Gold(I)-Catalyzed Oxidative 1,4-Additions of 3-En-1-ynamide with Nitrones via Carbon- versus Nitrogen-Addition Chemoselectivity

Article abstract of DOI:10.1021/acs.orglett.1c00055

This work reports gold-catalyzed 1,4-oxofunctionalizations of 3-en-1-ynamides with nitrones, yielding two distinct E-configured products. We obtained 1,4-oxoarylation products from 3-en-1-ynamides bearing C(4)-electron-donating substituents and 1,4-oxoamination products from those analogues bearing C(4)-aryl substituents. We propose that if vinylgold carbenes are stable, imines undergo a para-arylation on these gold carbenes. If vinylgold carbenes are highly electron-deficient, this N-attack is irreversible to enable 1,4-oxoaminations.

Full text of DOI:10.1021/acs.orglett.1c00055

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Gold(I)-Catalyzed Oxidative 1,4-Additions of 3‑En-1-ynamide with
Nitrones via Carbon- versus Nitrogen-Addition Chemoselectivity
Sudhakar Dattatray Tanpure, Balaji S. Kale, and Rai-Shung Liu*
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ABSTRACT: This work reports gold-catalyzed 1,4-oxofunctionalizations of
3-en-1-ynamides with nitrones, yielding two distinct E-configured products.
We obtained 1,4-oxoarylation products from 3-en-1-ynamides bearing C(4)-
electron-donating substituents and 1,4-oxoamination products from those
analogues bearing C(4)-aryl substituents. We propose that if vinylgold
carbenes are stable, imines undergo a para-arylation on these gold carbenes.
If vinylgold carbenes are highly electron-deficient, this N-attack is
irreversible to enable 1,4-oxoaminations.
ne notable innovation in gold catalysis is catalytic alkyne
oxidations using pyridine-based oxides,1 generating
versatile α-oxo gold carbenes (I) to achieve 1,2-oxidative
functionalizations.2 Such alkyne oxidations provide numerous
cyclic and acyclic molecules via treatment of these carbenes
with suitable nucleophiles (Scheme 1, eq 1). Despite their
as oxoarylation,3 further manifesting the reaction diversity.
Equation 2 shows one instance of gold carbene reactions in
which α-oxo gold carbenes reacted with released imines,
furnishing 1,2-oxoamination products.4 In this work, we report
1,4-oxidative additions of 3-en-1-ynamides5 with nitrones via
two independent routes. In the case of 3- or 4-alkyl-3-en-1-
ynamides, we obtained E-configured 1,4-oxoarylation products
in which the released imines attack at the vinylgold carbenes
via a p-aryl attack (eq 3), but for 5-aryl-3-en-1-ynamides,
imines attack at gold carbenes via a nitrogen (N)-attack,
yielding 1,4-oxoamination products with E-selectivity (eq 4).
Noteworthy is the use of 4-chlorophenyl-derived nitrone (R4 =
4-Cl); the oxidation still proceeds through a p-aryl attack path,
leading to a chloro substitution.
O
Scheme 1. 1,n-Oxidative Functionalizations of Alkynes
Table 1 summarizes the results for catalytic oxidations of 3-
en-1-ynamide (1a) with nitrone (2a) using various gold
catalysts; our target 3a in these tests was obtained as only an E-
configured isomer. Our initial test of LAuCl/AgNTf2 (L = IPr
and P(t-Bu)2(o-biphenyl)) in dry 1,2-dichloroethane near 25
°C delivered 1,4-oxoarylation product 3a in 53−55% yield,
together with diazene oxide 3′ and benzaldehyde in small
proportions (entries 1 and 2). For PPh3AuCl/AgNTf2 in 1,2-
DCE, compound 3a was obtained in 31% yield (entry 3). With
(PhO)3PAuCl/AgNTf2, we observed an enhanced efficiency,
giving compound 3a in 67% yield (entry 4). Variations of silver
salts as in (PhO)3PAuCl/AgX, (X = OTf, SbF6, BF4) in 1,2-
dichloroethane afforded compound 3a with satisfactory yields
(65−72%) with X = SbF6 being the most effective (entries 5−
synthetic significance, pyridines released in these oxidations
were treated as waste to render the reactions unable to meet
atom economy. We recently developed distinct alkyne
oxidations using nitrones as oxidants; this process releases
imines that are more chemically active than pyridines.1,3
Furthermore, the oxidations of alkynes with nitrones can
deliver various 1,2-oxidative addition products from not only
gold carbene intermediates but also a noncarbene process such
Received: January 7, 2021
Published: February 5, 2021
https://dx.doi.org/10.1021/acs.orglett.1c00055
© 2021 American Chemical Society
Org. Lett. 2021, 23, 1394−1399
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Table 1. Optimization of Gold Catalysts
b
yield (%)
entry
catalyst
solvent
time (h)
3a
3′
1a
2a
1
2
3
4
5
6
7
8
IPrAuCl/AgNTf2
LAuCl/AgOTf
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCM
THF
toluene
DMF
DCM
DCM
24
24
24
05
06
04
05
06
24
24
24
24
18
55
53
31
67
65
73
72
76
25
8
12
11
27
5
6
2−3
2−3
2−3
35
35
6
10
11
15
17
36
8
9
trace
trace
trace
30
45
75
PPh3AuCl/AgNTf2
(PhO)3PAuCl/AgNTf2
(PhO)3PAuCl/AgOTf
(PhO)3PAuCl/AgSbF6
(PhO)3PAuCl/AgBF4
(PhO)3PAuCl/AgSbF6
(PhO)3PAuCl/AgSbF6
(PhO)3PAuCl/AgSbF6
(PhO)3PAuCl/AgSbF6
AgSbF6
9
47
56
78
20
10
11
12
13
trace
38
72
15
2−3
10
trace
(PhO)3PAuCl/NaBARF
a
b
[1a] = 0.08 M. Isolated yields are obtained after purification from a silica column. L = P(t-Bu)2(o-biphenyl).
7). For (PhO)3PAuCl/AgSbF6 in other solvents, the yields of
compound 3a were as follows: DCM (76%), THF (25%),
toluene (8%) and DMF (trace) (entries 8−11). AgSbF6 alone
in DCM was also active for this transformation, rendering
compound 3a in 38% yield (entry 12). To verify the catalytic
activity of the gold catalyst, we prepared Ag1+-free
(PhO)3PAuCl/NaBARF, which afforded the desired product
3a in 72% yield (entry 13). X-ray diffraction of compound 3a
confirmed a 1,4-oxidative arylation product bearing an E-
configured skeleton.
and (PhO)3PAuCl/AgSbF6 (5 mol %) in DCM, the resulting
1,4-oxidative arylation products 3b−3l were obtained in E-
configurations predominantly (Table 2, entries 1−11). For
substrates 1b−1d bearing varried tosyl-derived sulfonamides
such as NTs(Me), NTs(c-Pr), and NTs(Bn), their 1,4-
oxoarylation products 3b−3d were obtained in 67−80% yields
with exclusive E-selectivity (E/Z > 25:1) (Table 2, entries 1−
3). We tested also the reaction on 3-en-1-ynamide 1e bearing
NTs(n-Bu), further delivering compound 3e with 60% yield
and E/Z = 13.3:1 (Table 2, entry 4). The molecular structure
of compound 3e was characterized with X-ray diffraction.
For 3-en-1-ynamides 1f and 1g bearing mesyl-derived
sulfonamides NMsPh, NMs(n-Bu), their resulting compounds
3f and 3g were obtained in 60−64% yields with a preferable E-
selectivity (E/Z > 10:1, entries 5−6). 3-En-1-ynamides 1h and
1i bearing various C(4)-alkyl groups (R2 = i-Pr and n-Bu) were
also applicable to these oxidative arylations, giving compounds
3h and 3i in 76−79% yields (entries 7−8). 3-En-1-ynamide 1j
bearing C(3)-substituted n-butyl afforded compound 3j in 72%
yield (E/Z = 12.5:1) (entry 9). We also prepared cyclo-
pentene- and cyclohexene-derived 3-en-1-ynamides 1k and 1l;
their corresponding products 3k and 3l were obtained in 64−
76% yield, with E/Z = 15.3:1 and 7.6:1, respectively (entries
10−11).
We prepared various 3-en-1-ynamides 1 to test the substrate
scope; the results are summarized in Table 2. With nitrone 2a
a,b
Table 2. Reactions of Various 3-En-1-ynamides
We assessed the substrate scope using various nitrones
bearing meta- and ortho-substituents on aniline moieties; these
results are summarized in Table 3. We first tested the reactions
on nitrones 2b−2d, bearing varied meta-substituents (R2 = Br,
Cl, Me); their corresponding desired products 4a−4c were
obtained with 58−79% yields (Table 3, entries 1−3). We also
examined ortho-substituted analogues 2e−2i, (R1 = Br, Cl, I, F,
Me), further affording the desired 1,4-oxoarylation products
4d−4h in 65−88% yields (entries 4−8). Finally, we examined
2-naphthyl-derived nitrone 2j, delivering compound 4i in 73%
yield (entry 9).
Apart from 1,4-oxoarylations, we have developed new 1,4-
oxoaminations with those enynes bearing 4-aryl substituents;
the results are provided in Table 4. Among these 1,4-
oxoamination products, X-ray diffraction of representative 5f
a
b
[1a] = 0.08 M. Isolated yields are obtained after purification from a
silica column.
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a,b
73−85% yields (Table 4, entries 7−9). X-ray diffraction of
compound 5f confirms our proposed 1,4-oxoamination
structure and its E-configuration. For nitrones 2o−2p bearing
electron-donating p-phenyl moieties (R3 = Me, O-Me), the
resulting products 5i−5j were obtained with 81−83% yields
(entries 10−11). m-Chlorophenyl-containing nitrone 2q (R4 =
Cl) afforded compound product 5k in 68% yield (Table 4,
entry 12). A summary of the results in Tables 2 and 4 indicates
that alkyl and 4-methoxyphenyl at position C(4) of 3-en-1-
ynamides prefer 1,4-oxoarylations, whereas their C(4)-phenyl
and their electron-deficient analogues produce 1,4-oxoamina-
tions.
Table 3. Nitrone Substrate Scope
We prepared nitrones 2m and 2o bearing 4-chloro- and 4-
methylphenyl-derived nitrones to seek a switch of chemo-
selectivity to 1,4-oxoamination. Notably, we still obtained 1,4-
oxoarylation product 3a in 40% yield via an electrophilic
substitution in which the phenylchloro moiety was replaced. In
contrast, we observed no reaction occurring for nitrone 2o. In
the presence of water, we observed no change of reaction
chemoselectivity for these two nitrones, but the yield of
compound 3a was slightly improved to 46%. In the case of
species 2o, we obtained no C- or N-addition product but a
large recovery yield of starting 1a and 2o. In this case, we
speculate that the gold catalyst is likely poisoned with the
released imine (vide infra). We also performed the oxidation of
3-en-1-ynamide 1a with a mixture of d5-nitrone 2r and its
imine in equal proportions; the resulting product d4-3a
contained only deuterated aniline at the 4-carbon position,
whereas its alkenyl proton was only protonated.
a
b
[1a] = 0.08 M. Isolated yields are obtained after purification from a
silica column.
a,b
Table 4. Gold-Catalyzed 1,4-Oxoaminations
Accordingly, nitrone is the only source to provide oxygen
and benzene for the 1,4-oxoarylation reaction of 3-en-1-
ynamide 1a. To measure the kinetic isotope effect, we ran a
reaction containing do-2a (1.0 equiv), d5-2r (1.0 equiv), and 3-
en-1-ynamide 1a (0.3 equiv); the resulting product was
obtained with d0-3a/d4‑3a = 1.00/1.00, showing no isotope
effect.
We postulate a mechanism for the 1,4-oxoarylation and 1,4-
oxoamination reactions of 3-en-1-ynamides (Scheme 2). A
summary of our results indicates that C(4)-alkyl and 4-
methoxyphenyl substituents preferably form 1,4-oxoarylation
products, whereas their phenyl and other electron-deficient
phenyl analogues preferably yield 1,4-oxoamination products.
a
b
[1] = 0.08 M. Isolated yields are obtained after purification from a
silica column.
Scheme 2. Plausible Mechanism for 1,4-Oxoamination and
1,4-Oxoarylation Reaction
was performed to verify the proposed structure. Most 1,4-
oxoamination products prefer only E-selectivity with E/Z >
20:1; those products with E/Z < 25:1 are indicated in Table 4.
We first tested 4-phenyl-3-en-1-ynamide 1m (R1 = Ph) with
nitrone 2a, affording amination product 5a in 78% yield (entry
1). We examined electron-withdrawing phenyl analogues 1n−
1o (R1= Cl and Br) that reacted with nitrone 2a to produce
compounds 5b−5c in 76−83% yields (Table 4, entries 2 and
3). When we tested the ynamide-containing electron-donating
group 1p (R1 = OMe) we obtained desired product 3m in 38%
yield with E/Z = 1.9:1 (entry 4). We also performed the
reactions on species 1q, bearing various sulfonamides NTs(i-
Pr), delivering compound 5d in 71% yield with E/Z = 14.2:1
(entry 5). Further, we tested several nitrones 2 with 4-phenyl-
3-en-1-ynamides (1m); see entries 6−12. For p-bromophenyl-
derived nitrone 2k, corresponding product 5e was obtained in
79% yield with E/Z = 8.8:1 (entry 6). We performed these
reactions on other para-substituted nitrones (R3 = CO2Et, Cl,
F, 2l−2n); their resulting products 5f− 5h were obtained in
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This mechanism also rationalizes the observed E-stereo-
selectivity of observed products 3 and 5. We previously
reported gold-catalyzed oxidations of ynamides with nitrones
to generate gold carbenes and imines; herein, we postulate
alkenylgold carbenes B′ that are also characterized with an
allylgold cation resonance B. These gold carbenes likely form
complex pairs with imines according to our deuterium-labeling
experiments. In the case of electron-withdrawing phenyl and
their electron-deficient analogues, their positive charge is
significant to react with imine at the more basic nitrogen,
yielding an addition intermediate C. This route leads to 1,4-
oxoamination product 5 via a subsequent hydrolysis
intermediate B. In the case of C(4)-alkyl- and 4-methox-
yphenyl-substituted analogues, the positive charge of allylgold
cation B (or B′) is small and stable; N-imine or carbene
complex C′ is easily dissociative to allow a p-aryl of the
released imine, forming species E. A subsequent loss of proton
of species E is, however, expected to be facile because of its
aromatization. This process produces 1,4-oxoarylation prod-
ucts if allylgold cations B/B′ are highly stable with a small
positive charge. We hypothesize that the C(4)-N-attack is
kinetically favorable because the nitrogen of the imine is more
nucleophilic than a benzene, whereas the p-aryl attack can
occur in a slow but irreversible process. In eq 6, we observed
Experimental procedures, characterization data, crystal-
lography data, and 1H NMR and 13C NMR for
representative compounds (PDF)
Accession Codes
CCDC 2048163, 2048168, and 2048171 contain the
supplementary crystallographic data for this paper. These
data can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Rai-Shung Liu − Frontier Research Center of Matter Science
and Technology, Department of Chemistry, National Tsing
Hua University, Hsinchu 30013, Taiwan, ROC;
orcid.org/0000-0002-2011-8124; Email: rsliu@
mx.nthu.edu.tw
Authors
Sudhakar Dattatray Tanpure − Frontier Research Center of
Matter Science and Technology, Department of Chemistry,
National Tsing Hua University, Hsinchu 30013, Taiwan,
ROC
Balaji S. Kale − Frontier Research Center of Matter Science
and Technology, Department of Chemistry, National Tsing
Hua University, Hsinchu 30013, Taiwan, ROC
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00055
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the Ministry of Science and Technology
(MOST 107-3017-F-007-002) and the Ministry of Education
(MOE 106N506CE1), Taiwan, for supporting this work.
no reaction between 3-en-1-ynamide 1a and nitrone 2o; we
rationalize this outcome with a postulated and stable complex
pair H because an alternative path is completely blocked. In
the case of 4-chlorophenyl-derived nitrone 2m, the mechanism
can be rationalized in a similar path.6 For the two paths, their
initial intermediates D and G bear Z-configured skeletons but
yield E-configured products 3 and 5 after protodeaurations.
In summary, we report gold-catalyzed oxidations of 3-en-1-
ynamides with nitrones to yield two distinct products. We
obtained 1,4-oxoarylation products7 from those ynamides
bearing electron-donating substituents at the alkene moieties
to render vinylgold carbenes stable. Initial N-attack of imines at
these gold carbenes is reversible; the chemoselectivity becomes
switched to 1,4-oxoarylations via p-arylations of imines at gold
carbenes. If substituents are less electron-donating, this initial
N-attack becomes irreversible because of the highly electron-
deficient nature of gold carbenes; the chemoselectivity is
favorable for 1,4-oxoamination products.8
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ASSOCIATED CONTENT
■
sı
* Supporting Information
n data, crystallography data, and H NMR and 13C NMR for
1
representative compounds (PDF). The Supporting Informa-
tion is available free of charge at https://pubs.acs.org/doi/
10.1021/acs.orglett.1c00055.
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(6) For a 1,4-oxoarylations of species 1a with nitrone 2m (eq 6),
removal of p-chloride is rationalized in the following mechanism. The
corresponding intermediate E′ becomes attacked by water to form the
same intermediate F and highly acidic HOCl that was identified by a
reported method. Hydrodeauration of species F affords E-configu-
rated product 3a initially that becomes rearranged to a mixture of Z-
and E-isomers under the reaction conditions. For analysis of HOCl,
see: Liu, C.; Gunten, U. V.; Croue, J.-P. Enhanced Bromate
Formation during Chlorination of Bromide- Containing Waters in
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Oxoarylations of Ynamides with Nitrones. Org. Lett. 2012, 14 (21),
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Catalyzed Intermolecular Oxyarylation of Alkynes: Unexpected
Regiochemistry in the Alkylation of Arenes. Org. Lett. 2009, 11,
4906−4909. (c) Sahani, R.-L.; Sahani, R.-L.; Liu, R.-S. Gold-
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with Nitrones to Yield Distinct Fused Indoles Bearing a Heterocyclic
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Gold-Catalyzed Intramolecular Redox Reaction of Sulfinyl Alkynes:
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Gold-catalyzed Intermolecular Oxidations of 2-Ketonyl-1-ethynyl
Benzenes with N-Hydoxyanilines to Yield 2-Aminoindenones via
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of Postulated α-Oxo Gold Carbenes Using Bidentate Ligands:
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ment of an Expedient Bimolecular Assembly of 2,4-Disubstituted
Oxazoles. J. Am. Chem. Soc. 2012, 134, 17412−17415. (d) Lu, B.;
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Indole through Gold Catalysis. Angew. Chem. 2011, 123, 8508−8512.
(e) Cai, J.; Wu, B.; Rong, G.; Zhang, C.; Qiu, L.; Xu, X. Gold-
catalyzed Bicyclization of Diaryl Alkynes: Synthesis of Polycyclic
Fused Indole and Spirooxindole Derivatives. Org. Lett. 2018, 20 (9),
2733−2736. (f) Ye, L.-W.; He, W.; Zhang, L. A Flexible and
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(5) For gold-catalyzed reactions of 3-en-1-ynamides, see selected
examples: (a) Giri, S. S.; Liu, R.-S. Gold-catalyzed [4 + 3]- and [4 +
2]-annulations of 3-en-1-ynamides with isoxazoles via novel 6π-
electrocyclizations of 3-azahepta trienyl cations. Chem. Sci. 2018, 9,
2991−2995. (b) Dateer, R. B.; Pati, K.; Liu, R.-S. Gold-catalyzed
synthesis of substituted 2-aminofurans via formal [4 + 1]-cyclo-
additions on 3-en-1-ynamides. Chem. Commun. 2012, 48, 7200−7202.
(c) Singh, R. R.; Liu, R.-S. Gold-Catalyzed Imination/Mannich
Reaction Cascades of 3-En-1-ynamides with Anilines and Aldehydes
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Organic Letters
pubs.acs.org/OrgLett
Letter
Oxygen-Transfer Redox and 1,3-Sulfonyl Migration. Chem. - Eur. J.
2011, 17, 1764−1767.
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https://dx.doi.org/10.1021/acs.orglett.1c00055
Org. Lett. 2021, 23, 1394−1399