Au(I)-Catalyzed Oxidative Functionalization of Yndiamides

Article abstract of DOI:10.1021/acs.orglett.1c01625

Yndiamides, underexplored cousins of ynamides, offer rich synthetic potential as doubly nitrogenated two carbon building blocks. Here we report a gold-catalyzed oxidative functionalization of yndiamides to access unnatural amino acid derivatives, using a wide range of nucleophiles as a source of the amino acid side chain. The transformation proceeds under mild conditions, is highly functional group tolerant, and displays excellent regioselectivity through subtle steric differentiation of the yndiamide nitrogen atom substituents.

Full text of DOI:10.1021/acs.orglett.1c01625

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Au(I)-Catalyzed Oxidative Functionalization of Yndiamides
Zixuan Tong, Olivia L. Garry, Philip J. Smith, Yubo Jiang, Steven J. Mansfield, and Edward A. Anderson*
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ABSTRACT: Yndiamides, underexplored cousins of ynamides, offer rich
synthetic potential as doubly nitrogenated two carbon building blocks. Here
we report a gold-catalyzed oxidative functionalization of yndiamides to access
unnatural amino acid derivatives, using a wide range of nucleophiles as a
source of the amino acid side chain. The transformation proceeds under mild
conditions, is highly functional group tolerant, and displays excellent
regioselectivity through subtle steric differentiation of the yndiamide nitrogen
atom substituents.
namides (1, Scheme 1a) are versatile functionalities that
find widespread use in organic synthesis,1 not least due to
oxidants in a variety of other gold-catalyzed transformations of
ynamides,6 and have also been demonstrated as successful
promoters of nucleophilic addition to ynamides under
Brønsted acid catalysis.7
Y
Scheme 1. Gold(I)-Catalyzed Oxidative Functionalization of
Ynamides, and Concept of This Work
Ynamides are particularly well-suited to gold or Brønsted
acid catalyzed oxidative functionalization via facile and
regioselective generation of ketene iminium ion intermediates.
Yndiamides 2 would be expected to benefit from similar
activation of the alkyne, but their pseudosymmetry poses a
challenge for regioselective functionalization. Here we describe
the development of an oxidative gold-catalyzed transformation
of yndiamides to α-functionalized aminoamides 3 via α-oxo
gold carbenes. These products correspond to unnatural amino
acid derivatives, motifs that are of great importance both in
medicinal chemistry8 and in the modification of protein
structure and function.9 We also report the realization of
regioselective yndiamide functionalizations, where subtle steric
effects were found to outweigh electronic considerations.
At the outset of our investigations, we tested the gold-
catalyzed ynamide oxidative functionalization using
Ph3PAuNTf2 as the catalyst, as employed by Ye and co-
workers,6a with yndiamide 2a as the substrate and 2-
chloropyridine N-oxide as the oxidant (Table 1, entry 1). To
our delight, the desired product 3a was isolated in good yield
(72%), albeit accompanied by small amounts (∼5%) of
inseparable side products.10 Changing the counterion
(Ph3PAuSbF6, entry 2) led to an improvement in yield
(80%), as did the use of a preformed NHC-Au(I) catalyst
(IPrAuNTf2, 82%, entry 3), but both exhibited equivalent side
product formation. We suspected this might be due to
the electron-donating nitrogen atom which enhances both
nucleophilicity and regioselectivity in their reactions.1a−c In
stark contrast, yndiamides (2, Scheme 1b)relatives of
ynamides that feature an additional nitrogen substituent at
the alkyne terminusare barely explored despite their
synthetic potential as diaminated, two-carbon building blocks.2
In previous work, we described the synthesis of yndiamides
and their reactivity in transition metal catalyzed cyclo-
isomerizations, which revealed them to be a rich source of
azacycles.2 However, their use in intermolecular bond-forming
processes has not been studied.
Following Zhang and co-workers’ seminal reports on the
generation of α-oxo gold carbenes with pyridine N-oxides,3
Davies et al. described the first examples of equivalent
oxidations of ynamides to α-imido gold carbenes.4 This work
led to an explosion of interest in gold-catalyzed oxidative
ynamide functionalization, with wide variation of both the
activating agent and nucleophile (Scheme 1a).1e,5 Pyridine N-
oxides and related activators have since been employed as
Received: May 12, 2021
Published: June 3, 2021
https://doi.org/10.1021/acs.orglett.1c01625
© 2021 American Chemical Society
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a
Table 1. Optimization of Reaction Conditions
Entry
Catalyst
PPh3AuNTf2
Yield (%)
b
1
2
3
72
b
PPh3AuSbF6
80
c
b
IPrAuNTf2
82
d
4
PPh3AuNTf2
59
41
42
81
−
5
6
7
8
9
(4-MeOC6H4)3PAuNTf2
(4-FC6H4)3PAuNTf2
IPrAuNTf2
e
−
f
IPrAuNTf2
HNTf2 (10 mol %)
84
78
f
10
a
Reactions conducted with 2a (0.10 mmol), 0.05 M; catalysts LAuX
were prepared in situ by premixing the corresponding LAuCl and AgX
salts, unless stated otherwise. Yields are isolated yields. DCE = 1,2-
b
dichloroethane. Product isolated with ∼5% inseparable impurities.10
c
d
IPrAuNTf2 was obtained commercially. Entries 4−9 conducted in
e
the presence of 4 Å molecular sieves. Reaction performed in absence
of gold catalyst. Reaction conducted at 0.5 M concentration, 1 h. IPr
f
= 1,3-bis(2,6-diisopropylphenyl)-1,3-dihydro-2H-imidazol-2-ylidene.
competitive trapping of the putative gold-carbene intermediate
by water;10 pleasingly, use of anhydrous DCE and inclusion of
4 Å molecular sieves suppressed side product formation, albeit
at a cost to the reaction yield (59%, entry 4). While other
gold(I) phosphine complexes offered no benefit (entries 5, 6),
use of the NHC-gold(I) catalyst IPrAuNTf2 afforded an
excellent yield of 3a (81%, entry 7).
No reaction was observed in the absence of gold catalyst
(entry 8). Performing the reaction at higher concentration (0.5
M) led to complete conversion within 1 h and a slight increase
in yield (84%, entry 9). We were also pleased to find that
triflimide (10 mol %) enabled the formation of 3a in good
yield (78%, entry 10).7a
Figure 1. Nucleophile scope of Au(I)- or HNTf2-catalyzed yndiamide
oxidative functionalization. Unless otherwise stated all reactions were
performed on 0.1 mmol scale at room temperature with [2a] = 0.5 M.
Yields refer to isolated yields after full conversion of 2a as indicated by
TLC analysis; yields in blue obtained using IPrAuNTf2, yields in red
With optimized conditions in hand for both gold- and acid-
catalyzed oxidative yndiamide functionalization, the scope of
the reaction was explored with respect to the nucleophile
(Figure 1). We first found that the gold-catalyzed reaction of
yndiamide 2a proved equally efficient at 1 mmol scale (0.48 g),
delivering 3a in 80% yield. The reaction also translated
smoothly to pyrrole, affording the 2-substituted pyrrole
aminoamide 3b in good yield (66%). However, use of
Brønsted acid catalyzed conditions resulted in a low yield of
3b as a 2:1 mixture of C2 and C3 pyrrole regioisomers (31%
combined yield), along with 25% of the double substitution
product 4b. The latter presumably arises by acid-promoted
elimination of TsBuNH from the initially formed aminoamide
3b to generate an intermediate pyrrolium ion, which is
captured by a further equivalent of pyrrole nucleophile.
In light of this side reaction, we elected to perform the
remainder of the substrate screen under gold catalysis.
Pleasingly, a range of other indoles and pyrroles proved
effective nucleophiles, affording products 3c−3h in high yields
(63−89%). The identities of four of these products were
confirmed by X-ray crystallography.11 For indoles 3c−3f both
electron-withdrawing and -donating groups were tolerated on
a
b
obtained using HNTf2. Reactions performed at 1 mmol scale.
c
Reactions performed at 80 °C. Reactions performed at 0.4 mmol
d
e
scale. Reactions performed at 0.2 mmol scale. Double addition
f
product 4n was isolated. tert-Butyldimethyl((1-phenylvinyl)oxy)-
silane was used as a nucleophile. g Reaction treated with 1 M HCl for
30 min after full conversion to give the corresponding ketone. 3b, 3g,
3g′, and 3q were determined by single crystal X-ray diffraction.11
the indole ring, with exclusive addition at the 3-position. N-
Methyl pyrrole afforded a mixture of C2 and C3 adducts, while
2,5-dimethylpyrrole gave solely the expected C3 adduct in
good yield (3h, 83%). Both O- and S-heterocycles were found
to require additional activating substituents, with benzannu-
lated heterocycles proceeding most efficiently (3i−k). No
reaction was observed using the parent nonactivated hetero-
cycles (furan etc.) even at elevated temperatures.10
An interesting reaction pattern was observed for anilines.
N,N-Disubstituted anilines react at the para position (3l, 75%),
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or at the ortho position when the para position is blocked (3m,
48%); interestingly, 3l was obtained in comparable yield under
Brønsted acid catalysis (71%). An N-monosubstituted aniline
also reacted at the para position to give the double substitution
product 4n, but reacted through the nitrogen atom when the
para position was masked (single addition, 3o). Finally, the
parent aniline failed to produce any desired product, with only
yndiamide decomposition observed.
Related methoxylated arenes displayed similar behavior:
while phenol and anisole proved unsuccessful, the more
electron-rich 2,6-dimethoxyphenol gave 3p in good yield
(72%), albeit requiring an extended reaction time. Heightened
reactivity was observed using 1,3,5-trimethoxybenzene, which
delivered 3q in excellent yield (91%). Two non-aryl carbon
nucleophiles were also tested; while a silyl enol ether produced
the desired product 3r (in low yield), decomposition was
observed using allyltrimethylsilane (3s). To our surprise, a
significant increase in the yield of 3r was observed using 10
mol % HNTf2 as catalyst (53%). The observation of double
substitution under Brønsted acid catalyzed conditions (Figure
1, 4b) offers potential for further functionalization of the
monosubstituted aminoamide products. Indeed, a rapid and
quantitative acid-catalyzed substitution of the α-sulfonamide
group in 3a using indole as nucleophile was achieved with just
5 mol % HNTf2 promoter, giving bis-indole acetamide 4a in
quantitative yield (Scheme 2a). This transformation was also
successful using pyrrole as the nucleophile, giving the bis-
heteroarylated product 4c in 83% yield. The two nitrogen
atoms in yndiamide 3l could also be further differentiated by
selective detosylation12 (Mg/NH4Cl, Scheme 2b), affording a
high yield of acetamide 5l from aminoamide 3l (84%). A
robustness test13 was also performed to assess functional group
tolerance (Scheme 2c); pleasingly, the reaction tolerated 10
out of 12 external additives covering a range of functional
groups, the exceptions being a thiol (73%) and 1,3-diol (46%).
The latter induced the formation of unidentified side products,
likely due to competing nucleophilic attack by the diol.
As noted, ynamide functionalizations typically benefit from
high regioselectivity due to the inherent polarization of the
alkyne. Achieving regiocontrol in yndiamide functionalization
was likely to be more challenging but could arise through
tuning of the two electron-withdrawing groups to render one
end of the alkyne more nucleophilic. As such, the unsym-
metrical yndiamides 2b and 2c (Scheme 3a) were subjected to
Scheme 3. Regioselectivity in Gold-Catalyzed Oxidative
a
Functionalization of Unsymmetrical Yndiamides
Scheme 2. Further Transformations of α-Aminoamides, and
a
Robustness Test
a
Reactions conducted with 0.1 mmol of yndiamide 2b−e. Standard
conditions: 2-chloropyridine N-oxide (2.0 equiv), indole (3.0 equiv),
IPrAuNTf2 (5 mol %), rt, 2 h. Yields in a refer to combined isolated
yield of both isomers. Yields in b refer to isolated yield of the major
isomer, apart from 3x/3x′ which were not separable. Regioisomer
1
ratios (r.r.) were determined by H NMR spectroscopic analysis of
the crude reaction mixture. See the Supporting Information for details
of assignment of regioisomers.
the oxidative functionalization using indole. However, only
moderate regioselectivity was achieved on replacing Ts with
either a more (p-F3CC6H4SO2, 3t/3t′, r.r. = 3.7:1) or less
(phosphoryl, 3u/3u′, r.r. = 1:4.3) electron-withdrawing group.
We hypothesized that the use of other pyridine N-oxides might
affect this ratio based on altered nucleophilicity. The use of
pyridine N-oxide itself led to a significant reduction in yield,
while 4-fluoropyridine N-oxide maintained similar reaction
efficiency; however, neither improved the regioselectivity of
the reaction.
An alternative solution to this problem is steric differ-
entiation of the two nitrogen atoms (Scheme 3b). Accordingly,
yndiamide 2d, featuring cyclohexyl and benzyl substituents,
delivered a single regioisomer of product 3v. The extent of this
a
Reactions in Scheme 2c were performed using 0.05 mol of 2a in 0.1
mL of anhydrous DCE; NMR yields of 3a are stated, which were
determined by quantitative H NMR experiments with dimethylsul-
fone as the internal standard.
1
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steric influence was challenged using ynamides 2e (i-Pr vs Bn)
and 2f (i-Pr vs n-Bu). This revealed that even a single methyl
branch α- to the ynamide nitrogen atom is sufficient to impart
high levels of regiocontrol in the functionalization. These
results suggest that the gold complex preferentially engages the
yndiamide proximal to the less-bulky nitrogen substituent, with
the exceptional regioselectivity arising from minimization of
steric repulsion, rather than electronic factors.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01625.
■
sı
Experimental procedures and characterization of com-
pounds synthesized (PDF)
Accession Codes
Scheme 4 shows a proposed reaction mechanism for the
gold-catalyzed transformation. π-Acid activation of the
CCDC 2082506−2082509 contain the supplementary crys-
tallographic 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.
Scheme 4. Proposed Reaction Mechanism for the Gold
AUTHOR INFORMATION
Corresponding Author
■
Edward A. Anderson − Chemistry Research Laboratory,
Oxford OX1 3TA, U.K.; orcid.org/0000-0002-4149-
0494; Email: edward.anderson@chem.ox.ac.uk
Authors
Zixuan Tong − Chemistry Research Laboratory, Oxford OX1
3TA, U.K.
Olivia L. Garry − Chemistry Research Laboratory, Oxford
OX1 3TA, U.K.
Philip J. Smith − Chemistry Research Laboratory, Oxford
OX1 3TA, U.K.
Yubo Jiang − Faculty of Science, Kunming University of
Science and Technology, Kunming 650500, China;
orcid.org/0000-0002-6066-4613
Steven J. Mansfield − Chemistry Research Laboratory, Oxford
OX1 3TA, U.K.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01625
yndiamide triple bond as gold complex A is followed by
attack of 2-chloropyridine N-oxide to give intermediate B. Two
pathways are then possible, the first of which involves
formation of an α-oxo gold carbene C via spontaneous loss
of pyridine, as has been proposed for other gold-catalyzed
oxidative process on alkynes or ynamides.3a,6a,14 Attack of the
nucleophile on C then affords adduct D, protodeauration15 of
which gives product 3 and regenerates the gold catalyst.
Attempts to trap the putative gold carbene via cyclo-
propanation were unsuccessful (see the Supporting Informa-
tion); however, the formation of such carbenes is known to be
favored by the strong σ-donating but weak π-acidic nature of
the IPr ligand.16 Alternatively, D could arise directly from B via
SN2′ displacement of the pyridine leaving group by the
nucleophile.
In conclusion, we have developed a gold-catalyzed oxidative
functionalization of yndiamides to afford unnatural amino
amide derivatives. Remarkable regioselectivity could be
induced by steric differentiation of the yndiamide substituents.
The broad functional group tolerance of this transformation
was highlighted by robustness tests, with the amide products
being suitable for further derivatization including addition of a
second heteroaromatic nucleophile. We anticipate that this
mode of activation should become a significant addition to the
field of yndiamide chemistry.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
P.J.S. and S.J.M. thank the EPSRC Centre for Doctoral
Training in Synthesis for Biology and Medicine for student-
ships (EP/L015838/1), generously supported by AstraZeneca,
Diamond Light Source, Defence Science and Technology
Laboratory, Evotec, GlaxoSmithKline, Janssen, Novartis, Pfizer,
Syngenta, Takeda, UCB and Vertex. Y.J. thanks the China
Scholarship Council (No. 201908535023) for financial
support. E.A.A. thanks the EPSRC for additional support
(EP/S013172/1).
REFERENCES
■
(1) (a) DeKorver, K. A.; Li, H.; Lohse, A. G.; Hayashi, R.; Lu, Z.;
Zhang, Y.; Hsung, R. P. Ynamides A Modern Functional Group for
the New Millennium. Chem. Rev. 2010, 110, 5064−5106. (b) Evano,
G.; Coste, A.; Jouvin, K. Ynamides: versatile tools in organic synthesis.
Angew. Chem., Int. Ed. 2010, 49, 2840−2859. Vinyl anion equivalents:
(c) Evano, G.; Michelet, B.; Zhang, C. The anionic chemistry of
ynamides: A review. C. R. Chim. 2017, 20, 648−664. (d) Evano, G.;
Blanchard, N.; Compain, G.; Coste, A.; Demmer, C. S.; Gati, W.;
Guissart, C.; Heimburger, J.; Henry, N.; Jouvin, K.; Karthikeyan, G.;
Laouiti, A.; Lecomte, M.; Martin-Mingot, A.; Métayer, B.; Michelet,
B.; Nitelet, A.; Theunissen, C.; Thibaudeau, S.; Wang, J.; Zarca, M.;
4891
https://doi.org/10.1021/acs.orglett.1c01625
Org. Lett. 2021, 23, 4888−4892

Organic Letters
pubs.acs.org/OrgLett
Letter
Zhang, C. A Journey in the Chemistry of Ynamides: From Synthesis
to Applications. Chem. Lett. 2016, 45, 574−585. (e) Hu, Y.-C.; Zhao,
Y.; Wan, B.; Chen, Q.-A. Reactivity of ynamides in catalytic
intermolecular annulations. Chem. Soc. Rev. 2021, 50, 2582−2625.
(2) Mansfield, S. J.; Christensen, K. E.; Thompson, A. L.; Ma, K.;
Jones, M. W.; Mekareeya, A.; Anderson, E. A. Copper-Catalyzed
Synthesis and Applications of Yndiamides. Angew. Chem., Int. Ed.
2017, 56, 14428−14432.
(3) (a) Ye, L.; Cui, L.; Zhang, G.; Zhang, L. Alkynes as Equivalents
of α-Diazo Ketones in Generating α-Oxo Metal Carbenes: A Gold-
Catalyzed Expedient Synthesis of Dihydrofuran-3-ones. J. Am. Chem.
Soc. 2010, 132, 3258−3259. (b) Ye, L.; He, W.; Zhang, L. Gold-
Catalyzed One-Step Practical Synthesis of Oxetan-3-ones from
Readily Available Propargylic Alcohols. J. Am. Chem. Soc. 2010,
132, 8550−8551. (c) Lu, B.; Li, C.; Zhang, L. Gold-Catalyzed Highly
Regioselective Oxidation of C−C Triple Bonds without Acid
Additives: Propargyl Moieties as Masked α,β-Unsaturated Carbonyls.
J. Am. Chem. Soc. 2010, 132, 14070−14072.
(4) Davies, P. W.; Cremonesi, A.; Martin, N. Site-specific
introduction of gold-carbenoids by intermolecular oxidation of
ynamides or ynol ethers. Chem. Commun. 2011, 47, 379−381.
(5) (a) Campeau, D.; León Rayo, D. F.; Mansour, A.; Muratov, K.;
Gagosz, F. Gold-Catalyzed Reactions of Specially Activated Alkynes,
Allenes, and Alkenes. Chem. Rev. 2020, DOI: 10.1021/acs.chem-
rev.0c00788. (b) Ye, L.-W.; Zhu, X.-Q.; Sahani, R. L.; Xu, Y.; Qian, P.-
C.; Liu, R.-S. Nitrene Transfer and Carbene Transfer in Gold
Catalysis. Chem. Rev. 2020, DOI: 10.1021/acs.chemrev.0c00348.
(c) Pan, F.; Shu, C.; Ye, L.-W. Recent progress towards gold-catalyzed
synthesis of N-containing tricyclic compounds based on ynamides.
Org. Biomol. Chem. 2016, 14, 9456−9465.
1107. Further details about the refinements, including disorder
modelling and restraints, are documented in the crystallographic data
deposited with the Cambridge Crystallographic Data Centre (CCDC
2082506−2082509).
(12) Dawande, S. G.; Kanchupalli, V.; Kalepu, J.; Chennamsetti, H.;
Lad, B. S.; Katukojvala, S. Rhodium Enalcarbenoids: Direct Synthesis
of Indoles by Rhodium(II)-Catalyzed [4 + 2] Benzannulation of
Pyrroles. Angew. Chem., Int. Ed. 2014, 53, 4076−4080.
(13) (a) Collins, K. D.; Glorius, F. A robustness screen for the rapid
assessment of chemical reactions. Nat. Chem. 2013, 5, 597−601.
(b) Gensch, T.; Teders, M.; Glorius, F. Approach to Comparing the
Functional Group Tolerance of Reactions. J. Org. Chem. 2017, 82,
9154−9159.
̌
̌
(14) (a) Schulz, J.; Jasíková, L.; Skríba, A.; Roithová, J. Role of
Gold(I) α-Oxo Carbenes in the Oxidation Reactions of Alkynes
Catalyzed by Gold(I) Complexes. J. Am. Chem. Soc. 2014, 136,
11513−11523. (b) Zhang, L. A Non-Diazo Approach to α-Oxo Gold
Carbenes via Gold-Catalyzed Alkyne Oxidation. Acc. Chem. Res. 2014,
47, 877−888. (c) Zheng, Y.; Zhang, J.; Cheng, X.; Xu, X.; Zhang, L.
Wolff Rearrangement of Oxidatively Generated alpha-Oxo Gold
Carbenes: An Effective Approach to Silylketenes. Angew. Chem., Int.
Ed. 2019, 58, 5241−5245.
(15) (a) Wang, C.; Ren, X.-R.; Qi, C.-Z.; Yu, H.-Z. Mechanistic
Study on Gold-Catalyzed Highly Selective Hydroamination of
Alkylidenecyclopropanes. J. Org. Chem. 2016, 81, 7326−7335.
(b) BabaAhmadi, R.; Ghanbari, P.; Rajabi, N. A.; Hashmi, A. S. K.;
Yates, B. F.; Ariafard, A. A Theoretical Study on the Protodeauration
Step of the Gold(I)-Catalyzed Organic Reactions. Organometallics
2015, 34, 3186−3195.
(16) Wang, Y.; Muratore, M. E.; Echavarren, A. M. Gold Carbene or
Carbenoid: Is There a Difference? Chem. - Eur. J. 2015, 21, 7332−
7339.
(6) (a) Li, L.; Shu, C.; Zhou, B.; Yu, Y.-F.; Xiao, X.-Y.; Ye, L.-W.
Generation of gold carbenes in water: efficient intermolecular
trapping of the α-oxo gold carbenoids by indoles and anilines.
Chem. Sci. 2014, 5, 4057−4064. (b) Shen, C. H.; Li, L.; Zhang, W.;
Liu, S.; Shu, C.; Xie, Y. E.; Yu, Y. F.; Ye, L. W. Gold-catalyzed tandem
cycloisomerization/functionalization of in situ generated alpha-oxo
gold carbenes in water. J. Org. Chem. 2014, 79, 9313−9318. (c) Liu,
J.; Zhu, L.; Wan, W.; Huang, X. Gold-Catalyzed Oxidative Cascade
Cyclization of 1,3-Diynamides: Polycyclic N-Heterocycle Synthesis
via Construction of a Furopyridinyl Core. Org. Lett. 2020, 22, 3279−
3285. (d) Dateer, R. B.; Pati, K.; Liu, R.-S. Gold-catalyzed synthesis of
substituted 2-aminofurans via formal [4 + 1]-cycloadditions on 3-en-
1-ynamides. Chem. Commun. 2012, 48, 7200−7202. (e) Xu, W.;
Chen, Y.; Wang, A.; Liu, Y. Benzofurazan N-Oxides as Mild Reagents
for the Generation of α-Imino Gold Carbenes: Synthesis of
Functionalized 7-Nitroindoles. Org. Lett. 2019, 21, 7613−7618.
(7) (a) Patil, D. V.; Kim, S. W.; Nguyen, Q. H.; Kim, H.; Wang, S.;
Hoang, T.; Shin, S. Brønsted Acid Catalyzed Oxygenative Bimolecular
Friedel−Crafts-type Coupling of Ynamides. Angew. Chem., Int. Ed.
2017, 56, 3670−3674. (b) Chen, Y.-B.; Qian, P.-C.; Ye, L.-W.
Brønsted acid-mediated reactions of ynamides. Chem. Soc. Rev. 2020,
49, 8897−8909. (c) Um, T.-W.; Lee, G.; Shin, S. Enantioselective
Synthesis of Tertiary α,α-Diaryl Carbonyl Compounds Using Chiral
N,N-Dioxides under Umpolung Conditions. Org. Lett. 2020, 22,
1985−1990.
(8) Blaskovich, M. A. T. Unusual Amino Acids in Medicinal
Chemistry. J. Med. Chem. 2016, 59, 10807−10836.
(9) Neumann-Staubitz, P.; Neumann, H. The use of unnatural
amino acids to study and engineer protein function. Curr. Opin. Struct.
Biol. 2016, 38, 119−128.
(10) See the Supporting Information for details.
(11) Low temperature single-crystal X-ray diffraction data for 3b, 3g,
3g′, and 3q were collected using a Rigaku Oxford SuperNova
diffractometer at 150 K. Raw frame data were reduced using
CrysAlisPro, and the structures were solved using ‘Superflip’ before
refinement with CRYSTALS. (a) Palatinus, L.; Chapuis, G. J. Appl.
Crystallogr. 2007, 40, 786−790. (b) Parois, P.; Cooper, R. I.;
Thompson, A. L. Chem. Cent. J. 2015, 9, 30. (c) Cooper, R. I.;
Thompson, A. L.; Watkin, D. J. J. Appl. Crystallogr. 2010, 43, 1100−
4892
https://doi.org/10.1021/acs.orglett.1c01625
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