Development of Chiral Ureates as Chiral Strong Br?nsted Base Catalysts

Article abstract of DOI:10.1021/jacs.9b13922

Recently, chiral Br?nsted bases having high basicity have emerged as a powerful tool in developing new catalytic enantioselective reactions. However, such chiral strong Br?nsted base catalysts are still very scarce. Herein, we report the development of a chiral anionic Br?nsted base having a N,N′-dialkyl ureate moiety as a basic site. Its prominent catalytic activity was demonstrated in the enantioselective addition reactions of α-thioacetamides as less acidic pronucleophiles with various electrophiles. Thus, the newly developed chiral catalyst with high accessibility and structural tunability would expand the scope of viable enantioselective transformations under Br?nsted base catalysis.

Full text of DOI:10.1021/jacs.9b13922

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Communication
Development of Chiral Ureates as Chiral Strong Brønsted Base Catalysts
Azusa Kondoh, Sho Ishikawa, and Masahiro Terada
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b13922 • Publication Date (Web): 11 Feb 2020
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Development of Chiral Ureates as Chiral Strong Brønsted Base
Catalysts
Azusa Kondoh‡, Sho Ishikawa†, Masahiro Terada*,†
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†Department of Chemistry, Graduate School of Science, Tohoku University, Aoba-ku, Sendai 980-8578, Japan
‡Research and Analytical Center for Giant Molecules, Graduate School of Science, Tohoku University, Aoba-ku, Sendai
980-8578, Japan
Supporting Information Placeholder
value of a N,N’-dialkyl urea in DMSO is estimated to be about
25,12 and hence its ureate form is potentially basic enough to
function as a strong Brønsted base catalyst, although ureates have
rarely been regarded as such. Second, ureas can function as a
substrate recognition site. For instance, various chiral ureas have
been developed and widely utilized as hydrogen bond donor
catalysts in enantioselective reactions.13 Considering that the
actual key species in the stereo-determining event of Brønsted
base-catalyzed reactions is the conjugate acid of the catalyst
molecule, chiral ureates would have great potential to serve as
chiral catalysts for controlling the stereochemical outcome.
Finally, the synthesis of chiral ureas is well-established, and thus
a diverse array of chiral ureates is readily available. The
accessibility and structural tunability of catalyst molecules are
important for their application in a variety of enantioselective
reactions. Herein we report the development of a new chiral
anionic Brønsted base having a N,N’-dialkyl ureate moiety as a
basic site (Figure 1). In addition, we describe its application in
enantioselective addition reactions of α-thioacetamides as less
acidic pronucleophiles, which proved its high potential as a chiral
strong Brønsted base catalyst.
ABSTRACT: Recently, chiral Brønsted bases having high
basicity have emerged as a powerful tool in developing new
catalytic enantioselective reactions. However, such chiral strong
Brønsted base catalysts are still very scarce. Herein, we report the
development of a chiral anionic Brønsted base having a N,N’-
dialkyl ureate moiety as a basic site. Its prominent catalytic
activity was demonstrated in the enantioselective addition
reactions of α-thioacetamides as less acidic pronucleophiles with
various electrophiles. Thus, the newly-developed chiral catalyst
with high accessibility and structural tunability would expand the
scope of viable enantioselective transformations under Brønsted
base catalysis.
In recent years, much attention has been paid to the
development of enantioselective reactions under Brønsted base
catalysis as a useful methodology for organic synthesis.1 This
methodology enables the direct transformation of pronucleophiles
into enantio-enriched compounds in a highly atom economical
fashion under mild reaction conditions. However, the scope of
applicable pronucleophiles is highly dependent on the basicity of
the catalyst molecules. Therefore, the pronucleophiles have been
primarily limited to compounds having a highly acidic proton due
to the insufficient basicity of conventional chiral tertiary amine
catalysts2 and other types of chiral uncharged organobase
catalysts, such as chiral guanidines, P1-phosphazenes,
iminophosphoranes and cyclopropenimines.3-6 In order to
overcome the intrinsic limitation of pronucleophiles and expand
the scope of viable enantioselective transformations that are
available under Brønsted base catalysis, we have been focusing on
the development of chiral Brønsted base catalysts possessing
much higher basicity than conventional chiral catalysts. Our
previous achievements, as well as those of other groups, with the
enantioselective reactions of less acidic pronucleophiles have
revealed the high potential of chiral strong Brønsted base catalysts
in developing new enantioselective reactions.7-9 However, such
chiral catalysts are still very scarce, and therefore, the
development of novel chiral strong Brønsted base catalysts,
particularly with unprecedented catalyst design, would open up a
O
O
R1
R2
R1
R2
N
N
N
N
H
H
H
deprotonation
1
N,N'-dialkyl urea
N,N'-dialkyl ureate
·
·
·
pKa ~25 (DMSO)
function as a substrate
recongnition site
high availability
application as chiral
strong Brønsted base
catalysts (this work)
·
O
O
Ph
Ph
Me
N
R
O
Ar
Bn
Bn
Bn
Ph
Bn
Ar
N
N
H
N
N
Bn
N
N
H
H
H
H
H
N
O
N
1a
HO
tBu
HO
O
Ph
tBu
tBu
1e : R = iPr, Ar = Ph
tBu
N
H
N
H
1d
R
1b
: R = OH
1f
: R = iPr, Ar = 1-naphthyl
1c
: R = NHBoc
1g
: R = Bn, Ar = Ph
new avenue to achieving
a variety of enantioselective
Figure 1. N,N’-Dialkyl ureas 1 as Brønsted base precatalysts.
transformations under Brønsted base catalysis. During the course
of our study on the development of chiral strong Brønsted base
catalysts, we envisioned utilizing an ureate, which is the conjugate
base of an urea, as a new motif of chiral Brønsted base
catalysts10,11 due to the distinctive features of ureas. First, pKa
In order to evaluate the viability of utilizing ureates as strong
Brønsted base catalysts, a preliminary study was conducted. Thus,
α-phenylthioacetamide 2a, whose pKa value in DMSO would be
about 25,14 was chosen as a less acidic pronucleophile by
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considering the importance of sulfur-containing chiral molecules
enantioselectivity was achieved by changing the substituent on the
chiral alkyl chain from phenyl groups to bulky 1-naphthyl groups
(entry 10). Finally, the optimum reaction conditions were
established by decreasing the reaction temperature to -20 °C with
1f as a precatalyst, and 4aa was obtained in 98% yield with 95%
ee (entry 11).
1
2
3
4
5
6
7
8
in various fields of chemistry,15 and treated with phenyl vinyl
sulfone (3a) as an electrophile in the presence of 10 mol% achiral
Brønsted bases having different basicities in toluene at room
temperature (Table 1). The use of P1-tBu (pKBH+ = 15.7 in
DMSO)16 resulted in very low conversion and most of 2a was
recovered (entry 1). In contrast, the use of stronger Brønsted bases
dramatically changed the reaction outcome. P2-tBu (pKBH+ = 21.5
in DMSO), P4-tBu (pKBH+ = 30.3 in DMSO), and NaOtBu
provided the corresponding adduct 4aa in 32%, 74%, and 95%
yields, respectively (entries 2-4). In addition, the application of
sodium N,N’-dibenzyl ureate generated in situ from N,N’-dibenzyl
urea (1a) by treatment with an equivalent amount of NaOtBu also
provided 4aa in excellent yield (entry 5). The results of this
preliminary study clearly suggest that the reaction requires a
catalyst with high basicity, and N,N’-dialkyl ureates can indeed
serve as strong Brønsted base catalysts. Based on these results, we
prepared several C1-symmetric chiral ureas 1b-1d having a chiral
alkyl chain connected with an additional coordination site, such as
a hydroxyl group, an amide moiety, and a Schiff base with a
phenoxide moiety, as precatalysts, and applied them to the
reaction (entries 6-8). In all cases, the reaction proceeded
smoothly to provide 4aa in almost quantitative yield. Furthermore,
to our delight, the use of 1d in combination with 20 mol%
NaOtBu for the deprotonation of both urea and more acidic
phenol moieties provided 4aa with 26% ee, whereas 1b and 1c
provided the product as a racemic mixture. Intensive screening of
catalyst molecules revealed that the introduction of a chiral amide
moiety on the other alkyl chain of the urea is highly effective to
improve the enantioselectivity, and the ureate generated from 1e
provided 4aa with 74% ee (entry 9).17 Further improvement of
At this stage, some control experiments were conducted. First,
the effect of inorganic bases for the generation of ureates was
investigated with precatalyst 1e (Scheme 1a). The use of KOtBu
and LiOtBu instead of NaOtBu resulted in the quantitative
formation of 4aa in a racemic fashion or no reaction, suggesting
that the countercation of the ureate is highly influential for
catalytic activity and enantiocontrol. In the case using NaHMDS,
a similar ee value was observed, implying the importance of the
sodium cation.18 Next, the relationship between the ee value of
catalyst and that of product was evaluated. Thus, in addition to
enantiomerically pure 1f, 1f having different ee values (20% ee,
40% ee, 60% ee, and 80% ee) were prepared and applied to the
reaction (Scheme 1b). A proportional relationship between the ee
values of the catalyst and the product was observed, indicating
that the monomeric ureate would catalyze the reaction. Finally, N-
mono-methylated ureas 1h and 1i, and urea 1j having a methyl-
capped phenoxide moiety were applied as the precatalysts
(Scheme 1c). When using 1h and 1i, the reaction proceeded
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Scheme 1. Control Experiments
a)
1e
(10 mol %)
O
O
base (20 mol %)
Ph
SO2Ph
Ph
SPh
+
SO2Ph
3a
N
N
toluene, rt, 0.5 h
Me SPh
4aa
Me
2a
Table 1. Screening of Reaction Conditionsa
base : NaOtBu
KOtBu
99% yield
99% yield
<1% yield
99% yield
74% ee
<1% ee
-
LiOtBu
NaHMDS
1
(10 mol %)
O
77% ee
O
base (10-20 mol %)
Ph
SO2Ph
Ph
SPh
+
SO2Ph
3a
N
b)
N
toluene, rt, 0.5 h
1f
(10 mol %)
NaOtBu (20 mol %)
O
Me SPh
O
Me
Ph
SO2Ph
2a
4aa
Ph
SPh
+
SO2Ph
N
N
toluene, 20 °C, 0.5 h
Me SPh
Me
2a
100
3a
4aa
base
(mol %)
yield of
ee of 4aa
recovery
entry
1
4aa (%)b
(%)c
of 2a (%)d
95
1e
2
-
-
-
-
P1-tBu (10)
P2-tBu (10)
P4-tBu (10)
NaOtBu (10)
<5d
32d
74d
>95d
>95d
99
-
-
>95
68
15
<1
<1
<1
<1
<1
<1
<1
<1
90
80
70
60
50
40
30
20
10
0
73
3
-
58
4
-
34
5
1a NaOtBu (10)
1b NaOtBu (10)
1c NaOtBu (10)
1d NaOtBu (20)
1e NaOtBu (20)
1f NaOtBu (20)
1f NaOtBu (20)
-
17
6
<1
<1
26
74
85
95
7
99
0
20
40
60
80
N
100
ee of 1f (%)
8
99
9
99
c)
1
(10 mol %)
NaOtBu (20 mol %)
O
10
11f
99
O
Ph
SO2Ph
Ph
SPh
SO2Ph
+
98
N
toluene, rt, 0.5 h
Me SPh
Me
aConditions: 2a (0.10 mmol), 3a (0.12 mmol), 1 (0.010 mmol)
with NaOtBu (0.010-0.020 mmol) or base (0.010 mmol), toluene
(1.0 mL), rt, 0.5 h. bIsolated yields unless otherwise noted.
cEnantiomeric excess of 4aa was determined by chiral stationary-
phase SFC analysis. dNMR yield(s) ePerformed for 12 h.
fPerformed at -20 °C.
2a
3a
4aa
1h
R1 = Me, R2 = H, Ar = Ph
Me iPr
O
Ar
99% yield, 80% ee
N
Ar
Bn
N
H
N
1i
O
R1
N
R1 = Me, R2 = H, Ar = 1-naphthyl
92% yield, 96% ee
R2O
1h j
-
NtBu
NtBu
NtBu
1j
N
P
N
N
R1 = H, R2 = Me, Ar = Ph
with NaOtBu (10 mol %)
99% yield, <1% ee
Me2N
P
NMe2 Me2N
P
N
NMe2
(Me2N)3P
P(NMe2)3
tBu
tBu
NMe2
P(NMe2)3
P(NMe2)3
P1-tBu
P2-tBu
P4-tBu
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smoothly to provide 4aa in high yields with good to high
2c proceeded smoothly to afford the corresponding products 4ba
and 4ca with high ee values. α-Methylthioacetamide 2d
underwent the reaction without any problem to provide 4da in
high yield with high enantioselectivity. However, the reaction of
α-methylthiopropionamide 2e did not proceed, and the starting
material was recovered fully. Further investigation of the reaction
scope revealed that the catalyst system was amenable to the use of
a variety of electrophiles with α-phenylthioacetamide 2a as a
pronucleophile (Scheme 2b). For instance, ethyl vinyl sulfone
(3b) and tert-butyl acrylate (7) were applicable as Michael
acceptors and the corresponding products 4ab and 8 were
obtained in high yields with good enantioselectivities. In the case
of tert-butyl acrylate, the ureate derived from 1g provided the
better result. The reaction with chalcone derivatives 9 also
proceeded, and the adducts 10 were obtained with good
diastereoselectivities and high enantioselectivities under slightly
modified reaction conditions. Furthermore, N-Boc imines 11 were
found to be a suitable electrophile, and the products 12 were
obtained in high yield with high diastereo- and enantioselectivities.
In this case, the reaction provided the products 12 with the
opposite absolute configuration at the α-position of the carbonyl
group to that of products 4, 8, 10.20
1
2
3
4
5
6
7
8
enantioselectivities. These results indicate that one of the two NH
protons of urea is not crucial to control the enantioselectivity of
the reaction. Thus, the introduction of a substituent on the
nitrogen atom is a potential option for the fine tuning of the chiral
catalyst molecule, although the additional manipulation is
required to synthesize N-mono-alkylated ureas, such as 1h and
1i.19 On the other hand, the use of 1j with 10 mol% NaOtBu
resulted in the formation of 4aa in racemic form, suggesting that
the phenoxide moiety plays an important role in the
stereoselective carbon-carbon bond forming event.
9
The scope of α-thioacetamides was investigated next (Scheme
2a). The reaction of N,N-dialkyl α-phenylthioacetamides 2b and
10
11
12
13
14
15
16
17
18
19
20
21
22
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59
60
Scheme 2. Substrate Scope
a)
1f
(10 mol %)
O
O
R1
SO2Ph
NaOtBu (20 mol %)
R1
SR3
+
SO2Ph
N
N
R2
toluene, 20 °C, 0.5 h
R2 SR3
2
3a
4
O
O
O
O
SPh
Me
SPh
Ph
SMe
Ph
SMe
N
N
N
N
In conclusion, we have developed a chiral anionic Brønsted
base having a N,N’-dialkyl ureate moiety as a basic site. Its high
Me
Me
Me Me
2e
2b
2c
93% yield
95% ee
2d
90% yield
88% ee
(0.5 h)
(2 h)
(2 h)
(20 h at rt)
>1% yield
activity as
a chiral strong Brønsted base catalyst was
98% yield
93% ee
demonstrated in enantioselective addition reactions of α-
thioacetamides as less acidic pronucleophiles with a variety of
electrophiles. The present reactions are difficult to achieve using
conventional chiral Brønsted base catalysts. Further studies are in
progress to develop new catalytic enantioselective transformations
with various types of less acidic pronucleophiles utilizing the
accessibility and structural tunability of the newly-developed
chiral catalysts.
1f 1g
or
b)
(10 mol %)
NaOtBu or NaHMDS
O
O
(20 mol %)

E
Ph
Ph
SPh
+
E
N
N
toluene, temp.
Me SPh
electrophile
Me
2a
O
SO2Et
Ph
N
SO2Et
3b
ASSOCIATED CONTENT
Me SPh
1f
with NaOtBu
90% yield
88% ee
4ab
20 °C, 0.5 h
Supporting Information
The Supporting Information is available free of charge on the
O
ACS
Publications
website.
CO2tBu
Ph
N
CO2tBu
7
Additional experimental results, experimental procedures, and
characterization data. (PDF )
Me SPh
1g
with NaOtBu
rt, 0.5 h
90% yield
89% ee
8
AUTHOR INFORMATION
O
Ar1
COAr2
Ar1
1g
Ph
COAr2
Corresponding Author
N
9
Me SPh
* E-mail: mterada@tohoku.ac.jp.
with NaHMDS
0 °C, 3 h
10
Notes
Ar1
Ar2
10
yield
dr
ee
The authors declare no competing financial interests.
10a
10b
10c
10d
10e
Ph
4-Cl-C6H4
Ph
Ph
62%
52%
67%
65%
54%
88 : 12
94 : 6
95 : 5
92 : 8
92 : 8
88%
93%
94%
93%
93%
ACKNOWLEDGMENT
3-F3C-C6H4 Ph
This research was supported by a Grant-in-Aid for Scientific
Research from the JSPS (No. 16H06354 to M.T. and No.
16K05680 to A.K.).
Ph
Ph
4-Br-C6H4
4-F-C6H4
Boc
Boc
N
O
HN
Ph
N
Ar
11
H
Ar
REFERENCES
Me SPh
1f
with NaHMDS
20 °C, 0.5 h
12
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12
yield
dr
ee
Ar
12a
12b
12c
12d
Ph
96%
96%
85%
95%
97 : 3
98 : 2
97 : 3
98 : 2
92%
82%
96%
92%
4-Br-C6H4
4-MeO-C6H4
2-naphthyl
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the presence of 30 mol % 15-crown-5. As a result, 4aa was obtained as a
racemic mixture.
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a
Chiral
(19) Preparation of mono-methylated ureas on the opposite nitrogen was
failed because of the difficulty of the condensation.
(20) The absolute configurations of 4 and the major diasteromers of 10
and 12 were determined by single-crystal X-ray diffraction analysis. See
the Supporting Information for details.
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a
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