Iron(III) catalyzed direct C–H functionalization at the C-3 position of chromone for the synthesis of fused chromeno-quinoline scaffolds

Article abstract of DOI:10.1016/j.tetlet.2019.06.024

This communication describes an iron-catalyzed route for the synthesis of 6-substituted chromeno[3,2-c]quinolin-7-one. The method developed does not require any pre-functionalization to execute the pivotal coupling reaction at the C-3 position of flavones

Full text of DOI:10.1016/j.tetlet.2019.06.024

Accepted Manuscript
Iron(III) catalyzed direct C-H functionalization at the C-3 position of chromone
for the synthesis of fused chromeno-quinoline scaffolds
T. Uday Kumar, Durba Roy, Anupam Bhattacharya
PII:
S0040-4039(19)30574-X
https://doi.org/10.1016/j.tetlet.2019.06.024
TETL 50865
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
24 April 2019
11 June 2019
12 June 2019
Please cite this article as: Kumar, T.U., Roy, D., Bhattacharya, A., Iron(III) catalyzed direct C-H functionalization
at the C-3 position of chromone for the synthesis of fused chromeno-quinoline scaffolds, Tetrahedron Letters (2019),
doi: https://doi.org/10.1016/j.tetlet.2019.06.024
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Iron(III) catalyzed direct C-H functionalization at the C-3 position of
chromone for the synthesis of fused chromeno-quinoline scaffolds
T. Uday Kumar, Durba Roy and Anupam Bhattacharya *
a Department of Chemistry, BITS-Pilani Hyderabad Campus, Hyderabad-500078, India
e-mail: anupam@hyderabad.bits-pilani.ac.in
Abstract: This communication describes an iron-catalyzed route for the synthesis of 6-substituted chromeno[3,2-c]quinolin-
7-one. The method developed does not require any pre-functionalization to execute the pivotal coupling reaction at the C-3
2
position of flavones. The final step involves the consecutive application of imine formation, Csp2-Csp coupling and oxidation
reaction, with aromatic aldehydes and 2-(2-aminophenyl)-4H-chromen-4-one as the reactants. Presence of electron
donating/withdrawing groups was well tolerated in the aldehydes and the method developed could also be extended to other
substituted 2-(2-aminophenyl)-4H-chromen-4-one’s. This is the first report of synthesis of 6-substituted chromeno[3,2-
c]quinolin-7-one’s via direct functionalization of the C-3 site of flavones.
Keywords: Chromones; chromeno-quinolines; FeCl3; cyclization
Introduction
Chromones and their C-2 phenyl substituted analogues (flavones) are important organic molecules bestowed with diverse
medicinally beneficial attributes. Some of the important pharmacological properties displayed by these compounds include
antimicrobial, antitumor and anti-inflammatory activity.1 Currently a lot of attention is also garnered by chromone-fused
heterocycles, available from natural as well as synthetic sources.2 Well known examples of this class include brosimone I and
cycloartocarpin, known for their tyrosinase inhibitory activity (Figure-1).3
OR
OH
O
O
O
HO
R=H(Brosimone I)
R=CH3(Cycloartocarpin)
Figure 1: Chemical structures of brosimone I and cycloartocarpin.
In continuation with our efforts on synthetic and biological studies of fused-heterocycles, synthesis of chromeno fused
quinoline was conceived. To the best of our knowledge, there are no reports on these molecules in the literature. Based on our
prior experience with oxazolo[4,5-c]quinolines/imidazo[4,5-c]quinolines synthesis,4 and their apparent similarity with
chromones, it was felt that the most straightforward route to the target molecules would involve cyclization at the unreactive C-3
position of chromone. Thus we envisaged the application of a Pictet-Spengler inspired approach would be most appropriate to
access the diverse chromeno[3,2-c]quinolin-7-one’s (Scheme-1).

Our previuos work:
X
X
N
N
R
Cu(OTf)2
or
Yb(OTf)3
+ RCHO
N
NH2
X = O/N-Ph
Current attempt:
O
O
N
O
O
+
RCHO
NH2
R
Scheme 1: Similarities between our previous results and our current attempt.
A general method for the functionalization of chromone at C-3 position usually involves lithiation followed by reaction with
an electrophile or Heck coupling between 3-halochromenes and appropriate alkenes.5,6 While both the aforementioned techniques
work efficiently and provide ample flexibility for obtaining structurally diverse 3-substituted chromones, prior activation of the
C-3 site can sometimes impact the overall yield of the reaction. Reaction at C-3 position by direct C-H functionalization using
Pd(II) based complexes have also been reported by several research groups. Most of these approaches rely on nucleophilic attack
of carbon-3 on Pd(II) catalyst as the first step to form C-3 palladated chromone, followed by subsequent step involving an
appropriate coupling partner.7 Kim et al., in their research efforts have reported palladium (II) catalyzed intermolecular
alkenylation at the C-3 position of chromone.8 Zhang and coworkers reported Pd(OAc)2 catalyzed coupling of chromone with
i
polyfluoroarenes.9 Reaction was facilitated by the addition of excess amount of Pr2S, which helped in improving the overall
yield of the reaction. The developed protocol was also extended to other heteroatom-substituted enones. Hong and co-workers in
a paper have reported the synthesis of benzofuran-fused chromones via C-3 selective functionalization of flavones and
subsequent C-O cyclization. The reaction was catalyzed by Zn(OTf)2 in the presence of Cu(OAc)2.10 The same group also
reported formation of flavone-fused benzopyran moiety in the presence of catalytic system comprising of Pd(acac)2, Cu(OAc)2,
Cs2CO3 and Al2O3.11 Initially, the C-3 alkenylated chromone was generated, which subsequently underwent intramolecular
cyclization to the target molecule. Zhao et al. has carried out C-3 sulfenylation of chromene using DMSO in the presence of
NH4I.12 Patel and co-workers reported Fe-(III) catalyzed C-3 functionalization of flavone using tert-butyl peroxybenzoate
(TBPB)/potassium persulphate (K2S2O8) as oxidant combinations.13
For our project, none of the existing methods looked attractive as we wanted to avoid final step involving both pre-
functionalization as well as C-H activation mediated direct C-C bond coupling. Given the inclusion of easy to oxidize aldehydes
in the final step, we were particularly hesitant about using palladium-based catalysts as all the reported reactions also included
stoichiometric amounts of additives as oxidants. As articulated previously, we decided to explore a Pictet-Spengler inspired
approach for the synthesis of the target molecules. Accordingly, a reterosynthetic strategy was proposed as depicted in Scheme 2.
Target molecule chromeno[3,2-c]quinolin-7-one 4 was supposed to be assembled from flavone 2 upon C-3 functionalization of
the chromone ring. Intermediate 2 was to be sourced from easily accessible 2-(2-nitrophenyl)-4H-chromen-4-one (1) via
reduction of its nitro functionality.

R'
O
R'
O
R'
O
O
O
O
1
NO2
R
NH2
RCHO
+
N
3
(Known synthesis using o-nitro benzaldehyde
and an appropriate o-hydroxy acetophenone)
2
4
Scheme 2: Reterosynthetic analysis of 6-substituted chromeno[3,2-c]quinolin-7-one.
Results and Discussion
Our efforts started from the synthesis of 2-(2-nitrophenyl)-4H-chromen-4-one (1a) which was prepared using well-established
literature protocols.14 Subsequently, reduction of the nitro group with Fe/NH4Cl lead to the formation of 2-(2-aminophenyl)-4H-
chromen-4-one (2a) (ESI). With compound 2a in hand, efforts were focused on screening for appropriate conditions to generate
the target molecules. Herein, the reaction between 2a and benzaldehyde was used as the model reaction (Table-1). Initially,
reactions were attempted with diverse Lewis and Bronsted acids (entry 1-6). While some of the reactions did not proceed beyond
the formation of aldimines, however with Yb(OTf)3 and FeCl3 target molecules were obtained in 20% and 32% yields,
respectively. Subsequent reactions (entry 7-10) were attempted with FeCl3 to screen for the appropriate solvent. The reaction
was successful only with nitrobenzene as a solvent, which gave compound 4a in 56% yield. Further adjustment of the amount of
catalyst did not improve the overall yield (entry 11-12). Reactions when carried out with FeCl3 (20 mol%) in the presence of
various oxidizing agents such as TBPB, TBHP as well as in the combination of TBPB-Oxone or TBPB-K2S2O8 did not result in
the formation of the final product (entry 13). Using Fe(acac)3, as a catalyst (entry 14), found suitable by Patel and co-workers in
their synthetic studies on C-3 functionalization of flavones13, did not yield the final product. When the reaction was attempted
under air with FeCl3 (20 mol%) as catalyst (entry 15), fused chromeno-quinoline molecule was obtained in 44% yield. Thus,
after thorough screening best results were obtained with 20 mol% FeCl3 as catalyst and nitrobenzene as a solvent at 180 °C under
nitrogen atmosphere (entry 10).
O
N
O
Figure 2: Structure of proposed aldimine intermediate.
Table 1: Screening of catalysts for the synthesis of chromeno[3,2-c]quinolin-7-one’s.
O
N
O
CHO
O
O +
catalyst, solvent
NH2

Catalyst
(20 mol%)
PTSA
CF3SO3H
CH3CO2 H
Yb(OTf)3
Cu(OTf)2
FeCl3
Time
(in hr)
12
12
12
12
12
12
12
12
12
6
6
6
12
12
6
Yield
(%)
-
-
-
20
-
32
-
-
Temp. (°C)
S.No.
Solvent
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1,4-Dioxane
1,4-Dioxane
-
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
DMF
90
90
110
90
90
90
140
140
90
180
180
180
180
180
180
FeCl3
FeCl3
FeCl3
DMSO
CH3CN
-
FeCl3
Nitrobenzene
Nitrobenzene
Nitrobenzene
Nitrobenzene
Nitrobenzene
Nitrobenzene
56
52
56
-
@
FeCl3
#
FeCl3
$%
FeCl3
Fe(acac)3
FeCl3
-
44*
All the reactions were carried out under nitrogen atmosphere unless mentioned;
* reaction was carried out under air atmosphere; @ Catalyst used 10 mol%;
# catalyst used 30 mol%; $3 equivalents of oxidant such as TBPB (tert-butylperoxy-
benzoate)/TBHP(tert-butylhydroperoxide)/oxone/K2S2O8 were used along with
the catalyst;% whenever two oxidants were used the ratio was 1:1(1.5 equivalents
each).
With optimized conditions in hand, we set out to demonstrate the substrate scope of the newly developed methodology. As
shown in Table 2, wide array of aromatic aldehydes were examined in the synthesis of chromeno[3,2-c]quinolin-7-one 4a-o. In
general, aldehydes possessing electron donating groups (such as -OMe, -OH) resulted in moderate yields of the corresponding
fused-chromeno products. Surprisingly, aldehyde bearing p-methyl group as the substituent gave comparatively better yield than
the aforementioned aldehydes. Screening substrates with electron-withdrawing substitutions (e.g. F, Cl, Br) yielded the cyclized
products in moderate to good yields. The yields were found to be effected by the electronegativity of the halogens. Best yield was
obtained using p-fluorobenzaldehyde, whereas, the yield was compromised in the case of p-bromobenzaldehyde. Extending the
scope of halogenated benzaldehydes to their di-chlorinated congeners yielded the target compounds in modest yield.
Interestingly, more sterically hindered 2,6-dichlorobenzaldehyde gave better yield then its 2,4-disubstituted isomer. Subsequent
reactions with p-phenylbenzaldehyde, thiophene-2-carboxaldehyde and pyridine-2-carboxaldehyde gave the final compounds in
yields ranging from 25 to 47%. Scope of the reaction was also evaluated using 2-(2-aminophenyl)-6-methyl-4H-chromen-4-one
and 2-(2-aminophenyl)-6-chloro-4H-chromen-4-one as substrates. Reaction carried out between 2-(2-aminophenyl)-6-methyl-
4H-chromen-4-one and benzaldehyde, gave the corresponding chromeno[3,2-c]quinolin-7-one analogue in 45% yield, whereas
with p-bromobenzaldehyde the yield of the final product was 40%. With 2-(2-aminophenyl)-6-chloro-4H-chromen-4-one and
benzaldehyde as substrate the final product was obtained in 52% yield. Our attempts with aliphatic aldehydes (acetaldehyde,
propionaldehyde, isovaleraldehyde and phenylacetaldehyde) were not fruitful and no products were obtained.
Table 2: Substrate screening
X
X
O
O
O
O
FeCl3 (20 mol%)
PhNO2, 180 oC
6 hour
+ RCHO
R
N
NH2
4a-o
2a [X = H]
2b [X = CH3]
2c [X = Cl]

O
4b =
4c =
4a =
56%
37%
61%
48%
F
Cl
HO
4e =
4h =
4f =
4i =
4d =
65%
53%
Cl
Cl
Br
4g =
Cl
Cl
48%
52%
35%
54%
Ph
4k =
4n =
4l =
4j =
S
N
25%
47%
Br
4o =
4m =
X = Cl
52%
X = CH3
45%
X = CH3
40%
A plausible mechanism was proposed to rationalize the product formation. The reaction appears to proceed through cationic
intermediate, similar to our previous observations (Scheme-3).4 The electrophilic attack of chromone ring via position 3 followed
by oxidative aromatization are envisioned as key steps in the synthesis of the target molecules. An alternative mechanism, based
on thermal 6π electrocyclization of imine intermediate followed by oxidative aromatization can also be considered. A similar
mechanism was suggested by Khan et al. in order to rationalize the synthesis of coumarin fused quinolines/dihydroquinolines.15
O
O
N
O
O
H
N
FeCl3
FeCl3
-H
O
N
O
O
[O]
O
-FeCl3
N
FeCl3

Scheme 3: Plausible mechanism for the formation of the target molecule.
Relatively modest to low yields and the requirement of comparatively high reaction temperature, prompted us to study the
putative aldiimine intermediate by DFT calculations. For this purpose the structure of the intermediate was optimized with the
Gaussian 09 [DFT/cam-b3lyp/6-311++g(d,p)]. The optimized geometry was employed to calculate the Mulliken charge
distribution, the HOMO and LUMO energy values [See SI for details]. The charge distribution showed comparable charges on
the two reaction centers, which in our opinion rationalize the modest to low yields seen in the reaction.
Conclusions
In summary, we have developed a direct iron-catalyzed route involving functionalization of C-3 position of flavones for the
2
synthesis of 6-substituted chromeno[3,2-c]quinolin-7-one. The developed method helps in coupling two Csp centers bearing
similar charges and works with easily available aromatic aldehydes having electron rich and electron deficient substituents.
Given the biological importance of flavones and quinolines, we feel that the devised method will find a lot of applications in the
domain of medicinal chemistry. Additionally, since many chromone/flavone based natural products are C-3 substituted, the
possibility of synthesizing these molecules without the aid of any additional activation or pre-functionalization step will prove to
be an attractive feature.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
TUK acknowledges BITS-Pilani for PhD fellowship. TUK and AB are grateful on behalf of Department of Chemistry,
BITS-Pilani Hyderabad campus to DST-India for FIST support (SR/FST/CSI-240/2012).
Notes and references
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Iron(III) catalyzed direct C-H functionalization at the
C-3 position of chromone for the synthesis of fused
chromeno-quinoline scaffolds
T. Uday Kumar,a Durba Roya and Anupam Bhattacharya *a
aDepartment of Chemistry, Birla Institute of Technology and Science-Pilani (Hyderabad Campus),
Hyderabad-500078, India.
E-mail: anupam@hyderabad.bits-pilani.ac.in
Highlights
 Functionalizing comparatively unreactive C-3 position of chromone
 Synthesis of hitherto unknown 6-substituted chromeno[3,2-c]quinolin-7-one’s

 Final step without any additional activation or pre-functionalization