Scope of Successive C-H Functionalizations of the Methyl Group in 3-Picolines: Intramolecular Carbonylation of Arenes to the Metal-Free Synthesis of 4-Azafluorenones

Article abstract of DOI:10.1021/acs.orglett.5b03071

A transition-metal-free, t-BuOOH mediated intramolecular carbonylation of arenes in 2-aryl-3-picolines via oxidative C-H functionalizations of the methyl group has been developed, providing an expedient synthesis of 4-azafluorenones. Distinct from the current literature wherein methylarenes have been used as acylating agents, 2-aryl-3-picolines in this study are transformed into aldehydes, which give 4-azafluorenones upon rapid intramolecular acylation. The study demonstrates the first example of intramolecular carbonylation of arenes utilizing a methyl group as latent carbonyl functionality.

Full text of DOI:10.1021/acs.orglett.5b03071

Letter
pubs.acs.org/OrgLett
Scope of Successive C−H Functionalizations of the Methyl Group in
3‑Picolines: Intramolecular Carbonylation of Arenes to the Metal-
Free Synthesis of 4‑Azafluorenones
Joydev K. Laha,* Krupal P. Jethava, and Sagarkumar Patel
Department of Pharmaceutical Technology (Process Chemistry), National Institute of Pharmaceutical Education and Research, S. A.
S. Nagar, Punjab 160062, India
S
* Supporting Information
ABSTRACT: A transition-metal-free, t-BuOOH mediated intramolecular
carbonylation of arenes in 2-aryl-3-picolines via oxidative C−H functionaliza-
tions of the methyl group has been developed, providing an expedient
synthesis of 4-azafluorenones. Distinct from the current literature wherein
methylarenes have been used as acylating agents, 2-aryl-3-picolines in this
study are transformed into aldehydes, which give 4-azafluorenones upon rapid
intramolecular acylation. The study demonstrates the first example of
intramolecular carbonylation of arenes utilizing a methyl group as latent
carbonyl functionality.
functionalizations of a methyl group, a widely sought yet elusive
transformation, remains unrealized.
4-Azafluorenones, a privileged molecular scaffold ubiqui-
tously found in natural products, display various biological
activities including antimicrobial, antimalarial, and DNA-
damaging activities (Figure 1).10 4-Azafluorenone derivatives
arbon−carbon (C−C) bond formation between two C−
2
3
CH bonds (sp, sp or sp C−H), traditionally known as
oxidative or cross-dehydrogenative coupling, has become the
central focus in C−C bond forming reactions obviating the use
of prefunctionalized substrates and alleviating the generation of
salt waste, thereby rendering superior sustainability and
environmental compatibility.1 The growing dependence on
these direct oxidative C−H functionalizations that feature
higher atom economy and sustainability has witnessed a hefty
evolution over the past two decades, which signifies the
importance of and emergent interest in this synthetic
technology. However, a fundamental challenge intrinsic to
these oxidative C−H functionalizations lies in achieving high
regioselectivity.2 The challenge is further exacerbated by the
requirement of achieving regioselective oxidative functionaliza-
tions of an unactivated sp3 C−H bond, especially under
transition-metal-free conditions. Nevertheless, successful real-
izations of multiple regioselective C(sp3)−H functionalizations
are among the various reaction tools celebrated in organic
chemistry.3
Figure 1. Compounds containing a 4-azafluorenone skeleton.
have found various other applications, for example, compound
1 as a thrombin inhibitor11 and 2 as an electron-transporting
host material capable of being fabricated into efficient organic
light-emitting devices (LED).12 Despite these diverse applica-
tions, the chemistry of 4-azafluorenones has been least
investigated.13
The strategies reported for the synthesis of 4-azafluorenones
fall in three categories: intramolecular Friedel−Crafts acylation
on 2-arylpyridines containing a carboxylic acid11,14 or an ester
group14a,15 appropriately placed on one of the two rings (Paths
A and B), biaryl linkage formation by intramolecular Heck
reactions on 3-aroylpyridines (Path C),10a,16 and a three-
component reaction (Path D, Scheme 1).17 Remarkably,
Sneickus et al. reported a more general approach to the
Oxidation of methylarenes to aryl methanols, aldehydes, and
carboxylic acids merits extensive discussion.4 Remarkably,
methylarenes have served as acylating agents for the carbon-
ylation of hetero(arenes) via successive oxidative C−H
functionalizations of the methyl group.5 While there has been
much effort devoted toward the catalytic oxidation of picolines
to pyridine carboxylic acids,6 oxidations of picolines followed by
in situ trapping of the aldehydes with amines or thiols yielding
pyridine carboxamides,7 cyanopyridines,8 or thiolesters9 are
especially noteworthy. Perhaps most importantly, picolines
have not been demonstrated to serve as acylating agent for the
direct acylation of arenes. Moreover, an intramolecular
carbonylation of arenes or heteroarenes via successive C−H
Received: October 22, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03071
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Letter
a
Scheme 1. Synthetic Approaches to 4-Azafluorenones
Table 1. Optimization Study
b
b
c
entry
oxidant
oxidants
additive
solvent
DCE
yield (%)
d
1
0
2
3
4
TBHP (4)
K2S2O8 (2)
TBHP (6)
TBHP (8)
TBHP (1 mL)
TBHP (8)
TBHP (8)
TBHP (8)
TBHP (8)
TBHP (8)
TBHP (8)
DCE
MeCN
DCE
DCE
DCE
DCE
DCE
35
30
58
e
5
70
e
6
63
7
TBAI (0.5)
trace
40−45
20
f
8
base
9
10
11
12
DMSO
40
MeCN/THF
trace
70
synthesis of azafluorenones from arylpyridines containing an
N,N-dialkylamide group in the presence of LDA.18 However,
synthesis of 4-azafluorenones has not been demonstrated in this
report. While several of these methods are elegant and appear
to be appealing, they suffer from limitations such as harsh
reaction conditions, use of elaborated synthetic precursors,
requiring multiple steps, and frequent use of transition metals.
Despite significant advances realized in 4-azafluorenone
synthesis largely using classical chemistry, important questions
still remain: (a) whether a methyl group on 2-aryl-3-picolines
could be used as a latent carbonyl functionality, (b) whether a
transition-metal-free as opposed to a transition-metal-catalyzed
oxidative approach could be developed, and (c) whether a
single, nontoxic oxidant that is compatible with environmental
safety could execute successive C−H functionalizations of a
methyl group. Nevertheless, a defined objective considering
these questions collectively would be a daunting challenge.
Remarkably, Glorius et al. and Studer et al. independently
reported the intramolecular carbonylation of arenes via C−H
functionalization of the aldehyde group present in 2-
arylbenzaldehydes yielding flurenones in good to excellent
yields.19 Inspired by their work, and based on our recent
experiences on sp2 C−H oxidative couplings in the synthesis of
biaryl sultams,20 heterobiaryl sultams,21 and carbazoles as well
as α-carbolines,22 we surmised that an intramolecular carbon-
ylation of arenes in 2-aryl-3-picolines via successive oxidative
C−H functionalizations of the methyl group, while an
ambitious objective, would be a distinct, straightforward
gateway to 4-azafluorenones. Herein, we describe a first report
on the intramolecular carbonylation of arenes via successive C−
H functionalization of a methyl group present in 2-aryl-3-
picolines. The successive C−H functionalization of a methyl
group present on a pyridine ring, a strategy previously
unexplored, is now unveiled. The optimized conditions in our
study are quite resourceful, warranting broad applications to the
synthesis of 4-azafluorenones.
g
DCB
e
h
13
TBHP
DCE
DCE
60
ei
,
14
15
16
TBHP (8)
TBHP (8)
TBHP (8)
48
ej
,
g
DCB
55
TEMPO (10)
DCE
0
a
3 (0.15 mmol), oxidants (2 equiv to large excess), additive (if any, 10
b
mol % to 150 mol %), DCE (1 mL), 100 °C, 30 h. Number of
equivalents in parentheses. Isolated yields. Oxidants used [oxygen,
DTBP (4 equiv), TBPB (4 equiv), (NH4)S2O8 (2 equiv), Oxone (2
c
d
e
equiv), DDQ (2 equiv), or PhI(OAc)2 (2 equiv)]. DCE (0.5 mL).
f
g
KOBu-t (1.5 equiv) or Li2CO3 (0.1 equiv). 1,2-Dichlorobenzene.
h
i
j
0.25 mL of 70% aqueous TBHP solution. 80 °C. 130 °C.
a large excess of TBHP was detrimental (entry 6). Thus,
heating a solution of 3 in DCE (200 mM) with 8 equiv of
TBHP gave 4 in 70% isolated yield. However, TBHP in
combination with TBAI, largely used for C−H functionaliza-
tions,23 was ineffective in our study (entry 7). In addition,
TBHP in the presence of a base resulted in reduced conversion
of 3 to 4 yielding a 40−45% yield of 4 (entry 8). Solventless
conditions or a different solvent gave varying yields of 4
(entries 9−12). TBHP in water gave a slightly reduced yield
(entry 13). Conversion of 3 to 4 is affected by lowering the
temperature or heating at higher temperature (entries 14−15).
Exposure of 3 to the standard conditions in the presence of 10
equiv of TEMPO, a radical trapping agent, could markedly
suppress the formation of 4, suggesting a free-radical
intermediate was involved in this reaction (entry 16).
We further investigated the scope of substrates that could
participate in the intramolecular carbonylation. The starting
materials (5−19) were easily prepared by Suzuki coupling of 2-
bromo-3-picoline with commercially available aryl boronic acids
or aryl pinacolboranes, prepared from aryl bromides (see
Supporting Information).24
2-Aryl-3-picoline 5 containing an electron-donating para-
OMe group on the phenyl ring worked well, yielding azafluo
renone 20 in 70% yield (Scheme 2, entry 1). However,
compound 6 containing a para-OCF3 group reacted less
effectively yielding azafluorenone 21 in reduced yield (24%)
together with 22 containing an aldehyde group (entry 2).
Evidently, the methyl group in 6 is oxidized to aldehyde, which
upon subsequent acylation, similar to that reported,19 could
give 21. However, unlike literature,19 an arene is acylated
intramolecularly with an aldehyde group present on a pyridine
ring. While a tert-butyl group produced an inferior result
We commenced our study with the C−H functionalizations
of readily available 2-phenyl-3-picoline (3) aiming at the
synthesis of azafluorenone 4. Initial efforts to effect annulations
using many oxidants that are generally used for methyl C−H
functionalizations are ineffective in this study (Table 1, entry
1). However, 4 equiv of TBHP in DCE were able to transform
3 to 4 in 35% yield (entry 2). Similarly, 2 equiv of K2S2O8 in
acetonitrile resulted in conversion of 3 to 4 with a comparable
yield (30%, entry 3). Greater conversion of 3 to 4 was apparent
using higher stoichiometries of TBHP (entries 4−5). However,
B
DOI: 10.1021/acs.orglett.5b03071
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Letter
yield (entry 13). In contrast, 18 produced a complex mixture of
products (entry 14). This dissimilarity could be explained by
the anomalous reactivity of two methyl groups present on the
phenyl ring. It is important to realize that the formation of 33
from 17 was pertinent to successive C−H functionalizations
occurring exclusively at the methyl group present on the
pyridine ring. Second, the intramolecular carbonylation
occurred exclusively on the sp2 C−H bond rather than the
sp3 C−H bond of the methyl group in the phenyl ring. Pivotal
to this study was the finding that a hydroxymethyl group at the
3-position of the pyridine ring gave an excellent yield (90%) of
azafluorenone 4 under the standard conditions. The relative
ease of intramolecular carbonylation with a hydroxymethyl
compared to a methyl group is particularly noteworthy (entry
15). Therefore, a hydroxymethyl group on the pyridine ring
could be a starting platform for heteroaroylation of arenes.
More importantly, carbonylation of arenes via transition-metal-
free oxidative C−H functionalizations of a hydroxymethyl
group present on pyridine is currently unavailable in the
literature.
Scheme 2. Substrates Scope for the 4-Azafluorenones
Synthesis
To gain further insight into the mechanism, we performed
additional experiments. The results of these experiments were
quite informative in formulating a plausible mechanism. While
compound 3 alone forms 4 under standard conditions, the
product 4 was not observed in the presence of excess (20
equiv) toluene (Scheme 3). A competitive C−H functionaliza-
Scheme 3. Control Experiments
tion of both methyl groups could explain, however, the
formation of multiple products in the reaction of 3 and excess
toluene. More interestingly, 3-picoline (35) itself that does not
have a 2-aryl group remained largely unreacted in the presence
of excess toluene. Only an intermolecular acylated product 36
was isolated albeit in low yield. Further optimization could
result in a new protocol for the direct C-2 aroylation of
pyridines, which remains unexplored in the literature. Never-
theless, this experiment implies that an aryl group at the 2-
position could facilitate C−H functionalization of the methyl
group on the pyridine ring. A crossover experiment involving 3
and 2-phenylpyridine (37) gave azafluorenone 4 under the
standard conditions. However, no crossover product that could
result from intermolecular reaction of 3 and 37 was observed.
This experiment suggests that the ortho-hydrogen of the phenyl
ring in 3 is vulnerable for direct acylation with aldehyde.
Based on these studies, a plausible mechanism is depicted in
Scheme 4. The formation of a radical from TBHP may be
initiated upon heating. Initially, hydrogen abstraction from the
methyl group could form a 3-picoline radical, which upon
subsequent proton abstraction could form a primary alcohol.
Oxidation of the primary alcohol could generate an aldehyde.
The aldehyde could form an aryl carbonyl radical by reaction
with TBHP, which upon subsequent acylation with arene
would deliver 4.
a
b
c
42 h. 36 h. 24 h.
producing azafluorenone 23 in 55% yield, a phenyl group
restored the yield (78%) (entries 3−4). A para-chloro group is
somewhat better than tert-butyl yielding azafluorenone 25 in
60% yield (entry 5). An electron-withdrawing group F or CF3
exerts a diminishing effect producing azafluorenone 26 or 27 in
reduced yields (43−46%) (entries 6−7). Dichloro- or
fluorophenyl-3-picoline 12 and 13 reciprocated the same
reactivity as that of monosubstituted derivatives 9 and 10,
respectively, affording azafluorenones 28 and 29 in comparable
yields (entries 8−9). 3-Picolines 14−15 having two electron-
donating groups, the same or different, were also viable
substrates yielding disubstituted azafluorenones 30−31 in 66−
68% yields (entries 10−11). Furthermore, 3-picoline 16
containing a highly substituted aryl group at the 2-position
furnished a trisubstituted azafluorenone 32 in 62% yield
suggesting that the intramolecular carbonylation may occur
irrespective of steric effects (entry 12). Under the standard
conditions, 2-arylpyridines containing two methyl groups, one
at the 3-position of the pyridine ring and another on the
benzene ring, for example 17, gave 4-azafluorenone 33 in 53%
C
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ASSOCIATED CONTENT
* Supporting Information
■
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The Supporting Information is available free of charge on the
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Experimental procedures, characterization data of new
1
compounds, and copies of H and 13C NMR spectra
(PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: jlaha@niper.ac.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We greatly appreciate the Science & Engineering Research
Board (SERB) of DST, New Delhi for financial support. KPJ
thanks the NIPER S.A.S. Nagar for a research fellowship.
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