Transition-Metal-Free Regioselective Alkylation of Quinoline N-Oxides via Oxidative Alkyl Migration and C?C Bond Cleavage of tert-/sec-Alcohols

Article abstract of DOI:10.1002/adsc.201701330

An unprecedented C2-alkylation of quinoline N-oxide derivatives via C?C bond activation of tert- and sec-alkyl alcohol is described using hypervalent iodine (III) reagent PhI(OAc)₂ (PIDA). This regioselective alkylation using mild hypervalent iodine reagents is more practical, operationally simple and transition metal free. The reaction proceeds efficiently with a broad range of substrates including quinoline, isoquinoline, and pyridine N-oxides using a variety of tert-/sec- alcohols. From experimental outcome, we also propose a rationalized mechanism, mediated by PIDA. (Figure presented.).

Full text of DOI:10.1002/adsc.201701330

Title: Transition-Metal-Free Regioselective Alkylation of Quinoline N-
Oxides via Oxidative Alkyl Migration and C-C Bond Cleavage of
tert-/sec- Alcohols
Authors: Subhash Ghosh and Chiranjit Sen
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Advanced Synthesis & Catalysis
10.1002/adsc.201701330
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Transition-Metal-Free Regioselective Alkylation of Quinoline
N-Oxides via Oxidative Alkyl Migration and C-C Bond
Cleavage of tert-/sec-Alcohols
Chiranjit Sen and Subhash C. Ghosh*
Natural Products and Green Chemistry Division and AcSIR, Central Salt and Marine Chemicals Research Institute (CSIR),
G.B. Marg, Bhavnagar-364002, Gujarat, India. E-mail: scghosh@csmcri.res.in
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
[8]
Abstract. An unprecedented C2-alkylation of quinoline N-
oxide derivatives via C-C bond activation of tert- and sec-
alkyl alcohol is described using hypervalent iodine (III)
using excess base was reported by Jain et al. for the
synthesis of
2
reagent PhI(OAc) (PIDA). This regioselective alkylation
using mild hypervalent iodine reagents is more practical,
operationally simple and transition metal free. The reaction
proceeds efficiently with a broad range of substrates
including quinoline, isoquinoline, and pyridine N-oxides
using a variety of tert-/sec- alcohols. From experimental
outcome, we also propose a rationalized mechanism,
mediated by PIDA.
Keywords: alkylation; C-C bond cleavage; transition-
metal-free; regioselective; N-oxides; PIDA
Alkylated quinoline and pyridine motifs represent a
significant class of molecules, as they possess the
fundamental structural unit for many biologically
active molecules, pharmaceuticals, and agro-
chemicals.[
1]
Thus, the development of new
methodology for the C-C bond construction of
quinoline and pyridine N-oxides have received
[2]
considerable efforts in recent years. However, only a
limited number of the direct regioselective alkylation
of quinoline and pyridine N-oxides are reported
(
Scheme 1) till date. In 2000, K. C. Nicolaou et al.
reported methylation of pyridine derived N-oxides
[3]
using Tebbes reagent via a carbene pathway.
Grignard reagents are frequently used as a nucleophile
for C2- alkylation/arylation of pyridine and other
[4]
heterocyclic N-oxides. The oxidative cross-coupling
of pyridine N-oxides with cycloalkane under the
influence of di-tert-butyl peroxide has been reported
by Itami and Li et al., where reaction proceeds via a
[
5]
radical pathway with poor regioselectivity. Fu and
Wu etal. reported Pd catalyzed cross-coupling reaction
of pyridine or quinoline N-oxides with alkyl
Scheme 1: Approaches for C2-alkylation of quinoline N-
oxide
bromides[
6]
and ethers
[7]
and copper-catalyzed
regioselective cross-coupling with N-tosylhydrazones
1
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Advanced Synthesis & Catalysis
10.1002/adsc.201701330
alkyl pyridine derivatives. In 2016, Cho et al. reported
the limitations of using transition metal catalyst
remains a challenge for the synthetic chemist.
base promoted alkylation of pyridine N-oxide using
9]
1
,1 diborylalkanes as an alkylating agent.[
In the light of annotations as mentioned above and
challenges, we report herein, a PhI(OAc) mediated
2
Table 1: Optimization of the reaction conditionsa
alkylative C-C σ bond activation of secondary and
tertiary- alcohols followed by alkylation of quinoline
N-oxide. Recently, photochemical methylation of
quinoline and pyridine derivatives with methanol
[14]
through C-O bond cleavage was reported. To the
best of our knowledge; this is an unprecedented metal
free approach for the synthesis of 2- alkyl quinoline N-
oxide derivatives featuring an alkylation through C−C
bond activation of sec-/tert- alcohols. It should be
Entr
y
Catalyst
Pd(OAc)
Oxidant
(equiv)
Base
Time
(h)
Yield of
mentioned that present study instigated with an3
b
3a (%)
unexpected observation during our efforts towards sp
c
1
2
PhI(OAc)
PhI(OAc)
PhI(OAc)
PhI(OAc)
PhI(OAc)
PhI(OAc)
PhI(OAc)
PhI(OAc)
PhI(OAc)
PhI(OAc)
PhI(OAc)
PhI(OAc)
2
2
2
2
2
2
2
2
2
2
2
2
(2)
(2)
(2)
(2)
(3)
(4)
(4)
(4)
(4)
(4)
(4)
(4)
K
2
CO
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
3
24
24
24
24
24
24
4
41
44
12
44
55
60
C-H functionalization of 8-amido quinoline N-oxides.
During the reaction optimization with different
solvents, we were amazed to isolate the C2-
methylated product.
c
2
Pd(OTf)
2
K
2
3
4
5
6
7
8
9
Cu(OTf)
2
K
2
-
-
-
K
2
K
2
When 8-(2,2-dimethylbutanamido)quinoline 1-
oxide (1a) was treated with iodobenzene in the
K
2
d
K
2
66
d
presence of Pd(OAc)
2
as a catalyst and PhI(OAc) as
2
-
-
-
-
-
-
-
-
-
-
Na
Cs
2
CO
3
3
4
57
d
an oxidant in tert-butanol (2a) solvent, a modest yield
(41%) of methylated product (3a) was obtained. The
desired methylated product is obtained in 44% yield
2
CO
4
50
d
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
CsOPiv
NaOH
4
49
d
4
45
d
when Pd(OTf)
Cu(OTf) produced comparatively much inferior
results (12%, entry 3). Interestingly, in the absence of
any transition metal catalyst, only PhI(OAc) gave
similar yield (44%, entry 4) with K CO as a base. To
our delight, yield increases significantly to 60%
entries 5-6), when loading of PhI(OAc) as increased.
used as catalyst (entry 2). However,
NaOAc
4
16
2
IBX (4)
PhI(OTf)
K
2
CO
CO
CO
CO
-
3
3
3
3
24
4
Nr
2
d
2
(4)
K
2
48
Oxone (4)
-
K
2
24
24
4
Nr
Nr
2
K
2
2
3
d
PhI(OAc)
2
(4)
11
(
2
areaction conditions: 1a 0.25 mmol, 2a (1 mL), PhI(OAc)
2-4 equiv.) as mentioned, base (2 equiv.) at 120 C in a
d
We have observed that starting material was not
entirely consumed even after 24h. To our anticipation,
PIDA might have decomposed in the reaction mixture.
Therefore, we planned to add the oxidant in batches: 2
equivalent at the beginning and one equivalent each
after 2h and 3h, which resulted in the reaction to
complete in 4h, and the yield increased significantly to
66 % (entry 7). It should be noted here that replacing
2
(
b
c
sealed tube; isolated yields; 2 equiv. PhI was used;
oxidant was added in 3 batches (beginning, 2h, 3h).
A metal-free approach for the methylation of pyridine
N-oxides using dicumylperoxide (DCP) reagents was
reported by Li and Wu et al.[ DCP also used as the
oxidant for benzylation of quinoline N-oxides with
toluene.[ Very recently, Dai and Xu et al. reported
alkylation of pyridine N-oxides using potassium
alkyltrifluoroborate as an alkylating agent with a
10]
K
2
CO
3
with other bases including Na
2
CO
3
, Cs
2
CO ,
3
cesium pivalate, NaOH, and NaOAC was not
successful, and leads to lower yield (entries 8-12).
Next, we examined other hypervalent iodine
reagents towards the same reaction. Surprisingly, no
reaction takes place with IBX (entry 13). However,
11]
[12]
photo-redox Ru catalyst via the radical pathway.
Clearly, the development of a regioselective and
efficient method for the alkylation of quinoline and
other heterocyclic N-oxide moieties under transition-
metal-free conditions highly anticipated. Meanwhile,
cleavage of the C-C sigma bond and its simultaneous
conversion into more complex products are highly
challenging and desirable reactions for the synthetic
chemists over the years.[
when we used PhI(OTf) little lower yield of desired
2
alkylated product was obtained (48%, entry 14). Even
when strong oxidant oxone used, no reaction was
observed (entry 15). Control experiments revealed that
both PhI(OAc)
2
and K
2
CO are essential to carry out
3
the reaction (entries 16-17).
With the optimized reaction condition in hand, we
next explored the scope and limitation of N-
heteroaromatic N-oxides by employing tert-butanol
(2a) as a methylating reagent and the results
summarized in Table 2. The reaction proceeds well
with a series of 8-alkylamido quinoline N-oxides,
furnishing corresponding methylated product in
moderate to good yields (3a-3d, Table 2). Aromatic
amides, 8-benzamido quinoline N-oxides also
provided good yields (3e, 53%) to corresponding 2-
13]
Till date, the most commonly recognized C-C sigma
bond activations are (i) release of ring strain and (ii)
directing group assisted C-C bond activation. In most
of the cases, expensive transition metal catalysts are
essential for the C-C bond activation and
functionalization. Thus, development of
a
methodology for C-C bond activation that overcomes
2
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Advanced Synthesis & Catalysis
10.1002/adsc.201701330
methylated products. In general, the reaction is well
tolerated with a variety of synthetically useful
functional groups; including amido (3a-3g), chloro
and bromo substituents (3f-3g), electron donating
methyl (3k-3n), and methoxy (3o) groups in different
was isolated (72%, entries 4a) almost exclusively with
a little-methylated product (7%, 3a). We were
fortunate to obtain single crystals of compound 4a, and
the structure was confirmed by the single crystal X-ray
diffraction analysis (Table 3, 4a) and (Figure S1,
supporting information). The reaction proceeds
Table 2: Substrate scope in direct methylation of N-
heteroaromatic N-oxides using tert-butanola
Table 3: Substrate scope in direct ethylation of
heteroaromatic N-oxides with tert-amyl alcohol
a
a
aReaction conditions: substrate 0.25 mmol, TAA (1 mL),
reaction conditions: substrate 0.25 mmol, t-BuOH (1 mL),
PhI(OAc)
2
(4 equiv.), K
2
CO
3
(2 equiv.) at 120 C in a sealed
2 2 3
PhI(OAc) (4 equiv.), K CO (2 equiv.) at 120 C in a sealed
tube for 4h; CCDC 1568886; reaction was carried out for
12h, oxidant was added in 3 batches (beginning, 2h, 3h).
b
b
c
tube for 4h; reaction was carried out for 12h, oxidant was
added in 3 batches (beginning, 2h, 3h).
positions of the quinoline moiety. Also, electron
withdrawing nitro group at the C-5 position provided
the products in good yield (3h). Moreover, the reaction
occurred very smoothly and afforded very good yield
smoothly with other 8- amido quinoline N- oxides and
afforded good yields (Table 3, entries 4b-4h). The
reaction has excellent compatibility with various
functional groups (4f-i, and 4o). Similar to the case of
methylation reaction, methyl substituted quinoline N-
oxides required longer reaction time (12h) and
(
62%, 3i) with the free hydroxy group at 8-position.
We observed that simple quinoline N-oxide and
methyl substituents in a different position of quinoline
moiety required longer reaction time (12h) to complete
and afforded lower yields compared to the 8-amido
quinoline N-oxides (42-49%, 3j-3n). On the other
hand, 6-methoxy quinoline N-oxides provided very
good yield on methylation reaction (48%, 3o).
Importantly, the alkylation reaction also goes
smoothly with other types of heterocyclic N-oxides
Table 4: substrate scope with other tertiary and secondary
alcoholsa
derived
from
pyridine,
isoquinoline,
and
benzo[h]quinoline (3p-3r) from moderate to good
yields. Encouraged by the facile synthesis of 2-methyl
quinoline and other heteroaromatic N-oxide
derivatives, the scope of the reaction was further
extended by using unsymmetrical tertiary alcohol, i.e.,
tert-amyl alcohol (2b) to check whether there is any
priority in the migration of alkyl group. To our delight,
when 8-(2, 2-dimethylbutanamido)-quinoline N-
oxides (1a) reacted with the tert-amyl alcohol (2b), the
reaction proceeds smoothly, and the ethylated product
3
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Advanced Synthesis & Catalysis
10.1002/adsc.201701330
reaction was completed in shorter time (within 2-4h).
Unfortunately, the use of isopropanol as a methylating
[15]
agent was unsuccessful,
optimized reaction conditions
under the present
aReaction conditions: substrate 0.25 mmol, 2-phenylpropan-
2
-ol (4 equiv), or 1-phenyl-propan-1-ol (4 equiv), toluene (1
mL), PhI(OAc) (4 equiv.), K CO (2 equiv.) at 120 C in a
sealed tube for 4h.
To elucidate the reaction mechanism, we have
carried out some controlled experiment as shown in
Scheme 2. When 1-phenyl propan-1-ol is used as an
alkylating agent in standard reaction condition, we
could identify the formation of benzaldehyde by
GCMS (eq. 1) along with the desired ethylated product.
The result indicates that the C-C bond cleavage of the
alcohol is one of the key steps. Again, when 8-(2, 2-
dimethylbutanamido) quinoline or 8-hydroxy
quinoline or quinoline (N-oxide free) is treated with
tert-butanol under standard reaction conditions, no
reaction takes place, suggesting that N-oxide group is
crucial for C2 alkylation and cleavage of tert- alcohol.
Next, upon addition of the radical scavenger, 2, 6-Di-
tert- butyl-4-methylphenol (BHT) or (2,2,6,6-
2
2
3
Tetramethylpiperidin-1-yl)oxyl
(TEMPO),
the
reaction is completely inhibited and we have identified
the TEMPO trapped methyl radical in GC-MS and
HRMS, indicating that reaction may proceed through
a single electron transfer (SET) pathway. Based on the
above experiments and previous literature report a
tentative reaction mechanism route is proposed as
shown in Scheme 2. At the onset, PIDA reacts with the
[16]
alcohol to form intermediate A, which reacts with
the quinoline N-oxide to form the compound B. Then,
it might proceed through a way homolytic C-C bond
[17]
cleavage of alcohols via a SET pathway, followed
by alkylation and aromatization to generate the 2-
alkylated product.
In summary, we have developed a highly efficient
and convenient system for the regioselective
ethylation/methylation of the quinoline and other N-
oxide system using tert-amyl alcohol or tert-butanol,
respectively. This alkylation method is transition
metal free, mediated by the mild hypervalent iodine
reagents, and proceeds through a C-C bond cleavage
of tertiary as well as secondary alcohols. Our method
has broad substrate scope and vast functional group
tolerances, including amide, alcohol, ether, nitro, and
halides. Further exploration of the regioselective
alkylation with other heteroaromatic substrates and
study on the detailed mechanism is currently in
progress.
Scheme 2: Control experiment for mechanism studies and
proposed mechanism
moderate yields were obtained (4k-4n). Pyridine,
isoquinoline, and benzo[h]quinoline N-oxides are also
capable and moderate to good yields were achieved
(
4p-4r) almost in all the cases.
To further demonstrate the synthetic utility of our
reaction, we turned our attention to another tertiary
alcohol, 2-phenylpropan-2-ol as an alkylating agent. In
this case, we reoptimized the reaction conditions (see
supporting information for details), where the reaction
was carried out in a sealed tube with four equiv. Experimental Section
alcohol, K
2
CO
3
(2 equiv.), and PhI(OAc) (4 equiv.) in
2
toluene (1 mL) at 120 C, for 4h. Under this condition,
we have chosen few substrates, and the solely
methylated product was obtained in moderate to good
yield (40-62%, Table 4a). However, we could not
observe aryl migration for any substrate.
General conditions
All reactions were carried out in oven-dried glassware under
standard reaction conditions. Tert amyl alcohol and tert-
butanol, 1-phenyl-propan-1-ol, 2-phenyl propan-2-ol and
other all chemicals were purchased from TCI and Sigma-
Aldrich and used without further purification. Solvents were
purchased from S. D. Fine chemicals Ltd India and dried by
standard procedure, kept over molecular sieves and then
used. Flash column chromatography purification of
compounds was carried out by gradient elution using ethyl
acetate (EA) and hexane and some cases with methanol. 1H/
Encouraged by the facile methylation and ethylation
of quinoline N-oxides with tertiary alcohols the scope
of the reaction. To our pleasure, the reaction with 1-
phenyl-propan-1-ol goes smoothly, and the ethylated
product was exclusively observed for a range of
substrates (Table 4b). Interestingly, most of the
1
3C NMR was recorded on 600/151 MHz NMR
spectrometer, in CDCl
3
, unless otherwise mentioned, using
4
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Advanced Synthesis & Catalysis
10.1002/adsc.201701330
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A
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[
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for this work. The authors thank Dr. E. Suresh and Dr. S. Neogi,
CSMCRI, for X-ray crystallographic analysis. The authors also
acknowledge the Analytical Discipline and Centralized Instrument
Facility of CSIR-CSMCRI for all characterization. CS thanks to
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