An ugi-type condensation of α-isocyanoacetamide and chiral cyclic imine under a new catalytic system

Article abstract of DOI:10.1055/s-0032-1316549

A new catalytic Ugi-type condensation of α-isocyanoacetamide and chiral cyclic imine is developed, where the combination of phenyl phosphilic acid and trifluoroethanol is exploited to promote the Ugi-type condensation with α-isocyanoacetamide for the first time. Under this new catalytic system, the reaction using the cyclic imines as relatively inertial substrates proceed well, and chiral 3-oxazolyl-morpholin/piperazine-2-one derivatives are synthesized with high yield and stereoselectivity. Furthermore, transformation of the condensation product to a novel fused tricyclic structure is attempted initially by treatment with maleic anhydride. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1316549

LETTER
▌1985
lAettner Ugi-Type Condensation of α-Isocyanoacetamide and Chiral Cyclic Imine
under a New Catalytic System
Ugi-Type Condensation of α-Isocyanoacetamide and Chiral Cyclic Imine
Sheng Li,a Ruijiao Chen,a Xiubing Liu,a Li Pan,a Liang Xia,a Xiaochuan Chen*a,b
a
Key Laboratory of Green Chemistry & Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064,
P. R. of China
b
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. of China
Fax +86(28)85413712; E-mail: chenxc@scu.edu.cn
Received: 25.04.2012; Accepted after revision: 24.05.2012
type condensation are rare. Up to now, only one enantio-
Abstract: A new catalytic Ugi-type condensation of α-isocyano-
selective catalytic version was achieved in the reaction of
acetamide and chiral cyclic imine is developed, where the combina-
aldehyde, aniline, and α-isocyanoacetamide in 56–90%
tion of phenyl phosphilic acid and trifluoroethanol is exploited to
promote the Ugi-type condensation with α-isocyanoacetamide for
ee.7 There has still not been a special study focused on the
the first time. Under this new catalytic system, the reaction using the stereoselectivity when employing chiral substrates. A lim-
cyclic imines as relatively inertial substrates proceed well, and chi-
ral 3-oxazolyl-morpholin/piperazine-2-one derivatives are synthe-
sized with high yield and stereoselectivity. Furthermore,
Ugi reactions permit the swift creation of diverse chiral
transformation of the condensation product to a novel fused tricy-
clic structure is attempted initially by treatment with maleic anhy-
ited number of precedents with chiral amines showed low
or no diastereoselectivity.8 Exploration of asymmetric
molecule libraries with potential applicability in medical
and agricultural chemistry, because optically pure com-
pounds are of utmost importance during the development
of most drugs. Recently, we reported an asymmetric Ugi
reaction of isocyanide, carboxylic acid, and chiral cyclic
imine 5.9 As a continuation of the study on developing
asymmetric reactions using 5, we report herein a catalytic
Ugi-type condensation of 1 and 5 with excellent stereose-
lectivity, by which asymmetric syntheses of new 3-oxazo-
lyl-morpholin/piperazine-2-one derivatives 6 are achieved
(Scheme 2). Phenyl phosphilic acid (7) in trifluoroethanol
(TFE), as a new system, is employed to catalyze this Ugi-
type condensation of α-isocyanoacetamide for the first
time.
dride.
Key words: catalytic Ugi-type condensation, α-isocyanoacet-
amide, oxazoles, phosphilic acid, asymmetric synthesis
The Ugi reaction and its many variants have been studied
widely and show great potential in generating molecular
complexity and diversity.1 Among them, the Ugi-type
condensation of α-isocyanoacetamide 1, amine 2, and oxo
compound 3 furnish a highly efficient access to the syn-
thesis of substituted oxazole derivatives 4 (Scheme 1).2
The reaction could proceed without or with promoters de-
pending on the reactivity of imine intermediate. The oxa-
zole unit is found in many bioactive natural products and
pharmaceutically relevant molecules,2a,3 and structure 4 is
applied in the design of important peptidomimetic plat-
forms.4 Moreover, based on abundant oxazole chemistry,5
the products containing oxazoles are likely to be convert-
ed into other complex scaffolds.
O
X
R3
O
H
N
O
P
H
R3
O
N
R2
R2
Ph
OH
CN
+
X
R1
N
TFE
R1
Y
O
Y
1
5
6
5a: R2 = Bn, R3 = Me, Y = O
5b: R2 = i-Pr, R3 = Me, Y = O
5c: R2 = Ph, R3 = Me, Y = O
5d: R2 = i-Pr, R3 = Et, Y = O
5e: R2 = Bn, R3 = Et, Y = O
5f: R2 = Bn, R3 = Me, Y = NMe
1a: R1 = H, X = morpholinyl
1b: R1 = Bn, X = morpholinyl
1c: R1 = i-Pr, X = morpholinyl
1d: R1 = Me, X = morpholinyl
1e: R1 = Ph, X = piperidinyl
1f: R1 = Ph, X = pyrrolidinyl
1g: R1 = Bn, X = piperidinyl
1h: R1 = Bn, X = diethylamino
NR2R3
R2R3NH2
O
R4
O
∗
CN
2
X
X
+
N
R1
R4CHO
R1
4 X = NR'R''
5g: R2 = Bn, R3 = Me, Y = Nn-Bu
1 X = NR'R''
3
Scheme 2 Asymmetric synthesis of heterocycles 6 from 1 and 5
Scheme 1 Representative Ugi-type reaction of an α-isocyanoacet-
amides, an amine, and an aldehyde
In the Ugi-type condensation reported previously, unsub-
stituted α-isocyanoacetamides are used rarely despite
their prospective utility, because of their inherent instabil-
ity and the side reactions, caused by the competing nu-
cleophilic methylene carbon, lead to more complexity and
uncertainty.10 Therefore, unsubstituted and substituted
isocyanoacetamides 1a,b were chosen to react with 5a for
the screening of suitable conditions that would work with
both substrates. In the absence of an additive, the reaction
Similar to the stereochemical issues in other Ugi reac-
tion,6 although one chiral center is generated in the course
of this reaction, highly stereoselective cases of this Ugi-
SYNLETT 2012, 23, 1985–1989
Advanced online publication: 04.07.2012
DOI: 10.1055/s-0032-1316549; Art ID: ST-2012-W0361-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

1986
S. Li et al.
LETTER
of 1 and 5 did not take place at all just by varying solvent action system is required for the promotion of the slow re-
and temperature. Under the previous (promoted) condi- action of 1 and 5.
tions for the Ugi-type reactions [Et3N·HCl (8), LiBr (9), or
In 2008, a phenyl phosphilic acid (7) catalyzed Ugi reac-
NH4Cl (10) as promoter, MeOH and toluene as solvent,
tion of aldehydes, amines, and isonitriles was reported.12
from r.t. to reflux],2b–d,8b,10a,11 the reaction was slow (Table
However, the potential of 7 on development of new cata-
lytic Ugi reactions did not receive attention after that. We
found that in our case, the reaction could be activated ef-
1, entries 1, 11, and 12). Simple prolongation of reaction
time resulted in serious decomposition of imines 5 and
tautomerization of 1 to 2H-oxazole 11, and the desired
fectively by 7. In the presence of 25 mol% of 7, the de-
product 6 was always obtained in low yield. This indicat-
sired product 6a was obtained in TFE at room temperature
ed that the Ugi-type condensation based on 5 proceeds
(Table 1, entry 2). Decreasing the amount of 7 or lowering
with much more difficulty than the precedent reaction. It
the temperature could partially inhibit the tautomerization
is possible that compounds 5, as the imines from the con-
of 1 to give better yield (Table 1, entries 3 and 4). Re-
densation of a primary amine and a ketone, are less active
placement of 7 with p-toluenesulfonic acid (12), a stron-
than the iminium counterpart from the secondary amine
ger Brønsted acid, led to a remarkable drop in yield (Table
and the imines from the aldehyde. So, a new efficient re-
1, entry 5). Increase of concentration within an appropri-
Table 1 Optimization of the Ugi-Type Condensation with 5a and 1a,ba
O
O
N
N
Bn
CN
H
N
O
N
catalyst
Bn
+
R1
O
∗
(x mol%)
R1
O
O
N
1a R1 = H
1b R1 = Bn
O
O
5a
6a R1 = H
6b R1 = Bn
O
P
H
tautomerization
LiBr
Et3N⋅HCl
Ph
OH
8
9
O
7
N
O
SO3H
N
Sc(OTf)3
NH4Cl
R1
13
11
10
12
Entry
R1
Solvent
Time (h)
Catalyst (x mol%)
Temp (°C)
Yield (%)
Recovered 5a (%)
1
2
H
MeOH
TFE
6
1.5
1.5
3
8 (200)
7 (25)
60
r.t.
trace
40
67
16
26
27
18
20
trace
0
H
3
H
TFE
7 (10)
r.t.
51
4
H
TFE
7 (25)
–40
–40
–40
r.t.
52
5
H
TFE
2.5
1.5
1
12 (25)
13 (10)
9 (100)
10 (150)
7 (25)
10
6
H
TFE
51
7
H
TFE
8
8
H
TFE
1
r.t.
12
9b
H
TFE
2.5
1
–40
r.t.
59
29
0
10b,c
11b,c
12b,c
13b,c
14b,c
15b,c
H
TFE
7 (10)
86
Bn
Bn
Bn
Bn
Bn
PhMe
PhMe
PhMe
TFE
24
72
12
4
9 (100)
10 (150)
7 (10)
80
trace
19
69
62
74
45
0
80
80
trace
30
13 (10)
7 (10)
–40
r.t.
TFE
1
93
a General conditions: 5a/1 = 1:1, c 0.2 M.
b c 0.4 M.
c Additional 1 was supplemented in midway (0.8 equiv for 1a, 0.4 equiv for 1b).
Synlett 2012, 23, 1985–1989
© Georg Thieme Verlag Stuttgart · New York

LETTER
Ugi-Type Condensation of α-Isocyanoacetamide and Chiral Cyclic Imine
1987
ate range might further improve the yield (Table 1, entry the single stereoisomer. In some cases another diastereo-
9). Nevertheless the consumption of 1 is always faster isomer was detected in small amount, nevertheless, dr val-
than 5, therefore supplement of 1 in midway is very effec- ues were all at least 10:1, as judged by NMR spectra (6a–
tive for thorough conversion of 5 and high yield of 6 (Ta- c,g,h) or separation (6k). The diastereoselectivity in this
ble 1, entries 10 and 15). In other solvents including reaction is better than in our previously reported three-
toluene,12 the catalytic effect of 7 clearly decreased (Table component Ugi reaction.9 The NOESY NMR spectra of
1, entry 13). Some other additives were also tried in TFE 6c and 6f were analyzed to determine the stereochemistry
(Table 1, entries 7 and 8), and only Sc(OTf)3 (13) promot- of the products. The NOE correlation not between Me-3
ed the reaction of 1a (Table 1, entry 6). However, for the and H-5 signals but between Me-3 and aromatic or ben-
substituted isocyanoacetamide 1b, the catalytic effect of zylic hydrogen illustrates the trans-relationship of the C-
13 was inferior than for the unsubstituted isocyanoacet- 3 oxazolyl and C-5 alkyl (R3) group, namely an S-config-
amide 1a (Table 1, entry 14 vs. entry 6).
uration at C-3 (Figure 1). It is reasonable that isocyano-
acetamide 1 as nucleophile preferentially approach imine
5 from the side opposite to the R1 group to generate pre-
dominant the trans product.9,14 Structurally, compounds 6
may be regarded as varied derivatives of chiral α,α-disub-
stituted oxazole-containing amino acids, which are of im-
portance for the design and synthesis of various
conformationally restricted and biologically active pseu-
dopeptides including galmic.15
The generality of this new catalytic Ugi-type condensa-
tion was next examined. Gratifyingly, under the mild con-
ditions the reaction of various compounds 1 and 5 all
proceeded quickly to give the desired products 613 in good
to excellent yields, whether R1 on oxazole is a hydrogen,
alkyl, or aryl group (Table 2). When the amino function
(X) in 1 is morpholinyl, most reactions were finished after
approximately one hour in high yield. For some isocyano-
acetamide units with other amino groups, the reaction pro- On the basis of reactivity of 5-aminooxazoles as electron-
cess seemed somewhat slow, and a higher amount of rich azadienes with dienephiles,16 some strategies to com-
catalyst was needed to accelerate it. Cyclic imines 5 bine the Ugi-type condensation and the Diels–Alder cy-
showed excellent stereoinduction for the new chiral qua- cloaddition have been developed to construct interesting
ternary carbon, and quite a few products were obtained as and complex scaffolds.8b,17 However, the asymmetric tan-
Table 2 Synthesis of 3-Oxazolyl-morpholin/piperazine-2-one Derivatives 6a–na
X
O
R3
H
N
O
R3
O
N
R2
R2
7
CN
X
R1
+
N
R1
Y
TFE
O
Y
1
5
6
Entry
R1
R2
R3
Y
X
Time (h)
Product
Yield (%)
dr
1
H
Bn
Bn
Bn
Bn
i-Pr
Ph
Me
Me
Me
Me
Me
Me
Et
O
morpholinyl
morpholinyl
morpholinyl
morpholinyl
morpholinyl
morpholinyl
morpholinyl
morpholinyl
morpholinyl
morpholinyl
piperidinyl
1
6a
6b
6c
6d
6e
6f
86
93
93
92
87
84
88
78
64
81
90
73
85
78
14:1
2
Bn
O
1
19:1
3
i-Pr
Me
Bn
O
1.25
1
12:1
4
O
single
single
single
14:1
5
O
1.25
1.25
1.25
1.25
1
6
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
Ph
O
7
i-Pr
Bn
Bn
Bn
Bn
Bn
Bn
Bn
O
6g
6h
6i
8
Et
O
10:1
9
Me
Me
Me
Me
Me
Me
NMe
Nn-Bu
O
single
single
13:1
10
11b
12b
13b
14c
1
6j
4
6k
6l
Bn
O
piperidinyl
4
single
single
single
Ph
O
pyrrolidinyl
1.5
2
6m
6n
Bn
O
diethylamino
a General conditions: TFE (0.4 M of 5), r.t., phenylphosphinic acid (0.1 equiv), 1a (1.0 + 0.8 equiv) or 1b–h (1.0 + 0.4 equiv).
b Conditions: 0.25 equiv phenylphosphinic acid were used.
c Conditions: 0.5 equiv phenylphosphinic acid were used.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1985–1989

1988
S. Li et al.
LETTER
O
O
O
N
R2
N
H
N
O
O
R2
toluene
110 °C
O
O
N
R1
N
+
R1
N
O
O
O
14
O
6d R1 = Me, R2 = Bn
6e R1 = Bn, R2 = i-Pr
15a R1 = Me, R2 = Bn, 43%
15b R1 = Bn, R2 = i-Pr, 40%
Scheme 3 Synthesis of fused tricyclic system 15 from 6 and 14
Supporting Information for this article is available online at
O
NOE
H
O
NOE
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
N
N
H H
O
H
N
O
3
N
5
3
5
Ph
References and Notes
H
H
N
i-Pr
N
i-Pr
O
O
O
O
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6c
6f
Figure 1 Configuration determination of products 6 by NOESY anal-
ysis
dem strategy to produce chiral heterocycles has not been
reported. Thus, the reaction of oxazoles 6d and 6e with
maleic anhydride (14) were initially attempted. After pri-
mary screening, heating a mixture of 6 and 14 in toluene
produced a kind of novel tricyclic framework 15 as the
single isomer, incorporating a pyrrolopyridine unit as well
as a morpholine (Scheme 3). The pyrrolopyridine, as an
analogous structure to the isoindolinones, nicotinamide,
etc., is a potential pharmacophore and synthetic interme-
diate.18 Heterocycles 15, which incorporate the medically
relevant morpholinone19 unit, may possess interesting
bioactivity.
In summary, the combination of phenyl phosphilic acid
and TFE was developed to catalyze the Ugi-type conden-
sation of α-isocyanoacetamide 1. Under the conditions,
asymmetric condensation of 1 and the relatively inert im-
ine 5 proceeded smoothly leading to 3-oxazolyl-morpho-
lin or piperazine-2-one derivatives 6, in which excellent
stereoselectivity of the new chiral center was achieved.
The new reaction system showed potential to explore
more Ugi-type condensations of α-isocyanoacetamides,
particularly those in which some inert substrates were
used. Moreover, aminooxazoles 6 reacted with maleic an-
hydride to form novel fused heterocycles 15. Further in-
vestigation on the post-transformation of 6 to interesting
chiral heterocycles such as 15 is ongoing.
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Acknowledgment
We thank Sichuan University Analytical and Testing Center for
NMR determination. We also thank Prof. Xiaoming Feng group for
optical rotation tests. This work was supported by grants from the
National Natural Science Foundation of China (No. 20802045 and
21172153), the National Basic Research Program of China (973
Program, No. 2012CB833200), and the Foundation of the Educati-
on Ministry of China for Returnees.
Synlett 2012, 23, 1985–1989
© Georg Thieme Verlag Stuttgart · New York

LETTER
Ugi-Type Condensation of α-Isocyanoacetamide and Chiral Cyclic Imine
1989
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To a mixture of imine 5a (42 mg, 0.21 mmol) and
isocyanides 1d (35 mg, 0.21 mmol) in TFE (0.5 mL) was
added phenyl phosphilic acid (3 mg, 0.021 mmol) at r.t.
under stirring. After 20 min, additional 1d (14 mg, 0.084
mmol) was added, and the mixture was stirred for another 40
min. The reaction was quenched with aq NaHCO3, and
extracted with CH2Cl2. The organic layers were dried over
Na2SO4 and concentrated. The residue was purified by flash
column chromatography on silica gel (PE–EtOAc = 3:2) to
afford product 6d; yield 92%; colorless gel; [α]D20 –31 (c 0.7,
in CH2Cl2). IR (neat): 3312, 2922, 2854, 1744, 1213, 1116,
753, 701 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.22–7.33
(m, 5 H), 4.33 (dd, J = 3.5, 10.5 Hz, 1 H), 4.19 (t, J = 10.4
Hz, 1 H), 3.72–3.78 (m, 4 H), 3.46–3.55 (m, 1 H), 2.88–2.93
(m, 4 H), 2.76 (dd, J = 5.1, 13.7 Hz, 1 H), 2.59 (dd, J = 8.7,
13.7 Hz, 1 H), 2.06 (s, 3 H), 1.73 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 167.8, 157.1, 151.7, 136.3, 128.9,
128.8, 127.0, 121.3, 74.3, 66.8, 60.8, 50.7, 49.6, 37.7, 25.9,
11.2 ppm. HRMS (ESI+): m/z calcd for C20H25N3O4Na [M +
Na]+: 394.1743; found: 394.1749.
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