CuCl/TMEDA/nor-AZADO-catalyzed aerobic oxidative acylation of amides with alcohols to produce imides

Article abstract of DOI:10.1039/c8sc01410h

Although aerobic oxidative acylation of amides with alcohols would be a good complement to classical synthetic methods for imides (e.g., acylation of amides with activated forms of carboxylic acids), to date, there have been no reports on oxidative acylation to produce imides. In this study, we successfully developed, for the first time, an efficient method for the synthesis of imides through aerobic oxidative acylation of amides with alcohols by employing a CuCl/TMEDA/nor-AZADO catalyst system (TMEDA = teramethylethylendiamine; nor-AZADO = 9-azanoradamantane N-oxyl). The proposed acylation proceeds through the following sequential reactions: aerobic oxidation of alcohols to aldehydes, nucleophilic addition of amides to the aldehydes to form hemiamidal intermediates, and aerobic oxidation of the hemiamidal intermediates to give the corresponding imides. This catalytic system utilizes O₂ as the terminal oxidant and produces water as the sole by-product. An important point for realizing this efficient acylation system is the utilization of a TMEDA ligand, which, to the best of our knowledge, has not been employed in previously reported Cu/ligand/N-oxyl systems. Based on experimental evidence, we consider that plausible roles of TMEDA involve the promotion of both hemiamidal oxidation and regeneration of an active Cu^II-OH species from a Cu^I species. Here promotion of hemiamidal oxidation is particularly important. Employing the proposed system, various types of structurally diverse imides could be synthesized from various combinations of alcohols and amides, and gram-scale acylation was also successful. In addition, the proposed system was further applicable to the synthesis of α-ketocarbonyl compounds (i.e., α-ketoimides, α-ketoamides, and α-ketoesters) from 1,2-diols and nucleophiles (i.e., amides, amines, and alcohols).

Full text of DOI:10.1039/c8sc01410h

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CuCl/TMEDA/nor-AZADO-catalyzed aerobic oxidative acylation of amides with
alcohols to produce imides
Kengo Kataoka,a Keiju Wachi,a Xiongjie Jin,*b Kosuke Suzuki,a Yusuke Sasano,c
Yoshiharu Iwabuchi,c Jun-ya Hasegawa,d Noritaka Mizunoa and Kazuya Yamaguchi*a
a Department of Applied Chemistry, School of Engineering, The University of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113-8656, Japan. E-mail: kyama@appchem.t.u-tokyo.ac.jp.
b Department of Chemistry and Biotechnology, School of Engineering, The University of Tokyo,
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan. E-mail: t-jin@mail.ecc.u-tokyo.ac.jp.
c Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University,
6-3 Aza-Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan.
d Institute for Catalysis, Hokkaido University, Kita 21 Nishi 10, Kita-ku, Sapporo 001-0021, Japan.
1

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Abstract
Although aerobic oxidative acylation of amides with alcohols would be a good complement to classical
synthetic methods for imides (e.g., acylation of amides with activated forms of carboxylic acids), to date, there
have been no reports on oxidative acylation to produce imides. In this study, we successfully developed, for
the first time, an efficient method for the synthesis of imides through aerobic oxidative acylation of amides
with alcohols by employing
a
CuCl/TMEDA/nor-AZADO catalyst system (TMEDA
=
teramethylethylendiamine; nor-AZADO = 9-azanoradamantane N-oxyl). The proposed acylation proceeds
through the following sequential reactions: aerobic oxidation of alcohols to aldehydes, nucleophilic addition
of amides to the aldehydes to form hemiamidal intermediates, and aerobic oxidation of the hemiamidal
intermediates to give the corresponding imides. This catalytic system utilizes O2 as the terminal oxidant and
produces water as the sole by-product. An important point for realizing this efficient acylation system is the
utilization of a TMEDA ligand, which, to the best of our knowledge, has not been employed in previously
reported Cu/ligand/N-oxyl systems. Based on experimental evidence, we consider that plausible roles of
TMEDA involve the promotion of both hemiamidal oxidation and regeneration of an active CuII‒OH species
from a CuI species. Here promotion of hemiamidal oxidation is particularly important. Employing the
proposed system, various types of structurally diverse imides could be synthesized from various combinations
of alcohols and amides, and gram-scale acylation was also successful. In addition, the proposed system was
further applicable to the synthesis of α-ketocarbonyl compounds (i.e., α-ketoimides, α-ketoamides, and
α-ketoesters) from 1,2-diols and nucleophiles (i.e., amides, amines, and alcohols).
2

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Introduction
Imides are very important structural motifs found extensively in various pharmaceuticals,1 natural products,2
and industrial materials.3 To date, various synthetic methods for imides have been developed, including (i)
acylation of amides with activated forms of carboxylic acids, such as acid chlorides, anhydrides, and esters
(Scheme 1a);4 (ii) Mumm rearrangement of isoimides (Scheme 1b);5 (iii) oxidative decarboxylation of amino
acids (Scheme 1c);6 (iv) carbonylative coupling of aryl halides and amides (Scheme 1d);7 and (v) oxygenation
of amides (Scheme 1e).8 Among these methods, acylation of amides with acyl chlorides in the presence of
(super)stoichiometric amounts of strong bases is the most frequently utilized. However, this antiquated
acylation method has a limited substrate scope and often suffers from low synthetic and atom efficiencies due
to the use of pre-functionalized substrates (i.e., activated forms of carboxylic acids), which results in
(super)stoichiometric amounts of wastes during both the acylation and pre-functionalization steps. Therefore,
development of novel, green, and efficient methods to synthesize imides is important. In this context, aerobic
oxidative acylation of amides with alcohols would provide a powerful alternative synthesis method given (i)
readily available amides and alcohols as substrates without pre-functionalization; (ii) aldehydes generated in
situ by oxidation of alcohols as the acylating reagent (using aldehydes as substrates is also possible); and (iii)
O2 as the terminal oxidant with water as the sole by-product. However, to the best of our knowledge, there are
no general and efficient methods for aerobic oxidative acylation of amides with alcohols (or even aldehydes) to
produce structurally diverse imides.
Inspired by recent developments in oxidative acylation of various nucleophiles, such as alcohols or
amines, with alcohols,9 we expected that oxidative acylation of amides with alcohols could be realized though
the following sequential reactions: (1) aerobic oxidation of alcohols to aldehydes, (2) nucleophilic addition of
amides to aldehydes to form hemiamidal intermediates, and (3) aerobic oxidation of the hemiamidal
intermediates to give the corresponding imide products (Scheme 1f). Because step (2) is in equilibrium and
the equilibrium constant is possibly small, the key to achieving the target reaction would be the development
of an efficient oxidation catalyst, particularly for step (3), to drive the reaction toward the imide products. In
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this study, to the best of our knowledge, we have successfully developed the first powerful and practical
method for synthesis of various types of structurally diverse imides through oxidative acylation of amides
with alcohols using O2 as the terminal oxidant by employing a CuCl/TMEDA/nor-AZADO catalyst system
(TMEDA = teramethylethylendiamine; nor-AZADO = 9-azanoradamantane N-oxyl) (Scheme 1f).
To date, numerous efficient Cu/ligand/N-oxyl catalyst systems have been developed for aerobic oxidation
of alcohols or amines.10 However, only one previous study has reported Cu/ligand/N-oxyl-catalyzed oxidative
acylation of nucleophiles with alcohols; Stahl and co-workers quite recently reported an elegant
Cu/ligand/ABNO catalyst system (ABNO = 9-azabicyclo[3.3.1]nonane N-oxyl) for aerobic oxidative
acylation of amines with alcohols to produce amides.11 In this study, we found, for the first time, that CuCl
combined with TMEDA and nor-AZADO was a highly generalizable and practical catalyst system to convert
a wide variety of alcohols and amides to produce the desired imides without tedious catalyst re-optimization
even with different alcohol/amide combinations. In addition, the proposed system was further applicable to the
synthesis of α-ketocarbonyl compounds from 1,2-diols and nucleophiles, such as amides, amines, and alcohols.
Notably, a readily available TMEDA ligand, which, to the best of our knowledge, has never been employed as
the ligand in previously reported Cu/ligand/N-oxyl oxidation catalyst systems, showed significantly superior
performance compared to commonly utilized pyridyl-based ligands, including bipyridines and phenanthrolines.
Based on experimental evidence, we concluded that plausible roles of TMEDA involve the promotion of both
hemiamidal oxidation and regeneration of an active CuII‒OH species by oxidation of a CuI species using O2.
Moreover, we found that nor-AZADO12, developed by Iwabuchi and co-workers, was more efficient for the
proposed acylation than other generally utilized N-oxyls, such as TEMPO,13 ABNO,14 and AZADO15
(TEMPO = 2,2,6,6-tetramethylpiperidine N-oxyl; AZADO = 2-azaadamantane N-oxyl).
Results and discussion
Optimization of reaction conditions
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Initially, we carried out oxidative acylation of 2-pyrrolidone (2a) with benzyl alcohol (1a) using a
CuCl/TMEDA/nor-AZADO catalyst system under 1 atm of O2 at room temperature (ca. 23°C) in
tetrahydrofuran (THF). Under the conditions described in Table 1 without molecular sieves 3A (MS 3A), the
desired 1-benzoyl-2-pyrrolidone (3aa) was obtained in 15% yield with a 75% yield of benzaldehyde (4a)
derived from the oxidation of 1a (Table 1, entry 1). To promote reactions effectively, activated (dried) MS 3A
was utilized frequently to remove water formed during the reactions in previously reported Cu/ligand/N-oxyl
catalyst systems.10,11 In the proposed system, the effect of activated MS 3A was also very significant; when
activated MS 3A was added to the reaction mixture in advance, 3aa was obtained in quantitative yield within
only 5 min (Table 1, entry 2). However, the reaction did not efficiently proceed in the presence of
non-activated MS 3A (containing ca. 20 wt% water) (Table 1, entry 3). Thus, water formed during the reaction
likely inhibits the reaction, and the use of activated (dried) MS 3A is very important to promote the reaction
effectively. During the catalytic turnover, the reaction solution was almost colorless. When 1a was completely
converted into 3aa (after 5 min, in the case of Table 1, entry 2), the reaction solution became light green.
Among the ligands examined, TMEDA was the best ligand for acylation of 2a with 1a (Table 1, entry 2).
We confirmed by careful GC and GC-MS analyses that the mass balance for TMEDA was almost preserved
and by-products derived from TMEDA were not detected at all after the reaction, thus indicating that
oxidative decomposition of TMEDA hardly occurred under the present reaction conditions. Other commonly
utilized ligands in previously reported Cu/ligand/N-oxyl catalyst systems for several oxidation reactions, such
as bpy (2,2’-bipyridyl), 4Mebpy (4,4’-dimethyl-2,2’-bipyridyl), 6Mebpy (6,6’-dimethyl-2,2’-bipyridyl), 4MeObpy
(4,4'-dimethoxy-2,2'-bipyridyl), phen (1,10-phenanthroline), MeOphen (4,7-dimethoxy-1,10-phenanthroline),
and TPA (tris(2-pyridylmethyl)amine), were all inferior to TMEDA under the same reaction conditions
(Table 1,
entries 4‒10).
Another
aliphatic
N-based
bidentate
ligand,
i.e.,
TEEDA
(N,N,N',N'-tetraethylethylenediamine), also promoted the reaction but was less effective than TMEDA
(Table 1, entry 11). These results indicate that ligands play a crucial role in the present reaction. Peralkylated
diamine ligands, particularly TMEDA, could effectively facilitate the reaction. Thus, TMEDA was the key to
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efficient acylation of amides with alcohols. The roles of TMEDA in the proposed catalyst system are
discussed in detail in a later section.
Various N-oxyls, such as nor-AZADO, TEMPO, ABNO, keto-ABNO (9-azabicyclo[3.3.1]nonane-3-one
N-oxyl),
AZADO,
1-Me-AZADO
(1-methyl-2-azaadamantane-N-oxyl),
5-F-AZADO
(5-fluoro-2-azaadamantane-N-oxyl), and 4-Cl-AZADO (4-chloro-2-azaadamantane-N-oxyl), were examined
for the acylation of 2a with 1a. Among these N-oxyls, nor-AZADO was the most effective for the acylation
(Table 1, entry 12). In the presence of the other N-oxyls (except for TEMPO), the reaction also proceeded
accordingly (Table 1, entries 13‒19). Other Cu sources, such as CuBr, CuI, CuOAc, and CuCl2, were much
less effective than CuCl (Table 1, entry 2 vs. entries 20‒23).16 Several control experiments revealed that
acylation did not proceed at all when lacking any one of CuCl, TMEDA, or nor-AZADO (Table 1, entries 24‒
26). In addition, 3aa was hardly obtained under 1 atm of Ar, which indicates that O2 functioned as the terminal
oxidant (Table 1, entry 27). THF was the best solvent for the proposed acylation system. We confirmed that
THF used in this study did not contain any peroxides before the reaction. In addition, after the reaction, no
peroxides were also detected in the reaction solution. Moreover, the reaction also efficiently proceeded using
THF containing an antioxidant 2,6-di-tert-butyl-p-cresol. When the solvent was changed from THF to
dichloromethane (DCM) or acetonitrile (MeCN), the yield of 3aa decreased drastically (Table S1, ESI†).
Substrate scope for imide synthesis
With the optimized reaction conditions in hand, we examined the substrate scope for the proposed
CuCl/TMEDA/nor-AZADO-catalyzed oxidative acylation of amides with alcohols. Various kinds of
structurally diverse imides could be synthesized starting from various combinations of alcohols and amides
(Tables 2 and 3). The substrates used in this study are summarized in Fig. S1, ESI†.
As shown in Table 2, various lactams could be acylated to produce the corresponding imides in moderate
to high yields. Various substituents, including an ester group on 5-membered lactams, reacted efficiently with
1a to afford the corresponding imides in high yields (Table 2, 3aa, 3ab, 3ac, and 3ad). When an
6

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enantiomerically pure lactam was used as the substrate, the corresponding imide was obtained in high yield
with retention of the stereochemistry (>99% ee) (Table 2, 3ad). In addition, 6- or 7-membered lactams were
good substrates for the present reaction, affording the corresponding imides in high yields (Table 2, 3ae and
3af). Heteroatom-substituted lactams, such as 2-oxazolidone and 1-methyl-2-imidazolidone, were also good
substrates, and acylation with various alcohols gave the corresponding imides in excellent yields (Table 2, 3ag,
3ah, 3dg, 3jg, 3kg, and 3hg). Benzylic alcohols with electron-donating or withdrawing substituents were all
good partners for 2a (Table 2, 3ba and 3ca). The acylation proceeded smoothly with various alcohols
containing heteroaromatic rings, such as furan, thiophene, pyridine, and indole rings (Table 2, 3dg, 3ea, 3fa,
and 3ga). An α,β-unsaturated alcohol, i.e., cinnamyl alcohol, also reacted efficiently with amides, affording the
corresponding imides without oxidation of the double bond (Table 2, 3ha and 3hg). The reaction proceeded
well even when aliphatic alcohols were used as acylating reagents (Table 2, 3ia, 3ja, 3ka, 3la, 3ma, 3ke, 3jg,
and 3kg). An acetal group was also tolerated in the present reaction (Table 2, 3la). Note that methanol could
be utilized as an efficient formylation reagent for 2a (Table 2, 3ia). Interestingly, when the reaction of styrene
glycol (1,2-diol) and 2a was performed, both the primary and secondary alcohol groups in styrene glycol were
smoothly oxidized to form the corresponding α-ketoaldehyde, followed by the reaction with 2a to afford the
corresponding α-ketoimide (Table 2, 3va).
Next, the scope for the acylation of primary amides was examined. The optimized conditions for lactams
turned out to be inefficient for acylation of benzamide (2i) with 1a, and only a stoichiometric amount of the
corresponding imide (3ai) with respect to Cu was obtained (Table S2, entries 1–3, ESI†). Acidic groups, e.g.,
carboxylic acids and phenols, have been shown to poison Cu/ligand/N-oxyl-catalyzed alcohol oxidation,
possibly by inhibiting formation of the requisite Cu-alkoxide species. The secondary imide has a pKa value
similar to that of a carboxylic acid, and thus we consider that strong bases can ensure that the imide is
deprotonated and unable to inhibit catalytic turnover. Indeed, the reaction proceeded efficiently in the presence
of potassium tert-butoxide (tBuOK), giving 3ai in quantitative yield (Table S2, entry 5, ESI†). Among the
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t
bases examined, BuOK was the best base additive (Table S2, entries 5 and 22–24, ESI†). Thus, we utilized
tBuOK for acylation of primary amides as required.
As shown in Table 3, various primary amides were acylated efficiently to give the corresponding imides.
Benzylic alcohols with electron-donating and electron-withdrawing substituents on the aromatic rings and
2-naphthalenemethanol successfully reacted with 2i to afford the corresponding imides (Table 3, 3ai, 3ni, 3oi,
3bi, 3pi, 3qi, 3ri, 3ci, 3si, and 3ti). When using 2-methylbenzyl alcohol for acylation of 2i, the yield of the
corresponding imide was not satisfactory, likely due to the steric hinderance of the 2-methyl group (Table 3,
3ni). Notably, with halo-substituted benzylic alcohols, the desired imides were obtained without
dehalogenation, which enables further functionalization of these imide products (Table 3, 3pi, 3qi, and 3ri).
Alcohols containing heteroaromatic rings, such as furan and thiophene rings, reacted efficiently with 2i
(Table 3, 3di, and 3ei). Aliphatic alcohols also reacted smoothly with 2i (Table 3, 3ji, and 3ki). However,
heteroatoms containing aliphatic alcohols were somewhat less effective acylation sources (Table 3, 3ui, and
3mi). Benzamides with various substituents on 2-, 3- or 4-positions were all similarly effective for acylation
with 1a (Table 3, 3aj, 3ak, 3al, 3am, and 3an). Halo-substituted benzamides were also acylated without
dehalogenation (Table 3, 3am and 3an). In addition, 3- and 4-picolinamides were efficiently converted into
the corresponding imides (Table 3, 3ap, and 3aq), while 2-picolinamide was less effective, possibly due to its
bidentate coordination to the active Cu center (Table 3, 3ao). An α,β-unsaturated amide, i.e., cinnamamide,
also reacted efficiently with 1a (Table 3, 3ar). An aliphatic amide could also be acylated with various alcohols,
including benzylic and aliphatic alcohols, to give the corresponding imides (Table 3, 3as, 3js, and 3ks).
To further demonstrate the practical applicability of the proposed CuCl/TMEDA/nor-AZADO-catalyzed
oxidative acylation system to produce imides, we performed gram-scale (10 mmol-scale) synthesis of
“aniracetam” (3ba), which is a class of racetams sold as an anxiolytic drug.1a When 4-methoxybenzyl alcohol
(1b) and 2a were used as starting materials, the reaction proceeded efficiently to obtain 2.0 g of 3ba (93%
isolated yield) (Scheme 2a). Next, using the proposed acylation method, we attempted to synthesize chiral
N-acyloxazolidinones (known as “Evans imides”), which are widely used as starting materials for various
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enantio-selective syntheses, such as alkylation, aldol reaction, and Michael addition.17 Although stoichiometric
amounts of CuCl and TMEDA were required, the acylation of a chiral oxazolidinone, i.e.,
(S)-4-benzyl-2-oxazolidinone (2t), with 1-propanol (1j) or cinnamyl alcohol (1h) gave the corresponding
Evans imides in moderate yields with >99% ee (Scheme 2b).
Reaction mechanism and roles of TMEDA
From the reaction profile for the CuCl/TMEDA/nor-AZADO-catalyzed oxidative acylation of 2-pyrrolidone
(2a) with benzyl alcohol (1a) to produce the corresponding imide 3aa, it is clear that the present reaction
proceeds via benzaldehyde (4a) as the intermediate (Scheme 1f, Table 1). In a separate experiment, we
confirmed that 3aa was obtained quantitatively starting from 4a and 2a (Table S3, entry 1, ESI†). A plausible
reaction mechanism for the proposed CuCl/TMEDA/nor-AZADO-catalyzed acylation of amides with alcohols
is shown in Scheme 3.18 Initially, CuI species A is oxidized by O2 to generate dicopper‒oxygen complex B,
which is then reduced by an alcohol to afford active CuII–OH species C (Scheme 3, steps 1 and 2).19 Species C
may be in equilibrium with CuII bis-ꢀ-hydroxo dimer C’.18b,20 Then, CuII-alkoxide species D is formed by
2
ligand exchange between species C and an alcohol with the liberation of water (Scheme 3, step 3). In the
presence of nor-AZADO (N-oxyl), an aldehyde intermediate was formed from species D concomitant with its
reduction to CuI species A and the formation of the corresponding N-hydroxylamine (N-oxyl–H) (Scheme 3,
step 4). Species A is then re-oxidized by O2 to afford species B, followed by its reduction by N-oxyl–H (or an
alcohol) to regenerate active CuII–OH species C to complete the catalytic cycle I (Scheme 3, steps 5 and 6).
Next, a hemiamidal intermediate is formed by nucleophilic addition of an amide to the aldehyde generated in
the catalytic cycle I (Scheme 3, step 7).21 The oxidation of the hemiamidal intermediate by a catalytic cycle as
with cycle I gives the final imide product (Scheme 3, cycle II)
Recently, Stahl et al. proposed the catalytic cycle I for Cu/ligand/N-oxyl-catalyzed aerobic alcohol
oxidation based on careful kinetic, spectroscopic, and quantum chemical studies.18,22 We consider that the
CuCl/TMEDA/nor-AZADO-catalyzed aerobic alcohol oxidation also proceeds through cycle I. Kinetic
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studies for CuCl/TMEDA/nor-AZADO-catalyzed oxidation of 1a to 4a revealed that the reaction rate showed
first-order dependence on O2 pressure (Fig. 1, II-a) and was nearly independent of the 1a concentration (Fig. 1,
II-b), thereby indicating that the regeneration of an active CuII‒OH species from a CuI species (Scheme 3, step
5 or 6) is included in the rate-limiting step. To reveal the effect of TMEDA, similar kinetic studies were
performed using a commonly utilized bpy ligand. When using bpy, the reaction rate exhibited first-order
dependence on O2 pressure (Fig. 1, I-a) and zero-order dependence on the 1a concentration (Fig. 1, I-b).
Therefore, the CuII‒OH regeneration is also included in the rate-limiting step in the case of bpy. From these
kinetic studies, we revealed that the rate for CuII‒OH regeneration using TMEDA was ca. twice that of using
bpy (Fig. 1). It is known that the reaction of CuI species and O2 gives various copper‒oxygen species and that
the reaction in the presence of suitable ligands yield an equilibrium mixture of a CuII side-on peroxo-bridged
2
dimer and a CuIII bis-ꢀ-oxo dimer (Scheme 4).23 To date, many reports have considered the formation and
2
reactivity of the bis-ꢀ-oxo dimer, and the following points have been discussed:24 (i) the bis-ꢀ-oxo dimer is a
better hydrogen-acceptor compared to the side-on peroxo-bridged dimer, (ii) peralkylated diamine ligands can
promote formation of the bis-ꢀ-oxo dimer, and (iii) the bis-ꢀ-oxo dimer prepared using TMEDA is relatively
stable, and its limited steric demands allow efficient oxidation (hydrogen abstraction) of exogenous substrates
(e.g., benzyl alcohol).19 We consider that the promotional effect of TMEDA for CuII‒OH regeneration is likely
due to the above-mentioned three points, i.e., increasing the concentration of the bis-ꢀ-oxo dimer (Scheme 3,
step 5) and/or promoting hydrogen abstraction from N-oxyl–H (or an alcohol) (Scheme 3, step 6).
Although TMEDA effectively promotes CuII‒OH regeneration, the big difference between acylation
using TMEDA and that using bpy (Table 1, entry 2 vs. entry 3) cannot be explained only by the
aforementioned promotional effect. Consequently, we consider that the effect of TMEDA should be most
obvious on the hemiamidal oxidation step in cycle II (possibly Scheme 3, step 9). Indeed, when acylation of
2a with 4a was carried out under the conditions described in Table S3, ESI†, the yields of 3aa using TMEDA
and bpy were 98% and 17%, respectively (Table S3, entries 1 and 2, ESI†).25 In addition, the production rate
(initial rate) of 3aa using TMEDA was at least ca. eight times greater than that using bpy. Therefore, we
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investigated the effect of TMEDA on the hemiamidal oxidation step in more detail. As mentioned previously,
we consider that the hemiamidal oxidation likely proceeds through the catalytic cycle II. To reveal this, the
following control experiments were conducted. When the acylation of 2a with 4a using
[Cu(OH)(TMEDA)]2Cl2 (Cu: 20 mol% with respect to 4a) instead of CuCl under non-aerobic conditions (1 atm
of Ar), a nearly stoichiometric amount of 3aa (16% yield base on 4a) with respect to the CuII species used was
produced, and then the reaction stopped (Scheme 5). This result is in accord with the left half of cycle II in
Scheme 3, i.e., once the CuII‒OH species C and N-oxyl are reduced to CuI species A and N-oxyl–H, respectively,
the catalytic turnover stops in the absence of O2. In addition, the monomeric CuII‒OH species C and CuII
2
bis-ꢀ-hydroxo dimer C’ are likely in equilibrium. After this non-aerobic reaction, O2 was introduced to the
reactor, and the reaction was continued successively. In this case, the yield of 3aa increased up to 92%
(Scheme 5). Therefore, O2 can act as the oxidant to re-oxidize CuI species A to regenerate the active CuII‒OH
species C (the right half of cycle II in Scheme 3), thereby leading to complete conversion of the substrates into
the desired imide product.
Next, kinetic studies for the acylation of 2a with 4a to produce 3aa were performed. When using bpy, the
production rate (initial rate) of 3aa showed saturation kinetics for O2 pressure (Fig. 2, I-a) and first-order
dependence on the 4a concentration (Fig. 2, I-b). The kinetic behavior for acylation using bpy was quite
different compared to that of the alcohol oxidation. We consider that the hemiamidal oxidation (Scheme 3,
step 9) is included in the rate-limiting step for the acylation of 2a with 4a using bpy under standard conditions
(1 atm of O2). Therefore, with the CuCl/bpy/nor-AZADO catalyst system, hemiamidal oxidation is
significantly more difficult than alcohol oxidation. Thus, the rates when using bpy are in the following order:
alcohol oxidation > CuII‒OH regeneration > hemiamidal oxidation. Note that the kinetic behavior for
acylation using TMEDA was quite different from that using bpy. The reaction rate for the
CuCl/TMEDA/nor-AZADO-catalyzed acylation exhibited first-order dependence on O2 pressure (Fig. 2, II-a)
and zero-order dependence on the 4a concentration (Fig. 2, II-b). In addition, the reaction rate for acylation of
2a with 4a was nearly the same as that for the oxidation of 1a to 4a (Fig. 2, II-a, II-b vs. Fig. 1, II-a, II-b).
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These results strongly indicate that CuII‒OH regeneration (Scheme 3, step 10 or 11) is included in the
rate-limiting step for the CuCl/TMEDA/nor-AZADO-catalyzed hemiamidal oxidation (acylation of 2a with
4a), as with the alcohol oxidation (oxidation of 1a) (vide supra). Therefore, with TMEDA, both the alcohol
oxidation and hemiamidal oxidation are significantly faster than the CuII‒OH regeneration.
From these kinetic results, we concluded that, in the proposed CuCl/TMEDA/nor-AZADO-catalyzed
acylation of amides with alcohols, TMEDA promotes both hemiamidal oxidation (Scheme 3, step 9) and CuII‒
OH regeneration (Scheme 3, step 5 or 6; Scheme 3, step 10 or 11), and that the effect of TMEDA on the
hemiamidal oxidation is very significant. In the proposed CuCl/TMEDA/nor-AZADO-catalyzed acylation of
amides with alcohols, CuII‒OH regeneration (Scheme 3, step 5 or 6, and Scheme 3, step 10 or 11) is the slower
step compared to alcohol and hemiamidal oxidation, thereby suggesting that CuI species A is in the resting
state. This is consistent with the above-mentioned color observation of the reaction solution, i.e., the reaction
solution was almost colorless during the catalytic turnover and became light green after complete conversion
of the substrates into the corresponding imides.
Synthesis of α-ketoamides and α-ketoesters
As above-mentioned, the proposed CuCl/TMEDA/nor-AZADO catalyst system was highly effective for the
oxidation of styrene glycol (1,2-diol) to the corresponding α-ketoaldehyde; when the reaction of styrene glycol
and amide 2a was carried out, the corresponding α-ketoimide was obtained (Table 2, 3va). We envisaged that
this method utilizing 1,2-diols could be further applied to the synthesis of various α-ketocarbonyl compounds.
From the mechanistic studies as described above, we chose a [Cu(OH)(TMEDA)]2Cl2/nor-AZADO catalyst
system for the studies of α-ketocarbonyl synthesis. We found that secondary amines (e.g., piperidine and
N-methylbenzylamine) and aniline could be utilized as the nucleophiles; in the presence of a small excess of
these amines, the reaction of styrene glycol gave their corresponding α-ketoamides in high yields (Table 4,
upper). Unfortunately, the use of primary aliphatic amines was unsuccessful. Moreover, various kinds of
alcohols, including aliphatic primary, aliphatic secondary, and benzylic ones, could also be utilized as the
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nucleophiles for the synthesis of their corresponding α-ketoesters (Table 4, lower). To the best of our
knowledge, to date, there are no reports on such α-ketocarbonyl synthesis methods using 1,2-diols and
nucleophilic reagents.
Conclusion
For the first time, we have successfully developed efficient CuCl/TMEDA/nor-AZADO-catalyzed aerobic
oxidative acylation of amides with alcohols. By employing the proposed CuCl/TMEDA/nor-AZADO catalyst
system, various kinds of structurally diverse imides, including Evans imides, could be synthesized starting
from various combinations of alcohols and amides. In addition, gram-scale production of aniracetam was also
successful. The proposed system was also applicable to the synthesis of α-ketocarbonyl compounds from
1,2-diols and nucleophiles, such as amides, amines, and alcohols. One of the most important key points in
realizing this efficient acylation system is the utilization of a TMEDA ligand, which, to the best of our
knowledge, has never been employed in previously reported Cu/ligand/N-oxyl catalyst systems. Based on
experimental evidence, such as kinetic and quantum chemical studies, we consider that the plausible roles of
TMEDA are the promotion of both hemiamidal oxidation and regeneration of an active CuII‒OH species from
a CuI species, and that the promotion of hemiamidal oxidation is crucial to realize efficient acylation. The
present catalytic system utilizes O2 as the terminal oxidant and produces water as the sole by-product, which
highlights its environmentally friendly nature. Moreover, the mild reaction conditions (e.g., room temperature
and ambient O2 pressure) are matched by excellent functional group tolerance and a very broad substrate
scope. We hope that the proposed catalyst system will find broad applications in fine chemical synthesis.
Experimental section
Instruments and reagents
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GC analyses were performed using a Shimadzu GC-2014 equipped with a flame ionization detector and
InertCap-5 capillary column (0.25 mm ID × 30 m length). HPLC analyses were performed on a Shimadzu
Prominence system using a UV detector (Shimadzu SPD-20A, 254 nm) equipped with a GL Science Inertsil
ODS-3 (4.6 mm ID × 250 mm length) using a methanol/water mixture (9/1 v/v) as an eluent. GC mass
spectrometry (GC-MS) spectra were recorded using a Shimadzu GCMS-QP2010 equipped with an InertCap-5
capillary column (0.25 mm ID × 30 m length) at an ionization voltage of 70 eV. Liquid-state NMR spectra
were recorded on a JEOL JNM-ECA-500 spectrometer. 1H and 13C NMR spectra were measured at 500.2 and
125.8 MHz, respectively, using tetramethylsilane as an internal reference (δ = 0 ppm). Enantiomeric excess
was determined by HPLC analyses performed on a Shimadzu Prominence system using a circular dichroism
chiral detector (JASCO CD-2095 Plus, 254 nm) equipped with a Daicel chiralcel OD-H column (4.6 mm ID ×
250 mm length) using an n-hexane/2-propanol mixture (1/1 v/v) as an eluent. The copper sources, ligands,
substrates (alcohols and amides), N-oxyls (except for 5-F-AZADO and 4-Cl-AZADO), MS 3A, and solvents
were obtained from Kanto Chemical, TCI, Wako, or Aldrich (reagent grade) and purified prior to the use as
required. 5-F-AZADO26a and 4-Cl-AZADO26b were prepared according to the procedures in the literatures.
MS 3A was dried under vacuum at 400°C with a heating mantle before using.
General procedures for oxidative acylation of amides with alcohols
The reaction was typically carried out according to the following procedures. CuCl (0.025 mmol, 5 mol%),
TMEDA (0.025 mmol, 5 mol%), nor-AZADO (0.015 mmol, 3 mol%), THF (2 mL), MS 3A (powder, 200 mg),
tBuOK (0.5 mmol, if required), and a Teflon-coated magnetic stir bar were placed successively in a Schlenk
tube (volume: ca. 20 mL), and the reaction mixture was stirred vigorously for 5 min at room temperature
(ca. 23°C). The reaction mixture was then purged with O2, connected to a balloon filled with O2 gas, and
stirred vigorously for 2 min at room temperature. Subsequently, a THF solution (0.5 mL) containing alcohol
(1.0 M), amide (1.1 M), and an internal standard (diphenyl, 0.2 M) was added to the reaction mixture, which
was then vigorously stirred at room temperature. After the reaction was complete, the conversion of substrates
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and the yields of the products were determined by GC or HPLC analysis. Then, MS 3A was removed by
filtration, and the filtrate was concentrated by evaporation. The crude product was subject to column
chromatography on silica gel (using a mixture of chloroform/acetone, n-hexane/diethyl ether, n-hexane/ethyl
acetate, or chloroform/methanol as the eluent), giving the pure product. The products were identified by
GC-MS and/or NMR (1H and 13C) analyses.
Acknowledgments
This work was supported in part by JSPS KAKENHI Grant Number 15H05797 for Precisely Designed
Catalysts with Customized Scaffolding and Grant Number 17K14860.
Notes and references
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J. Sperry, Synthesis, 2011, 3569.
Many efficient catalytic systems for the oxidative acylation of amines with alcohols to produce amides have
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For selected examples, see: (e) Y. Wang, D. Zhu, L. Tang, S. Wang and Z. Wang, Angew. Chem., Int. Ed.,
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ChemSusChem, 2015, 8, 1916. For reviews, including aerobic oxidative acylation with alcohols, see: (j) H.
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14 (a) J. Kim and S. S. Stahl, ACS Catal., 2013, 3, 1652; (b) J. E. Steves and S. S. Stahl, J. Am. Chem. Soc.,
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15 Y. Sasano, S. Nagasawa, M. Yamazaki, M. Shibuya, J. Park and Y. Iwabuchi, Angew. Chem., Int. Ed., 2014,
53, 3236.
16 As summarized in Table 1, the effect of anions of copper sources was very significant. As for Cu(I)
halides, the yields of 3aa decreased as the anion size became larger (Table 1, entries 2, 20, and 21). In
addition, when the reaction of 1a and 2a was carried out under the standard conditions in Table 1 using
CuCl in the presence of KI (5 mol%), the yield of 3aa dropped to 56% (cf. >99% without KI). One
possible explanation of the anion effect is that larger anions (softer bases) possibly inhibit the reaction
through their strong coordination to the Cu(I) center because Cu(I) is a soft acid, thus, stabilize the Cu(I)
species and retard the oxidation to the Cu(II) species. Note that such anion effect was not observed when
the reaction was performed in the presence of significant amounts of bases, e.g., tBuOK (see Table S4).
17 D. J. Ager, I. Prakash and D. R. Schaad, Chem. Rev., 1996, 96, 835.
18 (a) J. M. Hoover, B. L. Ryland and S. S. Stahl, J. Am. Chem. Soc., 2013, 135, 2357; (b) J. M. Hoover, B. L.
Ryland and S. S. Stahl, ACS Catal., 2013, 3, 2599.
19 A CuIII bis-ꢀ-oxo dimer prepared upon aerobic oxidation of CuI species in the presence of TMEDA is
2
capable of oxidizing benzyl alcohol. See: P. Kang, E. Bobyr, J. Dustman, K. O. Hodgson, B. Hedman, E. I.
Solomon and T. D. P. Stack, Inorg. Chem., 2010, 49, 11030.
20 T. Sonobe, K. Oisaki and M. Kanai, Chem. Sci., 2012, 3, 3249.
21 Control experiments for the acylation of benzamide (2i) with 4a revealed that the corresponding
dehydrative condensation product 6ai was formed only under the conditions where CuII species were
possibly formed (CuI + O2, Table S5, entries 1, 3, and 4, ESI†). Consequently, we consider that CuII
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species would promote the nucleophilic addition of amides to aldehydes likely according to the following
scheme.
R1
R1
O
O
N
LnCuII
O
N
R3
R2
LnCuII
O
R3
R2
22 B. L. Ryland, S. D. McCann, T. C. Brunold and S. S. Stahl, J. Am. Chem. Soc., 2014, 136, 12166.
23 For reviews, see: (a) L. M. Mirica, X. Ottenwaelder and T. D. P. Stack, Chem. Rev., 2004, 104, 1013; (b) E.
A. Lewis and W. B. Tolman, Chem. Rev., 2004, 104, 1047; (c) L. Q. Hatcher and K. D. Karlin, Adv. Inorg.
Chem., 2006, 58, 131; (d) C. E. Elwell, N. L. Gagnon, B. D. Neisen, D. Dhar, A. D. Spaeth, G. M. Yee and
W. B. Tolman, Chem. Rev., 2017, 117, 2059.
24 (a) S. Mahapatra, J. A. Halfen and W. B. Tolman, J. Am. Chem. Soc., 1996, 118, 11575; (b) S. Mahapatra, S.
Kaderli, A. Llobet, Y.-M. Neuhold, T. Palanché, J. A. Halfen, V. G. Young, T. A. Kaden, L. Que, Jr., A. D.
Zuberbühler and W. B. Tolman, Inorg. Chem., 1997, 36, 6343; (c) V. Mahadevan, Z. Hou, A. P. Cole, D. E.
Root, T. K. Lal, E. I. Solomon and T. D. P. Stack, J. Am. Chem. Soc., 1997, 119, 11996; (d) M. J. Henson, P.
Mukherjee, D. E. Root, T. D. P. Stack and E. I. Solomon, J. Am. Chem. Soc., 1999, 121, 10332; (e) V.
Mahadevan, M. J. Henson, E. I. Solomon and T. D. P. Stack, J. Am. Chem. Soc., 2000, 122, 10249; (f) L. Q.
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Chem. Biol., 2009, 13, 119.
25 When prolonging the reaction time to 2 h for the acylation of 2a with 1a under the conditions described
in Table 1, 3aa was obtained in 95% yield. Therefore, we considered that the bpy-based catalyst hardly
decomposed until the completion of the reaction.
26 (a) M. Shibuya, Y. Osada, Y. Sasano, M. Tomizawa and Y. Iwabuchi, J. Am. Chem. Soc., 2011, 133, 6497;
(b) S. Nagasawa, Y. Sasano and Y. Iwabuchi, Angew. Chem., Int. Ed., 2016, 55, 13189.
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a
Table 1 Optimization of the reaction conditions
H
O
O
Cu/ligand/N-oxyl
N
O
+
OH
Ph
Ph
O
Ph
N
O2
1a
2a
3aa
4a
Time
Conv. of
1a (%)
>99
>99
>99
>99
99
Yield (%)
3aa
15
Entry
Cu source Ligand
N-Oxyl
(min)
5
4a
75
<1
80
83
87
60
78
1
1b
2
3c
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuBr
CuI
TMEDA
TMEDA
TMEDA
bpy
nor-AZADO
nor-AZADO
nor-AZADO
nor-AZADO
nor-AZADO
nor-AZADO
nor-AZADO
nor-AZADO
nor-AZADO
nor-AZADO
nor-AZADO
nor-AZADO
TEMPO
5
>99
10
5
4
5
10
5
4Mebpy
5
2
6
6Mebpy
4MeObpy
5
70
<1
14
7
5
>99
8
8
phen
MeOphen
TPA
5
<1
<1
<1
21
9
5
7
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27d
5
38
28
72
38
5
TEEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
–
5
>99
>99
11
3
61
3
<1
31
ABNO
3
>99
90
66
45
62
54
55
46
30
6
keto-ABNO
AZADO
3
41
3
>99
>99
99
31
1-Me-AZADO
5-F-AZADO
4-Cl-AZADO
nor-AZADO
nor-AZADO
nor-AZADO
nor-AZADO
nor-AZADO
nor-AZADO
–
3
49
3
37
3
97
49
5
>99
15
69
5
<1
2
CuOAc
CuCl2
–
5
66
52
22
1
5
28
<1
<1
<1
<1
<1
5
6
CuCl
CuCl
CuCl
5
30
22
1
TMEDA
TMEDA
5
7
nor-AZADO
5
10
1
O
N
O
N
N
O
N
N
N
N
N
N
N
N
O
O
keto-ABNO
bpy
4Mebpy
6Mebpy
nor-AZADO
TEMPO
ABNO
MeO
OMe
MeO
OMe
F
Cl
N
N
N
N
N
N
O
N
O
N
O
N
O
4MeObpy
phen
MeOphen
AZADO
1-Me-AZADO
5-F-AZADO
4-Cl-AZADO
N
N
N
N
N
N
N
N
TMEDA
TEEDA
TPA
aReaction conditions: 1a (0.5 mmol), 2a (0.55 mmol), Cu source (5 mol%), ligand (5 mol%), N-oxyl (3 mol%),
activated MS 3A (200 mg), THF (2.5 mL), O2 (balloon), room temp. (ca. 23°C). Conversion and yields were
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b
determined by GC analysis. Without MS 3A. Using non-activated MS 3A (containing ca. 20 wt% water). Ar
c
c
(1 atm).
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Chemical Science
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Table 2 Substrate scope for acylation of lactams with alcoholsa
O
CuCl (5 mol%), TMEDA (5 mol%)
nor-AZADO (3 mol%)
O
O
O
HN
+
R
OH
R
N
MS 3A (200 mg)
1 (0.5 mmol)
THF (2.5 mL), O , room temp.
2
3
2 (0.55 mmol)
O
N
O
O
O
O
O
O
N
N
N
O
3aa, 92%b
3ab, 88%
3ac, 87%
3ad, 94%c OMe
O
N
O
O
O
O
O
O
N
O
N
N
N
O
3ae, 86%
3af, 95%
3ag, (>99%)
3ah, 98%
O
O
O
O
O
O
O
O
O
S
N
N
N
N
O
MeO
F3C
3ba, (>99%)
3ca, 85%
3dg, (93%)
3ea, (>99%)
O
O
O
N
O
O
O
O
O
N
N
N
H
N
HN
3ga, 81%d,e,f
3fa, (99%)
3ha, (88%)
3ia, (81%)d
O
O
O
O
O
O
O
O
Et
N
n-Hept
N
N
N
O
O
N
3ja, 87%
3ka, 87%
3la, 57%e
3ma, 78%
O
O
O
O
O
O
n-Hept
N
N
n-Hept
N
O
O
3kg, 88%
3jg, (90%)
3ke, 78%
O
O
O
N
O
N
O
3hg, (88%)
3va, (64%)e,g
O
aReaction conditions: 1 (0.5 mmol), 2 (0.55 mmol), CuCl (5 mol%),
TMEDA (5 mol%), nor-AZADO (3 mol%), MS 3A (200 mg), THF
(2.5 mL), O2 (balloon), room temp. (ca. 23°C), 1 h. Isolated yields are
b
c
d
e
shown. Values in parentheses are GC yields. 5 min. >99% ee. 24 h. 2
(1.0 mmol). fCuCl (10 mol%), TMEDA (10 mol%), nor-AZADO (6 mol%).
gK2CO3 (20 mol%).
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Page 23 of 31
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Table 3 Substrate scope for acylation of primary amides with alcoholsa
CuCl (5 mol%), TMEDA (5 mol%)
t
O
O
O
nor-AZADO (3 mol%), BuOK (0.5 mmol)
R1
1 (0.5 mmol)
OH
R2
R1
+
R2
NH2
N
H
MS 3A (200 mg)
2 (0.55 mmol)
3
THF (2.5 mL), O , room temp.
2
X = H: 3ai, 82%
2-Me: 3ni, 29%
3-OMe: 3oi, 80%
4-F: 3pi, 69%
4-Cl: 3qi, 71%
4-Br: 3ri, 78%
O
O
O
O
N
H
Ph
N
Ph
X
H
3ti, 67%
4-OMe: 3bi, 63% 4-CF3: 3ci, 78%
4-NO2: 3si, 87%
O
O
O
O
O
O
O
O
O
S
N
Ph
N
Ph
Et
N
Ph
n-Hept
N
Ph
H
H
H
H
3di, 79%
3ei, 65%
3ji, (91%)b
3ki, (85%b,73%c)
O
O
O
O
O
O
Y = 4-OMe: 3aj, 78%
3-OMe: 3ak, 54%
2-OMe: 3al, 60%
4-Cl: 3am, 67%
MeO
N
H
Ph
N
H
Ph Ph
N
H
Y
N
3ui, 33%b,d(34%)c,d
3mi, 47%e
3-Br: 3an, 73%
O
O
O
O
O
O
O
O
N
Ph
Ph
N
H
Ph
N
H
N
Ph
N
H
Ph
N
H
Ph
N
3ao, 42%
3ap, 72%
3aq, 81%
3ar, 82%
O
O
O
O
O
O
N
H
n-Hept
Et
N
H
n-Hept
n-Hept
N
H
n-Hept
3as, (71%)f
3js, 73%g
3ks, 78%g(65%)c
aReaction conditions: 1 (0.5 mmol), 2 (0.55 mmol), CuCl (5 mol%),
t
TMEDA (5 mol%), nor-AZADO (3 mol%), BuOK (0.5 mmol), MS 3A
(200 mg), THF (2.5 mL), O2 (balloon), room temp. (ca. 23°C), 24 h.
Isolated yields are shown. GC yields are shown in parentheses.
b4-Cl-AZADO (3 mol%), without tBuOK. cWithout tBuOK. d2i (1.0 mmol).
eCuCl (10 mol%), TMEDA (10 mol%), nor-AZADO (6 mol%), without
tBuOK. ftBuOK (0.25 mmol). g1-Me-AZADO (3 mol%), without tBuOK.
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Table 4 Synthesis of α-ketoamides or α-ketoesters from 1,2-diols and nucleophilesa
[Cu(OH)(TMEDA)] Cl (Cu: 5 mol%)
2
2
O
OH
nor-AZADO (3 mol%)
Nu
amine
or alcohol
H
Nu
OH
+
R
O
R
MS 3A (200 mg)
O
1 (0.5 mmol)
THF (2 mL), O , room temp.
2
8 or 9
H
N
O
O
N
N
O
8vc, (91%)b
O
O
8va, (99%)b
8vb, (79%)c
n-Pentyl: 9vα, (>99%)e
O
Me: 9vi, 82%d
Et: 9vy, 94%e
n-Propyl: 9vj, 89%e
n-Butyl: 9vz, 90%e
R' =
O
n-Hexyl: 9vβ, (>99%)e
R'
i-Propyl: 9vγ, (71%)e
Benzyl: 9va, (96%)e
O
O
O
O
9wi, (95%)e
9xi, (85%)f
O
O
O
aReaction conditions: Diol (0.5 mmol), amine (0.6 mmol) or alcohol
(2.5 mmol), [Cu(OH)(TMEDA)]2Cl2 (Cu: 5 mol%), nor-AZADO (3 mol%),
MS 3A (200 mg), THF (2 mL), O2 (balloon), room temp. (ca. 23°C).
Values in parentheses are GC yields. b2 h. c24 h. d5 min. e1 h. f30 min.
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Page 25 of 31
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(a) Acylation of amides with carboxylic acid derivatives
O
O
O
O
base
R1
N
R3
R2
+
+
HX
R3
R2
N
H
R1
X
X = halogen, OCOR, OR
(b) Mumm rearrangement
R2
O
O
O
R3
R1
N
R3
R2
R1
O
N
(c) Oxidative decarboxylation
O
R2
O
O
[O]
O
R1
N
R2
+
CO2
R1
N
R3
R3 OH
(d) Cabonylative cross-coupling
O
O
O
R1
X
+
CO
+
R3
R1
N
R2
R2
N
H
R3
X = Br, I, H
(e) Oxygenation of amides
O
O
O
[O]
R1
N
R2
R1
N
R2
R3
R3
(f) This work: aerobic oxidative acylation of amides with alcohols
O
O
O
CuCl/TMEDA/nor-AZADO
O2
R1
OH
R3
+
R1
N
R3
R2
R2
N
H
1/2 O2
H2O
1/2 O2
H2O
O
(1)
(3)
R3
R2
N
H
OH
O
R1
O
R1
N
R2
(2)
R3
Scheme 1 Synthetic methods for imides.
25

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a) Gram-scale synthesis of aniracetam
O
CuCl (5 mol%), TMEDA (5 mol%)
nor-AZADO (3 mol%)
O
H
N
OH
O
N
+
MeO
MS 3A (4 g)
THF (25 mL), O2, room temp.
MeO
1b
(10 mmol)
2a
(11 mmol)
Aniracetam 3ba
93% Yield (2.0 g)
b) Synthesis of Evans imides
O
O
H
N
Bn
O
N
+
OH
O
O
CuCl (1 equiv.), TMEDA (1 equiv.)
nor-AZADO (6 mol%)
Bn
1j
(0.5 mmol)
2t
3jt
50% Yield, >99% ee
(0.55 mmol)
MS 3A (200 mg)
THF (2.5 mL), O2, room temp.
O
O
H
N
Bn
O
Ph
N
+
OH
Ph
O
O
Bn
1h
(0.5 mmol)
2t
(0.55 mmol)
3ht
57% Yield, >99% ee
Scheme 2 Gram-scale aniracetam synthesis and Evans imide synthesis.
Reaction conditions for a): 1b (10 mmol), 2a (11 mmol), CuCl (5 mol%),
TMEDA (5 mol%), nor-AZADO (3 mol%), MS 3A (4 g), THF (25 mL), O2
(balloon), room temp. (ca. 23°C), 2 h; for b): 1 (0.5 mmol), 2 (0.55 mmol),
CuCl (1 eq.), TMEDA (1 eq.), nor-AZADO (6 mol%), MS 3A (200 mg),
THF (2.5 mL), O2 (balloon), room temp. (ca. 23°C), 24 h. Isolated yields are
shown.
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Page 27 of 31
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DOI: 10.1039/C8SC01410H
1/2O2
L = TMEDA
N-oxyl = nor-AZADO
1/2 [LCu]2(O2)
LCuI
N-oxyl–H
step 1
A
B
+
R1
R1
1
1/2
OH
O
O
step 2
R1
N
R3
R2
1/2
4
O
N-oxyl
3
R1
OH
1/2O2
LCuII–OH
LCuI
C
A
step 6
step 3
step 9
step 10
N-oxyl–H
H2O
R1
N-oxyl
1/2 [CuII(OH)(L)]2
R1
O
C’
LCuII
O
1/2 [LCu]2(O2)
1/2 [LCu]2(O2)
LCuII
H2O
O
N
R3
R2
cycle I
cycle II
B
D
B
E
step 5
step 4
N-oxyl
step 8
step 11
N-oxyl–H
LCuI
LCuII–OH
OH
O
1/2O2
N-oxyl
R1
A
C
R1
N
R2
O
+
R3
step 7
O
N-oxyl–H
1/2 [CuII(OH)(L)]2
R3
R2
N
H
C’
2
Scheme 3 Plausible reaction mechanism for proposed CuCl/TMEDA/nor-AZADO-catalyzed oxidative
acylation of amides with alcohols.
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O
O
O
O2
2LCuI
LCuII
CuIIL
LCuIII
CuIIIL
O
side-on peroxo-bridged dimer
bis-ꢀ-oxo dimer
Scheme 4 Reaction of a CuI species and O2 in the presence of suitable ligands.
[CuII(OH)(TMEDA)]2Cl2 (Cu: 20 mol%)
O
O
O
nor-AZADO (20 mol%)
+
Ph
N
Ph
HN
O
MS 3A (200 mg)
THF (2.5 mL)
room temp.
4a
0.5 mmol)
2a
(0.55 mmol)
3aa
(
(i) Ar (1 atm), 1 h, 16% yield
(ii) O2 (1 atm), 1 h, 92% yield
Scheme 5 Control experiments.
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Page 29 of 31
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DOI: 10.1039/C8SC01410H
CuCl/ligand/nor-AZADO
O2
Ph
OH
Ph
O
1a
4a
CuCl/bpy/nor-AZADO
I-a)
I-b)
1
0.8
0.6
0.4
0.2
0
0.3
0.2
0.1
O2: first order
alcohol: zero order
0
0
0.2
0.4
0.6
0.8
1
0
0.05
0.1
0.15
0.2
0.25
P (O2) (atm)
[1a]0 (M)
CuCl/TMEDA/nor-AZADO
II-a)
II-b)
2
0.5
0.4
0.3
0.2
0.1
1.5
1
0.5
0
O2: first order
alcohol: zero order
0
0
0.2
0.4
0.6
0.8
1
0
0.05
0.1
0.15
0.2
0.25
P (O2) (atm)
[1a]0 (M)
Fig. 1 Dependence of I) CuCl/bpy/nor-AZADO-catalyzed and II) CuCl/TMEDA/nor-AZADO-catalyzed
alcohol oxidation on a) the partial pressure of O2 and b) concentration of 1a. Line fit: R0 = 0.754P (O2) (I-a, R2
= 0.985), R0 = 1.672P (O2) (II-a, R2 = 0.992). Reaction conditions for a): 1a (0.2 M), CuCl (10 mM), ligand
(10 mM), nor-AZADO (6 mM), MS 3A (200 mg), THF (2.5 mL), O2 (0.2–1.0 atm), room temp. (ca. 23°C);
for b): 1a (0.04–0.20 M), CuCl (10 mM), ligand (10 mM), nor-AZADO (6 mM), MS 3A (200 mg), THF
(2.5 mL), O2 (0.2 atm), room temp. (ca. 23°C). Yields were determined by GC analysis. Raw data are
summarized in Fig. S2, ESI†.
29