Metal-free synthesis of N-fused heterocyclic iodides via C-H functionalization mediated by tert-butylhydroperoxide

Article abstract of DOI:10.1039/c5cc04013b

Direct, regioselective and metal-free synthesis of fused N-heterocyclic iodides is reported. This regioselective C-H functionalization is mediated by tert-butylhydroperoxide (TBHP), via dual activation of molecular iodine and a heterocyclic substrate, resulting in the in situ generation of electrophilic iodine species (I⁺), and free radical(s) ^tBuO^? or ^tBuOO^?, driving the iodination reaction.

Full text of DOI:10.1039/c5cc04013b

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Metal-Free Synthesis of N-Fused Heterocyclic Iodides via C-H
Functionalization Mediated by tert-Butylhydroperoxide
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Krishna K. Sharma, Dhananjay I. Patel and Rahul Jain*
www.rsc.org/
Direct, regioselective and metal-free synthesis of fused N- recently, directing group-assisted C-H iodination at the ortho-
heterocyclic iodides is reported. This regioselective C-H position to the directing group, catalyzed by palladium, rhodium,
functionalization is mediated by tert-butylhydroperoxide (TBHP), and other transition metals have been reported.7
via dual activation of molecular iodine and heterocyclic substrate,
The generalized methods of C-H bromination and chlorination of
resulting in the in situ generation of electrophilic iodine species the six membered N-fused heterocycles can not be extended to
(I+), and free radical(s) tBuO˙ or tBuOO˙, driving the iodination include iodination.8 Therefore, direct C-H iodination of N-fused
reaction.
heterocycles is a significant challenge, and has often been
(Hetero)aryl iodides are versatile synthons in organic synthesis, unsuccessful or limited due to several factors, including poor
useful for generating diversity in bioactive molecules. Higher regioselectivity, harsh reaction conditions and over-iodination.9 The
reactivity of aryl iodides compared to aryl bromides and aryl known methods for the direct C-2 iodination of N-fused
chlorides, and their ease in undergoing an oxidative addition heterocycles often requires metalation-based approaches.10
reaction due to a weaker carbon–iodine bond, makes them valuable
precursor in the transition metal-catalyzed transformations.1 The
aryl iodides are also susceptible to photolytic cleavage at the
carbon–iodine bond, and this property has been elegantly exploited
in various reports.2 In addition, (hetero)aryl iodides have found
applications in thyroid disease, anticancer treatment, X-ray imaging,
and several pharmacokinetics studies.3
Despite wide applications, (hetero)aryl iodides are expensive and
have limited commercial availability, compared to their bromide or
chloride counterparts. Traditional approaches to the synthesis of
(hetero)aryl iodides include, (i) widely used direct iodination
Scheme 1. Approaches to regioselective iodination of
(hetero)arenes
reaction of inactivated aromatic C-H bond that requires strong
Lewis acids or protonic acids conditions, but have limited
application to heterocycles, and are generally non-regioselective,4
and (ii) Sandmeyer reaction, which has a prerequisite of an
aromatic nitro or amino group and later generation of diazonium
salt (scheme 1).5 Buchwald et al. recently reported an aromatic
Finkelstein reaction to synthesize (hetero)aryl iodides from the
corresponding bromides via a trans-halogenation reaction using a
copper catalyst and a bidentate ligand.6 Although elegant, these
methods have limited functional group tolerance or substrates
scope, and (hetero)aryl iodides are obtained in multistep synthesis.
In the Sandmeyer and aromatic Finkelstein reactions, the iodination
at a specific position is governed by the electronic factors, and
position of nitro, amino and bromo groups of the substrates. More
Quinolines and structurally related heterocycles are one of
the most explored groups of compounds in drug discovery.
This ring system is present in a number of naturally occurring
bioactive molecules, and has application in material science.11
In our continuing work on quinolines as bioactive
compounds,12 we were interested in synthesizing C-3
iodinated quinolines and other related heterocycles under
mild reaction conditions upto multigram scale. However, to
the best of our knowledge, there is no generalized report on
the direct regioselective C-3 iodination of quinolines and
related heterocycles. Herein, we report the first metal-free,
direct and regioselective C-H iodination of N-fused
heterocycles using inexpensive molecular iodine. The reaction
proceeds via a dual activation strategy mediated by tert-
butylhydroperoxide (TBHP). The regioselectivity of the C-H
iodination is easily predictable (β-position to nitrogen) and is
not affected by the electronic and steric factors; a major
limitation of the reported C-H iodination protocols.4e
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Table 1. Optimization of the reactiona
With the optimized conditions, the substrate scope of the
reaction with various substituted quinolines and structurally
related heterocycles was investigated (table 2). As seen clearly,
electron-withdrawing groups, electron-donating groups, and
reactive functional groups were well tolerated during the
iodination reaction. The electron-donating group containing
quinolines, generally prone to over iodination underwent
facile regioselective C-H activation to afford C-3 heteroaryl
Entry
Oxidant
Iodine Temp. Solve
2a (%
Yield)b
n.r.c
(equiv.)
source
nt
1
2
3
4
5
6
Oxone (3)
m-CPBA (3)
H2O2(3)
I2
I2
I2
I2
I2
I2
RT
RT
RT
RT
RT
RT
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
n.r.c
iodides (table 2, entries 2b, 2g-j). The 8-substituted quinolines
n.r.c
(table 2, entries 1e-g, 1l-n) were also regioselectively iodinated
at the C-3 position.
(NH4)2S2O8 (3)
PhI(OAc)2 (3)
PhI(OCOCF3)2
(3)
n.r.c
n.r.c
As expected, the presence of electron-donating methoxy
group, electron-withdrawing nitro group and electron-neutral
bromo group containing quinolines due to their reduced
reactivity, took longer time for the completion of reaction
(table 2, entries 2e-g). Pre-halogenated quinolines were
iodinated without difficulty, although position of the halogen
group affected the kinetics, resulting in increased reaction
time (table 2, entries 2d-e, 2k-l). The reactive benzylic protons
were also tolerated under these conditions (table 2, entry
2h).13 Multi-substituted quinolines were also successfully C-3
iodinated, but reaction took between 16-24 hours, due to the
less reactivity of substrates owing to the steric hindrance
(table 2, entries 2l-n).
n.r.c
7
TBHP (3)
TBHP (3)
TBHP (6)
TBHP (8)
TBHP (8)
DTBP(8)
TBHP (8)
TBHP (8)
TBHP (8)
TBHP (8)
TBHP (8)
I2
RT
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMF
23
8
9
I2
I2
I2
I2
80 °C
80 °C
80 °C
90 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
34
67
92
87
10
11
12
13
14
15
16
17
I2
82
81
n.r.c
n.r.c
74
NIS
TBAI
I2
I2
I2
CHCl3
DMSO
78
aAll reactions were performed with substrate 1a (0.1 mmol), I2
(1.2 equiv.), solvent (2 mL). bisolated yield. 30% (w/w) H2O2
solution was used. 70% (v/v) solution of TBHP in water was
used. Reactions monitored by TLC up to 12 h. cNo reaction.
Table 2. Substrate scope of the iodination reaction
I
I2, TBHP
R
R
MeCN
N
N
1a-s
2a-s
I
MeO
I
O2N
I
The investigation began with the screening of a number of oxidants
at room temperature while using quinoline (1a) as a model
substrate and molecular iodine as the iodinating reagent in MeCN;
however, no iodination was observed (table 1, entries 1-6). The first
success was observed when 70% TBHP in water (3 equiv.) was used
as an oxidant in the presence of I2 (1.2 equiv.) in MeCN (2 mL) to
afford regioselectively 3-iodoquinoline (2a) in 23% yield after 12 h,
along with the unreacted starting material (table 1, entry 7).
Heating the reaction mixture at 80 ˚C, while keeping the reagents
ratio intact as described above afforded 3-iodoquinoline (2a) in 34%
yield, without any change in the regioselective nature of the
reaction (table 1, entry 8). Increasing the stoichiometry of TBHP to
six equivalents resulted in even higher conversion and yield of the
product (table 1, entry 9). Finally, the use of 8 equivalents of TBHP
at 80 ˚C afforded 3-iodoquinoline (2a) in 92% yield (table 1, entry
10). Further attempts to vary the stoichiometry of iodine and TBHP,
and temperature of the reaction did not improve yield of the
product. The use of di-tert-butylperoxide (DTBP) as the oxidant
under the optimized conditions produced 2a in 82% yield (table 1,
entry 12). The use of electrophilic iodinating reagent (NIS) afforded
2a in 81% yield (table 1, entry 13), while the use of
tetrabutylammonium iodide (TBAI) resulted in no reaction (table 1,
entry 14). The use of alternate solvents such as DMF, CHCl3 and
DMSO did not offer any advantage over MeCN as the solvent
medium of the reaction (table 1, entries 15-17). To determine the
catalytic nature of the reaction, an experiment was conducted
wherein catalytic amount of TBHP (20 mol%) and AgNO3 (20 mol%)
was used in the presence of I2 (1.2 equiv.), resulting in trace
formation of the product, and thereby indicating that the high
stoichiometry of TBHP is a desirable factor in the reaction.
N
N
N
2a
2d
, 92% (12 h)
2b
2c
, 85% (10 h)
, 91% (17 h)
I
I
Br
I
N
N
N
Br
NO2
, 84% (18 h)
2e
, 86% (20 h)
2f
, 86% (22 h)
I
I
H2N
I
N
N
N
OMe
2h, 93% (3 h)
2i
, 97% (45 min)
2g
, 84% (20 h)
Cl
NH2
I
F
I
I
N
N
N
OMe
2j
, 90% (2 h)
2k, 89% (18 h)
2l, 88% (16 h)
OMe
I
MeO
I
MeO
I
N
N
N
NO2
NO2
2m
, 83% (20 h)
2n, 82% (24 h)
2o, 88% (15 h)
I
I
I
I
N
N
N
I
N
N
2p, 82% (15 h)
2qa, 66% + 2qb, 7% (24 h)
N
N
I
I
I
N
N
N
2ra
, 61% +
2rb
, 9% (24 h)
2s
, 0% (24 h)
Substrate (0.25 mmol), I2 (1.2 equiv.), TBHP (8 equiv.), MeCN
(4 mL), 80 ˚C; reaction time in parentheses.
It was observed that any type of substitution at the C-8
position of the ring reduces the reactivity of quinolines,
2 | J. Name., 2012, 00, 1-3
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possibly due to the steric hindrance. Remarkably, highly regioselectivity of the reaction is possibly controlled via the C-2
reactive amino group was tolerated under these conditions as position (scheme 3d). It may be noted that the designed C-2
exemplified by the successful iodination of 6-amino- and 4- substituents in scheme 3d are used to block C-2 position of the
aminoquinolines (table 2, entries 2i-j). It is important to note substrates, thereby making it inaccessible for free radical
that 4-aminoquinolines constitute an essential class of initiated reaction. No iodination of 3-bromoquinoline was
antimalarial drugs, amply illustrated by the widely used observed under the optimized conditions confirming the
chloroquine, and these intermediates provide interesting absolute regioselectivity of the reaction (scheme 3e). We
scaffolds for derivatization, in the quest for new noted the iodination of quinoline-2-d (6a) at the C-3 position in
antimalarials.11,14 Similarly, 8-nitroquinoline and 6-methoxy-8- high yield, without any loss of deuterium atom at the C2
nitroquinoline were selectively iodinated in high yields (table position (scheme 3f). We have also carried out a time-
2, entries 2f, 2m). Noticeably, 6-methoxy-8-nitroquinoline dependent NMR study on 1a and 6a to obtain mechanistic
(
2m) is an intermediate for the marketed antimalarial drug insights of the reaction by taking aliquots from reaction
primaquine. Therefore, these iodinated quinolines have mixture at various time intervals. The presence of both
previously untapped applications in the possible derivatization substrate and product signals were traced in the 1H NMR study
and radiolabeling studies.
(see SI). To study the primary kinetic isotope effect (KIE), H/D
Next, the scope of other structurally related heterocycles KIE measurement with 1a and quinoline-3-d was carried out
was investigated under the optimized reaction conditions. resulting in the kH/kD ratio of 2.53. The secondary KIE
Isoquinoline,
benzo[h]quinoline,
phenanthroline,
and measurement (kH/kD) ratio of 0.83 was observed with the
bisquinoline were regioselectively iodinated under these experiment of 1a and quinoline-2-d (6a) (see SI).
conditions in high yields (table 2, entries 2o-r). In the case of
TBHP (8 equiv.)
I2 (1.2 equiv.)
I
I
I
(a)
(b)
(c)
(d)
substrates containing two reactive sites (table 1, entries 1q-r),
both mono- and di-iodinated products were obtained.
However, increasing the stoichiometry of iodine (2.4 equiv.)
and TBHP (16 equiv.) exclusively afforded diiodinated
products. Tunable fluorophores and one of the most widely
used bidentate ligand phenanthrolines and its iodinated
derivatives (table 2, entries 2qa-b) have potential application
in the synthesis of designer phenanthrolines.15 The extension
TEMPO (10 equiv.)
80 oC, MeCN, 24 h
N
N
N
N
N
1a
1a
2a (0%)
TBHP (8 equiv.)
I2 (1.2 equiv.)
TEMPO (1.5 equiv.)
80 oC, MeCN, 24 h
N
2a (17%)
TBHP (8 equiv.)
KI (1.2 equiv.)
80 oC, MeCN, 24 h
N
1a
2a (0%)
of this protocol on the iodination of pyridine (table 2, entry 2s
)
TBHP (8 equiv.)
I2 (1.2 equiv.)
80 oC, MeCN, 24 h
I
was unsuccessful, and is the subject of future investigation. To
the best of our knowledge, a number of substituted or
R
N
R
3a-e
4a-e (0%)
R = Br, Me, C(CH3)3, CO2Me, Ph
unsubstituted N-fused heterocycles (table 2, entries 1c-i, 1k-n,
I
TBHP (8 equiv.)
I2 (1.2 equiv.)
80 oC, MeCN, 24 h
Br
Br
1p-r) are iodinated for the first time, further amplifying the
utility of the reaction. The reaction was successfully applied to
achieve gram scale iodination of medicinally important
(e)
(f)
N
N
5a
6a
5b (0%)
TBHP (8 equiv.)
I2 (1.2 equiv.)
80 oC, MeCN, 24 h
I
intermediates (1m-n), in identical yields, albeit in a slightly
N
D
N
D
longer reaction time (Scheme 2).
6b (90%)
R
R
Scheme 3. Mechanistic investigation by control experiments
MeO
MeO
I
TBHP, I2
80 oC, MeCN, 24 h
N
N
HO-
tBuOOH
tBuO
+
NO2
NO2
2m. R = H (81%)
2n. R = OMe (80%)
1/2 I2
I
(I)
tBuOOH
+
H2O
+
tBuOO
HO-
Scheme 2. Gram scale experiments
I+
tBuOO or tBuO
(II)
The mechanism of the reaction was investigated by
conducting a series of control experiments (scheme 3). The
radical trapping experiments with the varying stoichiometry of
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), under the
optimized reaction conditions resulted in no product
formation (scheme 3a), and a drastic reduction in the yield
(scheme 3b). Thus, as anticipated, this reaction is possibly
radical by nature, wherein the generation of free radical is
mediated by TBHP. When reaction was tried with KI (source of
nucleophilic I-), no product formation was observed (scheme
3c). In another control experiment, iodination of a number of
C-2 substituted substrates failed, indicating that the
±
H
RO
(R = tBu or tBuO)
N
H
RO
N
H
N
[
TS-II]
[TS-I]
tBuO
or
-H+
I
tBuOO
H
I
[O]
RO
N
tBuOOH or tBuOH
N
[
TS-III]
Scheme 4. A plausible reaction mechanism
Upon the basis of the control experiments and some earlier
reports, a plausible catalytic cycle of the C-H activation
reaction is depicted in scheme 4.16 The electrophilic I+ species
were generated from I2 in the presence of TBHP (scheme 4,
equation I). It is proposed that the in situ generated alkoxy or
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7
For Pd-catalyzed reactions, please see: (a) D. Kalyani, A. R.
Dick, W. Q. Anani and M. S. Sanford, Org. Lett., 2006,
2523; (b) T.-S. Mei, R. Giri, N. Maugel and J.-Q. Yu, Angew.
Chem., Int. Ed., 2008, 47, 5215; (c) X. T. Ma and S. K. Tian,
Adv. Synth. Catal., 2013, 355, 337; For Rh-catalyzed
reactions, please see: (d) N. Schroeder, J. Wencel-Delord and
F. Glorius, J. Am. Chem. Soc., 2012, 134, 8298; (e) N.
Schroeder, F. Lied and F. Glorius, J. Am. Chem. Soc., 2015,
137, 1448. For Fe, Cu, and Ru-catalyzed examples, please
peroxy radical(s) reacts with the C2 position of 1a, and results
in radical cationic TS-I. Addition of H· to TS-I results in TS-II. The
C3 position of the quinoline ring is activated by the electron
movement (mesomeric effect) and reacts with the
electrophilic I+ (TS-III). Under the oxidative conditions, and the
loss of a proton and alkoxy/peroxy radical produced 2a
(equation II).
8
,
In conclusion, we report a regioselective C-H iodination
reaction of N-fused heterocycles under mild conditions, using
molecular iodine and TBHP. To the best of our knowledge, this
is the first generalized metal-free, direct and regioselective C-3
iodination protocol of N-fused heterocycles. This protocol
provides direct and easy access to several inaccessible C-3
iodinated quinolines, and structurally related heterocycles in
excellent yields. A number of control experiments provided a
plausible mechanism of this C-H functionalization reaction. As
discussed earlier, these N-fused heterocyclic iodides constitute
a group of synthetically demanding and medicinally important
compounds having great potential in further functionalization.
Acknowledgement
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Krishna K. Sharma thanks University Grant commission
(UGC), New Delhi for the award of Senior Research Fellowship.
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