N-Heterocyclic carbene-mediated redox condensation of alcohols

Article abstract of DOI:10.1039/c6cc04154j

N-Heterocyclic carbenes (NHCs) with a variety of oxidants promote the Mitsunobu-type coupling reactions of alcohols with phenols, carboxylic acids, and phthalimide. Experiments using a chiral alcohol indicate that these reactions proceed via S_N1 or S_N2 pathways depending on the polarity of the used solvents. The NHCs are consumed as reducing reagents to form their oxides as readily separable byproducts.

Full text of DOI:10.1039/c6cc04154j

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N-Heterocyclic Carbene-Mediated Redox Condensation of
Alcohols
Received 00th January 20xx,
Accepted 00th January 20xx
Terumasa Kato, Shin-ichi Matsuoka,* Masato Suzuki
DOI: 10.1039/x0xx00000x
www.rsc.org/
N-Heterocyclic carbenes (NHCs) with
a variety of oxidants
promote the Mitsunobu-type coupling reactions of alcohols with
phenols, carboxylic acids, and phthalimide. Experiments using a
chiral alcohol indicate that these reactions proceed
via SN1 or SN2 pathways depending on the polarity of the used
solvents. The NHCs are consumed as reducing reagents to form
their oxides as readily separable byproducts.
The Mitsunobu reaction1 is a synthetically useful redox
condensation2 of alcohols with pronucleophiles such as
phenols, carboxylic acids, thiols, and phthalimide (Scheme 1a).
Azodicarboxylates and phosphines have been generally used
as oxidants and reducing agents, respectively, but the
stoichiometric byproducts, hydrazine carboxylates and
phosphine oxides, are not easily removed from reaction
mixtures. To overcome such drawbacks and to expand the
reaction scope, a variety of the Mitsunobu protocols using
modified reagents3 and catalytic systems4 have been studied.
Alternative methods such as the Mukaiyama redox reaction,2,5
the sulfonyl transfer reaction,6 and the PhenoFluor-mediated
condensation7 have been also developed.
Scheme 1. Overview of redox reactions promoted by phosphines or NHCs
alcohol adduct is often used as a stable precursor. Wanzlick et
al. tried to prepare a NHC from the alcohol adduct of 1,3-
diphenylimidazolin-2-ylidene,12 and Enders et al. successfully
N-Heterocyclic carbenes (NHCs) have been widely used as
ligands for transition metal complexes and organocatalysts.8
NHCs have nucleophilic properties similar to phosphines, but
show a large number of the advantages in both ligand and
organocatalyst chemistries.8a In particular, the NHC-catalyzed
umpolung reactions of aldehydes9 and Michael acceptors10 via
nucleophilic (deoxy)-Breslow intermediates has been
extensively investigated. Among them, NHC catalysis under
oxidative conditions allows the formation of esters, amides,
and cyclic products from aldehydes, where a variety of
oxidants convert the key Breslow intermediates to acyl cation
equivalents11 (Scheme 1b). Since NHC is unstable under air, the
synthesized 1,2,4-triazol-5-ylidene NHC (A, in Table 1) by the
thermolysis of its air-stable alcohol adduct.13 In general, there
are equilibria between a free NHC with an alcohol, an NHC-
alcohol adduct, an azolium alkoxide, and an NHC-activated
alcohol (Scheme 1c).14 The alkoxide and the activated alcohol
serve as the intermediates for transesterifications14c, 15 and the
oxa-Michael addition.16 The adducts are interesting species
because of their relatively low thermodynamic stability.
However, the structure-stability relationship has not been
systematically studied, and there are no examples other than
the above-mentioned reactivities. Previously, we found the
transfer hydrogenation of activated unsaturated compounds
mediated by NHC and water.17 Given the many reactions
promoted by the oxidation of phosphines (e.g. Wittig reaction,
Staudinger reaction, and Appel reaction), this hydrogenation is
the first reaction of NHC as a reducing reagent to form the
NHC oxide. It should be noted that use of NHC as alternatives
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Table 1. Screening of oxidants using NHC Aa
Table 2. Reaction optimization using oxidant 2a
yield
yield
(%)b
entry
1
oxidant
entry
6
oxidant
(%)b
61
40
2
3
77
0
7c
54
temp
time yieldb
8
0
entry
NHC
base
solvent
(°C)
(h)
(%)
1
2
A
A
-
1,4-dioxane
THF
80
65
80
80
80
80
60
0
8
8
79
51
60
44
89
68
64
0
4
5
14
9d
11
0
-
3
A
-
toluene
1,2-dichloroethane
CH3CN
8
4
A
-
8
5
A
-
8
< 5
10
No oxidant
6
A
-
-
CH3CN
4
7
A
CH3CN
24
48
8
aReaction conditions, 4-cyanophenol; 0.22 mmol, n-butanol; 0.65 mmol, A;
0.24 mmol, oxidant; 0.24 mmol, 1,4-dioxane; 0.6 mL. bIsolated yield. c2.0
equiv of 8. d5.0 equiv. of 11.
8
A
-
CH3CN
9c
10
11
12
13
A
-
CH3CN
80
80
80
80
80
80
16
62
0
B
K2CO3
K2CO3
K2CO3
DIEAd
CH3CN
12
12
12
12
C
CH3CN
D-J
B-J
CH3CN
to phosphines is expected to lead to reaction discovery.
Herein, we report that the redox couple of NHC and an
oxidant promotes the Mitsunobu-type condensation of
alcohol with pronucleophiles such as phenols, carboxylic acids,
CH3CN
0
aReaction conditions, 4-cyanophenol; 0.22 mmol, n-butanol; 0.65 mmol, NHC ;
0.24 mmol, 2; 0.24 mmol, base; 0.24 mmol, solvent; 0.6 mL. bIsolated yield. 1.0
c
equiv. of n-butanol. dDIEA; N,N-diisopropylethylamine.
and phthalimide (Scheme 1c)
.
We initially focused on the synthesis of alkyl aryl ethers.
They are generally synthesized by the Williamson reaction or
transition metal-catalyzed reactions18,19 of environmentally
unfriendly halogenated reagents under highly basic conditions.
In this respect, the direct coupling reactions of alcohols with
phenols under neutral conditions by a Mitsunobu protocol are
quite attractive. We first investigated the redox condensation
of n-butanol with 4-cyanophenol by 1.1 equiv. of isolated NHC
sterically less hindered benzoquinones
3 and 4 proved to be
ineffective probably because of their side reactions with the
NHC (entry 3). A wide range of oxidants, such as nitrobenzene
(
5),
azobenzene
(
6),
phenazine
(
7),
2,2,6,6-
tetramethylpiperidine 1-oxyl free radical (TEMPO) (
8), and the
heterogeneous oxidant of MnO2 (11), afforded the product in
low to moderate yields (entries 4-7, and 9). The oxidants other
than
1 are inapplicable to the classical Mitsunobu reaction,
A
and 1.1 equiv. of various oxidants
°C for 12 h (Table 1). The use of diisopropyl azodicarboxylate
(DIAD) ( ), a common oxidant for the Mitsunobu reaction,
provided 4-butoxybenzonitrile in 61% yield (entry 1) and the
NHC oxide ( ) as a byproduct. This indicates that, similar to
1-11 in 1,4-dioxane at 100
because it is initiated by the nucleophilic attack of phosphines
to azodicarboxylates (Scheme 1a). Thus, this protocol using
NHC shows the advantage for the scope of oxidants, and this
condensation has a different mechanism from phosphine-
promoted counterpart (vide infra).
1
K
phosphines, the NHC can act as a reducing reagent for the
Mitsuinobu reaction. It is noteworthy that a variety of oxidants
can be employed, which is similar to the oxidation of the
Breslow intermediates.11 A tetrasubstituted diphenoquinone,
We then screened the solvents, reaction temperatures,
and NHCs, constantly using
2 as an oxidant (Table 2 and Table
S1 in Supporting Information). When a series of solvents such
as tetrahydrofuran, toluene, 1,2-dichloroethane, and
3,3',5,5'-tetra-t-butyl-4,4'-diphenoquinone (2) was found to be
acetonitrile were tested using NHC
A (entries 1-5), the reaction
the most effective oxidant to give the product in 77% yield
(entry 2). However,
in acetonitrile at 80 °C for 8 h afforded the product in the
highest isolated yield (89%, entry 5). Decreasing either the
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Scheme 3. Esterifications using NHC
A and oxidant 2.
Scheme 4. N-Alkylation of phthalimide using NHC A and oxidant 1.
Scheme 2. Substrate scope using NHC
A .
and oxidant 2a
reaction temperature or time led to the lower yields (entries 6-
8). However, decreasing the amount of n-butanol from 3 eq. to
1 eq. gave an almost comparable yield (entry 9). The
Ph
OH
O
2
A
Ph
CN
CN
1.1 equiv.
1.1 equiv.
HO
precursors of 1,2,4-triazol-5-ylidene NHCs,
also gave the product in 16% and 62% yields, respectively
(entries 10 and 11), while the other NHC precursors ( ), such
as imidazolium and thiazolium salts, were ineffective. In
entries 5 and 11, the corresponding NHC oxides, and , were
B or C, with K2CO3
toluene or CH3CN
80 °C, 48 h
90% ee
36% isolated yield, 90% ee
(in toluene)
2.0 equiv.
14% isolated yield, 54% ee
(in CH3CN)
Scheme 5. Condensation of (R)-(+)-1-phenylethyl alcohol in toluene or
D-J
acetonitrile.
K
L
isolated in 80% and 62% yields, respectively, which were
comparable to those of the produced ether. It is noteworthy
that
K and L were precipitated in the reaction mixture and
readily separated by filtration.
With better reaction conditions in hand, the substrate
scope was examined (Scheme 2). The corresponding ethers
were produced in moderate-to-high isolated yields from
various alcohols, such as isopropyl, benzyl, 4-bromobenzyl, 2-
phenylethyl, allyl, propargyl alcohols, while no product was
obtained from tert-butyl alcohol. Some phenols bearing
electron-withdrawing groups, such as ketones and esters, at
the para position are suitable substrates, giving the products in
96% and 89% yields, respectively. Other phenols such as 2-
cyanophenol,
4-bromophenol,
4-methoxyphenol,
4-
phenoxyphenol and 3-cresol resulted in low-to-moderate
yields.
We then expanded the scope of this redox reaction.
Esterifications of carboxylic acids as pronucleophiles were
Scheme 6. Proposed mechanism
promoted by NHC
A with oxidant 2. (Scheme 3, Table S2 in
Supporting Information). In a sealed vial under microwave
irradiation at 120 °C for 8 h, the corresponding esters were
obtained in moderate yields from propionic, benzoic, 4-
cyanobenzoic, and 3,5-dimethoxy benzoic acids. This redox
protocol also allows the N-alkylations of phthalimide (Scheme
4), the products of which are important precursors for the
phthalimide by the zwitterionic intermediate derived from
and
To clarify the reaction mechanism, reactions using chiral
A
1.
alcohol were performed (Scheme 5). The reaction of 2-
cyanophenol with (R)-(+)-1-phenylethyl alcohol (90% ee) in
toluene at 80 °C for 48 h afforded the condensation product
with complete inversion of configuration (90% ee). Although
the yields and conversions are less than moderate because of
the bulkiness of the two substrates, the optical purity of the
produced ether derived from 2-cyanophenol can be readily
analysed by HPLC. Use of a polar solvent, acetonitrile, induced
Gabriel amine synthesis. The combination of NHC
not effective in this case, but use of oxidant
A
and
2 was
1
instead of
2
enabled the reactions of phthalimide with n-butyl, benzyl, and
isopropyl alcohols to give the corresponding N-alkylated
products in good yields through the deprotonation of
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6
7
8
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the partial racemization of the product with 81% inversion
(54% ee). These results suggest the reaction mechanism in
Scheme 6. The NHC reacts with the alcohol to generate alcohol
adduct
II by
mono anion of
I
, which is subsequently oxidized into triazolium cation
through the hydride transfer. The generated bulky
2’) can deprotonate 2-cyanophenol. The
2
Hahn and M. C. Jahnke, Angew. Chem. Int. Ed., 2008, 47
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2
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the final step of a typical Mitsunobu reaction, where the
phosphonium undergoes the nucleophilic attack (Scheme 1a).
The polar solvent acetonitrile causes the cleavage of the O-C
bond of intermediate II to some extent to generate benzyl
cation III and the NHC oxide. The SN1 reaction of 2-
cyanophenol with III affords the racemized product.
9
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condensation of primary and secondly alcohols with various
phenols, carboxylic acids and phthalimide by the redox couple
of 1,2,4-triazol-5-ylidene NHCs and oxidants. The reaction
mechanism uniquely involves the oxidation and nucleophilic
substitution20 processes. In contrast to the classical Mitsunobu
reaction, 1) the reducing reagents, NHCs, act as a Brønsted
,
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base, 2)
a
wider range of oxidants, such as an
azodicarboxylate, a diphenoquinone, and TEMPO, can be used,
and 3) the byproducts, NHC oxides, are more readily removed.
Following our previous report,17 this is the second example in
which the NHCs work as the reduction agent. We believe that
NHC has further potential as a useful alternative in various
redox reactions.
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,
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