Organic Letters
Letter
limitations of these methods.9−12 Although I2 and NBS have
been used as metal-free catalysts in oxidation reactions, cross
dehydrogenative coupling (CDC) reactions,13,14 and even in
olefination reactions using benzylamines,13e,14b they cannot be
considered as “abundant”, as their natural abundance is poor.15
In sharp contrast, catalysis using chloride, the most abundant
anion present in seawater, has rarely been explored.16 In
addition, carrying out organic reactions using water as a green,
economical, nontoxic, and nonflammable solvent has become
one of the prime goals in sustainable organic synthesis in the
last two decades.17 Therefore, utilization of the ubiquitous
NaCl as the catalyst and water as the solvent for key organic
transformations is an attractive, sustainable, and inexpensive
alternative.
Herein, we report the highly E-selective olefination of
methyl substituted N-heteroarenes with benzyl amines and
alcohols in water using NaCl as the catalyst and aq TBHP as
the oxidant. The study has been extended to the synthesis of
five pharmaceutically important conjugated olefins which have
been carried out using water as the only solvent.
most sustainable solvent; (iv) no requirement of an external
ligand; (v) the method is base-free or requires only catalytic
amount of base; and (vi) the byproduct is t-BuOH which can
be reused if necessary (Scheme 2). We began our investigation
by examining the oxidative coupling of 4-methoxybenzylamine
2a with 2-methylquinoline 1a in aqueous medium using NaCl
as catalyst and aq TBHP as oxidant at 70 °C. The reaction was
carried out for 24 h, and we were able to isolate E-2-(4-
methoxystyryl) quinoline 4 in 42% yield. This result
encouraged us to study the effect of varying the reaction
parameters to improve the yields. To explore the role of the
cation, different chloride salts were tried such as NaCl, KCl,
MgCl2, and Et4NCl and the maximum yield was obtained with
using sodium chloride (20 mol %) and aq TBHP (4 equiv) at
100 °C (Scheme 3).
Scheme 3. Oxidative Coupling of 4-Methoxybenzylamine
a
with 2-Methylquinoline
In our previously reported work on NaCl catalyzed
oxidation of aromatic amines and alcohols to imines and
carboxylic acids, we observed that aldehydes were generated in
situ and subsequently converted to the corresponding imines
and carboxylic acids (Scheme 2).16 We were therefore keen to
a
Reaction conditions: 2-methylquinoline 1a (143 mg, 1 mmol), 4-
methoxybenzylamine 2a (240 mg, 1.75 mmol), NaCl (11.6 mg, 0.2
mmol), TBHP (70% in water, 360 mg, 4 mmol), and water (0.3 mL),
100 °C oil bath for 24 h.
Scheme 2. Advantages of NaCl as Catalyst for Olefination
Reaction in Water
Unlike aromatic amines, aromatic alcohols were not found
to oxidize to acids in the absence of a base such as NaOH.
Therefore, we carried out the olefination reaction of 4-
methoxybenzyl alcohol 3a with 2-methylquinoline 1a in
aqueous medium using NaCl as catalyst and aq TBHP as
oxidant at 70 °C in the presence of 50 mol % NaOH.
Unfortunately, 4-methoxybenzyl alcohol was mostly converted
to the corresponding 4-methoxybenzoic acid and we isolated
the olefin 4 in only 5% yield. After detailed studies (see the
catalytic amount of an organic base such as 4-dimethylamino-
pyridine (DMAP) increases the yield of the olefin up to 70%
using sodium chloride (20 mol %) and aq TBHP (4 equiv) at
100 °C (Scheme 4). While electrophilic halogenating reagents
Scheme 4. Oxidative Coupling of 4-Methoxybenzylalcohol
a
with 2-Methyl Quinoline
a
Reaction conditions: 2-methylquinoline 1a (143 mg, 1 mmol), 4-
methoxybenzyl alcohol 3a (241 mg, 1.75 mmol), NaCl (11.6 mg, 0.2
mmol), 4-dimethylaminopyridine (12.2 mg, 0.1 mmol), TBHP (70%
in water, 360 mg, 4 mmol), and water (0.3 mL), 100 °C oil bath for
24 h.
study whether the in situ generated aldehydes could be coupled
with N-containing heteroarenes under mild reaction conditions
to obtain the desired olefinic compounds.9−12 This method
would be highly sustainable and advantageous for several
reasons: (i) the alcohols and amines are readily available from
several industrial processes; (ii) NaCl is inexpensive and is a
readily available commodity; (iii) water is the greenest and
such as NBS in organic solvent have been used for the
olefination of benzylamines, no reports indicating the use of
anionic halogens are reported in the literature.14b Our attempts
to explore other halides such as Br− and I− for this reaction
resulted in lesser yields of the products (see the Supporting
B
Org. Lett. XXXX, XXX, XXX−XXX