with nitrones,
nitrosoarenes and other nitroxy (N-O) compounds.[1]
Molecules containing nitroxy functionalities have
widespread occurrence in many bioactive molecules
and alkaloids.[2] In the context of nitrone oxidants,
their catalytic reactions with alkynes using Au(I) and
Pt(II) catalysts generally follow two routes, involving
either (i) formation of gold carbenes[3] or (ii) 3,3-
This
work
reports
new
gold-catalyzed
annulations[6] of 4-hydroxy-1-oxo-but-2-ynes with
nitrones to deliver 1,3-dihydrooxazolo[3,4-a]indoles
(Eq 3), and hence provides the first examples that
internal alkynes can afford oxoarylation products via
sigmatropic
shifts
of
initial
alkenylgold
intermediates.[4] Route (ii) is also known for those
alkyne oxidations using sulfur oxides as the
oxidants.[5] Eqs. 1-2 show two prominent systems for
oxoarylation reactions using Pt(II) and Au(I) catalysts
a
3,3-sigmatropic rearrangement. Our DFT
calculations support this hypothesis although steric
interactions are involved. Apart from nitrones, we
demonstrate new annulations of the same 4-hydroxy-
1-oxo-but-2-ynes with imines to afford [3+2]-
annulation products 5 (Eq 4). Although compounds 3
and 5 are related to each other structurally, our
respectively;
intermediates ln-1 and ln-2 undergo
sigmatropic rearrangement to avoid Pt(II) and Au(I)
herein,
initial
alkenylmetal
a
3,3-
1
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10.1002/adsc.202001119
Advanced Synthesis & Catalysis
Table 1. Catalyst Screening and Optimization of
Conditions
Entr Catalyst
y
Solven
t
t
Yield of
(h) 3a
(%)[b]
1
2
3
4
LAuCl/AgNTf2
PPh3AuCl/AgNTf2
IPrAuCl/AgNTf2
DCM
DCM
DCM
20 41
18 61
16 69
24 38
(OPh)3PAuCl/AgNTf DCM
2
5
6
7
8
IPrAuCl/AgOTf
IPrAuCl/AgSbF6
IPrAuCl/AgNTf2
IPrAuCl/AgNTf2
AgNTf2
IPrAuCl/AgNTf2
IPrAuCl/NaBARF
IPrAuCl/AgBF4
DCM
DCM
DCE
18 52
18 55
20 60
toluene 24 57
9
DCM
DCM
DCM
DCM
DCM
24
-
[c]
10
11
12
13
16 53
24 28
24 15
24 30
IPrAuCl/AgBF6
[a][1] = 0.21 M.
Product yields are obtained after
[b]
control experiments reveal two independent pathways
for their formation.
purification by column chromatography (silica gel), IPr =
1,3-bis(diisopropylphenyl)imidazol-2-ylidene, L = P(t-
Bu)2(o-biphenyl), [c] Catalyst (5 mol%).
Results and Discussion
As Table 1 shows, we examined the reactions of
methyl 4-hydroxy-1-oxo-but-2-ynoate 1a with
nitrones 2a (1.5 equiv) using various gold catalysts;
such reactions were performed in DCM with 10
mol% catalyst loading. In the case of P(t-Bu)2(o-
We assessed the generality of these bicyclic
annulations using various 4-hydroxy-1-oxo-but-2-
ynes (1) and nitrone (2); the results are summarized
in Table 2. Under the optimized conditions, bicyclic
dihydrooxazolo[3,4-a]indole derivatives (3) were
produced exclusively. Entries 1-3 show the reactions
of methyl 4-hydroxy-1-oxo-but-2-ynoate 1a with
nitrones 2b-2d bearing p-substituted anilines (X=
OMe, Cl, H), yielding desired products 3b-3d at 83-
89%. For nitrones 2e-2g (X= Me, Cl, Br) bearing o-
substituted anilines, their corresponding products 3e-
3g were generated with 58-75 % yields (entries 4-6).
We tested the reactions on additional nitrones bearing
p-substituted imines 2h-2l (Y = t-Bu, OMe, Cl, Br, F),
further generating the expected bicyclic products 3h-
3l in 65-83% yields (entries 7-11), with electron-rich
substituents (Y = t-Bu, OMe) being more productive.
For o-, m-bromo-substituted imines as in nitrone 2m
and 2n, their corresponding products 3m and 3n were
obtained with 63% and 65% yields (entries 12-13).
We performed the reaction also on thiophene-derived
nitrone 2o that produced compound 3o with 80%
yield (entries 14).
biphenyl)AuCl/AgNTf2,
7-methyl-3-phenyl-1,3-
dihydrooxazolo[3,4-a]indole 3a was obtained in 41%
yield (entry 1). The yield of compound 3a was
improved to 61% with PPh3AuCl/AgNTf2 (entry 2),
and further improved to 69% with IPrAuCl/AgNTf2
(entry 3). When we employed electron-deficient
(PhO)3PAuCl/AgNTf2, the yield of compound 3a
decreased significantly to 38% (entry 4). Variations
of silver salts as in IPrAuCl/AgX, (X = OTf and
SbF6) failed to increase the catalytic efficiency with
52-55% yields of compound 3a (entries 5-6). For
IPrAuCl/AgNTf2 (10 mol%) in other solvents, the
yields of desired product 3a follow: DCE (60%) and
toluene (57%). AgNTf2 alone in DCM is entirely
inactive for this transformation and when we tried a
lower loading of IPrAuCl/AgNTf2 (5 mol%), the
desired product 3a was obtained in only 53% yield
(entry 10). We also tested the reaction with IPrAuCl
and other counter anions NaBARF, AgBF4, and
AgBF6, but then the yield of 3a dropped to 28%, 15%,
and 30% (entries 11-13). The structure of compound
3a was elucidated by X-ray diffraction,[7] which
revealed a bicyclic annulation between nitrone 2a and
internal alkyne 1a, resulting in formation of this
molecular framework after the loss of water.
We next assessed the scope of applicable 4-
hydroxy-1-oxo-but-2-ynes. For various alkyl 2-
ynoates (1b-1e, R1 = ethyl, isopropyl, isobutyl and
benzyl), their bicyclic annulations with standard
nitrone 2a rendered expected compounds 3p-3s in 40-
80% yields (entries 15-18), with electron-rich esters
being less efficient. This observation indicates that
2
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10.1002/adsc.202001119
Advanced Synthesis & Catalysis
Table 2: Gold catalyzed bicyclic annulations
Table 3: Synthesis of oxazolidine with imines
[b]
[a][1] = 0.15 M.
Product yields are obtained after
[c]
purification by column chromatography (silica gel)
Reaction temperature = 40 °C.
[b]
[a][1] = 0.21 M.
Product yields are obtained after
Structural characterization of compound 5a relied on
X-ray diffraction of its relative 5j (vide infra).[7]
purification by column chromatography (silica gel).
Table 3 depicts the substrate scope of these
[3+2]-annulations using various 4-hydroxy-1-oxo-
but-2-ynes (1) and imines (4). Most internal alkynes
herein were also effective for gold-catalyzed bicyclic
annulations when nitrones served as the reaction
partners. For 1-aryl-4-hydroxybut-2-yn-1-ones (R1 =
4-MeOC6H4, 4-ClC6H4), their annulations with imine
4a delivered oxazolidine species 5b and 5c with 73%
and 67% yields (entries 1-2). Alkyl-substituted
ketones (R1 = cyclopropyl, isopropyl and n-butyl)
also gave desired oxazolidines 5d-5f with 68-82%
yields (entries 3-5). We tested these imine
annulations with various alkynyl esters (R1 = OEt and
OPh), producing compounds 5g and 5h in 65% and
76% yields respectively (entries 6-7). We next tried
other imines bearing imino groups (X = Cl and Br);
their corresponding products 5i and 5j were generated
with 69% and 82% yields (entries 8-9). The
molecular structure of compound 5j was
characterized with X-ray diffraction.[7] For imines
bearing varied anilines (Y = H, OMe and Cl), their
corresponding products 5k-5m were obtained in
satisfactory yields (81-86%, entries 10-12). 3-
Thiophene-containing imine was also amenable to
this [3+2]-annulation to deliver compound 5n in 87%
yield (entry 13). For 4-methyl-4-hydroxy-but-2-yn-1-
ol (R2 = Me), its annulation with imine 2a produced
cis-configured oxazolidine 5o stereoselectively (dr =
10:1); the yield was up to 93% (entry 14).
coordination of esters to a gold catalyst decreases the
efficiency of these bicyclic annulations. We expanded
the scope to alkyl alkynones 1f, 1g (R1 = n-butyl, n-
pentyl) that became applicable substrates, producing
the desired 3t-3u with yields 80-83% (entries 19-20).
Accordingly, less basic alkynoates and alkynones are
more suitable for these bicyclic annulations. Finally,
we prepared methyl 4-methyl-4-hydroxybut-2-ynoate
1h that gave compound 3v (dr > 20:1) with 80%
1
yield as one single diastereomer (entry 21). Its H
NOE spectrum reveals a cis-configuration of the
oxazolidine ring.
In such nitrone annulations, we prepared 1-phenyl-
4-hydroxy-2-butyn-1-one 1i that afforded a different
product 5a via a reductive [3+2]-annulation (Eq 5);
species 5a can be visualized to result from a reductive
cleavage of the indole ring of our bicyclic indoles 3.
We accordingly tested the reaction again using an
imine 4a to replace nitrone 2a; this new process
greatly improved the yield of 5a up to 83% (Eq 6).
3
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10.1002/adsc.202001119
Advanced Synthesis & Catalysis
an oxoarylation product via a non-carbene route. We
examined the optimized geometry of TSbc that has a
long N-O bond of 1.70 Å, whereas the distance
between the two reacting carbons is estimated to be
4.25 Å. This information indicates that a [3,3]-
rearrangement actually occurs through an initial
lengthening of the nitroxy N-O bond to enable an aryl
attack at the alkenylgold carbon. Once the
oxoarylation intermediate
C
is formed, its
aromatization can occur via a 1,2-proton migration to
induce a loss of the gold fragment; the barrier is 89.5
kJ/mol to form species D (Figure 1 (b)). A final
bicyclic cyclization is achievable with a prior
coordination of the carbonyl of species E with the
gold catalyst, further forming iminium species F; the
activation barrier is only 26.8 kJ/mol. The last two
steps F→G and G→H are procedures of known
organic reactions; their feasibilities are also described
with our DFT calculations to involve a maximum
barrier of 94.6 kJ/mol.
Oxazolidine 5g might serve as an intermediate
Conclusion
for compound 3p in the course of the bicyclic
annulation of ethyl 4-hydroxybut-2-ynoate 1b with
nitrone 2a. This hypothesis proved invalid because
compound 5g was not convertible to its oxidized
form 3p in the presence of nitrones and gold catalyst
(Eq 7). To confirm their irrelevance, we performed
two reactions as depicted in Eqs 8-9. With nitrone 2p,
its reaction with methyl 4-hydroxy-1-oxo-but-2-yne
1a delivered compound 6 in 34% yield; its molecular
structure was characterized with X-ray diffraction
(Eq 8).[7,8] In contrast, the annulation of alkynoate 1a
with imine failed to deliver [3+2]-annulation product
5p (Eq 9). The two annulations of methyl 4-hydroxy-
1-oxo-but-2-yne 1a with nitrone 2p or imine 4h
hence proceeded through two independent paths. We
performed cross experiments on the two annulations.
In Eq 10, the reaction of species 1a with two imines
4a and 4b yielded only two annulation products 5q
and 5r according to 1H NMR spectral analysis.
Similarly, we observed no additional product in the
annulations of species 1a with two nitrones 2a and 2j
in the bicyclic annulations (Eq 11). Accordingly, both
imine and nitrone remains intact through these gold-
catalyzed annulations.
We performed density functional theory (DFT)
calculations[9] to elucidate the mechanism of the
nitrone oxidations. The Gibbs free energy surface of
the proposed mechanism is depicted in Figure 1. In
the nitrone oxidations, we find that the target
molecule 3d was produced from an attack of a nitrone
on gold-π-alkyne species A, resulting in the
formation of alkenylgold intermediates B (Figure 1
(a)). This process releases ∆G = -38.1 kJ/mol with
kinetic barrier ∆G‡ = 23.0 kJ/mol. We were unable to
locate the transition state to yield gold carbene
intermediates. Instead, a [3,3]-sigmatropic shift of
species B proved to be feasible even though a steric
interaction was encountered; the kinetic barrier is
78.6 kJ/mol with a release of energy of 79.1 kJ/mol.
Accordingly, an internal alkyne is also accessible to
This work reports two distinct gold-catalyzed
annulations for 4-hydroxy-1-oxobut-2-ynes. A new
bicyclic annulation [10] is achieved with nitrone as the
oxidant to yield 1,3-dihydrooxazolo[3,4-a]indoles
efficiently. Our DFT calculations reveal a [3,3]-
sigmatropic rearrangement of the initial alkenylgold
intermediates. When the same 4-hydroxybut-2-
ynoates are treated with imines and a gold catalyst,
oxazolidin-4-ylidene derivatives are produced in high
[11]
yields.
Although the structural skeletons of the
two annulation products seem to be related, our
control experiments revealed two independent
pathways for their formation.
Experimental Section
Typical procedure for synthesis of methyl 7-methyl-3-
phenyl-1,3-dihydrooxazolo[3,4-a]indole-9-carboxylate
(3a)
A catalytic flask was charged with IPrAuCl (27.21 mg,
0.04 mmol), AgNTf2 (17.0 mg, 0.04 mmol) and to this
mixture was added dry DCM (1 mL). The mixture was
stirred for 5 min at room temperature. To this solution was
added a DCM (1 mL) solution of 1a methyl 4-hydroxybut-
2-ynoate (50 mg, 0.4382 mmol) and nitrone 2a (138.85 mg,
0.65 mmol); the resulting solution was further stirred at
room temperature for 16 h. The solution was filtered over a
short Celite bed, and concentrated to form crude product
3a. Flash silica chromatography [EA/hexane (10:90)]
afforded the desired product 3a (93.0 mg, 0.30 mmol,
1
69%) as white solid; H NMR (600 MHz, CDCl3): δ 7.91
(d, J = 1.2 Hz, 1H), 7.44 ~ 7.38 (m, 3H), 7.36 ~ 7.34 (m,
2H), 6.86 (dd, J = 8.4, 1.8 Hz, 1H), 6.65 (m, 2H), 5.52 (dd,
J = 14.4, 2.4 Hz, 1H), 5.34 (dd, J = 14.4, 1.8 Hz, 1H), 3.90
(s, 3H), 2.41 (s, 3H); 13C NMR (125 MHz, CDCl3): δ
165.1, 147.3, 135.9, 132.0, 131.7, 130.4, 129.2, 129.0,
127.2, 123.9, 121.5, 110.0, 97.9, 91.2, 68.1, 51.0, 21.5;
ESIMS calcd. For C19H17NO3 [M+Na]: 330.1106; [M+Na]
found: 330.1107.
4
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10.1002/adsc.202001119
Advanced Synthesis & Catalysis
Figure 1. Gibbs free energy surface from DFT calculations. DCM is used as the solvent, and L represents IPr. The inset in
part (a) is the three-dimensional representation of the optimized structure of TSbc.
Typical procedure for synthesis of (E)-1-phenyl-2-(2-
phenyl-3-(p-tolyl)oxazolidin-4-ylidene)ethanone (5a)
chromatography [EA/hexane (10:90)] yielded the desired
product 5a (92 mg, 0.25 mmol, 83%) as brown liquid.
1
(92.2 mg, 83%); H NMR (600 MHz, CDCl3): δ 7.75 (d, J
= 7.4 Hz, 2H), 7.41 ~ 7.30 (m, 8H), 7.11 (d, J = 7.9 Hz,
2H), 6.92 (d, J = 8.0 Hz, 2H), 6.18 (s, 1H), 5.89 (s, 1H),
5.79 (d, J = 16 Hz, 1H), 5.51 (d, J = 16 Hz, 1H), 2.29 (s,
3H); 13C NMR (150 MHz, CDCl3): δ 188.9, 161.3, 140.1,
137.8, 137.1, 134.3, 131.0, 130.4, 129.8, 128.5, 128.1,
127.5, 127.3, 126.4, 96.6, 87.1, 74.3, 21.1; ESI-MS calcd.
For C24H21NO2 [M+Na]: 378.1470; [M+Na] found:
378.1464.
A catalytic tube was charged with IPrAuCl (19.38 mg,
0.03 mmol), AgNTf2 (12.10 mg, 0.03 mmol) and to this
mixture was added dry DCM (1 mL); the mixture was
stirred for 5 min at room temperature. To this solution was
added a DCM (1 mL) solution of 1i 4-hydroxy-1-
phenylbut-2-yn-1-one (50 mg, 0.31 mmol) and imine 4a
(91.43 mg, 0.46 mmol), and the resulting mixture was
further stirred at room temperature for 24 h. The solution
was filtered over a short Celite bed and concentrated in
vacuo to afford crude product 5a. Flash silica
5
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10.1002/adsc.202001119
Advanced Synthesis & Catalysis
Acknowledgements
9, 3066-3082; i) D. J. Gorin, B. D. Sherry, F. D. Toste,
Chem. Rev. 2008, 108, 3351-3378.
We thank the Ministry of Education (MOE 106N506CE1) and the
Ministry of Science and Technology (MOST 107-3017-F-007-
002), Taiwan, for financial support of this work.
[7] CCDC-2013288 (3a), CCDC-2013287 (5j), and
CCDC-2022885 (6) contain the supplementary
crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge
References
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
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[8] Formation of compound 6 (Eq 8) was produced from
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so that the distance became minimized to 4.25 Å. The
presence of an ortho-methyl group is expected to
increase this distance because this planarity is not
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[6] For gold-catalyzed annulation reactions, see selected
reviews: a) A. S. K. Hashmi, G. J. Hutchings. Angew.
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Rudolph, A. S. K. Hashmi. Chem. Commun.. 2019, 55,
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[11] For the [3+2]-imine annulations, the mechanism
proceeds through an independent route, explicitly
through an attack of imine at gold π-alkyne A’ to yield
species B’ that was trapped with a tethered alcohol to
form intermediate C’, and ultimately observed product
5a.
6
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10.1002/adsc.202001119
Advanced Synthesis & Catalysis
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10.1002/adsc.202001119
Advanced Synthesis & Catalysis
FULL PAPER
Gold-catalyzed Bicyclic and [3+2]-Annulations of
Internal Propargyl Alcohols with Nitrones and
Imines to Yield to Two Distinct Heterocycles
Adv. Synth. Catal. Year, Volume, Page – Page
Sayaji Arjun More† Tzu-Hsuan Chao,‡ Mu-Jeng
Chen‡,* and Rai-Shung Liu†,*
8
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