six-membered ring systems: with o and/or s atoms · 2018-01-18 · progress in heterocyclic...

CHAPTER6.46.4

Progress in Heterocyclic CISSN 0959-6380, http:/

Six-Membered Ring Systems: WithO and/or S AtomsClementina M.M. Santos*, Artur M.S. Silva***Department of Vegetal Production and Technology, School of Agriculture, Polytechnic Institute of Braganca,Braganca, [email protected]**Department of Chemistry & QOPNA, University of Aveiro, Aveiro, [email protected]

6.4.1. INTRODUCTION

The year 2011 was particularly rich in reviews involving the synthesis and transforma-

tions of a wide structural range of O- and S-6-membered heterocycles and some on

their biological properties, reflecting their importance for the scientific community.

An overview on the structure and biological activity of naturally occurring withano-

lides<11NPR705> and a review on structure, biological activity, and synthesis of plant

polyphenols<11AGE586>, marine natural products<11NPR196, 11NPR269>, and

aromatic cyclopenta[c]pyrans<11JHC747> have appeared. The synthesis of the various

structural subcategories of limonoids has also been surveyed <11EJO19>.

More specific reviews include a critical attempt to discuss a structure–activity

relationship among a series of trioxane- and tetraoxane-based compounds

<11CMC3889>, and a report on the bioactivity and scope of the synthetic methods

of chromenopyridines, with emphasis on multicomponent and robust methodologies,

as well as reactivity issues and medical applications <11CMC4761>. The powerful

synthetic strategy using the thiopyran template route to the enantio- and diastereo-

selective synthesis of polypropionates, and some natural products or synthetic key

intermediates, has been reviewed <11CC11375>.

The search for naturally occurring compounds for biological application remains an

important field of research, as demonstrated for the 16-membered macrolactone leioder-

matolide, isolated from a marine sponge<11AGE3219>. Despite the beneficial effect of

many of these compounds, some of them are very toxic. An update of risk assessment of

main marine biotoxins in the European Union <11TOX336>, as well as the traditional

remedies of Ciguatera fish poisoning in Pacific <11PTR947>, has been reviewed.

The scarce natural abundance of the biologically active natural products makes

them prime targets for the development of efficient and short total syntheses

<11HCA2215, 11EJO7097>, for the stereoselective synthesis of some common

moieties <11TL3654>, and for syntheses involving common intermediates

<11TA1249, 11TL6180>.

In many cases, a dihydropyran-2-one ring is a key intermediate in the total syn-

thesis of natural products. Ring-closing metathesis using Grubbs’ catalysts has been

hemistry, Volume 24 # 2012 Elsevier Ltd./dx.doi.org/10.1016/B978-0-08-096807-0.00015-4 All rights reserved. 443

http://dx.doi.org/10.1016/B978-0-08-096807-0.00015-4

444 C.M.M. Santos and A.M.S. Silva

applied to the synthesis of (þ)-goniodiol and derivatives <11TL438>, (þ)-

cryptofolione <11TL1003>, and (�)-cleistenolide <11T3815, 11TL2443>. Lacto-

nization mediated by CeCl3�7H2O also allowed the synthesis of (�)-cleistenolide

<11TL2306> and (�)-spicigerolide <11TA493>.

The synthesis of naturally occurring tetrahydropyran derivatives involves domino

and metal-catalyzed reactions <11TL6550, 11T4980>, while the unified asymmet-

ric syntheses of the natural products lachnone C (a4-chromanone) and diversonol

(atetrahydroxanthone) involve organocatalyzed domino reactions as the enantiose-

lective key step <11CEJ13706>. These types of reactions comprise three of the

hot and most studied transformations on O-6-membered heterocycles.

Following the dramatic growth of publications on the reactions catalyzed by gold

complexes, due to their mild reaction conditions and high group compatibility, the

synthesis of pyrans, and various ketals and spiroketal systems <11OBC4405>, and

also di- and tetrahydropyrans, pyran-4-ones, and chromene and xanthene derivatives

<11CR1657> have been discussed. The use of other metal-catalyzed reactions,

namely, the intermolecular dehydrogenative Pd-catalyzed Heck reactions, to prepare

pyran-4-ones, chromans, isochromans, coumarins, and isocoumarins <11CR1170>,

and the application of Bi(III) compounds from the “green-chemistry” perspective in

the total synthesis of several pyran derivatives <11CSR4649> have been reviewed.

The asymmetric hydration of di- and tri-enoates by Sharpless asymmetric dihydrox-

ylation combined with other metal-catalyzed reactions leads to a diverse array of

structurally complex and biologically important natural products <11CC8493>.

Many methodologies for the synthesis of naturally occurring coumarins have

been described, including improving well-known methods <11SC1514> and the

use of NbCl5 to catalyze a known condensation <11SC1486>. Recent advances

in cycloadditions of alkynes, as atom-economic controllable chemo- and regioselec-

tive reactions to construct pyranones, coumarins, and isocoumarins, were over-

viewed <11COC712>. The importance of coumarins was also highlighted in a

review on their antioxidant activity <11CMC3929> and in references to their

application in dye-sensitized solar cells <11PC569, 11PC1929>.

Reviews on catalytic asymmetric propargylation, describing the propargylation of

naphthols as a synthetic route to chromene and chroman derivatives <11CR1914>,

and on the synthesis of several heterocycles (e.g., pyran-2-ones, chromenes, and

isochromans) involving the electrophilic cyclization of alkynes containing a hetero-

atom <11CR2937> has appeared.

6.4.2. HETEROCYCLES CONTAINING ONE OXYGEN ATOM

6.4.2.1 Pyrans2,3,6-Trisubstituted 2H-pyran-5-carboxylates 1 are readily available from the reac-

tion of 2-alkyl-2-enals with acetoacetates and involve a Knoevenagel condensation

followed by a 6p-electrocyclization. These 2H-pyrans were transformed into the

corresponding 1,2,4-trioxane structures 2 by cycloaddition with singlet oxygen

(Scheme 1) <11EJO5469>.

CHOR2

R1

R4 OR3

O O O R2

R1

R4

O

R3OPiperidine

AcOH24–48 h

15 examples, 30–76%

O R2

H

R1

R4

O

R3OO O

O H

R2

R1

R4

O

R3OO O


O2, rose bengal

hn, MeOH, -78 �Ctrans-2

cis-2

1

Scheme 1

445Six-Membered Ring Systems: With O and/or S Atoms

2-Aryl-3,5-diformyl-2H-pyrans 3 are selectively prepared by FeCl3�6H2O-catalyzed

reaction of 1,1,3,3-tetramethoxypropane with aromatic aldehydes, while using

AlCl3�6H2O provided 4-aryl-3,5-diformyl-4H-pyrans 4 (Scheme 2) <11SL857>.

MeO OMe

OMe OMe

ArCHO

FeCl3×6H2O (10 mol%)

MeOH-AcOH (1:2), 50 ºC

AlCl3×6H2O (10 mol%)

DMAc–AcOH (1:2), 50 ºC

O

Ar

CHO

CHO

O

CHO

Ar

OHC



3

4DMAc = N,N-dimethylacetamide

Scheme 2

Magnetite or iron(III) oxide was successfully used in the tandem formation of

polysubstituted 4H-pyrans using the appropriate 1,3-dicarbonyl compounds and ali-

phatic or aromatic aldehydes (Scheme 3). This process involves an aldol condensa-

tion, a Michael-type addition, and a dehydrating annulation <11SL2017>.

R1

R2

O

O R3 H

O

OR1 R1

R2R2

R3

Fe3O4 or Fe2O3 (65 mol%)

MeCOCl (200 mol%)PhMe, 25 ºC, 3 h


Scheme 3

Phase transfer-catalyzed nucleophilic addition of 1,3-dicarbonyl compounds to

electron-deficient 1,3-conjugated enynes followed by cyclization affords 4H-pyran

derivatives (Scheme 4) <11OBC3375>.

OR1

Me R2

O O

O Me

O

R2

R1O 21 examples

40–81%

TBAF.3H2O (5 mol%)Cs2CO3 (3 equiv)

CH2Cl2, 60 ºC

TBAF = tetra-n-butylammonium fluoride

Scheme 4


A gold(III)-catalyzed regioselective tandem conjugate addition/annulation of

4-hydroxycoumarins or 4-hydroxy-6-methylpyran-2-one with a,b-unsaturatedketones furnished various coumarin or pyran-2-one-fused 4H-pyran derivatives

(Scheme 5) <11JOC9096>.

R1 R2

O R3

O O

X

OH

O O

X

O

R1

R3

R2

AuCl3/AgOTf (5 mol%)

PhMe, reflux, 6 h23 examples

45–98%

Scheme 5

An enantioselective organocatalytic conjugate addition of malononitrile or cya-

noacetate to conformationally restricted dienones led to chiral 4H-pyrans 5, which

are potent inhibitors of Mycobacterium tuberculosis (Scheme 6) <11JOC3797>.

R1 R1

O

NC R2

OH2N

R2R1

R1R2 = CN, CO2Et

F3C

CF3

NH

S

NH

N

6 (10 mol%)

PhMe, rt

23 examplesup to 99% yield, 99% ee

56

Scheme 6

Polyfunctionalized 4H-pyrans can be prepared by a one-pot, three-component

cyclocondensation of aryl aldehydes, malononitrile/ethyl cyanoacetate, and 1,3-

dicarbonyl compounds catalyzed by piperidine <11JHC124>, DABCO

<11SC2701>, Caro’s acid supported on silica gel (CA-SiO2) <11SC436>, baker’s

yeast <11TL5817>, and the enzyme lipase (Scheme 7) <11T9582>. This type of

one-pot reaction was also applied to the synthesis of biologically and pharmacologically

active 4H-pyrans using SiO2 nanoparticles as an inexpensive, reusable, and environmen-

tally benign catalyst <11TL1878>. Similar compounds are obtained by a tandem

Michael addition/cyclization reaction involving malononitrile, acetylene dicarboxylate,

and dimedone <11T6057>. A base-catalyzed two-component approach uses

a,b-unsaturated cyanoesters and dimedone derivatives <11SC2822>.

CN

R2

O

O O NH2

R2R1O

A: piperidine, sodium dodecyl sulfate, 80–100 �C, 5–60 min 12 examples, 66–91%B: DABCO (1,4–diazabicyclo[2.2.2]octane), 9 examples, 85–97%

H2O or EtOH H2O (1:1), reflux, 2 hC: CA-SiO2, EtOH–H2O (2:5), reflux, 17 min 10 examples, 92–95%B: DMAc, dry baker¢s yeast, rt, 30 h 13 examples, 48–83%E: lipase, EtOH–H2O (4:1), 35 �C, 1 h 31 examples, 76–97%

A, B, C

D, ER1CHO

–

Scheme 7


Coumarin-fused 4H-pyran derivatives are available from a one-pot, three-

component coupling reaction of aromatic aldehydes, malononitrile or ethyl cyanoa-

cetate, and 3- or 4-hydroxycoumarin, in the presence of nano-ZnO (Scheme 8)

<11TL4636>, DMAP [4-(dimethylamino)pyridine] <11TL5327>, or the ionic liq-

uid 2-hydroxyethanaminium acetate <11SC3573>, as catalysts. Using 4-hydroxy-

quinolin-2-(1H)-one instead of hydroxycoumarins, quinoline-fused 4H-pyrans

were obtained <11TL2597>. The same type of multicomponent reaction was used

for the synthesis of other coumarin-fused pyrans by the one-pot reaction of

4-hydroxycoumarin, aldehydes, and 1,3-dicarbonyl compounds, using the ionic

liquid 1,3-dimethyl-2-oxo-1,3-bis(4-sulfobutyl)imidazolidine-1,3-diium hydrogen

sulfate as catalyst <11TL2601>.

O O

OH CN

CN

O O

O

NH2

CN

Arnano ZnO

H2O, 70 �C, 2–4 h 10 examples65–91%

ArCHO

Scheme 8

Naphtho-fused 4H-pyrans are formed from a three-component reaction of aro-

matic aldehydes, malononitrile, and a- or b-naphthol, catalyzed by disodium hydro-

gen phosphate under solvent-free conditions <11SC3477>. Other derivatives are

prepared in moderate to good yields (65–94%) by one-pot reaction of alkyl isocya-

nides, dialkyl acetylenedicarboxylates, and hydroxynaphthalenes <11SC3714> or

a-tropolone <11HCA371>. Some examples were also obtained by one-pot

ZnCl2-catalyzed reaction of 2-hydroxynaphthalene-1,4-dione, cyanothioacetamide,

and aromatic aldehydes (Scheme 9) <11SC806>.

O

O

OH

SH2N

CNO

O

O NH2

Ar

NH2

S

ZnCl2EtOH, rt

9 examples85–92%

ArCHO

Scheme 9


A four-component synthesis of 4H-pyrano[2,3-c]pyrazoles involved ethyl acetoa-

cetate, hydrazines, malononitrile, and aldehydes and uses L-proline <11TL3228> or

g-alumina <11TL2523> as catalyst in aqueous media. Other combinations of

catalysts and solvents are used: L-proline in ionic liquids <11SC405> and Mg-Al

hydrotalcite in ethanol <11SC1320>.

An efficient gold(III)-catalyzed ring expansion of 1-oxiranyl-1-alkynylcyclopropanes

in the presence of N-(iodo and bromo)succinimides afforded cyclobutane-fused

3,4-dihydro-2H-pyrans (Scheme 10) <11CC1339>.

O R2

R1

H

ArOAr

XHO

H

R2

R1

X = Br or IAuCl3 (5 mol%)H2O (2 equiv.)

Ph3PO (5 mol%)NBS or NIS (1.2 equiv.)

CH2Cl2, rt12 examples, 56–75%

Scheme 10

The 3,4-dihydro-2H-pyran ring of bryostatin derivatives is prepared by a Rainier

titanium-induced ring-closing metathesis (Scheme 11) <11AGE8786, 11JA744>and a Ru-catalyzed tandem enyne coupling/Michael addition <11CEJ9789>.

MeO OPMB

OTBS

Me

OOBOMMe

TiCl4, ZnPbCl2, MeCHBr2

TMEDAMe

O OPMB

OTBS

Me

OBOMMe

TBS = t-butyldimethylsilylPMB = p-methoxybenzyl

BOM = benzyloxymethylTMEDA = N,N,N�,N�-tetramethylethylenediamine

Scheme 11

Inverse-electron-demand hetero-Diels–Alder (hDA) between electron-deficient

a,b-unsaturated carbonyl compounds and electron-rich dienophiles is an important

strategy for the synthesis of 3,4-dihydro-2H-pyrans. Novel spiro- and dispirodihy-

dropyrans were obtained in good yields by refluxing sterically hindered cycloalkyli-

dene derivatives with cyclic enol ethers or sterically hindered cycloalkylidene

cycloalkanes in refluxing toluene (Scheme 12) <11T1422>. An asymmetric hDA

reaction of six-membered cyclic ketones provided trans,cis-2,3,4-trisubstituted

3,4-dihydropyrans as major products <11AGE3484>.


R1

OR2

R3

n

OR5R4

O

R4

OR5R2

R1

R3n

PhMe

Reflux, 24 h

O

OR2

R1

R3

PhMe

Reflux, 24 hO


n

Scheme 12


Densely functionalized trans- and cis-3,4-dihydro-2H-pyran isomers are obtained

by tandem cross-Rauhut–Currier/cyclization reactions of a,b-unsaturated ketones

and activated alkenes (Scheme 13) <11T1768>.

R1 O

NC

R2

DABCO (20 mol%)

MeCN

OR1

NC

R2

HH

R3

OR1

NC

R2

R3

H

H

trans cis

17 examples61–98%R3

Scheme 13

The reaction of b,g-unsaturated a-keto esters with ethyl vinyl ether catalyzed by

copper(II) complexes of (þ)-S-ketopinic acid-based hydroxy oxazoline 8 afforded

trans-2,4-disubstituted chiral 3,4-dihydro-2H-pyrans 7, with up to 88% ee

(Scheme 14) <11SL1592>. A similar procedure used Eu(fod)3 as catalyst for a highly

diastereoselective and facially controlled hDA reaction to prepare dihydropyran

derivatives that are intermediates in the synthesis of natural lignans <11TL1608>.

A remarkably low catalyst loading (up to 0.05 mol%) of a chiral Er(OTf)3/N,N0-dioxide complex was used in the synthesis of 3,4-dihydro-2H-pyrans in excellent

yields, diastereo- and enantioselectivities <11CEJ8202>. Visible light photocatalysis

of symmetrical and unsymmetrical bis(enones) afforded 3,4-dihydro-2H-pyrans, as

single regioisomers in an intramolecular hDA reaction <11T4442>.

EtO OOR1

O

R2

O CO2R1

R2

EtO O CO2R1

R2

EtO

exo-7 endo-7

8 (10 mol%)Cu(OTf)2 (10 mol%)

EtOAc, 0 ºC

12 examples, 44–96%trans-isomer with up to 88% ee

OHO

N

8

Scheme 14


A new Ni-iminophosphine complex catalyzes the [4þ2] cycloaddition of enones

with allenes, providing highly substituted 3,4-dihydro-2H-pyrans, via oxidative

cyclization of the enone with a Ni(0) complex <11CC6150>.

An asymmetric [4þ2] annulation of allenoates with oxadienes in the presence of

a cinchona organocatalyst 10 led to 3,4-dihydro-2H-pyrans 9 with good to excellent

enantioselectivities (Scheme 15) <11AGE5361>. A similar annulation (a formal

[4þ2] cycloaddition) was used to make novel 3,4-dihydro-2H-pyran derivatives.

Using other cinchona alkaloids as catalysts, an asymmetric center at C-4 was created

with efficient stereocontrol <11OL5732>, while DABCO <11OL1138> and

DMAP <11OL1142> afforded dihydropyran-fused indoles and isatin derivatives,

respectively.

H

CO2Bn O

R1 CN

R2

OR1 CO2Bn

NC

R2

10 (20 mol%)

PhMe, -30 �C36 h

16 examples, 50–97%up to 99% ee

N

OMe

N

MeO

Prerequisite substituent

9 10

Scheme 15

The synthesis of 3,6-dihydro-2H-pyrans proceeds through a Lewis acid-catalyzed

6-endo-trig cyclization of b-hydroxy-g,d-unsaturated alcohols (Scheme 16)

<11T9870>.

BnO

OH OH

R2R1

OBnO

H HR2

R1

BF3×OEt2 (10 mol%)

CH2Cl2, rt 8 examples, 71–92%

Scheme 16

The FeCl3�6H2O-catalyzed bromocyclization of polysubstituted 2-tosyl-2,5-hexa-

dien-1-ol provides 2,3,4,6-tetrasubstituted 3,6-dihydro-2H-pyrans (Scheme 17)

<11SC1227>.

SO2TolR1

R2

HO O R2

SO2Tol

R1

Br

FeCl2×6H2O (5 mol%)NBS

THF/CH2Cl2, rt12 examples

81–97%

Scheme 17


Allenyl alcohols underwent Au(III)-catalyzed cyclization to give 3,6-dihydro-

2H-pyrans, which were also obtained by an asymmetric bromoetherification of

the same allenyl alcohols followed by a debromination reaction (Scheme 18)

<11CEJ5796>.

R1Ph

Ph MeHOH2C

OPh

Ph

R1

Me

OPh

Ph

R1

MeBr

R1 = Ph or 2-naphthyl

AuCl3 (10 mol%, 0.05 M MeCN solution)

CH2Cl2, rt

Pd(OAc)2 (10 mol%)LiBr, Cu(OAc)2

.H2O

K2CO3, MeCN, O2, rt

R1 = Ph

Bu3SnH (2.0 equiv)AIBN (30 mol%)PhMe, 80 °C

Scheme 18

3,6-Dihydro-2H-pyrans were obtained using the Toste protocol for the cycliza-

tion of propargylic ethers, with tris-2-furylphosphine (TFP) as ligand (Scheme 19)

<11CC9390>.

OCO2Me

R1

O

R1

CO2Me

OMe(TFP)AuCl (5%)AgBF4 (5%)

3 equiv. MeOH

CH2Cl2, rt1–20 h


Scheme 19

Catalytic Bi(OTf )3 initiates a cascade reaction involving an epoxide rearrange-

ment into an aldehyde electrophile, followed by an intermolecular addition of the

Z-d-hydroxyalkenylsilanes and an intramolecular silyl-modified Sakurai reaction to

afford cis-2,6-disubstituted 3,6-dihydro-2H-pyrans (Scheme 20) <11JOC9269>.

OR1

15 examples27–74%R1

OH

TMS O

R2 R3R3

R2

Bi(OTf)3×nH2O (5 mol%)

CH2Cl2, rt, 12 h

TfOH

Scheme 20

An efficient and diastereoselective synthesis of 4-alkyl/aryldihydro-11,12 and

4-methylene tetrahydropyrans 13 is obtained from the reaction of aldehydes and

homoallyl alcohols mediated by BF3�Et2O. 4-Amido tetrahydropyrans 14,15 are

obtained when nitrile nucleophiles are included in the reaction medium

(Scheme 21) <11OBC3428>. This oxonium-ene cyclization reaction can also be


applied in the synthesis of oxabicyclo[3.3.1]nonenes and substituted tetrahydropyrans

from the reaction of geraniol and aldehydes or epoxides <11OBC4626>.

R1 H R2 OH

O R3

BF3×Et2O (100 mol%)

benzene, rt0.5–3 h OR1 R3

R2

OR1 R3

R2

OR1 R3

BF3×Et2O (100 mol%)When R2 = Me

OR1 R3

R4OCHN

OR1 R3

R4OCHN22 examples

18 examples

benzene, rt30 min

11 12 13

14 15

R4CN

Scheme 21

Ring opening of diarylvinylidenecyclopropanes connected to alcohol-bearing

chains is promoted by halo reagents affording a variety of halogenated tetrahydropyr-

ans in moderate to good yields (Scheme 22) <11SL995>.

Ar1

Ar2Ar3

HOO

Ar1

Ar2

X

Ar3

X = Br, I, FHalo reagents

(NBS, NIS, Selectfluor)

MeCN 20 examples, 39–80%

Scheme 22

Substituted cis-2,6-tetrahydropyrans can be chemo- and diastereoselectively pre-

pared from z-hydroxy allylic alcohols (or acetates) with a catalytic FeCl3�6H2O

(Scheme 23) <11T5024>.

OHR1

R2R3O

R4

O

R4

R1

R2

FeCl3×6H2O (5 mol%)

CH2Cl2, rt

R3 = H or Ac

11 examples, 66–99%,dr > 90:10

Scheme 23

Tetrafluorotetrahydropyrans are obtained by a 6-exo radical cyclization of the

appropriate allyl ethers (Scheme 24) <11EJO4528>.

O R2

R1 CF2CF2SPh

n-Bu3SnHAIBN (cat.)

PhMe, reflux

OR1

F

FF

F

R27 examples, 53–84%

trans/cis76:24 to 89:11

Scheme 24


cis-2,6-Disubstituted tetrahydropyranylacetic acids can be prepared by a diaster-

eoselective Pd-cyclization–carbonylation–hydroxylation of hept-6-en-2-ols or

hexen-5-en-1,3-diols in moderate to good yields (40–88%) <11T4980>.

2,6-Disubstituted tetrahydropyrans were synthesized from 6-alkynyl-1,5-diols 16

in a gold(I)- (most efficient) or platinium(II)-mediated reaction. The metal induces

an initial Meyer–Schuster rearrangement yielding hydroxyenones 17 that undergo

an oxa-Michael addition (Scheme 25) <11SL1523>.

R1

OH OH

R1

OH O

A: Au(I) (3–18 mol%)

B: Pt(II) (4–11 mol%)


5 examples, 5–38%

O

R1

H H O16 17

Scheme 25

Gold(I)-catalyzed cyclization of monoallylic diols forms tetrahydropyrans. The

allylic alcohol stereochemistry controls the facial selectivity (Scheme 26)

<11OL1330>. Gold(I)-catalyzed exo-cyclization of 3,3-disubstituted 1,4-diynes

provides the corresponding 2-methylene tetrahydropyrans <11OL224>.

OH R2

OH

R1 Ph3PAuCl/AgOTf (1 mol%)

mol. sieves 4 ÅCH2Cl2, rt

O R2

R1* * 8 examples, 84–94%

Scheme 26

A series of allenyl ethers were transformed into two types of tetrahydropyrans fol-

lowing a hydride shift-cyclization sequence catalyzed by a Au(I) complex or

Br�nsted acid. A clear-cut divergence in product selectivity depended on the catalyst

(Scheme 27) <11JA7696>.

O

Ar

R4

R3

R1

R2

O

R2

R1 Ar

R3R4

orO

R2

R1

R4

Ar

R3

Cat. (4 mol%)

CH2Cl2, 20 �C1–10 h

Cat. = HNTf2 Cat. = O

t-Bu

t-Bu

PAuNCH3Ph

SbF63

-

+

Scheme 27

A mild and convenient Ni-catalyzed radical cyclization of organohalides led to

cis-2,6-substituted tetrahydropyrans; zinc in methanol is the reductant (Scheme 28)

<11OL2050>.

OPhCO2Me

R1

X

or SO2Ph

OPhCO2Me

or SO2Ph

R1X = I, Br NiCl2×DME (5 mol%)Pybox (6 mol%)

Zn, MeOH, 40 ºC, 2 hN

O

N N

O

Pybox4 examples, 88–93%

Scheme 28


Both SO3H-tethered imidazolium and tetrazolium ionic liquids are effective in

an intramolecular hydroalkoxylation of appropriate alkenyl alcohols giving tetrahy-

dropyran derivatives (Scheme 29) <11OBC374>.

OHR1

O

OH Ph O Ph

OH Ph

R1

R1

O Ph

R1

R1

OH

Ph

Ph

O

Ph

Ph

18 (50 mol%)

18 (100 mol%)

18 (100 mol%)

18 (100 mol%)

NX

NH2C CH2 SO3HH3C

3 4

TfOH

X = CH, N

18

R1

–

+

Scheme 29

Several Lewis acids catalyze the ring opening of methylenecyclopropanes with

propargyl alcohols and subsequent intramolecular Conia-ene reaction, leading to

3,5-dimethylenetetrahydropyrans, in a stepwise or a one-pot process (Scheme 30)

<11T763>.

CO2R1

CO2R1

R2

OH

R3

CO2R1R1O2C

O

R2

R3

O

R3

R2

CO2R1

CO2R1

Yb(OTf)3

DCE, 60 °C

InCl3/Et3N

1,2-DCE, 65 ºC

Eu(OTf)3/InCl3/Et3N

1,2-DCE, 85 °C5 examples, 17–39%


Scheme 30

Intra- and intermolecular oxa-Michael additions of alcohols are well-known

methods for the preparation of pyrans, but their enantioselective versions are compli-

cated due to a possible reversibility. Therefore, enantioselective versions were used in

the synthesis of some natural products <11CC7200, 11CC7440, 11OL5816>. An

organocascade kinetic resolution, initiated by a highly selective and rapidly reversible

oxa-Michael addition, provided enantioenriched cis-2,6-tetrahydropyrans (Scheme 31)

<11OL6460>. cis-2,6-Disubstituted tetrahydropyrans resulted from a stereoselective

Br�nsted acid-catalyzed intramolecular oxa-conjugate cyclization of a,b-unsaturated


thioesters<11OL1820> and ketones<11T5034, 11TL1003>. A similar diasteroselec-

tive oxa-Michael strategy was used to prepare naphthopyrans, which are intermediates

in the synthesis of several pyranonaphthoquinone antibiotics <11OBC5423>.

NH

PhPh

OTMSOH

O

H

X R1

O

X

OH

R1

O

X

OH

R1

O2N

Ph9 examples

(i) 19 (20 mol%)

PhNO2

(ii) THF×BF3 or NaBH4

PhCO2HPhMe, -30 �C

19

Scheme 31

The classical Prins cyclization reaction is one of the major methods for the syn-

thesis of di- and tetrahydropyrans. Two modifications, involving the triflate-trapped

Prins-adduct and the Mukayama-aldol–silyl-Prins reaction, were employed in the

total synthesis of (�)-civet <11T5107>. Tri- and tetrasubstituted tetrahydropyrans

can be prepared by an In(OTf)3-catalyzed one-pot reaction, involving allyl-E-crotyl-

boration–Prins cyclization reactions (Scheme 32). The Z-crotylboration–Prins

cyclization gives all syn-configuration <11TL4378>.

2 R2CHO

O R2R2

BrR1(i) In(OTf)3 (10 mol%)

CH2Cl2, -78

-78

�C, 1–48 h

(ii) TMSBr�C to rt, 8 h

15 examples70–85%

R1

B

R1 = H, OMeO

O

Scheme 32

Cu(OTf )2-bisphosphine catalyzes synthesis of tetrahydropyrans from 5-methyl-

5-hexen-1-ol and appropriate aldehydes mildly, in good yields and excellent

trans-diastereoselectivity via an olefin migration followed by a Prins cyclization

<11OL4328>.

4-Amidotetrahydropyrans result from a Sakurai–Prins–Ritter sequence between

allyltrimethylsilane, aldehydes, and nitriles, with iodine as catalyst (Scheme 33)

<11SC8>.

17 examples, 60–98%R1 H

OR2CNSiMe3 I2 (10 mol%)

rtO R1

NHCOR2

R1

Scheme 33

An asymmetric one-pot, four-component coupling reaction led to tetra- and

penta-substituted tetrahydropyrans with excellent enantioselectivity through a

Michael–Henry reaction–acetalization–Lewis acid-mediated allylation reaction. The


synthesis started with an organocatalyzed diasteroselective Michael reaction

(Scheme 34) <11AGE3774>.

NO2Ph

H

O

H

O

NO2

Ph

19 (5 mol%)p-nitrophenol

PhMe, rt15 min

evaporation

R1CHODBU

MeCN, rt3–12 h

CH2=CHCH2SiMe3

or Et3SiH

TiCl4, CH2Cl2-40-70 �C to �C

4–10 h

O

O2N

R1

Ph

6 examples, up to 99% ee

Scheme 34

6.4.2.2 [1]Benzopyrans and Dihydro[1]benzopyrans(Chromenes and Chromans)2H-Chromenes 20 can be synthesized by an enantioselective metal-free intramolec-

ular allylic substitution catalyzed by a chiral Br�nsted acid 21 (Scheme 35)

<11JA3732>, radical aromatic substitution of (2-halobenzyl)aryl ethers mediated

by t-BuOK <11CC9813, 11OL3242>, or Rauhut–Currier reaction of nitroolefins

with tethered a,b-unsaturated esters <11CEJ6484>.

OH

R3

OHR2

O

R2

R3

R1R1

O

O

Ph

PO

NH

SO2H

21 (5–10 mol%)

PhMe, -78 ºC

Ph


20

21

Scheme 35

Substituted 2H-chromenes are available from iron(III)-mediated intramolecular

alkyne-carbonyl metathesis <11JOC3539> and annulation tandem reac-

tion <11OL14>. Selective cycloisomerization of propargylic esters <11JA12972>and aryl propargyl ethers <11CC803, 11EJO2334>, promoted by gold catalysts, also

affords a wide range of functionalized chromenes (Scheme 36).

O R2

R1

R3

O

R3

R2

R1A: Ph3PAuNTf2, CH2Cl2B: Au/TiO2, 1,2-DCE

A: 17 examples, 81–97%

B: 13 examples, 82–96%

OR2

OPiv

Ar1

R1

O

OPiv

Ar1

R1R2

acyclic carbene×AuCl2

AgOTf

Piv = pivalate

18 examples, 59–94%up to >99% ee

Scheme 36


Knoevenagel condensation of carbonyl compounds with b-keto esters is a metal-free

approach for the synthesis of 2H-chromenes <11HCA248>. Domino oxa-

Michael–aldol condensation of a,b-unsaturated carbonyl compounds with salicylalde-

hydes in the presence of an organocatalyst <11EJO5031> and polystyrene resin-

supported salicylaldehydes in the presence of potassium carbonate <11SL161> provide

various 2H-chromene-type derivatives.

Under acidic conditions, the reaction of b,g-unsaturated a-keto esters with phe-

nols allows the one-pot synthesis of 4-aryl-2H-chromenes (Scheme 37). This selec-

tive cascade reaction is a complex process involving Friedel–Crafts alkylation,

cyclodehydration, intermolecular hydrogen transfer, and hydration <11OBC2868>.

15 examples72–90%

OH

R1

O

Ar

R1

Ph3CClmol. sieves 4 Å

TFA, reflux, 12 hO CO2R2

Ar

OH

CO2R2

Scheme 37

2,2-Dimethyl-2H-chromenes are obtained by a one-pot Re(I)-catalyzed reaction

of substituted phenols with 2-methyl-3-butyn-2-ol <11TL3926>, whereas

4-carbonitrile derivatives can be prepared by a one-pot tandem reaction of 2-(2-

hydroxyphenyl)acetonitrile with 1-aryl-2-bromoethanones in the presence of base

(Scheme 38) <11H(83)1355>.

OH

CN

ArR1

O

Br O

Ar10 examples, 29–99%

CN

R1

K2CO3, 1,4-dioxane

reflux, 4 h

Scheme 38

Highly functionalized 2H-chromenes are obtained by a one-pot formal [3þ3]

cycloaddition reaction of bromobenzoquinones and vinyl stannanes (Scheme 39).

The three-step sequence likely involves Stille coupling, HMPA-mediated enoliza-

tion, and thermal electrocyclic ring closure <11T9779>.

O

R1

R2

O

R3

Br

O

R1

R2

HO

R3

OMe

O

OMeBu3Sn

O Pd(PPh3)4 (1–2 mol%)HMPA (2–5%, v/v)

PhMe, reflux0.5–1.5 h

6 examples66–71%

HMPA = hexamethylphosphoramide

Scheme 39

The CuI-promoted aza-Diels–Alder reaction of 5-aminoindoles with

O-propargyl salicylaldehydes is performed in the ionic liquid [Bmim][BF4], and a

range of dihydro-2H-chromenes are obtained (Scheme 40) <11TL4857>.

O

R5


N

R4 R1

R3

R2H2N CHO

O

N

NR2

R1

R3

R4

R5

CuI (10 mol%)

[Bmim][BF4]90–95 �C

Scheme 40


The synthesis of 2-perfluoroalkyl 4H- and 2H-chromenylphosphonates is

conditions-controlled: regioselective cycloaddition of salicylaldehydes with perfluor-

oacetylphosphonates using i-Pr2NEt furnishes 4H-chromenes 22, while in the pres-

ence of triphenylphosphine, 2H-chromenes 23 are obtained as major products

(Scheme 41). The acid-catalyzed isomerization of the formed 4H-chromenes also

affords the corresponding 2H-regioisomers <11JOC71>.

R1OH

CHOR3

R2

P(O)(OEt)2

RF

RF = CF3

RF = C2F5

O

R3

R2

R1

OH

P(O)(OEt)2

RF

O

R3

R2

R1

P(O)(OEt)2

OH

RF

PPh3

DMSO, rt, 4–18 h

DMSO, rt, 3–18 h6 N HCl (10 mol%)CH2Cl2, rt, 6–18 h


18 examples96–99%

9 examples, 40–95%only RF = CF3

(i-Pr)2NEt

22

23

Scheme 41

2-Bromobenzyl bromide and b-keto esters undergo a Cu(I)-catalyzed domino

C-benzylation–O-arylation reaction in ligand-free conditions leading to the selective

formation of 4H-chromenes <11OL1972>. The Pd-catalyzed cascade reaction of

2-alkynylhalobenzenes with 2-alkynylphenols in the presence of tricyclohexylpho-

sphine (PCy3) as ligand affords indeno[1,2-c]chromenes (Scheme 42) <11CC5298>.

Br

R2

R1

OH

R4

R3

O

R3

R2

R4R1

Pd(OAc)2 (5 mol%)PCy3 (10 mol%)

NaOMe, 1,4-dioxanereflux

19 examples63–96%

Scheme 42

2-Amino-5-hydroxy-4H-chromenes are obtained in good yields (73–90%) by a

one-pot condensation reaction of resorcinols with 2-benzylidenemalononitriles

<11T8271>. Asymmetric 2-amino-4H-chromenes are readily accessible via a Mannich

cyclization–tautomerization cascade sequence in which malononitrile acts as both


nucleophile and electrophile, in the presence of bifunctional chiral thiourea organocata-

lyst 24 (Scheme 43)<11CEJ7781, 11TL6137>. Related derivatives result from tandem

Michael addition–cyclization reactions of cyclohexane-1,3-diones and 2-cyano-3-

phenylacrylates catalyzed by a Salen-Co(II) complex <11EJO137> or a bifunctional

chiral thiourea organocatalyst <11TL6792>, in good yields and enantioselectivity.

OH

HN

SO2Ph

R2

R1 CN

CN O

CN

NH2

HNR2

R124 (10 mol%)

Li2CO3

CH2Cl2, 0 �C9 examples, 81–94%

up to 89% ee

NH

S

NH N

CF3

F3C

24

OH

R1

NO2

CN

CN O

CN

NH2

NO2

R124 (10 mol%)

Et2O, rt


Scheme 43

Several cinchona-based catalysts 25 have been designed to perform the asymmet-

ric [4þ2] cycloaddition reaction of salicyl N-tosylimine derivatives with allenic

esters. The corresponding 4H-chromenes are obtained in moderate to good yields

and high enantioselectivity (Scheme 44) <11TA1239>.

OH

NR2

R1CO2R3

O

CO2R3HN

R2

R125 (10 mol%)

mol. sieves 4 ÅEt2O, 25 ºC, 24 h


N

OH

N

R425

Scheme 44

The synthesis of 4-substituted 2-amino-3-cyano-4H-chromenes can be achieved

by a one- or two-step sequence starting from salicylaldehydes, cyanoacetamide, and

isocyanides in moderate to good overall yields (30–77%) (Scheme 45) <11EJO848>.

Similar products arise from the Zn-catalyzed reaction of salicylaldehydes, malononitrile,

and indoles, in good yields (37–89%) and enantioselectivity (up to 90% ee)

<11OL4910>. Other multicomponent coupling reactions of triflates as aryne precur-

sors, DMF and ketones, or b-keto esters as active methylenes afford, respectively, chro-

menes and coumarins (Scheme 46) <11AGE6638>.

CHO

OH

R1

NCNH2

O

O

R1

NH

NH2

O

O

R1

NH2

CN

OHNR2

piperidine

EtOH, rt, 2 h

R2-CN

TFA, EtOHrt

R2-CN 1. piperidine 2. TFA, EtOH, rt

Scheme 45

TMS

OTf

R1

O

NMe2EWG

OR2

O

R1EWG

R2OH

O

R1EWG

O

TBAF, rt

rt

8 examples40–86%

5 examples27–86%

Scheme 46


Chromeno[40,30:4,5]thiopyrano[2,3-d][1,3]thiazol-4-ium-2-olates are obtained

by a domino Knoevenagel–hDA oxidation reaction based on the appropriate 2-(2-

propynyloxy)benzaldehydes and 4-thioxo-1,3-thiazolidin-2-one (Scheme 47)

<11TL2324>. When N-substituted 4-thioxo-1,3-thiazolidin-2-one <11TL2324>and 5-pyrazolones <11TL2853> react with 2-(2-propynyloxy)benzaldehydes, only

the Knoevenagel–hDA reaction took place. Indole-annulated dihydropyran[3,4-c]

chromenes result from the Knoevenagel condensation of O-propargylated salicylal-

dehydes with indolin-2-ones followed by a microwave-assisted intramolecular

hDA reaction of the formed adducts <11TL4337>.

R1 O

CHO SNH

S

O

O S

SN

O

R1NaOAc, AcOHreflux, 4 h

6 examples26–77%

Scheme 47

The total syntheses of two chromene natural products were accomplished in a

multistep sequence having the 2H-chromene 26 as the key intermediate. Racemic

vestitol was obtained in a 29% overall yield and bolusanthin III in 21% overall yield

(Scheme 48) <11SL1605>.

OH

OH

BnO

OMeBnO

O

I O

OH

BnO

O OBn

OMe

OBnOOBn

OMe

OHOOH

OMe

OHOOH

OMe

(i)

(ii)

(iii)(iv)

Reagents: (i) K2CO3, Me2CO, reflux 16 h, 78%; (ii) (a) PPh3×HBr, MeCN, rt, 1 h; (b) t-BuOK, MeOH,reflux, 24 h, 70%; (iii) Pd/C, EtOAc, H2 (2.4 bar), rt, 14 h, 84%; (iv) BCl3, pentamethylbenzene,CH2Cl2, -78 �C, 15 min, 61%

rac-vestitolbolusanthin III 26

Scheme 48


The asymmetric total synthesis of (�)-variabilin and (�)-glycinol involves a

Buchwald–Hartwig coupling reaction <11OL3686>, whereas forming the tricyclic

skeleton of phomactin A involved a Prins/Conia-ene cascade cyclization (Figure 1)

<11JOC6534>.

O

O

HO

OHOH

H

O

O

MeO

OMeOH

H

11 steps, 5.7% overall yield 13 steps, 3.0% overall yield

(-)-Variabilin (-)-Glycinol

O

O OHOH

H

Phomactin A

Figure 1

For heliannuol E and epi-heliannuol E, the asymmetric total synthesis needed 10

and 13 steps, respectively (Scheme 49). The formation of the chroman motif is con-

sidered to proceed through an intramolecular phenol attack on the sulfate moiety in

the former case and an acyl transfer-secondary carbocation capture sequence in the

latter <11TL5802>.

Br

OEt

O

9 stepsOH

OH

OS O

OO

O

HO

OH

Heliannuol E

(ii) H2SO4 20%ether/CHCl3

(i) K2CO3DMF/MeCN

82%

8 steps

OH

OH

OHAcO

OAc

OAc

OAc

O

HO 4 steps

O

HO

OH

epi-Heliannuol E

p-TsOHPhMe, rt

86%

Scheme 49

2H-Chromans are obtained by a diastereoselective Et3SiH/TMSOTf reductive

deoxygenation of substituted 2-sulfinylmethylchroman-2-ols and their methyl ketals

<11EJO3864>.

Several Rh(II) catalysts have been used for the decomposition of diazo compound

27; a diastereomeric mixture of chromans, resulting from the intramolecular

1,6-C��H insertion, and the Z-isomer of the b-elimination are the products obtained

(Scheme 50) <11T3071>.

CO2Me

ON2

Ph

Rh(II)

PhMe O Ph

CO2Me

O Ph

CO2Me

O Ph

CO2Me

27

Scheme 50


Bimetallic tandem cyclization of olefins proved to be a versatile route for the syn-

thesis of substituted chromans <11TL3509>; the presence or absence of base is

responsible for the chemoselectivity (Scheme 51). [5,6]-Bisbenzannelated spiroketals

are the major products of the tandem Wacker cyclization–aroxylation in the absence

of base, whereas 2-substituted chromans are formed in the presence of base through

tandem Wacker cyclization–Michael addition reaction <11SL1579>.


PdCl2 (10 mol%)

MeOH, O2, 60 ºC

8 exam

+

ples

OH

R1

R2

OH

R3

CuCl2 (20 mol%)

PdCl2 (10 mol%)

Cs2CO3 (20 mol%)MeOH, O2, rt

CuCl2 (20 mol%)

O O

R1

R2

R3

O

R1

R2

HO R3

36–71% 22–47%

OH

R1

R2

OMe

O

R3

Scheme 51

A stereoselective PtCl4-catalyzed cycloaddition reaction of o-quinone methides

with olefins affords trans-2,3-disubstituted chromans. The intramolecular version

led to decreased diastereoselectivity <11T3904>.

4-Amino-3-methylenechromans result from the CuI-catalyzed reaction of

O-propargyl salicylaldehydes with dialkylamines (Scheme 52). The mechanism

involves the formation of an iminium ion followed by intramolecular inverse elec-

tron demand ene-type reaction, with the loss of an alkyl group from the dialkylamine

<11T1617>.

CHO

+R1

ONHR2

2 R1

N

O

R2HCuI (10 mol%)PCy3 (10 mol%)

DMF, rt13 examples, 59–81%

Scheme 52

A (1:4) mixture of AgOTf/t-BuCl is implicated in the synthesis of

2,2-dimethylchromans through a hidden Br�nsted acid catalysis rather than a silver

catalysis of phenols and isoprene (Scheme 53) <11JOC9353>. A number of

2-arylchromans were synthesized through the aldol condensation of salicylaldehydes

and acetophenones and subsequent reduction and cyclization of the

20-hydroxychalcone intermediates <11TL6716>.

OH

R1

O

R1AgOTf (1 mol%)t-BuCl (4 mol%)

1,2-DCE, rt6 exam+ ples, 59–92%

Scheme 53


2-Acetyl-1-naphthol and ethyl 3-hydroxy-2-naphthoate undergo a Grignard

reaction, dehydration of the corresponding tertiary alcohols, and hDA dimerization

giving benzochromans 28 and 29 <11JHC952>.

O

HO

O

HO

28 29

Phosphine-mediated annulation of salicylaldehydes and g-substituted allenoates

provided several functionalized chromans 30 and 1,3-dienes 31, depending on the

phosphine catalyst (Scheme 54) <11T1053>.

CHO

OH

+R2

CO2Et

R1 O

R2

OH

CO2Et

R2

OH

CO2Et

R1

OH

P(4-ClC6H4)3

CH2Cl2, rt

PPh3

1,4-dioxanert

6 examples, 34–84% 13 examples, 47–92%R1 = H 3031

Scheme 54

Amine 34-catalyzed reaction of 2-(2-nitrovinyl)phenols with aldehydes led to

4-nitromethylchroman-2-ols 32, as asymmetric cascade Michael-acetalization

adducts. Further oxidation furnished the corresponding 3,4-dihydrocoumarins 33

(Scheme 55) <11OBC2715>. Using 34, b-tetralones reacted with a,b-unsaturatedaldehydes giving 4-substituted benzo[f]chroman-2-ols (50–99%) with high enantios-

electivity (up to 96%) <11OBC7510>.

R1

OH

+

NO2

R2 CHOR1

O

R2


OH

O2N

R1

O

R2

O

O2N

34 20 mol%)PhCO2H (20 mol%)

CH2Cl2, rt

IBXCHCl3reflux

NH

Ph

OTMSPh

32 33

34 IBX = 2-Iodoxybenzoic acid

Scheme 55

Aziridination of aryl cinnamyl ethers followed by intramolecular arylation provided

a one-pot synthesis of 3-amino-4-arylchromans. This regio-, diastereo- (dr>99:1),

and enantioselective (up to 95%) methodology used copper catalysts and chiral bis-

oxazoline ligands <11JOC7334>. An enantioselective synthesis of 4-aminochromans

35 was achieved by an organocatalyzed asymmetric cascade aza-Michael–Michael

addition reaction of anilines with nitroolefin enoates (Scheme 56) <11OL808>.

OCO2Et

NO2R

+

4

R3

R2

NH2

R1

O

HN

NO2

R4

R2

R1

CO2EtR3

N

MeO

HN

S

HN

CF3

CF3H

N

36 (10 mol%)

i-PrOH, 23 ºC

17 examples, 71–96%up to ee > 99%, dr = 95:5

35

36

Scheme 56


A series of novel structurally complex chroman derivatives resulted from a dom-

ino Knoevenagel–hDA reaction of 4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-

one 37 with O-propargylated 38 and O-allylated salicylaldehydes 39 (Scheme 57)

<11S3716>. In aqueous solution, 3-hydroxy-2-naphthalenemethanol and several

vinyl ethers <11JA5573> and immobilized vinyl ethers <11JA15730> undergo

light-induced hDA reaction to give benzo[g]chromans.

N N

OH

O

PhN N O

Ph

O O

R2R3

R1 N N OPh

O O

R2R3

R1

H

HR2

R1R3

O

CHO

R2R1R3

O

CHO

EDDAPhCl, reflux

EDDA, CuIPhCl, reflux

5 examples, 82–92% 7 examples, 84–95%EDDA = ethylenediammonium diacetate37

38 39

Scheme 57

Benzochromans are isolated from the reaction of salicylaldehydes and glycals

<11CC10266>, and of salicylaldimines and 2,3-dihydro-2H-furan <11CEJ13684>,

using Sc(OTf)3 as catalyst, and by FeCl3�6H2O-mediated dimerization of

2H-chromenes <11OL6480>. Other examples were obtained after oxidative cycliza-

tion of vinylogous esters in the presence of iodobenzene and m-chloroperbenzoic acid

<11CC11778>, and formal intramolecular 1,3-dipolar cycloaddition of ketoimines

under an organic Lewis acid cum oxidant (Scheme 58) <11CC1285>.

O R1

N CO2R2

Me

O

NMe

CO2R2

R1

HPhIOCH2Cl2, MgSO4

rt, 3 h


Scheme 58


In solvent-free conditions, the one-pot, three-component reaction of

2-naphthol, a,b-unsaturated aldehydes, and amines results in the preparation of

enantiopure benzo[f]chroman-2-amine derivatives (Scheme 59) <11TA1542>.

OH

CHO++

R1

R2

H2NR3

O

R2

R1

NH

R3

8 examples, 42–51%70 �C

12–72 h

Scheme 59

6.4.2.3 [2]Benzopyrans and Dihydro[2]benzopyrans(Isochromenes and Isochromans)A facile one-pot synthesis of isochromenes is carried out in the presence of a rho-

dium catalyst in the oxidative coupling reaction of benzyl alcohols and alkynes

<11JOC9548>. Gold(I)-catalyzed rearrangement of arylmethoxylated alkynylaziri-

dines gave spiro[isochroman-4,20-pyrrolines] in high yields <11CC6665>, while

the enantioselective cycloisomerization of alkynols is substrate controlled: electron-

donating groups provide isochromenes as major products via 6-endo-dig cyclization,

while electron-withdrawing groups induce 5-exo-dig cyclization to afford

1,3-dihydroisobenzofurans <11JOC8869>.

Tetrahydro-1H-isochromenes are obtained by a stereoselective sequential

three-component Michael addition–aldol–Horner–Wadsworth–Emmons–[4þ2]

cycloaddition reaction (Scheme 60) <11JOC1440>.

R1XLiO

R2

P(O)Ph 2

OHC+ +

R3 O

XR1

R2R3

DME

rt reflux7 examples

39–61%

Scheme 60

Microwave irradiation was applied to the cyclization of 2-bromobenzyl

propargyl ethers using Pd(PPh3)4 as catalyst and sodium formate as reducing agent.

A wide range of isochromans were prepared in a regio- and stereoselective process

(Scheme 61) <11SL2733>. The intramolecular hDA reaction of benzocyclobutenes

gave pyrrole- and pyridine-fused isochromans under microwave (mW) conditions

(Scheme 62) <11TL3413, 11TL3417>.

O

BrMeO

MeOR2

R1

R3

OMeO

MeO

R3

R1

R2

Pd(PPh3)4 (3 mol%)HCOONa

DMF–H2O (3:1)μW (300 W)

14 examples60–82%

Scheme 61

O

N

R2R3

R4R5

Bn

R1

O

n

R2R3

R4R5

O

NBn

n

O

H

R1

R2R3

R4R5

O

NBn

n

O

H

R1

cis trans

μW, 210 ºC

n = 1, PhBr

n = 2, 1,4-dioxane:H2O (10:1)

Scheme 62


6.4.2.4 Pyranones2H-Pyran-2-ones are accessible from an intramolecular ring-opening reaction of

vinylidenecyclopropane diesters catalyzed by Re2(CO)10 (Scheme 63). The regiose-

lective carbon–carbon bond cleavage is sensitive to the electronic properties of the

substituents <11EJO1099>.

R1O2C CO2R1

R2 O OR2

CO2R1Re2(CO)10 (5 mol%)H2O (10 or 20 equiv)

PhCl or 1,2-Cl2C6H4


Scheme 63

A Pd–NHC complex catalyzes the completely selective 6-endo-dig cyclization of

internal acetylenes to the corresponding pyran-2-ones in quantitative yields, using

the appropriate acidic conditions (Scheme 64) <11JOC9817>. Other pyran-2-

one-fused heterocyclic compounds were obtained by an alkaline CuI-mediated tan-

dem coupling oxacyclization reaction of b-iodo-a,b-unsaturated carboxylic acids

with terminal alkynes <11JOC8347, 11OBC1212>.

N

S

R1

O

R2

OO

SiMe3

N

S

R1

OO

OR2

Pd-NHC

CH2Cl2:BF3 Et2O (95:5)×

Scheme 64

Functionalized pyran-2-ones are obtained by annulation of alkynyl ketones with

b-keto esters in the presence of t-BuOK (Scheme 65) <11SC3147> or with active

methylene compounds in the presence of sodium hydride in DMSO at room tem-

perature <11SC2738>.

R1

O

R2 OEt

O

+

O

O O

O

R2

R1

PPh3 (25 mol%)t-BuOK (25–75 mol%)

CH2Cl2 or PhMe24 h

28 examples45–82%

Scheme 65


Gold(I)-catalyzed cascade reaction of propiolic acids and terminal alkynes pro-

vided substituted pyran-2-ones. Dimerization of propiolic acids occurred when a dif-

ferent counter ion is used (Scheme 66) <11OL2834>.

HO

R1

O R2

(Ph3P)AuCl (5 mol%)AgOTf (5 mol%)

CH2Cl2

(Ph3P)AuCl (5 mol%)AgSbF6 (5 mol%)

PhMe, rt

O

O

R2 R1

O

O

R1 OH

O

R1

2 examples, R1 = Ph, 81%; R1 = n-Pr, 56% 23 examples, 20–95%

Scheme 66

Dihydropyran-2-ones are readily available through a cascade epoxide opening

and lactonization of g-epoxy-a,b-enals, catalyzed by a thiazolium salt

<11OBC5948>. NHC-mediated annulation reactions of enals with vinyl ketones

also afford several 3,4-dihydro-2H-pyran-2-one derivatives <11TL5992>, the

asymmetric version occurring in a highly regio- and stereoselective way

<11AGE1910>. The reaction mechanism is consistent with a Michael-type addition

and subsequent intramolecular cyclization. Several chiral NHC-catalyzed annulation

reactions of a,b-unsaturated enals <11OL4080, 11OL4966> and ynals

<11CC8670> with 1,3-diketones (Scheme 67) allow the synthesis of functionalized

3,4-dihydro-2H-pyran-2-ones 40, with excellent enantioselectivities.

R1 CHOR2 R3

O O

O OR3

R1

R2

O

NN

NOMes

Cl

41 (10 mol%)

mol. sievesPhMe, 80 ºC, 8 h


40 41

+

-4 Å

Scheme 67

With NHCs as catalyst, the formal DA reaction of 2-(p-nitrobenzoyloxy)-3-

phenylpropanal with an b,g-unsaturated a-ketoester affords a 3,4-dihydropyran-2-

one with lower diastereoselectivity <11CC373>. However, a similar approach

using chiral NHC catalyst 43 for the reaction of chalcones with formylcyclopropanes

provides 3,4-dihydropyran-2-ones 42 with high diastereo- and enantioselectivities

(Scheme 68) <11OL5366>. DA reaction of enals and alkylidene diketones, cata-

lyzed by 43 <11OL4708>, and of a-halo-b-substituted propanal derivatives with

a,b-unsaturated ketones, catalyzed by 41 <11T9329>, gives 3,4-dihydropyran-2-

ones with excellent enantioselectivity. A wide range of derivatives are also formed

by the enantio- and diastereoselective cycloaddition reactions of b,g-unsaturated a-ketoesters with azalactones catalyzed by a chiral Br�nsted base <11CEJ1760>, or

with oxazolones catalyzed by cinchona alkaloid derivatives <11T3337>, and

Brassad-type diene with aliphatic aldehydes catalyzed by a In(III) complex

<11OL3868>.

R1

OCHO

Ar1 Ar2

O

O OAr2

Ar1

R1

O

43 (12 mol%)

DBU (10 mol%)mol. sieves

THF, rt31 examples, 32–99%

20:1 dr, 99% ee

NN

NOMe

-

s

BF442

43

+

+

4 Å

Scheme 68


An isothiourea catalyzes the highly diastereo- and enantioselective intermolecular

Michael addition–lactonization of arylacetic acids with b,g-unsaturated a-keto esters

giving the anti-3,4-disubstituted pyran-2-ones (Scheme 69) <11JA2714>.

ArOH

O

R1 CO2R2

O+

O O

R1

R2O2C

44 (10 mol%)t-BuCOCl, i-Pr2NEt

CH2Cl2, –30 ºC, 16 h

21 examples, 62–87%up to 98:2 dr and 99% ee

N

N

SPh44

Ar

Scheme 69

The preparation of fluorinated 5,6-dihydro-2H-pyran-2-ones is accomplished in

a multistep sequence starting from the fluoroallylboration of aldehydes. In the final

step, the lactonization of the d-hydroxy acids formed under Yamaguchi conditions

leads to the 5,5-difluoropyran-2-ones (Scheme 70) <11OL1302>. Oxidative ring

closure of 4-fluoro-1,5-dienols also affords 5-fluorodihydropyran-2-ones

<11JOC6525>. Regioselective cyclization of g,d-unsaturated carboxylic acids pro-

vides 5,6-dihydropyran-2-ones using diphenyl diselenide as catalyst and hypervalent

iodine reagents as oxidants <11OL6504>.

HO2C

R1

OH

F F

O

O

F FR1

(i) Et3N, THF, rt

(ii) DMAP, PhMereflux

2,4,6-Cl3C6H2COCl

7 examples

Scheme 70

3,3-Dichloro-4-hydroxytetrahydro-2H-pyran-2-ones were prepared by cathodic

reduction of 2,2-disubstituted 3-oxopropyl trichloroacetates in dichloromethane-

tetraethylammonium chloride. If the reaction mixture is kept at 3 �C for 18 h,

3-chloro-4-hydroxy-5,6-dihydropyran-2-ones are the products obtained

<11EJO4681>.

A three-component reaction of isocyanides, allyl ketones, and a,b-unsaturated car-boxylic acids followed by Ru-catalyzed ring-closing metathesis led to 5,6-dihydro-

pyran-2-ones (Scheme 71) <11EJO4335>. The same type of ring-closing metathesis

was applied in the synthesis of biologically active 5,6-dihydro-2H-pyran-2-ones

<11TA1749>.

R1CN

OR2 O

+ +

HO

R3

R1

HN

O

R1

HN

O

OR2

R3

OO O

R3

R2PhMe, 70 ºC

Ru-catalyst


rt

CH2Cl2

Scheme 71


The asymmetric bromolactonization of alkenoic acids catalyzed by thioureas and

thiocarbamates provides 3-bromotetrahydropyran-2-ones in moderate to good yields

(up to 95% ee) <11OL2738, 11TL4892>. A one-pot procedure, involving oxymer-

curation, cyclopropane ring opening, and reductive demercuration of cyclopropyl

aldols, resulted in a series of chiral tetrahydropyran-2-ones (Scheme 72)

<11OL3592>.

R1 R3

O

R2

OH

H

R4

O O

R2

OH

R3

R4


(i) Hg(OCOCF3)2, CH2Cl2, rt;then NaCl (aq.)

(ii) NaBH4, NaOH, MeOH

Scheme 72

In the synthesis of leiodermatolide, the tetrahydropyran-2-one 46 motif was pre-

pared by a samarium-catalyzed internal Reformatsky–aldol reaction of ester 45

(Scheme 73) <11SL191>. In the synthesis of gonithalamin analogues, the Pd-

catalyzed allylic oxidation of hept-6-enoic acids provides the appropriate

tetrahydropyran-2-one, under White conditions <11SL2689>. Lactonization to

the tetrahydropyran-2-one nucleus of leiocarpin C <11HCA1102> and (þ)-

tanikolide <11H(83)2601> was carried out with Amberlyst 15 in MeCN, while

for simplactones A and B Bu4NF in THF was used <11HCA1481>.

OBn O O O

Br

OBn O

Sm, CH2I2THF, –78 ºC

88%O

OH

45 46

Scheme 73

The construction of the 2,6-dihydropyran-3-one nucleus in (þ)-bresisamide was

based on a key Achmatowicz rearrangement of a properly functionalized furan moi-

ety <11OL3636>. Tetrahydropyran-3-ones can be synthesized through a tandem

carbonyl ylide formation–cycloaddition reaction of 2-diazo-3,6-diketoesters with

styrene or phenylacetylene, catalyzed by polymer-supported dirhodium(II) com-

plexes, under continuous flow conditions (Scheme 74) <11CEJ13992>.

OPhN2

CO2t-Bu

O

P+

+

+h

O

O

CO2t-BuPh

Ph

O

O

CO2t-BuPh

Ph

Ph O

O

CO2t-BuMe

Ph

OMeN2

CO2t-Bu

O

Rh(II) catalysts

PhCF3

Rh(II) catalysts

PhCF3

Scheme 74


Several sulfonamide organocatalysts have been developed for the asymmetric

hDA reaction of ethyl glyoxylate with Danishefsky’s diene. Treating the adduct with

trifluoroacetic acid gives the corresponding 2,3-dihydropyran-4-one (Scheme 75)

<11H(83)2525>. Enantioselective salen-Cr(III)-catalyzed reaction of this diene with

an aldehyde allows the preparation of the 2,3-dihydropyran-4-one core, an interme-

diate in the synthesis of galantinic acid <11EJO1223>.

TMSO

O

+

Me

HOEt

O

O

47 (30 mol%)

Et2O, –40 ºC, 24 hO

O

O

OEt

R2

NH

SR1O

ODanishefsky's diene

TFArt, 1 h

47

Scheme 75

The synthesis of several di- and tetrahydropyran-4-ones was accomplished by pal-

ladium cross-coupling reactions of thioesters with terminal alkynes or alkenylboronic

acids. In the final step, an intramolecular AgOTf-promoted oxa-conjugate cyclization

of the alkynyl and alkenyl derivatives led to dihydropyran-4-ones and tetrahydropyran-

4-ones, respectively (Scheme 76) <11T4995>. A similar reaction was used in the syn-

thesis of a dihydropyran-4-one precursor of diospongin A <11TA1725>.

OMPM

STol

O

R1

OMPM

O

R1

R2

OMPM

O

R1

R2

OH

O

R1

R2O R2R1

O

AgOTfCH2Cl2

rt

DDQpH 7

CH2Cl2, rt

OH

O

R1

R2

O R2R1

O

H2, Pd/C

(HO)2BR2

R2

CuI, Et3N

Pd(0)/ligand

Pd(0)/ligand

CuTC

DDQbuffer

buffer

pH 7CH2Cl2, rt

AgOTfCH2Cl2

rt

OMPM = methoxyphenylmethyloxy CuTC = copper(I) thiophene-2-carboxylate

Scheme 76

Tetrahydropyran-4-ones are available through an enantioselective Maitland–Japp

reaction using Chan’s diene as nucleophile. The reaction accommodates a wide


range of substituents in either the first or in the second aldehyde reaction partner

<11T4960>. Several gold(I)-phosphine complexes have been involved in the asym-

metric synthesis of tetrahydropyran-4-ones, in a two-step sequence starting from

4-(alkoxyalkyl)oxy-1-butynes, with a phosphine ligand playing an important role

in the diastereoselectivity (Scheme 77) <11CEJ1433>.

OEt

OR1 Me OR1 Me

+

O

OR1 Me

O(i) Au(I) (3 mol%)

CH2Cl2, rt

(ii) p-TsOH (10 mol%)rt, 1 h

Major Minor


Scheme 77

6.4.2.5 CoumarinsA tandem ring-closing metathesis–allylic oxidation sequence of o-allyloxystyrenes led to

the formation of polysubstituted coumarins <11CC5879>. Several coumarins were

also prepared by a Lewis acid-promoted cyclization of aryl 3-(dimethylamino)prop-2-

enoates, which are obtained from the appropriate phenols<11HCA185>. The selective

reaction of 3-(2-hydroxyphenyl)propiolates 48 with iodine is conditions-controlled:

using toluene as solvent gives coumarins 49, while DMF affords chromones 50

(Scheme 78) <11TL4164>.

OH

R1

CO2R2

O O

I

I

R1

O

O

CO2R2R1I2PhMe, 90 ºC

12 hDMF, 110 ºC

72 h

I2

4849 50

Scheme 78

Under solvent-free conditions, the synthesis of coumarins can be accomplished

either by hydroarylation of propiolates with substituted phenols using ZnCl2 as

catalyst <11S3692> or by Knoevenagel condensation of salicylaldehydes/phenols

and b-keto esters using a supported base as catalyst <11EJO2874> or mediated by

thiourea dioxide (Scheme 79) <11OBC6943>. Coumarin-type compounds are

obtained by a chemoselective Knoevenagel condensation of aromatic aldehydes with

Meldrum’s acid to give the corresponding 5-arylidene derivatives followed by a tan-

dem enol lactonization with a variety of active methylene compounds, using poly

(ethyleneglycol)-stabilized Ni nanoparticles as catalyst <11TL3666>.

CHOR1

OR2

O O

R1

O O

CHO

OH

OHR1

A: PS-TBD (10 mol%)

B: C(NH2)2SO2

(5 mol%)

B: C(NH2)2SO2

(5 mol%)

R1

O O

A: 5 examples, 60–96%



Scheme 79


Highly functionalized coumarins 51 result from the reaction of salicylaldehydes

with a,b-unsaturated aldehydes in the presence of catalytic amounts of NHC gener-

ated in situ from 52 (Scheme 80). This synthesis involves a redox esterification of

a,b-unsaturated aldehydes with simultaneous aldol condensation <11SL635>.

8-Formylcoumarins were also synthesized from salicylaldehydes and dimethyl

acetylenedicarboxylate by an aromatic electrophilic substitution mediated by a

vinyltriphenylphosphonium salt <11SL694>.


OH

CHO

+

R4

R3

R2

R1

R5

OH

R4

R3

R2

R1O O

R5

52 (20 mol%)Cs2CO3

o-xylene, 120 ºC

NN

Cl–

5251

+

Scheme 80

Ni-promoted cycloaddition of o-aroyloxybenzonitriles with alkynes offers direct

access to coumarins (Scheme 81). The mechanism involves an unusual cleavage of

two independent C��CN and C��CO bonds <11JA11066>.

O

CN

R3R2

Ar

O

R1

O O

R1


R3

R2

Ni(0) (10 mol%)

P(CH2Ph)3 (10 mol%)

MADPhMe, 120 °C,12 h

MAD = methylaluminium bis(2,6-di-t-butyl-4-methylphenoxide)

Scheme 81

A bimetallic Pt/Sc system catalyzed the reaction of tertiary amines and substituted

salicylaldehydes (Scheme 82). This one-pot synthesis involves aldol condensation,

cyclization, and ring-opening processes to obtain the 3-(aminoalkyl)coumarins

<11JOC342>.

N

CHO

OH

R3R1R2

n

n = 1,2O O

R3

R2

NH

R1

n

K2PtCl4 (5 mol%)Sc(OTf)3 (5 mol%)

1,4-dioxane/H2O (2:1)23 examples

27–71%

Scheme 82


A three-component coupling reaction of benzyne, DMF, and activemethylene com-

pounds readily formed 3-substituted aliphatic and aromatic coumarins<11CC8512>.

In solvent-free conditions, several 2H-chromene-2-thiones result from the reac-

tion of b-oxodithioesters and various salicylaldehyde-type compounds, catalyzed by

InCl3 in the presence of urea (Scheme 83) <11T584>.


R1

MeS

O

S

CHO

OH

R2

R3

CHO

OH

orInCl3, urea

100 °C

O S

O

R1

R2

R3

O S

O

R1or

Scheme 83

A bimetallic Pd/Cu system catalyzes the regiospecific synthesis of

3,4-dihydrocoumarins involving a [1,3]- or [3,3]-sigmatropic rearrangement and

cyclization of 2-(aryloxymethyl)prop-2-enoates (Scheme 84) <11SL3026>.

CO2Me

O

R1

CO2Me

O

R1

Pd(OAc)2 (5 mol%)Cu(OTf)2 (5 mol%)

[1,3]-sigmatropicrearrangement

O O

R2

R1

O

O

R1

Pd(OAc)2 (5 mol%)Cu(OTf)2 (5 mol%)

[3,3]-sigmatropicrearrangement



R2

Scheme 84

Highly enantio- and diastereoselective synthesis of 3,4-dihydrocoumarins is

achieved via a domino reaction of oxazolones with o-hydroxy aromatic aldimines

in the presence of organocatalysts. The cis- and trans-isomers are obtained as the

major products in the presence of guanidine 53 and bisguanidium salt 54, respec-

tively (Scheme 85) <11OL5060>. The asymmetric domino Michael–acetalization

reaction of 2-hydroxynitrostyrenes and 2-oxocyclohexanecarbaldehydes also

provides 3,4-dihydrocoumarins with good diastereo- and enantioselectivities

<11OBC382, 11OL5758>.

OH

N Ar1R1

NO

R2

R3O

O

R1

O

NHAr1

R3

NHCOR2

O

R1

O

NHAr1

R3

NHCOR2

cis-(3S,4S) trans-(3S,4R)

54.HBArF4

(5 mol%)

THF:PhMe (1:1)–20 °C

53 (10 mol%)

THF:PhMe (1:1)–20 °C

NN

N

H

1-adamantyl

CyNH

O

Cy

NN

N

H

CyNH

O

Cy

NN

N

H

Cy HN

O

Cy

Ph Phmajor major

H

5354

+

Scheme 85


The isolation and characterization of the isochromen-4-yl-gold(I) complex 55

allows rationalization of the glycosylation mechanism of glycosyl o-alkynylbenzoates

<11AGE8329>. The oxidative cyclization of o-alkynylbenzaldehydes promoted by

atmospheric oxygen and an NHC provides a mixture of phthalides and isocoumarins

<11OL2228>. Regioselective cyclization of 2-alkynylaryl esters promoted by FeCl3for the synthesis of several isocoumarins is conditions-controlled: the presence

and absence of a diorganyl dichalcogenide favor the presence and absence of the

chalcogen motif in the structure, respectively (Scheme 86) <11JOC6789>. Isocou-

marins are also obtained by regiocontrolled rearrangement of isobenzofurans

<11OL2086> and photochemical rearrangement of 3-(2-formylphenyl)acrylates

<11CC11098>. A diastereomeric mixture of 3,4,4a,7,8,8a-hexahydroisocoumarins

is produced by an intramolecular DA cycloaddition of ester-tethered 1,3,9-

decatrienes under microwave irradiation. The same types of isocoumarin are

formed by a microwave-assisted tandem Wittig–intramolecular DA cycloaddition

of 3,5-hexadien-1-yl a-bromoacetates with glyoxal derivatives or formaldehyde, in

the presence of PPh3 and 2,6-lutidine <11T179>.

O

OMe

R2

R1

O

R2

O

R1 O

R2

O

R1

YR3

FeCl3CH2Cl2

FeCl3, (R3Y)2

CH2Cl2

Y = Se, S, Te; R1 = H, Me; R2,R3 = alkyl, aryl

O

nBu

Au

O

PPh355

Scheme 86

(Thio)isocoumarins result from a one-pot decarboxylative cycloaddition of (thio)

phthalic anhydride with allenes catalyzed by a nickel(0) catalyst (Scheme 87)

<11OL1374>.

XR2

R1R3

R4

O

O

X

R2

R1

R4 R3

ONi(0) (10 mol%)

PMe2Ph

X = O, MeCN, reflux, 12 hX = S, PhMe, 80 °C, 12 h

Scheme 87


3,4-Dihydroisocoumarins are formed through a Heck–Matsuda reaction of an

o-carboxybenzenediazonium salt with styrenes. Palladium acts as Heck arylation

catalyst, and in some cases, there is an acid-catalyzed cyclization reaction

(Scheme 88) <11TL6342>.

CO2H

+N2BF4 R1

O

O

R1

Pd(OAc)2 (1 mol%)

EtOH, 80 °C, 1 h


Scheme 88

6.4.2.6 Chromones and ChromanonesTreating propargyl alcohols with Jones reagent provides a number of 2-methylchro-

mone-type compounds, in good yields (Scheme 89). The mechanism may involve an

oxidation to give propargyl ketones which isomerize to the corresponding 1,2-

allenic ketones followed by an intramolecular cyclization process <11JOC982>.

OH

R1

O

R1

8 examples,

8 examples,

71–83%

80–90%Me

OOH

Jones reagent

Me2CO, 0 °C

N

N O

O

MeO

R1N

NH

O

OH

O

R1

Scheme 89

The intramolecular O-arylation of appropriate substituted 1-(2-bromoaryl)pro-

pane-1,3-diones 56 under metal-free conditions provides a synthesis of 2-arylchro-

mones 57 <11AGE3769>, and of 3-(2-bromoaryl)-3-oxopropanal derivatives 58

with a Cu(I) catalyst gives a range of 3-arylchromones 59 (Scheme 90)

<11HCA1304>.

O Ar

R1 13 examples, 34–96%

Br

H

O O

Ar

R1

Br

Ar

O O O

R1

O

O

R1Ar

K2CO3, DMF

Cu(I), picolinic acid

K2CO3, DMF

metal-free27 examples, 66–99%

5657

58 59

Scheme 90


2-arylchromones are obtained by regioselective cyclization of o-alkynoylphenols

mediated by trifluoromethanesulfonic acid (TfOH) <11OL4526> or DMAP

<11T9993> and by gold-catalyzed intramolecular cyclization of similar O-protected

phenols, involving an electrophilic carbon-substituent transfer (Scheme 91)

<11TL2476>. The preparation of the naturally occurring flavonoid luteolin involves

a similar cyclization, catalyzed by cesium carbonate <11T4344>. The intramolecular

oxa-Michael oxidation of chalcones mediated by CuI-ionic liquid <11OBC6930>or Yb(OTf)3 <11JHC1356> affords a number of substituted 2-arylchromones in

good yields.

OH

R1

O

R1

PPh3AuCl (10 mol%)AgSbF6 (10 mol%)

1,2-DCE, 50 °C

A: TfOH (100 mol%)1,2-DCE, 40 °C


A: 13 examples, 40–96%B: 16 examples, 20–96%

Ar

O

OR2

R1

O

R1

Ar

O

R2

B: DMAP (10 mol%)DMF, 30 °C

Ar

O

O

Ar

Scheme 91

Several polysubstituted chromones have been synthesized from the reaction of

2,3-allenoic acids with arynes generated in situ. Nucleophilic addition is followed by

a rearrangement of the formed intermediate to give o-(1-oxo-2,3-allenyl)phenoxide,

which after an oxa-Michael addition and hydrolysis gives chromones (Scheme 92)

<11OL5196>. A few examples were also synthesized from an intramolecular hetero-

annulation of substituted 20-hydroxy-2-nitroacetophenones with carbon disulfide in

the presence of base <11TL254>.

TMS

OTfCO2H

R3R1

R2

R4

O

O

R4 20 examples60–92%

R3

R1

R2

KF, 18-crown-6

THF, 80 °C, 12 h

Scheme 92

A mixture of flavones (51–63%) and 3-aroylflavones (23–11%) is obtained from

the one-pot Baker–Venkataraman rearrangement of 20-hydroxyacetophenones,3 equiv. of aroyl chlorides, and potassium carbonate in wet refluxing acetone

<11TL3120>. An alternative multistep approach uses the same starting

materials for the formation of the substituted phosphonium bromides followed by

an intramolecular photochemical Wittig reaction in water (Scheme 93)

<11TL7189>. A number of functionalized derivatives also result from the one-pot

reaction of salicylaldehydes and arylacetylenes under dual catalysis of piperidine and

FeCl3, in good yields (74–87%) <11TL5610>.

O

R1

O

R2

PPh3

O

H2O, Et3N

hν


OH

R1

O

R1

O

R2

O

+

R2

COCl

+Br-

Scheme 93


Chiral triazolium salts have been used for an efficient asymmetric intramolecular

Stetter reaction of oxygen substrates 60, providing chroman-4-ones in excellent

yields with up to 97% ee (Scheme 94) <11AGE4983, 11AGE7982, 11OBC2072,

11SL1033>. Studies on the mechanism of this reaction prove that the first step is

an irreversible proton transfer process <11OL1742>. Similar compounds are

obtained using imidazolium salts <11CEJ5965>.

CHO

O R3

R1

O

O

R3R1

Catalyst

O

NN

NAr1

X-

R2

R2

R4 NNAr2 Ar2

X-

Triazolium salts Imidazolium salts60

+ +

Scheme 94

Tandem intramolecular oxa-Michael addition of a-alkylidene b-ketoestersfollowed by decarboxylation in the presence of cinchona alkaloid 61 leads to further

examples of chiral chroman-4-one derivatives (Scheme 95) <11T5389>.


O

CO2t-Bu

R1OH

R2 O

O

R2 R1

(i) 61 ( 20 mol%)PhCF3, rt

(ii) p-TsOH80 °C, 2 h

N

N

OH

O

Ph

H 61

Scheme 95

3-Aryloxypropanenitriles are available by oxa-Michael addition of phenols to

acrylonitriles, and their one-pot superacid-mediated Friedel–Crafts reaction affords

the corresponding chroman-4-ones (Scheme 96) <11TL4824>.

OH

R1 CNK2CO3

t-BuOH

O

R1CN

O

R1

10 examples(i) TfOH/TFA

(ii) H2O11–98%

50–93%

O

Scheme 96


Using anhydrous K2CO3 as catalyst, the aldol condensation of

o-hydroxyacetophenones with benzaldehydes in ethanol affords a mixture of chal-

cones 62 and flavanones 63. The chalcones 62 also cyclize to give the corresponding

flavanones 63 (Scheme 97) <11TL5020>.

OH R2

R1

O

O R2

R1

O

OHR2

R1

O

+ +

CHOA: EtOH, reflux

3–10 h

B: μW, 3–5 min

A: Me2CO, reflux, 3–5 h

B: μW, 3–4 min

12 examples

anhydr. K2CO3

anhydr. K2CO3

62 63

Scheme 97

An alternative approach involves a DABCO-catalyzed Claisen–Schmidt reaction

of o-hydroxyacetophenones with benzaldehydes to provide intermediates 64, fol-

lowed by an intramolecular dehydration with the modified Mitsunobu reaction to

afford the expected flavanones. The one-pot version occurs at reflux temperature

(Scheme 98) <11T4155>.

O R2

R1

O

OH

R2R1

O

OHC

H2O

9 examples

OH

R2R1

O OH

rt, 3 days

DIAD, PPh3, Et3N

THF, 0 °C to rt, 5 h

DIAD = diisopropyl azodicarboxylate

67–78%

64

DABCO,

DABCO,

H2O, reflux, 20 h

70–92%

75–84%

Scheme 98

6.4.2.7 Xanthenes and XanthonesHexahydroxanthenes are readily attained by tandem MOM-based cascade

cyclization–aromatic substitution when epoxides 65 are treated with BF3�OEt2(Scheme 99) <11JOC909, 11TL1628> and by cyclization of 2-geranylphenol deriv-

atives, catalyzed by a salt of a chiral phosphonous acid diester with with FSO3H

<11OL3130>.

O

MOM

O

R1 O

MOM

HHO

R1

CH2Cl2, -78 °C

BF3×OEt2

65

Scheme 99


A facile one-pot synthesis of substituted xanthenes involves the Lewis acid-

promoted Knoevenagel condensation of salicylaldehydes and cyclohexenone deriva-

tives followed by a sigmatropic hydrogen shift (Scheme 100) <11OBC1744>.

CHO

+R1

OH O

R2 R1

O

12 examplesA: 18–89%B: 30–96%

R2Sc(OTf)3 (5 mol%)

A: PhCl, reflux, 18–44 hB: PhCl, μW, 180 °C, 30 min

Scheme 100

A metal-free approach for the preparation of 14-aryldibenzoxanthenes was

achieved by the condensation of 2-naphthol with aromatic aldehydes using a

modified acid functionalized mesoporous silica (AFS) <11CC6677>,

N-bromosuccinimide (NBS) <11HCA429> or thiamine hydrochloride

<11SC3424> as catalysts (Scheme 101). A Ru(III)-catalyzed reaction of 2-naphthol

with aliphatic aldehydes gave the same type of 14-substituted dibenzoxanthenes

<11SC1427>.

CHOOH

O

R1R1

A: AFS, CH2Cl2, rt, 5 examples, 75–82%B: NBS, 110 15 examples, 87–97%C: thiamine hydrochloride, 150 °C,

°C,8 examples, 83–92%

A, B, C2

Scheme 101

A range of 9-substituted tetramethyloctahydroxanthene-1,8-diones were synthe-

sized from dimedone and a variety of aliphatic and aromatic aldehydes using either

InCl3 and P2O5 <11T3698> or silica sulfuric acid (SSA) as catalysts <11SC347>or the ionic liquid 3-(N,N-dimethyldodecylammonium)propanesulfonic acid hydro-

gen sulfate ([DDPA][HSO4]) (Scheme 102) <11JHC468>. Similar xanthene deriv-

atives were also prepared in a solid-phase synthesis using resin-bound propiolic acid

as Michael acceptor and cyclohexanediones <11S4027>.

O

+

O O

O OR1

A: InCl3 (15 mol%) or P2O5 (30 mol%), 100 °C 25 examples, 56–98%

B: SSA (10 mol%), 60–100 °C 6 examples, 73–90%

C: [DDPA][HSO4], H2O, 100 °C 12 examples, 87–97%

2A, B, C

R1CHO

Scheme 102


Multicomponent reactions of aldehydes, 2-naphthols, and dimedone derivatives

have been used for the synthesis of 12-aryltetrahydrobenzo[a]xanthen-11-ones

catalyzed by Caro’s acid/SiO2 <11SC307>, Cu/SiO2 <11SC2763>, and NH4Cl

<11SC2663> under solvent-free conditions, and even using p-toluenesulfonic acid

as catalyst and an ionic liquid as solvent (Scheme 103) <11JHC1388>. Similar xan-

thene derivatives are obtained via a comparable three-component reaction involving

aldehydes, 3,4-methylenedioxyphenol/2-naphthol, and 4-hydroxycoumarin/

2-hydroxy-1,4-naphthoquinone <11JHC83, 11JHC1379>.

O

OR3

R3OH

O

R1

R2

R2

R3

R3

O

A: solvent free

B: ionic liquidR1CHO

Scheme 103

1,4-Dioxygenated xanthones 69 were prepared by a novel application of the

Moore cyclization to a squarate derivative 66 leading to benzoylbenzoquinones 67

followed by oxidation and acid-catalyzed deprotection/cyclization. In some cases,

the last step gave mixtures of the desired xanthones 69 and spirocyclic ketones 68;

the latter could be converted into the former by treatment with potassium carbonate

(Scheme 104) <11OL4696>.

MeO

MeO OH

OOH

OPMB

R1

OO

O

MeO

MeO

OPMB

R1

O

O

MeO

MeO+

O R1

OMeO

MeO

OH O

R1

(i) PhMe, Δ60–83%

60–95%

(ii) Jones reagent80–90%

TFA

K2CO3, Me2CO, 24 hOH

O

6667

6869

Scheme 104

The products obtained from the hDA reaction of substituted 3-formylchromones

and acetylenedicarboxylates depend not only on the organocatalyst but also on the

substrate. Electron-donating groups (EDG) in the presence of 4-picoline led to the

formation of pyrano[4,3-c]chromene derivatives 70, while electron-withdrawing

groups (EWG) in 4-picoline or DMAP produced xanthones 71 (Scheme 105)

<11S97>.

R3

R2

R1

O

CHO

O

CO2R4

CO2R4

R2

R1

O

O

O

CO2R4

CO2R4

R1

O

O

CO2R4

CO2R4

R3

CO2R4

R1,R2 = EDG

R1,R3 = EWG

5 examples

4 examples

4-picoline

4-picoline or DMAP

DME, –18 °C to rt

DME, –18 °C to rt

DMAP = 4-dimethylaminopyridineDME = dimethoxyethane

70

71

Scheme 105


A Lewis base-catalyzed [4þ2] annulation reaction of electron-deficient

chromone-derived oxadienes and acetylene carboxylates afforded a series of

xanthone-type compounds <11CEJ5130, 11TL2265>. In the asymmetric version,

modified cinchona alkaloid 72 was used as enantiodifferentiating Lewis base catalyst

(Scheme 106) <11CEJ5130>.

O

R1

R2

R3

R4

O

CHO

+

R6

R5

PPh3 or PBu3

PhMe, 80 °CO

R1

R2

R3

R4

O

O

R5R6

12 examples17–82%

O

R1

R2

R3

R4

O

O

R5R6

10 examples15–67%

77–84% eeH

72 (20 mol%)

THF, –70 °C3 daysN

N

Ph

O

Ph

72

Scheme 106

The heterocyclic ring of tetrahydroxanthone and related structures are obtained

by a Pd-catalyzed cyclization of 2-(bromoaroyl)cyclohexanones <11OL1056>.

The parent xanthene and xanthone are obtained as by-products from the reaction

of dimethyl(thio)formamide with o-trimethylsilylphenyl triflate, in the presence of

CsF <11BCJ328>.

6.4.3. HETEROCYCLES CONTAINING ONE SULFUR ATOM

6.4.3.1 Thiopyrans and AnaloguesA range of tetrahydrothiochromen-5-ones were obtained in a one-pot, three-

component reaction of b-oxodithioesters, aldehydes, and cyclic 1,3-diketones, under

solvent-free conditions (Scheme 107) <11OL3762>.

R1 SMe

O S++ R2CHO

O

O R3

R3

S

R2 O

R3

R3MeS

O

R1P2O5 (20 mol%)

100 °C20 examples

72–90%

Scheme 107


An intramolecular Friedel–Crafts reaction is the key step for the preparation of an

enantioenriched thiochroman-4-one from a sulfur-Michael addition of a thiol to a

trifluorocrotonate <11OL4426>. The same key reaction was used in the synthesis

of several thioxanthene-type compounds from Morita–Baylis–Hillman adducts,

obtained by the reaction of 2-arylthioquinoline-3-carbaldehydes with activated

alkenes (Scheme 108) <11T3509>, and from diarylmethyl carbinols, resulting from

the addition of Grignard reagents to 4-(phenoxy or thiophenoxy)-2H-chromen-3-

carbaldehydes <11TL5951>.

N

CHO

S

R1

EWG

DABCOrt

N S

R1

OH

EWGH2SO4 or

CF3SO3H

N S

R1

EWG

R2

12 examples, 21–90%R2

R2

Scheme 108

LDA induces the cyclization of benzyl or 2-thienylmethyl hindered

1-propynylsulfones to afford 7H-thieno[2,3-c]thiopyran S,S-dioxides 73 and 1H-2-

benzothiopyran S,S-dioxides 74, respectively (Scheme 109) <11OL5330>.

SO2

R2

R1

R3

R1 = Ar-R4SO2

R3

R2

R4


R1 = 2-thienylSO2S

R3

R2


(i) LDA, –78 °C(ii) warm to rt, 45 min

(i) LDA, –78 °C(ii) warm to rt, 45 min

73 74

Scheme 109

The five-membered ring of 3-nitrobenzo[b]thiophene is enlarged to six-

membered ring in a ring-opening–ring-closing procedure, where the cyclization

conditions led to a diastereoselective synthesis of 4-nitrothiochroman S,S-dioxides

(Scheme 110) <11T8160>.

S

NO2

4 steps

NO2

SO2

NO2

Ar1

R1

Ar1

SO2CH2R1

(i) LiN(SiMe3)2, THF, –78 °C(ii) NH4Cl, 15 min


Scheme 110


Heating a mixture of thiophthalic anhydride with substituted alkynes led to

sulfur-containing compounds. Selective synthesis of thioisocoumarins is accom-

plished using Ni(0)/PPr3 as catalyst in the presence of a Lewis acid, whereas Ni

(0)/PMe3 as catalyst afforded thiochromones (Scheme 111) <11OL1912>.

S

O

+

O

R2R1

S

O

R1R2

S

O

R2

R1

Ni(0) (10 mol%)PMe3

benzene, 130 °C

Ni(0) (10 mol%)PPr3/MAD

PhMe, 130 °C



Scheme 111

6.4.4. HETEROCYCLES CONTAINING TWO OR MOREOXYGEN ATOMS

6.4.4.1 Dioxins and DioxanesChiral tricyclic dioxins result from the aryloxylation of cyclic b-keto esters with a

range of o-quinones in the presence of a cinchona alkaloid derivative 75 as catalyst

(Scheme 112) <11S1880>. The manganese(III) catalytic aerobic oxidation of tetro-

nic acids (a type of cyclic b-keto esters) and 1,1-disubstituted alkenes affords fused

1,2-dioxins <11H(83)1783>.

O

OR1

O

n =1,2n

O+

O

R275 (10 mol%)

TBME, –20 °CO

OHOOR1

On

R2


TBME= t-butyl methyl ether

N

N

NOHN

F3CCF3

75

Scheme 112

The intramolecular platinum-catalyzed cyclization of o-hydroxy propargylic

acetates in THF at room temperature provides cis-2,6-disubstituted 1,4-dioxanes in

excellent yields (Scheme 113) <11T5046>. The reaction of enantiopure 1,2-diols

and vinyl selenones as Michael acceptors followed by intramolecular displacement

of the PhSeO2 group also affords enantiopure 1,4-dioxanes <11CEJ993>.

OR2

R1

OAc OH [Cl2Pt(CH2CH2)]2

THF, rt O

O

R2

R1


Scheme 113


6.4.4.2 TetraoxanesNovel substituted 1,2,4,5-tetroxanes were prepared through the reaction of

gem-dihydroperoxides and cyclic acetals or orthoformates (Scheme 114)

<11TL107>.

OOH

OOH

OOH

OOH

OOH

OOHR1

EtO

EtO nn = 1,2

CH+ +

+

+

(OR3)3

R2

O O{ }

{ }

OOR1

nn = 1,2

O O

OOR2 OR3

O O

OOH OR3

R1 HO O

OOH OR3

R1 HR1

CH(OR3)3CH2Cl2

cis trans

6 examples

12 examples

4 examplesBF3×OEt2

Scheme 114

6.4.5. HETEROCYCLES CONTAINING BOTH OXYGEN ANDSULFUR IN THE SAME RING

6.4.5.1 OxathianesNHC 76 catalyzes the [2þ2þ2] cycloaddition reaction at �40 �C of ketenes with

carbon disulfide <11CC8388> or isothiocyanates <11OL6382> to obtain the corre-

sponding 1,3-oxathiane-6-ones in good yields and enantioselectivities (Scheme 115).

Ar1 R1

C

O

C

S

+

NBz

CS2

S

OOR1

Ar1

NR1

Ar1

Bz

S

OOR1

Ar1

SR1

Ar1

Cs2CO3

PhMe, –40 °C

CH2Cl2, –40 °C

Cs2CO3

N N

N

Ar3Ar2

Ar2

OR2

BF4

76 (12 mol%)

76 (12 mol%)



76

+

–

Scheme 115

Under solvent-free conditions, LiBr promotes a ring-opening–ring-closing

cascade of terminal epoxides with a-mercaptocarboxylic acids for the synthesis of

1,4-oxathiane-2-ones (Scheme 116) <11TL3614>. 4-Thiaflavanes are prepared

through an hDA reaction of o-thioquinones with styrenes (Scheme 117)

<11CEJ12396, 11OBC1352>.

OH

SNPhth

R1

R2O

O

S

R1

R2O

OR3

O

S

R1

R2O

OR3

CHCl3, 60 °C

Et3N

Scheme 117

O+

R1

HO O

R2HSS

O O

R2R1

LiBr (10 mol%)

Neat, rt16 examples, 77–93%

Scheme 116


6.4.5.2 SultonesSeveral functionalized benzo-d-sultones were synthesized through a domino Knoe-

venagel–hDA reaction of substituted sulfonates and 1,3-diones in water

(Scheme 118) <11T8484>.

S OO

R2

O

R1

O

+

OO

SO2

O

R1H

H

HO

R2O

SO2

O

R1H

H

HO

R2

reflux


H2O

Scheme 118

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