Ytterbium Triflate Catalyzed Synthesis o

SYNTHESIS0039-78 1 437-210X
© Georg Thieme Verlag Stuttgart · New York

2016, 48, A–AP A
review
Syn thesis R. Sakhuja et al. Review
Ytterbium Triflate Catalyzed Synthesis of Heterocycles

Rajeev Sakhuja
Z Z
Kasiviswanadharaju Pericherla Y Y
Y
W
X X Z X
Kiran Bajaj X X, Y = X, Y, Z = Y
Bharti Khungar X, Y, Z = CH, NH, O CH, NH, O, S W, X, Y, Z =
CH, NH, O, S
CH, NH, S, O
Anil Kumar*
X
Department of Chemistry, Birla Institute of Technology and Yb(OTf)3 X
X = NH, O
Science, Pilani 333031, Rajasthan, India X = NH
anilkumar@pilani.bits-pilani.ac.in
Fused Heterocycles Spiro-Heterocycles
Bridged Heterocycles
Downloaded by: Birla Institute of Technology & Science. Copyrighted material.

Received: 27.04.2016 tional acids with lanthanide trifluoromethanesulfonates
Accepted after revision: 23.06.2016
[Ln(OTf)3], also termed lanthanide triflates, has helped to
Published online: 01.12.2016
DOI: 10.1055/s-0036-1588321; Art ID: ss-2016-e0298-r overcome a number of the aforementioned drawbacks.3
Among the various lanthanide triflates, ytterbium tri-
Abstract Ytterbium(III) triflate is an efficient and water-tolerant Lewis flate [Yb(OTf)3], is known to be a useful Lewis acid that has
acid that has been used as a catalyst for a wide range of organic trans-
formations. Various three-, four-, five-, and six-membered, as well as
attracted significant attention in the field of organic syn-
fused, heterocycles have been synthesized using ytterbium triflate as thesis.4 It is probably one of the most effective of the lan-
catalyst in both organic and aqueous solvents. The reaction conditions thanide triflates, owing to its position near the end of the
are relatively mild and the catalyst can be readily recovered from the lanthanide series. As a Lewis acid, the hardness of the cat-
reaction mixtures to be reused. ion is important when coordinating with the hard base oxy-
1 Introduction
2 Three-Membered Heterocycles
gen. With the large number of protons in the nucleus, Yb3+
3 Four-Membered Heterocycles is one of the smallest lanthanides and the hardest acid of
4 Five-Membered Heterocycles the series. Therefore, the high Lewis acidity of Yb3+ may be
5 Six-Membered Heterocycles attributed to its small ionic radius.5 The incomplete number
6 Benzo-Fused Heterocycles
of electrons in the 4f orbital of Yb3+ results in a high tenden-
7 Non-benzenoid Fused Heterocycles
8 Spiroheterocycles cy for this orbital to become filled. Reaction conditions us-
9 Bridged Heterocycles ing this catalyst are generally mild and often only ambient
10 Conclusion temperatures and/or low-boiling solvents are required. The
catalyst is readily recovered from the reaction mixtures and
Key words lanthanide triflates, ytterbium triflate, Lewis acids, hetero-
can be reused with equivalent catalytic capacity.
cycles
A large number of reactions catalyzed by Yb(OTf)3 lead
to the construction of different heterocyclic frameworks of
1 Introduction biological importance. However, very few reviews are avail-
able that depict the importance of ytterbium triflate for the
A significant number of chemical transformations such synthesis of heterocycles. Kobayashi and co-workers pub-
as Friedel–Crafts reaction, esterification, hydration, dehy- lished a review on the role of rare-earth-metal triflates in
dration, isomerization, rearrangement, nitration, hydrolysis organic synthesis in 2002.3a To our knowledge, only one
and cracking processes in the petroleum industry are cata- specific review on the catalytic activity of ytterbium triflate
lyzed by acidic catalysts.1 Many of these reactions are car- has appeared since then.6 In light of the versatile catalytic
ried out using conventional acids such as H2SO4, HCl, AlCl3, activity of Yb(OTf)3 in the synthesis of various heterocyclic
TiCl4, SnCl4 and BF3·OEt2.2 The processes involving these compounds over the last decade, we thought it would be
conventional acids are associated with various drawbacks useful to provide a comprehensive review on the applica-
such as environmental pollution, waste effluence, corro- tions of ytterbium triflate for the synthesis of various het-
sion, tedious work-up procedure, and use of large amount erocyclic compounds that will prove to be extremely bene-
of catalyst, among others. Replacement of these conven- ficial for chemists working in academia and industry world-
wide. This review covers developments in the synthesis of
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–AP
B
Biographical Sketches
Rajeev Sakhuja received his Ph.D. based organogelators, cytotoxic anorectic and antipsychotic effica-
in synthetic organic chemistry in naphthoquinone dipeptides, and cy in rodents via actions at brain
2007 from the University of Delhi, Boltorn 1,2,3-triazole dendrimers. serotonin receptors. At present,
Delhi, India. Thereafter he pur- From 2010 to 2012, he worked as he is an assistant professor in the
sued postdoctoral research with a postdoctoral fellow with Profes- Department of Chemistry, BITS Pi-
Prof. Alan R. Katritzky at the Cen- sor Raymond Booth in the Depart- lani, Rajasthan, India since 2012.
ter of Heterocyclic Compounds, ment of Medicinal Chemistry, His research interests lie in the ar-
University of Florida, Gainesville, University of Florida, where his re- eas of synthetic organic, natural
USA (2008–2010), where he fo- search was focused on developing product and medicinal chemis-
cused on the synthesis of novel novel phenyl-dimethylaminote- tries.
photochromic 2H-chromene tralin (PAT) derivatives possessing
Kasiviswanadharaju Pericherla exam and received his Ph.D. from he is working as Technical Director

studied chemistry at D.N.R. Col- BITS Pilani, Rajasthan in 2015 un- in Tagoor Chemicals, India, a lead-
lege, Andhra University. From der the joint supervision of Prof. ing bulk drug intermediates man-
2007 to 2010, he was associated Anil Kumar and Prof. Bharti Khun- ufacturing facility. His research
with the Albany Molecular Re- gar. He was a visiting fellow at interests focus on the develop-
search Inc. Hyderabad Research Prof. Amitabh Jha’s laboratory at ment of new methods for the as-
Centre as a research scientist and Acadia University, Canada during sembly of bioactive aza-fused
was involved in the construction 2012–2013 with financial aid from heterocyclic motifs by employing
of novel synthetic libraries. He the Canadian Bureau for Interna- transition-metal-catalyzed C−H
cleared the Joint CSIR-UGC NET tional Education (CBIE). Presently, activation and functionalization.
Kiran Bajaj is working as a to 2008 she worked as a lectur- a postdoctoral fellow. The main
Young Scientist at BITS Pilani, er at Bharat Institute of Technol- focus of her research is in organ-
India. She received her Ph.D. in ogy, Meerut, India. She then ic synthesis and peptide chemis-
organic chemistry from C.C.S. moved to the University of Flori- try. She is currently engaged in
University, India with the late da and worked with Prof. Alan R. unveiling novel ligation tech-
Prof. Ashok Kumar. From 2004 Katritzky from 2008 to 2012 as niques in peptide chemistry.
Bharti Khungar is an associate of Rajasthan, Jaipur, India. Her re- formation, and screening their
professor in the Department of search focusses on the synthesis biological applications such as
Chemistry, BITS Pilani, Pilani Cam- of transition-metal complexes and antifungal, antibacterial, and anti-
pus, Rajasthan, India. She received exploring their uses, specifically viral activities.
her Ph.D. in 2002 from the De- developing them as catalysts for
partment of Chemistry, University carrying out simple organic trans-
Anil Kumar obtained his Ph.D. Department of Chemistry, BITS (2013) and the Dr. Arvind Kumar
from the Department of Chemis- Pilani, India as a lecturer in 2006, Memorial Award from the Indian
try, University of Delhi, Delhi, In- where he now holds an associate Council of Chemists (2014). His
dia under the guidance of Prof. S. professorship and heads the de- research interest lies in the devel-
M. S. Chauhan in 2004. After two partment. He was a Harrison opment of reaction methodolo-
years of postdoctoral research in McCain Visiting Professor in the gies, green chemistry, ionic liquids
the Department of Biomedical Department of Chemistry, Acadia and medicinal chemistry. He has
and Pharmaceutical Sciences, Uni- University, Canada during the published 135 research papers
versity of Rhode Island, Kingston, month of December 2012. He is a and contributed two book chap-
USA in the group of Prof. recipient of the ISCB Young Scien- ters.
Keykavous Parang, he joined the tist Award in Chemical Sciences
C
various three-, four-, five-, and six-membered, as well as 3 Synthesis of Four-Membered Heterocycles
fused, spiro, and bridged heterocycles using ytterbium tri-
flate as catalyst. 3.1 Oxetane and Azetidine
β-Lactones and β-lactams are examples of oxetane and

2 Synthesis of Three-Membered Heterocy- azetidine nuclei, respectively. Calter et al. reported the reac-
cles tion of acid chlorides and aldehydes in the presence of a ter-
tiary amine, a catalytic amount of a cinchona alkaloid
2.1 Aziridine (TMS-quinidine, TMSQD), and Yb(OTf)3 to produce β-lac-
tones in high diastereo- and enantioselectivities (Scheme
The Lewis acid catalyzed reaction between imines and 2).9 The diastereoselectivity was highly dependent on the
diazoesters is an important method for the synthesis of size of the Lewis acid used: ytterbium triflate gave high se-
aziridines. Yb(OTf)3 has been used as an efficient catalyst lectivity for the cis-isomer, while gadolinium or scandium
for the coupling of an ethyl diazoester with aromatic and al- triflates resulted in higher proportions of the trans-isomer.

iphatic imines at room temperature to yield aziridines in
good yields and high diastereoselectivities without the for- O
R Yb(OTf)3 (15 mol%), DIPEA O O
mation of by-products (Scheme 1, top).7 Owing to the un- Cl TMSQD (20 mol%), CH2Cl2 O R1 O R1
stable nature of imines derived from aliphatic amines, +
0 °C, 6 h
R R
three-component reactions involving aldehydes and amines R1CHO
R = OPh cis trans
were also performed (Scheme 1, middle). In all cases, the R1 = 4-O2NC6H4 82%, cis/trans = 91:9
cis-isomers of the aziridine products predominated. With
Scheme 2 Yb(OTf)3-catalyzed synthesis of β-lactones by cycloconden-
other Lewis acids such as TiCl4, AlCl3, SnCl2 or BF3·OEt2, low- sation of aldehydes and acid chlorides
er yields were obtained. Yb(OTf)3 also catalyzed the cou-
pling with 1-phosphono-2-aza-1,3-dienes, yielding 2- Similarly, Yb(OTf)3 was used as an effective catalyst for
ethoxycarbonyl-3-phosphonoaziridines in moderate yields the stereoselective synthesis of β-lactams through the [2+2]
(Scheme 1, bottom).8 No product was obtained in the ab- cyclocondensation of imines and acetyl chlorides in the
sence of Yb(OTf)3, whereas the use of Cu(OTf)2 resulted in pyridinium-based ionic liquid [Nbupy]BF4 (Scheme 3).10
the formation of diethylmaleate/fumarate as major by-
products with only traces of the aziridine derivative.
R O
COCl HN Yb(OTf)3 (5 mol %), [Nbupy]BF4
R
N + N
R R1 H 60 °C, 2 h
R1 R
R1 H N
62–76%
Yb(OTf)3 (0.1 equiv), hexane R = Ph, 4-MeC6H4, 4-EtC6H4, 4-ClC6H4
MS 4 Å, r.t. R1 COOEt
[Nbupy]BF4 = R1 = Ph, 4-O2NC6H4
R = CH(Ph)2 75–90%
R1 = Ph, 4-O2NC6H4, 4-MeOC6H4, cis/trans = 93:7 to 95:5 N
BF4
4-MeC6H4, 4-ClC6H4, 1-naphthyl n-Bu
R
Scheme 3 Yb(OTf)3-catalyzed synthesis of β-lactams by [2+2] cyclo-
condensation of imines and acetyl chlorides
R1CHO + RNH2 N
N2CHCOOEt
Yb(OTf)3 (0.1 equiv), hexane R1 COOEt
MS 4 Å, r.t.
R = Ph, PhCO, i-Pr, i-Bu, 60–86% Yb(OTf)3 was also reported to catalyze a two-compo-
Bu, c-Hex cis/trans = 70:30 to 95:5
nent reaction of silyl ketene thioacetals and pre-formed/in
situ generated imines, affording β-lactams in one pot
OEt
R1
N P
CO2Et (Scheme 4).11 The stereoselectivity was found to be affected
OEt
R2 O
R1
OEt by the structure of the starting ketenes and imines.
N P
Yb(OTf)3 (10 mol%), CH2Cl2 OEt
R2 O
r.t., 24 h
PMB OTBDMS Yb(OTf)3 (10 mol%) R2 R1 R2 R1
R1 = R2 = Me, Et 40–45% N
R1–R2 = -CH2(CH2)3CH2- R2 MeCN or MeNO2
+ SPy
R1 H N + N
r.t., 15 h
Scheme 1 Yb(OTf)3-catalyzed synthesis of aziridines from diazoesters H O PMB O PMB
trans cis
R1 = Ph, CH=CHPh, 2-thienyl, c-Hex, i-Bu
16–89%
R2 = Me, Et, i-Pr, OBn
trans/cis up to 98:2
Scheme 4 Yb(OTf)3-catalyzed synthesis of β-lactams by cycloconden-

sation of imines and silyl ketene thioacetals
D
4 Synthesis of Five-Membered Heterocycles R3

MeO2C
MeO2C CO2Me Yb(OTf)3 (1 equiv) R2
R3
4.1 Furan R1X +
Bu3SnH (5 equiv) MeO2C
R2 O Et3B (1 equiv), O2 R1 O
THF–CH2Cl2, –78 °C
50–79%
Furan constitutes an important structural motif for a
trans/cis ratio up to >50:1
wide variety of natural products and pharmaceuticals. Nu-
R1 = CH2OMe, Et, i-Pr, c-Hex, adamantyl, Ac
merous methods for the construction of furan and its satu- R2 = R3 = H, Me
rated analogue, tetrahydrofuran, have been reported in lit- X = Br, I
erature.12 One of the simplest approaches towards the syn- Scheme 7 Yb(OTf)3-catalyzed radical exo-cyclization for the synthesis
thesis of substituted tetrahydrofurans involves the of tetrahydrofurans
Yb(OTf)3-catalyzed cyclization of 1,4-diols (Scheme 5).13
The reaction was proposed to proceed through the forma- Ramachandran et al. reported the influence of Yb(OTf)3
tion of a benzylic carbocation, followed by intramolecular in the selective synthesis of γ-substituted α-alkylidene-γ-
substitution by the oxygen nucleophile. Yb(OTf)3 catalyzed butyrolactones or cis-β,γ-disubstituted α-methylene-γ-bu-

the reaction efficiently, but FeCl3 as catalyst gave better re- tyrolactones (Scheme 8).16 When (E)-methyl-2-(borameth-
sults. yl)butenoates and aldehydes reacted in the presence of
Yb(OTf)3, Zn(OTf)2, or TFA, the cis-β,γ-disubstituted α-
R
OH
methylene-γ-butyrolactones were formed exclusively, via
Yb(OTf)3 (20 mol%)
crotoborylation and lactonization. Higher yields of butyro-
2.5–4.5 h R1 R
R1 O
lactones were achieved in the presence of Yb(OTf)3 at room
OH
52–61% temperature.
R = H, Ph O
R1 = 2-thienyl, O
O R1
R1 OMe Yb(OTf)3 (20 mol%), toluene
+ R2CHO
Scheme 5 Yb(OTf)3-catalyzed synthesis of tetrahydrofurans by the cy- B
O r.t., 18–36 h O R2
O
clization of 1,4-diols O
70–95%
R1 = Me, Ph
Shi and Xu synthesized tetrahydrofuran derivatives by
R2 = t-Bu, i-Pr, PhCH2CH2, c-Hex
using the Yb(OTf)3-catalyzed [3+2] cycloaddition of methyl-
Scheme 8 Yb(OTf)3-catalyzed synthesis of γ-butyrolactones via Cope
enecyclopropanes with activated aldehydes or ketones in
rearrangement
good yields and with high stereoselectivities (Scheme 6).14
The reaction proceeded smoothly in dichloroethane (DCE)
at 50 °C in the presence of Yb(OTf)3; however, poor results Taddeo et al. reported the solvent-free Yb(OTf)3-cata-
were obtained with Zn(OTf)2 and Cu(OTf)2. lyzed cycloaddition reaction of acetylene dicarboxylates
with β-dicarbonyl compounds to synthesize substituted fu-
R1 rans in 91–98% yield (Scheme 9).17 The catalyst was recov-
R1 R2 O
Yb(OTf)3 (5 mol%), DCE
R2 ered by precipitation as Yb(OH)3 and was transformed back
EtO2C R3 50 °C EtO2C
O
into the triflate salt and reused several times. Reactions
R3 were also performed with other metal triflates (e.g., La, Eu,
48–86%
Gd), but better product yields were obtained with Yb(OTf)3.
R1 = Ph, 4-ClC6H4, 4-MeC6H4, 4-MeOC6H4, 3-PhOC6H4
R2 = H, Ph, 4-ClC6H4, 4-MeC6H4, 4-MeOC6H4 The enhanced reactivity of both the alkynoate and the β-di-
R3 = H, COOEt carbonyl compound is believed to be a result of their coor-
Scheme 6 Yb(OTf)3-catalyzed synthesis of tetrahydrofuran via [3+2] dination with the Yb3+ ion.
cycloaddition of methylenecyclopropanes with activated aldehydes or
ketones CO2R3
O
O
O O Yb(OTf)3 (10 mol%) R1
+ OR3
Sibi et al. reported the synthesis of tetrahydrofurans via R1 R2 80 °C

R2 OR3
CO2R3
the Yb(OTf)3-catalyzed tandem radical addition cyclization R1 = Me, Ph O O
of various nucleophilic radicals with β-alkoxyalkylidene- R2 = Me, Et, Ph, OEt 91–98%
3
R = Me, Et
malonates, where Bu3SnH was used as chain carrier and
Et3B/O2 as radical initiator (Scheme 7).15 The methodology Scheme 9 Yb(OTf)3-catalyzed synthesis of substituted furans by cy-
cloaddition of acetylene dicarboxylates and β-dicarbonyl compounds
was extended towards the synthesis of larger-ring oxacy-
cles as well. Detailed investigations were made to under-
stand the exo/endo selectivities in these radical cyclizations.
E
Li et al. reported the Yb(OTf)3-promoted one-pot syn- CO2Et

EtO2C
thesis of substituted furan derivatives from β-ketothioam- O S CO2Et Yb(OTf)3 (5 mol%), DCE
ides and arylglyoxals (Scheme 10).18 The reaction involves a R SMe
+
80 °C, 2–7 h S R1
1
R CO2Et
domino sequence of aldol condensation, N-cyclization, ring R
O
opening, O-cyclization, S-cyclization and Eschenmoser sul- R = Ph, 4-FC6H4, 4-ClC6H4, 3-ClC6H4, 2-ClC6H4, 2,3-Cl2C6H3,
56–94%
fide contraction. The mechanism suggested activation of 4-BrC6H4, 4-MeC6H4, 4-MeOC6H4, 2-thienyl, 2-furyl, Me
R1 = Ph, 4-FC6H4, 4-ClC6H4, 4-BrC6H4, 4-MeC6H4, 4-
the thiocarbonyl group by Yb(OTf)3 to give the O-cyclized MeOC6H4, 2-ClC6H4, 4-O2NC6H4
product.
Scheme 12 Yb(OTf)3-catalyzed synthesis of tetrahydrothiophenes by
R2
the reaction of donor–acceptor cyclopropanes with β-oxodithioesters
O O S O
Yb(OTf)3 (1.0 equiv), MeCN
R3
R1 CHO
+
R 2
N
H
r.t., 1.5 h R1 NHR3 4.3 Pyrrole
O
trace to 80%
Pyrrole is one of the most important heterocyclic com-

R1 = 4-FC6H4, 4-ClC6H4, 4-BrC6H4, 3-ClC6H4, 3-MeOC6H4,
4-MeOC6H4, 2-thienyl
pounds in medicinal chemistry and organic synthesis. Con-
R2 = Ph, 4-FC6H4, 4-ClC6H4, 4-BrC6H4, 3-ClC6H4, 2-FC6H4,
2-ClC6H4, 2-BrC6H4, 4-MeC6H4, 4-MeOC6H4, 2-thienyl, 2-furyl sequently, a tremendous number of procedures have been
R3= 4-FC6H4, 4-ClC6H4, 4-BrC6H4, 3-ClC6H4, 4-MeC6H4, developed for the construction of pyrroles.22 Su, Wu and co-
4-MeOC6H4, Bn, CH2CO2Et, c-Hex
workers reported an Yb(OTf)3-catalyzed approach for the
Scheme 10 Yb(OTf)3-catalyzed synthesis of substituted furan deriva- synthesis of pyrroles by the cyclization of γ-diketones with
tives from β-ketothioamides and arylglyoxals
hydrazides under solvent-free conditions (Scheme 13).23
Aryl hydrazides posessing electron-donating groups deliv-
France and co-workers synthesized a 2,3′-bifuran deriv- ered good yields of pyrroles, whereas hydrazides bearing
ative through a formal homo-Nazarov-type cyclization19 of electron-withdrawing groups afforded pyrroles in moder-
an alkylidene cyclopropane by using Yb(OTf)3 as a catalyst ate yields. Steric hindrance from ortho-substituents did not
(Scheme 11).20 It was suggested that the enolate oxygen in- have much effect on the outcome of the cyclization.
tramolecularly attacks on the alkylidene cyclopropane to
form the transient dihydrofuran intermediate that under- O O
Yb(OTf)3 (5 mol%)
NH2 + R3 R2 R3
N
goes aromatization to give the 2,3′-bifuran. R1 N R2 O
H 110–160 °C, 10–35 min HN
O
O R1
O
R1 = Me, PhOCH2, Ph, 2-ClC6H4, 2-EtC6H4, 73–99%
O MeO
Yb(OTf)3 (15 mol%), CH2Cl2 4-O2NC6H4, 4-MeOC6H4, 3-pyridyl
OMe O R2 = Me, Ph
MS 4 Å, 40 °C O R3 = Me, Ph
O CO2Et
CO2Et
33, 69% Scheme 13 Yb(OTf)3-catalyzed synthesis of substituted pyrroles from
γ-diketones and hydrazides
Yb(OTf)3 aromatization
O O
O MeO Another highly regioselective synthesis of tetrasubsti-
OMe
– Yb(OTf)3
O tuted pyrroles was achieved in the Yb(OTf)3-catalyzed
O CO2Et O
CO2Et three-component reaction between amines, 1,3-diketones
Yb(OTf)3
31 32 and 2-bromoacetophenone (Scheme 14).24 Yb(OTf)3 was
found to be a reusable catalyst and provided a series of sub-
Scheme 11 Yb(OTf)3-catalyzed synthesis of a bifuran derivative
through a formal homo-Nazarov-type cyclization stituted pyrroles in good yields. Moreover, these synthe-
sized pyrroles showed promising phosphodiesterase 4
(PDE4) inhibitory properties in vitro.
4.2 Thiophene
Ph COR
R1NH2
The Li research group developed an excellent synthesis O O O Yb(OTf)3 (0.1 mol%), MeCN
Br + N
of tetrahydrothiophenes by the Yb(OTf)3-catalyzed [3+2] Ph 80–85 °C, 5–12 h
R1
annulation of β-oxodithioesters with donor–acceptor cyclo- 55–75%
propanes (Scheme 12). The method provided good to excel- R1 = Ph, 3-ClC6H4, 3-BrC6H4, 4-BrC6H4, 2-F-4-BrC6H3,
lent yields (56–94%) of the tetrahydrothiophene deriva- 2-MeOC6H4, 4-MeOC6H4, 3,4-(MeO)2C6H3, 3-O2NC6H4,
4-HOC6H4, 1-naphthyl, Bn, CH2(3,5-Cl2C6H3)
tives.21 The salient features of the reaction are the use of β-
oxodithioesters as dipolarophiles and the regioselective Scheme 14 Yb(OTf)3-catalyzed synthesis of tetrasubstituted pyrroles
generation of tetrahydrothiophene through attack of the β- by multicomponent reaction of amines, 1,3-diketones and 2-bromo-
acetophenone
oxodithioester thiocarbonyl group to the cyclopropane.
F
A similar Yb(OTf)3-catalyzed three-component reaction when 4-methoxybenzenesulfonamide was used as the nu-
between ethyl pyruvate, aldehydes and anilines was report- cleophile, whereas use of benzene sulfonamide gave a low-
ed for the synthesis of 1,5-dihydro-2H-pyrrol-2-ones er yield of the corresponding pyrroles. Notably, the use of 4-
(Scheme 15).25 Here, Yb(OTf)3 showed better catalytic ac- nitrobenzenesulfonamide led to a mixture of unknown de-
tivity when compared to other mild acids such as AlCl3, composition products.
BF3·OEt2, ZnCl2, ZrCl4, TiCl4, SnCl2, and SiO2, and provided
good yields of the substituted lactams. Electron-rich alde- OH OH
R1
hydes as well as amines provided better yields when com- R
R R1
pared to precursors bearing electron-withdrawing substit- Yb(OTf)3 (10 mol%)
R
R2
uents. +
toluene
R R2
N
ArSO2NH2 100 °C, air, 1–22 h
NHR2 SO2Ar
O 23–98%
Yb(OTf)3 (20 mol%) R = Ph, 4-ClC6H4,4-MeC6H4, Me
R1CHO R2NH2 OEt
+ + R1 O R1 = H, Me, 4-ClC6H4, PhCH2CH2
N

r.t., 2 h R2 = Ph, 4-BrC6H4, 4-ClC6H4, 3,4-(OCH2O)C6H3
O
R2 Ar = Ph, 4-MeC6H5, 4-MeC6H4OC6H4
R1 = 4-MeOC6H4, 3,4-(MeO)2C6H3, 4-FC6H4, 2-ClC6H4, 62–84%
3-O2NC6H4, 4-O2NC6H4, 3-HOC6H4, i-Pr, n-Hex, c-Hex
Scheme 17 Yb(OTf)3-catalyzed synthesis of pyrroles from propargylic
R2 = 4-MeOC6H4, 3,4-F2C6H3, 2-Cl-4-BrC6H3, 2-Br-4-FC6H3,
2,4,6-Me3C6H2, 2,5-Et2-4-MeOC6H2, 2,4,6-Br3C6H2, Et, n-Pr 1,4-diols and aryl sulfonamides
Scheme 15 Yb(OTf)3-catalyzed synthesis of pyrrol-2-ones by three-

component reaction of pyruvates, aldehydes and anilines
Menéndez and co-workers reported a mechanochemi-
cal reaction between tert-butyl 2-[(4R,6R)-6-(2-aminoeth-
Konakahara and co-workers reported an Yb(OTf)3-cata- yl)-2,2-dimethyl-1,3-dioxan-4-yl]acetate and 4-methyl-3-
lyzed annulation of 2-azabutadienes with trimethylsilyl cy- oxo-N-phenylpentanamide to give an adduct which on fur-
anide to give 3-aminopyrrole derivatives (Scheme 16).26 Di- ther reaction with 1-(4-fluorophenyl)-2-iodo-2-phenyleth-
versely substituted azabutadienes underwent smooth con- anone in the presence of Yb(OTf)3/AgNO3, followed by hy-
version to afford moderate to good yields of the pyrroles. drolytic deprotection/lactonization, gave the highly func-
Gratifyingly, the reaction reached completion within two tionalized pyrrole-based atorvastatin lactone (Scheme
hours with only 5 mol% of Yb(OTf)3 in the case of azabuta- 18).28
dienes with a pyridin-4-yl substituent and delivered the
t-BuO NH2
corresponding pyridyl-substituted pyrrole in excellent O NHPh
yield. A one-pot four-component reaction of the oxazole- O O O
t-BuO
H
N
Yb(OTf)3 (1 mol%)
based functionalized silane, a nitrile, an aldehyde, and EtOH
+ O O O
trimethylsilyl cyanide afforded the oxazolyl-functionalized NHPh 40 °C, overnight
3-aminopyrrole derivatives in good yields.
O O
F
R2
R3 NH2
F
N R3 Yb(OTf)3 (20 mol%), THF Ph
+ Me3SiCN Ph
R2 N R1
r.t., 24 h
H O O I
R1
30–87% HO N i) Yb(OTf)3(1 mol%)
R1 = Ph 4-ClC6H4, 4-MeOC6H4, 3-Py NHPh AgNO3 (1 equiv)
R2 = Ph, 4-ClC6H4, 4-MeOC6H4 HSVM (20 Hz, 60 min)
R3 = 4-pyridyl, 5-isooxazolyl ii) 2 M HCl, MeOH, r.t., 3 h
O
Me
Me N Scheme 18 Yb(OTf)3-catalyzed syntheis of pyrrole-based atorvastatin
O
Me3Si 1. n-BuLi, THF, –70 °C, 1 h lactone
N 2. R1CHO, THF, –70 °C, 1 h NH2
O
+
4.4 Dioxolane
3. Me3SiCN, Yb(OTf)3 (20 mol%)
Ph R1
PhCN THF, r.t., 24 h N
H
R1 = Ph, 4-ClC6H4 41–53%
Carbon–carbon bond heterolysis of oxiranes is one of
Scheme 16 Yb(OTf)3-catalyzed synthesis of 3-aminopyrrole by annula- the most atom-economical and straightforward methods
tion of 2-azabutadienes with trimethylsilyl cyanide
for the generation of carbonyl ylides, used in cycloaddition
reactions. Zhang and co-workers reported the first method
Highly substituted pyrrole derivatives were synthesized for the Yb(OTf)3-promoted cycloaddition of oxiranyl dike-
in moderate to good yields by the Yb(OTf)3-catalyzed cy- tones with several aldehydes to yield cis-1,3-disubstituted
clization of 1,4-propargylic diols with aryl sulfonamides 1,3-dioxolanes in excellent yields and diastereoselectivities
(Scheme 17).27 Excellent yields of pyrroles were obtained
G
via generation of carbonyl ylides (Scheme 19).29 The scope O

O
TolS O O
of the reaction was studied by using aldehydes bearing elec- O TolS
TolS O
tron-donating, electron-withdrawing, and alkenyl groups.
N – N2
N R RH2C
Yb(OTf)3 (5 mol%) COR2 O R = H, 88:12
O MS 4 Å, CH2Cl2 O O Yb(OTf)3 R
O COR2 R = Me, 98:2
+ R1 COR2 TolS (0.5 equiv) a
R1 2 R3 H r.t., 1–30 h O O
COR 3 CH2N2, THF
R TolS O
R –78 °C O O O O
80–97% TolS
R1 = Ph, 4-MeC6H4, 4-BrC6H4, 4-MeO2CC6H4, N TolS
1-naphthyl, 4-ClC6H4, 3,4,5-(MeO)3C6H2, N
2-furyl, PhCH2CH2, Et, i-Bu, PhCH=CH – N2
R2 = Ph, Me R R RH2C
b
R3 = H, t-Bu, Me
R = H, 7:93
R = H, a/b = 21:79
Scheme 19 Yb(OTf)3-promoted synthesis of dioxolanes by the cyclo- R = Me, a/b = 25:75
R = Me, 2:98
addition of oxiranyl diketones

Scheme 21 Yb(OTf)3-catalyzed synthesis of pyrazolines via 1,3-dipolar

cycloaddition between 2-p-tolylsulfinyl cyclopentenones and diazo-
Similarly, the [3+2] cycloaddition of N-aryl imines and methane
epoxides catalyzed by Yb(OTf)3 under solvent-free condi-
tions afforded 1,3-oxazolidines in high yields.30
4.7 Imidazole
4.5 Oxathiolane
A three-component reaction of benzil with aldehydes
Oxathiolanes were synthesized by the reaction of alde- and ammonium acetate using Yb(OTf)3 was developed for
hydes and ketones with mercaptoethanol using Yb(OTf)3 in the synthesis of imidazoles under mild conditions (Scheme
the ionic liquid [bmim]PF6 (Scheme 20).31 Aryl carbonyl 22).33 The reactions proceeded smoothly, affording the cor-
compounds bearing electron-withdrawing groups on the responding 2,4,5-triarylimidazoles in good to excellent
aryl ring produced higher yields of the 1,3-oxathiolanes yields. Electron-rich benzaldehydes worked better than
when compared to substrates having electron-rich substit- their electron-deficient counterparts, and aliphatic alde-
uents. The scope of the methodology was extended to het- hydes afforded poor yields.
eroaryl, alicyclic, and aliphatic carbonyl compounds to af-
Ph
ford the corresponding oxathiolanes in good to excellent Ph O Yb(OTf)3 (5 mol%), AcOH, NH4OAc N
RCHO R
yields. The advantage of the reported methodology is that 70 °C, 2–6 h N
Ph O Ph
H
the catalyst, Yb(OTf)3 immobilized in the ionic liquid, can
17–94%
be recycled and reused several times without much loss in R = 4-MeOC6H4, 4-HOC6H4, 4-Me2NC6H4, 4-BrC6H4, 3-O2NC6H4,
4-O2NC6H4, 2-HOC6H4, 2,4-(HO)2C6H3, Et, n-Pr
activity.
Scheme 22 Yb(OTf)3-catalyzed synthesis of imidazoles via three-com-
O ponent reaction between benzil, aldehydes and ammonium acetate
Yb(OTf)3 (5 mol%), [bmim]PF6
HO SH O S
R1 R2 +
r.t., 1–20 h R1 R2
72–98%
Zhu and co-workers effectively utilized Yb(OTf)3 and
R1 = Ph, 4-MeC6H4, 4-MeOC6H4, 4-FC6H4, 4-O2NC6H4,
CH=CHPh, Me(CH2)8CH2, 3,4-(OCH2O)C6H3, AgOTf for the synthesis of imidazoles by the reaction of
i-PrCH(CH2)2CH(Me)CH2, 2-furyl, 3-pyridyl propargyl amines with tert-butylisonitrile (Scheme 23).34
R2 = H, Me, Ph
R1–R2 = CH2C6H4CH2CH2, CH2(CH2)3CH2
On the other hand, reaction of propargyl amines with pri-
mary and secondary alkylisonitriles and arylisonitriles in
Scheme 20 Yb(OTf)3-catalyzed synthesis of oxathiolanes by the reac-
tion of carbonyl compounds with mercaptoethanol
the presence of Yb(OTf)3, AgOTf and KOTf yielded 1,3,4,5-
tetrasubstituted imidazolium triflates. In this multiple-
catalyst system, the role of Yb(OTf)3 was to catalyze the in-
4.6 Pyrazole sertion of the isonitrile into the NH bond of the amine.
A scalable method for the synthesis of MacMillan imid-
Ruano et al. reported the Yb(OTf)3-catalyzed 1,3-dipolar azolidinones was developed by condensation of α-amino
cycloaddition between 2-p-tolylsulfinyl cyclopentenones amides with acyclic, aliphatic and aromatic carbonyl com-
and diazomethane yielding pyrazoline intermediates which pounds in the presence of catalytic amount of Yb(OTf)3 in
further decomposed into a mixture of cyclopropanes and very high enantioselectivities without loss in optical purity
olefins (Scheme 21).32 The evolution into cyclopropanes (Scheme 24).35
was dependent upon the type and equivalents of Lewis acid
used, the temperature, the solvent and the stereochemistry
of the pyrazoline intermediates.
H
R2 Yb(OTf)3 was also reported to catalyze the cyclization of

NHR2 Yb(OTf)3 (0.2 equiv), AgOTf (0.1 equiv) R1 N trisubstituted propargylic alcohols with arylamides for the
+ R4NC
R1 xylene, 130 °C preparation of substituted oxazoles (Scheme 26).36a The re-
R3 N
R3 action was applicable to a variety of substrates which af-
51–99%
R1 = CO2Me, Ph, 2-BrC6H4, Bn, 4-MeOC6H4, 4-ClC6H4, n-Pr, forded di- and tri-substituted oxazoles in moderate to ex-
2-furyl, 2-thienyl, 4-furyl, 4-thienyl
R2 = Bn, Ph, 4-MeC6H4, 3-BrC6H4CH2,4-BrC6H4CH2, cellent yields. The regiochemistry of the oxazole was oppo-
4-MeOC6H4CH2, 2,4,6-Me3C6H2CH2, CH(Me)Ph site to that of dual metal and Brønsted acid mediated
R3 = Ph, 4-BrC6H4, 2-MeOC6H4, 4-MeOC6H4, 3-MeC6H4, Bn
R4 = tBu
reactions.36b,c The mechanism suggests an initial metal-cat-
alyzed activation of the alcohol to give an ytterbium(III)-co-
ordinated complex that then undergoes elimination to give
R2
R1 the alkynyl and allenic cation species. The cyclization of
NHR2 Yb(OTf)3 (0.2 equiv), AgOTf (0.1 equiv) N
+ R3NC these cationic species with the aryl amide results in the for-
R1 KOTf (0.5 equiv), xylene, 140 °C
Bn N mation of the oxazole. Similarly, Yb(OTf)3 was also used as
–OTf
Bn R3
an efficient catalyst for the construction of 2,5-dihydroisox-

R1 = Ph, Bn 65–95%
R2 = Bn, CH(Me)Ph, 2,4,6-Me3C6H2CH2
azoles from propargylic alcohols and N-tosyl hydroxyl-
R3 = Cy, n-Bu, Bn, 2,4,6-Me3C6H2CH2 amines (Scheme 26).37 Yb(OTf)3 produced good yields of
Scheme 23 Yb(OTf)3-catalyzed synthesis of imidazoles and imidazoli- products when compared to other mild acids like BF3·OEt2,
um triflates by the reaction of propargyl amines with isonitriles Ag(OTf), Cu(OTf)2, TfOH and TsOH. Replacement of Yb(OTf)3
with I2 or NBS resulted in exclusive formation of the corre-
R1 O
sponding 4-halo-2,5-dihydroisooxazole.
O
O
Yb(OTf)3 (1.0 mol%), CHCl3 OH
R1 NHMe + HN N R3
R2 R3 Me R2 R1 R1 R3
NH2 reflux, 8 h
R2
R2 R3 Yb(OTf)3 (10 mol%) R4CONH2 N
R1 = H, 3-indolyl, N-benzyl-3-indolyl, Ph 22–96% C
>99% ee CH2Cl2, r.t., 2–6 h R1 R4
R2 = Me, t-Bu, 5-methyl-2-furyl O
R3 = H, t-Bu, Me R1 R2 R3 R2 R3
37–91%
R1 = H, Me, Ph, 4-FC6H4, 4-ClC6H4, 4-BrC6H4, 4-MeC6H4
Scheme 24 Yb(OTf)3-catalyzed synthesis of imidazolidinones from α-
R2 = Me, Ph, 4-FC6H4, 4-ClC6H4, 4-MeC6H4
amino amide R3 = H, Me, n-Bu, 2-thienyl, Ph, 4-FC6H4, 4-ClC6H4, 4-MeC6H4
R4 = Me, Ph, 2-MeC6H4, 3-MeC6H4, 4-MeC6H4, 4-MeOC6H4, 4-ClC6H4, 4-BrC6H4
OH
R2 R3 R1 R1 Ts
4.8 Oxazole and Isoxazole Yb(OTf)3 (10 mol%)
R1 N
TsNHOH O
C
CH2Cl2, r.t., 2–6 h
Oxazoles and isoxazoles exhibit a wide range of biologi- R3
R1 R2 R3 R2 R3 R2
cal activities in the field of medicinal chemistry. Some of 30–82%
R1 = H, Ph, 4-MeOC6H4, 4-MeC6H4, 4-FC6H4,
the already marketed isoxazole-based drugs include 4-BrC6H4, 3-BrC6H4, 2-BrC6H4, n-Bu, TMS
valdecoxib as a COX-2 inhibitor and both cloxacillin and di- R2 = Ph, 4-MeOC6H4, 4-MeC6H4, 4-ClC6H4
R3 = Me, Ph, 4-ClC6H4, 4-MeC6H4, 4-MeOC6H4
cloxacillin as β-lactamase-resistant antibiotics. As previ-
ously discussed, carbon–carbon bond heterolysis of ox- Scheme 26 Yb(OTf)3-catalyzed synthesis of oxazoles and isoxazoles
iranes generates carbonyl ylides in an efficient manner. To from propargylic alcohols
this end, Yb(OTf)3 was used as a catalyst for the [3+2] cy-
cloaddition of N-aryl imines and epoxides under solvent- Garcia-Tellado and co-workers utilized Yb(OTf)3 to de-
free conditions to yield 1,3-oxazolidines in high yields velop a domino one-pot, multicomponent approach for the
(Scheme 25).30 synthesis of 1,3-oxazolidines (Scheme 27).38 Initally, enol-
protected propargylic alcohols were prepared by the tri-
R3
R3 ethylamine-catalyzed reaction of methyl propiolate and ali-
N Yb(OTf)3, CH2Cl2 N
O
+ R2 phatic aldehydes. A thermally driven amine addition gave
40 °C, 2 h R
R R1
R2 O R1 the enamine, which, in the presence of Yb(OTf)3, under-
R = CH2Cl, Ph, CH2OBn
77–96% went cyclization to form the oxazole in good yield. The
R1 = Ph, 4-O2NC6H4, 3-O2NC6H4, 4-MeOC6H4, 4-ClC6H4 same transformation was aslo achieved by an initial or-
R2 = H, Ph
R3 = Ph, 4-MeC6H4, 2-MeC6H4, 3-ClC6H4, 4-ClC6H4 ganocatalyzed domino process followed by a microwave-
assisted amine addition and cyclization.
Scheme 25 Yb(OTf)3-promoted synthesis of oxazolidine via cycloaddi-
tion of epoxides with imines
I
R1 CO2Me O
(i) Et3N, DCE, 0 °C, 1 h R1
(ii) R2NH2, reflux, overnight CN R1 HO
N O
R1CHO O N N
CO2Me + R2 Ga(Oi-Pr)3/Yb(OTf)3/Schiff base (1:0.95:1) R2
Bn R2 R3
(iii) Yb(OTf)3 (10 mol %), reflux, 24 h
+ N
CH2CO2Me
O CH2Cl2, MS 4 Å, −20 °C, 24–48 h Bn
R1 = Me, Et, n-Hex, i-Pr, pent-4-en-1-yl
54–71%
R2 = Bn, allyl, Bu, Ph 70–95%
R3 H
88–98% ee
Scheme 27 Yb(OTf)3-catalyzed synthesis of 1,3-oxazolidines through a R1–R2 = CH2CH2OCH2CH2, (CH2)5
domino multicomponent approach R1 = R2 = Et
R3 = Ph, 4-ClC6H4, 4-MeOC6H4, 3-furyl, 3-
thienyl,
PhCH2CH2, PhCH=CH, MeCH2CH2CH2CH=CH
The cyclodehydration–condensation of hippuric acid, Schiff base:
N
aromatic aldehydes, and acetic anhydride, catalyzed by N
Yb(OTf)3 under solvent-free conditions, provided a straight- OH

HO
forward approach for the synthesis of 4-arylidene-2-phe-
OMe
nyl-5(4)-oxazolones (Scheme 28).39 Yb(OTf)3 showed high MeO

catalytic reactivity in terms of the amount of catalyst and Scheme 29 Yb(OTf)3-catalyzed synthesis of oxazole analogues by
the product yields when compared to the other catalysts asymmetric α-addition of α-isocyanoacetamides to aldehydes
screened, including anhydrous NaOAc, Cu(OTf)2, Mg(OTf)2,
Sr(OTf)2, and Zn(OTf)2. COOR1 R1OOC COOR1
R1OOC Yb(OTf)3/toluene
H
C O N R2
O r.t., 48 h R2
N
Yb(OTf)3 (10 mol%), Ac2O N R O
N CO2H
H + RCHO R1 = Me, Et, Bn
73–95%
40 °C, 0.5–5 h O R2 = SO2Me, SO2Ph, SO2(4-MeC6H4),
O
SO2(2-O2NC6H4), SO2(4-O2NC6H4),
81–91%
SO2(4-BrC6H4), SO2[2,4-(O2N)2C6H3],
R = Ph, 4-MeC6H4, 4-MeOC6H4, 2-ClC6H4, 4-ClC6H4, SO2[2,4,6-(i-Pr)3C6H2], COPh
3-O2NC6H4, 4-O2NC6H4, 2,4-Cl2C6H4, 3-indolyl, n-Pr
Scheme 30 Yb(OTf)3-catalyzed synthesis of isoxazolidine derivatives
Scheme 28 Yb(OTf)3-catalyzed synthesis of 4-arylidene-2-phenyl- by domino intramolecular hydroamination and ring-opening
5(4)-oxazolones
The heterodinuclear Ga(Oi-Pr)3/Yb(OTf)3–Schiff base amines, and alkenes (Scheme 31).42 It was documented that
complex was used to yield oxazole analogues with high en- nitrone formation is accelerated by using Yb(OTf)3, however
antioselectivities by the asymmetric α-addition of α-isocy- this does not happen with Lewis acids that themselves are
anoacetamides to aryl, heteroaryl, alkenyl and alkyl alde- deactivated or decomposed in the presence of an amine and
hydes (Scheme 29).40 The dinucleating Schiff base ligand, water. The reactions showed good to excellent endo selec-
derived from o-vanillin and a chiral diamine, was capable of tivities, and not only aromatic aldehydes but also aliphatic
incorporating the two metals Ga and Yb into its inner and and heterocyclic aldehydes reacted easily. Furthermore, N-
outer cavities, respectively, and thus formed the optimum phenylmaleimide and enones all proved to be good sub-
catalyst in terms of both reactivity and enantioselectivity. strates. The asymmetric reaction of benzylbenzylideneam-
The use of group 13 element catalysts, such as Et2AlCl, ine N-oxide with 3-(2-butenoyl)-1,3-oxazolidin-2-one us-
Al(Oi-Pr)3, and In(Oi-Pr)3, for the inner cavity instead of ing a chiral ytterbium catalyst (prepared from ytterbium
Ga(Oi-Pr)3 gave diminishing results. triflate, (R)-(+)-1,1′-binaphthol and 1,2,6-trimethylpiperi-
Shi and Wu reported the Yb(OTf)3-catalyzed domino in- dine) resulted in the desired isoxazolidine in 72% yield with
tramolecular hydroamination and ring-opening of sulfon- perfect diastereoselectivity (not shown).
amide-substituted 1,1-vinylidenecyclopropane diesters to
yield five-membered N,O-heterocyclic products containing O R1
R2
N
an alkyne moiety in good to excellent yields (Scheme 30).41 H
Yb(OTf)3 was found to be the best catalyst among all Lewis R1CHO R2NHOH R3 COR4
Yb(OTf)3 (20 mol%), toluene
acids screened, including Bi(OTf)3, BF3·OEt2, Ln(OTf)3, + endo
O +
Sc(OTf)3, Ti(Oi-Pr)4 and HOTf. MS 4 Å, r.t., 10 h
O R1
R2
The nitrone–olefin [3+2] cycloaddition is a 1,3-dipolar R4 R3 N
H
cycloaddition in which the nitrone acts as the 1,3-dipole, R3 COR4
and the alkene or alkyne acts as dipolarophile to yield an R1 = Ph, Ph(CH2)2, Bn, 1-naphthyl, 2-furyl; R2 = Ph, Bn exo
R3 = H, Pr; R4 = Me, NCH2CH2OCO 53–93%
isoxazoline or isoxazolidine system. Kobayashi et al. report- R3R4 = PhNCO
ed the Yb(OTf)3-catalyzed synthesis of isoxazolidine deriva-
Scheme 31 Yb(OTf)3-catalyzed synthesis of isoxazolidine by three-
tives in high yields and high diastereoselectivities by the component reaction via nitrone generation
three-component coupling reaction of aldehydes, hydroxyl-
J
In the same year, Jørgensen et al. also reported the O R2

BnN
Yb(OTf)3-catalyzed 1,3-dipolar cycloaddition reaction of
N O
alkenes with nitrones to form isoxazolidines in high yields O O R1
and selectivities (Scheme 32).43 The products were ob- O N R2
Yb(OTf)3/(S)-BINOL/amine
(20 mol%)
O O
tained with high endo-selectivity, which was dependent on +

CH2Cl2 endo
+
amount and type of molecular sieves added. The reaction –
O + Bn
MS 4 Å, r.t.
O R2
N
was also carried out in the presence of different chiral li- BnN
N O
gands and high endo-selectivities and enantiomeric excess R1 H
R1
values up to 73% were obtained by using 2,6-bis[4(S)-iso- O O
exo
propyl-2-oxazolidin-2-yl]pyridine (PyBOX) as a chiral li- R1 = Ph, 4-ClC6H4, 4-MeOC6H4, 1-naphthyl, 2-furyl, Et 82–93%
gand complexing with Yb(OTf)3. R2 = H, Me, Pr endo/exo = 53:47 to >99:1
amine = Et3N, (i-Pr)2NEt, cis-1,2,6-TMP, (R)-MPEA, ee = 79–96%
(S)-MPEA, (R)-MNEA, (S)-MNEA
O O
Scheme 33 Yb(OTf)3-BINOL/amine-catalyzed synthesis of isoxazoli-

O N R3 Yb(OTf)3 (10 mol%), CH2Cl2
O
or R2
N
R3 dine from nitrones and alkenes; TMP = 1,2,6-trimethylpiperidine,
+ Yb(OTf)3·H2O/PyBOX (20 mol%), solvent MPEA = N-methyl-bis(1-phenylethyl)amine, MNEA = N-methyl-bis[1-(1-
–O
+ R2 MS 4 Å, 5 h to 4 d R1 N O
naphthyl)ethyl]amine
N
endo O
O
R1 6–95%
R1 = Ph, 4-MeC6H4 endo/exo = 63:37 to 93:7
ee = 8–73% R (R)-Ph-pybox Ph R
R2 = Ph, Pr, Bn R R
3 Ph Yb(OTf)3 (1 equiv)
R = Me, Pr
Et3N, CH2Cl2 N
solvent = CH2Cl2, THF, Et2O, dioxane, MeNO2, toluene NOH + N X N X
0 °C, 12 h or r.t., 3 h O
Cl
Scheme 32 Yb(OTf)3-catalyzed synthesis of isoxazolidines via nitrone– O O O O
olefin [3+2] cycloaddition X = O, N(i-Pr) 60–89%
R = Me
O O
N
Kobayashi and Kawamura also reported an enantiose-
N N
lective 1,3-dipolar cycloadditions between alkenes and ni- Ph Ph
(R)-Ph-pybox
trones in the synthesis of isoxazolidine derivatives cata-
lyzed by heterochiral ytterbium(III) catalysts (Scheme 33).44 Scheme 34 Yb(OTf)3/Ph-Pybox-catalyzed synthesis of isoxazolidine
from benzohydroximoyl chloride and alkenes
The catalysts were prepared from Yb(OTf)3, (S)-1,1′-binaph-
thol and different amines. The chiral induction in the reac-
tions was dependent on the combination of the chirality of The effect of molecular sieves (MS 4 Å) on the chiral yt-
BINOL and the amine. The cycloadducts were obtained in terbium(III) complex catalyzed 1,3-dipolar cycloaddition
excellent yields with excellent diastereo- and enantioselec- was further demonstrated where complete reverse enantio-
tivities. Nitrones derived from aromatic and heterocyclic al- facial selectivity was observed in the absence of MS 4 Å.46
dehyde gave satisfactory results, while low endo/exo selec- The chiral catalyst system, consisting of Yb(OTf)3, (S)-BINOL,
tivity was observed for a nitrone derived from an aliphatic and N-methyl-bis[(R)-1-(1-naphthyl)ethyl]amine [(R)-MNEA]
aldehyde. Apart from 3-(2-alkenoyl)-1,3-oxazolidin-2-one was found to be effective for the enantioselective cycloaddi-
derivatives, the use of N-phenylmaleimide as a dipolaro- tion between nitrones and enamides to generate the corre-
phile also gave the isoxazolidine derivative with good yield sponding isoxazolidines in high yields and excellent enan-
and selectivity. tioselectivities (Scheme 35). Both of the cycloadduct enan-
Yamamoto et al. reported an asymmetric method for the tiomers could be synthesized using the same catalytic
synthesis of isoxazolidine derivatives by the cycloaddition system by varying the achiral additives, nitrone and MS 4 Å.
reactions of a nitrone, generated from benzohydroximoyl This report unmasked the novel role played by the molecu-
chloride, with a dipolarophile having a 4,4-dimethyloxazo- lar sieves as not simply a dehydration agent.
lidinone as a coordination auxiliary using the chiral Lewis Komatsu and co-workers reported the synthesis of isox-
acid Yb(OTf)3-pybox (Scheme 34).45 The isoxazolidine de- azolidines by the Yb(OTf)3-catalyzed diastereoselective 1,3-
rivatives were obtained in high enantiomeric excess; how- dipolar cycloaddition of nitrones with enamides (Scheme
ever, higher enantiomeric excess was obtained for dipolaro- 36).47 The diastereoselectivity was controlled by an appro-
philes having an unsubstituted oxazolidinone group when priate choice of solvent and auxiliary on the alkenyl moiety
the reaction was performed at relatively high temperature of the dipolarophile. The oxazolidinone or 2-pyrrolidinone
in the presence of Yb(OTf)3 and Ph-Pybox. auxiliary exhibited endo-selectivity with toluene as a sol-
vent and imidazolidinone or succinimide as auxiliary gave
rise to exo-selectivity with acetonitrile as the solvent.
K
Bn O R1
tion in the presence of Yb(OTf)3, the selectivity of the reac-
N
tion changed significantly, and the endo isomer was ob-
R2 N
O tained as a single diastereoisomer.
O O
O
O
H H
R1 N Yb(OTf)3/(S)-BINOL/(R)-MNEA 3S,4R,5S R2 CO2Me
O (20 mol%) (without 4 Å MS) 1 – H
CH2Cl2 R O
N+ N H H
+ or R1 O Ph
r.t., 20 h Yb(OTf)3 (20 mol%) R2 Ph
Bn O O R2 toluene, r.t., 24 h all-trans
H
Bn 1
N N R
+ + N
or R1 O CO2Me
Ph H
H R2 Yb(OTf)3 (20 mol%) H H regioisomer
R2 N R2 CO2Me
O neat, 70 °C, 8 h
O H CO2Me H
1 N
R = H, Me, n-Pr O
R1 O Ph
R2 = Ph, 1-naphthyl, 2-furyl, Et 3R,4S,5R R1 = Ph, 4-ClC6H4
3,4-cis-4,5-trans
(with 4 Å MS) R2 = Ph, 4-O2NC6H4
72–90%, up to 88% ee, >99% endo

Scheme 37 Yb(OTf)3-catalyzed synthesis of isoxazolidine from methyl

Scheme 35 Chiral Yb(OTf)3/molecular sieves catalyzed synthesis of cinnamate
isoxazolidine from nitrones and alkenes
Qian et al. reported the Yb(OTf)3-catalyzed 1,3-dipolar

Ph Ph cycloaddition of nitrones with vinyl ethers yielding isoxaz-
N R1
olidines in good yields and high stereoselectivities (Scheme
O N
R2 38).49
O
O Yb(OTf)3 (10 mol%)
Ph O endo Ph
solvent
R1 N
N + + Ph O– N R
r.t. Yb(OTf)3 (10 mol%), THF
Ph N EtO O
Ph Ph +
R2 R1 r.t.
N
R1 = Me, Et R EtO
O N
R2 = COOMe, Et R2 60–83%
R = Ph, 4-MeOC6H4, 4-MeC6H4, 4-ClC6H4, 2-furyl
R1R2 = CH2CH2CH2CO, COCH2CH2CO, O
CH2CH2N(Me)CO, CH2CH2SCS
exo Scheme 38 Yb(OTf)3-catalyzed synthesis of isoxazolidines from ni-
solvent = toluene, MeCN, EtCN, i-PrCN, t-BuCN
22–71% trones and a vinyl ether
endo/exo = 5:95 to 91:9
Scheme 36 Yb(OTf)3-catalyzed synthesis of isoxazolidine from ni-

The 1,3-dipolar cycloaddition between a substituted in-
trones and α,β-unsaturated amides
denone and a variety of in situ generated nitrones was re-
ported to proceed smoothly in the presence of Yb(OTf)3 to
Banerji and co-workers performed the cycloaddition of give indenoisoxazolidines in high yields (Scheme 39).50 The
diarylnitrones with methyl cinnamate under refluxing tolu- exo isomer dominated over endo under these conditions.
ene or solvent-free conditions and isolated a mixture of two Sc(OTf)3 also worked equally well and gave similar exo/endo
diastereoisomeric cycloadducts (all-trans and 3,4-cis-4,5- product ratios.
trans) and one regioisomeric cycloadduct.48 However, a re-
NHAc O
markable change in selectivity by using Yb(OTf)3 as catalyst –O R NHAc O
HH
in either toluene at room temperature or under solvent-free N Yb(OTf)3 (0.2 equiv), benzene
R1
conditions at 70 °C was observed and only one of the two R1 r.t., 18 h
N
H O
diastereoisomers, the 3,4-cis-4,5-trans cycloadduct, was 81–88%
R
R = Bn, 4-MeOC6H4CH2, 3,4-(MeO)2C6H3CH2
obtained (Scheme 37). The reaction was believed to be pri- R1 = 4-MeOC6H5
(exo/endo = 98:2)
marily controlled by the interaction between the highest

Scheme 39 Yb(OTf)3-catalyzed synthesis of indenoisoxazolidine
occupied molecular orbital (HOMO) of the nitrone and the
lowest unoccupied molecular orbital (LUMO) of the dipola-
rophile. By the application of ytterbium triflate, that acts as A polymer-supported synthesis of isoxazolidine deriva-
an electron acceptor, the LUMO energy of the dipolarophile tives was also developed, using Yb(OTf)3-catalyzed 1,3-di-
was lowered by coordination of the α,β-unsaturated car- polar cycloaddition reactions of polymer-supported ni-
bonyl to Yb(OTf)3. As a result of the decreased energy gap trones with alkenes (Scheme 40).51 The obtained polymer-
between the interacting FMOs, a rate acceleration of the re- supported isoxazolidine derivatives were cleaved from the
action was achieved. The selectivity may also be due to this polymer support by DDQ to give substituted isoxazolidines.
concomitant coordination. So, with 1,3-dipolar cycloaddi- Aromatic, aliphatic and heterocyclic nitrones reacted
smoothly and one derivative was obtained from an alkyne
L
instead of an alkene. The transformation of 3-acyl-1,3-ox- Various 5-substituted 1H-tetrazoles were synthesized in
azolin-2-one group into various other functional groups on low to excellent yields (23–98%) by Yb(OTf)3-catalyzed re-
solid support was also explored. action of substituted nitriles with sodium azide in N,N-di-
methylformamide (Scheme 43).54 Aryl nitriles with elec-
R2 tron-withdrawing substituents at the para-position gave
O R3
O
O O better yields than those with electron-donating substitu-
Yb(OTf)3 (20 mol%) N
N R1 toluene, r.t., 20 h O ents. This was attributed to the electrophilicity of the ni-
R1 trile carbon likely being improved by the presence of elec-
+ H
O
DDQ tron-withdrawing substituents. Similarly, aliphatic nitriles
CH2Cl2/H2O
were found to be less reactive than aryl nitriles and gave the
R2 R3
corresponding tetrazoles in only low to moderate yields
O R2
R1 = i-Bu, Ph, 4-ClC6H4, 4-MeOC6H4, 2-furyl, 2-thienyl, 1-naphthyl
N (31–50%). ortho-Substituted aryl nitriles provided even
R2 = H, Me, Et, Pr, CO2Me
R3
lower yields, possibly owing to steric effects.
R3 = Me, O R1

O
N N N
O 47–89% Yb(OTf)3 (10 mol%), DMF
RCN + NaN3 N
R N
100–120 °C, 16–24 h H
Scheme 40 Yb(OTf)3-catalyzed polymer-supported synthesis of isox-
azolidine derivatives R = Ph, 4-ClC6H4, 2-ClC6H4, 4-FC6H4, 4-NCC6H4,
23–98%
4-NCC6H4, 2-O2NC6H4, 4-O2NC6H4, 4-BrC6H4,
4-MeOC6H4, 4-MeC6H4, 2-MeOC6H3CH2, PhCH=CH,
2-thienyl, MeCH3, i-Bu, heptyl
4.9 Triazole
Scheme 43 Yb(OTf)3-catalyzed synthesis of 5-substituted 1H-tetra-
zoles
The Yb(OTf)3-catalyzed intermolecular cyclization of
hydrazonyl chlorides with nitriles provided an excellent
methodology for the synthesis of a series of 1,3,5-trisubsti- 5 Synthesis of Six-Membered Heterocycles
tuted 1,2,4-triazoles (Scheme 41).52 A catalytic amount of
Yb(OTf)3 was enough to complete the reaction and to afford 5.1 Pyran
good yields of triazoles.
The pyran nucleus constitutes an integral part of many
R2
biologically active natural products such as coumarins, ter-
Cl N
H
N + R3CN
Yb(OTf)3 (20 mol%), PhCl N
R3 penoids, flavonoids, anthraquinones, and various alka-
1 R2
R N reflux, 4 h, N2 R1 N loids.55 These compounds possess a wide range of biological
107 48 70–85% activities such as antimicrobial, antiviral, antitumor, anti-
R1 = Ph, 4-MeC6H4 proliferative and central nervous system related activities.
R2 = Ph, 4-O2NC6H4
R3 = Me, Ph, 4-MeOC6H4, CH2CO2Et
The Maitland–Japp reaction56 is a useful method for the
synthesis of tetrahydropyran derivatives, and Yb(OTf)3 was
Scheme 41 Yb(OTf)3-catalyzed synthesis of 1,3,5-trisubstituted 1,2,4-
effectively utilized in the one-pot multicomponent
triazoles
Maitland–Japp reaction with Chan’s diene57 as the nucleo-
phile to give tetrahydropyran-4-ones in excellent yields
4.10 Tetrazole (Scheme 44).58 The diastereoselectivity of the reaction was
greatly dependent on the nature of the Lewis acid and di-
Heterocycloaddition via three-component reaction of ene used. Yb(OTf)3 gave the cis-isomer as the major prod-
amines, triethyl orthoformate and sodium azide in the uct, whereas the trans-isomer dominated when TiCl4 was
presence of a catalytic amount of Yb(OTf)3 afforded tetra- used. Clark and Martin reported an Yb(OTf)3-catalyzed
zoles in good yields (Scheme 42).53 Maitland–Japp reaction in the preparation of a tetrahydro-
pyran-4-one key intermediate during the synthesis of the
R
Yb(OTf)3 (20 mol%), MeOC2H4OH N
N antibiotic natural product centrolobine (Scheme 44).59
RNH2 HC(OEt)3 NaN3 N
100 °C, 6–9 h N These modifications led to a reduction in the number of
71–91%
synthetic steps and an increase in overall yield of the tar-
R = Ph, 3-MeC6H4, 4-MeC6H4, 2-ClC6H4, 4-ClC6H4, 2-Me-3-ClC6H3,
2-Me-5-ClC6H3, (S)-1-phenylethyl, 2-pyridyl, furfuryl geted centrolobine. Yb(OTf)3 favored the formation of the
Scheme 42 Yb(OTf)3-catalyzed synthesis of tetrazoles via three-
cis-isomer over the trans, in a ratio of 2:1, and gave 92%
component reaction yield.60
M
O O
(i) R1CHO, Yb(OTf)3 (50 mol%)
MeO2C S
OMe OTMS −78 °C, 40 min Tol
TMSO (ii) R2CHO, TFA R2 O R1 CH2CHO SOTol SOTol

−78 °C to r.t., 2 h Yb(OTf)3 (1.1 equiv), solvent O
+ O
+
R1 = Ph, i-Pr, n-Pr 75–98% OMe MS 4 Å
R2 = Ph, 4-OMeC6H4, CH2CH2C=CH2, CH2OBn cis/trans up to 10:1 R R R
O O
R1O MeCN, –40 °C, 54%, 92:8
MeCN/CH2Cl2, –78 °C, 32%, 94:6
R = H, R1= SiMe2tBu
O MeCN, –40 °C, 57%, 88:12
R = Me, R1 = SiMe3 MeCN/CH2Cl2, –78 °C, 49% 88:12
MeO OH
(±)-centrolobine
Scheme 46 Yb(OTf)3-catalyzed synthesis of 2,3-dihydro-4H-pyran-4-
ones
Scheme 44 Yb(OTf)3 -catalyzed synthesis of tetrahydropyran-4-ones
via Maitland–Japp reaction
Arai and co-workers also reported hetero-Diels–Alder

The intramolecular hydroalkoxylation/cyclization of δ,ε- reactions of chiral 3-(p-tolylsulfinyl)-2-furaldehyde with
unsaturated alcohols, including primary and secondary, as Danishefsky’s diene in the presence of lanthanide catalysts
well as aliphatic and aromatic, was carried out by using to yield furyl-substituted 2,3-dihydro-4H-pyran-4-ones
Yb(OTf)3 and few other lanthanide triflates, such as (Scheme 47).64 With Ln(OTf)3 (Ln = Yb, Nd, Sm), the cyclo-
La(OTf)3 and Sm(OTf)3, in room-temperature ionic liquids addition proceeded smoothly to produce excellent yields
(RTILs) for the preparation of substituted pyran derivatives and diastereomeric excesses; a reversal of diastereoselectiv-
(Scheme 45).61 Yb(OTf)3 was found to be the most efficient ity was observed with Eu(thd)3.
catalyst for this transformation, and Markovnikov-type se-
O O
lectivity was observed. OMe
S Tol S Tol
Ln(OTf)3 (1.0 equiv), THF O
+
R1 CHO
R1 R1 –20 °C, 2 h
HO R2 Yb(OTf)3 (1 mol%), [C2mim][OTf] R1 O TMSO O O
R2
R3 R2 60–120 °C, 3 h R3 O
R2
when Ln = Yb 83%; 93% de
49–93% Nd 68%; 98% de
Sm 73%; 97% de
R1 = H, Ph, allyl
R2 = H, Me
Scheme 47 Yb(OTf)3-catalyzed synthesis of furyl-substituted 2,3-dihy-
R3 = H, Me
dro-4H-pyran-4-ones
Scheme 45 Yb(OTf)3-catalyzed synthesis of pyran derivatives
Yip et al. utilized an Yb(OTf)3-assisted palladium-cata-

The hetero-Diels–Alder reactions of (S)-2-[2-(p-tolyl- lyzed carbocyclization of γ-heteroalkenyl β-ketoamides to
sulfinyl)phenyl]acetaldehyde with Danishefsky’s62 and re- prepare dihydropyran derivatives (Scheme 48).65 The pres-
lated dienes took place in the presence of Yb(OTf)3 to afford ence of Yb(OTf)3 greatly enhanced the reaction kinetics of
2,3-dihydro-4H-pyran-4-ones (Scheme 46).63 The reaction the cylization process and gave regioselective products in
proceeded in a stereoselective manner and was mediated excellent yields. In addition, the methodology was extended
by a remote sulfinyl group (1,5-asymmetric induction). The towards the synthesis of seven- and eight-membered-ring
ratio of stereoisomer was solvent-dependent, with di- N- and O-heterocycles.
chloromethane and acetonitrile being found to be the best
Yb(OTf)3 (1 equiv)
solvents that led to a mixture of adducts. The use of other O O
PdCl2(MeCN)2 (10 mol%) O O
THF
Lewis acids like Ti(Oi-Pr)4, BF3·OEt2, In(OTf)3, and Yb(Oi-Pr)3 NMe2 NMe2
as catalysts did not improve the reactivity but instead de- X O2 (1 atm), r.t., 3.5–9 h X
creased the stereoselectivity. The optimized conditions X = O, N-Boc, N-Ts 54–98%
used acetonitrile as solvent at –40 °C or a mixture of aceto-
Scheme 48 Yb(OTf)3-assisted palladium-catalyzed synthesis of dihy-
nitrile and dichloromethane at –78 °C along with MS 4 Å as
dropyran derivatives
an additive.
Sibi et al. reported a synthesis of tetrahydropyrans via

Yb(OTf)3-catalyzed tandem radical addition cyclizations of
β-alkoxyalkylidenemalonates using Bu3SnH as chain carrier
and Et3B/O2 as radical initiator (Scheme 49).15 Detailed
mechanistic studies suggested that endo-cyclized six-mem-
N
bered-ring products were isolated in greater yields with cis- reversed the π-facial selectivity. Good to excellent diaste-
selectivity, when the exo pathway was blocked with substi- reomeric excess of the π-facial selectivity of the (3R,4R)-
tutions. endo isomer were obtained. The effect of different solvents
or additives on the diastereoselectivities was also exam-
R1X MeO2C CO2Me ined. In the absence of any coordinative additive or solvent,
Yb(OTf)3 (25 mol%), Bu3SnH, Et3B, O2 R1
O
+
O
the two-binding-point dienophile formed a chelate with
THF/CH2Cl2, –78 °C, 3 h
O
6-endo cyclization the ytterbium, while in the presence of the coordinative ad-
MeO OMe
72–85% ditive DMSO, at least four or five molecules of DMSO com-
dr up to 14:1
O peted with the dienophile in coordinating to the ytterbium
cation, resulting in a monodentate coordination in equilib-
R1 = CH2OMe, Et, i-Pr, c-Hex, adamantyl, Ac
rium. The dienophile is attacked from the less hindered Si-
Scheme 49 Yb(OTf)3-catalyzed synthesis of tetrahydropyrans via tan- face of the chelation complex and from the Re-face of the
dem radical addition cyclization monocoordination form by the diene.

O O
Pedrosa and co-workers reported the one-pot synthesis Ph Ph O O
Yb(OTf)3 (10 mol%), solvent
of enantioenriched trisubstituted tetrahydro-2H-pyran-2- +
N O N O
ones (lactones) in good yields by sequential stereoselective 25 °C, 3 h
Ph S
Ph S Bn
Bn
organocatalyzed Michael addition of ketones to enals, fol- solvent = CH2Cl2, THF,
lowed by Yb(OTf)3-catalyzed diastereoselective Tishchenko THF–H2O (9:1), DMSO, DMF 93–99%
reaction and lactonization (Scheme 50).66 The reaction endo/exo = 48:52 to 89:11
de = 64 to >99%
showed good results for benzyl ketones and ketosulfones as
nucleophiles, and for both β-substituted alkyl and aryl Scheme 51 Yb(OTf)3-catalyzed synthesis of thiopyrans
enals as electrophiles. For a few cases, the hydroxy ester
failed to cyclize to give the lactone product. The lactones 5.3 Piperidine
were obtained as the single diastereoisomers because the
mixture of the anti and syn diastereomers epimerized to Substituted piperidines are key building blocks for the
the syn hydroxy ester during the oxido-reduction step. The synthesis of many bioactive compounds and natural prod-
mechanism revealed coordination of Yb to both carbonyl ucts. 4-Methylenepiperidines were synthesized in one pot
groups of the Michael addition product, giving a mixture of by the condensation of 4-amino-2-(trimethylsilylmeth-
two activated diastereomeric complexes. The unstable acti- yl)but-1-ene with different aldehydes in the presence of 10
vated complex isomerized to the stable one, with all the mol% Yb(OTf)3 at room temperature, followed by the tosyla-
substituents in equatorial positions. Addition of i-PrOH to tion of nitrogen, in high yields (Scheme 52).68 The products
the activated complex was on the external less hindered Re- were further utilized as substrates for palladium-catalyzed
face of the formyl, giving chelated hemiacetal complex. In- cross-coupling reactions.
tramolecular hydride transfer and subsequent cyclization
TMS
gave the final product.
O (i) Yb(OTf)3 (10 mol%), r.t., 10–15 h
O
Yb(OTf)3 R H (ii) TsCl, pyridine N R
O R1 O i-PrO2C
(10 mol%) OH NH2 Ts
benzene O
H R3 i-PrOH, 75 °C R = H, (MeO)2CH, CO2Et, n-Pr, i-Pr, t-Bu, Ph, 73–96%
R1 R3 75 °C R1 R3 4-MeOC6H4, 4-ClC6H4, 2-pyridyl, PhCH=CH
R2 R2 R2
R1 = Me, Et, n-Pr, Ph, 4-MeOC6H4, 4-O2NC6H4, 2-furyl 48–62%
Scheme 52 Yb(OTf)3-catalyzed synthesis of 4-methylenepiperidines
R2 = Ph, SO2Ph, 2-Py (48–98% ee)
R3 = Ph, 2-Py, CF3
An Yb(OTf)3 and AgOTf co-catalyzed reaction between
Scheme 50 Yb(OTf)3-catalyzed synthesis of tetrahydro-2H-pyran-2-
ones dimethyl malonate and an oxime yielded trimethyl 3,5,5-
piperidonetricarboxylate in quantitative yeild (Scheme
53).69 The reaction was not successful in the absence of ei-
5.2 Thiopyran ther of the two catalysts Yb(OTf)3 or AgOTf. In addition, the
ratios of the malonate and oxime were critical to the distri-
An efficient synthesis of an oxazolidinyl-substituted bution of the desired cyclic tricarboxylate and the by-
thiopyran was achieved by Yb(OTf)3-catalyzed asymmetric product, tetramethyl propane-1,1,3,3-tetracarboxylate. The
hetero-Diels–Alder cycloaddition of 2,4-diphenyl-1-thiabu- mechanism of the one-pot reaction is believed to be a dom-
ta-l,3-diene with (S)-N-acryloyl-4-benzyl-1,3-oxazolidin-2- ino sequence of a Mannich reaction, a Hoffmann elimina-
one (Scheme 51).67 Yb(OTf)3 accelerated the reaction and tion, and a Michael addition.
O
O O O O reaction that involves reaction of an aldehyde with two

MeO OMe equivalents of a β-keto carbonyl compound and a nitrogen
Yb(OTf)3 (30 mol%), AgOTf, CH2Cl2 MeO OMe
+ donor such as ammonium acetate or ammonia.72 Wang et
reflux, 17 h N OMe
BnO N CH2 BnO al. explored the utility of Yb(OTf)3 in the synthesis of 4-sub-
O O stituted 1,4-dihydropyridines by Hantzsch condensation at
quantitative
room temperature (Scheme 56).73 Diversely substituted ar-
Scheme 53 Yb(OTf)3/AgOTf co-catalyzed synthesis of trimethyl 3,5,5- omatic and aliphatic aldehydes afforded good yields of the
piperidonetricarboxylate corresponding 1,4-dihydropyridines. A remarkable increase
in reaction kinetics was observed with Yb(OTf)3 compared
Rivero and co-workers synthesized enantiopure trisub- to other Lewis acid catalysts such as ZnCl2, AlCl3, FeCl3 and
stituted piperidines by Yb(OTf)3-catalyzed sequential ring- NdCl3, and the catalyst Yb(OTf)3 was recovered quantita-
opening of the epoxide and the aziridine rings of the start- tively and used for subsequent repeat reactions up to four
ing epoxyaziridine by the amino group of the chiral α-ami- cycles. Recently, Natale and co-workers described using the
no ester (Scheme 54).70 Yb(OTf)3 activated both epoxide Hantzsch reaction to generate sterically hindered 4-isoxaz-

and aziridine ring-opening processes and the correspond- olyl-1,4-dihydropyridines using Yb(OTf)3 (Scheme 56).74
ing piperidines were obtained in quantitative yields in The combination of Yb(OTf)3 with (R)-3,3′-bis(2,4,6-triiso-
shorter reaction time even when it was used in a catalytic propylphenyl)-1,1′-bi-2-naphthol cyclic monophosphate
amount as compared to the other catalysts. [(R)-TRIP] produced moderate yields of chiral 4-isoxazolyl-
1,4-dihydropyridines and 4-isoxazolylquinolones with high
O
Bn enantioselectivities.
O R1
O N Yb(OTf)3 (1 equiv) OMe
R1 NaHCO3(5 equiv), MeCN N
+ OMe O R2 O
Cl– R2CHO NH4OAc Yb(OTf)3 (5 mol%), EtOH
NH3 r.t., 96 h
N + R1 R1
Bn HO NHBn O O
Bn r.t., 5 h
N R N R
Bn Bn R R1 H
R1 = i-Pr, CH2CO2Me
quantitative
85–95%
R = Me; R1 = OEt
Scheme 54 Yb(OTf)3-catalyzed synthesis of trisubstituted piperidines R–R1 = CH2C(Me)2CH2
via ring opening of an epoxyaziridine R2 = Ph, 4-MeC6H4, 4-MeOC6H4, 4-HOC6H4, 4-Me2NC6H4, 4-
Ph2NC6H4, 4-FC6H4, 4-BrC6H4, 2-furyl, 2-thienyl, 3-pyridyl, Et, n-Pr
N
for R2 O R = Me, R1 = OEt, 42–68%
=
Dureault and co-workers reported Yb(OTf)3-catalyzed Ar
Ar = 1'-naphthyl, 1'-(2''-methoxynaphthyl),
H3C
ring-opening reactions of a bis-aziridine with allyl alcohol 3-PhOC6H4, 4-PhOC6H4, 3,4-(BnO)2C6H3,
9'-anthryl, 3,4-(MeO)2C6H3, 4-PhC6H4
or water, followed by intramolecular heterocyclization to
afford the corresponding substituted piperidine (azapyra- Scheme 56 Yb(OTf)3-catalyzed synthesis of 1,4-dihydropyridines via
Hantzsch reaction
nose) along with an azafuranose derivative (Scheme 55).71
The relative ratio of the product distribution was found to
be dependent on the Lewis acid employed for the reaction. Barluenga et al. reported a multicomponent reaction be-
Traditional Lewis acids such as BF3·OEt2 gave poor selectivi- tween alkenyl bromides, silyl imines and morpholine for
ty in the reaction with allyl alcohol. the regioselective synthesis of trisubstituted pyridines us-
ing Pd2(dba)3 and Yb(OTf)3 as catalysts (Scheme 57).75 The
Boc Boc
N N reaction proceeds via initial formation of an enamine by
NHBoc
Boc BocHN OR Pd-catalyzed alkenylation of morpholine, followed by the
Yb(OTf)3 (10 mol%) Boc
N
BnO OBn neat or THF
N formation of a 2-aza-1,3-butadiene by cross-coupling of the
+
20 °C, 2–20 h
+
silyl imine with the alkenyl bromide, then by an Yb(OTf)3-
ROH BnO OR
OBn
BnO OBn catalyzed hetero-Diels–Alder reaction to give the cyclic ad-
R = H, allyl
50–55% 27% duct. Finally, elimination of morpholine gave the dihydro-
pyridine, which on aromatization provided the trisubstitut-
Scheme 55 Yb(OTf)3-catalyzed synthesis of piperidines via ring open-
ing of a bis-aziridine ed pyridine. The authors also demonstrated the synthesis in
a one-pot process which offered good yields of the pyri-
dines. Use of Yb(OTf)3 was necessary to enhance the reac-
5.4 Pyridine tivity of the 2-azadiene in the hetero-Diels–Alder reaction.
Among the several methods known for constructing the

pyridine nucleus, the Hantzsch pyridine/dihydropyridine
synthesis is an extremely popular multicomponent organic
P
R1 O
R1 R1
drochloride in aqueous solution (Scheme 60).78 The reac-
Pd2(dba)3, DavePhos, t-BuONa
N TMS
+ + Yb(OTf)3 (20 mol%), toluene tion involved the sequential condensation of Schiff bases
Br N
H R2 90 °C, 14 h N R2 resulting from the aldehyde and the amine. Pyridinium
O
48–62% products were the outcome of oxidation or disproportion-
ation reactions. The reaction of phenylacetaldehyde with
O
N N benzylamine gave only the corresponding pyridinium de-
H
R1 O R1 rivative in 75% yield; the 2,3-dihydropyridinium product
Pd(0)
N
R1
R 1
Yb(OTf)3 was not obtained.
N N
R1 R1 O R1
Br N TMS R R R R
R2 R2
Yb(OTf)3, H2O
R2 N 3 RCH2CHO + BnNH3Cl + Ph + + Ph
N H N N
Pd(0) Bn Bn
R2 R1 = Ph, 4-MeC6H4, 4-MeOC6H4
56–75%
R2 = 4-ClC6H4, 4-MeC6H4, 4-MeOC6H4, 4-
R = n-Bu 1:3

Me2NC6H4
R = Ph 100:0
Scheme 57 Yb(OTf)3-catalyzed synthesis of trisubstituted pyridines
Scheme 60 Yb(OTf)3-catalyzed synthesis of 2,3-dihydropyridinium
and pyridinium derivatives
An application of the Bohlmann–Rahtz heteroannula-

tion between β-amino esters and alkynones using a catalyt- While studying the diastereoselective inverse-electron-
ic amount of Yb(OTf)3 yielded highly functionalized pyri- demand aza-Diels–Alder reaction of N-aryl-1-azadienes de-
dines in good to excellent yields (Scheme 58).76 ZnBr2 was rived from α-amino acids and enamine dienophiles,
also successful in catalyzing this annulation. Palacios and co-workers observed that in the presence of
Yb(OTf)3, the N-aryl-1-azadienes dimerized, thereby regio-
R1 R2
O and stereoselectively forming the tetrahydropyridines
CO2Et
NH2 Yb(OTf)3, toluene through an aza-Diels–Alder reaction in chloroform at room
EtO O R2 N R1
temperature (Scheme 61).79 The imine group of the tetrahy-
68–93% dropyridine (when R1 = 4-MeC6H4) was unstable and hydro-
R1 = Me, Ph
R2 = Ph, Et, SiMe3 lyzed during the workup procedure.
Scheme 58 Yb(OTf)3-catalyzed synthesis of pyridines by the Bohl-
R1 R1
mann–Rahtz heteroannulation
EtOOC N Yb(OTf)3 (10 mol%), CHCl3 EtOOC N R2
r.t., 72 h N
R1
Medvedeva et al. reported the microwave-assisted R2 R2 COOEt
Yb(OTf)3-catalyzed reaction of pyridin-2-amine with 3- R1 = 4-O2NC6H4, 4-MeC6H4 76–81%
trimethylsilylprop-2-ynal to yield N-(pyridin-2-yl)-2- R2 = 4-O2NC6H4
trimethylsilylethynyl-1,2-dihydropyridine-3,5-dicarbalde- Scheme 61 Yb(OTf)3-catalyzed synthesis of tetrahydropyridine from

hyde in 80% yield (Scheme 59).77 Notably, the presence of N-aryl-1-azadienes
the Lewis base DABCO led to trimerization of 3-trimethylsi-
lylprop-2-ynal to give 4-trimethylsilylethynyl-4H-pyran-
2,6-dicarbaldehyde. Feng and co-workers demonstrated the Yb(OTf)3-cata-
lyzed aza-Diels–Alder reaction of trans-1-methoxy-2-
methyl-3-trimethylsiloxybuta-1,3-diene with N-benzhy-
N
N NH2 Yb(OTf)3 (5 mol%), MeCN/H2O SiMe3 dryl imines in toluene at room temperature to give the cor-
+ N responding 2,5-disubstituted 2,3-dihydro-4-pyridones in
OHC SiMe3 MW, 700 W, 6 min
high yields.80 Several Lewis acids such as LiOTf, Cu(OTf)2,
OHC CHO
Sc(OTf)3, Zn(OTf)2 were screened for the above reaction and
80%
the authors observed that scandium, zinc and ytterbium
Scheme 59 Yb(OTf)3-catalyzed synthesis of dihydropyridines
triflates gave similar results. The same products were also
obtained by Yb(OTf)3-catalyzed three-component reaction
Wang and co-workers reported the synthesis of 2,3-di- of the diene with aldehydes and amines under solvent-free
hydropyridinium and pyridinium derivatives by the lantha- conditions in 51–86% yields (Scheme 62).
nide-promoted reactions of aldehydes and benzylamine hy-
Q
Ph2HC RCHO O R2
N NH2
(i) Yb(OTf)3 (10 mol%)
CHPh2 NCHPh2 CH2Cl2, r.t., 12–48 h R3
Yb(OTf)3 (20 mol%) N H R1 NH
R Yb(OTf)3 (20 mol%) +
toluene
OMe R2 (ii) Cl O
O R r.t., 6 h R4 R1
OMe r.t, 6 h R3
O Cl
62–99% 51–86% (iii) MeOH 52–96%
TMSO R4
TMSO
R1 = H, CO2Et, Ph
R = Ph, 2-MeC6H4, 4-MeC6H4, 2-MeOC6H4, 2-ClC6H4, 3-MeOC6H4, 4-MeOC6H4, R2 = R3 = R4 = H, Me
4-ClC6H4, 4-FC6H4, 2-furyl, 2-pyridyl, PhCH=CH, i-Pr, n-Pr, c-Hex
Scheme 64 Yb(OTf)3-catalyzed solid-supported synthesis of tetrahy-
Scheme 62 Yb(OTf)3-catalyzed synthesis of 2,5-disubstituted 2,3-di- dropyridines
hydro-4-pyridones from trans-1-methoxy-2-methyl-3-trimethylsiloxy-
buta-1,3-diene
Wunsch and co-workers reported a solid-supported
synthesis of N-unsubstituted 2,3-dihydropyridin-4(1H)-
Weinreb and co-workers reported an efficient strategy ones using an Yb(OTf)3-catalyzed aza-Diels–Alder reaction

for the enantiospecific construction of Securinega alkaloids. of resin-supported imines with Danishefsky’s diene
Here, Yb(OTf)3 efficiently promoted the annulation of the (Scheme 65).83 The cleavage of N-unsubstituted 2,3-dihy-
phyllanthine A ring scaffold by way of an aza-Diels–Alder dropyridin-4(1H)-ones from the resin was achieved with
reaction between the precursor imine and Danishefsky’s di- TFA. It was observed that anhydrous THF was the best-suit-
ene (Scheme 63).81 Yb(OTf)3 was reported to be an efficient ed solvent and the highest product yield was obtained by
and mild catalyst for the [4+2] cycloaddition, while tradi- using a temperature gradient of 0 to 25 °C for this reaction.
tional Lewis acids such as SnCl4 and TiCl4 resulted in low
O
yields of adducts possibly due in part to the sensitivity of (i) Yb(OTf)3, THF
the ketal and silyl ether functionalities to strong acids. It N R MeO OTMS 0–25 °C, 20 h
was also reported that the same transformation could be (ii) TFA
N R
H
achieved without any catalyst, but under high pressure (12 R = i-Pr, c-Hex, t-Bu, Ph 46–71%
kbar), to provide a good yield (71%) of the cyclic adduct.
Scheme 65 Yb(OTf)3-catalyzed solid-supported synthesis of 2,3-dihy-
dropyridin-4(1H)-ones
OMe
N N
Yb(OTf)3 (20 mol%), MeCN
TBSO O + O TBSO O
O r.t., overnight O Creswell et al. used a polymer-supported quench meth-
OTMS
84% odology for the parallel purification of combinatorial librar-
N ies of dihydropyridones (Scheme 66).84 The hetero-Diels–
H O Alder reaction of imines with an excess of Danishefsky’s di-
MeO
ene in the presence of Yb(OTf)3 gave a mixture of the 1,2-
phyllanthine O
disubstituted 2,3-dihydro-4-pyridone along with a by-
Scheme 63 Yb(OTf)3-catalyzed annulation of the A ring in the synthe- product 4-methoxybut-3-en-2-one, which was removed by
sis of phyllanthine using the polyamine resin to give good yields of the pure di-
hydropyridone products.
A solid-supported synthesis of tetrahydropyridine de-
rivatives was developed, using an Yb(OTf)3-catalyzed aza- O
Diels–Alder reaction using aminomethylated polystyrene R2

N
resin as the immobilized amine component with an alde- Yb(OTf)3
N R2
O
R1 (0.1 equiv)
hyde and a diene (Scheme 64).82 Yb(OTf)3, when compared MeCN R1
(i) resin, CH2Cl2
+
to other Lewis acids such as La(OTf)3, Nd(OTf)3, Dy(OTf)3, MeO
+
(ii) filter
MeO N R2
(iii) EtOAc, 1 N HCl
AlCl3, and MgCl2, gave good to excellent yields of the tetra-
OTMS R1
hydropyridine derivatives. The [4+2] products were re- 50–95%
O
leased from the polymer bound by a ‘traceless’ procedure, purity 80–95%
R1 = Bn, Ph(CH2)2, Ph(CH2)3, Ph(CH2)4,
involving tertiary amine N-dealkylation using 1-chloroethyl
2-CH2(C5H9O), 2-CH2(C4H3O), CH2NH2
chloroformate followed by methanolic decomposition of 2-(CH2)2[C4H3N(Me)], 2-CH2(C4H3S)
the resulting carbamate. R2 = PhC6H4, 4-FC6H4, 4-BnOC6H4 N CH2NH2
N
H
resin
Scheme 66 Yb(OTf)3-catalyzed synthesis of 2,3-dihydro-4-pyridones

using a polymer-supported quench methodology
R
Furman and co-workers reported the Yb(OTf)3-cata- S
lyzed cycloaddition reaction of Schiff bases with electron- Me3Si R2

R2 N
Me3Si S N Yb(OTf)3
rich silyloxy dienes to give 2-substituted 2,3-dihydropyri-
R1
dones (Scheme 67).85 Various types of aromatic and ali- R1
phatic imines were cleanly and rapidly converted into the R1 = Ph, 2-BrC6H4, 4-NCC6H4, 4-MeOC6H4, 4-ClC6H4 53–66%
corresponding 2-substituted 2,3-dihydropyridones in the R2 = Bn, 4-MeOC6H4CH2
presence of 10 mol% of Yb(OTf)3. The product obtained Scheme 69 Yb(OTf)3-catalyzed synthesis of δ-thiolactams
upon a subsequent rhodium-catalyzed intramolecular cy-
cloaddition reaction afforded the indolizidine skeleton.
Wang and co-workers reported the Ln(OTf)3-catalyzed
O
aza-Diels–Alder reaction between aldehydes, benzylamine
OTMS
SnMe3 Yb(OTf)3 (10 mol%) hydrochloride and dienes in water to give the cycloadducts,
MeCN
R N SnMe3 tetrahydropyridines (Scheme 70).88 Among various lantha-
N R 30 °C, 6–12 h
nide triflates screened for the reaction, Yb(OTf)3 and

OMe
R = Ph, 4-MeC6H4, 4-MeOC6H4, 4-ClC6H4, 2-furyl, i-Pr, c-Hex 69–90%

Pr(OTf)3 were found to be the most effective, whereas
Gd(OTf)3 delivered lower yields of adducts. The catalytic
Scheme 67 Yb(OTf)3-catalyzed synthesis of 2,3-dihydropyridones
process greatly reduced the limitations of aza-Diels–Alder
from electron-rich silyloxy dienes
reactions, and aldehydes other than formaldehyde and gly-
oxylate worked well to provide the corresponding adducts
Barluenga et al. reported an imino-Diels–Alder reaction in good yields. The reactions of various dienes other than
between a variety of aminotrienes and N-ω-vinylimines in cyclopentadiene also gave excellent yields. Moreover, the
the presence of Yb(OTf)3 for the synthesis of substituted di- lanthanide triflates could be recovered easily and reused af-
hydropyridones (Scheme 68).86 The substituted dihydropy- ter the product was extracted with dichloromethane.
ridones were then convereted into polysubstituted 1-azabi-
cyclic alkaloid scaffolds via ring-closing metathesis in the R5 R4
R4 R3 R5
presence of the first-generation Grubbs ruthenium catalyst. Yb(OTf)3, H2O
R1CHO + BnNH3Cl +
Through modifications of both cycloaddition partners, bi- r.t., 12–20 h
R2 N R1
R3
cyclics featuring a piperidine ring fused to various-sized R1 = H, Et, n-pentyl, Ph, Bn R2 Bn
rings (six- to nine-membered) were synthesized in good R2 = R3 = R4 = R5 = H, Me
yields. Scheme 70 Yb(OTf)3-catalyzed synthesis three-component reaction

for the tetrahydropyridines by aza-Diels–Alder reaction
R1
R1
m
N n
Yb(OTf)3 (20 mol%), THF
rt, overnight
m 5.5 Oxazine
+ N
n
PhHN R2 TFA, CH2Cl2, r.t., 15 min
O R2 The cycloaddition of methylenecyclopropanes89 is a
R1 = H, OMe, OAc 45–52% powerful tool in organic synthesis for a variety of synthetic
R2 = Ph, 4-MeOC6H4, 2-BrC6H4, 4-FC6H4,
applications. Wang and co-workers reported Yb(OTf)3-pro-
CO2Me
m = 0–1 moted reactions of methylenecyclopropane diesters with
n = 1–4 C,N-diarylnitrones to yield, exclusively, the distal [3+3]-cy-
Scheme 68 Yb(OTf)3-catalyzed synthesis of dihydropyridones for ring- cloaddition products, 1,2-oxazinane-4,4-dicarboxylates,
closing metathesis with high site-, regio- and stereoselectivities in moderate to
excellent yields (Scheme 71).90 The authors demonstrated
Aoyagi et al. reported the Yb(OTf)3-catalyzed [4+2] cy- the use of a wide range of electronically and structurally di-
cloaddition of an in situ generated allenyltrimethylsilylthio- verse methylenecyclopropanes and C,N-diarylnitrones;
ketene with imines to yield unsaturated δ-thiolactams in however, the reactions of C,N-dialkylnitrones with meth-
moderate to good yields (Scheme 69).87 One of the δ-thio- ylenecyclopropane did not give positive results, probably
lactam products was further converted into 4-azafluoren- due to the intrinsic instability of such nitrones to Lewis
one, a synthetic precursor of onychine. acids. Among other Lewis acids tested, such as Sc(OTf)3 and
Mg(ClO4)2·6H2O, Yb(OTf)3 gave the best results in THF.
S
R1 R3 O CO2Me
R1 N R2
–O R4 Yb(OTf)3 (20 mol%), THF CO2R 2 Yb(OTf)3 (5 mol%) R3 O R2
N N Yb(OTf)3 (5 mol%) CO2Allyl
+ R1 toluene
CO2R2 CO2R2 toluene
40–50 °C, 5–72 h +
R3 O MS 4 Å, r.t., 24 h R1 + R3NHOH
CO2R2 N R3 MS 4 Å, r.t., 24 h
CO2Me MeO2C CO2Allyl
R 4 R2 R1CHO
R1 = Ph, 4-MeOC6H4, 4-MeC6H4, 4-BrC6H4, 4-ClC6H4, 63–94%
51–98% CO2Allyl
Bn, PhCH2CH2, PhCH2CH2CH2, n-heptyl, 1-naphthyl
R2 = Me, Et
R1 = Ph, 4-MeOC6H4, 4-O2NC6H4, 4-NCC6H4, 2-furyl, 2-thienyl, PhCH=CH
R3 = Ph, 4-MeOC6H4, 3-MeC6H4, 4-MeC6H4, 2-furyl
R2 = H, Ph, 2-furyl
R4 = Ph, 3-ClC6H4, 4-ClC6H4, 4-BrC6H4, 4-MeC6H4, Me
R3 = Ph, 4-tolyl, 4-MeOC6H4, 4-MeO2CC6H4
Scheme 71 Yb(OTf)3-catalyzed synthesis of 1,2-oxazinane-4,4-dicar-
Scheme 74 Yb(OTf)3-catalyzed synthesis of tetrahydro-1,2-oxazines
boxylates
via [3+3] cycloaddition
Curini and co-workers reported an Yb(OTf)3-catalyzed 5.6 Thiazine

synthesis of 3,4,5-trisubstituted 3,6-dihydro-2H-1,3-ox-

azines through the one-pot domino three-component reac- Chakraborty and Putatunda also synthesized 2-amino-
tion of acetylene dicarboxylates with amines and formalde- 4H-1,3-thiazines in good to excellent yields by a one-pot
hyde under solvent-free conditions (Scheme 72).91 The re- multicomponent reaction between arylaldehydes, arylacet-
ported domino sequence proceeded via hydroamination, ylenes, and thiourea using Yb(OTf)3 and concentrated HCl
Prins reaction, cyclization and subsequent dehydration. (Scheme 75).92 It has been suggested that the coordination
of Yb(OTf)3 with both aldehyde and thiourea advanced the
R1O2C condensation process and use of Bronsted acid accelerated
O
Yb(OTf)3 (10 mol%)
R1O2C CO2R1 + R2NH2 + HCHO the removal of water to give an iminium-type intermediate.
R1O2C N
r.t., 6 h
The final product was obtained by a hetero-Diels–Alder re-
R2
R1 = Me, Et action and subsequent deprotonation.
50–72%
R2 = Ph, 4-O2NC6H4, 4-MeOC6H4, 4-BrC6H4,
2-MeOC6H4, 2-O2NC6H4, n-Bu, c-Hex
Yb(OTf)3 (0.5 mmol) R2
Scheme 72 Yb(OTf)3-catalyzed synthesis of 3,4,5-trisubstituted 3,6- S concd HCl (1.5 mmol), MeCN
R1 N
dihydro-2H-1,3-oxazines + + R2CHO
H2N NH2 Δ, 20 h
R1 S NH2
R1 = Ph, 4-FC6H4, 4-MeC6H4 62–79%

Chakraborty and Putatunda used Yb(OTf)3 and concen- R2 = Ph, 2-naphthyl, 2-ClC6H4, 4-ClC6H4, 4-BrC6H4, 4-FC6H4,
3,4-F2C6H3, 4-MeC6H4, 2-MeOC6H4, 4-MeOC6H4, 3-O2NC6H4
trated HCl for the one-pot multicomponent synthesis of 2-
amino-4H-1,3-oxazines using arylaldehydes, arylacety- Scheme 75 Yb(OTf)3-catalyzed synthesis of 2-amino-4H-1,3-thiazines
lenes, and urea (Scheme 73).92 A wide variation of the sub-
stituents on both arylaldehydes and arylacetylenes was tol- 5.7 Pyrimidine
erated, and good to excellent product yields were obtained.
The Biginelli reaction is a useful and highly explored
Yb(OTf)3 (0.5 mmol) R2 multicomponent reaction for the synthesis of the pyrimi-
O
concd HCl (1.5 mmol), MeCN
R1 + + R2CHO N dine nucleus,94 a component of many biologically active
H2N NH2 Δ, 20 h
R1 O NH2
compounds. Wang et al. reported an Yb(OTf)3-catalyzed
R1 = Ph, 4-FC6H4, 4-MeC6H4 62–79% one-pot Biginelli-type reaction of aromatic and aliphatic al-
R2 = Ph, 2-naphthyl, 2-ClC6H4, 4-ClC6H4, 4-BrC6H4, 4-FC6H4,
dehydes with β-dicarbonyl compounds and thiourea to give
3,4-F2C6H3, 4-MeC6H4, 2-MeOC6H4, 4-MeOC6H4, 3-O2NC6H4
dihydropyrimidinethiones (Scheme 76).95 The reaction was
Scheme 73 Yb(OTf)3-catalyzed synthesis of 2-amino-4H-1,3-oxazines
catalyzed by 5 mol% of Yb(OTf)3 at 100 °C for 60–90 min-
utes under solvent-free conditions. As compared to the
In an approach to tetrasubstituted pyrroles, Kerr and co- classical Biginelli reaction, the yields of the desired prod-
workers synthesized tetrahydro-1,2-oxazines as intermedi- ucts were increased (from 20–50% to 81–91%) and the reac-
ates by the Yb(OTf)3-catalyzed two- or three-component tion time was shortened (from 18–48 hours to 60–90 min-
coupling of aldehydes, hydroxylamines (or isolated ni- utes). Little difference in product yield was observed by us-
trones) and cyclopropanes via [3+3] cycloaddition (Scheme ing other metal triflates such as Sc(OTf)3, and La(OTf)3;
74).93 The utility of the developed methodology was also however, Yb(OTf)3 was more effective and could be reused
extended towards the synthesis of the anticholesterol drug three times without loss in catalytic activity. Along the
atorvastatin by a two-pot strategy with a few modifica- same lines, Csámpai and co-workers performed three-com-
tions. ponent Biginelli reactions on formylferrocene with 1,3-di-
oxo-components and thiourea to afford a series of novel fer-
rocene-containing dihydropyrimidines.96 Boric acid and
T
Yb(OTf)3 were the two catalytic systems screened, with Ar

Yb(OTf)3 (10 mol%)
Yb(OTf)3-catalyzed reactions giving higher yields for sub- O ArCHO
ligand (10 mol%), THF
RO2C R
NH
CO2R +
strates with aromatic substituents due to complexation to X r.t., 20–30 h
N X
the Yb(III) species. For 1,3-cyclohexanedione and dime- H
H2N NH2
done, boric acid provided good yields of the corresponding 73–90%
R = Et, i-Pr 87–99% ee
fused pyrimidines. Ar = Ph, 3-O2NC6H4, 3-FC6H4, N Ph Ph N
2-ClC6H4, 3-HOC6H4, 2-HOC6H4,
4-BrC6H4, 2-furyl, styryl, Bn
S N N
O O R3
OH HO
H2N NH2 R3 H Yb(OTf)3 (5 mol%), MeCN R2 NH
O O reflux
R1 N S ligand
H
R1 R2
3–92% Scheme 78 Yb(OTf)3-catalyzed asymmetric synthesis of dihydropyrim-
R1 = Me, Ph, CH2CO2Me, CH2CO2Et idines
R2 = Me, OMe, OEt, Ot-Bu, N(Et)2, Ph
R1–R2 = CH2C(Me)2CH2, CH2CH2CH2

R3 = Ph, 4-MeOC6H4, 4-O2NC6H4, 4-ClC6H4, 2,4-Cl2C6H3,
i-Pr, n-Bu, 3-O2NC6H4, PhCH=CH, PhCH2CH2, ferrocenyl O R1
O O R2O
O O Yb(OTf)3, toluene P
Scheme 76 Yb(OTf)3-catalyzed synthesis of substituted dihydropyrim- P OR
2 R2O NH
R1 H H2N NH2
idinethiones OR2
N O
H
R1 = Ph, 4-FC6H4, 4-ClC6H4, 4-MeC6H4, 4-MeOC6H4, 2,4-Cl2C6H3, 15–58%
3-ClC6H4, 2-BrC6H4, 4-BrC6H4, 4-O2NC6H4, 2-naphthyl, 2-furyl
Similarly, Yb(OTf)3 played a significant role in the con- R2 = Me, Et
struction of 3,4-dihydropyrimidine-2(1H)-(thi)ones via Scheme 79 Yb(OTf)3-catalyzed synthesis of dihydropyrimidines bear-

three-component reaction of β-keto esters, aldehydes, and ing a phosphoryl moiety
(thio)urea. The synthesized 3,4-dihydropyrimidin-2(1H)-
ones were evaluated for HIV-1 replication inhibition activi-
ties (Scheme 77).97 6 Synthesis of Benzo-Fused Heterocycles
O X Yb(OTf)3 (10 mol%), THF

Ar
6.1 Benzofuran
CO2Et
ArCHO + CO2Et + reflux, 20 h
HN
H2N NH2
X N Fu et al. reported a novel gold-catalyzed rearrangement
Ar = 2-HOC6H4, 3-HOC6H4, 4-HOC6H4, 3-MeOC6H4, H
of allylic oxonium ylides to prepare dihydrobenzofuran-3-
4-ClC6H4, 4-FC6H4, 3-O2NC6H4, 4-O2NC6H4, 4-NCC6H4
X = O or S ones (Scheme 80).100 While optimizing the reaction condi-
tions for the rearrangement, the authors found Yb(OTf)3 to
Scheme 77 Yb(OTf)3-catalyzed synthesis of 3,4-dihydropyrimidin-
2(1H)-ones be a superior co-catalyst when compared to other acids
such as Sc(OTf)3, BF3·OEt2 and MsOH. The reaction scope
was extended to aliphatic substrates, and good yields were
An asymmetric version of the Biginelli reaction using obtained for the cyclized products.
Yb(OTf)3 and chiral hexadentate ligand 186 was also devel-
oped (Scheme 78).98 High yields and excellent enantioselec- R4
R1 IPrAuNTf2, N-oxide R4
O
R3
tivities were obtained for the dihydropyrimidine products. Yb(OTf)3 (1.1 equiv), DCE R1
The catalyst was recovered through pH-controlled ex- 80 °C, 3 h O

O R2 R2
traction and reused several times without much loss in en- R3 48–81%
antioselectivity. R1 = H, Cl, CO2Et, CO2Bn, CONEt2
Cl Cl
Dihydropyrimidines bearing a phosphoryl moiety were R2 = H, Me
R3 = H, Me N-oxide =
synthesized by a one-pot cyclocondensation reaction of al- R4 = 4-t-Bu, 4-Me, 5-Me, 5-MeO, 5-F, 5-Cl N
dehydes, urea, and O,O-dialkyl-2-oxopropanephosphonates O
using Yb(OTf)3 as the catalyst (Scheme 79).99 Different cata-
Scheme 80 Gold and Yb(OTf)3 catalyzed rearrangement of allylic oxo-
lyst systems and various solvents were screened and nium ylides
Yb(OTf)3 was found to be the most effective catalyst. Nota-
bly, aliphatic aldehydes, including propionaldehyde and bu-
tyraldehyde, were resistant to this reaction. In a synthesis of radermachol, a bright red pigment iso-
lated from Radermachera xylocarpa K. Schum, the benzofu-
ran ring was constructed by the condensation of a β-keto
ester with 2-(2-iodobenzoyl)naphthalene-1,4-dione using
Yb(OTf)3 as a catalyst in good yield (Scheme 81).101
U
O O I R1
R4
OH O I R2 R5
N R1
Yb(OTf)3 R3 R4 CO2R6
O
H2O/MeCN CO2Me Yb(OTf)3 (5 mol%), sealed tube CO2R6
O r.t. to 120 °C, 2 h to 7 d N R2
O
MeO2C R1, R2, R3, R4 = H, Me, Bn, OMe R3
84%
radermachol R5 = H, CH=CH2, Me, Ph, CH=CHPh 36–79%
R6 = Me, Et
Scheme 81 Yb(OTf)3-catalyzed synthesis of a benzofuran derivative R6O2C CO2R6
6.2 Indole R5
R8
N
MeO2C
CO2Me
MeO2C
CO2Me
R7 R5 R7
R7 R5 N N
Tetrahydroindolizines were synthesized in one step and +
Yb(OTf)3 (10 mol%), toluene R8 R8
in moderate yields by successive intra- and intermolecular

80 °C
cis trans
alkylations of 2-substituted 1-(4,4-diethoxybutyl)pyrroles, R7 = Ph, 2-furyl, 4-MeOC6H4, 2-thienyl 62–96%
cis/trans 99:1 to 55:45
catalyzed by Yb(OTf)3 (Scheme 82).102 R8 = Bn, n-Bu, i-Pr
R5 = Ph, vinyl
R6 = Me
R N R R Scheme 83 Yb(OTf)3-catalyzed [3+2] annulations of 1,1-cyclopropane

OEt N N OEt diesters to give 2,3-cyclopentanoindolines and pyrrolidines
r.t., 3 d
OEt OEt
R = Me, Ph 40–45%
Shao and Yang illustrated a new method that utilized
Scheme 82 Yb(OTf)3-catalyzed synthesis of tetrahydroindolizines by unactivated and optically active Δ1-pyrroline species as
successive intra- and intermolecular alkylations
coupling partners with Danishefsky-type dienes to achieve
a range of bicyclic hydroxyindolizidinones via a highly dia-
Kerr et al. showed that 3-alkyl-substituted indoles un- stereoselective aza-Diels–Alder cycloaddition in good yields
derwent a [3+2] annulation when treated with 1,1-cyclo- (Scheme 84).106 The optimization studies indicated that
propane diesters in the presence of Yb(OTf)3 to afford 2,3- Yb(OTf)3 was the most prominent catalyst for the [4+2] cy-
cyclopentanoindolines (Scheme 83).103 The 2-alkylated in- cloaddition among the other catalysts screened, including
dole resulting from a rearrangement was also formed in AgOTf, ZnCl2, AlCl3, and BF3·OEt2. The methodology was ap-
about 5% yield or less as a by-product in few cases; it was plied to the synthesis of the natural and non-natural poly-
formed in larger amount when the reactions were per- hydroxylated indolizidines lentiginosines and (–)-2-epi-ste-
formed at higher temperatures. The reactions were feasible viamine.
at elevated temperatures or at ultra-high pressure: for steri-
OTMS OR2
cally hindered substituents, the latter was required. For R2O OR2 O
Yb(OTf)3 (50 mol%), CH2Cl2
substituted cyclopropane diesters, the nucleophilic attack + OR2
–40 to 0 °C, 3 h N
occurred exclusively at the substituted carbon and the reac- MeO R1 N
R3
tion showed significant regio- and diastereoselectivities. R1 R3

R1 = H, Me
62–73%
With aromatic or olefinic substituents, the reaction took R2 = MOM, TBS, Boc, Bn
dr 5:1 to >99:1
R3 = H, CH2OBn
place at ambient temperature and pressure. Yb(OTf)3 also
OH OH
catalyzed the addition of 1,1-cyclopropane diesters with in H OH H H
situ generated aldimines, by the reaction of primary amines OH OH OH

N N N
or anilines with aldehydes, to give pyrrolidines in high dia-
stereoselectivities (Scheme 83).104 Both primary alkyl OH
(+)-lentiginosine (–)-lentiginosine 2-epi-(–)-steviamine
amines and primary anilines were well tolerated in the re-
action; however, aryl and heteroaryl aldehydes produced Scheme 84 Yb(OTf)3-catalyzed synthesis of bicyclic hydroxyindoli-
zidinones by aza-Diels–Alder reaction between Δ1-pyrroline and
far more satisfactory results than their aliphatic counter-
Danishefsky-type dienes
parts. The presence of a strongly electron-withdrawing
group on the aldehyde (e.g., p-nitrobenzaldehyde) pro-
duced some difficulties and did not yield the expected Yb(OTf)3 was used to catalyze the high-temeperature
product. 2-Carboalkoxy-4-indolyl butanoates were ob- intramolecular Diels–Alder reaction of Ugi/IMDAF (IMDAF =
tained in cases where the indole was not substituted at the intramolecular Diels–Alder reactions of furans) adducts
3-position.105 possessing an acetylenic amide to afford isoindolinones in
high yields (Scheme 85).107
V
OH worked well with a wide range of aromatic, unsaturated,

R1 OH
Yb(OTf)3
R1
tauto- R 1 and aliphatic aldehydes, and gave good to excellent yields of
O dioxane merization the target benzimidazoles.
O
100 °C O
NHBn N
O N NHBn NH2 N
N R2C(OEt)2 Yb(OTf)3 (0.5 mol%)
2
R O R2 NHBn
R1 R1 R2
O + or
R2 90 °C, 1–2 h [for R2C(OEt)2] N
O NH2 H
R1 = H, Me, Ph R2CHO r.t., 30 min [for R2CHO]
77–91%
R2 = Bn, t-Bu 40–95%
R1 = H, Me, Cl, NO2, OMe, CO2Me
Scheme 85 Yb(OTf)3-catalyzed synthesis of isoindolinones via intra- R2 = H, Me, Et, Ph, trans-PhCH=CH, i-Bu,
molecular Diels–Alder reaction c-Hex, Me2C=CHCH2CH2CH(Me)CH2
Scheme 87 Yb(OTf)3-catalyzed synthesis of benzimidazoles

6.3 Indazole
6.5 Benzopyran
Kumar and co-workers reported a simple, efficient and

economical Yb(OTf)3-catalyzed one-pot three-component Yb(OTf)3·xH2O was used in the cyclocondensation of
condensation of substituted hydrazines, aldehydes and 1,3- α,β-unsaturated ketones with active methylene com-
diketones in [bmim]BF4 to achieve N2-substituted tetrahy- pounds, yielding benzo[b]pyran derivatives in very high
droindazolines (Scheme 86).108 Yb(OTf)3 was an effective yields (Scheme 88).112 Yb(OTf)3·xH2O was found to be a bet-
catalyst and provided excellent product yields. Diversely ter catalyst than Zn(OTf)2 and Mg(OTf)2 in terms of yield,
substituted aryl and heteroaryl hydrazines as well as aryl and showed high activity even after four cycles of reuse.
aldehydes reacted smoothly under the optimized condi-
O
tions. The synthesized compounds were then evaluated for
R3
their antiproliferative and Src kinase inhibitory activities. R1 R2
Yb(OTf)3·xH2O, THF/toluene (1:3)
O R2
R3
+
O O 80 °C
ArNHNH2
CHO O O R1
+
O R1
Yb(OTf)3 (20 mol%), [bmim]BF4 92–96%
X R3 R3
100 °C, 2 h X
R2 N Ar
X O R2 R1 = Ph, 4-ClC6H4, 3-O2NC6H4, 4-MeOC6H4, 4-MeC6H4
R1 R2 X N
R2 R2 = Ph, 4-MeC6H4, 3-HOC6H4
R3 = H, Me
Ar = Ph, 4-MeC6H4, 3-MeOC6H4, 4-MeOC6H4, 3,4-(MeO)2C6H3, 48–88%
2-HO-4-MeOC6H3, 4-HOC6H4, 2-FC6H4, 3-ClC6H4, 4-ClC6H4,
Scheme 88 Yb(OTf)3-catalyzed cyclocondensation of α,β-unsaturated
2-pyridyl, 2-thienyl
R1 = 3,4-Cl2C6H3, 3-Cl-4-MeC6H3, c-Hex, 4-t-BuC6H4
ketones with active methylene compounds
R2 = H, Me
X = CH2, O
Scheme 86 Yb(OTf)3-catalyzed synthesis of N2-substituted tetrahy- The Yb(OTf)3-catalyzed isomerization of 2′-hydroxy-

droindazolines chalcones (or 2′-aminochalcones) provided an excellent
strategy for the synthesis of flavonones (or quinolinones) in
6.4 Benzimidazole moderate to good yields (Scheme 89).113 Yb(OTf)3 in
[bmim][BF4] ionic liquid was found to be the best catalyst
The condensation reaction between carbonyl com- among a number of others, such as Ce(OTf)3, In(OTf)3,
pounds and o-phenylenediamine in the presence of a cata- Zn(OTf)2, Ba(OTf)2, Er(OTf)3, Y(OTf)3, Sc(OTf)3, and TsOH.
lyst is an important reaction for synthesis of benzimidaz-
O O
oles.109 Wang et al. reported an effective method for the Yb(OTf)3 (30 mol%), [bmim][BF4]
synthesis of benzimidazoles by the reaction of o-phenyl-
130 °C, 4–6 h (X = O)
enediamines with orthoesters (Scheme 87).110 Optimiza- XH R 130 °C, 5–360 min (X = NH) X R
tion studies revealed that Yb(OTf)3 was more suitable as R = Ph, 4-ClC6H4, 3-ClC6H4, 4-MeOC6H4, 4-MeC6H4,
20–86% for X = O
60–93% for X = NH
3-O2NC6H4, 4-O2NC6H4, 2,4-(MeO)2C6H3, 2-furyl
catalyst than traditional Lewis acids such as AlCl3, FeCl3,
and SnCl2, and provided good to excellent yields of benzim- Scheme 89 Yb(OTf)3-catalyzed synthesis of flavonones and quinoli-
idazoles under solvent-free conditions. Quantitative recov- nones
ery and reusability of Yb(OTf)3 after the reaction, and the
solvent-free conditions, were mentioned as advantages of Yb(OTf)3 was used as a catalyst in the Pechmann con-
the reported methodology. In the same year, Curini et al. densation reaction of phenols with β-keto esters to afford
synthesized benzimidazoles by the reaction between o- 2H-chromen-2-ones under solvent-free conditions
phenylenediamines and aldehydes using a catalytic amount (Scheme 90).114 The catalyst was reused without any de-
of Yb(OTf)3 under solvent-free conditions.111 The method crease in the yield.
W
O O O O method A
OH R
Yb(OTf)3 Yb(OTf)3 (1 mol%), [BPy]BF4
R1 R1
OEt 2
110 °C, 3–7 h
85 °C 60 min R + RCHO
R2
OH method B
R1 = OH, Me, Ac Yb(OTf)3 (5 mol%) O
78–95%
R2 = Me, H 90 °C, 0.5–10 h 80–95% (method A)
50–96% (method B)
Scheme 90 Yb(OTf)3-catalyzed synthesis of 2H-chromen-2-ones via
Pechmann condensation Method A: R = Ph, 3-ClC6H4, 4-ClC6H4, 3-BrC6H4, 4-BrC6H4, 3-FC6H4, 4-FC6H4,
3-O2NC6H4, 4-O2NC6H4, 4-NCC6H4, 4-MeC6H4, 4-MeOC6H4, 2-pyridyl
Method B: R = Ph, 4-ClC6H4, 4-BrC6H4, 4-O2NC6H4, 3-O2NC6H4, 4-FC6H4,
The reaction of Meldrum’s acid with differently substi- 4-HOC6H4, 4-MeOC6H4, Et, n-Pr
tuted 2-hydroxybenzaldehydes or 2-hydroxyacetophe- Scheme 92 Yb(OTf)3-catalyzed one-pot synthesis of aryl-14H-diben-

nones catalyzed by Yb(OTf)3 under microwave irradiation zo[a,j]xanthenes
and solvent-free conditions provided an excellent method
for the generation of coumarin-3-carboxylic acids in good
to excellent yields (Scheme 91).115 The reaction rate was not The synthesis of xanthones was achieved by the micro-

influenced by the electronic nature of the substituents, and wave-assisted Yb(OTf)3-catalyzed Friedel–Crafts reaction of
both 2-hydroxybenzaldehydes and 2-hydroxyacetophe- 2-hydroxybenzoic acids and differently substituted phenols
nones having either electron-donating or electron-with- under solvent-free conditions (Scheme 93).118 The reaction
drawing substituents reacted smoothly to give, selectively, was believed to proceed through formation of benzophe-
the desired products in excellent yields. none via an initial Friedel–Crafts acylation of the phenol
substrate with 2-hydroxybenzoic acid followed by ring clo-
O
O R2 sure. The latter step took place by displacement of the hy-
Yb(OTf)3 (10 mol%) CO2H
R2 +
O droxyl group coordinating the metal centre by the hydroxyl
R1 MW (200 W, 80 °C), 5 min R1
O O on the adjacent ring. The method avoided the use of a
OH O O
92–98% strong acid like trifluoromethanesulfonic acid as co-cata-
R1 = H, 5-NO2, 4-NO2, 5-Br, 5-Cl, 4-OMe, 5-OH, 4-N(Et)2
R2 = H, Me lyst, and diphenylether 2-carboxylic acid as the starting
material. Su and co-workers reported a synthesis of xan-
Scheme 91 Yb(OTf)3-catalyzed synthesis of coumarin-3-carboxylic
acids under microwave irradiation thones, thioxanthones, 1-azaxanthones and 1-azathioxan-
thones by an Yb(OTf)3-catalyzed intramolecular Friedel–
Crafts reaction under solvent-free conditions.119
Yb(OTf)3 was also used to catalyze the condensation of
O
β-naphthol and substituted benzaldehydes in ionic liquids
COOH Yb(OTf)3 (10 mol%)
to yield aryl-14H-dibenzo[a,j]xanthenes in one pot + ArOH R
R
(Scheme 92).116 Among a series of catalysts screened, in- OH
MW (200 W), 5 min O
cluding AlCl3, Zn(OTf)2, Bi(OTf)3, Yb(OTf)3, Yb(OTf)3·xH2O, R = H, 5-OH, 5-NO2
72–98%
Sc(OTf)3, Y(OTf)3, La(OTf)3, and Sr(OTf)2 in [BPy]BF4, ArOH = m-cresol, orcinol, phloroglucinol, resorcinol, pyrogallol,
4-nitrophenol, 4-chlorophenol, 7-hydroxycoumarin, 4-methyl-7-
Yb(OTf)3 was found to be the most effective in terms of hydroxycoumarin
yield and it prevented the formation of uncontrolled by- Scheme 93 Yb(OTf)3-catalyzed synthesis of xanthones under micro-
products. Yb(OTf)3 proved to be an efficient catalyst for the wave irradiation
same reaction under solvent-free conditions to yield a se-
ries of aryl- and alkyl-14H-dibenzo[a,j]xanthenes in good
to excellent yields (Scheme 92, method B).117 Both electron- Wei and Zhang reported the first example of an
rich and electron-deficient benzaldehydes worked well, giv- Yb(OTf)3-catalyzed tandem synthesis of isochromanones
ing high yields of products; however, aliphatic aldehydes via selective C–C bond cleavage followed by Friedel–Crafts
gave lower yields even after longer reaction times. cyclization of oxiranyl ketones in excellent yields (Scheme
94).120 The selective ring opening by C–C bond cleavage
rather than C–O cleavage in the oxiranes provided syntheti-
cally useful aryl-fused pyrans, which can undergo further
transformations like alkylation and elimination.
X
O O Along these lines, Yb(OTf)3 was used as an efficient cat-

O O
1. Yb(OTf)3 (10 mol%), CH2Cl2
MS 4 Å , 25 °C, 15 h OR
alyst for the Povarov-type [4+2] cycloaddition between N-
OR Ar1
Ar1 O 2. MeI, t-BuOK, THF, 25 °C, 15 h O benzylideneanilines and vinyl ethers to yield quinolines in
Ar2
Ar2
moderate to good yields (Scheme 96).125 The reaction of di-
Ar1 = 3,4,5-(MeO)3C6H2, 3,5-(MeO)2C6H3, 40–88% hydrofuran and 3,4-dihydro-2H-pyran afforded the corre-
N-methyl-2-indolyl, N-methyl-3-indolyl dr > 50:1
Ar2 = 4-MeOC6H4, 4-MeC6H4, 4-NCC6H4, 4-FC6H4,
sponding tetrahydroquinolines in 53–54% yields. The reac-
4-ClC6H4, 4-BrC6H4,1-naphthyl tion of N-benzylidene-4-methoxyaniline with silyl enol
R = Me, Et, t-Bu
ethers afforded 4-siloxytetrahydroquinolines in 64% yield as
Scheme 94 Yb(OTf)3-catalyzed synthesis of isochromanones from ox- a mixture of cis- and trans-diastereoisomers.
iranyl ketones
R1 R3 R2O R3
Yb(OTf)3
6.6 Quinoline N R3 MeCN
R4 R4
+ or
R4 OR2 N R1 N R1
H
Quinolines are pharmacologically important heterocy-

cles that exert several biological activities such as antima- R1 = c-Hex, Bn, Ph 47–74% 53–64% (88:12)
larial, antibacterial, antiasthmatic, antihypertensive, and R2 = Me, SiMe3
R3 = Me, Ph
antiinflammatory.121 Among the various reported synthesis
R4 = H
of quinolines, the acid- or base-catalyzed Friedländer annu- R2–R4 = CH2CH2, CH2CH2CH2
lation is an important synthetic methodogy that involves Scheme 96 Yb(OTf)3-catalyzed Povarov reaction in the synthesis of
the subsequent condensation and dehydration of two dif- quinolines and tetrahydroquinolines
ferent carbonyl compounds.122 Yb(OTf)3 was used as a cata-
lyst for the condensation reaction between 2-aminoaryl
carbonyl compounds and α-methylene ketones to yield sub- An Yb(OTf)3-catalyzed one-pot aza-Diels–Alder reaction
stituted quinolines and naphthyridine derivatives (Scheme was developed for the synthesis of 3-arylbenzo[f]quinoline-
95).123 A significant drop in the quinoline yield was ob- 1,2-dicarboxylate derivatives via three-component reaction
served when other metal triflates, including Y(OTf)3, of (hetero)aryl aldehydes, naphthalene-2-amine and but-2-
Sc(OTf)3, and Bi(OTf)3, were used. ynedioates (Scheme 97).126 For aliphatic aldehydes, namely
phenylacetaldehyde, propionaldehyde, butyraldehyde and
O R1
Yb(OTf)3 (5 mol%) n-heptaldehyde, the desired products were not obtained.
R3 R2 CH2Cl2 R3
R1 + Wang and co-workers also used Yb(OTf)3 as catalyst for the
O r.t., 1–2 h
X NH2 X N R2 Povarov reaction of aldehydes, anthracen-2-amine and but-
R1 = H, Me, Ph 75–95% 2-ynedioates to give 3-arylnaphtho[2,3-f]quinoline-1,2-di-
R2 = H carboxylate derivatives (Scheme 97).127 It was proposed
3
R = Ac, CO2Et
R2–R3 = CH2CH2, CH2CH2C(O), CMe2CH2C(O)
that initially an intermediate was formed from the but-2-
X = CH, N ynedioate and the Yb(OTf)3-activated Schiff base formed by
Scheme 95 Yb(OTf)3-catalyzed synthesis of substituted quinoline and the reaction of the aldehyde with the amine. This interme-
naphthyridine derivatives diate then isomerized to 3,4-dihydrobenzo[f]quinolone or
3,4-dihydronaphtho[2,3-f]quinoline, which on aerial oxida-
tion resulted in the formation of the final product.
The Povarov reaction, a subset of aza-Diels–Alder reac-
tions, is characterized by the [4+2] cycloaddition between NH2
an unactivated iminium ion as dienophile and an appropri- R1CHO CO2R2

CO2R2
ate diene, and holds enormous potential for the synthesis of + Yb(OTf)3 (1 mol%), toluene
six-membered heterocyclic compounds.124 This reaction R2O2C CO2R2 80 °C, 8–15 h N R1
combines three reactive components – an aldehyde, an 76–92%
amine and a diene – in aqueous solution to generate nitro- R1 = Ph, Bn, 4-FC6H4, 3-FC6H4, 4-ClC6H4, 3-ClC6H4, 4-MeC6H4,
4-BrC6H4, 4-MeOC6H4, 4-O2NC6H4, 4-ClC6H4, 2-FC6H4,
gen-containing heterocyclic compounds. However, the re- 4-BrC6H4, 2,4-Cl2C6H3, 3,4-Cl2C6H3, 3,4-OCH2OC6H3,
action has been limited to the use of either formaldehyde or 3,4-Me2C6H3, 2-thienyl, piperizinyl
R2 = Me, Et
activated aldehydes, such as glyoxylates, as the aldehyde
component. Less reactive aldehydes, such as acetaldehyde, Scheme 97 Yb(OTf)3-catalyzed synthesis of benzo[f]quinoline and
and dienes other than cyclopentadiene, traditionally give naphtho[2,3-f]quinoline derivatives
poor yields. Several methods have been developed to en-
hance the yields and to increase the reaction scope using An enantioselective Povarov-type aza-Diels–Alder reac-
Yb(OTf)3 as catalyst. tion between achiral N-alkylidine- or N-arylidene-2-hy-
droxyaniline with achiral dienophiles was reported to pro-
Y
ceed efficiently using a chiral catalyst prepared from H

Yb(OTf)3 and (R)-BINOL in the presence of DBU and an addi- 110 °C, 6 h
n
RCHO H
tive [either 2,6-di-tert-butyl-4-methylpyridine (DTBMP) or +
or
NH2 N R
2,6-di-tert-butylpyridine (DTBP)] to afford 8-hydroxyl- n
ultrasound 50 °C, 40 min
H
1,2,3,4-tetrahydroquinoline derivatives in high yields and n = 1, 2

16–86%
high diastereo- and enantioselectivities (Scheme 98).128 R = Ph, 4-BrC6H4, 4-ClC6H4, 4-MeC6H4, 4-MeOC6H4, 4-HOC6H4,
4-NCC6H4, 4-O2NC6H4, 2-O2NC6H4, 2-pyridyl, 2-thienyl, 2-furyl,
2 3 3 5-methyl-2-furyl, 2,4-Me2C6H3, 2,4-Cl2C6H3, 2,4-F2C6H3
R R R
Yb(OTf)3, (R)-(+)-BINOL (10–20 mol%)
DBU, DTBP, MS 4 Å, CH2Cl2 R2 Scheme 100 Yb(OTf)3-catalyzed synthesis of tetrahydroquinolines and
+ hexahydrophenanthridines
–45 to –15 °C, 20 h
N R1
H
N OH
R1
OH 58–90% The Yb(OTf)3-catalyzed aza-Diels–Alder reactions of cy-
R1 = Ph, 1-naphthyl, c-Hex cis up to >99% clopentadiene and 1,3-cyclohexadiene with various substi-
R2, R3 = OEt, OBu ee up to 91%
tuted N-arylimines in acetonitrile or an ionic liquid at room

R2–R3 = CH=CHCH2, OCH2CH2
temperature gave tetrahydroquinoline and hexahydro-
Scheme 98 Yb(OTf)3/(R)-BINOL-catalyzed enantioselective synthesis
phenanthridines derivatives in moderate to high yields
of tetrahydroquinolines
(Scheme 101).131 Equally good results were obtained by us-
ing Sc(OTf)3 in acetonitrile or an ionic liquid. The product
Similarly, substituted 2-acyltetrahydroquinolines were yield was found to be quite low, however, in the reaction of
synthesized by an Yb(OTf)3-catalyzed three-component 1,3-cyclohexadiene with N-arylimines.
Povarov reaction of α-oxo aldehydes, anilines, and dieno-
philes (Scheme 99).129 Interestingly, only cis-cycloadducts R2 R2
were formed under the depicted conditions. Under slightly N Yb(OTf)3 (10 mol%) n
MeCN or IL
modified conditions, diversely substituted 2-acyltetrahy- H + n N
r.t., 24 h H R1
droisoquinolines were obtained. n = 1, 2
R1 28–84%
R1 = 4-Me, 4-Cl, 4-Br, 4-OMe, 2,4-Me2, 2,4-Cl2 IL =

O R1 N
Yb(OTf)3 (0.1 equiv) H 2,4-Me2, 2,4-Cl2, 2-OH-5-Br, 3,4-benzo
R1 R2 = Me, Br CF3SO3–
R2 CHO MgSO4 (6.5 equiv) N
H2N H
+ H
MeCN, 0 °C then r.t. R2
N
O
H Scheme 101 Yb(OTf)3-catalyzed synthesis of tetrahydroquinolines and
16–75% hexahydrophenathridines in acetonitrile or an ionic liquid
R1 = H, Cl, Me, OMe
R2 = Ph, t-Bu, c-Pr
1,2,3,4-Tetrahydroquinolines were also synthesized by
Scheme 99 Yb(OTf)3-catalyzed synthesis of 2-acyltetrahydroquino-
lines the reaction of an in situ generated imine with another α-
branched aldehyde in the presence of a catalytic amount of
Yb(OTf)3 (Scheme 102).132 The yields of the two-step syn-
Pelit and Turgut described the Yb(OTf)3-catalyzed thesis were in the range of 60 to 70%.
Povarov-type aza-Diels–Alder reaction of cyclopentadiene
Nu
and 1,3-cyclohexadiene with N-arylimines, formed in situ R1
R1 R3
from the corresponding aromatic aldehyde and 1-naphthyl- R3R4CHCHO
NuH, Yb(OTf)3
R3
amine, in toluene to give tetrahydroquinoline and hexahy- N R2
N R2
H
drophenanthridine derivatives (Scheme 100).130 The reac- R1 = H, Me, MeO, F, Cl
60–70%
R2 = aryl, alkyl, heteroalkyl, CO2Et
tion was performed under both conventional heating and R3, R4 = alkyl, O-alkyl
ultrasonic irradiation. Higher yields were obtained in short- NuH = alkyl-OH, ArSH, H2O
er reaction times with ultrasonic irradiation in every case. Scheme 102 Yb(OTf)3-catalyzed synthesis of tetrahydroquinolines
The ultrasound method was equally effective for aromatic from α-branched aldehydes
aldehydes with electron-donating and electron-withdraw-
ing groups as well as for heteroaromatic aldehydes. Similarly, a fluorous-phase synthesis of tetrahydroquin-
oline derivatives was achieved by a three-component reac-
tion between fluorous benzaldehydes, anilines and isobu-
tyraldehyde using Yb(OTf)3 as catalyst under microwave irr-
radiation (Scheme 103).133 The products were further
transformed into biaryl-substituted oxazabicy-
clo[3.3.1]nonanes through a cycloaddition with coumarin
Z
and a subsequent Suzuki coupling. Microwave irradiation Kiselyov et al. reported the Yb(OTf)3-catalyzed solid-
and fluorous-phase extraction were additional advantages, supported synthesis of polysubstituted tetrahydroquino-
in that they led to faster reactions and simplified product lines by the three-component reaction of a 4-aminophenyl-
purifications. alanine derivative immobilized on solid support with alde-
hydes and olefins using only 0.1 mol% of Yb(OTf)3 in aceto-
C8F17O2SO CHO
C8F17O2SO nitrile (Scheme 106).136 Treatment of the resulting resin-
Yb(OTf)3 (1 mol%) H
EtOH
N bound product with 15% TFA in dichloromethane gave tet-
+
MW, 50 °C, 20 min
rahydroquinolines in 60–90% yields. This methodology was
i-PrCHO i-Pr R
H2N R extended to solid-supported synthesis of tricyclic tetrahy-
OEt
74–89% droquinolines by the concomitant formation of the Schiff
R = H, OMe
base followed by intramolecular trapping of the alkene.
Scheme 103 Yb(OTf)3-catalyzed microwave-assisted fluorous-phase
synthesis of tetrahydroquinoline derivatives

O O O OH
The Su research group synthesized 2,2,4-trimethyl-1,2- O O
dihydroquinolines by the reaction of anilines with acetone Yb(OTf)3 (0.1 mol%) NHCOPh NHCOPh
NHCOPh MeCN/CH2Cl2 TFA
catalyzed by Yb(OTf)3 in the ionic liquid [bmim][BF4]
(Scheme 104).134 The reusability of solvent and catalyst, R3CHO R1 R1
+
good yields of quinolines, and the mild reaction conditions R1 R2 HN HN
R2 R2
are the salient features of this methodology. NH2
Ph Ph
R1 = H, Me
R2 = 4-MeOC6H4, 3,4-(MeO)2C6H3, 3,6-Me2C6H3
NH2 O
Yb(OTf)3 (10 mol%), [bmim][BF4] R1–R2 = CH2CH=CH
R R R3 = Ph, 4-ClC6H4, 3-MeOC6H4, 4-O2NC6H4
+
r.t., 30 min N
R = H, 2-Me, 3-Me, 4-Me, 2-Et,
H Scheme 106 Yb(OTf)3-catalyzed solid-supported synthesis of polysub-
2-Cl, 4-Cl, 4-Br, 2-CO2Me 62–81% stituted tetrahydroquinolines
Scheme 104 Yb(OTf)3-catalyzed synthesis of 2,2,4-trimethyl-1,2-dihy-

droquinolines in ionic liquid
Janda and co-workers synthesized a resin-bound
Yb(OTf)3 that was successfully used for the synthesis of tet-
Cyclization of an N-silylenamine with 2-methylene-1,3- rahydroquinoline adducts via aza-Diels–Alder reaction of
cyclohexanediones catalyzed by Yb(OTf)3 provided an ex- an imine and a vinyl ether (Scheme 107).137 The resin-
cellent strategy for the synthesis of 2,3-disubstituted bound catalyst was easily recycled and used many times
5,6,7,8-tetrahydroquinolin-5-ones in moderate to good without any loss of activity.
yields (Scheme 105).135 Lewis acids were used as an addi-
OEt
tive to activate the carbonyl group of the starting diones.
When the reaction was carried out in the presence of a cat- N Ph Yb(OTf)3–P/S resin (10 mol%)
alytic amount of Hf(OTf)4 or Yb(OTf)3, the cyclization pro- MeCN/CH2Cl2, r.t., 1 h N Ph

H
ceeded at room temperature to afford the corresponding OEt
93%
tetrahydroquinolin-5-one derivatives in moderate to good trans/cis = 13:87
yields. Surprisingly, Yb(OTf)3 showed higher efficiency even Scheme 107 Synthesis of tetrahydroquinolines using resin-bound
at low concentration (2 mol%) and afforded good product Yb(OTf)3
yields.
O
O O Yb(OTf)3 (2 mol%) Kobayashi et al. reported an Yb(OTf)3-catalyzed aza-
R1 R1
1,4-dioxane Diels–Alder reaction for the convenient synthesis of tetra-
R3
TMSHN R2 r.t., 40 h
R2 N hydroquinoline and dihydropyridin-4-one derivatives
R3 R3 R3
(Scheme 108).138 The authors demonstrated a unique reac-
34–77%
tivity of imines as dienes as well as of dienophiles under
R1 = 2-pyridyl, 3-methyl-5-isoxazolyl, CONMe2, CO2t-Bu
R2 = Ph, 4-MeOC6H4, 4-ClC6H4, n-Bu, 2-pyridyl certain conditions to yield the tetrahydroquinolines in good
R3 = H, Me to excellent yields. In addition, aniline on reaction with
Scheme 105 Yb(OTf)3-catalyzed synthesis of tetrahydroquinolin-5- phenylglyoxal hydrate and Danishefky’s diene gave the cor-
one derivatives responding N-phenylpyridin-4-one derivative in 76% yield.
AA
R3 R4 obtained in good yields with high selectivities. Further

R3 Yb(OTf)3
R1 N MeCN
R1 studies while screening an array of dienophiles indicated
+
R2 R4 that when imines reacted with cyclopentadiene as the di-
N R2
R1 = H, OMe, Cl H enophile, Yb(OTf)3 provided 56% yield of the cycloaddition
66–98%
R2 = Ph, CO2Me product, whereas BF3·OEt2 resulted in only traces of ad-
R3 = OMe, OEt, SPh, OTMS
R4 = Me, Ph
ducts.141 When Danishefsky’s diene was treated with
imines under the reaction conditions, the corresponding
O
NH2 O Yb(OTf)3 tetrahydropyridine isomer was obtained as the sole prod-
OTMS MeCN
+
Ph
OH uct with either of the two catalytic systems; this product is
+ Ph
OMe
OH N the result of the cycloaddition taking place with the imine
Ph O
acting as the dienophile. The final tetrahydroquinolines
76%
were treated under acidic conditions to provide the aroma-
Scheme 108 Yb(OTf)3-catalyzed synthesis of tetrahydroquinoline and
tized 2-trifluoromethylquinolines in good yields.
pyridin-4-one derivatives via aza-Diels–Alder reaction

R2
OMe R1 OMe
A three-component reaction of 1,4-phenylenediamine + R1 R2
Yb(OTf)3, MeCN
with aryl aldehydes and aryl acetylenes was successfully F3C N r.t., 0.25–6 h
F3C N
H
catalyzed by Yb(OTf)3 to yield novel N-arylmethyl-6-amino-
R1 = H 56–90%
2,4-diarylquinolines (Scheme 109).139 The domino process R2 = Et, Bu, SPh, NHCO2Bn, Ph cis: 64 to >98%
was expected to proceed via Povarov reaction, dihydroquin- R1–R2 = OCH2CH2, NHCH2CH2
oline oxidation and imine reduction. Among the twelve cat- Scheme 110 Yb(OTf)3-catalyzed synthesis of trifluoro-substituted tet-
alysts screened, Yb(OTf)3 proved to be an effective Lewis rahydroquinoline derivatives
acid to afford good yields of the tandem products. The au-
thors successfully demonstrated further functionalization 6.7 Isoquinoline
of the products by deprotection of the N-benzyl group and
a second Povarov reaction catalyzed by Yb(OTf)3 to achieve The Pictet–Spengler reaction is one of the most widely
symmetrical as well as unsymmetrical anthrazolines. used methods for the synthesis of tetrahydroisoquinoline
derivatives. It proceeds by way of a two-step methodology
R1 R1 involving acid-catalyzed condensation of an aliphatic amine
R2
NH2 N with an aldehyde followed by cyclization.142 Kobayashi and
CHO
Yb(OTf)3 (5 mol%), MeCN co-workers screened several catalyst systems for such a
+
80 °C, 14 h N
H
synthesis of tetrahydroisoquinoline derivatives and found
NH2 R1
R2 that a catalytic amount of Yb(OTf)3 in the presence of a de-
26–61%
R1 = H, 4-Me, 4-OMe, 3,4,5-(OMe)3, (i) Pd/C, HCO2NH4 hydrating agent, such as molecular sieves, at room tempera-
4-F, 4-Cl, 3-NO2, 4-NO2 1 2
(ii) Ar CHO, Ar CCH R1 = H ture were the optimal conditions (Scheme 111).143 The re-
R2 = Ph, 4-n-BuC6H4, 4-n-PentC6H4, Yb(OTf)3 (5 mol%)
4-MeOC6H4 MeCN, 80 °C, 14 h
sults suggest that the regioselectivity in the Pictet–Spengler
Ar2 reaction was determined by kinetic control rather than
N thermodynamic control.
Ar1 = Ph, 4-MeC6H4 Ar1 N
Yb(OTf)3 (10 mol%) HO
Ar2 = Ph, 4-t-BuC6H4
HO MS 3 Å, CH2Cl2
48–62% + RCHO NH
NH2 25 °C, 24 h
R
Scheme 109 Yb(OTf)3-catalyzed Povarov reaction for the synthesis of R = Ph, 4-t-BuC6H4, 2-pyridyl, i-Bu 90–99%
N-arylmethyl-6-amino-2,4-diarylquinolines
Scheme 111 Yb(OTf)3-catalyzed synthesis of isoquinoline derivatives
via Pictet–Spengler reaction
Bégué and co-workers used Yb(OTf)3 for the synthesis of
tetrahydroquinoline derivatives bearing an α-trifluoro- Ethyl 1,2,3,4-tetrahydroisoquinoline-1-carboxylates
methyl group at the C-2 position, by an intermolecular were synthesized in moderate to good yields by the reac-
[4+2] cycloaddition of the α-trifluoromethyl-N-arylaldi- tion of N-toluenesulfonyl-β-phenethylamines with ethyl
mine, derived from trifluoroacetaldehyde and p-anisidine, chloro(phenylselanyl)acetate in the presence of a catalytic
with electron-rich alkenes (Scheme 110).140 The reaction amount of Yb(OTf)3 in dichloroethane (Scheme 112).144
occurred cleanly at room temperature and the product was
AB
Wei and Zhang also reported an Yb(OTf)3-catalyzed tan-

R
SO2Tol dem synthesis of isoquinolines via selective C–C bond
N
H Yb(OTf)3, DCE R
N cleavage followed by Friedel–Crafts cyclization of aziridinyl
OH SO2Tol
reflux
CO2Et
ketones in excellent yields (Scheme 115).120 The selective
Se
Ph OEt
22–81% ring opening by C–C bond cleavage rather than C–N cleav-
Cl
age in the aziridines provided synthetically useful isoquino-
R = Cl, Br, OMe, H lines, which can undergo further transformations like al-
Scheme 112 Yb(OTf)3-catalyzed synthesis of ethyl 1,2,3,4-tetrahy- kylation and elimination.
droisoquinoline-1-carboxylates
O OH
MeO CO2Et Yb(OTf)3 (10 mol%) MeO CO2Et
CH2Cl2
N Ts
The intramolecular Friedel–Crafts reaction of aryl-sub- MeO Ar
4 Å MS, 25 °C, 15 h MeO
NTs
stituted propargylic alcohols using FeCl3·6H2O or Yb(OTf)3 OMe OMe Ar

as catalyst gave functionalized tetrahydroisoquinolines

Ar = Ph, 4-ClC6H4, 4-BrC6H4, 4-O2NC6H4, 4-i-PrC6H4 55–89%
(Scheme 113).145 A higher yield of the tetrahydroisoquino- Scheme 115 Yb(OTf)3-catalyzed synthesis of isoquinolines from
line was obtained from the methylsulfonyl-substituted sub- aziridinyl ketones
strate as compared to the benzylamino-substituted propar-
gylic alcohol containing a phenylsulfonyl group. Reaction 6.8 Benzothiazine
conditions such as reaction time and moisture had to be
controlled in the case of FeCl3·6H2O being used as the cata- A chemoselective methodology for the synthesis of bio-
lyst. On the other hand, Yb(OTf)3 proved effective and was active 2-amino-3,1-benzothiazines was achieved by the
found to be a better choice for the large-scale syntheses of Yb(OTf)3-catalyzed reaction of o-aminocinnamate with iso-
this type of product. thiocyanates under solvent-free conditions (Scheme
116).147 The reaction was believed to proceed through for-
mation of the thiourea, which would then undergo a thia-
OH Yb(OTf)3 (5 mol%), MeNO2 Ph Michael addition type reaction from the S-terminal of hte
N
Ph C thiourea to form the 2-amino-3,1-benzothiazine. Aryl iso-
Ph 70 °C, 0.5–3 h N Ph
SO2R thiocyanates with both electron-deficient and electron-rich
RO2S
R = Ph, 4-ClC6H4, 4-BrC6H4, 4-O2NC6H4, Me 79–90% substituents were well tolerated and gave good yields of the
corresponding products. On the other hand, lower yields
Scheme 113 Yb(OTf)3-catalyzed synthesis of tetrahydroisoquinolines
via intramolecular Friedel–Crafts reaction of aryl-substituted propargyl- were obtained from alkyl isothiocyanates and extended re-
ic alcohols action times were required.
N NHR
NH2
Yb(OTf)3 (1 mol%), neat
The one-pot synthesis of cis-isoquinolonic acid deriva- + RNCS
S
50–70 °C, 4–48 h
tives was achieved by the multi-component reaction of ho- OEt
mophthalic anhydride with aldehydes and amines at ambi- CO2Et
O
ent temperature in the presence of Yb(OTf)3 in good to ex- R = Ph, 4-FC6H4, 4-ClC6H4, 4-BrC6H4, 4-O2NC6H4, 79–98%
4-MeC6H4, 4-MeOC6H4, 3-MeOC6H4, 3-ClC6H4,
cellent yields (Scheme 114).146 Among the various catalysts 2-ClC6H4, 2-FC6H4, Me, c-Hex
tested for the model reaction of homophthalic anhydride Scheme 116 Yb(OTf)3-catalyzed synthesis of bioactive 2-amino-3,1-
with benzaldehyde and aniline, Yb(OTf)3 was found to be benzothiazines
optimal in affording the corresponding cis-1-oxo-2,3-di-
phenyl-1,2,3,4-tetrahydro-4-isoquinoline carboxylic acid in
high yield without formation of any trans-isomer. 6.9 Quinazoline
O
O
Yb(OTf)3 (2 mol%) The Wang research group reported an Yb(OTf)3-cata-
R2
O
R1CHO R2NH2
CH2Cl2 N
H
lyzed one-pot synthesis of quinazolin-4(3H)-ones by the re-
r.t., 2 h
O R1 action of anthranilic acid with amines and orthoesters un-
H
COOH der solvent-free conditions (Scheme 117).148 The relatively
R1 = Ph, 4-MeOC6H4, 4-Me2NC6H4, n-Pr, i-Pr, 78–93%
2-MeC6H4, 2-O2NC6H4, 4-O2NC6H4 short reaction time, the reusability of the catalyst, and ex-
R2 = Ph, Bz, 4-MeC6H4, 3,4-Me2C6H3, i-Pr,
cellent product yields were the main advantages of this
c-Hex, 4-ClC6H4, 4-BrC6H4
method. Yb(OTf)3 provided better results than other lantha-
Scheme 114 Yb(OTf)3-catalyzed synthesis of cis-isoquinolonic acid de- nide triflates and traditional Lewis acids such as ZnCl2,
rivatives
AlCl3, and SnCl2.
AC
O 7.1 Furo[3,4-b]pyran
CO2H
Yb(OTf)3 R2
N
HC(OR1)3 R2NH2
60–80 °C, 2–5 h Trans-fused bicyclic γ-lactones were synthesized in the
NH2 N
presence of a catalytic amount of Lewis acid. The intramo-
75–99%
R1 = Me, Et lecular hetero-Diels–Alder reaction of a β-alkoxy-substitut-
R2 = Ph, 2-MeC6H4, 3-MeC6H4, 4-MeC6H4, 3,4-Me2C6H3,
4-EtC6H4, 3-MeOC6H4, 4-MeOC6H4, 2-ClC6H4, 3-ClC6H4, ed conjugated nitroalkene with δ,ε-unsaturated alcohols in
4-ClC6H4, 4-FC6H4, 2-O2NC6H4, Bn, 3-O2NC6H4, the presence of Yb(OTf)3 proceeded stereoselectively to af-
4-O2NC6H4, 2,4-(O2N)2C6H3
ford bicylic nitronates that were finally transformed into
Scheme 117 Yb(OTf)3-catalyzed one-pot synthesis of quinazolin- the corresponding γ-lactones in good yields (Scheme
4(3H)-ones
119).152 The intermediate nitronate was isolated by adding
molecular sieves (4 Å) to the reaction mixture. With the use
6.10 Quinoxaline of TiCl4 as a Lewis acid, the desired product was not ob-
tained, whereas in the absence of the catalyst Yb(OTf)3 (10
Wang et al. demonstrated Yb(OTf)3 to be a superior mol%) at high temperature, the reaction proceeded to form

Lewis acid that was efficient in catalyzing Phillips-type het- the desired product in very low yield. Several other Lewis
erocyclization reactions of o-phenylenediamines and alkyl acids such as Sc(OTf)3, Hf(OTf)3, Cu(OTf)2, Cu(ClO4)2·6H2O
oxalates to give quinoxaline-2,3-diones under solvent-free and Zn(ClO4)2·6H2O were also screened; they were all found
conditions (Scheme 118).149 Various reactive functionalities to be effective promoters, but the best results were ob-
were well tolerated and the corresponding quinoxaline-2,3- tained by using Yb(OTf)3 or Ni(ClO4)·6H2O.
diones were obtained in good yields. The catalyst was re-
O
covered from the aqueous layer and recycled up to three NO2 Yb(OTf)3 (10 mol%) R3
O
H R3
O
H
EtO CH2Cl2 N O R2
times without much decrease in the efficiency. Venable et R2 O
r.t. R1 O
al. coupled methyl trimethoxyacetate with o-phenylenedi- R2 R3 R1
R1 H R1 H
amines using a catalytic amount of Yb(OTf)3 to yield 3- OH
38–68%
R1 R1
methoxyquinoxalin-2-ones in moderate to good yields.150
R1, R2, R3 = H, Me
The reaction proceeded regioselectively, resulting in only
the single isomer when 3-substituted 1,2-phenylenedi- Scheme 119 Yb(OTf)3-catalyzed synthesis of γ-lactones from β-alkoxy-
amines were subjected to the reaction conditions. Recently, nitroalkenes
Kumar and co-workers also reported an acid-catalyzed mi-
crowave-assisted synthesis of 2-phenylimidazo[1,2-a]pyr- Wang and co-workers explored the catalytic activity of
idylquinoxalin-2(1H)-ones via Hinsberg heterocyclization Yb(OTf)3 in the electrophilic cyclization of some glyoxalate-
between 2-phenylimidazo[1,2-a]pyridine-3-glyoxalates derived unsaturated imines to obtain fused amino γ-lactone
and o-phenylenediamine.151 Montmorillonite K-10 and products. The reaction proceeded stereoselectively, with
Yb(OTf)3 were found to be effective catalysts for this hetero- the trans-isomer as the primary product (Scheme 120).153
cyclization reaction. This preference was explained by the transition state favor-
ing the ester moiety in an equatorial position.
OMe
MeO OMe R2O O
R1 R1 R1 R1 R1
NH2 R1 H
N OMe N O
MeO O R2O O O i) Na2SO4, CH2Cl2
NH NH
n NH3 ii) Yb(OTf)3 (10 mol%) n n
Yb(OTf)3 Yb(OTf)3 OEt
N O NH2 N O H
H (10 mol%) (5 mol%) O O
H
toluene 80 °C, 1 h O
52–78% 78–89% O O
100 °C, 4 h R2
R1 = 3-Cl, 5-CF3, 3-Me, R1 = H, Me, NH2, Cl, NO2 n = 1, 2 a 23–72% b
3-NO2, 4,5-Cl2, 5-Cl, 5-CF3 R2 = Et, i-Pr, n-Bu R1, R2 = H, Me a/b = 1:3 to 10:1
Scheme 118 Yb(OTf)3-catalyzed synthesis of quinoxaline-2,3-diones Scheme 120 Yb(OTf)3-catalyzed synthesis of to γ-lactones from glyox-
and quinoxaline-2-ones alate-derived unsaturated imines
7 Synthesis of Non-benzenoid Fused Het- 7.2 Furo[2,3-c]oxazines

erocycles
Pagenkopf and co-workers reported the Yb(OTf)3-cata-
Yb(OTf)3 has also been effectively used as catalyst for lyzed [4+2] cycloaddition of donor–acceptor cyclobutanes
the synthesis of a large number of non-benzenoid fused and nitrosoarenes to give furo[2,3-c]- and furo[3,2-e]tetra-
heterocycles. This section provides a brief overview of these hydro-1,2-oxazines (Scheme 121).154 Excellent regioselec-
Yb(OTf)3-catalyzed reactions. tivity was observed except for a few electron-deficient ni-
AD
trosoarenes, and the products were obtained in good to ex- 2,3-dihydrofuran or 3,4-dihydro-2H-pyran) and trimethyl
cellent yields as single diastereomers. From among the orthoformate in the presence of a catalytic amount of
other metal triflates screened, Yb(OTf)3 provided the maxi- Yb(OTf)3 at ambient temperature (Scheme 123).156
mum yields. The formation of one regioisomer indicated
OMe
that the nitrogen, and not the oxygen, of the nitroso func- H
CHO Yb(OTf)3
tional group was acting as the nucleophile. R
CH2Cl2
R
+ + CH(OMe)3 n
O n r.t. O
OH H
H CO2Et
O R = H, Br, OMe, OEt, OBn 75–92%
CO2Et R
n = 1, 2
Yb(OTf)3 H H
O N O O R
H
(2–10 mol%) O
CO2Et +
N
CO2Et
Scheme 123 Yb(OTf)3-catalyzed synthesis of furo[2,3-b]benzopyrans
+
N
CH2Cl2, r.t. and pyrano[2,3-b]benzopyrans
R O H CO2Et H CO2Et
R = Ph, 4-BrC6H4, 4-ClC6H4, 3-BrC6H4, 3-ClC6H4,

29–93% (d.r. 3:1 to >20:1)
7.4 Furo[3,2-f]chromene
4-AcC6H4, 3-AcC6H4, 4-EtO2CC6H4, 2,4-Br2C6H3,

3,4-Cl2C6H3, 4-O2NC6H4, 4-MeC6H4, 4-MeOC6H4,
4-NCC6H4 Alvey et al. synthesized various furo[3,2-f]chromenes by
Scheme 121 Yb(OTf)3-catalyzed synthesis of furo[2,3-c]- and furo[3,2-
the reaction of quinonemethides, generated in situ from the
e]tetrahydro-1,2-oxazines reaction of 4-formyl-5-hydroxybenzofurans and trimethyl
orthoformate, with 2-methylpropene in the presence of a
catalytic amount of Yb(OTf)3 (Scheme 124).157 The reaction
Pagenkopf and co-workers also reported the [4+3] cyc- proceeded through formation of the o-quinonemethide fol-
loaddition of 2-alkoxy-1,1-dicarboxylate activated donor– lowed by [2+4] cycloaddition reaction with the alkene to
acceptor cyclobutanes with a variety of nitrones to yield generate the pyran ring. The thus-synthesized furo[3,2-
2,3,4,6,7-substituted oxazepines in moderate to high yields f]chromenes were evaluated for antimycobacterial activi-
(Scheme 122).155 In most of the cases, either a diastereo- ties.
meric mixture (at 0 °C) or a single diastereomer (at 22 °C)
R1 CHO
was obtained in varying yields. Surprisingly, when naphth-
OH
OMe
yl- or cinnamyl-substituted nitrones were subjected to the R2 Yb(OTf)3 (5 mol%) R1
CH2Cl2
reaction conditions, only a single diastereomer was ob- O O
served rather than a diastereomeric mixture, similar to the + 25 °C, 60 h, then TSA R2
reflux, 1 h O
HC(OMe)3
results obtained with N-alkyl substitution. A pyran-fused
R1 = H
cyclobutane and ethoxy-substituted cyclobutane were
R2 = H, Me, 6-bromo-2-pyridyl,
found to react with nitrones to produce the corresponding 6-bromo-3-pyridyl, Ph
R1–R2 = (CH2)4
diastereomeric oxazepine cycloadducts in varying ratios.
R1
O
H R2
Ph O–
EtO2C CO2Et Yb(OTf)3 Ph O R2 O
N+ 4 Å MS, CH2Cl2 N
R3 11–56%
+ R2
R1 0–22 °C, 0.25–25 h R1 H Scheme 124 Yb(OTf)3-catalyzed synthesis of furo[3,2-f]chromenes
R3 CO2Et
EtO2C
R1 = Ph, 4-OMeC6H4, 4-ClC6H4, CH=CHPh, 2-naphthyl 43–95%
R2 = OEt
3
7.5 Pyrrolo[3,4-b]quinoline
R =H
R2–R3 = OCH2CH2, OCH2CH2CH2
The Yb(OTf)3-catalyzed cyclization of N-cinnamoyl-α-
Scheme 122 Yb(OTf)3-catalyzed synthesis of oxazepines by [4+3] cy-
cloaddition of donor–acceptor cyclobutanes with nitrones aminoaldehydes with different aromatic amines led to the
formation of a tricyclic product, the corresponding hexahy-
dro-1H-pyrrolo[3,4-b]quinolin-1-one as a mixture of dia-
7.3 Furo[2,3-b]benzopyran and Pyrano[2,3-b]ben- stereomers with stereoselectivities favoring the more stable
zopyran anti–trans–anti product (Scheme 125).158 A mild Lewis
acid, triflic acid, was also tested but was too harsh for the
Furo[2,3-b]benzopyrans and pyrano[2,3-b]benzopyrans protected amino acid analogue. Cyclization of the less bulky
were synthesized in excellent yields with high diastereose- O-tert-butylserine derivative was less selective.
lectivity by cyclization of o-hydroxybenzaldehydes with
AE
R1 O S N R4
NH2 R1 S
O H R1 NH2
Yb(OTf)3 (5 mol%), silica gel
DMB Yb(OTf)3 (0.2 equiv) N R1
N MeCN + R4
N DMB MW, 300 W, 5 min R3
R2
O R2 CN R3 R2
25 °C NH2
R3 R3
R2 O R1 = H, Me 75–96%
R1 = O-t-Bu-Tyr, O-t-Bu-Ser, Trp, ε-Boc-Lys, Leu, Phe 63–93% R2 = Me, 4-ClC6H4
R2 = 4-MeOC6H4, 4-FC6H4 R1–R2 = (CH2)4, (CH2)3
3
R = H, 4-OMe, 4-F R3 = Me, Ph, 4-FC6H4, 4-ClC6H4, 3-ClC6H4,
4-MeC6H4, 4-MeOC6H4, 4-O2NC6H4, 2-pyridyl
Scheme 125 Yb(OTf)3-catalyzed synthesis of hexahydro-1H-pyrro- R4 = H, Me
lo[3,4-b]quinolin-1-one; DMB = 2,4-dimethoxybenzyl R3–R4 = (CH2)4, (CH2)3
Scheme 127 Yb(OTf)3-catalyzed synthesis of aminothieno[2,3-b]pyri-

A multicomponent stereoselective synthesis of polysub- dines
stituted hexahydropyrrolo[3,2-c]quinolines was described
in high yields with good stereoselectivities, wherein 7.7 Imidazo[1,2-a]azepine
Yb(OTf)3 was used as a catalyst for the reaction between

two imines and a bis(silyl)dienediolate (Scheme 126).159 Raimondi and co-workers effectively utilized Yb(OTf)3
The reaction was believed to proceed through a novel 1,2- for the synthesis of imidazo[1,2-a]azepines by the reaction
dinucleophilic engagement of the two imines in a sequen- of the corresponding 2,2′-diaryldialdehyde with a 1,2-di-
tial vinylogous Mannich/Mannich/Pictet–Spengler process amine (Scheme 128).161 Other acids such as TiCl4 and triflic
forming four σ-bonds and four stereogenic centers in a one- acid were also screened in this reaction, but the best yields
pot transformation. Out of eight possible diastereomers, were obtained by using Yb(OTf)3.
one major isomer was obtained typically with good yield
and selectivity. N R1
NH2 Yb(OTf)3 (1.0 equiv)
CHO R2 CH2Cl2
PMP N
N CHO R1 R2
25–40 °C, 12 h
EtO2C NH2
R3 H PMP R2
OTMS
R1 N N
Yb(OTf)3
R3 23–93%
R2 OEt NH R1, R2 = Ph
TFA R1–R2 = (CH2)4
OTMS
1
H R
R1 = Ph, 4-MeC6H4, 4-MeOC6H4, 4-t-BuC6H4, 3-furyl 50–88% Scheme 128 Yb(OTf)3-catalyzed synthesis of imidazo[1,2-a]azepines
R2 = H, 4-MeO, 4-Me2N, 2-MeO up to 98% de
R3 = Ph, 4-MeC6H4, 3-MeC6H4, 4-t-BuC6H4, 4-
MeOC6H4, 7.8 Imidazo[4,5-c]quinoline
4-ClC6H4, 4-FC6H4, 4-NCC6H4, 3-ClC6H4, 2-naphthyl,
2-furyl, 2-thienyl, c-Hex, t-Bu
Recently, Bhattacharya and co-workers reported an effi-
Scheme 126 Yb(OTf)3-catalyzed synthesis of hexahydropyrrolo[3,2-
c]quinolines; PMP = p-methoxyphenyl cient protocol for the synthesis of 1,4-diaryl-substituted
imidazo[4,5-c]quinolines through a modified Pictet–
Spengler reaction of 2-(1-aryl-1H-imidazol-5-yl)aniline
7.6 Thieno[2,3-b]pyridine with aromatic aldehydes using 20 mol% of Yb(OTf)3 as a cat-
alyst (Scheme 129).162 The reaction involves the formation
Aminothieno[2,3-b]pyridines were efficiently synthe- of the imine followed by electrophilic attack on the imidaz-
sized by the reaction of 2-aminothiophene-3-carbonitriles ole ring at the C4-position. Finally, aerial oxidation results
and ketones in the presence of Yb(OTf)3 (Scheme 127).160 in the formation of desired product.
The reaction was carried out under microwave irradiation
under solvent-free conditions and silica gel was employed R1 R1
as a supporting medium. The products were obtained in N N

short reaction times with good to excellent yields. Yb(OTf)3 R2
N
Yb(OTf)3, PhNO2 R2 N
gave the best results among all the catalysts screened. The + R4CHO
150 °C
catalyst can be reused and recycled without much loss in R3 NH2 R3 N R4
activity up to three times. The reaction was believed to pro- R1 = H, Cl 44–77%
ceed through an SN2-type pathway. R2 = H, OMe

R3 = H, CF3, OMe
R4 = Ph, 4-MeC6H4, 4-F3CC6H4, 4-NCC6H4, 4-MeOC6H4, 2-HOC6H4,
3-HOC6H4, 4-HOC6H4, 6-HOC6H4, 4-FC6H4, 2-thienyl
Scheme 129 Yb(OTf)3-catalyzed synthesis of imidazo[4,5-c]quinolines

by a modified Pictet–Spengler approach
AF
7.9 Oxazolo[3,4-a]pyridine 7.11 Imidazo-Fused Heterocycles
In 2014, during the total synthesis of a naturally occur- A two-step one-pot procedure was developed by
ring iminosugar, castanospermine, a palladium-catalyzed Ninkovic and co-workers for the synthesis of fused imidaz-
intramolecular C−H allylic oxidation with a piperidinyl N- oles from o-aminonitro(hetero)aryl compounds and triethyl
carbamate (as an O-nucleophile) yielded an oxazolidinone- orthoformate (Scheme 132).166 Brief investigations, to find
fused piperidine derivative (Scheme 130).163 It was found the most suitable catalytic system, revealed that iron pow-
that reaction was promoted by a catalytic amount of der and acetic acid along with a catalytic amount of
Yb(OTf)3. The presence of a Lewis acid was crucial; without Yb(OTf)3 was optimal for this one-pot sequential synthesis
it, only trace amounts of product were isolated. Sc(OTf)3 and offered a series of fused imidazoles in good to excellent
was found to be equally effective for this transformation, yields.
whereas Zn(OTf)2 was much less effective.
NO2 Fe/Yb(OTf)3 (3 mol%) N
Ar/ OEt AcOH Ar/
R HetAr + HetAr

NH2 EtO OEt 75 °C, 2 h N
O O O O O H
O
Ph S S Ph 20–99%
N Ar = benzo, 4,5-Me2C6H2, 5-MeOC6H3, 4-
Pd(OAc)2 N NCC6H3, 5-F3CC6H3, 4,5-Cl2C6H3
HetAr = pyridyl, pyrazinyl, thienyl, isooxazolyl
Yb(OTf)3, benzoquinone
BnO OBn BnO OBn
OBn
Scheme 132 Yb(OTf)3-catalyzed synthesis of fused imidazoles
OBn (–)-castanospermine
R = Bn, Et, t-Bu 30–70%

Snider and Liu developed a short and convergent route
Scheme 130 Yb(OTf)3-catalyzed synthesis of piperidinyl N-carbamate
for the synthesis of (±)-deoxypenostatin A. Therein, the
Yb(OTf)3-mediated intramolecular Diels–Alder reaction of a
7.10 Pyrido[3,4-b]indole hydrated trienyl glyoxylate was found to be the key step
that yielded the corresponding lactone in high stereoselec-
Ganesan and Srinivasan performed a Lewis acid cata- tivity (Scheme 133).167 The minor isomer was expected to
lyzed Pictet–Spengler reaction of tryptophan methyl ester be formed via initial Diels–Alder reaction followed by pyran
and tryptamine with aliphatic and aromatic aldehydes un- ring opening to the cyclopentadienyl cation. Fortunately,
der microwave irradiation to obtain 2,3,4,9-tetrahydro-1H- isomerization was suppressed in the presence of 2,6-di-
pyrido[3,4-b]indoles (Scheme 131).164 A catalytic amount of tert-butylpyridine. Substrates containing sensitive func-
Yb(OTf)3 showed higher efficiencies for this transformation tionalities, such as ketals, underwent hydrolysis under the
than the other Lewis acids tested, including In(OTf)3, reaction conditions.
Sm(OTf)3, YbCl3, Sc(OTf)3, Ce(OTf)3, YCl3, InCl3, Zn(OTf)2,
H
AlCl3 and TiCl4. The addition of an ionic liquid such as O O
[bmim]Cl–AlCl3 was found to be an effective additive for the H H
reactions of less reactive tryptamine and aldehydes. The H

O
H
O
H
Yb(OTf)3 (20 mol%)
Nakagawa research group also reported an Yb(OTf)3/TMSCl- O CHO MeCN/CH2Cl2 C7H15
major
catalyzed Pictet–Spengler reaction on indole-based ni- H 2,6-di-tert-butylpyridine
deoxypenostatin A
+
trones or imines to synthesize tetrahydro-β-carbolines or 25 °C, 18 h
H
O O
tetrahydropyrido[3,4-b]indoles in excellent yields.165 Use of C7H15
H H
either Yb(OTf)3 or TMSCl alone as catalyst resulted in lower O
H
yields. H
C7H15
H minor
Yb(OTf)3 (10 mol%) N R2
R1
CH2Cl2 Scheme 133 Yb(OTf)3-mediated intramolecular Diels–Alder reaction
R2CHO
NH3 100 °C, MW, 30 min NH of a hydrated trienyl glyoxylate
N
H
R1
R1 = H, CO2Me 85–96%
R2 = Ph, 4-O2NC6H4, 4-MeOC6H4, c-Hex, 3,4,5-(MeO)3C6H2 7.12 Cyclopenta[b][4,7]phenanthroline
Scheme 131 Yb(OTf)3-catalyzed synthesis of 2,3,4,9-tetrahydro-1H-
pyrido[3,4-b]indoles via Pictet–Spengler reaction Wang and co-workers described the Yb(OTf)3-catalyzed
three-component reaction of aromatic aldehydes, quinolin-
6-amine and cyclopentane-1,3-dione for the synthesis of
8,9-dihydro-11-aryl-7H-cyclopenta[b][4,7]phenanthrolin-
10(11H)-ones (Scheme 134).168 Yb(OTf)3 was found to be
AG
superior to other catalysts such as Ag(OTf), Cu(OTf)2, R2 O R3

R2
Zn(OTf)2, Y(OTf)3, and Fe(OTf)2, and it provided good yields N
MeO2C
of the phenanthrolinone derivatives. Yb(OTf)3 (10 mol%) N
MeO2C
toluene R1
+
O 4 Å MS, r.t., 10 min
R3 O
O MeO2C CO2Me
42–68%
NH2 Ar
ArCHO + + TfOH CH2Cl2
NH
reflux, 10–16 h
N R1 R3 R1
O
R1 = Ph, 4-MeC6H4, 4-ClC6H4, n-Pr
Ar = 2-FC6H4, 2-ClC6H4, 4-ClC6H4, 3-BrC6H4, 4-BrC6H4, 4-MeC6H4, N O
R2 = Ph, 4-ClC6H4, 4-MeOC6H4 N
3-MeOC6H4, 3,4-Cl2C6H3, 2,3-Cl2C6H3, 2,4-Cl2C6H3, 3,4-Me2C6H3 82–92%
R3 = H, Br, OMe
R2
Scheme 134 Yb(OTf)3-catalyzed synthesis of 8,9-dihydro-11-aryl-7H- MeO2C CO2Me
cyclopenta[b][4,7]phenanthrolin-10(11H)-ones
79–85%
Scheme 136 Yb(OTf)3-catalyzed synthesis of piperidine derivatives

7.13 Pyrido[2,3-c]coumarin

from nitrones
The use of Yb(OTf)3 for the cycloaddition reaction of 2-

azadienes with various electron-rich alkenes afforded 7.14 Benzo[h][1,6]naphthyridine
1,2,3,4-tetrahydropyrido[2,3-c]coumarins as endo/exo dias-
tereomeric mixtures in moderate to excellent yields Menéndez and co-workers reported an Yb(OTf)3-cata-
(Scheme 135).169 A series of 1,2,3,4-tetrahydropyrido[2,3- lyzed Povarov reaction of 1,4-dihydropyridines with imines
c]coumarins were also synthesized by a three-component for the synthesis of hexahydrobenzo[h][1,6]naphthyridines
version of this reaction, involving in situ formation of the 2- (Scheme 137).171 The reaction generated three adjacent ste-
azadiene by condensation of the 3-aminocoumarin with an reocenters. The two diastereomers obtained both possessed
aldehyde. The corresponding pyrido[2,3-c]coumarins were a cis arrangement between the two ring-fusion hydrogens;
formed upon oxidation of the Povarov adducts with various these were also cis with respect to the carboxylate group in
oxidizing agents. the major diastereomer.
R4 R2
R1 CO2Et R1 CO2Et
R1 R4 N N
Yb(OTf)3 (5 mol%), MeCN H
N Yb(OTf)3 (10 mol%)
+ R2
R3 R1 R2 NH MeCN
r.t. to reflux, 5 min to 8 h R2 H
O O R3 + r.t., 1.5 h
N CO2Et
O O H
N CO2Et
R1 = H 25–90% R3
2
R = PhS, EtO, Ph, 4-BrC6H4, 4-MeOC6H4 R1 = allyl, n-Bu R3 61–75%
R1–R2 = OCH2CH2CH2, OCH2CH2 R2 = H, Me
R3 = H, 8-OMe, 6-Br, 6-NO2, 6-OMe R3 = Me, OMe
R4 = 2-naphthyl, 3-coumaryl, 4-MeO2CC6H4 4-O2NC6H4, 4-Ac-N-(CO2Me)pyrrol-2-yl
Scheme 137 Yb(OTf)3-catalyzed synthesis of hexahydroben-
Scheme 135 Yb(OTf)3-catalyzed synthesis of 1,2,3,4-tetrahydropyri- zo[h][1,6]naphthyridines
do[2,3-c]coumarins
Yb(OTf)3-catalyzed [3+3] cycloaddition of substituted 7.15 Triazaacenaphthylene

1,1-vinylidenecyclopropane diesters with nitrones led to
regioselective formation of the piperidine derivatives, that An efficient and convenient approach was developed by
underwent ring closure to afford the indole derivatives in Sun et al. for the synthesis of 3-aminoimidazo[1,2-a]pyri-
the presence of trifluoromethanesulfonic acid in excellent dines or -pyrazines using an Yb(OTf)3-catalyzed one-pot
yields (Scheme 136).170 three-component reaction of 6-alkynyl-2-aminopyridines
or -pyrazines with aldehydes and isocyanides (Scheme
138).172 The synthesized 3-aminoimidazo[1,2-a]pyridine or
-pyrazine derivatives were further converted into function-
alized cycloazines through intramolecular cyclization with
alkynes in a 6-endo-dig fashion in the presence of Ag2CO3;
good to excellent yields were obtained.
AH
X OTMS
Yb(OTf)3 X N N R2
Ag2CO3 X
N NH2 (10 mol%) R3 R3 TMSO OEt Yb(OTf)3 (20 mol%)
EtOH N (10 mol%) N
R1 MeCN/H2O N R1
+ 65 °C, 4 h NH 65 °C, 12 h N R1 NH2 + O r.t., 4 h
R2NC R3CHO R2
R2 EtO2C O
R1 R2 H
1 R1 OH 56–84%
R = Ph, 4-MeC6H4, 4-F3CC6H4, 4-FC6H4, 28–85%
4-MeOC6H4, n-Bu, i-Bu, CH2c-Pent R1 = H, Me, t-Bu, Cl
R2 = 4-MeOC6H4, c-Hex, CH2CO2Et, CH2c-Hex R2 = Ph, 4-MeOC6H4, 4-MeC6H4, 4-t-BuC6H4, 4-
R3= Ph, 4-MeOC6H4, 2-pyridyl, n-Bu NCC6H4,
X = CH, N 4-O2NC6H4, 4-FC6H4, 4-ClC6H4, 3-ClC6H4, 2-ClC6H4,
2-BrC6H4, 2-naphthyl, 2-thienyl, CO2Et, t-Bu, c-Hex
Scheme 138 Yb(OTf)3-catalyzed synthesis of imidazo[1,2-a]pyridines
and imidazo[1,2-a]pyrazines Scheme 140 Yb(OTf)3-catalyzed synthesis of tetrahydropyrrolo[2,1-
b]benzoxazoles
7.16 Pyrazolo[3,4-d]pyrimidine
Kerr and co-workers reported the Yb(OTf)3-catalyzed

Bundy et al. reported that the use of a catalytic amount diastereoselective synthesis of substituted pyrrolo-isoxazo-
of Yb(OTf)3 in the Fischer indolization of pyrimidine hydra- lidines by intramolecular reaction of E-oxime ethers pos-
zones led to the formation of pyrazolo[3,4-d]pyrimidines sessing cyclopropane diesters in excellent yields (Scheme
shown in Scheme 139 instead of the expected pyrrolo[2,3- 141, left).175 A simple reversal of addition order of catalyst
d]pyrimidines.173 Other Lewis acids such as BF3·OEt2, ZnCl2, and substrate resulted in the formation of two discrete
and PCl3 provided only complex and intractable mixtures. diastereomers of the substituted homochiral pyrrolidines in
a highly selective manner from either enantiomer of an
alkoxyamino-tethered cyclopropane diester. In general, the
N N Ar use of the E-isomer gave trans as the only product with the
Ar Yb(OTf)3 (10 mol%), decalin
N N exception of some cases in which minor amounts of the cis
N
N N N
N 190 °C, 4–18 h
N N N product were also obtained. The stereochemical outcome of
the reaction was found to be entirely dependent on the ge-
ometry of the initial oxime ether, and by reversing the order
Ar = Ph, C9N2H7
of addition of the substrate and catalyst, the stereochemical
Scheme 139 Yb(OTf)3-catalyzed synthesis of 2,4-diaminopyrazo- outcome of the reaction itself was reversed. The same re-
lo[3,4-d]pyrimidines
search group also reported the Yb(OTf)3-catalyzed diaste-
reoselective synthesis of structurally complex fused bicy-
7.17 Pyrrolo[2,1-b]benzoxazole and Pyrrolo[1,2- clopyrazolidines using a novel intramolecular annulation of
b]pyrazole hydrazinoethyl 1,1-cyclopropane diesters (Scheme 141).176
Only the 2,5-trans adduct, or a mixture of cis (major) and
Boomhoff and Schneider accomplished the synthesis of trans adducts, was formed, depending upon the order of ad-
novel tetrahydropyrrolo[2,1-b]benzoxazoles through the dition of the catalyst and aldehyde. The Yb(OTf)3-catalyzed
Yb(OTf)3-catalyzed three-component, one-pot [3+2] cy- hydrazone formation between the hydrazine and aldehyde,
cloannulation of a bis(silyl)dienediolate with aldehydes and followed by cyclization, yielded only the 2,5-trans adduct.
2-aminophenols (Scheme 140).174 The reaction generated In contrast, when the Yb(OTf)3-catalyzed formation of pyra-
four new σ bonds and two new stereogenic centers and zolidine occurred first, followed by reaction with the ap-
proceeded with good yields and excellent diastereoselectiv- propriate aldehyde, the result was a mixture of the 2,5-cis
ities. The synthesized benzoxazoles were shown to be high- adduct as the major component, along with the 2,5-trans
ly valuable synthetic intermediates to provide access to ste- adduct as the minor product. The authors also demonstrat-
reochemically controlled proline derivatives. ed that the chirality was maintained when homochiral cy-
clopropanes were employed.
AI
R1 X R1 method A
CO2Et
method A method B
NH2 Yb(OTf)3 (5 mol%) R1
X X R2 R5 R2 CO2Et
N R2 Yb(OTf)3 H MS 4 Å, CH2Cl2, r.t., 3 d
N i) Yb(OTf)3 CO2Et
+
CH2Cl2 R2 CH2Cl2, 30 min R3 N
O O CO2Et
method B R3 N
CO2Me ii) R1R2CO Yb(OTf)3 (5 mol%), MS 4 Å O O R5
R1 MeO2C R4
CH2Cl2 CO2Me toluene, r.t., 8 kbar, 1 d R4
MeO2C CO2Me CO2Me 310
R1 = Ph, 4-MeOC6H4, 4-ClC6H4 method A: 61–92%
R1 = H method A: 75–99% (trans major) R2 = H, Me, Et method B: 5–94%
method B: 50–100% (cis major) R3 = H, Me
R2 = Ph, 4-MeOC6H4,
4-O2NC6H4, 2-naphthyl, R2–R3 = (CH2)4
2-furyl, 3-(N-tosyl)indolyl, R4 = H, Me, CH2Cl, n-Pr, Ph
Hex, i-Pr, t-Bu R5 = Ph, 4-MeOC6H4, 4-ClC6H4, vinyl, (E)-styryl, 2-thienyl
X = O, NH
Scheme 143 Yb(OTf)3-catalyzed synthesis of oxazino[2,3-b]oxazines
Scheme 141 Yb(OTf)3-catalyzed synthesis of pyrrolo-isoxazolidines
7.18 Isoquinolino[2,1-a]quinazoline Oxazino[2,3-b]oxazines have also been synthesized by

the Yb(OTf)3-catalyzed [3+3] cycloaddition of donor–accep-

Pal and co-workers reported a novel Yb(OTf)3-catalyzed tor cyclopropanes with nitronates under high pressure
cascade reaction between isatoic anhydride, amines and o- (Scheme 143, method B).179 The reaction produced bicyclic
alkynyl benzaldehydes for the synthesis of fused quinazoli- nitrosoacetals in good yields and with excellent stereoselec-
nones (Scheme 142).177 It was proposed that initially the N- tivities. 6-Monosubstituted nitronates underwent the cy-
substituted o-aminobenzamide was generated by the reac- cloaddition reaction smoothly, while 6,6-disubstituted ni-
tion of isatoic anhydride with the amine, and then conden- tronates required prolonged reaction times. Nitronates with
sation with the benzaldehyde and further intramolecular bulky substituents at R3 underwent a severe reduction of
C−N bonding sequence resulted in good yields of the fused the reaction rate. Toluene was found to be the most suitable
quinazolinones. These compounds showed inhibition of tu- solvent for this transformation presumably due to the fact
mor necrosis factor-α (TNF-α) in vitro and were expected to that the nonpolar medium decreases the stability of the un-
have potential therapeutic applications. productive nitronate–Lewis acid complex; in addition,
high-pressure reactions that proceed through polar transi-
R1NH2 O
O tion states are usually accelerated when performed in non-
Yb(OTf)3 (10 mol%) R1
OHC
DCE
N polar media.
O +
25–30 °C, 48 h N
N
H
O
R2 R2
7.20 Pyrimido[4,5-b]indole
R1 = Me, c-Pr, 4-MeC6H4, 4-ClC6H4, Bn, 64–78%
HOCH2CH2, 4-FC6H4, Ph, 4-FC6H4CH2 Majumder and Bhuyan reported a solvent-free
R2 = Ph, 4-MeC6H4
Yb(OTf)3-catalyzed one-pot three-component reaction of
Scheme 142 Yb(OTf)3-catalyzed synthesis of fused quinazolinones aromatic aldehydes, oxindoles, and thiourea or urea to syn-
thesize a series of pyrimido[4,5-b]indoles in good yields
7.19 Oxazino[2,3-b]oxazine (Scheme 144).180 The catalyst was recovered and reused
without much loss in activity. The mechanism suggested
Synthesis of oxazino[2,3-b]oxazines, possessing two the formation of a ureide by the Michael addition of urea to
fused six-membered rings, was achieved by Gorbacheva et the Yb(OTf)3-catalyzed cross-aldol condensation product of
al. via [3+3] cycloaddition of 3-methyl-5,6-dihydro-4H-1,2- the aldehyde with the oxindole. Expulsion of water fol-
oxazine-N-oxides (nitronates) with donor–acceptor cyclo- lowed by aerial oxidation of the ureide gave the pyrimidi-
propanes in the presence of Yb(OTf)3 and molecular sieves none derivatives.
(Scheme 143, method A).178 Excellent yields of the bicyclic
compounds were obtained, as well as high stereoselectivi- R1CHO R1
R2
ties. Moreover, Sc(OTf)3 also produced good yields similar to X Yb(OTf)3 (10 mol%) NH
+ neat X
those obtained with Yb(OTf)3, whereas other traditional O H2N NH2 N
100 °C, 1 h N
N
Lewis acids like SnCl4, TiCl4, and Cu(OTf)2 gave diminished H
R2
yields of the annelated products. The yields decreased in the R1 = Ph, 4-MeC6H4, 4-MeOC6H4, 4-ClC6H4,
49–72%
absence of molecular sieves, presumably due to the partial 4-BrC6H4, 4-O2NC6H4, 4-HOC6H4
R2 = H, Me, Ac
hydrolysis of the starting nitronates. X = O, S
Scheme 144 Yb(OTf)3-catalyzed synthesis of pyrimido[4,5-b]indoles
AJ
7.21 Oxazino[3,2-a]isoquinoline The 3-methylenecepham system, an important inter-

mediate for cephalosporin antibiotic manufacture, was pre-
Wu and co-workers reported the synthesis of tetrahy- pared by the thia-ene-type reaction of seco-penicillin
dro-1,2-oxazine-fused 1,2-dihydroisoquinolines by cooper- sulfinyl carboxylates using Yb(OTf)3 as catalyst (Scheme
ative catalysis of AgOTf and Yb(OTf)3 for the tandem cy- 147, top).183 The best conditions for the cyclization starting
clization/[3+3] cycloaddition of 2-alkynylbenzaldoximes from the corresponding acetate involved the use of
with donor–acceptor cyclopropanes (Scheme 145).181 The Yb(OTf)3·9H2O (10 mol%) in nitromethane at room tem-
use of AgOTf led to the formation of the isoquinoline-N-ox- perature. An analogous sulfinyl chloride with sodium piv-
ide, and among a variety of solvents screened such as THF, aloate (1 equivalent) in nitromethane underwent cycliza-
toluene, MeCN, DMF, CH2Cl2, and DCE, toluene was found to tion in the presence of Yb(OTf)3 (10 mol%) to afford the cor-
be the most effective. The substituent attached at the ter- responding 3-methylenecepham β-sulfoxide in 49% isolated
minal alkyne moiety in 2-alkynylbenzaldoximes was criti- yield along with a minor amounts of the α-sulfoxide
cal to the reaction outcome: the presence of an aliphatic (Scheme 147, bottom).
group such as butyl and cyclopropyl led to complex reac-

O
tion mixtures and the expected product was not isolated in O
H
O
H S R Phth
these cases. Phth O Yb(OTf)3·9H2O (10 mol%) S
MeNO2
N
N 20 °C
R1 O
OH O
N CO2Me
CO2Me CO2Me
Yb(OTf)3 (10 mol%) MeO2C R3 R = Me, 73%
AgOTf (5 mol%), toluene R = Ph, 50%
+ R2 O
N
80 °C
R3 CO2Me O
R1 R2 H H
CO2Me N S
36–92% PhO
R1 = H, 3-F, 3,4-OCH2O, 3,4,5-(OMe)3 O N

R2 = Ph, 4-MeOC6H4 O O
H H S
R3 = H, Ph N Cl Yb(OTf)3 (10 mol%) CO2PNB
PhO NaOPv, MeNO2 49%
Scheme 145 Yb(OTf)3/AgOTf-catalyzed synthesis of of tetrahydro-1,2- O N 20 °C, 40 h
+
oxazine-fused 1,2-dihydroisoquinolines O H H
O
N S
CO2PNB PhO
O N
An efficient synthesis of 1-aryl-1,2-dihydronaph- O
CO2PNB
tho[1,2-e][1,3]oxazin-3-ones was successfully attempted 4%
via Yb(OTf)3-catalyzed three-component coupling of β-
Scheme 147 Yb(OTf)3-catalyzed synthesis of the 3-methylenecepham
naphthol, benzaldehydes, and urea.182 Among the catalysts motif by a thia-ene reaction; PNB = p-nitrobenzyl
screened, Yb(OTf)3, I2 and P2O5 were shown to be effective
catalysts for this three-component reaction (Scheme 146).
It was observed that the formation of 1-aryl-1,2-dihy- Two coumarin-pyrrole-isoquinoline pentacycles were
dronaphtho[1,2-e][1,3]oxazin-3-ones was possible only at prepared by the Yb(OTf)3-catalyzed coupling of 4-chloro-3-
high temperatures (140–150 °C) and 14-aryl-14H-diben- nitro-2H-chromen-2-one and 1-substituted isoquinolines
zo[a,j]xanthenes were isolated at lower temperatures (90– by Yang and co-workers (Scheme 148).184 Yb(OTf)3 was
100 °C). found to be best Lewis acid for this transformation among
the various catalysts tested, including AlCl3, FeCl3, NiNO3,
R
CHO
BF3·OEt2, Sc(OTf)3, Ga(OTf)3, and Bi(OTf)3. The reaction of 4-
R R
chloro-3-nitro-2H-chromen-2-one with 1-methylisoquino-
+ H
N O line in the presence of 10 mol% Yb(OTf)3 gave 54% yield of
O Yb(OTf)3 (10 mol%)
O + 6a,14a-dihydro-6H-chromeno[4′,3′:4,5]pyrrolo[2,1-a]iso-
H2N NH2 140–150 °C, 5 min
quinolin-6-one. Similarly, the use of 1-benzylisoquinoline
+
O
OH gave the corresponding coumarin-pyrrole-isoquinoline
50–95% major at 90–100 °C
pentacycle in 17% yield.
R = H, 3-NO2, 3-F, 4-F, 2-Cl, 3-Cl, 4-Cl, 2,4-Cl2, 4-Br,

2-CF3, 4-Et, 4-i-Pr, 2-Me, 3-Me, 4-Me, 4-OMe, 3,4-(OMe)2
Scheme 146 Yb(OTf)3-catalyzed synthesis of 1-aryl-1,2-dihydronaph-

tho[1,2-e][1,3]oxazin-3-ones
AK
rangement arose from one of the two possible chelation

N sites between O-3, O-4 (2.85 Å) and O-5, O-4 (2.72 Å). The
ionic radius of the Lewis acid was responsible for the selec-
Yb(OTf)3 (10 mol%), xylene N tive binding to either or both chelation pockets, leading to
reflux, overnight
different product distribution.
Cl O O
NO2 54%
OH O
O O OH
5 4 Yb(OTf)3 O
O O O CH2Cl2, HFIP
3
MS 4 Å HO O OH
N HO O 2
50 °C, 12–24 h
1
N
Bn HO OH 72%
Yb(OTf)3 (10 mol%), xylene

O O Scheme 150 Yb(OTf)3-catalyzed synthesis of benzofuro[3,2-b]chrom-
reflux, 36 h
17%
enone

Scheme 148 Yb(OTf)3-catalyzed synthesis of coumarin-pyrrole-
isoquinoline pentacycles 8 Spiroheterocycles
7.22 Thiochromeno[3,2-e][1,3]thiazine An asymmetric oxa-Diels–Alder reaction of isatins and

but-3-en-2-ones to generate spirooxindole tetrahydropyra-
Khan and co-workers reported an Yb(OTf)3-catalyzed nones was developed utilizing cooperative bifunctional
pseudo-four-component hetero-Diels–Alder reaction for enamine–metal Lewis acid catalysis (Scheme 151).187 The
the regioselective synthesis of di- and trisubstituted 3,4-di- combination of Yb(OTf)3 with ligand (S)-N-(pyridin-2-yl-
hydrothiochromeno[3,2-e][1,3]thiazin-5(2H)-one deriva- methyl)pyrrolidine-2-carboxamide showed the best enan-
tives from 4-hydroxydithiocoumarin, ammonium acetate tioselectivity (74.5% ee). The methodology included the in
or primary amines, and aldehydes (Scheme 149).185 The re- situ formation of the dienamine from the corresponding
action was applicable to a wide variety of substrates and in- but-3-en-2-one and a catalytic amount of an amine ligand.
volved ring-closure with the formation of C–C, C–N and C–S A broad range of isatins with various substituents reacted
bonds in a single step. Initially, Knoevenagel product and with the substituted butenones to generate the desired
imine are formed by the reaction of an aldehyde with 4-hy- spirooxindole tetrahydropyranones in good yields and with
droxydithiocoumarin and amine, respectively. The cycload- excellent chemoselectivities.
dition of Knoevenagel product with imine in the presence
of Yb(OTf)3 gave the final product. R2
O O O
R1 Yb(OTf)3 (10 mol%)
R1 O
ligand (20 mol%), CH2Cl2
OH O +
50–70 °C, 4–48 h O
N R2
H N
O R1 H
Yb(OTf)3 (5 mol%) R1 = 5-F, 5-NO2, 5-Cl, 5-Br, 5-Me, 5,7-Me2, 5-MeO 65–84%
R2
S S MeCN or EtOH N R2 = Ph, 4-MeC6H4, 4-MeOC6H4, 4-ClC6H4, 4-O2NC6H4,
+ R2NH2 3-O2NC6H4, 1-naphthyl, 2-naphthyl, 2-thienyl, i-Pr N
60 °C S S R1
R1CHO or NH
NH4OAc 70–85% NH
R1 = Ph, 4-MeC6H4, 4-MeOC6H4, 2-FC6H4, 2-ClC6H4,

ligand O
2-BrC6H4, 3-FC6H4, 4-ClC6H4, 4-BrC6H4, 2-O2NC6H4,
4-O2NC6H4, 4-NCC6H4, 2-naphthyl Scheme 151 Yb(OTf)3-catalyzed synthesis of spirooxindole tetrahydro-
R2 = Bn, 4-MeC6H4CH2, n-Bu, H
pyranones
Scheme 149 Yb(OTf)3-catalyzed synthesis of 3,4-dihydrothiochrome-
no[3,2-e][1,3]thiazin-5(2H)-one derivatives
Another example of spiro compounds was reported by
Shi and co-workers, wherein Yb(OTf)3 was utilized for the
7.23 Benzofuro[3,2-b]chromenone intramolecular regioselective [3+2] cycloaddition of func-
tionalized nitrones to give the corresponding spiro com-
Porco and co-workers used Yb(OTf)3 for the double pounds in good yields and with high regioselectivities
Claisen rearrangement of a bis(allyloxy)flavone substrate to (Scheme 152).188 The nitrones themselves were obtained
construct the hydrobenzofuro[3,2-b]chromenone core of through Lewis base catalyzed cascade reaction between
sanggenon A and sanggenol F (Scheme 150).186 Other metal isatin-derived oximes and an allenic ester. Moreover, the
triflates produced the single-rearrangement product along targeted bridged cycloadducts were also achieved in a one-
with the double-rearrangement product in varying ratios. pot approach with good yields by combining the two cata-
According to DFT calculations, the 3-allyl or 5-allyl rear- lytic systems.
AL
CO2Et OMe
H EtO2C
H
O H O
Yb(OTf)3 (20 mol%) EtO2C O
N CHN2 MeO MeO
R1 MS 4 Å, toluene
N
CO2Et O O O O
100 °C, 36 h O
O Ar O + O
N
N R1 Ar Ar
Rh2(OAc)4 Yb(OTf)3
R2
R2 (10 mol%)
57–70% MS 4 Å, CH2Cl2 exo O endo O
HO OMe r.t., 1 h 37–99%
N exo/endo = 97:3 to 88:12
R1 O
CO2Et (i) P(4-FC6H4)3, toluene 50 °C, 3 h Ar = Ph, 4-O2NC6H4, 4-MeOC6H4,
O + BnOCH2, n-Pr, i-Pr, c-Hex
N (ii) Yb(OTf)3 (20 mol%), MS 4 Å,
100 °C, 36 h O
R2
R1 MeO MeO
R1 = H, 5-Cl, 5-Me, 6-Me R1 R1
R2 = Me, Bn, CPh3, CH2CH=CH N N N
R2 O + O
R2 R2
Scheme 152 Yb(OTf)3-catalyzed synthesis of spirooxindole

Yb(OTf)3
(10 mol%)
CH2Cl2, r.t., 1 h exo O endo O
62–92%
9 Bridged Heterocycles exo/endo = 98:2 to 73:27
R1 = Ph, 2-MeC6H4, 4-ClC6H4

R2 = 2-BnOC6H4, Ph, 2-MeOC6H4,
Suga et al. reported the catalytic use of Yb(OTf)3 in the 4-BnOC6H4, 4-ClC6H4
1,3-dipolar cycloadditions of 2-benzopyrylium-4-olate, Scheme 153 Yb(OTf)3-catalyzed 1,3-dipolar cycloaddition between 2-

generated from the Rh2(OAc)4-catalyzed decomposition of benzopyrylium-4-olate and aldehydes or imines
o-methoxycarbonyl-α-diazoacetophenone (Scheme 153).189
Generally, high exo-selectivity was observed. However, in sition of the diazoacetophenone with dimethyl fumarate,
the reaction with aliphatic aldehydes, Yb(OTf)3 could not the addition of Yb(OTf)3 did not change the stereoselectivi-
control the selectivity, whereas very high exo-selectivity ty, but the combination of Yb(OTf)3 and MS 4 Å increased
was observed for benzyloxyacetaldehyde. An asymmetric the 6-endo,7-exo selectivity. The 1,3-dipolar cycloaddition
induction in the Yb[(S)-BNP]3-catalyzed reaction of 2-ben- reaction of 2-benzopyrylium-4-olate with acrylic acid de-
zopyrylium-4-olate with benzyloxy acetaldehyde was also rivatives in the presence of Yb(OTf)3 was also reported to
investigated. Cycloaddition with imines such as N-[2-(ben- result in exo-selectivity (up to 87:13).192 The ionic radius of
zyloxy)benzylidene]aniline catalyzed by Rh2(OAc)4 in the the rare earth metal element strongly influenced the stere-
absence of Lewis acid also gave the dimeric products of the oselectivity of this reaction: a larger or smaller ionic radius
corresponding carbonyl ylides instead of the desired 1,3-di- than that of Lu3+ or Yb3+ resulted in decreased exo-selectivi-
polar cycloaddition products. In contrast, in the presence of ty.
Lewis acids such as Yb(OTf)3, the 1,3-dipolar cycloaddition
MeO
products were obtained with high enantioselectivity with-
O O
out formation of dimeric product (Scheme 153). For this re- O
MeO R MeO R
action, several rare earth metal triflates Tm(OTf)3, Ho(OTf)3, N N
Yb(OTf)3
Eu(OTf)3, Sm(OTf)3, La(OTf)3 and Sc(OTf)3 were compared, O CH2Cl2 or Et2O O + O
+ O O
and all enabled the cycloaddition reaction. The lanthanoid r.t., 1 h
H H
triflates like Yb(OTf)3 and La(OTf)3 provided much higher O N O O O
endo exo
yields than other Lewis acids, and also gave high exo-selec- R 76–100%
endo/exo = 78:22 to 96:4
tivity. The exo-selectivity observed was probably due to the R = Me, Et, Ph
steric stability of the exo-cycloadduct.190 Scheme 154 Yb(OTf)3-catalyzed 1,3-dipolar cycloaddition of 2-benzo-
Interestingly, endo-cycloadducts were obtained selec- pyrylium-4-olate with N-methylmaleimides
tively in the Yb(OTf)3-catalyzed 1,3-dipolar cycloaddition
reaction of 2-benzopyrylium-4-olate, again generated in The combination of (S,S)-Pybox-Ph and Yb(OTf)3 was
situ from o-methoxycarbonyl-α-diazoacetophenone in the found to be a promising catalytic system in terms of enan-
presence of Rh2(OAc)4, with N-methylmaleimides in CH2Cl2 tioselectivity of the exo-cycloadduct in the 1,3-dipolar cy-
or diethyl ether (Scheme 154).191 The same reaction, when cloadditions of 2-benzopyrylium-4-olate (R1 = Me) with 3-
catalyzed by CuOTf (20 mol%) or CuCl–Yb(OTf)3 (5 mol%) acryloyl-2-oxazolidinones; however, the enantioselectivity
under reflux conditions, also gave the endo-selective prod- of the endo-cycloadduct was extremely low. It was also ob-
uct in moderate yield. Reaction with Rh2(OAc)4 (5 mol%) as served that increasing the addition time from one hour to
the catalyst in the absence of any Lewis acid in refluxing three resulted in an increased exo-selectivity (70:30) as
benzene gave cycloadducts with exo-selectivity (endo/exo = well as high enantioselectivity (91% ee) of the exo-adduct.
11:89). However, during the Rh2(OAc)4-catalyzed decompo- The reaction with the same complex in dichloromethane at
AM
–25 °C yielded exo-cycloadducts in high yields with high R1 H

R4
diastereo- (exo/endo = 82:18) and enantioselectivities (96% R2 H
CF3
ee) (Scheme 155, method A).193 Further, the asymmetric O O Ph
R4 N
1,3-dipolar cycloadditon reaction between the carbonyl R1
CF3
Yb(OTf)3 (5–10 mol%) R3
ylide derived from o-(p-bromobenzyloxy)carbonyl-α-di- R2
R5
toluene Ph
+
azoacetophenone (R1 = 4-BrC6H4CH2) and 3-crotonoyl-2- N R6
reflux, 48 h R1 H
oxazolidinone (R2 = Me) catalyzed by the (4S,5S)-Pybox- R2 R2 H
3
4,5-Ph2-Yb(OTf)3 system yielded the corresponding endo- 1
R CF3
R = H, OMe
adducts in high enantioselectivity (Scheme 155). In con- R2 = H, Me, OMe, F
O
R3 N
trast, the cycloaddition reaction of 3-acryloyl-2-oxazolidi- R3 = H, Me R3 R4
R4 = H, Me, Et, Bn
none (R2 = H) in the presence of Yb(OTf)3 provided the exo- R5 = Bn, i-Pr
adducts.194 R6 = Ph, i-Pr
Scheme 156 Yb(OTf)3-catalyzed construction of bicyclo[3.2.2]nonane

O
skeleton

O
OR1 O O R1O
N O
O N N
O R2
Ph (10 mol%)
Yb(OTf)3 (10 mol%)
Ph Ivanova et al. reported the Yb(OTf)3-catalyzed [4+3] cy-
O CH2Cl2 O exo cloaddition between 2-arylcyclopropane diesters and 1,3-
+
O O method A: –25 °C, 6 h O diphenylisobenzofuran to yield two isomeric tetrahydro-
method B: MS 4 Å, r.t. to reflux, 6 h O
R1O
O 5H-5,9-epoxybenzo[7]annulenes in excellent yields
R2 N O N
(Scheme 157).196 The reaction was considered to be an ana-
O R2
logue of the Diels–Alder reaction, with donor–acceptor cy-
R1 = Me, i-Pr, 4-BrC6H4CH2
R2 = H, Me, Et, Ph, CO2Et
endo clopropanes as the dienophiles. Among a number of cata-
O
method A: 89%; exo/endo 88:12
lysts screened, such as SnCl4, TiCl4, BF3·OEt2, TMSOTf and
method B: 15–57%; endo/exo ≤ 99:1 EtAlCl2, Yb(OTf)3 in refluxing dichloromethane gave the
Scheme 155 [3+2]-Cycloaddition using a chiral Lewis acid complex of best results.
(S,S)-Pybox-Ph and Yb(OTf)3
O Ph CO2R2
CO2R2
Akiyama and co-workers observed Yb(OTf)3-catalyzed R1
double C(sp3)–H bond functionalizations triggered by a se- R1 Ph
CO2R2 Ph
quential hydride shift and cyclization process. The resulting +
Yb(OTf)3, CH2Cl2 H
O +
bicyclo[3.2.2]nonane skeleton was constructed by a [1,6]- CO2R2 r.t. to reflux, 3–24 h
CO2R2
O Ph
and [1,5]-hydride shift sequence, and the linear tricyclic Ph
CO2R2
skeleton by a [1,4]- and [1,5]-hydride shift sequence, from R1 = Ph, 4-FC6H4, 4-MeOC6H4, 3,4,5-(MeO)3C6H3, H
2-thienyl, 2-furyl
{[(N,N-dialkylamino)methyl]phenyl}-1,1,1-trifluorobut-3- R2 = Et, Me Ph
R1
en-2-one derivatives (Scheme 156).195 The course of reac- 84–92%
tion was affected by altering the electrophilic moiety. Ac-
Scheme 157 Yb(OTf)3-catalyzed synthesis of tetrahydro-5H-5,9-ep-
cording to the theoretical studies, resonance stabilization in oxybenzo[7]annulene
the benzylidene carbonyl moiety and the steric repulsion of
the α-substituent were responsible for changing the reac-
tion course. The hydride shift process was affected by the 10 Conclusion
acyclic nature of the N,N-dialkylamine moiety: in the case
of an isoquinoline-type substrate, a single-hydride-shift ad- This review highlights the diverse features and the
duct was obtained. unique efficiency of ytterbium triflate in a wide range of
transformations to construct different heterocyclic frame-
works of biological importance. Many of the reactions de-
veloped using ytterbium triflate as catalyst are alternative
methods for classical reactions where stoichiometric and
hazardous Lewis acids are used. Because of the ease of han-
dling, non-corrosive nature, low toxicity, moisture- and air-
stability, recyclability and re-usability of Yb(OTf)3, and its
superior catalytic activity even in the presence of Lewis
bases, there is enormous potential for using ytterbium tri-
flate to develop greener and sustainable large-scale synthe-
ses of heterocyclic compounds.
AN
It is hoped that this review will prove to be extremely (24) Reddy, G. R.; Reddy, T. R.; Joseph, S. C.; Reddy, K. S.; Meda, C. L.
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