Gold(I)-Catalyzed Highly Enantioselective [4 + 2]-Annulations of Cyclopentadienes with Nitrosoarenes via Nitroso-Povarov versus Oxidative Nitroso-Povarov Reactions

Article abstract of DOI:10.1021/acscatal.0c01293

This work reports gold-catalyzed highly enantioselective nitroso-Povarov reactions between cyclopentadienes and nitrosoarenes in cold dichloroethane, in which nitrosoarenes serve as 4π-electron donors and cyclopentadienes as 2π-donors. High enantioselecti

Full text of DOI:10.1021/acscatal.0c01293

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Letter
Gold(I)-Catalyzed Highly Enantioselective [4+2]-Annulations
of Cyclopentadienes with Nitrosoarenes via Nitroso-
Povarov versus Oxidative Nitroso-Povarov Reactions
Prakash Jadhav, Jia-Xuan Chen, and Rai-Shung Liu
ACS Catal., Just Accepted Manuscript • Publication Date (Web): 30 Apr 2020
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ACS Catalysis
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Gold(I)-Catalyzed Highly Enantioselective [4+2]-Annulations of Cy-
clopentadienes with Nitrosoarenes via Nitroso-Povarov versus Oxi-
dative Nitroso-Povarov Reactions
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Prakash D. Jadhav, Jia-Xuan Chen and Rai-Shung Liu*
Frontier Research Center for Matter Science and Technology, Department of Chemistry, National Tsing-Hua Universi-
ty, Hsinchu, Taiwan, ROC
KEYWORDS: nitrosoarenes, cyclopentadienes, gold, enantioselections, nitroso-povarov.
ABSTRACT: This work reports gold-catalyzed highly enantioselective nitroso-Povarov reactions between cyclopentadienes
and nitrosoarenes in cold dichloroethane, in which nitrosoarenes serve as 4-electron donors and cyclopentadienes as 2-
donors. High enantioselectivity has been achieved for substrates over a wide scope. With the same chiral catalyst, nitroso-4-
fluorobenzenes in these reactions under DCM/THF/water/air led to oxidative nitroso-Povarov reactions also with high en-
antioselectivity. We performed 18O-labeling experiments to confirm that both water and O2 participate in the reactions;
these data support a mechanism involving nitrosoarenes as nucleophiles and gold--dienes as electrophiles.
Nitrosoarenes[1] are versatile building blocks to undergo
catalytic cycloadditions with alkynes,[2] allenes[3] and 1,3-
dienes.[4] Catalytic cycloadditions of 1,3-dienes with
nitrosoarenes proceed exclusively through hetreo-Diels-
Alder reactions;[5] their asymmetric versions have been
extensively studied because of their widespread
applications in the synthesis of drug intermediates, natural
products
or
bioactive
molecules.[5-7]
Excellent
enatioselectivity has been achieved for electron-rich 1,3-
dienes bearing an amino or alkoxy group,[6] which can react
satisfactorily with nitrosoarenes over a broad scope (eq 1).
For unfunctionalized 1,3-dienes, high enantioselectivity is
known only for cyclopentadienes and 2-nitrosopyridines
using chiral Cu catalysts (eq 2).[7]
The advent of gold catalysis has inspired new
functionalizations of alkynes with weak nucleophiles,[8] but
the development of gold catalysis on electrophilic
activations of 1,3-dienes has not progressed, showing no
examples in asymmetric reactions.[9] We recently
reported[10a] gold catalyzed [4+2] reactions between
nitrsoarenes and 1,3-dienes, in which dienes work as
reactive alkenes and nitrosoarenes serve as 4-donors like
N-arylimines in Povarov reactions[11] (eqs 3-4). We thus
named the reactions as nitroso-Povarov reactions. To
highlight the utility of this new catalysis, this work reports
the first success of their enantioselective versions with ee
up to 99%. We also discover that the same
cyclopentadienes are also reactive toward nitroso-4-
fluorobenzenes in DCM/THF/water under air, leading to
novel oxidative nitroso-Povarov reactions with high
enantioselectivity. The occurrence of two asymmetric
processes confirms a mechanism involving gold--dienes (I)
as electrophiles and nitrosoarenes as nucleophiles; the
other process involving gold-bound nitroso species as elec-
trophiles is unlikely to occur.
As cyclopentadiene derivatives readily undergo self di-
merizations, we employed 1-allenyl-4-ene 1a as the precur-
sor of cyclopentadiene 1a’;[10] theses precursors can be
stored at room temperature for a few days. This one-pot
operation gave the desired product 3a in better yields. In a
standard operation, initial species 1a was treated with a
gold catalyst in DCE (25 °C) for 5 min to ensure a complete
formation of cyclopentadienes 1a’ before treatment with
nitrosobenzene 2a. We examined various cationic gold(I)
catalysts Ln(AuCl)2/AgX bearing chiral bisphosphine lig-
ands Ln (n=1-5, Table 1, entries 1-12). The use of
L1(AuCl)2/AgNTf2 (L1 = (R)-3,5-t-Bu-4-MeO-MeOBIPHEP) in
DCE (25 °C, 10 min) afforded the desired product (+)-3a in
78% yield and 61% ee (entry 1). Cooling the reaction at 0 0C
greatly improved the enantiopurity of (+)-3a to 87% ee
(entry 2). To our pleasure, the reaction in DCE (-30 °C, 9 h)
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Table 1. Optimization of [4+3]-Annulation
regioselective annulations of nitrosoarenes with the more
1
2
3
4
5
6
7
8
substituted alkenes of cyclopentadienes 1’. We first tested
the reactions on C1-aryl-substituted vinylallenes 1b-1g (X =
Me, OMe, Br, Cl, CO2Me and OTBS), affording the annulation
products (+)-3b-3g in 63-84% yields with excellent ee
values (88-99%, entries 1-6). The absolute configurations
of bromo-containing product (+)-3d was determined by an
X-ray diffreaction.[12] These annulations were amenable to
their 3- and 2-substituted phenyl derivatives 1h-j (R1 = 3-
XC6H4, X = Me, Cl; R1 = 2-MeC6H4), yielding desired (+)-3h-j
in 58-78% yields with 88-91% ee (entries 7-9). For species
1k, bearing R1 = 2-naphthyl, its resulting product (-)-3k
was obtained in 81% yield with 87% ee (entry 10). C(1)-
heteroaryl substituted vinylallenes 1l and 1m (R1 = 2- and
3-thienyl) were also suitable to these enantioselective
annulations, furnishing (+)-3l and (+)-3m in 73-77% yield
with 83% and 96% ee respectively (entries 11-12). With R1
= phenyl, we varied the R2 or R3 substituents of vinylallenes,
1n-1o with one butyl group; the resulting products (+)-3n
and (+)-3o were also produced in 65%-67% yields,
together with 81% and 71% ee (entries 13-14). But for
vinylallenes bearing a R2 = phenyl group [R3 = Me (1p) and
R3 = H, (1q)], compounds (+)-3p and (-)-3q were obtained
in 60-65% with 94% ee (entry 15-16). We aslo prepared
all-alkyl-substituted allenylene 1r that could not be
converted to the desired annulation product 3r with this
chiral gold catalyst (entry 17).
(+)-3a
Yield/ee
(%)c
Ligand
(L*)
Temp./Time
(°C/h)
Entry
X
Solvent
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1
2
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
NTf2
NTf2
NTf2
SbF6
OTf
DCE
DCE
DCE
DCE
DCE
DCM
toluene
DCE
DCE
DCE
DCE
DCE
25/10 min
0/1.5
78/61
77/87
76/96
74/92
71/91
72/94
75/95
75/58
74/62
75/88
75/92
74/96
3
-30/9
-30/9
-30/9
-30/9
-30/9
-30/9
-30/9
-30/9
-30/9
-30/9
4
5
6
NTf2
NTf2
NTf2
NTf2
NTf2
NTf2
NTf2
7
8
9
10
11
12
Table 2. Enantioselective nitroso-Povarov reaction wth
various vinylallenes
a[1a] = 0.2 M. bProduct yields are obtained after purification
c
from a silica column. The ee values were determined by
chiral HPLC analysis on a chiral stationary phase.
further increased the ee up to 96% (entry 3). We varied
silver salts with AgSbF6 and AgOTf to afford (+)-3a in 91-
92% ee (entries 4-5). For L1(AuCl)2/AgNTf2, the ee values
0
were 94% in DCM and 95% in toluene, both at -30 C (en-
tries 6-7). For a less bulky catalyst like L2(AuCl)2/AgNTf2 (L2
= (R)-(+)-MeO-BIPHEP) in DCE (-30 0C, 9 h), compound (+)-
3a was obtained with 58% ee and 75% yield (entry 8). We
b
a[1a] = 0.2 M. Product yields are obtained after purification
switched to L3(AuCl)2/AgNTf2 (L3
=
(R)-3,5- Xyl-
from a silica column. cThe ee values were determined by chiral
HPLC analysis on a chiral stationary phase.
MeOBIPHEP), further delivering (+)-3a with 62% ee and
74% yield (entry 9). The use of L4(AuCl)2/AgNTf2 (L4 = (R)-
3,5-t-Bu-MeOBIPHEP) gave (+)-3a with 88% ee (entry 10).
We next examined these enantioselective annulations
with various nitrosoarenes 2 to assess the reaction general-
ity (Table 3). For nitrosoarenes 2b-2h bearing electron-
donating group (CH3, i-Pr) or an electron withdrawing
group (Cl, Br, F, NO2, or CO2CH2CH3) at the para-phenyl po-
sitions, their enantioselective annulations afforded desired
products (+)-4b-4f and (-)-4g-4h in 71-79% yields with ee
levels ca. 86-98% (entries 1-7). Among them, small 4-chloro
derivative 4d was achieved with the best enantioselectivity
0
For L5 = (R)-SEGPHOS, its catalytic annulation (-30 C, 9 h)
afforded (+)-3a with 92% ee (entry 11), but its substituted
form L6 increased the ee value to 96%. The absolute config-
uration of (+)-3a was inferred from its bromo-containing
relatives (+)-3d.
Under these optimized conditions, we assessed these
new enantioselective reactions with various vinylallenes
(Table 2). All resulting products
3
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ca. 98% ee. For meta-phenyl nitroso species 2i and 2j (R2 =
Cl and Br), their resulting products (+)-4i and (+)-4j were
obtained with 97% and 92% ee, respectively (entries 8 and
9). Again, the chloro-containing product (+)-4i was efficient
to achieve high enantioselectivity. Alkenes such as styrenes,
cyclopentene, acrylate were unreactive toward nitro-
soarenes. Furans, indoles, benzofurans were inapplicable
substrates.[13] Cyclohexadienes reacted with nitrosoarenes
to give nitroso-Diels-Alder products.[14]
In Table 3, we obtained one minor product (-)-5a in
13% yield using nitroso-4-fluorobenzene 2e (entry 5). To
our pleasure, we developed also novel oxidative nitroso-
Povarov reactions when vinylallene 1a, fluoro-containing
nitroso 2f, water and air were treated with chiral gold
catalysts. Other nitrosoarenes like nitrosobenzene 2a and
4-chlorophenyl derivative 2d were inapplicable substrates
although nitroso species 2d was found reactive with acyclic
dienes in such oxidative nitroso-Povarovreactions.[10a]
performed with L1(AuCl)2/AgNTf2 (5/10 mol %). As shown
in Table 4, various para-pheny-substituted vinylallenes 1b-
1d, 1s and 1h (X = Cl. Br, Me and CF3) became appropriate
substrates to react well with nitroso-4-fluorobenzene 2f,
further yielding products (-)-5b-5f in good yields (61-67%)
and excellent ee levels (90-97%, entries 1-5). The absolute
configuration of the bromo-containing product (-)-5c was
determined by X-ray analysis.[12] 2-Thienyl derived sub-
strate 1l gave the corresponding product (-)-5g in 59%
yields and 80% ee. For 2- and 3-phenyl-substituted vinyl-
allenes 1j and 1i, their annulation products (-)-5h and (-)-
5i were produced in 61-62% yields and 80% and 96% ee
values. We tested the reactions on various 3-substituted-4-
flurophenylnitroso 2k-n, further providing the correspond-
ing products (-)-5j-5m in 65-73% yields and 87-97% ee
(entries 9-12). With nitroso-2,4-difluorobenzene 2o, the
desired product (-)-5n was obtained in 68% yield and 55%
ee (entry 13).
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Table 3. Enantioselective nitroso-Povarov reaction wth
various nitrosoarenes
Table 4. The Scope of [5+1]-Annulations
b
a[1a] = 0.2 M. Product yields are obtained after purification
from a silica column. cThe ee values were determined by
chiral HPLC analysis on a chiral stationary phase. dan
oxidative annulation product (-)-5a was obtained in 13%
yield and 95.0% ee
b
a[1a] = 0.1 M. Product yields are obtained after purification
from a silica column. cThe ee values were determined by
chiral HPLC analysis on a chiral stationary phase
We further examined this asymmetric annulation for an
acyclic diene 6a using the same chiral catalyst; its resulting
product 6b via an oxidative annulation was obtained in only
14% ee, possibly due to its flexible conformation to render
the enantioselectivity ineffective (eq 6). For an ethyl-derived
acyclic diene 6c (E/Z = 1.9:1), its asymmetric reaction gave 6d
as two diastereomers in racemic forms. Large alkyl group is not
favorable for the enantioselectivity. This trend is consistent
We conducted this reaction involving chiral catalyst
L1(AuCl)2/AgNTf2 (L1 = (R)-3,5-t-Bu-4-MeO-MeOBIPHEP) to
0
run the reaction in DCM/THF/H2O under air at -20 C , the
yield of our target (-)-5a was 62% with the ee up to 95% ee
(eq 5). The absolute configuration of compound (-)-5a was
inferred from X-ray diffraction of its bromo derivative (-)-
5c (vide infra). With the same chiral L1(AuCl)2/AgNTf2,
oxidized form (-)-5a and its non-oxidized form (+)-4f have
the same configurations at one tertiary carbon and one-
tertiary O-carbon. Notably, our new target (-)-5a was not
accessible from the non-oxidized form (+)-4f with gold
catalyst under DCM/THF/H2O/air (eq 5).
We assessed the substrate scope of these new oxidative
annulations using various vinylallenes 1 and nitroso-4-
fluorobenzenes 2f, 2k-2o; these asymmetric reactions were
with our observations for cyclopentadienes as shown by
vinylallenes 1n and 1o (entries 13-14, Table 2). We performed
gram-scale reactions on the two enatioselective annulations.
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In CH2Cl2/THF/water, the transformation of vinylallene 1a configurations and high enantiopurity; this information
1
2
3
4
5
6
7
8
into (-)-5a in air was achieved with 57% yield and 95% ee
under standard conditions (eq 7). The reductive cleavage of
enantiopure (-)-5a (95% ee) with zinc powder in
MeOH/H2O/AcOH produced the desired products (-)-8a to
retain their initial enantiopurities (eq 7). As depicted in
Scheme 1, vinylallene 1a (5.88 mmol) delivered product
(+)-3a in 72% yield (1.17 g) and 94% ee. A reductive
cleavage of this product with Zn in MeOH/H2O/AcOH
afforded (+)-7a with 94% ee and 88% yield. The
indicate that they have a common intermediate. As shown
in Scheme 2, we postulate that this bulky chiral catalyst
preferably coordinates selectively with only one face of the
less substituted C(1,2)-olefin to form Au--diene A. This
argument is inferred by an experiment using N-hydroxy
aniline that serves only as a nucleophile (eq 9). In this pro-
posed mechanism, an oxygen-attack of nitroso species 2f at
this -diene A proceeds trans to gold catalyst, yielding al-
lylgold species B bearing a nitrosonium moiety. Different ee
values of products (-)-5a and (+)-4f indicates this A-B
transformation is reversible. A ring closure of intermediate
B affords cis-fused bicyclic species C, further yielding the
observed product (+)-4f. Alternatively, intermediate B can
be trapped with water to generate intermediates D and E
sequentially before a ring closure. A final step is the O2-
oxidative aromatization of resulting cyclization species F to
form compound (-)-5a and water. This process rationalizes
our 18O-labeling results (eq 8) that both O2 and H2O serve as
the oxygen sources in the products. Here, HF became pro-
duced, but its weak acidity rendered fluoride less dissocia-
tive, to allow the existence of active L1Au+ catalyst. In the
presence of water, only 9% HF is dissociative but free fluo-
ride anion will react with HF again to yield HF2- anion.[15]
An alternative pathway is an addition of nitrosoarene
at gold coordinated-olefin; this pathway might be likely to
occur. But it will also lead to a competitive 1,4-addition to
give nitroso Diels-Alder product as shown in eqs 1-2. In
contrast, the mechanism in Scheme 2 will not have a side
reaction.
9
Scheme 1. Chemical functionalizations of the cyclic
nitroxyl product (+)-3a
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compound
(+)-7a
was
protected
with
1,1’-
carbonyldiimidazole (CDI) to yield a conformationally rigid
product (+)-7b with 94% ee and 92% yield, which was
elaborated stereoselectively into the compound (+)-7c with
m-CPBA epoxidation.
*
We performed 18O-labeling experiments involving O2
*
and H2 O (*O = 99% 18O) respectively (eq 8). Treatment of
cyclopentadiene 1a’ with nitroso-4-fluorobenzene 2f and
LAuCl/AgNTf2 (L = P(t-Bu)2(o-biphenyl, 10/20 mol %) in
DCM/THF/H218O under O2 afforded compound 5a bearing
high 18O content (16O:18O = 1:1.3). In contrast, the same re-
action under 18O2/H2O yielded 18O-containg product *O-5a
bearing 20% 18O content. Both H2O and O2 thus proved to be
the oxygen sources for the ketone groups of compound 5a.
Herein, we did not observe an 18O-exchange between com-
pound 5a and H218O in the presence of gold catalyst. Inter-
estingly, N-hydroxy aniline also enabled this [4+2]-
annulation, but in a very slow process. We performed its
asymmetric version using chiral L1(AuCl)2/AgNTf2 (2.5/5
Scheme 2. Postulated mechanisms for the two asym-
metric reactions
0
mol %) in DCE (25 C, 10 h), but the resulting product 3a
was completely racemic with only 22% yield (eq 9). In con-
trast, nitrosobenzene 2a afforded the product (+)-3a in
61% ee within 10 min (Table 1, entry 1). Accordingly, for-
mation of compound 3a relies on an attack of N-hydroxy
aniline at gold--diene, irrelevant to its oxidized form 2a
(eq 9).
Before this work, asymmetric functionalization of 1,3-
dienes as a 2--donor has no examples in gold catalysis.[17]
This
work
reports
the
first
gold(I)-catalyzed
enantioselective nitroso-Povarov reactions between
substituted cyclopentadienes and commonly used
nitrosoarenes[16] over a wide scope. Most of these [4+2]-
annulations were obtained in satisfactory yields with high
ee levels. With the same chiral gold catalyst, the same cy-
clopentadienes reacted well with nitroso-4-fluorobenzenes
in DCM/THF/H2O under air, yielding oxidative nitroso-
Povarov products with excellent enantioselectivity. We per-
formed 18O-labeling experiments to confirm that both water
and O2 are the oxygen sources for the ketone group of re-
With chiral L1(AuCl)2/AgNTf2, two enantioselective cycliza-
tion products (+)-4f and (-)-5a bear the same (3S, 9S)-
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(4) (a) Bodnar, B. S; Miller, M. J. The Nitrosocarbonyl Het-
ero-Diels–Alder Reaction as a Useful Tool for Organic
Syntheses. Angew. Chem. Int. Ed. 2011, 50, 5630-5647.
(b) Yamamoto, Y.; Yamamoto, H. Eur. J. Org. Chem.
2006, 2013-2043. (c) Vogt, P. F.; Miller, M. J. Develop-
ment and applications of amino acid-derived chiral
acylnitroso hetero Diels-Alder reaction. Tetrahedron
1998, 54, 1317-1348. (d) Denmark, S. E.; Thorarensen,
A. Tandem [4+2]/[3+2] Cycloadditions of Nitroal-
kenes. Chem. Rev. 1996, 96, 137-165. (e) Waldmann, H.
Asymmetric Hetero Diels-Alder Reactions. Synthesis
1994, 1994, 535-551. (f) Streith, J.; Defoin, A. Synthesis
1994, 1994, 1107-1117. (g) Yamamoto, H.; Momiyama,
N. Rich chemistry of nitroso compounds. Chem. Com-
mun. 2005, 3514 – 3525. (h) Yamamoto, H.; Kawasaki,
M. Nitroso and Azo Compounds in Modern Organic
Synthesis: Late Blooming but Very Rich. Bull. Chem.
Soc. Jpn. 2007, 80, 595-607.
sulting products. Our experimental data indicate an initial
1
2
3
4
5
6
7
8
attack of nitrosoarenes at gold--dienes to induce high en-
antioselectivity. The use of gold--diene intermediates in
asymmetric catalysis is a viable tool to access enantiopure
compounds.[13-14, 17]
ASSOCIATED CONTENT
Supporting Information
Experimental procedures, characterization data, crystallog-
raphy data, and 1H NMR and 13C NMR for representative com-
pounds (PDF)
This material is available free of charge via the Internet at
http://pubs.acs.org..
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AUTHOR INFORMATION
Corresponding Author
Rai-Shung Liu*
Email: rsliu@mx.nthu.edu.tw
(5) (a) Zhang, Y.; Stephens, D.; Hernandez, G.; Mendoza, R.;
Larionov, O. V. Catalytic Diastereo- and Enantioselec-
tive Annulations between Transient Nitrosoalkenes
and Indoles. Chem. Eur. J. 2012, 18, 16612-16615. (b)
Zimmer, R.; Collas, M.; Czerwonka, R.; Hain, U.; Reissig,
H.-U. A New Access to Pyrrolizidine Derivatives: Ring
ACKNOWLEDGMENT
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.
Contraction
of
Methyl
(E)-[1,2-Oxazin-3-
yl]propenoates. Synthesis 2008, 2, 237-244. (c)
Guimarães, E.; Lemos, A.; Lopes, M. Reactions of nitro-
sovinylphosphonates with electron-rich alkenes and
heterocycles. Phosphor. Sulfur Silicon 2007, 182,
2149-2155. (d) Boyko, Y. D.; Dorokhov, V. S.; Sukho-
rukov, A. Y.; Ioffe, S. L. Conjugated nitrosoalkenes as
Michael acceptors in carbon–carbon bond forming re-
actions: a review and perspective. Beilstein J. Org.
Chem. 2017, 13, 2214-2234. (e) Mokar, B. D.; Liu, J.;
Liu, R.-S. Brønsted Acids Enable Three Molecular Rear-
rangements of One 3-Alkylidene-2H-1,2-oxazine Mole-
cule into Distinct Heterocyles. Org. Lett. 2018, 20,
1038-1041.
REFERENCES
(1) For recent reviews on the catalytic nitroso cycloaddi-
tions, see: (a) Sukhorukov, A. Y.; Ioffe, S. L. Chemistry
of Six-Membered Cyclic Oxime Ethers. Application in
the Synthesis of Bioactive Compounds. Chem. Rev.
2011, 111, 5004-5041. (b) Huple, D. B.; Ghorpade, S.;
Liu, R.-S. Recent Advances in Gold‐Catalyzed N‐ and O‐
Functionalizations of Alkynes with Nitrones, Nitroso,
Nitro and Nitroxy Species. Adv. Synth. Catal. 2016, 358,
1348-1367. (c) Huang, J.; Chen, Z.; Yuan, J.; Peng, Y. Re-
cent Advances in Highly Selective Applications of Ni-
troso Compounds. Asian J. Org. Chem. 2016, 5, 951-
960.
(2) (a) Ieronimo, G.; Mondelli, A.; Tibiletti, F.; Maspero, A.;
Palmisano, G.; Galli, S.; Tollari, S.; Masciocchi, N.;
Nicholas, K. M.; Tagliapietra, S.; Cravotto, G.; Penoni, A.
A simple, efficient, regioselective and one-pot prepara-
tion of N-hydroxy- and N-O-protected hydroxyindoles
via cycloaddition of nitrosoarenes with alkynes. Syn-
thetic scope, applications and novel by-products. Tet-
rahedron 2013, 69, 10906-10920. (b) Penoni, A.;
Palmisano, G.; Zhao, Y.-L.; Houk, K. N.; Volkman, J.;
Nicholas, K. M. On the Mechanism of Nitrosoarene-
Alkyne Cycloaddition. J. Am. Chem. Soc. 2009, 131, 653-
661.
(3) (a) Liu, J.; Skaria, M.; Sharma, P.; Chiang, Y.; Liu, R.-S.
Ground-state dioxygen undergoes metal-free [3 + 2]-
annulations with allenes and nitrosoarenes under am-
bient conditions. Chem. Sci. 2017, 8, 5482-5487. (b)
Sharma, P.; Jadhav, P. D.; Skaria, M.; Liu, R.-S. Stereose-
lective annulation between an allene, an alkene, and
two nitrosoarenes to access bis(isoxazoliodine) deriv-
atives. Org. Biomol. Chem. 2017, 15, 9389-9397. (c)
Kawade, R. K.; Liu, R.-S. Copper-catalyzed three-
component annulations of alkenes, nitrosoarenes, and
N-Hydroxyallylamines to form fused oxazi-
nane/isoxazolidine heterocycles. Angew. Chem., Int. Ed.
2017, 56, 2035-2039.
(6) (a) Yamamoto, Y.; Momiyama, N. Yamamoto, H. Enan-
tioselective Tandem O-Nitroso Aldol/Michael Reac-
tion. J. Am. Chem. Soc. 2004, 126, 5962-5963. (b)
Momiyama, N.; Yamamoto, Y.; Yamamoto, H. Dia-
stereo- and Enantioselective Synthesis of Nitroso
Diels−Alder-Type Bicycloketones Using Dienamine:ꢀ
Mechanistic Insight into Sequential Nitroso Al-
dol/Michael Reaction and Application for Optically
Pure 1-Amino-3,4-diol Synthesis. J. Am. Chem. Soc.
2007, 129, 1190-1195. (c) Yamamoto, Y.; Yamamoto,
H. Catalytic Asymmetric Nitroso‐Diels–Alder Reaction
with Acyclic Dienes. Angew. Chem. Int. Ed. 2005, 44,
7082-7085. (d) Jana, C. K.; Studer, A. Divergent Reac-
tions for Racemates: Catalytic, Enantioselective, and
Regiodivergent Nitroso Diels–Alder Reactions. Angew.
Chem. Int. Ed. 2007, 46, 6542-6544. (e) Pous, J.;
Courant, T.; Bernadat, G.; Iorga, B. I.; Blanchard, F.;
Masson, G. Regio-, Diastereo-, and Enantioselective Ni-
troso-Diels–Alder Reaction of 1,3-Diene-1-carbamates
Catalyzed by Chiral Phosphoric Acids. J. Am. Chem. Soc.
2015, 137, 11950-11953.
(7) Maji, B.; Yamamoto, H. Catalytic Enantioselective Ni-
troso Diels–Alder Reaction. J. Am. Chem. Soc., 2015,
137, 15957-15963.
(8) For gold-catalyzed cycloaddition reactions, see select-
ed reviews: (a) Hashmi, A. S. K. Gold-Catalyzed Organic
Reactions. Chem. Rev. 2007, 107, 3180-3211. (b) Patil,
N. T.; Yamamoto, Y. Coinage Metal-Assisted Synthesis
of Heterocycles. Chem. Rev. 2008, 108, 3395-3442. (c)
Abu Sohel, S. M.; Liu, R.-S. Carbocyclisation of Alkynes
with External Nucleophiles Catalysed by Gold, Plati-
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ACS Catalysis
Page 6 of 8
num and Other Electrophilic Metals. Chem. Soc. Rev.
ary aromatic amines. Angew. Chem., Int. Ed. 2013, 52,
14084-14088.
(12) Crystallographic data of compounds (+)-3d, (-)-5c and
9b were deposited in Cambridge Crystallographic Data
Centre: (+)-3d-CCDC 1977836, (-)-5c-CCDC 1977846,
9b-CCDC 1998656.
2009, 38, 2269-2281. (d) Muratore, M. E.; Homs, A.;
Obradors, C.; Echavarren, A. M. Meeting the Challenge
of Intermolecular Gold(I)-Catalyzed Cycloadditions of
Alkynes and Allenes. Chem. Asian J. 2014, 9, 3066-
3082.
1
2
3
4
5
6
7
8
(9) (a) Brouwer, C.; He, C. Efficient gold-catalyzed hy-
droamination of 1,3-dienes. Angew. Chem. Int. Ed.
2006, 45, 1744-1747. (b) Faustino, H.; Lopez, F.;
Castedo, L.; Mascarenas, J. L. Gold(I)-catalyzed inter-
molecular (4 + 2) cycloaddition of allenamides and
acyclic dienes. Chem. Sci. 2011, 2, 633-637. (c) Ting, C.-
M.; Hsu, Y.-L.; Liu, R.-S. Gold-catalyzed isomerization of
unactivated allenes into 1,3-dienes under ambient
conditions. Chem. Commun. 2012, 48, 6577-6579. (d)
González, A. Z.; Toste, F. D. Gold(I)-Catalyzed Enanti-
oselective [4 + 2]-Cycloaddition of Allene-dienes. Org.
Lett. 2010, 12, 200-203.
(10) (a) Chen, C.-N.; Liu, R.-S. Gold‐catalyzed [4+2] Annula‐
tions of Dienes with Nitrosoarenes as 4ꢀπ Donors: Ni-
troso‐Povarov Reactions. Angew. Chem., Int. Ed. 2019,
58, 9831-9835. (b) Mokar, B. D.; Jadhav, P. D.; Pandit Y.
B.; Liu R.-S. Gold Catalyzed (4 + 2)-Annulations be-
tween α-Alkyl Alkenyl Gold Carbenes and Benzisoxa-
zoles with Reactive Alkyl Groups. Chem. Sci. 2018, 9,
4488-4492. (c) Bhunia, S.; Liu, R.-S. Gold-Catalyzed
(13) As stated in our previous report (ref 10a), common al-
kenes such as styrenes, cyclopentene, acrylate were
unreactive toward nitroarenes. Furans, indoles, benzo-
furans were inapplicable substrates because they do
not form -complex with Aucomplex.
(14) Cyclohexadienes reacted with nitrosoarenes to follow
nitroso-Diels-Alder reaction; one example is provided
below. The molecular structure of compound 9b was
characterized by X-ray diffraction study.
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17
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21
22
23
24
25
26
27
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29
30
31
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33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(15) Prkić, A.; Giljanović, J.; Bralić, M.; Boban, K. Direct Po‐
tentiometric Determination of Fluoride Species by Us-
ing Ion-Selective Fluoride Electrode. Int. J. Electrochem.
Sci., 2012, 7, 1170-1179.
(16) For gold-catalyzed N,O-functionalizations of alkynes
using nitrosoare-nes, see selected examples: (a)
Murru, S.; Gallo, A. A.; Srivastava, R. S. Gold-Catalyzed
Synthesis of 3-Arylindoles via Annulation of Nitro-
soarenes and Alkynes. ACS Catal. 2011, 1, 29-31. (b)
Jadhav, A. M.; Bhunia, S.; Liao, H.-Y.; Liu, R.-S. Gold-
Catalyzed Stereoselective Synthesis of Azacyclic Com-
pounds through a Redox/[2 + 2 + 1] Cycloaddition
Cascade of Nitroalkyne Substrates. J. Am. Chem. Soc.
2011, 133, 1769-1771. (c) Chen, C.-H.; Tsai, Y.-C.; Liu,
R.-S. Gold‐Catalyzed Cyclization/Oxidative [3+2] Cy‐
cloadditions of 1,5‐Enynes with Nitrosobenzenes
without Additional Oxidants. Angew. Chem., Int. Ed.
2013, 52, 4599-4603. (d) Pagar, V. V.; Jadhav, A. M.;
Liu, R.-S. Gold-Catalyzed Formal [3 + 3] and [4 + 2] Cy-
cloaddition Reactions of Nitrosobenzenes with
Alkenylgold Carbenoids. J. Am. Chem. Soc. 2011, 133,
20728-20731. (e) Singh, R. R.; Liu, R.-S. Gold-catalyzed
1,2-iminonitronation of electron-deficient alkynes
with nitrosoarenes to afford α-imidoyl nitrones. Chem.
Commun. 2014, 50, 15864-15866. (f) Kale, B. S.; Liu,
R.-S. Gold-Catalyzed Aromatizations of 3-Ene-5-siloxy-
1,6-diynes with Nitrosoarenes To Enable 1,4-N, O-
Functionalizations: One-Pot Construction of 4-
Hydroxy-3-aminobenzaldehyde Cores. Org. Lett. 2019,
21, 8434-8438.
1,3-Addition of
a sp3-Hybridized C−H Bond to
Alkenylcarbenoid Intermediate. J. Am. Chem. Soc.
2008, 130, 16488-16489. (d) Lee, J. H.; Toste, F. D.
Gold(I)-Catalyzed Synthesis of Functionalized Cyclo-
pentadienes. Angew. Chem. Int. Ed. 2007, 46, 912-914.
(e) Funami, H.; Kusama, H.; Iwasawa, N. Preparation of
Substituted Cyclopentadienes through Platinum(II)‐
Catalyzed Cyclization of 1,2,4‐Trienes. Angew. Chem.,
Int. Ed. 2007, 46, 909-911.
(11) For asymmetric Povarov reactions, see: (a) Akiyama,
T.; Morita, H.; Fuchibe, K. Chiral Brønsted Acid Cata-
lyzed Inverse Electron-Demand Aza Diels-Alder Reac-
tion. J. Am. Chem. Soc. 2006, 128, 13070-13071. (b)
Liu, H.; Dagousset, G.; Masson, G.; Retailleau, P.; Zhu, J.
Chiral Brønsted Acid-Catalyzed Enantioselective
Three-Component Povarov Reaction. J. Am. Chem. Soc.
2009, 131, 4598-4599. (c) Xu, H.; Zuend, S. J.; Woll, M.
G.; Tao, Y.; Jacobsen, E. N. Asymmetric Cooperative Ca-
talysis of Strong Brønsted Acid–Promoted Reactions
Using Chiral Ureas. Science 2010, 327, 986-990. (d)
Dagousset, G.; Zhu, J.; Masson, G. Chiral Phosphoric Ac-
id-Catalyzed Enantioselective Three-Component Pova-
rov Reaction Using Enecarbamates as Dienophiles:
Highly Diastereo- and Enantioselective Synthesis of
Substituted 4-Aminotetrahydroquinolines. J. Am. Chem.
Soc. 2011, 133, 14804-14813. (e) Shi, F.; Xing, G.-J.;
Zhu, R.-Y.; Tan, W.; Tu, S. A Catalytic Asymmetric Isa-
tin-Involved Povarov Reaction: Diastereo- and Enanti-
oselective Construction of Spiro[indolin-3,2 ′ -
(17) For 1,3-dienes as 4--donors in asymmetric gold ca-
talysis, see selected examples: (a) Mauleon, P.; Zeldin,
R. M.;
Access to [4 + 2] and
́
Gonzalez, A. Z.; Toste, F. D. Ligand-Controlled
[4 + 3] Cycloadditions in Gold-
́
Catalyzed Reactions of Allene-Dienes. J. Am. Chem. Soc.
2009, 131, 6348-6349. (b) Alonso, I.; Trillo, B.; Lopez,
quinoline] Scaffold. Org. Lett. 2013, 15, 128-131. (f)
Chen, Z. L.; Wang, B. L.; Wang, Z. B.; Zhu, G. Y.; Sun, J. W.
Complex Bioactive Alkaloid‐Type Polycycles through
Efficient Catalytic Asymmetric Multicomponent Aza‐
Diels–Alder Reaction of Indoles with Oxetane as Di-
recting Group. Angew. Chem., Int. Ed. 2013, 52, 2027-
2031. (g) Luo, C. S.; Huang, Y. A Highly Diastereo- and
Enantioselective Synthesis of Tetrahydroquinolines:
Quaternary Stereogenic Center Inversion and Func-
tionalization. J. Am. Chem. Soc. 2013, 135, 8193-8196.
(h) Min, C.; Mittal, N.; Sun, D. X.; Seidel, D. Conjugate-
base-stabilized Brønsted acids as asymmetric cata-
lysts: enantioselective Povarov reactions with second-
F.;
́
Montserrat, S.; Ujaque, G.; Castedo, L.; Lledos, A.;
as, J. L. Gold-Catalyzed [4C+2C] Cycloaddi-
Mascaren
́
̃
tions of Allenedienes, including an Enantioselective
Version with New Phosphoramidite-Based Catalysts:
Mechanistic Aspects of the Divergence between
[4C+3C] and [4C+2C] Pathways. J. Am. Chem. Soc.
2009, 131, 13020-13030; (c) Gonzalez, A. Z.; Toste, F.
D. Gold(I)-Catalyzed Enantioselective [4 2]-
Cycloaddition of Allene-dienes. Org. Lett. 2010, 12,
́
+
200−203. (d) López F.; Mascareñas J. L. Gold(I)-
Catalyzed Enantioselective Cycloaddition Reac-
tions. Beilstein J. Org. Chem. 2013, 9, 2250–2264. (e)
Faustino, H.; Lopez, F.; Castedo, L.; Mascaren
́ ̃as, J. L.
Gold(I)- catalyzed Intermolecular (4 + 2) Cycloaddi-
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tion of Allenamides and Acyclic Dienes. Chem. Sci.
2011, 2, 633−637. (f) Alonso, I.; Faustino, H.; Lopez, F.;
Mascaren as, J. L. Enantioselective Gold(I)-Catalyzed
Intramolecular (4 + 3) Cycloadditions of Allenedienes.
Angew. Chem., Int. Ed. 2011, 50, 11496−11500. (g)
Francos, J.; Grande-Carmona, F.; Faustino, H.; Iglesias-
1
2
3
4
5
6
́
̃
Sigu
̈
enza, J.; Díez, E.; Alonso, I.; Fernandez, R.; Lassal-
s, J. L. Axially Chiral
etta, J. M.; Lopez, F.; Mascaren ́ ã
Triazoloisoquinolin-3- ylidene Ligands in Gold(I)-
Catalyzed Asymmetric Intermolecular (4 + 2) Cycload-
ditions of Allenamides and Dienes. J. Am. Chem. Soc.
2012, 134, 14322-14325. (h) Brazeau, J. F.; Zhang, S.;
Colomer, I.; Corkey, B. K.; Toste, F. D. Enantioselective
Cyclizations of Silyloxyenynes Catalyzed by Cationic
Metal Phosphine Complexes J. Am. Chem. Soc. 2012,
134, 2742−2749.
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