Dioxygen-Mediated Decarbonylative C-H Alkylation of Heteroaromatic Bases with Aldehydes

Article abstract of DOI:10.1002/chem.201503809

An operationally simple and economical method for the direct alkylation of heteroaromatic bases employing readily available aldehydes as alkyl radical precursors and molecular oxygen as a reagent is presented. This simple transformation demonstrates a broad substrate scope with respect to aldehydes and nitrogen heterocycles, enabling the introduction of several medicinally important yet challenging alkyl moieties, such as ethyl, isopropyl, tert-butyl, and cyclohexyl to the different classes of heterocyclic bases in good to excellent yields. A simple method for the direct alkylation of heteroaromatic bases with aldehydes as inexpensive alkyl radical precursors and molecular oxygen as a reagent is presented. This transformation demonstrates a broad substrate scope with respect to aldehydes and nitrogen heterocycles, enabling the introduction of various alkyl moieties to heterocyclic bases (>40 examples) in good to excellent yields.

Full text of DOI:10.1002/chem.201503809

DOI: 10.1002/chem.201503809
Communication
&
CÀH Functionalization
Dioxygen-Mediated Decarbonylative CÀH Alkylation of
Heteroaromatic Bases with Aldehydes
Subhasis Paul and Joyram Guin*[a]
aldehydes as alkyl radical precursors, these methods however
suffer several disadvantages such as the use of overstoichio-
metric amount of peroxide as initiator and oxidant,[15] metal
salt as additive,[16] or UV light irradiation.[17] In view of the
growing environmental concern with regard to waste manage-
ment, the development of a general, efficient and metal-free
method for the direct alkylation of nitrogen heterocycles with
aldehydes avoiding the use of stoichiometric amount of re-
agent would be highly desirable.
Abstract: An operationally simple and economical
method for the direct alkylation of heteroaromatic bases
employing readily available aldehydes as alkyl radical pre-
cursors and molecular oxygen as a reagent is presented.
This simple transformation demonstrates a broad sub-
strate scope with respect to aldehydes and nitrogen het-
erocycles, enabling the introduction of several medicinally
important yet challenging alkyl moieties, such as ethyl,
isopropyl, tert-butyl, and cyclohexyl to the different classes
of heterocyclic bases in good to excellent yields.
We therefore envisioned that the well-investigated auto-oxi-
dation of aldehyde,[18] which allows mild and selective genera-
tion of acyl radical by using O2 as a reagent, could lead to the
formation of alkyl radical by decarbonylation under suitable re-
action conditions. The generated alkyl radical is expected to
combine with the electrophilic nitrogen heterocycles to afford
the corresponding alkylated products (Scheme 1). Although
Alkyl-substituted nitrogen-containing heterocyclic compounds
are extremely important molecules because these structural
motifs are found in a broad range of highly potent drug mole-
cules[1] and in many biologically relevant compounds.[2] Al-
though diverse synthetic strategies, including transition-metal-
catalyzed cross-coupling with functionalized substrates[3] and
hydroheteroarylation of olefins,[4] have been developed, the
direct CÀH alkylation through homolytic aromatic substitution
(HAS)[5] of alkyl radicals with electron-deficient nitrogen hetero-
cycles (Minisci reaction) remains the most straightforward ap-
proach to such compounds.[6] However, a major drawback of
this process is the limited access to alkyl radicals. Initially, alky-
lation of nitrogen heterocycles was accomplished with alkyl
radicals derived from alkyl carboxylic acids[7] or halides.[8] Later,
alkyl boron compounds,[9] zinc bis(alkanesulfinate) salts,[10] per-
oxides,[11] and hydrocarbons[12] were used as the sources of
alkyl radicals for electrophilic nitrogen heterocycle functionali-
zation. Despite all of these developments, the existing meth-
ods often require expensive starting materials or catalysts in
combination with stoichiometric amounts of metallic or non-
metallic oxidants.
Scheme 1. Aerobic CÀH alkylation of nitrogen heterocycles with aldehydes.
the auto-oxidation of aldehyde has been utilized in aerobic hy-
droacylation[19] and epoxidation[20] of olefins, this approach re-
mains unexplored for the direct alkylation of heteroaromatic
bases. Herein, a successful implementation of this strategy to
the CÀH alkylation of nitrogen heterocycles with inexpensive
aldehydes in the presence of O2 is described. This method
does not require any additional reagent or catalyst.
Aldehydes, however, are readily available and inexpensive
bulk chemicals that have been utilized as a source of acyl radi-
cals, which are known to deliver the corresponding alkyl radi-
cals through decarbonylation under suitable reaction condi-
tions.[13,14] Although there have been few reports on the decar-
bonylative CÀH alkylation of heteroaromatic bases employing
In accordance to the concept presented in Scheme 1, we
began our study with the reaction of aldehyde 1a with pro-
tonated isoquinoline under various reaction conditions in the
presence of O2 (see the Supporting Information). After having
optimized procedure in hand, the scope of this transformation
was evaluated with structurally different aldehydes (Table 1).
The a-branched aldehydes 1a–d furnished the corresponding
alkylated products 2a–d in good yields (60–82%, isolated
products; Table 1, entries 1–4) with no detectable amount of
the acylated products 3a–d. Although a small amount of the
[a] S. Paul, Dr. J. Guin
Department of Organic Chemistry, Indian Association for the Cultivation of
Science, 2A & 2B Raja S. C. Mullick Road
Jadavpur, Kolkata 700032 (India)
E-mail: ocjg@iacs.res.in
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201503809.
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acylation was significantly reduced with linear aldehydes.
This could be attributed to the fact that the formation of
primary alkyl radical by decarbonylation of the correspond-
ing acyl radical is unfavorable.[14e]
Table 1. Aldehyde substrate scope with isoquinoline.[a]
Having explored variation of aldehydes, the scope of this
transformation was evaluated on a broad range of nitrogen
heterocyclic compounds. The title reaction allowed incorpo-
ration of the challenging isopropyl moiety to a wide range
of different classes of heterocyclic bases with various sub-
stituents (Table 2). The products 4–40 were isolated in
yields ranging from 31 to 97%, with predominant regiose-
lectivity at the 2- and 4-positions of the heterocycles. Where
more than one active site was present, both the mono- and
bis-alkylated products were formed.[21] Pyridine moieties
having cyano, acetyl, 2,4-difluorophenyl, tert-butyl, methyl,
phenyl, and p-methoxyphenyl groups rendered the corre-
sponding alkylated products 4–12 in good isolated yields.
4,4’-Di-tert-butyl-2,2’-bipyridine could be converted to the
desired product 13 in 83% yield. Quinoline and its deriva-
tives were alkylated smoothly with this procedure (14–16).
The incorporation of ethyl, isopropyl, and cyclohexyl moiet-
ies to lepidine delivered the medicinally important com-
pounds 17–19. Notably, the products 18 and 19 have been
reported to exhibit tuberculosis inhibitory activity.[1a] The
isopropyl-substituted acridine 20 was synthesized in 43%
yield. Isoquinolines bearing nitro and bromo functionality
furnished the corresponding alkylated products 21 and 22,
respectively. The reaction proved scalable, with isoquinoline
performing well on gram scale, delivering the alkylated
product 2a in 72% yield. The quinoxaline derivative, quina-
zoline, phthalazine, 4-hydroxyquinazoline, benzimidazole,
and benzothiazole were all alkylated by this method (23–
28; 38–97%). The isopropyl, tert-butyl, and cyclohexyl-sub-
stituted thiazoles 29–31 were also synthesized in good
yields.
Entry
Aldehyde
(equiv)
Alkylated
product
t
[h]
Yield
[%]
Selectivity[b]
[%]
1[c]
12
12
16
12
12
82
66
60
76
78
>99
>99
>99
>99
88
2
3
4
5
6
12
12
21
60
58
32
90
90
31
7
8[c]
The substrate scope study was continued with naturally
occurring nitrogen heterocycles (Table 2). With this simple
procedure, the introduction of hindered isopropyl, tert-
butyl, and cyclohexyl moieties were accomplished selective-
ly at the C6 position of nicotine, giving access to the alkylat-
ed products 32–34 (51–81%). Likewise, biologically impor-
tant purine bases, such as caffeine and theophylline, were
easily converted into the corresponding alkylated deriva-
tives 35–40 in good yields (40–65%). Notably, the direct in-
troduction of isopropyl group to caffeine, which is an other-
wise challenging reaction,[7c,10a,17,22] could be performed on
gram scale.
9[c]
25
20
71
75
45
40
10[c]
[a] Reaction conditions (unless otherwise stated): Isoquinoline (1.0 equiv), tri-
fluoroacetic acid (TFA; 1.5 equiv), aldehyde (6–20 equiv), 1,2-dichloroethane
(DCE; 1.5M solution of isoquinoline); combined yields of the isolated materi-
als; [b] selectivity refers to the ratio between alkylated and acylated prod-
ucts, determined by H NMR spectroscopic analysis of the crude mixture and
by GCMS analysis for entries 1–4; [c] conc.=0.15m.
1
acylated isoquinolines 3e–g were formed from aldehydes 1e–
g, the corresponding alkylated isoquinolines 2e–g were isolat-
ed as major products (Table 1, entries 5–7). Surprisingly, cyclo-
propanecarboxaldehyde (1h) was found to be less reactive,
furnishing the alkylated product 2h in a much lower yield and
selectivity (Table 1, entry 8). The linear aldehydes 1i and 1j
could be included in this procedure. Accordingly, ethyl- and n-
propyl-substituted isoquinolines 2i and 2j were isolated along
with the acylated products 3i and 3j in good combined yields
(Table 1, entries 9 and 10). The selectivity for alkylation over
To further test the versatility of this transformation,
a one-pot sequential CÀH alkylation of a given nitrogen het-
erocycle was performed with two different aldehydes
(Scheme 2). Accordingly, when 4-acetylpyridine was allowed to
react with aldehydes 1d and 1a successively, the desired tri-
functionalized pyridine 41 was isolated in 24% yield.
A proposed reaction mechanism that reconciles our experi-
mental results with literature precedents is depicted in
Scheme 3. The auto-oxidation of aldehyde has been shown to
involve acyl radical 42, which delivers the carboxylic acid 44
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Table 2. Nitrogen heterocycle substrate scope.[a]
[a] Reaction conditions (unless otherwise stated): Heterocycle (1.0 equiv), TFA (1.5–4.5 equiv), aldehyde (6–20 equiv), DCE (1.5m solution of heterocycle),
12–65 h; yields refer to isolated products; [b] conc.=1.5m; [c] 25% acylated product was formed; [d] 6% bis-alkylated product at C2 and C8 positions
1
was isolated; [e] 3% acylated product was formed; [f] 5% acylated product was formed; [g] yields indicated in parentheses determined by H NMR spectro-
scopic analysis of the crude mixture using mesitylene as internal standard; [h] 12% acylated product was formed; [i] conc.=0.75m.
Scheme 2. One-pot differential CÀH alkylations of 4-acetylpyridine with 1d
and 1a.
through a peracyl radical 43.[19e] The acyl radical 42 is thus ex-
pected to deliver the corresponding alkyl radical through de-
carbonylation under the optimized reaction conditions. It is
probable that this alkyl radical reacts with the protonated het-
Scheme 3. Proposed reaction mechanism.
erocycle 45 to form the radical cation 46, which furnishes the
alkylated product 47 after rearomatization with O2 or hydro-
peroxide radical. Presumably, the minor acylated product re-
sulted, in some cases, from the addition of acyl radical 42 to
heterocycle 45.[23] It is important to note that this reaction in
air gave moderate yield of the desired product. In addition,
a trace amount of the desire product was realized when the re-
action was performed without using O2 or acid (see the Sup-
porting Information).
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In conclusion, we have developed a metal-free, scalable, and
operationally simple protocol for the direct alkylation of nitro-
gen heterocycles employing inexpensive aldehydes as alkyl
radical precursors and molecular oxygen as a reagent. The
methodology enables the incorporation of various structurally
diverse and medicinally important alkyl moieties to the differ-
ent classes of biologically relevant nitrogen-rich heterocycles in
good yields. Many of the products reported herein are new
chemical entities that could be valuable building blocks for
drug discovery. Exploration of this simple and reagent-free
methodology for the generation of alkyl radicals from alde-
hydes towards alkylation of other potential radical acceptors is
the current research interest of our group.
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Acknowledgements
We gratefully acknowledge generous financial support from
the Science and Engineering Research Board, India (Nos. SB/
S5/GC-08/2014 and SB/S1/OC-52/2013) and the CSIR for a fel-
lowship to S.P. J.G. sincerely thanks Dr. T. K. Paine for various in-
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Keywords: auto-oxidation
heterocycles · oxygen · radical reactions
·
CÀH
functionalization
·
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Received: September 23, 2015
Published online on October 23, 2015
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