The document discusses the biological significance and synthesis of chromenes, a class of cyclic organic compounds with various natural phenolic derivatives. It highlights the diverse biological properties of 2H-chromenes, including their roles in cancer treatment and anti-inflammatory effects, and outlines various synthetic routes for their preparation. Additionally, the document covers specific examples of chromene compounds and their pharmacological applications.

1. CHROMENEs: BIOLOGICAL IMPORTANCE
&SYNTHESIS
BY
Dr. Mohd Kamil Hussain
Asst Professor
Govt Raza PG College Rampur

2. Benzopyran is a cyclic organic compound that results from the
fusion of a benzene ring to a heterocyclic pyran ring. According to
IUPAC nomenclature it is called chromene.
2H-chromene 4H-chromene1H-isochromene 3H-isochromene
O
R
R
2,2-dialkyl2H-chromene
2H-chromene are constituents of considerable number of natural phenolic compounds
including flavanoids, coumarins, rotenoids, stilbenoids, and chromene glycosides.
 These compounds are widely distributed in nature and almost every class of natural
phenolic compounds include members that feature a 2,2-dialkylchromene ring system
 2H-Chromens have been extensively as a consequence of their widespread natural
occurrence and extremely diverse biological property.
2H-chromenes,which are also known as 2H-1-benzoprans, are an important family of
oxygen hetrocycles that have a benzo-fused-2H-Pyran ring system.

3. Tephrosin is a natural fish poison found in the
leaves and seeds of Tephrosia purpurea.it
shows anti cancer activity in human cancer
cell lines
Acronycine is an antineoplastic agent
isolated from Acronychia baueri
Anti-cancer chromenes
Anti-leukemia Calanone from Calophyllum
teysmannii var. inophylloide

4. Calanolide A is a new, experimental non-nucleoside
reverse transcriptase inhibitor (NNRTI) first acquired
from Calophyllum lanigerum
Inophyllum B is a potent non-nucleoside inhibitor of
reverse transcriptase human immunodeficiency virus
type 1(HIV-1 RT) from Calophyllum ionophyllum
Mallotochromene isolated from of Mallotus
japonicu. have been tested for their ability to
inhibit the activity of human immunodeficiency
virus (HIV)-reverse transcriptase

5. Daleformis, a phytoalexin from the roots fo
Dalea filiciformis: an inhibitor of endothelin
converting enzyme
O
O
O Me
Me
H
H
HO
HO
Pongapinone A inhibits the production of interleukin-1
(anti nflamatory) from pongamia pinnata
Seselin possesses both anti-inflammatory and
antinociceptive properties. Seselin from
Plumbago zeylanica

6. Antibacterial chromene
lupinifolinol
fromTephrosia lupinifolia
from Hypericum drummondii
Drummondin A
Drummondin D
O
OH
O
O
HO
HO

7. Selective protein kinase inhibitors
Protein kinases are enzymes catalyze phoshphorylation of protien or other organic
molecule, usually on the serine, threonine, or tyrosine amino acids.
Phosphorylation is a necessary step in some cancers and inflammatory diseases.
Inhibiting the protein kinases, and therefore the phosphorylation, can treat these
diseases.
A protein kinase inhibitor is a type of enzyme inhibitor that specifically blocks the
action of one or more protein kinases.Therefore, protein kinase inhibitors are used as
drugs.
O O O
OHO
O
Robustic acid and warangalone from the insecticidal plant Derris scandens is a
selective and potent inhibitor of rat liver cyclic AMP-dependent protein kinase
catalytic subunit
Phytochemistry. 1997 ,44,787-96
O O
OH O
warangaloneRobustic acid

8. Cannabichromene
Cannabichromene is a cannabinoid found in the
cannabis plant.play a role in the anti-inflammatory
and anti-viral effects.
Both were isolated from the fungus Daedalea quercina.
show antioxidative and anti-inflammatory

9. Cancer Res. 1997,57, 3429-3435 and references therein
Phytochemistry 1997, 44, 787-796.
Inhibitors of electron transport chain

10. J. Chem. Pharm. Bull. 1994, 42, 1056-1062
Phytochemistry 2000, 53, 981-985
Phytochemistry 1997, 45, 1297-1298.
Phytochemistry 1994, 36, 1073-1076
Miscellaneous biologicaly active chromene containing
natural products
O
OMe
O
HO
OH
OO
OH
HO
Robustic Acid
specific inhibitor of cyclic amp-dependent protein kinas O
O
O
OH
Shinflavanone
Inhibitors of OCL bone reabsorption
O
OMe
OO
OH
Clausenidin
Inhibitor on interferon-y-induced nitricoxide genration
Artocarbene
Inhibitor of tyrosinase
O
NH
Grinimbine
Inhibitor of Cyclooxygenase

11. Biosynthetic pathway of 2H-chrome
R
OH
R1
R2
OPP
R2
R1
OH
R
O
R1
R2
R+
The most widely accepted hypothesis involves the abstraction of a hydride ion from the
benzylic position of isoprenylated phenol by a quinone- like enzyme cofactor. The resultant
ortho-quinone methide undergoes An electrocyclization reaction to afford the 2H-Chromene.
OH
R1
R2
R
HH
O
R1
R2
HH
O
R1
R2
HH
-2e
R R
O
R1
R2
R
O
R1
R2
R
Abstraction of
a hydride ion
Electrocyclization
Ring Closure mechanism of 2H-chrome:

12. Mechanism of photochromism of 2H-Chromene
The 2H-Chromene undergoes a reversible ring opening reaction on irradiation with UV light that
lead to the open-form.the molecule then can revert to ring-closed form via a thermal pathway. this
mechanism was later Confirmed by the reduction of the open form with lithium aluminum hydride
at low temperature.
O
UV
O
Closed- form
colourless
Open-form
Coloured
O O
Ph
Ph
Ph
Ph
UV
OH
Ph
Ph
LiAlH4

13. O OR OR
OR
O OHR OR
R
R1
RMgI/ THF
H+
BMS
1.ArMgI/ THF
R
D
IB
A
L-H
,toluene
2. H+ toluene
Synthesis of chromene from Coumarin

14. General routes for the synthesis of chromenes
J.Chem.soc.perkin trans I 1994,653-657 Eur. J. Org. Chem. 2010, 1339–1344
R OH
OH
Br O
+
O
O
R OR
O
Br
R
O
O
R
R1
OR
R1
1.K2CO3/Acetone
2. PPA
1.NaBH4
2.H+
Ar-Br, Pd(OAc)2,tBu3P.HBF4
KHCO3
PBr3
1.NaBH4
2.H+
R OH
O
OH
O
O
R
+
OR
1.NaBH4
2.H+
PPA
OR
Br
PBr3

15. OH
OH
Br
O
+
R
HO
O
R
O
BrPh3P
O
R
O
O
R1
R1
R
K2CO3/Acetone
reflux
PPh3HBr
MeONa
CH3CN
MeOHReflux
OH
R1
O
R1
R
OR1
R
O
(HCHO)2
Aq Me2NH/ EtOH
1.NaBH4
2.H+
Org. Lett. 2008 10, 5007-5010, Synth.commun 1982,1110
Synthesis of Chromene via Wittig olifination and Kabbe condensation

16. 2,3-di Aryl chromene as potential Selectivee Estrogen Receptor Modulators
(SERMs)
OHO
OH
O
N
O
OH
O
N
OHO
OH
O
N
OO
O
O
N
O
O
O
O
N
CDRI 85/287
EM-800 (SCH 57050)
Anti-estrogen- prodrug
Eli Lilly and Co.
(EM-652·HCl (SCH 57068·HCl, acolbifene)
pure Anti-Estrogen
Eli Lilly and Co.
potent antiestrogenic agent
CDRI
potent antiestrogenic agent
CDRI
a potent estrogen antagonist

17. A general route for the synthesis of 2,3-di Aryl chromene
a.piperidine (0.3 equiv.), benzene,reflux.b 1-(2-chloroethyl)piperidine monohydrochloride Cs2CO3,
Acetone. C. MeLi (3 equiv.),THF, d. 19:1 acetic acid–water, 90C, J Label Compd Radiopharm 2004; 47: 741–752
R
O
R1
OH
O H
OH
R
O
R1
OH
OH
O
O
OH
R
R1
+
+
O
O
O
R
R1
N
R
O
R1
OH
O
N
O
R1
R
O
N
a
b b
Resolution
c
R + S

18. A general route for the synthesis of 2,3-diaryl chromene
a.Piperidine, benzene,reflux.b NaBH4, EtoH,c Acetic acid d. 1-(2-chloroethyl)piperidine
monohydrochloride K2CO3, Acetone
R
O
R1
OH
O H
OH
R
O
R1
OH
OH
O
OH
R
R1
+
+
O
R1
R
OH
O
R1
R
O
N
O
R1
R
O
N
a
b-c b-c
Resolution
O
R1
R
O
N
d
O

19. Reaction of Phenols with α,β-unsaturated aldehydes
The base promoted chromenylation reaction of phenols with α,β-unsaturated has been a popular
Method to prepare a 2H-Chromene. This method has found widespread application in the synthesis
Of natural products, such as total synthesis of(+)-Leocarpin and (+)-lsohemileocarpin
OH
OHO O
Me Me O
OHO
Me
Me
Pyridine
+
4 Steps
O
Me
Me
O
O
O
O
O
Me
Me
O
O
(+)-Leocarpin (+)-lsohemieocarpin
Pyridine catalyzed chromenylation reaction:
Synth.commun 1993,23,3019.
Hetrocycles 1984, 22,1719
Tetrahedron 1990,46, 2031

20. Preparation of 2H-Chromene via Aromatic lithiation reaction
A series of 2,2-di alkyl-2H-1-benzopyrans have been synthesized using aromatic lithiation reaction as a key
step,followed by treatment of α, β- unsaturated aldehydes. Cruz-Almanza and Co workers have reported the
synthesis of 2H-Chromene by the 1,2-addition of reaction of an appropriately protected aryl lithium compound
to an α, β- unsaturated aldehydes,on subsequent deprotection and cyclization of α, β- unsaturated aldehydes.
Heterocycles,1994,37 ,759
LiRO
OR
O
R1 R2 OH
OH
R1
R2
RO
O
R1
R2
RO
+
R = MOM,MEM, MTM,THP,Bn,Me Carbinol
Two natural product related compounds O-methylcordeachromene, O-methyldectayochromenol as well as
tricyclic 2H-Chromene have been prepared by this methods.
O Me
MeO
O-methylcordeachromene
O
Me
MeO
O-methyldectayochromenol
O
Me
HO
MeMe
Tricyclic-2H-Chromene

21. Reaction of titanium or magnesium salts of phenols with α,β-unsaturated aldehydes
Titanium or magnesium salts of phenols have also been reacted with α,β-unsaturated
aldehydes. This method has provided a facile synthesis of naturally occurring 2H-
Chromenes, such as precocenes 1&2 as well as evodinol.
Tetraheron,1997,53,12621 Mutagenesis. 1989 May;4(3):216-20.,
OM
O
R1
R2 O
R1
R2
+
M = Ti(IV), Mg
R Toluene 110 0C
R = H,Me,OMe,Ph,OH,NMe2 COMe
R
O
Me
Me
O
O
HO
Evodinol
O
Me
Me
O
Precocene 1
O
Me
Me
O
Precocene 2
O
Anti-juvenile harmones
Ageratum houstonianum

22. Phenylboronic acid-promoted condensation of phenol with α,β-
unsaturated aldehydes
The Phenylboronic acid-promoted condensation of phenol with α,β-unsaturated aldehydes has
been found to Be a convenient and mild method that complements classical routs for the
synthesis of 2H-Chromenes.Reaction of 3-methoxy phenol with citral afforded the
cannabichromene analogue.
O OH
O R
OO
Me
R
Me
PhB(OH)2 Toluene
Reflux
O
B
O
Ph
Me
Me
R
O Me
Me R
-PhBO
Via
R = Me, CH2CH2CH=C(Me)2
OO
Me
Me
Me
Cannabichromene analogue
+
Synthesis 1998, 279 and ref. therein

23. Preparation of 2H-Chromene via rearrangement of
propargyl Ethers
R
OH
R1
R2
R3
X
R
O
R1
R2
R3
O
R2
R3
R1
R
K2CO3 / Acetone
reflux
PhNMe2
reflux
+
R
O
R1
R2
R3
O
R1
C R2
R3
R
O
R1
C R2
R3
R
H O
R2
R3
R1
R
Via
X = Cl,Br, R = H OMe, Me,Cl,CN,NO2
A particularly useful synthesis of 2H-Chromenes involves the thermal rearrangement of
propargyl Ethers in a solvents of high boiling point. the reaction is proposed to proceed via
claisen- like [3,3]-sigmatropic rearrangement,followed by a[1,5] sigmatropic shift.An
electrocyclization reaction then complete the process
Tetrahedron.lett,2001,42,1091

24. Ring-Closing Olefin Metathesis
Ring-Closing Olefin Metathesis has been developed into a practical and highly efficient procedure for
a diverse array of 2H-Chromene derivatives . A series of substituted 2H-Chromenes were prepare in
high yields by the ring closing metathesis using a ruthenium carbene catalyst.
J. Org. Chem. 1998, 63, 864-866
R2
OH
O
R1
R3
R4
O
R1
R2
R4
R3
X
O
R2
R3
R4
R1
1.K2CO3 / Acetone
2. MTPPB,NaH
[Cl2(PCy3)2Ru=CHPh]
RCM
R1
/ R2
/ R3
/ R4
= H /Alkyl /Cl/ or diffrent sibstituens
+
Ru
Ph
PCy3
PCy3
Cl
Cl

25. Simultaneous Synthesis of Both Rings of Chromenes via a Benzannulation/o-Quinone Methide
Formation/Electrocyclization Cascade.
A new route to the chromene ring system has been developed which involves the reaction of an a,ß-
unsaturated Fischer carbene complex of chromium with a propargyl ether bearing an alkenyl group on
the propargylic carbon.
This transformation involves a cascade of reactions that begins with a benzannulation reaction and is
followed by the formation of an o-quinone methide, and finally results in the emergence of a chromene upon
an electrocyclization
(CO)5Cr
OMe
H
R2
R1
PO R4
R7
R6
R5R3
C
R3
R1
R2
MeO
R7
R6
R5
R4
PO
O
H(OC)3Cr
Benzannulation
R3
R1
R2
MeO
R7
R6
R5
R4
O
(OC)3Cr
MeO
H
R2
R1
PO R4
R7
R6
R5
R3
C
O
-HOP
O-Quenone
methide
formation
O
R3
MeO
R2
R1
R4
R5
R6
R7
Electrocyclization
Oxidative workup
+
J. Am. Chem.Soc. 2012, 134, 1357-1362

26. O
MeO
O
MeO
O
MeO
O
MeO
O
MeO
O
MeO
O
O
Some Examples
MeO Cr(CO)5
R
R1
OTBS
O
MeO
R
R1
Solvents1.
2. FeCl3-DMF
Solvents = DCM, Toluene,Acetonitrile
(OC)5Cr
OMe
R
OP
+
+
O
H
H
R
MeO1.(iPr)2EtN,Toluene
2. FeCl3-DMF
J. Am. Chem.Soc. 2012, 134, 1357-1362

27. 2H-Chromenes from Salicylaldehydes by a Catalytic Petasis Reaction
The Petasis condensation of vinylic or aromatic boronic acids, aromatic aldehydes, and amines is
assisted by a hydroxy group adjacent to the aldehyde moiety. The products derived from
salicylaldehydes and vinylboronic acids undergo cyclization to 2H-chromene compounds with ejection
of amine upon heating.
CHO
R
R2
R1
B
HO
HOOH
+
O R1
R2
R
R2NH
Dioxane
O
O
O
OH
O
O
O O O
O
Examples
Org. Lett. 2000 ,2,4063-4065
R1 = alkyl, phenyl, R2 = Alkyl, phenyl

28. Synthesis of ‘‘4-aryl-4H-chromene’’ as Anti-angiogenic /proliferative agent
‘‘4-aryl-4H-chromene compounnds were synthesized by the condensation of 3-(dimethylamino)phenol
Benzaldehyde and malonitrile in ethanol in the presence of piperidine
N OH
CHO
CN
CN O
CN
NH2N
R
R
Piperidine
EtOH
+
+
O
CN
NH2N
O
O
CN
NH2N
NO2
O
CN
NH2N
CF3
Anti-angiogenic/proliferativeAgents on blood vessel’s endothelial cells
Med Chem Res. 2011, 20, 920–929

29. Synthesis Of a Thieno-2H-chromene -Amino Acid Derivative
S
HO
Br
OH
O
O
S
Br
O
O
O
Al2O3 Ac
Toluene
+
NH2S
(Boc)2N
MeO2C
SO
O
O
HN
S
N(Boc)2
MeO2C
Pd(OAc)2
BINAP
Cs2CO3
A new photochromic thieno-2H-chromene r-amino acid derivative was prepared by C-N palladium-
catalyzed cross- oupling of a bromothieno2H-chromene with the aminated aromatic side chain of the
methyl ester of a N,N-diprotected amino acid.
Its good photochromic properties demonstrated by flash photolysis and continuous irradiation indicate a
possible application in ophthalmic lenses. It may also be inserted into peptides to give photoinduced
reversible structural changes
Org. Lett.2005,7, 4811-4814

30. Iron-Catalyzed Synthesis of Functionalized 2H-Chromenes via Intramolecular
Alkyne Carbonyl Metathesis
An iron-catalyzed intramolecular alkynealdehyde metathesis strategy of the alkynyl ether of salicylaldehyde
derivatives has been developed which works under mild reaction conditions to produce the functionalized 2H-
chromene derivatives
This protocol is compatible toward a wide range of functional groups, such as methoxy, fluoro, chloro,bromo,
and phenyl group
This method provides an atom-economical and environmentally friendly approach for the synthesis of a series
of substituted 2H-chromenes.
H
O
O
R2
R1
R1
O
R2
O
H
O
O
R2
R1
FeCl3
R1
O
R2
O
FeCl3
R1
O
R2O
Iron Salt Catalyzed Intramolecular Alkyne-
Aldehyde Metathesis
nucleophilic attack
cyclization by intramolecular
nucleophilic
oxetene intermediate
( 2+2) cycloreversion
FeCl3
MeCN
R1
= Cl,Br,Ph,OMe
R2
= Alkyl,Aryl
J. Org. Chem. 2011, 76, 3539–3544

31. Gold(III)-Catalyzed Efficient and Highly Selective Synthesis
of Functionalized 4H-Chromenes
O
H
O
H H
O
H O
+ 2H2O
AuCl3 / AgOTf
DCE
Tandem annulation
Highly Chemo Selective water being the only side product
O O
O
O
O
J. Org. Chem. 2010, 75,1309-1312

32. Ormeloxifene
Ormeloxifene (also known as centchroman) is one of the selective estrogen receptor modulators, or SERMs, a
class of medication which acts on the estrogen receptor. It is best known as a non-hormonal, non-steroidal oral
contraceptive which is taken once per week. In India, ormeloxifene has been available as birth control since the
early 1990s, and it is currently marketed there under the trade name Saheli.Ormeloxifene has also been licensed
under the trade names Novex-DS, Centron and Sevista.
Developed by CDRI
Ormeloxifene is primarily used as a contraceptive but may also be effective for
dysfunctional uterine bleeding and advanced breast cancer.
O
O
O
N

33. Synthesis of Ormeloxifene
O
OH
O
HO
OEtO
O
OH
OO OH
OH
OHO
O
OH
O
O
O
O
N
O
O
O
N
+
Ac2O,TEA
MeMgBr
HCl / EtOH
K2CO3
H2
Levormeloxifene (Centchroman)