N-Heterocyclic carbene (NHC) catalyzed chemoselective acylation of alcohols in the presence of amines with various acylating reagents

Article abstract of DOI:10.1039/c3sc00099k

This edge article reports the synthesis and full characterization including X-ray analysis of three different acylazolium ions. The reactivity of these acylazolium ions as acylating reagents of amines and alcohols is discussed. Whereas benzylamine slowly reacts with the acylazolium ions, benzyl alcohol acylation does not occur. However, upon activation of the alcohol with an N-heterocyclic carbene (NHC) as catalyst, efficient esterification is achieved. Importantly, benzylester formation is obtained in the presence of benzylamine upon selective alcohol activation by the NHC. High level DFT calculations reveal that alcohol activation occurs by strong H-bond formation between the NHC and the alcohol thereby increasing the nucleophilicity of the alcohol. For oxidatively generated acylazolium ions under NHC catalysis, the carbene has a dual role (cooperative catalysis): (a) the NHC is used for generation of the acylazolium ion and (b) the NHC is used for activation of the alcohol in the subsequent acylation step. NHC-catalyzed selective acylation of benzyl alcohol in the presence of benzylamine can also be achieved with trifluoroethyl and hexafluoroisopropylesters as acylation reagents. Moreover, an enol acetate also shows high O-selectivity as a chemoselective acetylation reagent. Kinetic and mechanistic studies are provided and some examples of the chemoselective acylation of amino alcohols are presented.

Full text of DOI:10.1039/c3sc00099k

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EDGE ARTICLE
N-Heterocyclic carbene (NHC) catalyzed chemoselective
acylation of alcohols in the presence of amines with
various acylating reagents†
Cite this: DOI: 10.1039/c3sc00099k
a
a
a
b
*
¨
Ramesh C. Samanta, Suman De Sarkar, Roland Frohlich, Stefan Grimme
and Armido Studer
a
*
This edge article reports the synthesis and full characterization including X-ray analysis of three different
acylazolium ions. The reactivity of these acylazolium ions as acylating reagents of amines and alcohols is
discussed. Whereas benzylamine slowly reacts with the acylazolium ions, benzyl alcohol acylation does
not occur. However, upon activation of the alcohol with an N-heterocyclic carbene (NHC) as catalyst,
efficient esterification is achieved. Importantly, benzylester formation is obtained in the presence of
benzylamine upon selective alcohol activation by the NHC. High level DFT calculations reveal that
alcohol activation occurs by strong H-bond formation between the NHC and the alcohol thereby
increasing the nucleophilicity of the alcohol. For oxidatively generated acylazolium ions under NHC
catalysis, the carbene has a dual role (cooperative catalysis): (a) the NHC is used for generation of the
acylazolium ion and (b) the NHC is used for activation of the alcohol in the subsequent acylation
step. NHC-catalyzed selective acylation of benzyl alcohol in the presence of benzylamine can also be
achieved with trifluoroethyl and hexafluoroisopropylesters as acylation reagents. Moreover, an enol
acetate also shows high O-selectivity as a chemoselective acetylation reagent. Kinetic and mechanistic
studies are provided and some examples of the chemoselective acylation of amino alcohols are
presented.
Received 11th January 2013
Accepted 4th March 2013
DOI: 10.1039/c3sc00099k
www.rsc.org/chemicalscience
In the literature we found only a few examples of the
selective O-acylation of amino alcohols. Some lipases are able
Introduction
Protecting groups (PG) are highly important in complex natural
product synthesis.1 Although an ideal synthesis asks for a pro-
tecting-group-free approach,2 in most cases the use of PGs is
unavoidable. Therefore, we regard the development of novel
protecting group strategies as important. It is well known that
amines are far better nucleophiles than alcohols.3 Selective
acylation of an alcohol in the presence of an amine has gener-
ally to be conducted via amine protection, alcohol acylation
followed by amine deprotection (three-step protocol, Scheme 1).
The highly challenging direct acylation of the less reactive
alcohol in a one-step approach is far more economically valu-
able but highly challenging.
to acylate the hydroxymethyl group in serine-containing
dipeptides bearing free NH2-termini4 and highly chemo-
selective acylation of amino alcohols via transesterication was
recently achieved using a tetranuclear zinc cluster as catalyst.5
We report herein our ndings on the N-heterocyclic carbene
(NHC) catalyzed acylation of alcohols in the presence of
amines using various acyl donors.6 NHCs7,8 have been shown to
activate alcohols in transesterications,9 for conjugate addi-
tions,10,11 in domino cyclizations of propargyl alcohols with
isocyanates,12 and in ring-opening polymerizations of
lactones.13
a
¨
Organisch-Chemisches Institut and NRW Graduate School of Chemistry, Westfalische
¨
¨
Wilhelms-Universitat, Corrensstraße 40, 48149, Munster, Germany. E-mail: studer@
uni-muenster.de; Fax: +49 251 83-36523; Tel: +49 251 83-33291
bMulliken Center for Theoretical Chemistry, University of Bonn, Beringstr. 4, D-53115,
Bonn, Germany. E-mail: grimme@thch.uni-bonn.de; Fax: +49 0228 73-9064; Tel: +49
0228 73-2351
† Electronic supplementary information (ESI) available: Experimental section,
reaction kinetics, theoretical methods and NMR spectra. CCDC 919089 and
919090. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c3sc00099k
Scheme 1 O-Acylation of amino alcohols via a three-step or a one-step strategy.
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Results and discussion
Acylation with various acylazolium ions
We recently communicated the oxidative chemoselective ester-
ication of various amino alcohols with cinnamaldehyde using
oxidative NHC-catalysis (Scheme 2).6,14,15 The inexpensive 1,3-
dimethyltriazolium iodide was used as a precatalyst and DBU
was added for in situ carbene generation. These processes have
been conducted with the readily available mild organic oxidant
1 (ref. 16 and 17) and esters 2a–g were isolated in good to
excellent yields with complete chemoselectivity. The corre-
sponding amides derived from N-acylation were not identied.
Acylazolium salt 3 formed via oxidation of the corresponding
Breslow-intermediate acts as the acylating reagent in these
chemoselective esterications.
Scheme 3 Preparation of 5a and 5b and application of N,N0-dimethylimidazo-
lium iodide as an NHC precursor for oxidative esterification.
In order to study the reactivity of such acylazoliums we
prepared three derivatives of 3 and analyzed their reactivity as
stoichiometric acylating reagents. Lithiation of N-methylimid-
azole was achieved with n-BuLi in THF at ꢀ78 ꢁC in the presence
of TMEDA. Addition of methyl benzoate, methyl 3-phenyl-
propionate or methyl cinnamate afforded the ketones 4a, 4b
and 4c in good yields (Scheme 3).18 N-Methylation with MeOTf
in Et2O at room temperature and purication by recrystalliza-
tion eventually provided acylazolium salts 5a, 5b and 5c. Prep-
aration of 5c was recently reported.14g
Aminocyclohexanol was esteried with benzaldehyde under
oxidative conditions and 2h was isolated in 90% yield with
complete chemoselectivity. Compared to the 1,3-dimethyl-
triazolidene, the imidazolidene was less reactive and a higher
catalyst loading had to be used (10 mol%). NaH (30 mol%) was
applied as a base due to the lower acidity of the N,N0-dimethy-
limidazolium iodide compared to the triazolium salt. Never-
theless, this result clearly reveals that the dimethylimidazole
derived acylazolium ion 5a shows the same chemoselectivity as
the corresponding triazolium derived congeners and therefore
the acylating reagents 5a–c are adequate model compounds to
study the reactivity for acylazolium ions of type 3.
To check whether imidazolium salts of type 5 are adequate
model compounds for acylating reagent 3, we tested the N,N0-
dimethylimidazolium iodide as a catalyst precursor in a che-
moselective oxidative esterication reaction. trans-4-
We also obtained crystals of 5a and 5b suitable for X-ray
analysis (Fig. 1). The structure of 5c was recently reported by
us.14g,19 In 5b, the plane of the heterocycle is nearly coplanar
with the carbonyl p-system (angle O9C8C1N5 ¼ 2.8ꢁ) thereby
ideally activating the carbonyl group towards nucleophilic
attack. In contrast, the CO p-bond and the imidazolium plane
in phenylacylazolium 5a are twisted (angle O1C6C2N3 ¼ 29.8ꢁ).
Moreover, the carbonyl p-system and the phenyl plane are also
twisted by 34.0ꢁ (angle O1C6C7C8) for steric reasons. In the
conjugated acylazolium salt 5c, the CC and CO double bonds
are almost coplanar (angle C8C7C6O1A ¼ 6.2ꢁ) but the imida-
zolium plane and the carbonyl p-system (angle O1AC6C2N5 ¼
33.5ꢁ) are twisted. Bond lengths of the CO double bonds are
similar in all three structures (5a: 121 nm; 5b: 121 nm; 5c:
122 nm).
We then studied the reaction of 5a with benzyl alcohol (1.5
equiv.) and/or benzylamine (1.5 equiv.) in the absence or in
the presence of the free carbene, IMes (1,3-bis(2,4,6-trime-
thylphenyl)imidazol-2-ylidene, 1 equiv. or 0.2 equiv.).20 Reac-
tions were conducted in an NMR tube at room temperature in
THF-D8 (Table 1). In the absence of free carbene, no reaction
with BnOH was observed (entry 1). However, upon adding
IMes (1 equiv.) esterication was completed within the time
necessary to transfer the sample into the NMR probe and to
record the spectrum (less than 7 min) clearly documenting the
activating effect of IMes on this process (entry 2). Note that
IMes did not react with 5a. Using 0.2 equiv. of IMes, the
Scheme 2 Chemoselective O-acylation of amino alcohols via oxidative NHC
catalysis.
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dimethylimidazolidene generated during reaction mediated
esterication in that case. Indeed, repeating the experiment in
the presence of IMes (1 equiv.) provided benzyl benzoate with
complete chemoselectivity (entry 6). IMes loading could be
reduced to 0.2 equiv. at 60 ꢁC without decreasing selectivity
(entry 7). Hence, 5a reacts slowly without the help of free
carbene with benzylamine whereas reaction with the less
reactive benzyl alcohol has to be catalyzed by a free carbene. If
the carbene is present in the solution, selective esterication
occurred in the presence of amine.
The effect of the structure of the azolium ion on the
acylation reaction was investigated next. To this end, esteri-
cation was performed at room temperature with benzyl
alcohol (1 equiv.) using a 1 : 1 : 1 mixture of the three acyla-
zolium ions (5a, 5b and 5c, 2 equiv. each) in the presence of
IMes (1 equiv.) in THF-D8 and selectivity was determined
using 1H NMR spectroscopy. The benzoylazolium 5a was the
most reactive reagent in this series (3.3 times more reactive
than 5b and 4.3 times more reactive than 5c). As can be seen
in the X-ray structure of 5a, the phenyl ring is not in conju-
gation with the carbonyl group which leads to a higher
reactivity likely due to the inductive effect despite the more
efficient steric shielding by the phenyl group. The lower
reactivity of the cinnamoyl derivative 5c with respect to 5b
can be explained by the conjugation of the styrene moiety
with the carbonyl group. Moreover, in 5b in contrast to 5c the
activating imidazolium ring is nearly perfectly coplanar with
the carbonyl p-bond, thereby activating the electrophile
towards nucleophilic attack.
To elucidate the activation mode of the carbene in these
acylation reactions, we studied the interaction of 1,3-dimethyl-
triazolidene, that was successfully applied in the catalytic
process (see Scheme 1), with methylamine and methanol using
computational chemistry. Quantum chemical calculations on
NHC–MeNH2 and NHC–MeOH H-bonded complexes were per-
formed (for details see the ESI†). Interaction energies (kcal
Fig. 1 Molecular structures of acylazoliums 5a (top), 5b (middle) and 5c
(bottom).
reaction was signicantly slower and at higher temperature molꢀ1) at the B97-D/TZVPP21 and MP2/CBS levels employing the
(60 ꢁC) quantitative conversion was achieved (entry 3, 24 h). B97-D optimized structures are presented in Fig. 2. For
Reaction of 5a with benzylamine occurred smoothly at rt (1 h, comparison, the values with NH3 as H-acceptor were calculated
entry 4). Interestingly, benzoylation of a mixture of benzyl- (MeOH–NH3: ꢀ7.2 (B97-D) and ꢀ7.1 (MP2); MeNH2–NH3: ꢀ3.5
amine and benzyl alcohol (1.5 equiv. each) in the absence of (B97-D) and ꢀ3.4 (MP2)). We found strong H-bonding for NHC–
IMes for 2 h provided benzyl benzamide (25%) and benzyl MeOH with a dissociation energy of ꢂ11 kcal molꢀ1 and large
benzoate (75%, entry 5). Since esterication occurred only in elongation of the OH bond.22 In agreement with the calcula-
the presence of free carbene, likely the N,N0- tions, NMR-experiments revealed that methanol is not
Table 1 Acylation with 5a
Entry
BnOH (equiv.)
BnNH2 (equiv.)
IMes (equiv.)
PhCO2Bn
PhCONHBn
1
1.5
1.5
1.5
—
1.5
1.5
1.5
—
—
—
1.5
1.5
1.5
1.5
—
—
—
—
—
>99%
25%
—
2
1.0
0.2
—
—
1.0
0.2
>99%
>99%
—
75%
>99%
>99%
3a
4
5
6
7a
—
a
Reaction conducted at 60 ꢁC.
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the uncatalyzed background amidation (kabmg ide) and the cor-
responding catalyzed process (kacamtide).
Upon changing the concentration of the carbene precursor
in the catalytic reaction, the amount of free carbene in the
reaction mixture will be changed accordingly. Based on the
performed reactivity studies of acylazolium ions towards alco-
hols (see Table 1) the uncatalyzed background esterication
with the bulky isopropanol should not occur (kebsgter is very small
and the process negligible). Hence, lowering the initial
concentration of the triazolium salt should lead to a lowering of
the ester–amide ratio because the uncatalyzed amide selective
reaction with kabmg ide will contribute to a larger extent. In fact, the
ester–amide ratio increased from 1.80 : 1 to 2.17 : 1 on going
from 0.5 to 2.5 mol% triazolium precatalyst (0.5 mol%: 1.80 : 1
(24% combined yield); 1 mol%: 1.99 : 1 (56%); 1.5 mol%:
2.09 : 1 (73%); 2 mol%: 2.16 : 1 (79%); 2.5 mol%: 2.17 : 1
(73%)). The change of the ester–amide ratio fully supports our
suggestion that a second equivalent of free carbene is involved
in the product determining acylation step.24 Moreover, we also
proved that PhCH]CHCO2iPr does not react with allylamine
under the applied conditions showing that the ester–amide
ratio measured reects the kinetic product ratio.
Fig. 2 DFT structures (B97-D/TZVPP) of NHC–MeOH (left) and NHC–MeNH2
complexes (right), and the binding energies (kcal molꢀ1). Intermolecular CH, CO,
˚
CN distances are given in A. Changes of OH, NH lengths relative to free MeOH and
MeNH2 are given in italics (positive means elongation).
deprotonated by IMes. We did not identify any signal for the
protonated carbene. In contrast, phenols are readily deproto-
nated by IMes.23
The calculated gas phase structure of the NHC–MeOH
complex agrees well with an X-ray structure of a similar
complex.9 Moreover, good agreement between DFT and MP2
levels was noted. With MeNH2, the binding energy is halved. A
similar picture was calculated for NH3 as an H-acceptor. Specic
interactions of the carbene with the H-donor can therefore be
excluded and results reect basicity of the carbene as compared
to the amine.
Based on these theoretical studies we suggest that the
chemoselectivity in these acylation reactions is achieved by
selective activation of the alcohol by strong H-bonding with
the NHC which leads to an increase of the nucleophilicity of
the alcohol. Hence in the acylation step two carbenes are
involved. To further support this mechanism we conducted
kinetic experiments and analyzed for second order depen-
dence of the overall rate with respect to the carbene concen-
tration. However, since acylation is likely not the rate
determining step in these oxidative esterications, the second
order rate constant with respect to the NHC should not be
observed. Indeed, the kinetic experiments revealed rst order
dependence of the overall rate with respect to the NHC
concentration under catalytic conditions (see ESI†). Moreover,
we found zero order dependence of the overall rate with
respect to the alcohol concentration (conducted under the
typical conditions used in catalysis with 2 mol% NHC catalyst
and 37 or 62 equivalents of MeOH, see ESI†). These kinetic
studies show that the acylation step is not the rate limiting
step in the catalytic cycle.
Based on the experimental results and on the theoretical
studies we conclude that activation of the alcohol occurs by
strong H-bonding of the alcohol with the NHC. For oxidatively
generated acylazolium ions under NHC catalysis (see Scheme 2),
the carbene acts as a cooperative catalyst and has a dual role:
(a) the NHC is used for generation of the acylazolium ion and (b)
the NHC is used for activation of the alcohol in the subsequent
acylation step.
Other acylation reagents for chemoselective esterication
The experimental and theoretical results indicated that the key
for successful selective O-acylation of amino alcohols is a result
of the selective activation of the alcohol and not caused by the
intrinsic reactivity of the acylazolium ion. Therefore, we
assumed that other acylating reagents, which show low reac-
tivity towards amines (slow background amidation), should be
To experimentally prove that a second carbene is involved
in the acylation step under catalytic conditions, we investi-
gated the oxidative esterication of cinnamaldehyde in the
presence of iPrOH and allylamine. For this particular pair of
nucleophiles we found that selectivity for ester (PhCH]
CHCO2iPr) formation is not complete. A signicant amount of
amide PhCH]CHCONHCH2CH]CH2 was formed under
standard conditions and the ester–amide selectivity was
readily measurable via gas chromatography. PhCH]CHCO2iPr
ester
can be formed via background reaction of 3 with iPrOH (k
)
bg
ester
and via the carbene catalyzed process with k
according to
cat
the kinetic equation depicted below. Amidation can occur via Fig. 3 Various acylating reagents studied.
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eligible for NHC-catalyzed chemoselective O-acylation of alco- occurred with high chemoselectivity at room temperature
hols in the presence of amines. We therefore included tri- (entry 15). The thioester 8 is the least reactive reagent in this
uoromethyl benzoate 6a, hexauoroisopropyl benzoate 6b, series and even in the presence of IMes only little conversion
ester 6c, enol acetate 7 and thioester 8 in our studies (Fig. 3).25 was achieved (entries 16 and 17).
The enol acetate is commercially available and the uorinated
We also studied the relative reactivity of the benzoylating
esters were readily prepared from benzoylchloride or reagents 5a, 6a, and 6b towards esterication by conducting
PhCH2CH2COCl and the corresponding alcohol in the presence competition experiments. To this end, two different acylating
of NEt3 (see ESI†). Thioester 8 was obtained by analogy using reagents (2 equiv. each) were mixed in THF-D8 in the pres-
ethyl mercaptan.
ence of BnOH (1 equiv.) and IMes (1 equiv.) at room
Acylation studies were performed with benzyl alcohol (1.5 temperature. Reactions were allowed to run till quantitative
equiv.) and/or benzylamine (1.5 equiv.) in the absence or in the conversion and the relative reactivity was estimated based on
presence of IMes in THF at room temperature for 24 h. Reac- consumed acylating reagent using 1H NMR spectroscopy.
1
tions were either followed by H NMR spectroscopy or by gas Since experiments were not performed under pseudo rst
chromatography (Table 2).
order conditions with respect to the benzoylating reagents,
Benzyl alcohol did not react with 6a at room temperature ratios given do not correspond to relative ratios of the abso-
(entry 1). However, upon addition of IMes (10 mol%) quanti- lute rate constants of the two reactions considered. In the
tative transesterication occurred within 24 h (entry 2). At competition experiment between 6a and 6b, the latter (6b)
lower catalyst loading (2.5 mol%), complete benzoylation was underwent transesterication with complete selectivity.
achieved at higher temperature (60 ꢁC, entry 3). At room Competition of 5a with 6a afforded exclusively the 5a-derived
temperature, benzylamine was not acylated (entry 4). Pleas- ester and 5a underwent selective reaction also in the presence
ingly, IMes-catalyzed benzoylation of benzyl alcohol in the of 6b. These results are in agreement with the fact that both
presence of benzylamine with 6a occurred with complete 5a and 6b underwent room temperature amidation in the
chemoselectivity and benzyl benzoate was quantitatively reaction with benzylamine (see Table 1, entry 4 and Table 2,
formed (entry 5). The same reactivity was also obtained with entry 9). Hence an ideal reactivity window for stoichiometric
the aliphatic active ester 6c (entry 11). As expected, the hexa- chemoselective acylating reagents exists. The borders are set
uoroisopropyl ester 6b is more reactive than 6a and a slow by ester 6b (too reactive) and the thioester 8 (not reactive
background reaction with benzylamine was observed (entry 9). enough) and in this regard we consider triuoroethyl ester 6a
However, transesterication only occurred upon activation of and enol acetate 7 as the most valuable stoichiometric acyl-
benzyl alcohol with IMes (entries 6–9). Due to the competing ation reagents for this purpose. However, upon selective
background amidation, chemoselectivity was not complete activation of the alcohol, chemoselective esterication in the
with 6b as the acylating reagent (entry 10). Enol acetate 7 did presence of amines can also be achieved with the more
not acetylate BnOH at room temperature (entry 12), but reactive reagents 5a–c and 6b.
quantitative esterication was achieved using IMes (10 mol%)
as catalyst (entry 13). We observed a slow background reaction
of benzylamine with 7 (entry 14). However, the IMes catalyzed
acetylation of benzyl alcohol in the presence of the amine
Kinetics of the reaction of triuoroethyl ester 6a with
HO(CH2)2O(CH2)2OEt in the presence of IMes
We investigated the benzoylation of HO(CH2)2O(CH2)2OEt (10
equiv.) with 6a in THF-D8 to give PhCO2(CH2)2O(CH2)2OEt in
Table 2 Acylation with various acylating reagents
Entry NuH Reagent IMes (mol%) Ester Amide
the presence of IMes at different carbene concentrations (0.15,
0.18, 0.23 and 0.29 equiv.) at ꢀ20 C. Reactions were followed
ꢁ
by 1H NMR spectroscopy. Since H-bonding of the NHC with
the alcohol is strong (see above) and since the alcohol was
used in a large excess with respect to the NHC, we assume
that all of the “free” NHC is H-bonded with HO(CH2)2O-
(CH2)2OEt (equilibrium of NHC and ROH to form NHC–HOR
lies completely on the right side). From the exponential decay
of 6a, the pseudo-rst-order rate constants kobs (Mꢀ1 sꢀ1) were
obtained for the different carbene concentrations ([NHC–
HOR] remains constant, see ESI†). The plot of kobs versus the
concentration of IMes was linear (Fig. 4). This proves that
transesterication is rst order with respect to IMes and
validates our picture of the alcohol activation by a carbene
moiety, as suggested above (see calculations).26 The slope of
the linear plot of kobs with [NHC] (equal to [NHC–HOR H-bond
complex]) gave the second-order rate constant k ¼ 1.8 ꢃ 10ꢀ2
Mꢀ1 sꢀ1 for the reaction of the IMes–HO(CH2)2O(CH2)2OEt
H-bonded complex with 6a.
1
BnOH
BnOH
BnOH
BnNH2
6a
6a
6a
6a
—
10
2.5
—
10
—
10
2.5
—
10
10
—
10
—
10
—
10
—
—
—
—
—
—
—
—
—
42%
26%
—
—
—
45%
—
—
2
>99%
>99%
—
>99%
—
75%
76%
—
65%
>99%
—
3a
4
5
6
BnOH/BnNH2 (1/1) 6a
BnOH
BnOH
BnOH
BnNH2
BnOH/BnNH2 (1/1) 6b
BnOH/BnNH2 (1/1) 6c
BnOH
BnOH
BnNH2
BnOH/BnNH2 (1/1)
BnOH
6b
6b
6b
6b
7
8a
9
10
11
12
13
14
15
16
17a
7
7
7
7
8
8
>99%
—
>99%
—
BnOH
25%
—
a
Reaction conducted at 60 ꢁC.
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Therefore, the chemoselectivity obtained for alcohol acetylation
in the presence of an amine (see Table 2, entry 15) is likely
caused by deprotonation of the alcohol and not by NHC acti-
vation of the alcohol.
NHC catalyzed chemoselective acylation of amino alcohols
either with 6a or with benzaldehyde under oxidative
conditions
To document the potential of 6a as a chemoselective O-acylation
reagent, we conducted acylations of various amino alcohols (1 to
1.5 equiv.) with 6a (1 to 1.2 equiv.) at room temperature in THFfor
24 h by using IMes as a catalyst (10 mol%, method A, Scheme 5).
Results are compared with those obtained for chemoselective
benzoylation of the same amino alcohols with benzaldehyde
using oxidative carbene catalysis with IMes as catalyst (method
B). These oxidative esterications were conducted on various
amino alcohols (1.5 equiv.) with 3 mol% of IMes, benzaldehyde (1
equiv.) and 1 equiv. of oxidant 1 in THF at rt. As a third method we
again applied oxidative carbene catalysis and replaced the IMes
Fig. 4 Linear dependence of the IMes concentration on kobs for the IMes cata-
lyzed reaction of 6a with HO(CH2)2O(CH2)2OEt.
Mechanism of the reaction of enol acetate 7 with
HO(CH2)2O(CH2)2OEt in the presence of IMes
In contrast to 6a, enol acetate 7 reacted with IMes efficiently to
form the corresponding acetylazolium salt.27 We rst investi-
gated the rate constant for the reaction of IMes with 7 at
ꢁ
different temperatures (ꢀ40, ꢀ35, ꢀ30, ꢀ25 C) under pseudo
rst order conditions using 10 equiv. of 7 by monitoring the
consumption of IMes (see ESI†). The corresponding room
temperature pseudo rst order rate constant k ¼ 5.7 ꢃ 10ꢀ2 Mꢀ1
sꢀ1 was calculated using the kinetic parameters obtained from
the Eyring plot.
We then studied the kinetics of the reaction of 7 with
HO(CH2)2O(CH2)2OEt (10 equiv.) at room temperature in THF-
D8 in the presence of IMes at different concentrations (0.079,
0.098, 0.12 and 0.15 equiv.) to give AcO(CH2)2O(CH2)2OEt. The
intermediate acetylazolium ion was not identied by NMR
spectroscopy, instead product ester was observed directly.
Kinetic experiments were conducted in analogy to those
reported for 6a and we found a linear dependence of the IMes
concentration on the rate of product ester formation and the
second-order rate constant k ¼ 5.5 ꢃ 10ꢀ2 Mꢀ1 sꢀ1 was obtained
from the slope (see ESI†).
The value of this rate constant is similar to that of the rate
constant for the reaction of 7 with IMes which indicates that
transesterication likely occurs via acyl transfer from 7 to IMes
as the rate determining step followed by fast base-mediated
acylation of HO(CH2)2O(CH2)2OEt with the intermediately
formed acetylazolium salt (Scheme 4, R ¼ (CH2)2O(CH2)2OEt).
Deprotonated acetone generated in the initial IMes acylation
step acts as a base to deprotonate HO(CH2)2O(CH2)2OEt.
Scheme 5 Products 2h, 9–14 from selective O-acylation of various amino
alcohols using methods A, B and C ([a] isolated as the corresponding N-Boc-pro-
tected amine).
Scheme 4 Suggested two-step mechanism for reaction of 7 with ROH in the
presence of IMes.
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carbene with the cheaper 1,4-dimethyl-1,2,4-triazol-5-ylidene
(method C). Products 2h, 9–14 obtained in these studies are
shown in Scheme 5. For all substrates investigated, the
corresponding products of N-benzoylation or N,O-bisbenzoyla-
tion were not identied and all methods (A, B and C) worked well
for most of the compounds tested.
Acknowledgements
We thank the NRW Graduate School of Chemistry for support-
ing our work (stipend to R.C.S.) and the SFB858 (project Z1) for
supporting our work.
For all substrates the IMes catalyzed acylation with 6a
(method A) delivered the best result. In the chemoselective
oxidative esterication, the 1,4-dimethyl-1,2,4-triazol-5-ylidene
provided 10–30% higher yields as compared to the analogous
process catalyzed by IMes. In the benzoylation of p-aminobenzyl
alcohol we noted oxidation of the substrate under the condi-
tions applied for oxidative catalysis. Therefore, the benzoate 13
was isolated in only 25% yield (method C was not applied to this
substrate). For sterically hindered secondary alcohols the
oxidative esterication with IMes as catalyst failed (see 2h).
Hence, method A outperforms the oxidative esterication since
yields are higher in all reactions investigated and substrates
sensitive towards oxidation are tolerated.
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´
´
We have reported the highly selective acylation of various amino
alcohols in the presence of amines using acylazolium ions and
NHCs as catalysts. Such acylazolium ions can be generated
in situ via oxidative carbene catalysis from the corresponding
aldehydes (cooperative carbene catalysis). Alternatively, they
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Selective acylation is not restricted to acylazolium ions as
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17 Recent applications of the Kharasch oxidant in oxidative 24 Surprisingly, a further increase of the carbene precatalyst
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led to lower ester–amide selectivities (3 mol%: 2.06 : 1
(77%); 4 mol%: 1.93 : 1 (79%); 5 mol%: 1.87 : 1 (77%); 10
mol%: 1.41 : 1 (67%)). This behaviour is currently not
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rate constantunderpseudorst order conditions(largeexcess
of IMes) revealed a rate constant for that acyl transfer reaction
of k ¼ 4.3 ꢃ 10ꢀ5 Mꢀ1 sꢀ1. This is clearly far smaller than the
measured overall rate constant for the IMes catalyzed
transesterication which shows that acyl transfer to IMes is
kinetically not competent and transesterications do not
occur via acylazolium ions (see ESI†).
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19 CCDC 857879 contains the supplementary crystallographic 27 (a) Y. Suzuki, K. Yamauchi, K. Muramatsu and M. Sato,
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