Nitrosoarene-Catalyzed HFIP-Assisted Transformation of Arylmethyl Halides to Aromatic Carbonyls under Aerobic Conditions

Article abstract of DOI:10.1021/acs.orglett.1c02272

A rare metal-free nucleophilic nitrosoarene catalysis accompanied by highly hydrogen-bond-donor (HBD) solvent, 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), organocatalytically converts arylmethyl halides to aromatic carbonyls. This protocol offers an effective means to access a diverse array of aromatic carbonyls with good chemoselectivity under mild reaction conditions. The activation of arylmethyl halides by HFIP to generate stable carbocation and autoxidation of in situ generated hydroxylamine to nitrosoarene in the presence of atmospheric O2 are the keys to success.

Full text of DOI:10.1021/acs.orglett.1c02272

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Letter
Nitrosoarene-Catalyzed HFIP-Assisted Transformation of Arylmethyl
Halides to Aromatic Carbonyls under Aerobic Conditions
Suman Pradhan, Vishali Sharma, and Indranil Chatterjee*
Cite This: Org. Lett. 2021, 23, 6148−6152
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ABSTRACT: A rare metal-free nucleophilic nitrosoarene catalysis accompanied by highly hydrogen-bond-donor (HBD) solvent,
1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), organocatalytically converts arylmethyl halides to aromatic carbonyls. This protocol offers
an effective means to access a diverse array of aromatic carbonyls with good chemoselectivity under mild reaction conditions. The
activation of arylmethyl halides by HFIP to generate stable carbocation and autoxidation of in situ generated hydroxylamine to
nitrosoarene in the presence of atmospheric O2 are the keys to success.
romatic aldehydes and ketones are vastly abundant,
oxidative transformation of arylmethyl halides to carbonyl
Areadily found in several natural products, and usually compounds have also been documented in the past few
decades (Scheme 1a)17−20 Recently, in 2018, Lambert and co-
recognized for their pleasant fragrances. These organic
workers have come up with a newly modeled benzo[c]-
cinnoline (BCC) catalyst for synthesizing aldehydes from alkyl
halides (Scheme 1b).21 This unique invention organocatalyti-
cally oxidizes primary alkyl halides involving nucleophilic
attack, prototropic shift and hydrolysis as key steps.
For the last couple of years, our laboratory has devoted
attention toward exploring nitrosoarene reactivity. Recently,
we displayed that aerobic O2 (as a terminal oxidant) could
oxidize in situ generated hydroxylamine derivatives to produce
analogous nitrosoarene and engage it in a catalytic process as a
redox catalyst.22 This was our first thought process behind the
documentation of exclusive and O2-coupled metal-free organo-
catalytic oxidation approach. It is to be noted that a
compounds are very much cherished not only for their
ubiquity in nature, but also as valuable building blocks and
feedstock for organic synthesis.1 The direct oxidation of
oxygen-containing molecules can offer corresponding alde-
hydes or ketones using stoichiometric or catalytic processes.2
In this context, previously, several transition-metal-based O2-
coupled oxidation routes have been documented.3 The use of
metal traces is necessary to carry out the redox process in order
to inhibit the direct oxidation of organic molecules alone with
molecular oxygen.4 Simultaneously, to achieve two comple-
mentary methods, i.e., organocatalytic oxidation of desired
molecule and reduction of molecular oxygen, enormous effort
has been given from the scientific community.5−7
̈
stoichiometric reaction involving an extension of Krohnke
Apart from these direct oxidative techniques, another
alternative method for synthesizing of aromatic carbonyls is
from arylmethyl halides.8 Along this line, in most of the cases,
stoichiometric oxidants and transition-metal-based catalysts9
have been used for this purpose. Several name reactions, for
oxidation of 2-hydroxy-4-nitrobenzylpyridinium bromide to
produce 2-hydroxy-4-nitrobenzaldehyde was reported by
Walker’s group using stoichiometric N,N-dimethyl-p-nitro-
soaniline as a crucial reactant.23 To develop a catalytic process,
we strategically hypothesized that the nucleophilic engagement
of nitrosoarene V with benzyl halides 1 (via SN1 or SN2) might
generate nitrosonium ion intermediate VI (Scheme 1c, this
example, Hass−Bender oxidation,10 Sommelet oxidation,11
13
Kornblum oxidation,12 Krohnke reaction, and Ganem
̈
oxidation14 are well-known in the literature. These oxidation
processes suffered from many drawbacks and challenges: (1)
formation of unwanted byproducts, (2) harsh reaction
conditions, and (3) functional group intolerance.15 In pursuit
of a suitable, alternative, and metal-free organocatalytic
expedient decorum, transition-metal-free stoichiometric oxida-
tive approaches have been reported right through.16 Alongside,
few environmentally benign organocatalytic methodologies for
Received: July 7, 2021
Published: July 21, 2021
https://doi.org/10.1021/acs.orglett.1c02272
© 2021 American Chemical Society
Org. Lett. 2021, 23, 6148−6152
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a
Scheme 1. (a) Transition-Metal-Free Oxidative Pathway of
Synthesizing Aromatic Aldehydes and Ketones; (b) BCC-
Catalyzed Oxidation Technique; (c) Proposed Work:
Nitrosoarene Catalysis
Table 1. Optimization Study and Reaction Set-up
b
entry
catalyst
solvent
additive yield (%)
1
2
3
A
A
DCM, MeOH, IPA, TFE
HFIP
HFIP
−
−
−
−
−
−
−
−
<10−15
42
40−45
52
45
48
50
58
45
69
<15
72
<5
25
NR
B, C, D, E
c
4
F
F
F
F
F
F
F
F
F
F
F
F
HFIP
5
6
7
HFIP:IPA (4:1)
HFIP:MeCN (4:1)
HFIP:DCM (4:1)
HFIP:DCM (1:1)
HFIP:DCM (1:1)
HFIP:DCM (1:1)
HFIP:DCM (1:1)
HFIP:DCM (1:1)
DCM
c
8
cd
,
9
H2O
Et3N
DIPEA
NaOAc
NaOAc
NaOAc
NaOAc
c
10
11
12
13
14
15
c
ce
,
f
HFIP:DCM (1:1)
HFIP:DCM (1:1)
a
work, mechanistic hypothesis). Deprotonation can then furnish
nitrone intermediate VII, which readily hydrolyzes to harness
aromatic carbonyl and hydroxylamine derivative VIII (reduced
form of V). In aerobic conditions, the autoxidation of
hydroxylamine helps to close the catalytic cycle by regenerating
nitrosoarene together with H2O2 as a sole byproduct. This will
represent a transition-metal-free catalytic process for the
synthesis of aromatic carbonyls. Herein, we have presented a
nucleophilic nitrosoarene-catalyzed mild, efficient, and oxida-
tive transformation technique to deliver ready feedstock
aromatic carbonyls from corresponding arylmethyl halides
under aerobic conditions (Scheme 1c, this work).
To pursue our thought process, the oxidative transformation
of benzyl bromide (1a) was studied (Table 1; for full table see
SI) in an open atmosphere at 55 °C (in a preheated oil bath)
with nitrosobenzene (A, 10 mol %) as a catalyst in aprotic
solvent DCM. A gradual change from aprotic to protic
solvents, the yield of the desired product formation was
increased significantly and a moderate yield was obtained in
HFIP as a solvent (Table 1, entries 1−2). These significant
changes in the yield indicated that nitrosobenzene is not
nucleophilic enough to push the conversion in an SN2 manner.
Strong hydrogen-bond-donor (HBD) solvent HFIP24 rather
ionizes the C−X (X = halogen) bond and generates a reactive
carbocation intermediate, which turned out to be a crucial and
essential factor for the conversion.
This astonishing finding with HFIP is corroborated with the
literatures reported earlier.25 We screened several other
nitrosoarene as catalysts (entry 3), among them 1-methyl-4-
nitrosobenzene (F) proved to be the best catalyst with 52%
yield of benzaldehyde in HFIP (entry 4). Very pleasingly, with
the implementation of the cosolvent (entries 5−8) explicitly
when DCM was mixed with HFIP (1:1), the desired oxidative
product 2a was isolated in 58% yield (entry 8). Use of H2O as
an additive did not give satisfactory conversion of 2a (entry 9).
The introduction of base as an additive in the reaction medium
guided us to achieve an adequate yield of 2a (entries 10−12).
Reaction conditions: 1a (1.0 equiv, 0.2 mmol), nitrosoarene (10 mol
%, 0.02 mmol), base (1.0 equiv, 0.2 mmol), solvent (undistilled, 0.4
b
M), 55 °C, air, 12 h. Yields were determined using 1,3,5-
c
1
trimethoxybenzene as an internal H NMR standard. Isolated yield.
d
e
25% of PhCH2OH was isolated along with 2a. 1.0 mmol scale
f
reaction provided 64% (68 mg) isolated yield of 2a. Reaction
conducted at room temperature. NR = No Reaction.
NaOAc as a base gave the best result by furnishing 2a in 72%
isolated yield (entry 12). However, without HFIP as a solvent,
in the presence of NaOAc, only a trace amount of 2a was
formed (entry 13). A reduced yield (25%) of product 2a was
found at room temperature reaction conditions (entry 14).
The reaction was completely shut down in the absence of
catalyst F (entry 15).
During exploration of substrate scope, starting from simple
benzyl bromide to electron-rich arylmethyl halides such as Me,
tBu, SMe, OBn, OMe groups as substituents on the aromatic
ring, irrespective of their position, produced respective
aldehydes 2a−i in good to excellent yields (62−95%). Mesityl
benzyl bromide also responded to the reaction purveying 2j in
70% yield. Benzyl chloride and 1-(chloromethyl)-4-isopropyl-
benzene also produced benzaldehydes 2a′ and 2e′, respec-
tively, albeit in moderate to good yield (53% and 75%
respectively). Benzyl bromides bearing halogen atom (Cl, Br,
and F) at different positions of the aromatic ring (ortho, meta,
and para) reacted smoothly to furnish the resultant substituted
aryl aldehydes 2k−p in good yields (57−64%). Fluoride as
leaving group also provided corresponding aromatic aldehydes
2l′ and 2m′ in moderate yields. This methodology was also
effectively applied over electron-poor arylmethyl bromides to
convert them into aldehydes 2q,r in low to moderate yields.
The oxidation was also efficiently worked with polycyclic
arylmethyl bromides and 2s,t were isolated in good yields. The
present reaction etiquette can also be applied to allylic bromide
derivative to obtain cinnamaldehyde 2u in 50% yield.
Unfortunately, aliphatic and heterocyclic methyl halides did
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c
Scheme 2. Substrate Scope
a
b
c
Volatile compounds. 15 mol % of catalyst F. Reaction conditions: 1 (1.0 equiv, 0.2 mmol), F (10 mol %, 0.02 mmol), NaOAc (1.0 equiv, 0.2
mmol), HFIP/DCM (1:1) (0.5 mL), 55 °C, air, 12 h. Yields mentioned are isolated yields.
b
not respond to our optimized reaction conditions (for details,
see SI).
Scheme 3. Control Experiments
After compelling exploration of primary arylmethyl
bromides, we set our goal for synthesizing aromatic ketones
from secondary arylmethyl bromides (R1 ≠ H). In this regard,
acetophenone 2aa and 4-methylacetophenone 2ab were
afforded in moderate yields. When R1 = aryl group, the
conversion went very smoothly to equip several substituted
benzophenone derivatives 2ac−ae in satisfactory outcome
(61−70%). Delightfully, some important classes of aromatic
ketones such as 9-fluorenone 2af, xanthone 2ag, 5-
dibenzosuberenone 2ah, and anthraquinone 2ai (with 15
mol % of catalyst F) were synthesized in good yield (53−75%)
applying this current methodology (Scheme 2).
With our current oxidation decorum in hand, we were keen
to apply the methodology to synthesize drug molecules in a
transition-metal-free pathway. A pharmaceutical drug used for
breast cancer treatment, DMU-212 (5),26 was synthesized via
Wittig reaction with aldehyde 4 in excellent yield (see SI,
section 8 for details). Prior to this conversion, one of the key
starting materials 3,4,5-trimethoxybenzaldehyde 4 was synthe-
sized from analogous benzyl bromide 3 using our standard
reaction condition with 63% yield.
To extend this current methodology’s applicability, we
performed chemoselective reactions taking advantage of the
higher reactivity of benzylic bromides (see SI, section 8 for
details). Marginally higher loading of catalyst (15 mol %)
selectively oxidized benzylic bromide to aromatic carbonyl
compounds leaving other aliphatic C-halogen bonds intact. For
example, substrates 6 and 8 were chemoselectively converted
to their carbonyl counterparts 7 and 9, respectively with
moderate yield.27
a
b
Freshly distilled solvents were used in glovebox. Reaction
conditions: 1 (1.0 equiv, 0.2 mmol), F (10 mol %, 0.02 mmol),
NaOAc (1.0 equiv, 0.2 mmol), HFIP/DCM (1:1) (0.5 mL), 55 °C,
12 h. Yields mentioned are isolated yields.
H2O level >5 ppm) using dry and freshly distilled solvent.
After the dedicated time, trace amount (<5%) of product 2a
was isolated (Scheme 3, part i), verifying that O2 has an
unprecedented impact in this transformation. The trace
amount of yield also indicates the importance of water for
the hydrolysis of nitrone intermediate VII.28 As proposed,
terminal oxidation of arylhydroxylamine to nitrosoarene can be
achieved by molecular oxygen to yield H2O2 as byproduct,
closing the nitroso-organocatalytic cycle.29a Beside this, the
terminal oxidation of arylhydroxylamine to nitrosoarene can
also be accomplished using H2O2.29b The role of H2O2 in this
terminal oxidation step was further proved when the optimized
reaction was conducted under inert atmosphere (without O2)
with 1 equiv of H2O2 (35 wt % of H2O solution), producing 2a
and benzyl alcohol (formed due to the presence of water in
H2O2, 35 wt % of H2O solution) in 40% and 12% isolated
yield, respectively (Scheme 3, part ii). This result indicates that
H2O2 is indeed a feasible oxidant for the reoxidation of
arylhydroxylamine to nitrosoarene.
To have a clear picture of the mechanistic pathway, we
executed some control experiments (Scheme 3). At first, the
role of aerobic O2 was investigated by setting up the standard
reaction with 1a at inert atmosphere (in Glove-Box, O2 and
On the basis of the control experiments and literature
evidence,21,22,25 a plausible O2-coupled nitroso-organocata-
lyzed reaction mechanism is proposed in Scheme 4. It is
evident that the use of HFIP, one of the most potent HBD
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conditions has exquisitely enabled the controlled oxidation
protocol.
Scheme 4. Proposed Mechanistic Pathway
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c02272.
Experimental procedures, mechanistic evidence, and
spectral data for the newly synthesized products
(PDF)
FAIR data, including the primary NMR FID files, for
compounds 2a−2ai, 4, 5, 7, 9, and VII (ZIP)
AUTHOR INFORMATION
Corresponding Author
■
Indranil Chatterjee − Department of Chemistry, Indian
Institute of Technology Ropar, Rupnagar, Punjab 140001,
India; orcid.org/0000-0001-8957-5182;
Email: indranil.chatterjee@iitrpr.ac.in
solvents (α = 1.96),25b has an imperative role in our reaction.
According to our proposed pathway, strong hydrogen bonding
interaction between benzyl halide 1 and HFIP initiates the
process by forming complex II. This complex is then
transformed into carbocationic intermediate IV via the
polarization of C-halogen bond (intermediate III) along with
hydrogen bonded halide species. The nucleophilic trapping of
IV with nitrosoarene V prompts the formation of nitrosonium
ion intermediate VI, which undergoes α-deprotonation to yield
nitrone intermediate VII (detected by NMR and HRMS; for
details see SI). The active nitrone intermediate VII is prone to
hydrolysis to give the desired aromatic carbonyl compound
along with hydroxylamine derivative VIII. Finally, the
oxidation of hydroxylamine (either by O2 or H2O2)29
regenerates nitrosoarene catalyst by closing the catalytic cycle
(path a). Alternatively, the carbocationic intermediate IV can
be trapped by H2O to generate benzyl alcohol IX as an
intermediate which would have been further oxidized (either
under aerobic conditions or in the presence of nitrosoarene) to
provide the desired carbonyl compound. The control experi-
ment with benzyl alcohol IX indicates that IX cannot be an
intermediate (see SI, section 9a).
The proposal of arylhydroxylamine as an intermediate in our
suggested catalytic cycle was verified by running the reaction
with catalytic amount of 4-methylphenylhydroxylamine (see
SI, section 9b for details). Slight changes in the solvent
concentration (1.6 M, rest remained same, 0.8 mmol reaction
scale) gratifyingly provided the desired product 2a in 56% yield
using 10 mol % of 4-methylphenylhydroxylamine as a catalyst.
This experiment strongly supports the mechanism proposed by
us.
Authors
Suman Pradhan − Department of Chemistry, Indian Institute
of Technology Ropar, Rupnagar, Punjab 140001, India
Vishali Sharma − Department of Chemistry, Indian Institute of
Technology Ropar, Rupnagar, Punjab 140001, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02272
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
I.C. wishes to acknowledge financial assistance from SERB,
DST, India (ECR/2018/000098), and IIT Ropar. S.P. thanks
IIT Ropar for his research fellowships. V.S. is a postgraduate
student at IIT Ropar.
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