Straightforward synthesis of ethers: Metal-free reductive coupling of tosylhydrazones with alcohols or Phenols

Article abstract of DOI:10.1002/anie.201001704

(Figure Presented) Ethers made easy: Heating a solution containing a tosylhydrazone and either a phenol or an alcohol in the presence of K ₂CO₃ leads to the corresponding ethers (see scheme; MW=microwave, Ts=tosyl). The reaction is fairly general for the preparation of aryl alkyl and alkyl alkyl ethers, and represents a new method for the reductive etherification of carbonyl compounds.

Full text of DOI:10.1002/anie.201001704

Angewandte
Chemie
DOI: 10.1002/anie.201001704
Synthetic Methods
Straightforward Synthesis of Ethers: Metal-Free Reductive Coupling of
Tosylhydrazones with Alcohols or Phenols**
Josꢀ Barluenga,* Marꢁa Tomꢂs-Gamasa, Fernando Aznar, and Carlos Valdꢀs*
One approach to the design of sustainable synthetic routes is
to develop advantageous, alternative reactions to well-estab-
lished chemical transformations. Catalytic reactions are gen-
erally preferred in the context of sustainable chemistry;[1,2]
however, metal-catalyzed reactions may also present prob-
lems associated with the high cost of precious metals and
ligands, and the need to dispose of and eliminate the
sometimes toxic metals once the reaction has been com-
pleted. For this reason, metal-free reactions that could exhibit
the same levels of efficiency and selectivity as metal-catalyzed
reactions are highly desirable.
with silyl ethers in the presence of a hydride source and a
Lewis acid catalyst.[8] This type of chemistry could be suitable
for the preparation of unsymmetrical ethers not easily
available through the above-mentioned methods.
We have recently reported a new metal-free carbon–
carbon bond-forming reaction between tosylhydrazones and
boronic acids (Scheme 1a).[9] This reaction can be envisioned
The Williamson synthesis is the most typical method for
the preparation of ethers.[3] However, this reaction is limited
in that it requires hard bases, which reduces the functional
group tolerance of the method. Moreover, the scope of the
reaction is restricted by the need for good leaving groups, and
importantly, the sensitivity to steric bulk; therefore, the
synthesis of ethers derived from secondary and tertiary
alcohols is still a challenging problem. One alternative to
the Williamson ether synthesis is the condensation of alcohols
catalyzed by Brønsted or Lewis acids; however, this approach
is generally limited to the preparation of symmetrical ethers.
Selective methods have been developed, but require specific
combinations of alcohols, such as primary alcohols with
benzylic or allylic alcohols, to avoid the formation of
undesired symmetrical systems.[4] Among the methods for
the synthesis of ethers based on SN2 displacement reactions,
the Mitsunobo reaction is a powerful and widely employed
procedure for the synthesis of aryl alkyl ethers;[5] however, it
is not atom economical and is environmentally unfriendly
because of the need to use stoichiometric amounts of an
azodicarboxylate and a phosphine.[6] For all these reasons, the
development of general methodologies for the preparation of
ethers is still challenging.[7]
Scheme 1. a) Metal-free reductive coupling of tosylhydrazones and
boronic acids. b) Metal-free reductive etherification of tosylhydrazones
discussed in this work. Ts=tosyl.
as a very simple way to carry out a reductive coupling of a
carbonyl compound, a transformation of high synthetic
relevance. In continuing with our interest in metal-free
processes employing tosylhydrazones, the synthesis of ethers
by reductive etherification with alcohols or phenols emerged
as an attractive transformation to study (Scheme 1b). The
combination of the diazo compound generated from the
tosylhydrazone[10] with a hydroxylic compound would result
in the formation of an ether, through an insertion reaction of
[11]
À
the incipient carbene into the O H bond.
À
Although many O H insertion processes with phenols
have been reported before, most of the examples involve
diazo compounds stabilized by electron-withdrawing groups
such as diazo ketones or diazo esters.[12,13] Moreover, the
majority of the transformations are acid-[14] or transition-
metal-catalyzed reactions,[15] as well as photochemical trans-
formations.[16] Additionally, the thermal decomposition of
diazo compounds in the presence of alcohols is extremely
rare.[17–19]
A less popular approach for the synthesis of ethers is the
reductive coupling of carbonyl compounds. Most of these
methods involve the reaction of carbonyl or acetal groups
Taking all these aspects into consideration, we decided to
study in detail the reaction of tosylhydrazones with phenols
and alcohols for the purpose of developing a new, useful,
metal-free reductive etherification starting from carbonyl
compounds. First of all, we focused on the reactions with
phenols, which would lead to a new method for the synthesis
of aryl ethers, a structural motif present in a variety of
compounds having pharmaceutical activity.[20] To explore the
reactivity of the N-tosylhydrazones towards phenols we
selected the model reaction between the hydrazone derived
from p-tolyl methyl ketone (1a) and p-bromophenol (2a;
Table 1, entries 1–4).
[*] Prof. J. Barluenga, M. Tomꢀs-Gamasa, Prof. F. Aznar, Dr. C. Valdꢁs
Instituto Universitario de Quꢂmica Organometꢀlica
“Enrique Moles”
Universidad de Oviedo, c/Juliꢀn Claverꢂa 8, 33006 Oviedo (Spain)
Fax: (+34)98-510-3446
E-mail: barluenga@uniovi.es
acvg@uniovi.es
[**] This work was supported financially by DGI of Spain (CTQ2007-
61048/BQU) and Consejerꢂa de Educaciꢃn y Ciencia of Principado
de Asturias (IB08-088). A FPU predoctoral fellowship for M.T.-G.
from MCINN of Spain is gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201001704.
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4993

Communications
Table 1: Reductive coupling between tosylhydrazones 1 and phenols 2 by
conventional heating.[a]
Table 2: Influence of solvents and bases in the MW-promoted synthesis
of 3a by reductive coupling between hydrazone 1a and phenol 2a.[a]
Entry
Base
Solvent
Volume [mL]
Yield [%][b]
1
2
3
4
5
6
7
K3PO4
NaOH
LiOtBu
K2CO3
K2CO3
K2CO3
K2CO3
dioxane
dioxane
dioxane
dioxane
THF
1.5
1.5
1.5
1.5
1.5
1.2
1.5
65
38
–
72
68
64
78
Entry
Ether 3
Yield [%][b]
1
2
3
4
5
32[c]
55[d]
55[e]
74
PhF
PhF
83[f]
[a] Reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), base (3.5 equiv),
1558C, 1 h. The reactions were carried out in a Biotage Initiator
synthesizer at constant temperature. [b] Yield of the isolated ether 3a.
6
70
71
72
70
81
7[g]
8
resulted in an increased yield of 72%. A screen of solvents
and bases (Table 2) revealed that K2CO3 was the best base to
achieve the desired reaction (Table 2, entry 4). Moreover, we
were pleased to find that experiments performed in dioxane,
THF, or PhF proceeded with acceptable conversions and
yields (Table 2, entries 4, 5, and 7). The influence of the
temperature was also investigated and it was confirmed that
reactions run at 1558C gave the best results. These optimi-
zation studies concluded that the transformation could be
best achieved by employing the reaction conditions listed in
entry 7 of Table 2. Importantly, as in the conventionally
heated reactions, a 2:1 excess of phenol was found to deliver
the highest level of conversion. The MW-promoted reactions
are advantageous in this particular transformation when
compared to the reaction run using conventional heating: the
higher reaction temperature allowed the processes to take
place much faster, and in general, with slightly higher yields
(Table 1, entries 4, and 6–9 versus Table 3, entries 1–5).
The scope of the process was studied under the optimized
reaction conditions. The transformation proceeds very effi-
ciently with a wide range of tosylhydrazones derived from
aldehydes and ketones (Table 3). Therefore, hydrazones
conjugated with aromatic systems undergo reaction to
afford the desired products in high yields, regardless of their
steric or electronic nature (Table 3, entries 1, 7, 9, 10, and 15).
In the case of aliphatic substrates, the ethers are again formed
in good yields (Table 3, entries 11 and 12). Furthermore, the
transformation proceeds with cyclic hydrazones (Table 3,
entries 13 and 14). Moreover, the mixed acetal 3p could be
also prepared by using the MW procedure. We next evaluated
the diversity of substituted phenols that could be employed in
the reaction and found the reaction to be extremely general.
Both electron-withdrawing (Table 3, entries 1, 3, 4, and 5) and
electron-donating substituents (Table 3, entries 2 and 9), as
well as ortho-, meta-, and para-substitution patterns are well
tolerated (Table 3, entries 6, 2, and 3, respectively).
9
10[g]
[a] Reaction conditions: Tosylhydrazone
1 (0.3 mmol), phenol 2
(0.6 mmol), K2CO3 (3.5 equiv), dioxane (1 mL), 1108C, 24 h. [b] Yield
of isolated product. [c] Dioxane (2 mL), 1108C, 12 h. [d] Mesitylene
(2 mL) 1408C, 12 h. [e] Dioxane (2 mL) 1108C, 24 h. [f] Reaction was
carried out on a 25 mmol scale. [g] 1.2 mL of dioxane employed.
The first attempts gave encouraging results. The reaction
run in the presence of K2CO3 and using dioxane as the solvent
at 1108C afforded the aryl ether 3a in 32% yield (Table 1,
entry 1). Upon heating the reaction mixture at 1408C in
mesitylene an important increase in the yield from 32 to 55%
was observed (Table 1, entry 2). A similar yield was obtained
at 1108C when dioxane was used as the solvent and the
reaction time was doubled from 12 to 24 hours (Table 1,
entry 3). Finally, it was found that with 1 mL of solvent, the
reaction proceeded with substantially higher yield (Table 1,
entry 4).
The reaction conditions used for entry 4 of Table 1 were
applied to a series of phenols giving rise to the corresponding
aryl ethers 3 in good yields, regardless of the electronic nature
of the substituents on the phenol (Table 1, entries 6–9).
Interestingly, under these conditions the reaction can be
scaled up very efficiently. For instance, when the synthesis of
3a was conducted on a 25 mmol scale, the aryl ether was
obtained in an excellent yield of 83% (Table 1, entry 5).
Moreover, it should be highlighted that the use of a
hydrazonate derived from methyl benzoate (R1 = Ph, R2 =
OCH3)[21] furnished the mixed acetal 3p, which is difficult to
synthesize by other methods (Table 1, entry 10).
As expected, halogen-substituted phenols proved to be
suitable substrates, which lead to products that can undergo
additional transformations by metal-catalyzed cross-cou-
plings (Table 3, entries 1 and 6). The functional group
tolerance is noteworthy given that potentially sensitive
groups such as ester, aldehyde, nitro, and CF3 groups are
unaffected under the reactions conditions (Table 3, entries 3,
7, 4, and 5, respectively).
At this point, because of the high temperatures and long
reaction times required for the thermally induced O H
À
insertion, we decided to examine microwave (MW) irradi-
ation as an energy source to facilitate this chemical reaction.
As a first attempt, treatment of the hydrazone 1a with the
phenol 2a in dioxane at 1408C for one hour gave ether 3a in
63% yield, whereas performing the reaction at 1558C
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Angewandte
Chemie
Table 3: Microwave-promoted reductive coupling between tosylhydra-
zones 1 and phenols 2.[a]
phenol were added, and the mixture was then subjected to the
reaction conditions of the reductive coupling. The ether 3 was
isolated, although with a slight decrease in the yield
(Scheme 2).
Entry
t
[h]
T
[8C]
Vol.
[mL]
Ether 3
Yield
[%][b]
1
2
3
4
5
6
1
1
1
2
1
2
155
155
160
160
155
165
1.5
1.4
1.4
1.4
1.2
1.4
78
82
80
78
52
80
Scheme 2. MW-promoted one-pot reductive coupling.
At this point, we decided to investigate the alcohols as
suitable substrates for this transformation. Delightfully, the
reductive etherification could be also performed, although it
was necessary to slightly modify the reaction conditions.
Whereas an excess of the hydroxy source was necessary for
the insertion of phenols, for the insertion of alcohols the best
results were obtained with a 2:1 excess of the hydrazone.
As presented in Table 4, the reaction seems to be general
with regard to the structure of the alcohol, because primary,
secondary, tertiary, benzylic, and allylic systems led to the
corresponding products. Again, the unusual and appealing
mixed acetal 6 f (Table 4, entry 6) was obtained by this simple
reaction from the hydrazonate of methyl benzoate.
7
1
160
1.4
40
8
2
2
2
2
155
155
155
155
1.4
1.4
1.2
1.4
52
81
73
52
In summary, we have described a new procedure for the
synthesis of ethers by a formal reductive etherification of
9
À
carbonyl compounds. This metal-free C O bond-forming
10[c]
11
reaction proceeds through the base-promoted decomposition
of tosylhydrazones in the presence of phenols or alcohols, and
À
results in the insertion reaction of the carbene into the O H
bond. Notably, the starting materials are readily available and
stable; tosylhydrazones are readily synthesized from carbonyl
compounds and carbonyl substrates can be directly employed
in a one-pot fashion to generate the tosylhydrazone in situ.
Furthermore, the operational simplicity of the process and the
high functional group tolerance are remarkable. Taking into
account that the ether functionality is present in a number of
organic compounds, we believe that this methodology may
become a very useful tool in organic synthesis.
12[c]
2
155
1
70
13[c]
14
1
1
1
1
155
155
155
155
1.2
1.4
1.2
1.2
67
44
70
81
15
Received: March 22, 2010
Published online: June 2, 2010
16
Keywords: alcohols · ethers · ketones · phenols ·
tosylhydrazones
.
[a] Reaction conditions: Tosylhydrazone
1 (0.3 mmol), phenol 2
(0.6 mmol), K2CO3 (3.5 equiv), PhF (1–1.6 mL), 155–1658C, 1–2 h.
[b] Yield of isolated product. [c] Reaction conditions: Tosylhydrazone 1
(0.6 mmol), phenol 2 (0.3 mmol).
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Communications
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Alcohol 5
t
Ether 6
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[%][b]
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