Metal-Free Oxidative Cross Esterification of Alcohols via Acyl Chloride Formation

Article abstract of DOI:10.1002/adsc.201500912

A novel metal-free oxidative cross esterification of alcohols has been achieved using trichloroisocyanuric acid as an oxidant. The alcohols were converted in situ into their corresponding acyl chlorides, which were then reacted with primary and secondary aliphatic, benzylic and allylic alcohols and phenols. A wide variety of esters was obtained in satisfactory yields.

Full text of DOI:10.1002/adsc.201500912

UPDATES
DOI: 10.1002/adsc.201500912
Metal-Free Oxidative Cross Esterification of Alcohols via Acyl
Chloride Formation
Silvia Gaspa,a Andrea Porcheddu,b and Lidia De Lucaa,*
a
Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari, via Vienna 2, 07100 Sassari, Italy
Fax: (+39)-079-229-559; phone: (+39)-079-229-495; e-mail: ldeluca@uniss.it
Dipartimento di Scienze Chimiche e Geologiche, Università degli Studi di Cagliari, Cittadella Universitaria, 09042
b
Monserrato, Italy
Received: September 14, 2015; Revised: November 4, 2015; Published online: January 5, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500912.
Abstract:
A
novel metal-free oxidative cross
Currently, acceptorless alcohol dehydrogenations
(AADs) are of great interest (Scheme 1, pathway 3).
Although, with respect to atom economy, these trans-
formations do not require a hydrogen acceptor, never-
esterification of alcohols has been achieved using
trichloroisocyanuric acid as an oxidant. The alco-
hols were converted in situ into their corresponding
acyl chlorides, which were then reacted with pri-
mary and secondary aliphatic, benzylic and allylic
alcohols and phenols. A wide variety of esters was
obtained in satisfactory yields.
Keywords: acyl chlorides; alcohols; esters; metal-
free reaction; trichloroisocyanuric acid
The ester group is one of the most significant and
abundant functional group in organic chemistry and
can be found in many natural products, polymers,
pharmaceuticals and synthetic intermediates.[1] Tradi-
tionally, esters are prepared by a nucleophilic substi-
tution between carboxylic acid derivatives (carboxylic
halides, anhydrides and active esters) and alcohols.[2]
A recent alternative approach is the oxidative esterifi-
cation of aldehydes with alcohols, but the required al-
dehydes are normally obtained by selective oxidation
of alcohols.[3] Alcohols are easily available and stable
compounds, and are contained in many naturally oc-
curring organic molecules. For these reasons, the
direct conversion of alcohols to esters is a highlight of
green and sustainable chemistry.[4]
A large number of metal-catalysed oxidative cross
esterifications of alcohols have been reported
(Scheme 1, pathway 1), but prevalently furnish methyl
esters (methanol is used as a solvent),[5] require large
excess of oxidants[6] and sometimes are limited with
respect to catalyst accessibility.[7]
An important milestone in this context are the hy-
drogen transfer oxidations of primary alcohols to
methyl esters (Scheme 1, pathway 2) catalysed by
transition metals, such as Ru[8] and Ir.[9]
Scheme 1. Esters from alcohols.
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Metal-Free Oxidative Cross Esterification of Alcohols
theless they necessitate elevated temperatures to
remove H2 from the equilibrium and prevalently are appearance of the alcohol, and after 5 days, the corre-
self esterifications of primary alcohols.[10]
sponding benzoyl chloride (Table 1, 3) was quantita-
The reaction was monitored by TLC until the dis-
The methods outlined above consist of the forma- tively formed. This reaction mixture, containing the
tion of a hemiacetal intermediate, which is subse- acyl chloride generated in situ, was treated with hep-
quently oxidised to the ester (Scheme 1, pathways 1, 2 tanol (Table 1, 4a, 1 mmol) and NEt3 in the presence
and 3). Many drawbacks, connected to the formation of a catalytic amount of DMAP (2 mmol/10 mol%) at
and reactivity of the hemiacetal, limit the substrate 08C, and after 1 h at room temperature the desired
scopes of these reactions. For these reasons we have ester was formed in 97% yield (Table 1, 5a, entry 1).
investigated the possibility to develop a more general In order to decrease the amount of the benzyl alcohol
methodology to transform directly primary alcohols 1a, the same reaction was carried out employing
into esters. We have envisioned use of an alternative 1.1 mmol of 1a and the desired ester 5a was obtained
method to bypass the hemiacetal formation and to in 96% yield (Table 1, 5a, entry 2). Then the reduction
avoid the use of a large excess of oxidant and alco- of the TCCA amount was investigated. When
hols. Our goal was to carry out a general metal-free 2.0 mmol (Table 1, 2, entry 3) and 1.1 mmol (Table 1,
methodology that would be able to transform alcohols 2, entry 4) of TCCA were used the ester 5a was ob-
into acyl chlorides, which would then react with all tained with comparable and satisfying yields. After
classes of alcohols providing the corresponding esters the optimised stoichiometric ratio of the reactants
(Scheme 1, pathway 4). Due to our interest in the oxi- was established, in order to shorten the reaction time,
dative transformations of alcohols[11] and in relation the first step of the methodology was carried out
to our recently reported metal-free oxidative esterifi- under microwave dielectric heating at 808C for 2 h
cation of aldehydes,[12] we tested the possibility to (Table 1, entry 5) and for 4 h (Table 1, entry 6) but
transform directly primary alcohols into esters by the a mixture of unreacted benzyl alcohol 1a, benzalde-
use of trichloroisocyanuric acid (TCCA). TCCA is an hyde and benzoyl chloride 3 was recovered. After the
economical, commercially available, and non-toxic ox- reaction conditions were optimised, the scope of the
idising[13] and chlorinating[14] reagent, frequently used reaction was tested (Scheme 2). In general, all reac-
for swimming-pool, dishware, house, hotel and public tions proceeded without any significant side products,
places disinfection, and in fruit and vegetable preser- and the corresponding esters 5a–t were obtained in
vation.[15] To the best of our knowledge, no similar satisfying yields.[16]
transformation of alcohols to esters via acyl chloride
formation are known to date.
The methodology was applied to variously substi-
tuted benzylic alcohols, affording a wide range of
We began our investigation by treating benzyl alco- esters. Neither the electronic properties nor steric ef-
hol (Table 1, 1a, 2.0 mmol) with TCCA (Table 1, 2, fects of substituents on the aromatic ring of the ben-
3.0 mmol) in dichloromethane (3.25 mL) at room zylic alcohols were found to have any effect on the re-
temperature.
action. Both electron-donating groups, such as benzyl-
ic C H (Scheme 2, product 5f), aliphatic groups
À
Table 1. Screening of the reaction conditions.
(Scheme 2, products 5g and 5t) and phenylic residues
(Scheme 2, products 5h and 5i), and electron-with-
drawing groups, such as NO2 (Scheme 2, product 5r),
were well tolerated providing the desired esters in
good yields. Benzylic alcohol with carbonyl substitu-
ents like a ketone gave good results too (Scheme 2,
product 5k). The reaction carried out on alcohols with
halide substituents on the aromatic ring gave the cor-
responding esters, which could be further transformed
by traditional cross-coupling reactions (Scheme 2,
products 5l–q). We studied the reaction of benzylic al-
cohols with various primary and secondary alcohols.
Primary linear (Scheme 2, products 5a and 5b) and
branched aliphatic alcohols (Scheme 2, products 5c,
5f, 5h, 5m, 5o and 5q) furnished the corresponding
esters in satisfactory yields. Notably, more sterically
hindered secondary alcohols, such as cyclohexanol
(Scheme 2, product 5i) and heptan-3-ol (Scheme 2,
product 5p) were also suitable for delivering the cor-
responding esters.[17] Benzylic alcohols, which may
quickly oxidise to the corresponding aldehydes, in-
Entry
1a (mmol)
TCCA (mmol)
Yield [%][a]
1
2
3
4
5
6
2.0
1.1
1.1
1.1
1.1
1.1
3.0
3.0
2.0
1.1
1.1
1.1
97[b]
96[b]
95[b]
95[b]
[c]
–
–
[d]
[a]
Isolated yields.
[b]
[c]
[d]
Reaction performed at room temperature.
Reaction performed at 808C (MWI) for 2 h.
Reaction performed at 808C (MWI) for 4 h.
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Silvia Gaspa et al.
Scheme 2. Investigation of the substrate scope of the reaction.
stead reacted successfully providing the desired esters
(Scheme 2, products 5d, 5e, 5g and 5n). Alcohols with
unsaturation, such as (Z)-dec-6-en-1-ol, but-3-yn-1-ol
and prop-2-en-1-ol were also effectively employed in
this oxidative esterification (Scheme 2, products 5j, 5k
and 5l). We were delighted to notice that phenols,
which are weak nucleophiles, reacted successfully
(Scheme 2, products 5s and 5t).[18]
A possible reaction mechanism is reported in
Scheme 3. Alcohol A reacts with TCCA, generating
a hypochlorite compound B which readily loses hy-
drogen chloride to form the aldehyde C.[19] On the
basis of previously published papers, aldehyde C is
then converted into the acyl chloride D following
a radical pathway.[12,20] In the last step, the acyl chlo-
Scheme 3. A plausible reaction mechanism.
ride D reacts with alcohol E to give the corresponding the mechanistic details are currently underway in our
ester F.[21]
laboratory.
In conclusion, a novel example of metal-free cross
oxidative esterification of alcohols to esters is report-
ed. The transformation in situ of benzyl alcohols to
acyl chloride provides the methodology with a very
wide scope. Notably the methodology has an optimal
stoichiometric molar ratio of reactants, and makes use
of mild reaction conditions and cheap and easily
available reagents. In no case was the self coupling
Experimental Section
Heptyl Benzoate (5a); Typical Procedure
TCCA (0.256 g, 1.1 mmol) was portionwise added over
a period of 1–2 min to a solution of benzyl alcohol (0.119 g,
product formation observed. Additional studies on 1.1 mmol) in 3.25 mL dichloromethane under a dry argon at-
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Metal-Free Oxidative Cross Esterification of Alcohols
mosphere and at room temperature. The resulting suspen-
sion was stirred at room temperature for 5 days under dry
argon (the reaction was monitored by TLC until disappear-
ance of benzyl alcohol). Then the reaction mixture was
cooled to 08C, stirred under an inert atmosphere of dry
argon and heptanol (0.116 g, 1.0 mmol) was dropwise added
via syringe followed by dropwise addition of NEt3 (0.202 g,
2.0 mmol) and then DMAP (0.012 g, 10 mol%) at once.
After completion of the addition, the reaction mixture was
left to stir at room temperature until disappearance of the
heptanol (monitored by TLC, the reaction is usually com-
plete in about 1 h). Then the solvent was removed under
vacuum, and the residue purified by flash chromatography
(hexane/ethyl acetate=4.5/0.5). The expected ester 5a was
then obtained as a colorless oil; yield: 0.209 g (95%); Rf =
0.593 (hexane/ethyl acetate=4.5/0.5). 1H NMR (400 MHz,
CDCl3): d=8.05 (d, J=8.0 Hz, 2H), 7.54 (t, J=7.4 Hz, 1H),
7.43 (t, J=7.6 Hz, 2H), 4.31 (t, J=6.7 Hz, 2H), 1.80–1.73
(m, 2H), 1.48–1.26 (m, 8H), 0.89 (t, J=6.6 Hz, 3H);[22]
13C NMR (100 MHz, CDCl3): d=166.6, 132.7, 130.5, 129.5,
128.3, 65.1, 31.7, 28.9, 28.7, 26.00, 22.6, 14.0;[22] IR (neat):
n=2956, 2929, 2857, 2359, 2341, 1721, 1602, 1585, 1467,
1453, 1275, 1112, 1027, 711 cmÀ1.[2,3]
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Silvia Gaspa gratefully acknowledges Sardinia Regional Gov-
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(P.O.R. Sardegna F.S.E. Operational Programme of the Au-
tonomous Region of Sardinia, European Social Fund 2007–
2013-Axis IV Human Resources, Objective l.3, Line of Activ-
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