Cobalt-catalyzed alkylation of methyl-substituted N-heteroarenes with primary alcohols: Direct access to functionalized N-heteroaromatics

Article abstract of DOI:10.1039/c9cc08448g

Phosphine free, air and moisture stable Co(NNN) complex catalyzed alkylation of various methyl-substituted N-heteroarenes with alcohols is reported. Following the borrowing hydrogen methodology, a variety of methyl-substituted N-heteroarenes can be functionalized efficiently. To understand the mechanism of this reaction various kinetic and control experiments were carried out.

Full text of DOI:10.1039/c9cc08448g

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Cobalt-catalyzed alkylation of methyl-substituted
N-heteroarenes with primary alcohols: direct
access to functionalized N-heteroaromatics†
Cite this: Chem. Commun., 2020,
56, 249
Received 29th October 2019,
Accepted 27th November 2019
Anju Mishra, Ambikesh D. Dwivedi, Sujan Shee and Sabuj Kundu
*
DOI: 10.1039/c9cc08448g
rsc.li/chemcomm
Phosphine free, air and moisture stable Co(NNN) complex catalyzed
alkylation of various methyl-substituted N-heteroarenes with alcohols
is reported. Following the borrowing hydrogen methodology, a
variety of methyl-substituted N-heteroarenes can be functionalized
efficiently. To understand the mechanism of this reaction various
kinetic and control experiments were carried out.
Development of new synthetic methods to replace the rare noble
metal based-catalysts by more economical and earth-abundant base
metal catalysts has been in high demand in the past few decades.1
In this respect, cobalt-based catalysts have been receiving increasing
attention from the scientific community because of their availability,
low cost, and low toxicity. By using cobalt complexes a variety of
Scheme 1 Transition-metal catalyzed alkylation of methyl-substituted
N-heteroarenes with alcohols.
Following this strategy, several precious metal (e.g. Ir, Ru,
organic transformations, such as (de)hydrogenation,2 C–C and Pt) complex catalyzed C(sp3)–H bond functionalizations of
coupling,3 C–H bond activation,4 borylation,5 hydrosilylation,6 N-heteroaromatics using alcohols were well explored in the
polymerization,7 etc., were explored.8
literature.14 Recently, a few reports were published for the base
N-heteroarenes and their alkyl derivatives are one of the metal-catalyzed a-olefination as well as alkylation of methyl-
important building blocks in the synthesis of various pharma- substituted N-heteroarenes.15 However, to the best of our
ceutical, agricultural, and materials science related compounds.9 knowledge cobalt catalyzed alkylation of C(sp3)–H bonds of
Metal catalyzed C(sp3)–H bond functionalization provides a useful N-heteroarenes using alcohols following the borrowing hydrogen
tool to access diverse N-heteroaromatic products.10 Traditionally, methodology has not been reported yet (Scheme 1).
alkylation of N-heteroarenes was accomplished by using pre-
We recently developed an air and moisture-stable Co(NNN)Br2
functionalized electrophiles, such as alkyl halides, allylic carbonates, complex which was found to be effective for the sustainable
or esters. However, these methods suffer from the generation of synthesis of a variety of N-heterocyclic compounds like quinoxa-
undesired excess amount of salt waste and harsh reaction lines, quinolines, and 2-alkylaminoquinolines.16 In our continuous
conditions.11 Therefore, the use of lignocellulose derived alcohols effort toward developing efficient protocols to construct new C–C
as the alkylating agent becomes a promising alternative for the bonds via a hydrogen auto-transfer strategy,17 herein, we report
C(sp3)–H bond alkylation of methyl-N-heteroaromatics.12 The Co(NNN) complex catalyzed C(sp3)–H bond functionalization
borrowing hydrogen methodology has been widely used for of methyl-substituted N-heteroarenes by using alcohols as an
the construction of C–X (X = C, N) bonds, by using alcohols as alkylating agent.
an alkylating agent.13 In this eco-friendly process, only water is
produced as the by-product which makes this process cleaner of methyl-substituted N-heteroarenes, 2-methylquinoline (1a)
To find the optimum reaction conditions for the alkylation
and greener.
and benzyl alcohol (2a) were selected as model substrates and the
reaction between them was thoroughly investigated. Initially, the
reaction of 1a (0.6 mmol) with 2a (0.3 mmol) in the presence of
catalyst-A and KOtBu was carried out in toluene for 24 h which
gave 87% yield of 3a. The yield of the desired alkylated product
Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur-208016,
India. E-mail: sabuj@iitk.ac.in
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c9cc08448g was much higher in the presence of catalyst-A as compared to the
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Table 1 Optimization of the cobalt-catalyzed alkylation of 2-methyl-
quinoline with benzyl alcohola
Table 2 Alkylation of 2-methylquinoline with various primary alcoholsa
Entry
Catalyst
Base (equiv.)
Solvent
Yield of 3ab (%)
1
2
3
4
5
6
7
8
Cat. A
CoBr2
Cat. A
Cat. A
Cat. A
Cat. A
Cat. A
Cat. A
—
Cat. A
Cat. A
Cat. A
Cat. A
Cat. A
Cat. A
Cat. A
KOtBu (1.5)
KOtBu (1.5)
NaOH (1.5)
KOH (1.5)
CsOH (1.5)
Cs2CO3 (1.5)
NaOMe (1.5)
KOtBu (1.0)
KOtBu (1.5)
—
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
1,4-Dioxane
m-Xylene
p-Xylene
Toluene
Toluene
87
20
5
31
32
0
34
47
1
1
74
2
37
18
57
68
9
10
11c
12
13
14
15d
16e
KOtBu (1.5)
KOtBu (1.5)
KOtBu (1.5)
KOtBu (1.5)
KOtBu (1.5)
KOtBu (1.5)
a
Reaction conditions: 2-methylquinoline (1a) (0.6 mmol), alcohol
derivatives (0.3 mmol), catalyst-A (10 mol%), KOtBu (0.45 mmol),
toluene (2 mL), 150 1C (oil bath temperature), 24 h, isolated yields.
b
c
Catalyst-A (15 mol%). 36 h.
a
Reaction conditions: 2-methylquinoline (1a) (0.6 mmol), benzyl alco-
variety of methyl-substituted N-heteroarenes using various primary
alcohols was explored and the results are summarised in Table 3.
First, the alkylation of 2-methylquinoxalines with primary alcohols
was selected. Utilizing this catalytic system, alkylation of
2-methylquinoxalines worked well using a variety of alcohols
bearing both electron-donating and electron-withdrawing
groups (Table 3, entries 4a–4g). For instance, primary alcohols
substituted with methyl, methoxy, and chloro groups under the
standard reaction conditions afforded the desired products in
excellent yields (Table 3, entries 4b–4d). Interestingly, cyclic
aliphatic alcohols and more challenging long-chain alkyl alcohols
also reacted smoothly under the optimized reaction conditions and
furnished the expected alkylated N-heteroarenes in good yields
(Table 3, entries 4e–4f). In addition, 1-naphthylmethanol also
reacted efficiently (Table 3, entry 4g). This catalytic protocol was
hol (2a) (0.3 mmol), catalyst-A (10 mol%), KOtBu (0.45 mmol), toluene
(2 mL), 150 1C (oil bath temperature), 24 h. GC yields (n-dodecane was
b
c
d
used as the internal standard). Catalyst-A (5 mol%). 140 1C (oil bath
temperature). e 2-Methylquinoline (0.3 mmol), benzyl alcohol (0.6 mmol).
metal precursor CoBr2 (Table 1, entries 1–2). Subsequently, we
screened the different bases; out of them KOtBu gave the maxi-
mum yield as compared to the others (Table 1, entries 3–7).
Afterward, other solvents such as 1,4-dioxane, m-xylene,
p-xylene, and toluene were screened and toluene delivered the
highest yield of 3a (Table 1, entries 12–14). The yield of 3a was
reduced by decreasing the oil bath temperature and by lowering
the amount of 2-methylquinoline (Table 1, entries 15 and 16).
Finally, the optimized reaction conditions were found to be
10 mol% of catalyst-A and 1.5 equivalent of KOtBu at 150 1C in
24 h using toluene as a solvent which furnished 87% of 3a.
With the optimized reaction conditions in hand, the applic-
ability of the present catalytic system was explored by taking a
variety of primary alcohols and the results are summarized in
Table 2. Alkylation of 2-methylquinolines tolerated various
primary alcohols. The reaction of 4-methyl benzyl alcohol and
2-methyl benzyl alcohol with 2-methylquinoline gave 87% and
88% yields of the desired alkylated products (Table 2, 3b–3c).
Alkylation with 4-methoxy and 3-methoxybenzyl alcohols
afforded the corresponding products in 78% and 74% yields,
respectively (Table 2, 3d–3e). However, heteroatom-containing
alcohols such as thiophen-2-ylmethanol and furan-2-ylmethanol
provided lower yields of the desired products (3f, 3h). Additionally,
1-naphthylmethanol afforded smooth conversion to the expected
a-alkylated product under the optimized reaction conditions (3g).
The possibilities of expanding this reaction for the synthesis of
long-chain alkylated N-heteroarenes were also explored by reacting
them with aliphatic alcohols such as n-hexanol (3i).
Table 3 Alkylation of methyl-substituted N-heteroarenes with various
primary alcoholsa
Encouraged by the finding that Co(NNN) complex is an
effective catalyst for the a-alkylation of 2-methylquinolines,
a
Reaction conditions: alcohol derivatives (0.3 mmol), methyl-substituted
N-heteroarenes (0.6 mmol), catalyst-A (10 mol%), KOtBu (0.45 mmol),
the potential of this catalytic procedure for the alkylation of a toluene (2 mL), 150 1C (oil bath temperature), 24 h, isolated yields. b 36 h.
250 | Chem. Commun., 2020, 56, 249--252
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also successfully extended for the alkylation of 2-methylpyrazine.
The reaction was well tolerated with different substituted benzyl
alcohols under the standard reaction conditions (Table 3,
entries 4h–4j). Afterward, the alkylation of 2,6-dimethylquinoline
was carried out which gave the corresponding product in moderate
yield (Table 3, entry 4k).
Alkyl derivatives of 1-benzyl-2-methylbenzimidazole are
regarded as an important heterocyclic motif due to their wide
range of pharmacological and biological activities including
anticancer, antiviral, antihypertensive, anti-HIV and anti-diabetic
activity.18 In view of their wide-ranging activities, the synthesis
of benzimidazoles and their alkyl derivatives becomes highly
significant. Hence, we tested alkylation of 1-benzyl-2-methyl-1H-
benzoimidazole following the optimized reaction conditions.
To our delight, several alcohols efficiently participated in this
Scheme 3 Control experiments for the alkylation of 2-methylquinolines.
C(sp3)–H bond functionalization of 1-benzyl-2-methyl-1H-benzo- yield (Scheme 3b). The transfer hydrogenation of 3a0 by benzyl
imidazole and afforded the corresponding alkylated products in alcohol under optimized reaction conditions afforded the
excellent yields (Table 4).
hydrogenated product 3a in 80% yield (Scheme 3c). These
The practical applicability of this catalytic protocol was further experiments clearly indicate that the reaction proceeds through
extended by the preparative scale synthesis of various alkylated the a-olefinated intermediate 3a0 which further undergoes catalytic
N-heteroarenes. Following the optimized reaction conditions, hydrogenation (Scheme 3c) to afford the desired a-alkylated
alkylation of various substrates using alcohols as an alkylating product 3a and in this reaction benzyl alcohol acts as the hydrogen
agent was carried out which smoothly provided the corres- donor. In another experiment, initially, catalyst-A (10 mol%) was
ponding products in good yields (Scheme 2).
treated with 2.5 equiv. of LiBEt3H and subsequently it was utilized
To get insight into the reaction mechanism, a series of for the coupling between 2-methylquinoline and benzyl alcohol in
control experiments were performed. The coupling of 1a with the presence of a slightly lower amount of base (0.5 equiv.) which
2a was monitored at different time intervals (ESI,† Fig. S1). afforded the desired alkylated product in 82% yield (Scheme 3d).
Initially, the formation of 3a and 3a0 was observed with a sharp This result indicated that probably the in situ generated
decrease in the concentration of 2a which eventually led to the (NNN)Co(I)–H complex is the active catalyst for the reaction.16,19
formation of product 3a. Under the optimized reaction conditions, However, we were unable to characterize this active Co(I)–H
after 12 h, yields of 3a and 3a0 were 39% and 16% respectively species by 1H-NMR spectroscopy probably due to its paramagnetic
(Scheme 3a). The formation of 2-styrylquinoline (3a0) in the initial nature.20
stage of the reaction (as shown in ESI,† Fig. S1) certainly indicated
that 3a0 was an intermediate in this reaction.
Based on the result of these mechanistic investigations and
the previous literature reports14b–d,15c,d a plausible mechanism for
The reaction of benzaldehyde with 1a in the presence the C(sp3)–H bond alkylation of methyl-substituted N-heteroarenes
of KOtBu as a base produced 2-styrylquinoline (3a0) in 60% was proposed (ESI,† Fig. S2). In the initial step, dehydrogenation of
the alcohol leads to the formation of an aldehyde which under-
goes base mediated aldol condensation with methyl-substituted
N-heteroarenes to afford an a-olefinated intermediate. Further
catalytic hydrogenation of the a-olefinated intermediate gave
Table 4 Alkylation of 1-benzyl-2-methyl-1H-benzoimidazole with various
benzyl alcoholsa
the desired a-alkylated N-heteroarenes.
In summary, an effective, economical and greener strategy
for the Co(II) catalyzed alkylation of methyl-substituted N-hetero-
arenes with alcohols was developed. To the best of our knowledge,
this is the first example of the cobalt-catalyzed functionalization of
C(sp3)–H bonds in methyl N-heteroarenes using alcohols.
A variety of alkylated N-heteroarenes were synthesized by coupling
of various alcohol derivatives with different methyl-substituted
a
Reaction conditions: alcohol derivatives (0.3 mmol), 1-benzyl-2-methyl-
N-heteroarenes. The synthetic utility of this process was also
established by the preparative scale synthesis of different alkylated
N-heteroarenes. To understand the mechanism various kinetic
and control experiments were carried out. Notably, the absence
of any expensive and sensitive phosphine ligands and an
easy-to-synthesize air and moisture stable Co(NNN) complex
make this an appealing methodology for accessing a variety of
alkylated N-heteroarenes.
benzimidazole (0.6 mmol), catalyst-A (10 mol%), KOtBu (0.45 mmol),
toluene (2 mL), 150 1C, 24 h, isolated yields.
Scheme 2 Preparative scale synthesis.
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