Metal-Free O-Selective Direct Acylation of Amino Alcohols Through Pseudo-Intramolecular Process

Article abstract of DOI:10.1002/ejoc.201801589

Efficient α-aryl-β-keto ester acylation of amine accompanied by the elimination of ethyl phenylacetate was achieved owing to the pseudo-intramolecular process. The eliminated ethyl phenylacetate could be recycled by conversion into an α-aryl-β-keto ester upon treatment with an acyl chloride in the presence of lithium bis(trimethylsilyl)amide, by which the atom economy considerably increased. Acylation using an α-aryl-β-keto ester is highly sensitive to the bulkiness of the nucleophile, which facilitated the regioselective-acylation of the less hindered amino group in diamine without protecting the other. The transacylation of α-aryl-β-keto ester with N-alkylamino alcohol resulted in chemoselective O-acylation without protecting the amino group because the hydroxy group was attracted to the reaction site of the keto ester by forming an ammonium salt. Transacylation was demonstrated to be a practically useful tool for organic synthesis because this protocol can be conducted under mild conditions with simple manipulations in the absence of any additives such as metal catalyst and base.

Full text of DOI:10.1002/ejoc.201801589

A Journal of
Accepted Article
Title: Metal-Free O-Selective Direct Acylation of Amino Alcohols via
Pseudo-Intramolecular Process
Authors: Soichi Yokoyama, Hiroshi Shibauchi, Haruyasu Asahara, and
Nagatoshi Nishiwaki
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801589
Link to VoR: http://dx.doi.org/10.1002/ejoc.201801589
Supported by

10.1002/ejoc.201801589
European Journal of Organic Chemistry
FULL PAPER
Metal-Free O-Selective Direct Acylation of Amino Alcohols via
Pseudo-Intramolecular Process
Soichi Yokoyama,[a,b] Hiroshi Shibauchi,[a] Haruyasu Asahara,[a,b,c] and Nagatoshi Nishiwaki*[a,b]
Abstract: Efficient a-aryl-b-keto ester acylation of amine
accompanied by the elimination of ethyl phenylacetate, was
achieved owing to the pseudo-intramolecular process. The
eliminated ethyl phenylacetate could be recycled by converting to an
a-aryl-b-keto ester upon treatment with an acyl chloride in the
presence of lithium bis(trimethylsilyl)amide, by which atom economy
considerably increased. Acylation using an a-aryl-b-keto ester is
highly sensitive to the bulkiness of the nucleophile, which facilitated
the regioselective-acylation of the less hindered amino group in
diamine without protecting the other. The transacylation of a-aryl-b-
keto ester with N-alkylamino alcohol resulted in chemoselective O-
acylation without protecting the amino group because the hydroxy
group was attracted to the reaction site of the keto ester by forming
an ammonium salt. Transacylation was demonstrated to be a
practically useful tool for organic synthesis because this protocol can
be conducted under mild conditions with simple manipulations in the
absence of any additives such as metal catalyst and base.
selectivity depended on the bulkiness of the N-alkyl group of
diamine.[1] These reagents were also effective for recognition of
the presence of
a
methyl group at the a-position.[4-6]
Regioselective control for the acylation of 3,4-diaminopyridine
was also achieved by using acetyl chloride or tert-butyl
dicarbonate.[7]
Selective N-acylation of amino alcohols was performed by using
lipase[8] and dibutyltin oxide[9] as a catalyst, and both methods
were conducted under microwave irradiation. N-Acylation of a,b-
diamino alcohol was also reported.[10] Regarding O-acylation of
amino alcohols, only a few reports are found in the literature
(Scheme 1). A combination of 2,2’-bipyridyl-6-yl carboxylate and
cesium
fluoride
underwent
O-acetylation
of
4-(2-
hydroxyethyl)aniline, however, O,N-diacetylation also occurred
(eq. 1).[11] RajanBabu et al. demonstrated selective O-acylation
of 2-hydroxymethylpiperidine by acetyl transfer reaction from
isopropenyl acetate in the presence of Y5(OPri)13O catalyst (eq.
2).[12] Recently, excellent methods have been developed using
µ-oxo-dinuclear iron(III) salen complex (eq. 3),[13] alkoxy-bridged
dinuclear cobalt complex (eq. 4),[14] (Bu4N)6·[g-HGeW10O36] (eq.
5)[15] and N-heterocyclic carbine (eq. 6),[16] by which O-acylation
of versatile amino alcohols was achieved. However, these
methods require special reagents or metal catalysts, which
prompted us to study the transacylation as a general and metal-
free protocol for the selective acylation.
Introduction
Acylation is one of the fundamental reactions for chemical
conversion, and numerous methods and acylating reagents have
been developed. However, it is still challenging even now to
acylate an amino/a hydroxy group of polyamines/amino alcohols
selectively without any modification or protection of the other
sites. Among selective acylation methods, monoacylation of a
polyamine possessing plural equivalent amino groups is
relatively easy.[1,2] Recognition between primary and secondary
amino groups in N-alkyl-1,2-diaminoethanes was possible by
using acylimidazole,[1] 3-acyl-1,3-thiazolidine-2-thione,[3] N-acyl-
2-amino-1,3-thiazoline,[4] N,N-diacyl-2-trifluoromethylaniline,[5]
and N-acyl-N-mesyl-2-fluorolaniline,[6] although the control of the
Meanwhile, we previously disclosed several efficient reactions,
that proceed in a similar manner to an intramolecular reaction,
even in the absence of additives.[17-19] Of these reactions,
transacylation is illustrated in Scheme 2. The enolic hydroxy
group of a-aryl-b-keto ester 1 is highly acidic and attracts the
nearby amine 2 due to the formation of an ammonium enolate 3.
When the amine is liberated from the ammonium salt 3 under
equilibrium conditions, the nucleophilic amine 2 is located close
to the electrophilic keto ester 1, which is called an ‘intimate pair.’
The nearness facilitates an efficient reaction to produce amide 4
and the deacylated product 5.[18] This reaction proceeds in an
intramolecular reaction although it is actually intermolecular
[a]
Dr. S. Yokoyama, Mr. H. Shibauchi, Dr. H. Asahara, Prof. Dr. N.
Nishiwaki
1
reaction. It is a “pseudo-intramolecular reaction.” The H NMR
School of Environmental Science and Engineering
Kochi University of Technology
monitoring study demonstrated that the rate of the transacylation
is not affected by the polarity of the solvent, which is one of the
features of intramolecular reactions.[19] Although the
transacylation is expected to be a useful tool for elaborate
synthesis, this reaction faces several drawbacks. As the diversity
of commercially available b-keto esters is low, limited acyl groups
can be introduced. Furthermore, compound 5 formed during the
transacylation, is wasted, which considerably diminishes the
atom economy of this protocol. In this work, the acylation of
waste compound 5 by acyl chloride 6 or acid anhydride 8 was
Tosayamada, Kami, Kochi 782-8502, Japan
E-mail: nishiwaki.nagatoshi@kochi-tech.ac.jp
Homepage: http://www.env.kochi-tech.ac.jp/naga/nishiwaki-lab.html
Dr. S. Yokoyama, Dr. H. Asahara, Prof. Dr. N. Nishiwaki
Research Center for Material Science and Engineering
Kochi University of Technology
[b]
[c]
Dr. H. Asahara
Division of Applied Chemistry, Graduate School of Engineering
Osaka University
Yamadaoka 2-1, Suita, Osaka 565-0871, japan
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801589
European Journal of Organic Chemistry
FULL PAPER
studied[20] to prepare a-aryl-b-keto ester 1, which addresses the
above problems.
O
OH
O
O
CsF
+
+
H2N
H2N
O
N
O
eq. 1
rt
DMF
N
O
Y5(OPri)13O
OH
O
eq. 2
eq. 3
N
rt
neat
N
H
H
O
O
NH2
NH2
cat. A
O
+
Ph
O
O
CF3
PhMe
120 °C
HO
Ph
O
Ph
O
cat. B
HO
eq. 4
eq. 5
5 NH2
+
+
5 NH2
Ph
O
O
PhMe
110 °C
O
O
(Bu4N)6 [g-H2GeW10O36]
Ph
O
HO
5 NH2
5 NH2
Ph
DMSO
20 °C
O
+
_
N
N
NH2
N
I
NH2
O
O
NaH
THF
+
eq. 6
Oxidant C
rt
Ph
O
Ph
H
HO
But
O
A
B
C
N
Co
O
But
O
But
N
N
O
O
O
N
N
O
O
O
Co
N
O
N
O
But
Fe
Fe
O
N
O
But
But
Scheme 1. Reported O-selective acylation of amino alcohols without
protecting the amino group.
In addition to high efficiency, high sensitivity to the steric bulk is
a unique feature of transacylation. Because versatile a-aryl-b-
keto esters 1 could be prepared by the acylation of 5, the
influence of the steric factor on this reaction was determined
systematically, and the regio-/chemoselective acylations of
diamines and amino alcohols were also investigated.
We firstly screened the bases for the acylation of 2,4-
dinitrophenylacetate 5 by p-toluoyl chloride 6a (Table 1). When
sodium hydride was used, acylation proceeded to generate a
44% yield of target material 1a together with doubly acylated
product 7a (Entry 1). Bulky bases were used to suppress excess
acylation. While potassium t-butoxide exhibited
a similar
reactivity to sodium hydride, lithium bis(trimethylsilyl)amide
(LiHMDS) could generate a 57% yield of 1a in without any
detectable 7a (Entries 2 and 3). Furthermore, conducting the
Results and Discussion
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801589
European Journal of Organic Chemistry
FULL PAPER
reaction at 0 °C with longer reaction time enhanced the yield of
1a up to 90% (Entries 4–7).
+
R2NH3
R2NH2
H
H
_
O
O
O
O
O
O
O
R2NH2
O
R1
DNP
OEt
2
R1
OEt
R2
R1
OEt
OEt
+
R1
N
H
DNP
DNP
DNP
H
intimate pair
1
3
4
5
DNP: 2,4-dinitrophenyl
Scheme 2. Transacylation of 1 with amine by pseudo-intramolecular reaction
group caused side reactions, the cinnamoyl and ethoxymalonyl
groups persisted under the experimental conditions and
generated keto esters 1i–k (Entries 8–11, respectively). Both the
acyl and aroyl groups were efficiently transferred upon treatment
of the obtained a-aryl-b-keto esters 1a, 1c, 1d, and 1j and two
disadvantages of transacylation with propylamine, i.e., the low
diversity of 1 and generation of 5, were successfully overcome
(Table S1).
Table 1. Assessment of bases and temperatures for the synthesis of a-
aryl-b-keto ester 1a.
OH
O
O
1) Base
(2.0 equiv.)
THF, 20 min
Tol
OEt
O
DNP
1a
OEt
DNP
O
O
5
2)
Table 2. Assessment of the substituent of acid chloride for the synthesis of
a-aryl-b-keto ester 1.
Tol
Cl
Tol
OEt
2
6a (1.0 equiv.)
DNP
O
DNP: 2,4-dinitrophenyl
Tol: 4-methylphenyl
7a
O
OH
O
LiHMDS
R
Cl
Entry
Base
Temp.
Time
(h)
3
Yield (%)[a]
(2.0 equiv.)
6 (1.0 equiv.)
OEt
R
OEt
THF, 20 min
DNP
DNP
(°C)
rt
1a
44
39
57
7
7a
12
9
5
5
DNP: 2,4-dinitrophenyl
1
1
2
3
4
5
6
7
NaH
24
39
21
83
11
7
Entry
1
R
Yield of 1 (%)[a]
Recovery of 5 (%)[a]
t-BuOK
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
rt
3
p-Tol
a
b
c
d
e
f
90
84
42
42
40
0
trace
9
rt
3
0
2
Ph
-78
0
3
0
3
Me
33
36
35
88
68
—
3
61
74
90
0
4
Et
0
6
0
5
i-Pr
0
24
0
4
6
t-Bu
[a] Determined by 1H NMR
7
c-Hex
H2C=CH-
PhC=CH-
EtO-COCH2-
ClCH2-
g
h
i
25
trace
38
10
44
8
Under the optimized conditions, various acid chlorides 6 were
employed for the acylation of 2 (Table 2). Aroyl chlorides 6a and
6b efficiently reacted with 5 to generate the corresponding keto
esters 1a and 1b, respectively (Entries 1 and 2). In contrast, the
yields of keto esters 1c–g were lower in the presence of the more
reactive aliphatic acid chlorides 6c–g (Entries 3–7). These
results were presumably due to the high reactivity of products
1c–g, which undergo competitive deacylation resulting in the
recovery of starting material 5. It was also possible to introduce
a functionalized acyl group (Entries 8–11). While the acryloyl
9
57
76
24
10
11
j
k
[a] Determined by 1H NMR
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801589
European Journal of Organic Chemistry
FULL PAPER
also efficiently transferred to the primary amino group of 9 by
transacylation (Entries 7 and 10).
Table 3. Transacylation of a-aryl-b-keto ester 1, acid chloride 6, or acid
anhydride 8 with N-methylethylenediamine 9.
[21]
O
H
OH
O
Table 4. Evaluation of recognition ability of the transacylation using 1,2-
diaminopropane 13.
N
R
N
H
H
R
OEt
N
H2N
10
DNP
O
9 (1 equiv.)
NH2
1
or
N
R
CHCl3
1 d
R
N
H2N
O
H
O
11
O
14
15
H
NH2
1 or 6 or 8
R
X
N
R
H2N
N
R
H2N
O
CHCl3
1 d
R
N
X = Cl
6
H
O
OCOR 8
O
(1 equiv.)
12
13
Entry
Reagent
Temp.
Yield (%)[a]
H
N
R
R
N
R
(°C)
rt
10
90
17
16
30
16
96
94
21
43
94
2
11
0
12
0
H
O
1
Me
1c
6c
8c
6c
8c
1c
1d
6d
8d
1a
6a
1j
16
Yield (%)[a]
2[b]
3[b]
4[b]
5[b]
6
Me
rt
10
8
36
41
25
40
0
Entry
Reagent
R
Temp.
(°C)
rt
14
6
15
16
42
24
18
0
Me
rt
1[b]
2[b]
3[b]
4
Me
6c
8a
8a
1c
1d
1a
1j
6
3
Me
-30
-30
70
rt
17
6
Me
Me
rt
17
37
99
99
99
99
73
82
Me
0
Me
-30
rt
24
0
7
Et
0
0
Me
8 [b]
9[b]
10
11[b]
12[c]
Et
rt
3
39
26
0
5
Et
rt
0
0
Et
rt
8
6
p-Tol
CH2COOEt
Me
rt
0
0
p-Tol
p-Tol
CH2COOEt
rt
0
7
rt
0
0
rt
2
48
0
8
1c
1a
70
70
20
12
0
rt
99
0
9
p-Tol
0
[a] Determined by 1H NMR [b] 1 equiv. of triethylamine was added. [c] N-
[a] Determined by 1H NMR [b] 1 equiv. of triethylamine was added.
Ethylethylenediamine was used as a substrate.
Next, recognizing the ability of these acylating agents, the
existence of the methyl group at a-position in the diamine was
evaluated using 1,2-propanediamine (13) as a substrate. When
acid chloride 6c or acid anhydride 8c was used, a mixture of 14,
15, and diacylated compound 16 was obtained,[21] indicating that
the presence of a-methyl group was not recognized (Entries 1–
3 in Table 4 and Entries 1–5 in Table S2). To the contrary, the
transacylation recognized subtle difference of two amino groups
in 13 to generate N-(2-amino-1-propyl)acetamide (14c)
exclusively (Entry 4 in Table 4). The reaction using 1d and 1a
also generated quantitative yields of the corresponding
compounds 14d and 14a, respectively (Entries 5 and 6 in Table
4). High regioselectivity was still observed when the reaction was
conducted at 70 °C (Entries 8 and 9). a-Aryl-b-keto ester 1 was
confirmed to serve as an acylating agent for the regioselective
acylation of diamines without the necessity for any modification
of the similar, but somewhat bulkier, amino group.
Transacylation using a-aryl-b-keto ester 1 is sensitive to the
bulkiness of amine 2,[18] which has the potential to facilitate regio-
and chemoselective acylation; however, there has been no
systematic study of this. With regard to the selective acylation of
diamines without any protection, only a few reports are found.[1,3
–
6]
For comparison, keto ester 1, acid halides 6, and acid
anhydrides
8
underwent
the
reaction
with
N-
methylethylenediamine 9 (Table 3). The transacylation of 1c with
9 resulted in exclusive acylation at the primary amino group
without any protection of the secondary amino group, even in the
absence of a base (Entry 1). However, acid chloride 6c and acid
anhydride 8c could not recognize the two amino groups of 9, and
double acylation also occurred, which could not be suppressed
at -30 °C (Entries 2–5). During transacylation using 1c, high
selectivity was maintained and only 10 was generated, even at
70 °C (Entry 6). Furthermore, propanoyl and toluoyl groups were
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801589
European Journal of Organic Chemistry
FULL PAPER
Table 5. Transacylation using amino alcohol 17.
O
N
OH
O
O
H
1c or 6c
or 8c
CHCl3
1 d
OH
OH
H2N
OH
18
H2N
Tol
N
H
O
17
(1 equiv.)
H2N
(1 equiv.)
20
21 (71%)
CHCl3
rt, 5 d
19
OH
O
O
Tol
Entry
Acylating Reagent
Yield (%)[a]
H2N
Tol
OEt
O
DNP
1a
18
19
22 (28%)
1[b]
2[b]
3
6c
8c
1c
82
99
99
15
0
Scheme 3. Transacylation of 1a with 2,2-dimethyl-2-aminoethanol 20.
0
[a] Determined by 1H NMR [b] 1 equiv. of triethylamine was added.
Table 6. Chemoselective acylation of N-alkyl-ethanolamines 23-26.
R2
OH
OH
O
N
n
H
R1
OEt
R2 = Me 23, Et 24
O
O
R2
O
n
R1
DNP
1
O
Me
OH
n
i-Pr 25, t-Bu 26
R1
N
R2
N
Me
N
But
(1 equiv.)
H
O
or
O
CHCl3
O
R2 = Me 27, Et 28
i-Pr 29, t-Bu 30
R2 = Me 31, Et 32
i-Pr 33, t-Bu 34
35
X = Cl 6
R1
X
OCOR 8
Entry
Acylating reagent
R1
Amino alcohol
Temp.
Time
(d)
1
Yield of product (%)[a]
R2
n
1
1
1
1
1
1
1
1
2
3
1
2
3
(°C)
rt
N-Acylated product
O-Acylated product
1[b,c]
2[b,d]
3[b]
4[b]
5
Me
6c
6c
6c
8c
1c
1c
1c
1c
1c
1c
1a
1a
1a
t-Bu
t-Bu
Et
26
30
35
23
49
40
96
95
34
0
34
31
37
29
60
0
Me
26
-30
rt
1
30
34
Me
24
1
28
28
Me
Et
24
rt
1
28
28
Me
Me
Et
23
rt
4
27
31
6
Me
24x
25
rt
5
28cx
29
32cx
33
0
7
Me
i-Pr
t-Bu
Et
rt
5
66
94
88
75
92
86
84
8
Me
26
rt
4
30
34
9
Me
24y
24z
24x
24y
24z
rt
6
28cy
28cz
28ax
28ay
28az
9
32cy
32cz
32ax
32ay
32az
10
11
12
13
Me
Et
rt
6
19
0
p-Tol
p-Tol
p-Tol
Et
rt
1
Et
rt
7
8
Et
rt
7
8
[a] Determined by 1H NMR. [b] 1 equiv. of triethylamine was added. [c] 35 was obtained in 16% yield. [d] 35 was obtained in 6% yield.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801589
European Journal of Organic Chemistry
FULL PAPER
+
O
Et
OH
Et
OH
Et
N
N
n
OH
n
N
n
N-acylation
OH
N
H
H2
H
_
n = 1
n = 1 24x, n= 2 24y
n= 3 24z
OH
O
O
O
Et
O
O
28cx
OEt
OEt
OEt
DNP
1c
DNP: 2,4-dinitrophenyl
DNP
36
DNP
37
Et
O
n
N
O-acylation
H
O
n > 2
32cy, 32cz
Scheme 4. A plausible mechanism of the O-acylation of 2-(ethylamino)ethanol 24.
When amino alcohol 17 reacted with acetyl chloride 6c, both the
amino and hydroxy groups were acylated, even at -30 °C (Entry
1 in Table 5 and Entry 1 in Table S3). Although acid anhydride
8c only underwent N-acylation, triethylamine was required to
capture the acid generated during the reaction (Entry 2 in Table
5 and Entries 4–8 in Table S3). However, transacylation using a-
aryl-b-keto ester 1c required neither protection of the hydroxy
group, nor the addition of a base, which solely generated N-
acylated product 18[21] entirely (Entry 3 in Table 5).
isolated product in CDCl3 was monitored for more than 1 d
(Figures S1–S4).
Table 7. List of reaction order n and rate constant k
[A]0 (mM)[a]
n
k (M-1 sec-1)
2.6 × 10−4
8.6 × 10−5
1.4 × 10−5
200
41
2.0
1.5
1.4
The chemoselective acylation of a hydroxy group in an amino
alcohol usually requires protection of the amino group or use of
metal catalyst as shown in Scheme 1. Hence, it is more
challenging to acylate a hydroxy group directly without any
contrivance under catalyst free conditions. To achieve the
selective O-acylation, a substituent was introduced at the a-
position of the amino group, however, no positive effect was
observed, even though a bulky substituent was introduced, such
as a phenyl or benzyl group (Table S4). The two methyl groups
of 20 prevented N-acylation to some extent and generated a
small amount of O-acylated product 22, but the chemoselectivity
was not satisfactorily controlled (Scheme 3 and Entries 3 and 4
in Table S5). Hence, N-substituted amino alcohols 23–26 were
employed. When acetyl chloride 6c or acetic anhydride 8c was
used, both N- and O-acylation proceeded (Entries 1–4 in Table
6). In contrast, transacylation using 1c facilitated O-acetylation
(Entries 5–8 in Table 6), and chemoselective acylation was
completely achieved when the t-butyl group was introduced into
the amino group (Entry 8 in Table 6). When aroylation occurred,
the introduction of a N-substituent larger than ethyl group was
suitable for selective O-acylation (Entries 1–4 in Table S6).
Interestingly, the chemoselectivity was considerably affected by
the distance between an amino and a hydroxy group of 24
(Entries 6 and 9–13 in Table 6 and Entries 9–14 in Table S6).
While 2-(ethylamino)ethanol 24x only underwent N-acetylation
(Entry 6 in Table 6), 3-(ethylamino)propanol 24y and 4-
(ethylamino)butanol 24z generated O-acetylated 32cy and 32cz
as main products (Entries 7 and 8 in Table 6). A similar tendency
was observed during aroylation using 1a, which efficiently
generated the corresponding O-toluoyl esters 32ax–32az
(Entries 11–13 in Table 6 and Entries 12–14 in Table S6). It
should be emphasized that interconversion between products 28
and 32 was not observed at all even though a solution of each
8.9
[a] [A]0 is the initial concentration of ammonium enolate derived from 1a and
24x.
In our previous work, we monitored the transacylation between
1
1c and propylamine by H NMR with different concentration of
the reaction mixture.[19] Although the reaction rate varied
depending on the concentration, it became almost same in highly
diluted solutions, and the reaction order was lower than second
order. These results imply that not only a first order reaction but
also a second order reaction proceed in the present system. So,
the reaction of 1a and 24x was also monitored in the same way,
and results are shown in Table 7 and Figure S5. As the
concentration of the reaction mixture decreased, reaction order
and reaction rate decreased, which is a similar tendency to the
previous work.
A plausible mechanism for the chemoselectivity by the length of
the alkyl spacer is illustrated in Scheme 4. Transacylation was
initiated by the formation of ammonium enolate 36, from which
an amine was liberated to provide intimate pair 37.[18] Since the
quantitative formation of ammonium salt 36 was confirmed just
after addition of the amino alcohol 24x to a solution of keto ester
1, the higher reaction order is caused by the intermolecular
reaction between two intimate pairs (Figure 1). When 2-
(ethylamino)ethanol 24x was used, the hydroxy group of intimate
pair 37x was located too far from the reaction site to attack the
electrophilic carbonyl carbon due to the short alkyl chain, thus,
N-acylation proceeded to exclusively generate 28cx. However,
3-(ethylamino)propanol 24y and 4-(ethylamino)butanol 24z have
a long enough alkyl spacer enough to locate the hydroxy group
near the electrophilic carbonyl carbon, which facilitates the O-
acylation which predominantly generates 32cy and 32cz.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801589
European Journal of Organic Chemistry
FULL PAPER
General procedure for preparation of compound
phenylacetate 5
1
from
DNP
To a solution of a-(2,4-dinitrophenyl)ethyl acetate 5 (0.254 g, 1.0 mmol)
in THF (5 mL), was slowly added 1.1 M lithium bis(trimethylsilyl)amide
(1.8 mL, 2.0 mmol) in THF over 10 min at 0 °C under nitrogen. After
stirring the mixture for 20 min at 0 °C, p-toluoyl chloride (0.13 mL, 1.0
mmol) was added, and stirred for further 1 d with keeping the temperature.
The reaction was quenched with addition of 3 M HCl (2.0 mL, 6.0 mmol),
and extracted with ethyl acetate (20 mL ´ 3). The organic layer was dried
over MgSO4, filtered and evaporated in vacuo. The product was purified
with column chromatography on silica gel (dichloromethane as an eluent)
to afford yellow solid 1a (0.268 g, 0.72 mmol, 72%). When other acid
chlorides were used, experiments were conducted in the same way.
OEt
H
O
O
O
n
+
H
H
H
N
N
Et
n Et
O
H
O
O
OEt
DNP
Ethyl
3-hydroxy-3-(4-methylphenyl)-2-(2,4-
Figure 1. Intermolecular reaction between two intimate pairs.
dinitrophenyl)propenoate (1a). Yield 0.335 g, 0.90 mmol, 90% (enol
form/keto form = 73/27); yellow solid; mp 99–100 °C. 1H NMR (400 MHz,
CDCl3) enol form: δ 1.17 (dd, J = 7.2, 7.2 Hz, 3H), 2.30 (s, 3H), 4.09 (dq,
J = 7.2, 10.8 Hz, 1H), 4.29 (dq, J = 7.2, 10.8 Hz, 1H), 7.03 (d, J = 8.0 Hz,
2H), 7.14 (d, J = 8.4 Hz, 1H), 7.18 (d, J = 8.0 Hz, 2H), 8.11 (dd, J = 2.4,
8.4 Hz, 1H), 8.80 (d, J = 2.4 Hz, 1H), 13.57 (s, 1H); keto form: δ 1.24 (t,
J = 7.2 Hz, 3H), 2.42 (s, 3H), 4.27 (q, J = 7.2 Hz, 2H), 6.43 (s, 1H), 7.29
(d, J = 8.0 Hz, 2H), 7.83 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 8.0 Hz, 2H), 8.44
(dd, J = 2.4, 8.4 Hz, 1H), 8.88 (d, J = 2.4 Hz, 1H); 13C NMR (100 MHz,
CDCl3) enol form: δ 13.7 (CH3), 21.5 (CH3), 61.9 (CH2), 100.0 (C), 119.9
(CH), 126.4 (CH), 129.0 (CH), 129.1 (CH), 130.7 (C), 136.4 (CH), 137.7
(C), 145.7 (C), 146.5 (C), 149.8 (C), 170.3 (C), 173.2 (C); keto form: δ
14.0 (CH3), 21.8 (CH3), 55.4 (CH), 62.8 (CH2), 120.5 (CH), 127.2 (CH),
129.0 (CH), 129.8 (CH), 132.7 (C), 133.7 (CH), 135.0 (C), 141.6 (C),
147.5 (C), 148.9 (C), 167.0 (C), 190.9 (C); IR (ATR/cm-1) 1337, 1537,
1605, 1643; HRMS (ESI/TOF) m/z Calcd. for C18H16N2O7Na [M+Na]+
395.0850, Found 395.0865.
Conclusions
A method for recycling ethyl phenylacetate 5 generated by
transacylation was developed. The quantitative acylation of ethyl
phenylacetate 5 was achieved upon treatment with LiHMDS as
a base, generating a-aryl-b-keto esters 1 by acid chloride 6, by
which the atom economy was considerably improved. The
obtained a-aryl-b-keto esters 1 underwent transacylation with
alkylamine 2, quantitatively generating amides 4. This protocol
facilitates regioselective acylation by the recognition of the
different environments of the two amino groups in diamines 9
and 13, which is not conducted by alternative acylating agents
such as acid chloride 6 and acid anhydride 8. Furthermore, the
reactions of N-alkylated aminoalcohols 23–26 with a-aryl-b-keto
esters 1 achieve chemoselective O-acylation as the hydroxy
group approached the carbonyl carbon of the keto ester caused
by the pseudo-intramolecular process.
2-Ethoxycarbonyl-1,3-bis(4-methylphenyl)-2-(2,4-dinitrophenyl)-1,3-
propanedione (7a). Yield 0.162 g, 0.33 mmol, 33%; white solid; mp 159–
160 °C. 1H NMR (400 MHz, CDCl3) δ 0.98 (t, J = 7.2 Hz, 3H), 2.27 (s, 3H),
2.45 (s, 3H), 4.05 (q, J = 7.2 Hz, 2H), 6.99 (d, J = 8.4 Hz, 2H), 7.12 (d, J
= 8.4 Hz, 1H), 7.32 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 8.10 (d,
J = 8.4 Hz, 2H), 8.19 (dd, J = 2.4, 8.4 Hz, 1H), 8.94 (d, J = 2.4 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 13.7 (CH3), 21.4 (CH3), 21.8 (CH3), 61.6
(CH2), 119.7 (C), 120.1 (CH), 126.2 (C), 127.2 (CH), 129.2 (CH), 129.35
(CH), 129.41 (CH), 130.5 (CH), 131.2 (C), 136.3 (CH), 138.8 (C), 141.3
(C), 144.9 (C), 147.2 (C), 149.2 (C), 156.9 (C), 163.0 (C), 164.4 (C); IR
(ATR/cm−1) 1342, 1357, 1510, 1534, 1611, 1624, 1735; HRMS (ESI/TOF)
m/z Calcd. for C26H22N2O8Na [M+Na]+ 513.1268, Found 513.1263.
This method can be conducted with simple experimental
manipulations under mild conditions without necessity to use
specific base and/or metal catalyst agents. These features are
advantageous compared with conventional reagents for the
selective acylation. Hence, this protocol will be an
environmentally
benign
tool
for
the
synthesis
of
polyfunctionalized compounds.
Ethyl 3-hydroxy-2-(2,4-dinitrophenyl)-3-phenylpropenoate (1b).[22]
Yield 0.301 g, 0.84 mmol, 84% (enol form/keto form = 75/25); yellow solid,
mp 133–135 °C. 1H NMR (400 MHz, CDCl3) wnol form: δ 1.18 (dd, J =
7.2, 7.2 Hz, 3H), 4.10 (dq, J = 7.2, 10.8 Hz, 1H), 4.29 (dq, J = 7.2, 10.8
Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 7.22–7.36 (m, 5H), 8.10 (dd, J = 2.4,
8.4 Hz, 1H), 8.80 (d, J = 2.4 Hz, 1H), 13.57 (s, 1H); keto form: δ 1.24 (t,
J = 7.2 Hz, 3H), 4.32 (q, J = 7.2 Hz, 2H), 6.46 (s, 1H), 7.48–7.52 (m, 2H),
7.61–7.65 (m, 2H), 7.84 (d, J = 8.4 Hz, 1H), 7.94–7.96 (m, 1H), 8.46 (dd,
J = 2.4, 8.4 Hz, 1H), 8.90 (d, J = 2.4 Hz, 1H); 13C NMR (100 MHz, CDCl3)
enol form: δ 13.7 (CH3), 62.0 (CH2), 100.5 (C), 119.9 (CH), 126.3 (CH),
128.4 (CH), 128.9 (CH), 130.9 (CH), 133.6 (C), 136.3 (CH), 137.4 (C),
146.6 (C), 149.8 (C), 170.2 (C), 172.9 (C); keto form: δ 13.9 (CH3), 55.5
(CH), 62.8 (CH2), 120.5 (CH), 127.2 (CH), 128.8 (CH), 129.1 (CH), 133.6
(CH), 134.4 (CH), 134.8 (C), 135.2 (C), 147.5 (C), 148.8 (C), 166.9 (C),
191.3 (C); IR (ATR/cm-1) 1337, 1537, 1620, 1730, 1745; HRMS
(ESI/TOF) m/z Calcd. for C17H18N6O7 [M+NH4]+ 376.1139, Found
376.1152.
Experimental Section
General
The melting points were determined on SRS-Optimelt Automated Melting
Point System, and were uncorrected. All the reagents and solvents were
commercially available and used as received. The 1H NMR spectra were
measured on a Bruker Ascend-400 at 400 MHz with tetramethylsilane as
an internal standard. The 13C NMR spectra were measured on a Bruker
Ascend-400 at 100 MHz, and assignments of 13C NMR spectra were
performed by DEPT experiments. The high-resolution mass spectra were
measured on an AB SCIEX Triple TOF 4600. The IR spectra were
recorded on a JASCO FT/IR-4200 spectrometer.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801589
European Journal of Organic Chemistry
FULL PAPER
Ethyl 3-hydroxy-2-(2,4-dinitrophenyl)-2-butenoate (1c).[18] Yield 0.124
g, 0.42 mmol, 42% (enol form/keto form = 93/7); yellow needles; mp 93–
95 °C. 1H NMR (400 MHz, CDCl3) enol form: δ 1.13 (dd, J = 7.2, 7.2 Hz,
3H), 1.92 (s, 3H), 4.05 (dq, J = 7.2, 10.8 Hz, 1H), 4.22 (dq, J = 7.2, 10.8
Hz, 1H),7.53 (d, J = 8.4 Hz, 1H), 8.43 (dd, J = 2.4, 8.4 Hz, 1H), 8.84 (d, J
= 2.4 Hz, 1H), 13.14 (s, 1H); keto form: δ 1.29 (t, J = 7.2 Hz, 3H), 2.48 (s,
3H), 4.29 (q, J = 7.2 Hz, 2H), 5.42 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H), 8.48
(dd, J = 2.4, 8.4 Hz, 1H), 8.89 (d, J = 2.4 Hz, 1H);13C NMR (100 MHz,
CDCl3) enol form: δ 13.8 (CH3), 20.0 (CH3), 61.5 (CH2), 99.8 (C), 120.1
(CH), 126.7 (CH), 135.3 (CH), 136.6 (C), 147.2 (C), 149.7 (C), 170.0 (C),
174.3 (C); keto form: δ 13.9 (CH3), 30.2 (CH3), 61.0 (CH), 62.8 (CH2),
120.4 (CH), 127.2 (CH), 134.0 (CH), 134.7 (C), 147.2 (C), 149.7 (C),
166.5 (C), 198.1 (C); IR (ATR/cm-1) 1337, 1537, 1643; HRMS (ESI/TOF)
m/z Calcd. for C12H12N2O7Na [M+Na]+ 319.0537, Found 319.0543.
13.8 (CH3), 25.4 (CH2), 25.5 (CH2), 25.5 (CH2), 29.1 (CH2), 29.4 (CH2),
42.3 (CH), 61.4 (CH2), 97.9 (C), 120.1 (CH), 126.6 (CH), 135.1 (CH),
136.7 (C), 147.2 (C), 149.9 (C), 170.4 (C), 180.7 (C); keto form δ 14.0
(CH3), 25.6 (CH2), 28.3 (CH2), 28.7 (CH2), 51.2 (CH), 58.0 (CH), 62.7
(CH2), 120.3 (CH), 127.0 (CH), 133.7 (CH), 134.4 (C), 147.2 (C), 149.9
(C), 166.7 (C), 203.7 (C); IR (ATR/cm-1) 1337, 1537, 1599, 1643, 1649;
HRMS (ESI/TOF) m/z Calcd. for C17H20N2O7Na [M+Na]+ 387.1163,
Found 387.1162.
Ethyl
3-hydroxy-2-(2,4-dinitrophenyl)-5-phenyl-2,4-pentadienoate
(1i).[23] Yield 0.146 g, 0.38 mmol, 38%; yellow solid, mp 53–55 °C. 1H
NMR (400 MHz, CDCl3) δ 1.16 (dd, J = 7.2, 7.2 Hz, 3H), 4.09 (dq, J = 7.2,
10.8 Hz, 1H), 4.27 (dq, J = 7.2, 10.8 Hz, 1H), 6.28 (dd, J = 0.8, 15.6 Hz,
1H), 7.30–7.41 (m, 5H), 7.60 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 15.6 Hz,
1H), 8.46 (dd, J = 2.4, 8.4 Hz, 1H), 8.90 (d, J = 2.4 Hz, 1H), 13.14 (s, 1H);
13C NMR (100 MHz, CDCl3) 13.7 (CH3), 61.7 (CH2), 100.5 (C), 118.2 (CH),
120.3 (CH), 126.6 (CH), 127.9 (CH), 128.8 (H), 130.0 (CH), 134.8 (C),
136.1 (CH), 140.1 (CH), 147.2 (C), 149.7 (C), 167.4 (C), 170.2 (C), one
signal was not observed because of the overlapping; IR (ATR/cm-1) 1340,
1530, 1582, 1600, 1629, 1646; HRMS (ESI/TOF) m/z Calcd. for
C19H16N2O7Na [M+Na]+ 407.0850, Found 407.0842.
Ethyl 3-hydroxy-2-(2,4-dinitrophenyl)-2-pentenoate (1d).
Yield 0.105 g, 0.34 mmol, 34% (enol form/keto form = 85/15);
yellow oil. 1H NMR (400 MHz, CDCl3) enol form: δ 1.11 (dd, J =
7.6, 7.6 Hz, 3H), 1.12 (dd, J = 7.2, 7.2 Hz, 3H), 2.13 (dq, J = 2.8,
7.6 Hz, 1H), 2.14 (dq, J = 2.8, 7.6 Hz, 1H), 4.05 (dq, J = 7.2, 10.8
Hz, 1H), 4.23 (dq, J = 7.2, 10.8 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H),
8.42 (dd, J = 2.4, 8.4 Hz, 1H), 8.83 (d, J = 2.4 Hz, 1H), 13.18 (s,
1H); keto form: δ 1.14 (dd, J = 7.2, 7.2 Hz, 3H), 1.28 (t, J = 7.2
Hz, 3H), 2.72 (dq, J = 4.0, 7.2 Hz, 1H), 2.85 (dq, J = 4.0, 7.2 Hz,
1H), 4.27 (q, J = 7.2 Hz, 2H), 5.46 (s, 1H), 7.78 (d, J = 8.4 Hz,
Diethyl 3-hydroxy-2-(2,4-Dinitrophenyl)-2-pentenedioate (1j).[18] Yield
0.063 g, 0.17 mmol, 17%; yellow oil. 1H NMR (400 MHz, CDCl3) δ 1.13
(dd, J = 7.2, 7.2 Hz, 3H), 1.25 (dd, J = 7.2, 7.2 Hz, 3H), 3.07 (d, J = 15.2
Hz, 1H), 3.21 (d, J = 15.2 Hz, 1H), 4.01–4.29 (m, 4H), 7.70 (d, J = 8.4 Hz,
1H), 8.44 (dd, J = 2.4, 8.4 Hz, 1H), 8.88 (d, J = 2.4 Hz, 1H), 13.05 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 13.7 (CH3), 14.0 (CH3), 39.5 (CH2), 61.9
(CH2), 61.9 (CH2), 102.4 (C), 120.2 (CH), 127.1 (CH), 135.1 (CH), 135.6
(C), 147.6 (C), 149.5 (C), 167.5 (C), 168.2 (C), 169.9 (C); IR (ATR/cm-1)
1337, 1537, 1643, 1651, 1659, 1730, 1738, 1742; HRMS (ESI/TOF) m/z
Calcd. for C15H16N2O9Na [M+Na]+ 391.0748, Found 391.0748.
1H), 8.47 (dd, J = 2.4, 8.4 Hz, 1H), 8.86 (d, J = 2.4 Hz, 1H); 13
C
NMR (100 MHz, CDCl3) enol form: δ 10.7 (CH3), 13.8 (CH3), 26.7
(CH2), 61.5 (CH2), 98.9 (C), 120.1 (CH), 126.7 (CH), 135.2 (CH),
136.6 (C), 147.2 (C), 149.8 (C), 170.2 (C), 178.2 (C); keto form:
δ 7.7 (CH3), 13.9 (CH3), 36.5 (CH2), 59.8 (CH), 62.8 (CH2), 120.3
(CH), 127.0 (CH), 133.9 (CH), 134.6 (C), 147.5 (C), 149.0 (C),
166.6 (C), 201.1 (C); IR (ATR/cm-1) 1337, 1537, 1643, 1651,
1730, 1746; HRMS (ESI/TOF) m/z Calcd. for C13H14N2O7Na
Ethyl 4-chloro-3-hydroxy-2-(2,4-dinitrophenyl)-2-butenoate (1k).
Yield: 0.135 g, 0.41 mmol, 41%; yellow oil; 1H NMR (400 MHz, CDCl3) δ
1.14 (dd, J = 7.2, 7.2 Hz, 3H), 3.77 (d, J = 12.0 Hz, 1H), 3.98 (d, J = 12.0
Hz, 1H), 4.08 (dq, J = 7.2, 10.8 Hz, 1H), 4.28 (dq, J = 7.2, 10.8 Hz, 1H),
7.72 (d, J = 8.4 Hz, 1H), 8.50 (dd, J = 2.4, 8.4 Hz, 1H), 8.92 (d, J = 2.4
Hz, 1H), 12.94 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 13.7 (CH3), 40.8
(CH2), 62.3 (CH2), 102.3 (C), 120.3 (CH), 127.3 (CH), 134.7 (CH), 134.7
(C), 147.8 (C), 149.4 (C), 168.2 (C), 169.7 (C); IR (ATR/cm-1) 1337, 1537,
1599, 1643, 1694, 1730; HRMS (ESI/TOF) m/z Calcd. for
C12H11ClN2O7Na [M+Na]+ 353.0147, Found 353.0157.
[M+Na]+ 333.0693, Found 333.0683.
Ethyl 3-hydroxy-4-methyl-2-(2,4-dinitrophenyl)-2-pentenoate (1e).
Yield 0.117 g, 0.36 mmol, 36% (enol form/keto form = 91/9); yellow oil.
1H NMR (400 MHz, CDCl3) enol form: δ 1.05 (d, J = 6.8 Hz, 3H), 1.11 (dd,
J = 7.2, 7.2 Hz, 3H), 1.16 (d, J = 6.8 Hz, 3H), 2.31 (qq, J = 6.8, 6.8 Hz,
1H), 4.03 (dq, J = 7.2, 10.8 Hz, 1H), 4.22 (dq, J = 7.2, 10.8 Hz, 1H), 7.51
(d, J = 8.4 Hz, 1H), 8.42 (dd, J = 2.4, 8.4 Hz, 1H), 8.81 (d, J = 2.4 Hz, 1H),
13.19 (s, 1H); keto form: δ 1.16 (d, J = 6.8 Hz, 3H), 1.21 (d, J = 6.8 Hz,
3H), 1.28 (t, J = 7.2 Hz, 3H), 2.95 (qq, J = 6.8, 6.8 Hz, 1H), 4.26 (q, J =
7.2 Hz, 2H), 5.69 (s, 1H), 7.80 (d, J = 8.4 Hz, 1H), 8.45 (dd, J = 2.4, 8.4
Hz, 1H), 8.84 (d, J = 2.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) enol form:
δ 13.8 (CH3), 19.3 (CH3), 31.9 (CH), 61.4 (CH2), 97.8 (C), 120.0 (CH),
126.7 (CH), 135.2 (CH), 136.6 (C), 147.2 (C), 149.8 (C), 170.4 (C), 181.2
(C); keto form: δ 13.9 (CH3), 18.1 (CH3), 18.3 (CH3), 41.4 (CH), 58.0 (CH),
62.7 (CH2), 120.3 (CH), 127.0 (CH), 133.7 (CH), 134.6 (C), 147.4 (C),
149.1 (C), 166.7 (C), 204.6 (C); IR (ATR/cm-1) 1337, 1537, 1599, 1643,
1649, 1730; HRMS (ESI/TOF) m/z Calcd. for C14H16N2O7Na [M+Na]+
347.0850, Found 347.0838.
General procedure of the transacylation of
diamine or amino alcohol
-aryl- -keto ester with
a b
To a solution of a-(2,4-dinitrophenyl)-b-keto ester 1a (186 mg, 0.5 mmol)
in CHCl3 (2.0 mL), was added 1,2-diaminopropane 13 (43 µL, 0.5 mmol),
and the resultant solution was stirred for 1 day at room temperature. After
the solvent was removed under the reduced pressure, the mixture was
treated with column chromatography on silica gel to afford deacylated
ester 5 (121 mg, 0.476 mmol, 96%, eluted with dichloromethane) and
compound 14a (64.9 mg, 0.495 mmol, 99%, eluted with methanol). When
other keto esters, diamines, and amino alcohols were used, reactions
were conducted in a similar way.
Ethyl 3-cyclohexyl-3-hydroxy-2-(2,4-dinitrophenyl)propenoate (1g).
Yield 0.084 g, 0.23 mmol, 23% (enol form/keto form = 90/10); yellow oil.
1H NMR (400 MHz, CDCl3) enol form δ 0.95–1.08 (m, 2H), 1.11 (dd, J =
7.2, 7.2 Hz, 3H), 1.56–1.62 (m, 4H), 1.65–1.71 (m, 4H), 1.92–1.97 (m,
1H), 4.03 (dq, J = 7.2, 10.8 Hz, 1H), 4.21 (dq, J = 7.2, 10.8 Hz, 1H), 7.49
(d, J = 8.4 Hz, 1H), 8.42 (dd, J = 2.4, 8.4 Hz, 1H), 8.83 (d, J = 2.4 Hz, 1H),
13.25 (s, 1H); keto form δ 0.95–1.08 (m, 2H), 1.17–1.21 (m, 4H), 1.28 (t,
J = 7.2 Hz, 3H), 1.65–1.78 (m, 4H), 2.63–2.70 (m, 1H), 4.27 (q, J = 7.2
Hz, 2H), 5.67 (s, 1H), 7.79 (d, J = 8.4 Hz, 1H), 8.45 (dd, J = 2.4, 8.4 Hz,
1H), 8.84 (d, J = 2.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) enol form δ
N-[(2-Hydroxy-1,1-dimethyl)ethyl]-4-methylbenzamide (21).[21] Yield:
74 mg, 0.355 mmol, 71%; brown oil. 1H NMR (400 MHz, CDCl3) δ 1.40 (s,
6H), 2.38 (s, 3H), 3.68 (s, 2H), 3.80–4.05 (br, 1H), 6.04–6.25 (br, 1H),
7.21 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 21.4 (CH3), 24.7 (CH3), 56.4 (C), 70.7 (CH2), 126.9 (CH), 129.2
(CH), 131.9 (C), 142.1 (C), 168.4 (C); IR (ATR/cm-1) 1057, 1454, 1504,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801589
European Journal of Organic Chemistry
FULL PAPER
1537, 1632, 1643, 3379; HRMS (ESI/TOF) m/z Calcd. for C12H17NO2Na
Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 15.0 (CH3), 20.9 (CH3), 26.3 (CH2),
26.5 (CH2), 44.0 (CH2), 49.1 (CH2), 64.3 (CH2), 171.1 (C); IR (ATR/cm-1)
1046, 1240, 1734, 3309; HRMS (ESI/TOF) m/z Calcd. for C8H18NO2
[M+H]+ 160.1332, Found 160.1337.
[M+Na]+ 230.1152, Found 230.1159.
2-Amino-2-methylpropyl 4-methylbenzoate (22). Yield: 29 mg, 0.14
mmol, 28%; brown oil. 1H NMR (400 MHz, CDCl3) δ 1.39 (s, 6H), 2.35 (s,
3H), 3.66–4.00 (br, 2H), 4.25 (s, 2H), 7.15 (d, J = 8.0 Hz, 2H), 7.95 (d, J
= 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 21.6 (CH3), 24.3 (CH3), 52.8
(C), 70.3 (CH2), 126.5 (CH), 129.1 (CH), 129.9 (C), 144.1 (C), 166.2 (C);
IR (ATR/cm-1) 1105, 1267, 1612, 1713, 1730; HRMS (ESI/TOF) m/z
Calcd. for C12H18NO2 [M+H]+ 208.1332, Found 208.1339.
3-Aza-1-pentyl 4-methylbenzoate (32ax).[26] Yield: 95 mg, 0.460 mmol,
92%; yellow oil. 1H NMR (400 MHz, CDCl3) δ 1.41 (t, J = 7.2 Hz, 3H), 2.37
(s, 3H), 3.10 (q, J = 7.2 Hz, 2H), 3.31 (t, J = 5.2 Hz, 2H), 4.66 (t, J = 5.2
Hz, 2H), 5.90–6.42 (br, 1H), 7.21 (d, J = 8.0 Hz, 2H), 7.98 (d, J = 8.0 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ 11.6 (CH3), 21.6 (CH3), 43.1 (CH2),
45.9 (CH2), 60.3 (CH2), 126.4 (C), 129.2 (CH), 130.0 (CH), 144.2 (C),
166.3 (C); IR (ATR/cm-1) 1107, 1269, 1454, 1613, 1713; HRMS
(ESI/TOF) m/z Calcd. for C12H18NO2 [M+H]+ 208.1332, Found 208.1338.
N-(2-Hydroxyethyl)-N-methylethanamide (27).[21] Yield: 55 mg, 0.465
mmol, 93%; brown oil. 1H NMR (400 MHz, CDCl3) δ 2.12 (s, 3H), 2.31-
2.54 (br, 1H), 3.08 (s, 3H), 3.56 (t, J = 5.2 Hz, 2H), 3.79 (t, J = 5.2 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ 21.8 (CH3), 37.6 (CH3), 51.3 (CH2),
61.7 (CH2), 172.8 (C); IR (ATR /cm-1) 1020, 1052, 1402, 1623, 3380;
HRMS (ESI/TOF) m/z Calcd. for C5H11NO2Na [M+Na]+ 140.0682, Found
140.0676.
4-Aza-1-hexyl 4-methylbenzoate (32ay). Yield: 104 mg, 0.470 mmol,
94%; brown oil. 1H NMR (400 MHz, CDCl3) δ 1.39 (t, J = 7.2 Hz, 3H), 2.30
(tt, J = 6.4, 7.2 Hz, 2H), 2.39 (s, 3H), 3.00 (q, J = 7.2 Hz, 2H), 3.05 (t, J =
7.2 Hz, 2H), 4.44 (t, J = 6.4 Hz, 2H), 5.48–5.68 (br, 1H), 7.21 (d, J = 8.0
Hz, 2H), 7.88 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 11.8 (CH3),
21.6 (CH3), 26.2 (CH2), 43.1 (CH2), 44.8 (CH2), 61.8 (CH2), 127.0 (C),
129.1 (CH), 129.6 (CH), 143.9 (C), 166.6 (C); IR (ATR/cm-1) 1107, 1271,
1537, 1612, 1713; HRMS (ESI/TOF) m/z Calcd. for C13H20NO2 [M+H]+
222.1489, Found 222.1498.
N-Ethyl-N-(2-hydroxyethyl)ethanamide (28cx)[21] Yield: 61 mg, 0.465
mmol, 93%; brown oil. 1H NMR (400 MHz, CDCl3) δ 1.21 (t, J = 7.2 Hz,
3H), 2.13 (s, 3H), 3.37 (q, J = 7.2 Hz, 2H), 3.52 (t, J = 4.8 Hz, 2H), 3.54–
3.62 (br, 1H), 3.77 (t, J = 4.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 13.9
(CH3), 21.3 (CH3), 45.0 (CH2), 49.4 (CH2), 62.6 (CH2), 172.6 (C); IR
(ATR/cm-1) 1059, 1467, 1624, 3414; HRMS (ESI/TOF) m/z Calcd. for
C6H14NO2 [M+H]+ 132.1019, Found 132.1024.
5-Aza-1-heptyl 4-methylbenzoate (32az). Yield: 112 mg, 0.475 mmol,
95%; brown oil. 1H NMR (400 MHz, CDCl3) δ 1.42 (t, J = 7.2 Hz, 3H), 1.86
(tt, J = 6.4, 7.2 Hz, 2H), 2.05 (tt, J = 7.2, 7.2 Hz, 2H), 2.38 (s, 3H), 2.99 (t,
J = 7.2 Hz, 2H), 3.02 (q, J = 7.2 Hz, 2H), 3.06–3.99 (br, 1H), 4.29 (t, J =
6.4 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 7.89 (d, J = 8.0 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 11.1 (CH3), 21.6 (CH3), 22.8 (CH2), 26.2 (CH2), 42.7
(CH2), 46.8 (CH2), 63.6 (CH2), 127.3 (C), 129.1 (CH), 129.6 (CH), 143.7
(C), 166.5 (C); IR (ATR/cm-1) 1109, 1273, 1454, 1612, 1713; HRMS
(ESI/TOF) m/z Calcd. for C14H22NO2 [M+H]+ 236.1645, Found 236.1654.
N-(2-Hydroxyethyl)-N-(2-propyl)ethanamide (29).[21] Yield: 48 mg, 0.33
mmol, 66%; brown oil. 1H NMR (400 MHz, CDCl3) δ 1.20 (d, J = 6.4 Hz,
6H), 2.17 (s, 3H), 3.29–3.42 (br, 1H), 3.45 (t, J = 4.0 Hz, 2H), 3.74 (t, J =
4.0 Hz, 2H), 4.04 (sep, J = 6.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
21.0 (CH3), 21.8 (CH3), 43.9 (CH2), 49.8 (CH), 64.4 (CH2), 173.0 (C); IR
(ATR/cm-1) 1052, 1197, 1347, 1420, 1616, 3380; HRMS (ESI/TOF) m/z
Calcd. for C7H16NO2 [M+H]+ 146.1196, Found 146.1182.
3-Aza-4-methyl-1-pentyl 4-methylbenzoate (38).[27] Yield: 109 mg,
0.495 mmol, 99%; yellow liquid. 1H NMR (400 MHz, CDCl3) δ 1.11 (d, J
= 6.0 Hz, 6H), 2.39 (s, 3H), 2.80–2.87 (br, 1H), 2.92 (sep, J = 6.0 Hz, 1H),
3.01 (t, J = 5.6 Hz, 2H), 4.42 (t, J = 5.6 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H),
7.91 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 21.6 (CH3), 22.6
(CH3), 45.6 (CH), 48.5 (CH2), 64.4 (CH2), 127.4 (C), 129.1 (CH), 129.6
(CH), 143.7 (C), 166.6 (C); IR (ATR/cm-1) 1109, 1267, 1504, 1556, 1713;
HRMS (ESI/TOF) m/z Calcd. for C13H20NO2 [M+H]+ 222.1489, Found
222.1497.
3-Aza-4-methyl-1-pentyl ethanoate (33).[24] Yield: 25 mg, 0.170 mmol,
34%; brown oil. 1H NMR (400 MHz, CDCl3) δ 1.07 (d, J = 6.0 Hz, 6H),
1.44–1.64 (br, 1H), 2.07 (s, 3H), 2.83 (sep, J = 6.0 Hz, 1H), 2.85 (t, J =
5.2 Hz, 2H), 4.17 (t, J = 5.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 20.9
(CH3), 22.9 (CH3), 45.7 (CH2), 48.4 (CH2), 64.5 (CH2), 171.0 (C); IR
(ATR/cm-1) 1046, 1244, 1369, 1740; HRMS (ESI/TOF) m/z Calcd. for
C7H15NO2Na [M+Na]+ 168.0995, Found 168.0988.
3-Aza-4,4-dimethyl-1-pentyl acetate (34).[21] Yield: 75 mg, 0.47 mmol,
3-Aza-4,4-dimethyl-1-pentyl 4-methylbenzoate (39).[27] Yield: 116 mg,
0.495 mmol, 99%; yellow liquid. 1H NMR (400 MHz, CDCl3) δ 1.14 (s, 9H),
2.10–2.31 (br, 1H), 2.39 (s, 3H), 2.95 (t, J = 5.6 Hz, 2H), 4.40 (t, J = 5.6
Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 7.91 (d, J = 8.0 Hz, 2H); 13C NMR (100
MHz, CDCl3) δ 21.6 (CH3), 28.9 (CH3), 41.4 (CH2), 50.5 (C), 65.3 (CH2),
127.5 (C), 129.1 (CH), 129.6 (CH), 143.6 (C), 166.6 (C); IR (ATR/cm-1)
1101, 1269, 1537, 1632, 1713, 1728; HRMS (ESI/TOF) m/z Calcd. for
C14H22NO2 [M+H]+ 236.1645, Found 236.1656.
94%; Yellow oil. 1H NMR (400 MHz, CDCl3) δ 1.12 (s, 9H), 2.06 (s, 3H),
2.15–2.32 (br, 1H), 2.82 (t, J = 5.6 Hz, 2H), 4.16 (t, J = 5.6 Hz, 2H); 13
C
NMR (100 MHz, CDCl3) δ 20.9 (CH3), 28.8 (CH3), 41.2 (CH2), 50.6 (C),
64.9 (CH2), 171.0 (C); IR (ATR/cm-1) 1070, 1233, 1713, 1730, 1746;
HRMS (ESI/TOF) m/z Calcd. for C8H18NO2 [M+H]+ 160.1332, Found
160.1327.
4-Aza-1-hexyletanoate (32cy).[25] Yield: 64 mg, 0.44 mmol, 88%; brown
oil. 1H NMR (400 MHz, CDCl3) δ 1.47 (t, J = 7.2 Hz, 3H), 2.06 (s, 3H),
2.27 (tt, J = 6.0, 8.0 Hz, 2H), 3.03 (t, J = 8.0 Hz, 2H), 3.07 (q, J = 7.2 Hz,
2H), 4.19 (t, J = 6.0 Hz, 2H), 5.30 (s, 1H); 13C NMR (100 MHz, CDCl3) δ
11.2 (CH3), 20.8 (CH3), 25.5 (CH2), 43.0 (CH2), 44.5 (CH2), 61.2 (CH2),
170.9 (C); IR (ATR/cm-1) 1048, 1245, 1740, 3378; HRMS (ESI/TOF) m/z
Calcd. for C7H16NO2 [M+H]+ 146.1176, Found 146.1181.
Keywords: Chemoselectivity • Regioselectivity • Acylation •
Amino alcohols • Steric hindrance
[1]
[2]
S. K. Verma, R. Ghorpade, A. Pratap, M. P. Kaushik, Green Chem.
2012, 14, 326–329.
a) K. Pappas, X. Zhang, W. Tang, S. Fang, Tetrahedron Lett. 2009, 50,
5741–5743; b) A. Oganesyan, I. A. Cruz, R. B. Amador, N. A. Sorto, J.
Lozano, C. E. Godinez, J. Anguiano, H. Pace, G. Sabih, C. G. Gutierrez,
Org. Lett. 2007, 9, 4967–4970; c) Z. Zhang, Z. Yin, N. A. Meanwell, J.
F. Kadow, T. Wang, Org. Lett. 2003, 5, 3399–3402.
5-Aza-1-heptyl ethanoate (32cz). Yield: 74 mg, 0.465 mmol, 93%;
brown oil. 1H NMR (400 MHz, CDCl3) δ 1.12 (t, J = 7.2 Hz, 3H), 1.57 (tt,
J = 6.4, 7.2 Hz, 2H), 1.68 (tt, J = 7.2, 7.2 Hz, 2H), 2.04 (s, 3H), 2.25–2.34
(br, 1H), 2.65 (t, J = 7.2 Hz, 2H), 2.67 (q, J = 7.2 Hz, 2H), 4.07 (t, J = 6.4
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801589
European Journal of Organic Chemistry
FULL PAPER
[3]
Y. Nagao, K. Seno, K. Kawabata, T. Miyasaka, S. Takao, E. Fujita,
Chem. Pharm. Bull. 1984, 32, 2687–2699.
Chem. Comum. 2011, 47, 4938–4940; f) Y. Nakaike, N. Taba, S. Itoh,
Y. Tobe, N. Nishiwaki, M. Ariga, Bull. Chem. Soc. Jpn. 2007, 80, 2413–
2417.
[4]
[5]
T. H. Kim, G.-Y. Yang, Tetrahedron Lett. 2002, 43, 9553–9557.
Y. Murakami, K. Kondo, K. Miki, Y. Akiyama, T. Watanabe, Y.
Yokoyama, Tetrahedron Lett. 1997, 38, 3751–3754.
K. Kondo, E. Sekimoto, K. Miki, Y. Murakami, J. Chem. Soc., Perkin
Trans. 1 1998, 2973–2974.
[18] N. Nishiwaki, D. Nishida, T. Ohnishi, F. Hidaka, S. Shimizu, M. Tamura,
K. Hori, Y. Tohda, M. Ariga, J. Org. Chem. 2003, 68, 8650–8656.
[19] S. Hirai, H. Asahara, S. Hirao, J. Sawayama, R. Sugimoto, K. Saigo, N.
Nishiwaki, RSC Adv. 2014, 4, 4889–4892.
[6]
[7]
[8]
[9]
S. Caron, N. M. Do, R. E. McDermott, S. Bahmanyar, Org. Proc. Res.
Dev. 2006, 10, 257–261.
[20] Acylation of phenylacetate is also reported: a) V. A. Bodunov, E. E.
Galenko, A. V. Galenko, M. S. Mikhali, A. F. Khlebnikov, Synthesis 2018,
50, 2784–2798; b) P. Drouhin, R. J. K. Taylor, Eur. J. Org. Chem. 2015,
2333–2336; c) A. Kimata, H. Nakagawa, R. Ohyama, T. Fukuuchi, S.
Ohta, T. Suzuki, N. Miyata, J. Med. Chem. 2007, 50, 5053–5056; d) T.
Misaki, R. Nagase, K. Matsumoto, Y. Tanabe, J. Am. Chem. Soc. 2005,
127, 2854–2855.
M. Kidwai, R. Poddar, P. Mothsra, Beilstein J. Org. Chem. 2009, 5,
No.10.
A. Morcuende, M. Ors, S. Valverde, B. Herradón, J. Org. Chem. 1996,
61, 5264–5270.
[10] T. Stoz, P. Dittmar, D. Grimler, M. Testa, Org. Proc. Res. Dev. 2006, 10,
1184–1191.
[21] The structures of all products are confirmed by comparison of the
spectral data with those of authentic samples which are available from
commercial source.
[11] T. Mukaiyama, F.-C. Pai, M. Onaka, K. Narasaka, Chem. Lett. 1980,
563–566.
[12] M.-H. Lin, T. V. RajanBabu, Org. Lett. 2000, 2, 997–1000.
[13] R. Horikawa, C. Fujimoto, R. Yazaki, T. Ohshima, Chem. Eur. J. 2016,
22, 12278–12281.
[22] I. R. Gambhir, S. S. Joshi, J. Org. Chem. 1962, 27, 1899–1901.
[23] W. Borsche, M. Lewinsohn, Ber. Deutsch. Chem. Gessellschaft. 1933,
66B, 1792–1801.
[14] Y. Hayashi, S. Santoro, Y. Azuma, F. Himo, T. Ohshima, K. Mashima,
J. Am. Chem. Soc. 2013, 135, 6192−6199.
[24] K. Lee, H.-S. Park, I.-A. Ahn, H.-J. Yoo, J.-Y. Kim, D.-Y. Choi, H.-J. Yim,
K.-H. Chung, D.-S. Shim, S.-K. Lee, Y. Kondoh, R. Hirabayashi, S.
Honda, H. Kaku, J.-i. Shishikura, H. Ito, T. Kurama, PCT Int. Appl. 2005,
WO 2005047251.
[15] K. Sugahara, N. Satake, K. Kamata, T. Nakajima, N. Mizuno, Angew.
Chem. Int. Ed. 2014, 53, 13248−13252.
[16] R. C. Samanta, S. De Sarkar, R. Fröhlich, S. Grimme, A. Studer, Chem.
Sci. 2013, 4, 2177−2184.
[25] R. M. Ispiryan, L. I. Belen’skii, Y. L. Gol’dfarb, Izv. Akad. Nauk. Kazakh.
SSR, Ser. Khim. 1967, 2513–2522.
[17] a) N. Nishiwaki, Synthesis 2016, 48, 1286–1300; b) H. Asahara, S.
Takeda, K. Saigo, N. Nishiwaki, Tetrahedron Lett. 2015, 56, 2504–
2507; c) N. Nishiwaki, S. Hirao, J. Sawayama, H. Asahara, R. Sugimoto,
K. Kobiro, K. Saigo, Tetrahedron 2014, 70, 402–408; d) S. Hirao, K.
Kobiro, J. Sawayama, K. Saigo, N. Nishiwaki, Tetrahedron Lett. 2012,
53, 82–85; e) N. Nishiwaki, S. Hirao, J. Swayama, K. Saigo, K., Kobiro,
[26] J. R. Reasenberg, S. D. Goldberg, J. Am. Chem. Soc. 1945, 67, 933–
939.
[27] This compound appears in only Supporting Information.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801589
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents
FULL PAPER
Key Topic*
R2
OH
OH O
Ar
Author(s), Corresponding Author(s)*
N
n
R2
O
n
R1
H
R1
OEt
N
Page No. – Page No.
H
"Selective O-acylation"
O
Title
Acylation using an a-aryl-b-keto ester facilitated the regioselective-acylation of the less
hindered amino group in diamine without protecting the other. The transacylation using N-
alkylamino alcohol resulted in chemoselective O-acylation without protecting the amino
group in the absence of metal catalyst. These reactions proceed efficiently because of the
pseudo-intramolecular process.
*Selective Acylation
This article is protected by copyright. All rights reserved.