Hypervalent iodine-mediated selective oxidative functionalization of (thio)chromones with alkanes

Article abstract of DOI:10.1002/chem.201400186

C-C bond formation is the most fundamental way for the chain propagation in organic molecules. This achievement through tandem oxidation of two different C-H bonds represents the state of the art in organic synthesis. Selective functionalization of the ubiquitous aliphatic C-H bonds offers an attractive option for this oxidative cross-coupling methodology. To develop such a methodology under mild and metal-free conditions remains challenging. Herein, we report hypervalent iodine-mediated selective oxidative functionalization of aliphatic C-H bonds of alkanes with chromones and (thio)chromones. A wide range of alkanes, both cyclic and acyclic, has been found to react selectively and predictably in good yields. The developed methodology is also the first report of a direct oxidative functionalization of the C-2 position of (thio)chromones with alkanes to access bioactive compounds. Hypervalent iodine: An efficient I^III-mediated selective oxidative functionalization of alkanes with chromones and (thio)chromones has been developed. The developed methodology provides a direct access to the 2-alkyl chromones under metal-free and ambient conditions. Both cyclic and acyclic alkanes can be selectively functionalized (see scheme).

Full text of DOI:10.1002/chem.201400186

DOI: 10.1002/chem.201400186
Communication
&
Synthetic Methods
Hypervalent Iodine-Mediated Selective Oxidative
Functionalization of (Thio)chromones with Alkanes
Rishikesh Narayan[a] and Andrey P. Antonchick*[a, b]
bonds are engendered in the products. Therefore, products are
more labile under reactions conditions and undergo over-func-
tionalization. Despite these challenges, a lot of progress has
been made in the area of oxidative functionalization of Csp3ÀH
bond to form carbon–heteroatom bonds.[5] Similarly, Csp3ÀC
bond formation through cross-dehydrogenative coupling has
been achieved, but mostly by metal catalysis in combination
with various oxidants.[6] Only a few mild and metal-free ap-
proaches for coupling with simple alkanes have been repor-
ted.[6d–e,7] Herein, we report a selective oxidative Csp3ÀH bond
functionalization of simple alkanes with chromones and (thio)-
chromones under metal-free and ambient conditions.
Abstract: CÀC bond formation is the most fundamental
way for the chain propagation in organic molecules. This
achievement through tandem oxidation of two different
CÀH bonds represents the state of the art in organic syn-
thesis. Selective functionalization of the ubiquitous ali-
phatic CÀH bonds offers an attractive option for this oxi-
dative cross-coupling methodology. To develop such
a methodology under mild and “metal-free” conditions re-
mains challenging. Herein, we report hypervalent iodine-
mediated selective oxidative functionalization of aliphatic
CÀH bonds of alkanes with chromones and (thio)chro-
mones. A wide range of alkanes, both cyclic and acyclic,
has been found to react selectively and predictably in
good yields. The developed methodology is also the first
report of a direct oxidative functionalization of the C-2 po-
sition of (thio)chromones with alkanes to access bioactive
compounds.
As part of our continued interest in the area of CÀH func-
tionalization,[7,8] we have recently developed an iodine(III)-
mediated[9] oxidative functionalization of simple alkanes with
a variety of nitrogen heterocycles.[7] Based on the observations
made during this study, we proposed that the alkyl radical
generated under these conditions possess nucleophilic charac-
ter. Nevertheless, the developed transformation is limited to
electron-poor nitrogen-containing heterocycles. As a part of
applying this methodology in the direct synthesis of bioactive
compounds, we concentrated on utilizing chromone as the po-
tential substrate. Chromone is an important structural motif
present in many biologically important molecules.[10] Chro-
mone alkaloids are abundant naturally occurring alkaloids
forming the core of flavonoids. Derivatives of 2-alkylchromones
have gained prominence as an extremely important class of in-
hibitors for a variety of biological targets (Figure 1).[11]
The CÀC bond represents the most essential and most abun-
dant link in all organic molecules.[1] The quest for ever more ef-
ficient ways to construct CÀC bonds represents a challenge for
the synthetic chemists. One of the many ingenious ways to
achieve this lays in cross-dehydrogenative coupling.[2] This
methodology constructs carbon–carbon bonds through
tandem oxidation of two CÀH bonds present in the two cou-
pling partners. The obvious benefit of this strategy is the small-
er number of synthetic steps required to reach the target mol-
ecule, thereby making the synthesis highly efficient.[3] Aliphatic
Csp3ÀH bonds are omnipresent in organic molecules. Direct
functionalization of aliphatic Csp3ÀH bonds in a selective and
predictable manner embodies a significant challenge in organ-
ic synthesis, because these bonds are of the least reactive
bonds.[4] The apparent difference in reactivity of various types
of aliphatic Csp3ÀH bonds is not appreciable. Furthermore,
during the functionalization of simple alkanes, weaker CÀH
[a] Dr. R. Narayan, Dr. A. P. Antonchick
Max Planck Institute fꢀr Molekulare Physiologie
Abteilung Chemische Biologie
Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
Fax: (+49)231-133-2499
Figure 1. Representative structures of biologically relevant 2-alkylchromones.
E-mail: andrey.antonchick@mpi-dortmund.mpg.de
[b] Dr. A. P. Antonchick
Many approaches have been developed for the C-2 func-
tionalization of chromones over the years. However, most of
these efforts have been directed towards introducing aryl sub-
stituents to obtain flavones. Syntheses of 2-alkyl chromones in-
Technische Universitꢁt Dortmund, Fakultꢁt Chemie
Chemische Biologie, Otto-Hahn-Strasse 6, 44227 Dortmund (Germany)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201400186.
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volve the usage of aliphatic aldehyde, which undergoes exten-
sive self-condensation under the reaction conditions. Other
multistep sequences have been developed to circumvent this
problem and obtain C-2 alkyl chromones.[12] Recently, direct
metal-catalyzed functionalization methods at the C2-position
of chromones with pre-functionalized compounds have been
developed.[13] For example, a silver-nitrate-catalyzed homolytic
decarboxylative alkylation with aliphatic carboxylic acid has
been reported.[13c] Nevertheless, this transformation led to the
formation of mixtures of alkylated chromones and chroma-
nones and has a limited scope. Very recently, an elegant regio-
selective palladium-catalyzed oxidative arylation of chromones
through double CÀH activation has been reported.[14] In this
perspective, a dehydrogenative cross-coupling of chromones
with alkanes would not only represent a significant advance-
ment in the functionalization of alkanes, but also provide
a very efficient access to biologically important 2-alkyl chro-
mones (Scheme 1).
Table 1. Optimization of the reaction conditions.[a]
Entry Oxidant [equiv]
Additive [equiv] Solvent t [h] Yield [%]
1
2
3
4
5
6
7
8
PhI(O2CCF3)2 (2)
PhI(O2CCF3)2 (3)
PhI(O2CCF3)2 (4)
PhI(O2CCF3)2 (3)
PhI(O2CCF3)2 (3)
PhI(O2CCF3)2 (3)
PhI(O2CCF3)2 (3)
PhI(OAc)2 (3)
C6F5I(O2CCF3)2 (3) NaN3 (3)
PhI(OH)OTs (3)
(BzO)2 (4)
PhI(O2CCF3)2 (3)
PhI(O2CCF3)2 (3)
PhI(O2CCF3)2 (3)
PhI(O2CCF3)2 (3)
PhI(O2CCF3)2 (4)
PhI(O2CCF3)2 (4)
NaN3 (2)
NaN3 (3)
NaN3 (4)
NaN3 (3)
NaN3 (3)
NaN3 (3)
NaN3 (3)
NaN3 (3)
CH2Cl2
CH2Cl2
CH2Cl2
PhH
C2H4Cl2 16
CHCl3
MeOH
CH2Cl2
CH2Cl2
CH2Cl2
4
4
4
16
42
58
58
16
42
16
16
24
16
16
33
n.d.
n.d.
<10
20
9
10
11[b]
12
13
14[c]
15[d]
16[e]
17[f]
NaN3 (3)
–
C2H4Cl2 16
50
TMSN3 (3)
tBu4NN3 (3)
NaN3 (3)
NaN3 (3)
NaN3 (4)
NaN3 (4)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
24
24
24
8
10
10
n.d.
n.d.
31
61
64
72
[a] Reaction conditions: 1a (0.14 mmol), cyclohexane (2.8 mmol), in sol-
vent (1.0 mL) at RT. [b] The reaction was carried out in 1,2-dichloroethane
at reflux. [c] The reaction was carried out at a concentration of 0.025m.
[d] Oxidant and additive were added in two portions of 1.5 equiv each.
[e] Oxidant and additive were added in batches of 1.0 equiv in 1 h inter-
vals. [f] Oxidant and additive were added in batches of 0.5 equiv in 1 h in-
tervals. n.d.=not determined, C2H4Cl2 =1,2-dichloroethane.
C6F5I(O2CCF3)2 and PhI(OH)OTs were used instead of PhI-
(O2CCF3)2, the product 2a was obtained in substantially lower
yields of 10 and 20%, respectively (Table 1, entries 9-10). When
benzoyl peroxide was used as the oxidant in 1,2-dichloro-
ethane at reflux, 50% of 2a was obtained without using any
additives (Table 1, entry 11). Various peroxide oxidants, such as
tert-butyl hydrogen peroxide (TBHP), di-tert-butyl peroxide
(DTBP), and lauroyl peroxide did not initiate the radical reac-
tion at all (see the Supporting Information for the details).
Then, various azide sources, such as trimethylsilyl azide, tert-
butylammonium azide, and phosphoryl azide were applied,
but they all failed to give any product (Table 1, entries 12 and
13, and the Supporting Information). At this stage, with the
best yield of 58%, we thought to further improve the efficien-
cy of the reaction based on the use of the PhI(O2CCF3)2/NaN3
system. During the screening, we observed the formation of
a side-product, which was identified as the product of double
addition of cyclohexyl radical across the 2,3-double bond in
chromone. We thought that the formation of this side-product
could be suppressed by either dilution of the reaction medium
or by addition of some hydrogen radical source. The radical re-
actions are known to be affected by the dilution of the reac-
tion medium. When this reaction was carried out under much
dilute condition of 0.025m, the yield of the product plummet-
ed to 31% (Table 1, entry 14).
Scheme 1. Synthetic disconnection for oxidative C-2 functionalization of
chromone derivatives.
Initially, the oxidative coupling of chromone 1a with cyclo-
hexane in the presence of two equivalents of PhI(O2CCF3)2 and
NaN3 as the additive in CH2Cl2 at ambient temperature was
tested. We were delighted to obtain the desired coupling
product 2a in 42% yield (Table 1, entry 1). When the amount
of PhI(O2CCF3)2 and NaN3 was increased to three equivalents,
a substantial improvement in the yield of product 2a to 58%
was observed (Table 1, entry 2). Further increase in the amount
of oxidant and additive did not result in any improvement
(Table 1, entry 3). Then we carried out a thorough screening of
various solvents (Table 1, entries 4–7 and the Supporting Infor-
mation). However, none of the screened solvents gave better
results compared with CH2Cl2. Benzene could give the product
2a in 16% yield (Table 1, entry 4). Other chlorinated solvents,
such as 1,2-dichloroethane and CHCl3, also gave the product
2a in inferior yields of 42 and 33% respectively (Table 1, en-
tries 5–6). The use polar solvents, such as EtOAc, MeOH, and
CH3CN, led to no reaction, and no product was observed
(Table 1, entry 7, and the Supporting Information). Afterwards,
various oxidants were screened. No product was detected in
the presence of PhI(OAc)2 (Table 1, entry 8). When compounds
A variety of hydrogen donors, such as Et3SiH, PhSiH3, 1,4-cy-
clohexadiene (CHD), and NaBH4, were tested. Of these, CHD
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gave the product in 42% yield, whereas NaBH4 gave a compa-
rable yield of 58% (see the Supporting Information for details).
Nevertheless, we were unable to suppress the formation of the
dialkylated product completely. We also observed in many
cases that the conversion remained incomplete even after pro-
longed reaction time. To overcome this, we planned to add
PhI(O2CCF3)2 and NaN3 in small batches. When a total of three
equivalents of PhI(O2CCF3)2 and NaN3 was added in two batch-
es of 1.5 equivalents each, slight increase in the yield to 61%
was detected (Table 1, entry 15). Following this hint, the reac-
tion was carried out by addition of one equivalent batch of
the reagents, which increased the yield to 64%. In a 0.5 equiva-
lent batch-mode addition, best yield of 72% was obtained
(Table 1, entries 16–17). Syringe pump addition of PhI(O2CCF3)2
over a period of 4 h resulted in reduced yield of 48%. Finally,
we decided to use PhI(O2CCF3)2 and NaN3 in 0.5 equivalent
batch-addition mode as the optimal reaction condition.
After obtaining the optimized reaction conditions, we ex-
plored the scope of this hypervalent iodine-mediated cross-de-
hydrogenative coupling of chromones and alkanes. First of all,
the variation in the alkane part of the reaction was studied.
The reaction was found to work well with a range of cycloal-
kanes of various ring sizes. Cyclopentane reacted to give the
corresponding product 2b in 58% yield (Figure 2). Similarly, cy-
cloheptane and cyclo-octane also underwent smooth coupling
to form products 2c and d in 62 and 63% yields, respectively.
An exclusive 38 site selectivity was observed for substituted cy-
cloalkanes (Figure 2, compounds 2e and f). The product of
cross-coupling with methylcyclopentane was obtained in 60%
yield. Reaction with 1,4-dimethylcylohexane gave the corre-
sponding product 2 f in 62% yield as trans/cis 5:1 isomer mix-
ture. 1,1’-Dimethylcyclohexane also reacted well with 6-methyl-
chromone to form the corresponding product 2g as a mixture
of positional isomers in the ratio of C2/C3/C4 1:12:5 and a com-
bined yield of 57%. Only small amount of the regioisomer, cor-
responding to the functionalization at the sterically hindered
C2 position, was observed. The regioisomer ratio at C-3 and C-
4 positions correlates with the relative abundance of CÀH
bonds at the given position. For linear acyclic alkanes, exclu-
sive 28 site selectivity was observed (Figure 2, products 2h–i).
The products were obtained as mixture of regioisomers at 28
sites. A notable selectivity of functionalization at C-2 position
was observed. For example, in the case of n-hexane, the
number of CÀH bonds at C-2 and C-3 positions is equal. Fur-
thermore, the difference in CÀH bond dissociation energies for
the process of n-hexane dissociation to 2-hexyl and 3-hexyl
radicals is negligible (0.1–0.3 kcalmolÀ1).[15] Therefore, the ex-
pected ratio of regioisomers at C2 and C3-positions is 1:1;
however, obtained isomer ratio was 2.6:1. Applications of an
acyclic branched alkane led to selective formation of the prod-
uct with exclusive 38 site selectivity (Figure 2, product 2j).
After studying the scope of alkanes in cross-coupling, we
turned our attention towards substituted chromones. Various
chromones containing electron-donating, as well as electron-
withdrawing, substituents reacted selectively at C-2 position
with cyclohexane to give the corresponding products in good
yields (Figure 2, compounds 2k–q). Chromones substituted
Figure 2. Scope of alkanes in cross-dehydrogenative coupling. Reaction con-
ditions: chromone 1 (1 equiv), alkane (20 equiv), PhI(O2CCF3)2 (4 equiv), and
NaN3 (4 equiv) in CH2Cl2 (1 mL) at RT. [a] Isomer ratio was determined based
on H NMR analysis. The structure of the major isomer is shown. [b] 34% of
chromone was recovered.
1
with halogens at C6-position gave the corresponding products
in 45–60% yield (compounds 2k–m). Remarkably, 6-bromo-2-
cyclohexylchromone (2m) has been found to possess extreme-
ly potent antifungal properties with an inhibitor concentration
(IC50) value of 7 ngcmÀ2.[11d] 6-Methylchromone gave the cross-
coupling product 2p in good yield of 76%. Similarly, other
electron-donating substituents, such as methoxy group, also
reacted well to give the product 2n in 71% yield. Even 6-iso-
propoxy-substituted chromone was tolerated well under the
reaction conditions (2o). This is notable, because the tertiary
CÀH bond of isopropoxy group is weaker and more reactive
under radical conditions compared with CÀH bonds of cyclo-
hexane. a-Naphthochromone underwent facile cross-coupling
with cyclohexane to give product 2q in an appreciable 45%
yield. This compound has been known to induce apoptosis of
hepatocarcinoma cells with an IC50 value of 2.9 mm.[11e] More-
over, highly conjugated aromatic systems, such as naphtho-
chromone, are prone to oxidation under hypervalent iodine in-
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duced oxidative conditions. To our delight, (thio)chromone
reacts well under these conditions to form the cross-coupled
product 2r in good yield of 76%. Oxidation of the sulfur in the
(thio)chromone to corresponding sulfone or sulfoxide was not
observed, thus, indicating towards the chemoselective nature
of the oxidative conditions. Similarly, when the (thio)chromone
was cross-coupled with hexane, the corresponding product 2s
was obtained as a mixture of C2 and C3 regioisomers with
2.5:1 ratio. Methylcyclopentane reacted selectively at the 38
site to give product 2t in 71% yield. Comparatively, the site se-
lectivity of alkane for the dehydrogenative cross-coupling was
found to be similar for both chromones and (thio)chromones.
In both cases, desired products were formed selectively by
functionalization of C2-position of (thio)chromone under mild
reactions conditions. Furthermore, formation of by-products
corresponding to alkanes’ polyfunctionalization, homodimeri-
zation, and over-oxidation were not detected.
ize unactivated Csp3ÀH bonds with naturally abundant and
biologically important chromones and (thio)chromones under
ambient conditions. It also represents a significant advance-
ment in the important and challenging area of metal-free
Csp3ÀCsp2 cross-dehydrogenative coupling.
Experimental Section
General procedure for the synthesis of 2-alkyl(thio)chromones: To
a dry screw capped vial chromone (0.14 mmol) was added and dis-
solved in 1 mL of CH2Cl2. To this solution 20 equiv of alkane was
transferred followed by the addition of 0.5 equiv each of
PhI(O2CCF3)2 and NaN3 under vigorous stirring at ambient tempera-
ture. The rest of the PhI(O2CCF3)2 and NaN3 (final amount used:
4 equiv) were added as batches of 0.5 equiv each with an interval
of 1 h. The progress of the reaction was monitored by thin layer
chromatography (ethyl acetate/petroleum ether mixture). Upon
completion, the reaction mixture was quenched by the addition of
triethylamine and the reaction mixture was directly subjected to
silica-gel column chromatography using ethyl acetate/petroleum
ether mixture as eluent to obtain the pure product.
After exploring the scope of the cross-dehydrogenative cou-
pling of chromones and alkanes, we turned our attention to
the mechanism of the coupling. The formation of the products
2 was substantially suppressed in the presence of radical scav-
engers, such as (2,2,6,6-tetramethylpiperidin-1-yl)oxy (TEMPO).
This fact clearly points to the involvement of radicals in the re-
action. Based on this observation, a mechanistic rational has
been proposed in Scheme 2. At first, PhI(O2CCF3)2 reacts with
NaN3 through ligand exchange of trifluoroacetate for azide to
form species A. This species undergoes thermolysis to gener-
ate an azide radical and an iodine-centered radical B. The azide
radical abstracts a hydrogen atom from alkane to generate the
alkyl radical C and hydrazoic acid. The alkyl radicals generated
through this process possess nucleophilic character and attack
the chromone at the most electrophilic C-2 position to gener-
ate radical D. This species was oxidized to the cross-coupled
product 2.
Acknowledgements
We gratefully acknowledge Prof. Dr. Herbert Waldmann for his
generous support.
Keywords: CÀH activation · chromones · iodine · metal-free
conditions · oxidative coupling
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Received: January 16, 2014
Published online on && &&, 0000
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Communication
COMMUNICATION
&
Synthetic Methods
R. Narayan, A. P. Antonchick*
&& – &&
Hypervalent Iodine-Mediated Selective
Oxidative Functionalization of
(Thio)chromones with Alkanes
Hypervalent iodine: An efficient IIII-
mediated selective oxidative functionali-
zation of alkanes with chromones and
(thio)chromones has been developed.
The developed methodology provides
a direct access to the 2-alkyl chromones
under metal-free and ambient condi-
tions. Both cyclic and acyclic alkanes
can be selectively functionalized (see
scheme).
&
&
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!