Radical C?H Acylation of Nitrogen Heterocycles Induced by an Aerobic Oxidation of Aldehydes

Article abstract of DOI:10.1002/asia.201900857

An aerobic radical approach for the synthesis of unsymmetrical heteroaryl ketones is described herein. The reaction involves cross-dehydrogenative coupling between aldehydes and heteroaromatic bases with molecular oxygen (O₂). The key aspect of the method is the generation of reactive acyl radical via homolytic activation of aldehyde C?H bond using O₂ as the sole oxidant. The reaction has a good substrate scope with respect to aldehydes and functionalized nitrogen heterocycles. Based on our mechanistic studies, a radical chain pathway is suggested for the reaction. A synthetic application of the method is demonstrated in the formal synthesis of natural alkaloid (±) angustureine.

Full text of DOI:10.1002/asia.201900857

CHEMISTRY
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Accepted Article
Title: Radical C-H Acylation of Nitrogen Heterocycle Induced with
Aerobic Oxidation of Aldehyde Subhasis Paul, Manotosh Bhakat
and Joyram Guin*[a]
Authors: Subhasis Paul, Manotosh Bhakat, and Joyram Guin
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Radical C-H Acylation of Nitrogen Heterocycle Induced with
Aerobic Oxidation of Aldehyde
Subhasis Paul, Manotosh Bhakat and Joyram Guin*[a]
Abstract: Herein we describe an aerobic radical approach for the
developed employing aldehyde as acyl radical precursor and O2
as a sole oxidant.
synthesis of unsymmetrical heteroaryl ketone. The reaction involves
cross-dehydrogenative
coupling
between
aldehydes
and
heteroaromatic bases with molecular oxygen (O2). The key aspect of
the method is the generation of reactive acyl radical via homolytic
activation of aldehyde C-H bond using O2 as the sole oxidant. The
reaction demonstrates good substrate scope with respect to
aldehyde and functionalized nitrogen heterocycles. Based on our
mechanistic studies, a radical chain pathway is suggested for the
reaction. Synthetic application of the method is demonstrated in the
formal synthesis of natural alkaloid (±) angustureine.
Introduction
Carbonyl compounds particularly ketones are found in various
bioactive molecules and bulk chemicals.[1] They are versatile
precursors of numerous valuable functional groups such as
amine, alcohol, imine, oxime, ester, olefin etc. The addition of
activated acyl moiety across an unsaturated carbon-carbon
bond represents the most straightforward approach to ketone
molecules. This strategy has also been adopted in synthesizing
unsymmetrical aromatic ketones involving Lewis acid mediated
acylation of aromatic hydrocarbons (so called Friedel-Crafts
acylation reaction).[2] However, such protocol remains
challenging for electron deficient aromatic hydrocarbons
particularly nitrogen containing heteroaromatic bases.[3] As a
result, the oxidative radical C-H acylation through homolytic
aromatic substitution (HAS)[4],[5] of nitrogen heterocycles with
Scheme 1. a) General mechanism for aldehyde auto-oxidation. b) Aerobic
radical hydroacylation of activated olefin. c) Aerobic radical C-H alkylation of
heteroaromatic bases and d) aerobic radical C-H acylation of nitrogen
heterocycle.
acyl
radical
became
important.
Indeed,
significant
advancements on radical C-H acylation of nitrogen heterocycles
using aldehydes as acyl radical precursors have been
reported.[6] However, existing methods require stoichiometric
amount of synthetic oxidants such as K2S2O8, peroxides, PIDA
and others along with additives or catalysts to generate acyl
radical from aldehyde.[6] These toxic reagents not only produce
substantial amount of by-products but increase the overall cost
of the process also. In view of the increasing demand towards
green and sustainable chemical process, molecular oxygen (O2)
is recongnised as an ideal oxidant for the oxidative organic
transfromations.[7] We thus wonder whether an efficient method
for the direct C-H acylation of heteroaromatic bases could be
In order to develop an aerobic radical method for the
synthesis of acylated nitrogen heterocycles, efficient generation
of acyl radical via homolytic activation of aldehyde C-H bond
would be needed under O2 atmosphere. We noted that aerobic
oxidation of aldehyde to carboxylic acid involves acyl radical,
which forms peracyl radical upon reaction with excess molecular
oxygen.[8] The resulting peracyl radical abstracts hydrogen atom
from the aldehyde thus forming acyl radical and peracid, which
finally decomposes to the corresponding carboxylic acid
(Scheme 1a). Despite the known report of aldehyde auto-
oxidation process and synthetic potential of acyl radicals, the
development of radical C(sp2)-H acylation of arenes using auto-
oxidation of aldehyde remains challenging.[9]
[a]
S. Paul, M. Bhakat, Dr. J. Guin
The research group of Caddick has elegantly developed
aerobic radical hydroacylation of electron deficient olefin using
auto-oxidation of aldehyde (Scheme 1b).[10] Recently, our group
and others have introduced an efficient approach to alkyl radical
through decarbonylation of acyl radical that is formed via auto-
oxidation of α-branched aldehyde (Scheme 1c).[11] This novel
School of Chemical Sciences
Indian Association for the Cultivation of Science
2A & 2B Raja S. C. Mullick Road, Jadavpur, Kolkata-700032 (India)
E-mail: ocjg@iacs.res.in
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strategy of generating alkyl radical has been implemented in
developing aerobic radical C-H alkylation of protonated
heteroaromatic bases.[12] During this study, we noticed that a
minor acylated product was formed with α-unbranched aldehyde.
Based on this observation, we wondered whether an efficient
method for the aerobic C-H acylation of heteroaromatic bases
via cross-dehydrogenative coupling (CDC)[13] between aldehyde
and heteroarens could be developed using auto-oxidation of
aldehyde. Since aldehyde auto-oxidation has never been utilized
in developing CDC process and in light of high synthetic value of
the acylated nitrogen heterocycles, we became interested in
developing this reaction further (Scheme 1d).
To improve the reaction efficacy of the aerobic C-H acylation
process, we envisaged that the rate of formation of alkyl radical
from the acyl radical should be minimized. Since high thermal
energy may facilitate the decarbonylation of acyl radical, it would
be important to perform the reaction at reduced reaction
temperature in comparison to the alkylation process.
Furthermore, the use of α-unbranched aldehydes could be
beneficial for the acylation process, as the formation of primary
alkyl radical via decarbonylation of the corresponding acyl
radical is energetically unfavourable.[14]
Table 1. Reaction development.[a,b]
Entry
Solvent
Temp
(°C)
TFA
(equiv)
Conv. (%)
Ratio
(2a:2'a)
1[c]
2
EtOAc
EtOAc
EtOAc
EtOAc
MeCN
DCE
90
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
0.5
1.0
2.0
1.5
1.5
1.5
51(38)
82
99:1
90:10
87:13
70:30
65:35
51:49
72:18
-
95
3[c]
4
100
115
100
100
100
100
100
100
100
100
100
100
92(72)
95
5
66
6
63
7
Toluene
MeOH
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
18
8
N.R.
68(32)
84(59)
89(62)
70
9[c]
10[c]
11[c]
12[d]
13[e]
14[c,f]
86:14
86:14
85:15
87:13
86:14
85:15
Results and Discussion
In accordance to our hypothesis, we began our studies on the
aerobic C-H acylation of nitrogen heterocycles using
isoquinoline and n-butanal as model substrates under various
reaction conditions (Table 1). When the reaction was performed
with isoquinoline (1 equiv), TFA (1.5 equiv) and n-butyraldehyde
(8 equiv) in ethyl acetate at 90 °C, the acylated product 2a was
obtained in 38% isolated yield (entry 1). By performing the
reaction at slighly higher reaction temperature, the yield of the
desired product 2a was improved. However, the formation of a
small amount of the corresponding alkylated product was also
noticed (entries 2-4). By maintaining the reaction temperature at
100 °C, the reaction afforded good yield of the acylated product
with 87:13 ratio between acylated and alkylated products (entry
3). Effect of solvents on the reaction efficacy was then evaluated.
Accordingly, the reaction was carried out in different solvents
(entries 5-8). These studies revealed that the originally used
ethyl acetate remained the superior solvent for the reaction.
Further optimization studies with varying the amount of TFA
established the necessity of a stoichiometric amount of the acid
for the aerobic CDC process (entries 9-11). Importantly, no
product formation was realized in the absence of TFA and other
Brønsted acids (PTSA, MeCO2H, MeSO3H, Ph2PO4H) tested in
this process gave inferior results (See Electronic Supplementary
Information). The reaction could also be performed by reducing
the amount of aldehyde (entry 12 and 13). However, complete
consumption of isoquinoline could not be achieved. No
improvement on the yield of the acylated product 2a was
realized when the reaction was performed using 10 equivalent of
aldehyde (entry 14).
84
94(69)
[a] Reaction conditions: isoquinoline (0.2 mmol, 1.0 equiv), n-butanal,
TFA, solvent at 90-115 °C under O2 atmosphere. [b] % of conversion of
isoquinoline and ratio of acylated and alkylated products (2a:2'a) were
determined by GC-mass analysis of the crude reaction mixture. [c]
Isolated yield of the acylated product is mentioned in parenthesis. N.R =
No reaction. [d] With 4 equiv of aldehyde. [e] With 6 equiv of aldehyde. [f]
With 10 equiv of aldehyde.
different aldehydes (Scheme 2). Accordingly, the reaction was
performed with different linear aldehydes, delivering the
corresponding products 2a-e in moderate to good yields with
selectivity (s) between acylated and alkylated products ranging
from 81 to 99%. The iso-valeraldehyde was converted to the
ketone 2f in good yield and selectivity. Various α-branched
aldehydes 1g-j were also examined to the aerobic C-H acylation
process furnishing both the acylated and alkylated product in
good combined yield with 47-67% selectivity towards aacylated
product.
Interestingly,
cyclopropanecarboxaldehyde
(1k)
afforded the corresponding acylated product 2k in moderate
yield with excellent selectivity toward acylation reaction. The
reaction found to be ineffective with aromatic aldehydes. This is
may be due to inefficient auto-oxidation of aromatic aldehydes.
Substrate scope studies of the aerobic C-H acylation
reaction were then carried out with a broad range of nitrogen
heterocyclic compounds under the optimized reaction conditions
(Scheme 3). The acylated products 3-30 were isolated in good
yields with predominant regioselectivity at the 2- and 4-positions
Having identified the optimized reaction condition, substrate
scope of the reaction was evaluated using isoquinoline and
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protected quinine[15] was transformed to the corresponding
acylated derivatives 25-27 in good yields with different
aldehydes. The acylated quinines could find application in
organic synthesis as novel organocatalysts. Furthermore,
diversification of fasudil, a potent Rho-kinase inhibitor and
vasodilator,[16] was achieved with this simple aerobic radical C-H
acylation protocol. The reaction enabled incorporation of
different acyl moieties into the protected fasudil derivatives,
furnishing acylated fasudils 28-30 in good yields and excellent
selectivity toward acylation process.
To illustrate synthetic utility of the aerobic C-H acylation
process, a preparative scale experiment was performed using
1.0 g of isoquinoline, which resulted in 1.1 g of the acylated
product 2a with 71% isolated yield along with a minor alkylated
product of 6%. Furthermore, a variety of valuable isoquinoline
derivatives[17] were prepared from the product 2a through simple
chemical transformation of the carbonyl functional group
(Scheme 4). The chiral amine 31 was prepared by performing
reductive amination of the product 2a. The reduction of ketone
with NaBH4 afforded the chiral alcohol 32. The ketone 2a was
easily transformed to the ester 33 upon Baeyer Villiger oxidation.
Hydrazone 34 was prepared by the condensation of 2a with
phenyl hydrazine. Wittig olefination of the ketone 2a afforded the
corresponding olefin 35 in 43% isolated yield.
[a] Reaction conditions: isoquinoline (0.2 mmol, 1.0 equiv), aldehyde (8-12
equiv), TFA (1.5 equiv), EtOAc (1.3 mL, 0.15 M) at 100 °C under O2
atmosphere; isolated yields of the acylated products are given; structure of
major product is drawn; selectivity (s) between acylated and alkylated
products determined by GC-mass analysis of the crude reaction mixture. [b]
Performed at 115 °C. [c] Combined yields of acylated and alkylated
products are given. [d] Performed at 60 °C. [e] Performed at 70 °C.
Scheme 2. Substrate scope.[a]
of heterocycles. The formation of a minor amount of the
alkylated product was also realized in some cases. Selectivity
(s) between acylated and alkylated product was determined by
GC-mass analysis of the crude reaction mixture. Various
functionalized isoquinolines possessing phenyl, substituted
phenyl, naphthyl, bromo, benzamide substituents were
effectively transformed to the corresponding ketones 3-9 in good
yields and selectivity. Importantly, biologically relevant
sulphonamide substituted isoquinoline derivatives were suitable
for the aerobic radical acylation reaction (products 10 and 11).
Various functionalized quinoline derivatives underwent smooth
acylation reaction, enabling the synthesis of the corresponding
acylated quinoline derivatives 12-17 in good isolated yields. With
this protocol, 7,8-benzoquinoline was transformed to the
corresponding acylated derivative in good yield (product 18).
Nitrogen heterocycle bearing more than one heteroatom such as
quinazoline, substituted quinazoline, benzimidazole, thiazole
were effectively acylated in this process (products 19-22).
Pyridine and its derivatives were found to be challenging
substrates for the aerobic radical acylation process, furnishing
the products 23 and 24 in very low yields.
Scheme 4. Post-modification of the acylated product.
Synthetic application of the method was further
demonstrated in the preparation of naturally occurring alkaloid
(±) angustureine (Scheme 5).[18] By carrying out the title reaction
using quinoline and n-pentanal, the ketone 36a was synthesized
as major product along with the 4-acylated derivative 36b. The
mixture of regioisomeric ketones were then transformed to the
corresponding hydrazone derivatives upon treatment with MOC-
hydrazine. Mixture of hydrazones 37a and 37b were reduced to
the compounds 38a and 38b. At this stage, the minor
Substrate scope studies of the aerobic C-H acylation
reaction were further carried out using various functionalized
and biologically important alkaloids (Scheme 3). Accordingly,
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[a] Reaction conditions: heteroycles (0.2 mmol, 1.0 equiv), n-butanal (8-15 equiv), TFA (1.5-4.5 equiv), EtOAc (1.34 mL, 0.15 M) at 100 °C under O2
atmosphere; isolated yields of the acylated products are given; structure of major product is drawn. [b] Selectivity (s) between acylated and alkylated
products determined by GC-mass analysis. [c] Combined yield of acylated and alkylated product is given. [d] dNMR yield using mesitylene as internal
standard.
Scheme 3. Substrate scope.[a,b]
regioisomer 38b was separated out by column chromatography
and the synthesis of (±) angustureine was continued using the
major isomer 38a. The Brønsted acid catalyzed hydrogenation
of heterocyclic ring of 38a afforded the compound 39 in excellent
yield. The synthesis of (±) angustureine could be completed via
N-methylation of the 39 with methyl iodide.[19]
For better understanding of the reaction mechanism, several
other experiments were performed. The reaction did not afford
any desired product in the absence of TFA (Scheme 6). This
clearly indicates that the electron deficient nitrogen heterocycle
is the active radical acceptor. The reaction furnished only trace
amount of the desired product when performed under argon
atmosphere and a sluggish reactivity with air (Scheme 6). These
results suggest that molecular oxygen plays an important role for
the reaction as green oxidant. Furthermore, the reaction was
completely inhibited in the presence of various radical
scavengers like TEMPO, BHT and para-quinol (Scheme 7). GC-
Mass analysis of the crude reaction mixture of TEMPO
experiment provided
a signal at m/z = 199.15, which
corresponds to the TEMPO-ester A. The ester A could be
originated via McLafferty rearrangement[20] of the acyl-TEMPO
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our hypothesis with experimental data. It is known in the
literature that the generation of acyl radical from aldehyde could
be achieved at reduced reaction temperature in the presence of
a suitable radical initiator.[6] We thus performed the radical
acylation reaction using 10 mol% AIBN, which yielded desired
acylated product at 80 °C. When this experiment was repeated
in the absence of AIBN, poor result was obtained (Scheme 8). It
is also reported that metal additives particularly Co(II) and Co(III)
promote aldehyde auto-oxidation process.[6h,9b] Accordingly, the
reaction was performed using catalytic amount of Co-salt, which
Scheme 5. Formal synthesis of (±) Angustureine.
adduct B. Based on this result, we conclude that the reaction is
most likely followed a radical pathway.
Scheme 8. Reactions performed at 80 °C with and without AIBN.
afforded the expected product in low yield at 50 °C after 24 h
(Scheme 9). These results may suggest that the formation of
acyl radical from aldehyde using molecular oxygen as a sole
reagent is indeed a difficult step. As a result, the reaction needs
to be carried out at 100 °C to obtain acceptable yield of the
desired product.
Scheme 6. Reactions performed in absence of TFA or O2.
One of the key steps of the aerobic radical C-H acylation
reaction is the in situ formation of acyl radical from aldehyde. We
expected that the use of elevated reaction temperature (100 °C)
might facilitate the initiation step of aldehyde auto-oxidation
process. Additional experiments were then performed to support
Scheme 9. Reactions performed in the presence of Co(II)/Co(III) salts.
Based on the results obtained in our studies and the
literature precedents, a possible radical chain mechanism is
depicted in Scheme 10 for the reaction. Auto-oxidation of
aldehyde affords acyl radical. By intercepting, the acyl radical 40
with the protonated nitrogen heterocycles forms the radical
cation 41, which provides the desired acylated product after
oxidation. Presumably, the minor alkylated product arises
through the addition of an electron rich alkyl radical that is
generated in situ via decarbonylation of the acyl radical to
electron
deficient
nitrogen
heterocycle
followed
by
rearomatization of the radical cation 42. The in situ generated
acyl radical is known to react with excess O2 thus decomposes
to the corresponding carboxylic acid. The formation of carboxylic
acid was confirmed by GC-mass analysis of the crude reaction
Scheme 7. Reactions performed in the presence of radical scavengers.
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mixture. As a result, a slight excess of aldehyde was required to
achieve decent chemical yield of the desired product.
Acknowledgements
We gratefully acknowledge the generous financial support from
Science and Engineering Research Board, India
(EMR/2016/006344) and CSIR for fellowship to S.P. and M. B.
Conflict of Interest
The authors declare no conflict of interest.
Keywords: Ketones; Aerobic oxidation; Acyl radical; Molecular
oxygen; Nitrogen heterocycles
[1]
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Scheme 10. Proposed reaction mechanism.
Conclusions
In conclusion, we have presented a metal- and synthetic
oxidant-free method for the direct incorporation of acyl moiety at
C(sp2)-H bond of nitrogen heterocycles using inexpensive
aldehydes and molecular oxygen. The key aspects of the
method include a) the generation of reactive acyl radical via
auto- oxidation of aldehyde, b) convenient reagent and solvent
c) operational simplicity and d) scalability. Based on our
mechanistic studies, a radical chain mechanism is proposed for
the process in which acyl radical formation from aldehyde is
likely the most difficult step of the process. The method offers
easy access to various functionalized heteroaryl-alkyl ketones in
good yield and functional group tolerance.
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Experimental Section
General Procedure for the C-H acylation of nitrogen heterocycles
using aldehyde and O2: To an oven dried screw cap tube (10.0 mL)
equipped with a magnetic stir bar, heteroarene (0.2 mmol, 1.0 equiv) and
TFA (1.5-4.5 equiv; amount is specified in the individual experiment)
were added. The mixture was diluted with EtOAc (1.4 mL, 0.15 M) and
allowed to stir at room temperature for five minutes. After complete
protonation of the heteroarene (confirmed by TLC analysis), the solution
was purged with oxygen (O2) balloon for 5 minutes at 0 °C. To the cold
solution, an appropriate aldehyde (6-15 equiv; amount is specified in the
individual experiment) was added, flashed with oxygen (O2) and placed
in a pre-heated oil bath at 100 °C for 36-115 h. The reaction was allowed
to cool at room temperature and neutralized with saturated aqueous
solution of NaHCO3 (3.0 mL). The mixture was diluted with distilled water
(3.0 mL) and the organic layer was extracted with ethyl acetate (3×4.0
mL). The combined organic layer was washed with brine, dried over
anhydrous Na2SO4 and concentrated under reduced pressure. The crude
material was purified by column chromatography to afford the desired
acylated product.
[6]
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Minisci, J. Chem. Soc. C 1971, 1747-1750; n) G. P. Gardini, F. Minisci,
J. Chem. Soc. C 1970, 929-929.
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Chem. Int. Ed. 2014, 53, 74-100; c) M. Klussmann, D. Sureshkumar,
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10.1002/asia.201900857
Chemistry - An Asian Journal
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Title
An aerobic synthesis of unsymmetrical heteroaryl ketone via
cross-dehydrogenative coupling between aldehydes and
heteroaromatic bases is described. The reaction involves the
direct addition of acyl radical generated in situ from aldehyde
auto-oxidation process to a range of electron-deficient nitrogen
heterocycle. With this simple reaction protocol, various
functionalized heteroaryl-alkyl ketones are synthesized in
moderate to good yields. The synthetic potential of the method is
further established by a formal synthesis of the natural alkaloid
(±) angustureine. Finally, a radical chain mechanism is proposed
for the reaction.
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