DEAD-Promoted Oxidative Ugi-Type Reaction Including an Unprecedented Ugi Amidation Assisted by Dicarboxylic Acids

Article abstract of DOI:10.1002/ejoc.201701323

A mild and metal-free DEAD-promoted (DEAD = diethyl azodicarboxylate) oxidative Ugi-type reaction of tertiary amines has been demonstrated. The reaction gives easy access to α-amino amides and imides with diverse functional groups in good isolated yields. This Ugi-type approach achieves an unprecedented synthesis of α-amino amide analogues with the assistance of dicarboxylic acids, and not water, for the introduction of the carbonyl oxygen atom of the amide moiety. Mechanistic studies indicated that the dicarboxylic acids may readily undergo an intramolecular annulation, instead of the Mumm rearrangement, to give the desired amide with one molecule of anhydride released.

Full text of DOI:10.1002/ejoc.201701323

A Journal of
Accepted Article
Title: Novel DEAD-Promoted Oxidative Ugi-Type Reaction Including an
Unprecedented Ugi-Amidation Assisted by Dicarboxylic Acids
Authors: Jiankun Wang, Yilin Sun, Guangji Wang, and Le Zhen
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701323
Link to VoR: http://dx.doi.org/10.1002/ejoc.201701323
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10.1002/ejoc.201701323
European Journal of Organic Chemistry
FULL PAPER
Novel DEAD-Promoted Oxidative Ugi-Type Reaction Including an
Unprecedented Ugi-Amidation Assisted by Dicarboxylic Acids
Jiankun Wang,[a] Yilin Sun,[a] Guangji Wang,*[a] and Le Zhen*[a]
Abstract: A mild and metal-free DEAD-promoted oxidative Ugi-type
reaction of tertiary amines has been demonstrated, giving facile
access to α-amino amides and imides with diverse functional groups
in good isolated yields. This Ugi-type approach achieves an
unprecedented synthesis of α-amino amide analogues with the
assistance of dicarboxylic acids, but not water, for the introduction of
carbonyl oxygen of the amide moiety. Mechanistic studies indicated
that the dicarboxylic acids may readily undergo an intramolecular
annulation, instead of the Mumm rearrangement, affording the
desired amide with one molecule of anhydride released.
by 1,5-hydride shift.[5] Nevertheless, it is still of great significance
to develop more efficient and practical oxidative Ugi-type
reactions without the assistance of metal catalysts.
Diethyl azodicarboxylate (DEAD) is mostly known for the
essential role in the Mitsunobu reaction,[6] as well as its strong
electrophilic character and particular transformation for Huisgen
zwitterion.[7] Recently, DEAD-promoted oxidation of tertiary
amines has been revealed in numerous chemical reactions.[8.9]
In 2008, the pioneering work was performed by Li’s group.
Tertiary amines treated with DEAD were oxidized to the
corresponding enamine, reacting with sulfonyl azide through 1,3-
dipolar addition (Scheme 1, eq 2).[9b] Later, the same group
widened their concept in DEAD-promoted alkynylation and
hydration of tertiary amines (Scheme 1, eq 3 and 4).[9c,d] Quite
recently, a wide range of nucleophiles were successfully applied
for the oxidative cross dehydrogenative coupling (CDC) of the α-
positions to nitrogen mediated by DEAD or other
azodicarboxylates (Scheme 1, eq 5).[9e-i] Mechanistic study
established by Akiyama and colleagues revealed DEAD as a
bifunctional reagent (both oxidant and base) in DEAD-promoted
oxidative coupling of THIQ derivatives.[9i] As the above studies
revealed, the DEAD-assisted oxidations are general and efficient,
which encourage us to eagerly incorporate this promising
dehydrogenation approach into novel versions of oxidative Ugi-
type reaction.
Introduction
The Ugi reaction is now a cornerstone multicomponent reaction
(MCR) to construct privileged structures for chemical libraries
and drug research. Extensive studies have been devoted to the
advancement of this isocyanide-based transformation.[1,2] In
traditional Ugi processes, primary amines are always required
due to the involvement of the irreversible acyl migration (Mumm
rearrangement); secondary or tertiary amines, by contrast, are
rarely employed, because of the failure of the key transacylation
at the amino nitrogen. Over the recent decade, an assortment of
attractive Ugi-type variants utilizing secondary amines as
starting materials has been developed.[3] Notably, isocyanide-
based MCRs of secondary amines under oxidative conditions
were pioneeringly developed by Zhu's group, employing IBX as
a mild and efficient oxidant.[3b] This significant work first
introduced the concept of oxidative Ugi-type reaction, extending
the scope and versatility of MCRs. Furthermore, we are also
fascinated by the oxidative Ugi-type reactions of tertiary amines,
in which the substrates are directly converted into iminium ions
under varying oxidants, followed by the nucleophilic attack of
isocyanides (Scheme 1, eq 1).[4] For example, three-component
assemblies using copper and peroxides as oxidants were
reported by Xie in 2010.[4a] Alternatively, photoredox-catalyzed
oxidative Ugi-type reactions were first accomplished by
Rueping’s group in 2013.[4c] However, it is noteworthy that the
catalysts used are limited to metal Lewis acid or Ru-/Ir-based
photoredox ones, potentially limiting the practicality in gram-
scale synthesis and reducing the operational simplicity of
oxidative Ugi-type reactions. We recently reported a Brønsted
acid-catalyzed two starting materials-three components reaction
(2SM-3CR) involving the oxidation of tertiary amines triggered
Oxidative
Reactions of
Amines
Tertiary
Ugi-type
R2
R2
O
O
R2
R1
C
R1
R1
R4
R5
CuCl, TBHP;
or
=
R4
N
N
N
[O]
N
H
[O]
N
[Ir(ppy)2bpy]PF6
Ru(bpy)
(1)
R5COOH
R3
R3
R3
3
2
Cl , visible
light
iminium ions
Oxidation of
Amines
DEAD-promoted
Tertiary
DEAD
O
N
+
SO2N3
N
(2)
(3)
(4)
(5)
S
N
O
R2
N
R2
DEAD
R2
R1
N
R3
+
R1
5 mol CuI
%
DEAD
H2O
N
N
O
R2
N
R2
=
azodicarboxylates
NuH
nitromethane,
malonate,
enol
silyl
ether,
dimethyl
H
Nu
+
N
NuH
R1
R1
CDC reaction
et al
acetophenone,
R3
R3
This Work
iminium ion A
Ar
N
N
COOEt
Ar
N
EtOOC
H
EtOOC
N
H
N
N
N
N
COOEt
COOEt
C
COOEt
N
R
R
H
O
(6)
N
Ar
O
Mumm
rearrangement
N
NAr
1
Ar
O
R
N
O
2
N
O
O
intermediate B
[a]
Ms. J. Wang, Ms. Y. Sun, Prof. Dr. G. Wang, Dr. L. Zhen
Key Laboratory of Drug Metabolism and Pharmacokinetics, China
Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009,
Jiangsu, China
Scheme 1. Oxidative Ugi-type Reactions and DEAD-promoted Oxidation of
Tertiary Amines
E-mail: i_m_zhenle@163.com
guangjiwang@hotmail.com;
http://yjsy.cpu.edu.cn/_t283/05/55/c6478a66901/page.htm
We preliminarily supposed that N-aryl 1,2,3,4-tetrahydro-
isoquinolines could experience novel oxidative Ugi-type
Supporting information for this article is given via a link at the end of
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10.1002/ejoc.201701323
European Journal of Organic Chemistry
FULL PAPER
reactions mediated by DEAD. The plausible reaction pathway
was illustrated in Scheme 1, eq 6. The iminium ion A could be
formed via a nucleophilic addition-initiated dehydrogenation of 1,
pairing with its basic counter anion (1H-DEAD anion).[9b-d] Next,
iminium ion A would readily undergo the nucleophilic attack of
the isocyanide, and meanwhile the 1H-DEAD anion could
deprotonate the acetic acid, giving rise to the imino anhydride
intermediate B. The subsequent Mumm rearrangement could
occur at the isocyanide nitrogen, facilitating the complete of the
oxidative Ugi-type reaction and furnishing bisamide 2. DEAD,
doubly functioned as both oxidant and base, transformed into
2H-DEAD.
azodicarboxylate (DBAD) was used, 2a was isolated only in 10%
yield (Table 1, entry 3). To our delight, excellent yields were
obtained when DCM or toluene was selected as solvent (Table 1,
entries 4−5). However, other solvents led to a decreased
reactivity (Table 1, entries 6−8). Twice the amount of DEAD,
TosMIC or AcOH were tested, providing no yield improvement
(Table 1, entries 9−11). The pretreatment of 1a with DEAD did
not affect the yield (Table 1, entry 12). According to the above
results, the oxidative Ugi-type reaction of 1a, TosMIC (1.1 equiv)
and AcOH (1.1 equiv), with DEAD (1.1 equiv) as the oxidant,
was optimally carried out in DCM (0.1 M) at room temperature.
The scope of substrates 1 and isocyanides were next
explored under the optimized reaction conditions (Scheme 2).
Electron-donating groups (e.g., 4-methyl and 2-methoxy) and
electron-withdrawing group (e.g., 4-bromo) on the nitrogen-
linked benzene ring were well-tolerated, giving the
corresponding products 2b−d in 79−88% yields. In addition, a
substrate carrying 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
moiety provided 2e in 68% yields. To probe the generality of this
protocol further, various isocyanides were subjected to the
oxidative Ugi-type reaction, furnishing the corresponding
products 2f−h in 60−77% yields.
Results and Discussion
Table 1. Optimization of Reaction Conditions. [a]
azodicarboxylate (1.1 equiv),
N
TosMIC
AcOH
(1.1 equiv),
(1.1 equiv)
N
solvent
4 h
rt,
N
Ts
O
(0.1 M),
2a
O
1a
Entry
1
Azodicarboxylate
DEAD
Solvent
Yield[b]
75
DEAD
(1.1 equiv),
(1.1 equiv),
(1.1 equiv)
R3 NC
R2
N
R2
AcOH
CH3CN
CH3CN
CH3CN
DCM
O
R1
N
DCM
4 h
R1
rt,
(0.1 M),
N
R3
O
2
2
DIAD
64
1
O
N
3
DBAD
10
N
N
N
O
O
O
O
Br
N
O
N
O
N
O
N
O
4
DEAD
85
Ts
Ts
2a
Ts
2b
Ts
O
2c
2d
, 88%
, 85%
, 83%
,79%
5
DEAD
toluene
DCE
86
O
N
N
N
N
O
6
DEAD
78
O
O
O
O
N
O
N
O
N
O
N
O
O
7
DEAD
THF
21
2f
, 60%
2g
2h
, 61%
Ts
2e
, 68%
, 77%
8
DEAD
DMF
36
9[c]
10[d]
11[e]
12[f]
DEAD
DCM
86
Scheme 2. Scope of Substrates 1 and Isocyanides
DEAD
DCM
82
DEAD
(1.1 equiv),
TosMIC
(1.1 equiv),
DEAD
DCM
70
N
R1COOH
(1.1 equiv)
N
DCM
4 h
rt,
Ts
N
O
2
(0.1 M),
DEAD
DCM
83
R1
O
1a
[a] 1a (0.3 mmol), azodicarboxylate (0.33 mmol), TosMIC (0.33 mmol), AcOH
(0.33 mmol), solvent (3.0 mL). DEAD and TosMIC were added at the same
time. [b] Isolated yield. [c] DEAD (0.66 mmol). [d] TosMIC (0.66 mmol). [e]
AcOH (0.66 mmol). [f] 1a was treated with DEAD for 2 h, and subsequently
TosMIC and AcOH were added. TosMIC = p-toluenesulfonyl isocyanide. DIAD
= diisopropyl azodicarboxylate. DBAD = di-tert-butyl azodicarboxylate.
N
N
N
N
Ts
N
O
Ts
N
O
Ts
N
O
Ts
BocHN
N
O
O
O
O
O
2l R2
2m R2
2i
2k
=
, 82%
, 75%
, 71%
,
67%
2j
H,
R2
=
,
83%
60%
Cl,
2n
R2
=
,
OMe,
N
N
N
We commenced our study using 2-phenyl-1,2,3,4-tetrahydro-
isoquinoline 1a and p-toluenesulfonyl isocyanide (TosMIC) as
model substrates, choosing AcOH as a third component. The
reaction was carried out in the presence of 1.1 equiv of
azodicarboxylate at room temperature for 4 hours. With DEAD
and diisopropyl azodicarboxylate (DIAD) in CH3CN, the reaction
proceeded smoothly to afford the desired product 2a in
moderate yield (Table 1, entries 1−2). When di-tert-butyl
Ts
N
O
Ts
N
O
Ts
N
O
O
O
O
O
2o
, 62%
, 68%
, 75%
2q
2p
OAc
Cl
Scheme 3. Scope of Acids
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10.1002/ejoc.201701323
European Journal of Organic Chemistry
FULL PAPER
After having identified the desired compatibility of derivatives
of 1 and isocyanides, we turned our attention into the reactivity
of acid (Scheme 3). An array of acids was well-tolerated in this
reaction: branched and cyclic acids (e.g., 2-ethylbutyric acid and
cyclobutane carboxylic acid) were suitable reactants, providing
2i and 2j in good yields. N-(tert-Butoxycarbonyl)glycine
performed smoothly to afford 2k in 71% yields. The reactivity
remained when benzoic acids (e.g., benzoic acid, 4-
chlorobenzoic acid, 4-methoxybenzoic acid) were used, giving
access to 2l−n in 60−83% yields. Cinnamic acid was also tested,
and the desired product 2o was isolated in 62% yields.
Interestingly, the derivatization of pharmacologically active
compounds was also achieved with our method. The aspirin
derivative 2p was prepared in 75% yields, and the amidation of
the active metabolite of clofibrate provided 2q in 68% yields.
yields (Table 2, entry 10), which demonstrated the dicarboxylic
acid indeed participated the reaction, but did not just act like a
mediator for water addition to the nitrilium ion.
Table 3. Scope of Substrates 1 and Isocyanides.
DEAD
(1.1 equiv),
(1.1 equiv),
R3 NC
R1
N
succinic acid
R1
(1.1 equiv)
R2
N
R3
R2
N
H
O
DCM
6 h
rt,
(0.1 M),
1
3
Entry
1
1
R1
H
H
H
H
R2
R3
3
Yield[a]
82
1a
1b
1c
1d
1e
1f
H
CH2Ts
CH2Ts
CH2Ts
CH2Ts
CH2Ts
CH2Ts
CH2Ts
Cy
3a
3b
3c
3d
3e
3f
4-Me
2
79
2-OMe
3
78
Table 2. Optimization of the Ugi-amidation Conditions. [a]
4-Br
H
4
85
DEAD
TosMIC
dicarboxylic
(1.1 equiv),
(1.1 equiv),
N
O
N
acid
Ph
6,7-OMe
5
65
n =
1-3
TsCH2
1a
NR
RN
n
O
=
R
solvent
6 h
Ts
rt,
(0.1 M),
N
O
NPh
O
H
O
5-OMe
H
6
72
3a
not observed
6,
1g
1a
1a
1a
1a
7-NO2
H
3g
3h
3i
7
55
Entry
Additives
Solvent
DCM
Yield[b]
H
H
H
H
H
8
70
1[c]
2[d]
3
33
37
82
73
50
71
69
78
trace
10
succinic acid
glutaric acid
succinic acid
glutaric acid
malonic acid
succinic acid
succinic acid
succinic acid
H2O (5 equiv)
H
t-Bu
9
43
DCM
H
Bn
3j
10
11
62
DCM
H
CH2CO2Et
3k
72
DCM
4
[a] Isolated yield.
Table 4. Scope of Noncyclic Anilines.
DCM
5
CH3CN
DCE
6
DEAD
R2
N
R2
N
O
R2
N
O
(1.1 equiv),
(1.1 equiv),
R1
R1
R1
TosMIC
acid
N
Ts
(1.1 equiv)
N
Ts
7
or
H
toluene
(0.1 M)
C,
O
N2 80 o 24 h
5h
4
,
5a-c,
5d-f,
5g
toluene
DCM
8
Entry
4
R1
R2
Acid
5
Yield[a]
47
9
10[e]
succinic acid + H2O (5 equiv)
DCM
4a
4b
4c
4a
4b
4c
4d
4d
H
Me
Me
Me
Me
Me
Me
Et
AcOH
AcOH
AcOH
5a
5b
5c
5d
5e
5f
1
2
3
4
5
6
7
8
4-Me
4-Br
H
[a] 1a (0.3 mmol), DEAD (0.33 mmol), TosMIC (0.33 mmol), dicarboxylic acid
(0.33 mmol), solvent (3.0 mL). [b] Isolated yield. [c] succinic acid (0.18 mmol).
[d] glutaric acid (0.18 mmol). [e] succinic acid (0.06 mmol).
59
52
succinic acid
succinic acid
succinic acid
AcOH
61
Since diverse acids were applicable, we attempted to employ
dicarboxylic acids to afford dimeric products 6 (Table 2).[10] To
our surprise, 6 were not observed during the reaction using 0.6
equiv of succinic acid or glutaric acid, but, even more
interestingly, amide 3a was obtained instead (Table 2, entries
1−2). Next, we doubled the amount of dicarboxylic acids, making
a dramatic improvement in the isolated yield of 3a (Table 2,
entries 3−4). Malonic acid was also tolerated in the reaction
(Table 2, entry 5).[11] DCM was a better choice than other
solvents examined, including CH3CN, DCE and toluene (Table 2,
entries 6−8). Notably, unlike in the typical truncated Ugi reaction,
water was poor nucleophilic reagent for attacking the nitrilium
ion (Table 2, entry 9). We reduced the equivalent of succinic
acid by the addition of exogenous water, providing 3a only in 10%
4-Me
4-Br
H
49
55
5g
5h
15
H
Et
succinic acid
11
[a] Isolated yield.
With optimal conditions in hand, we investigated the influence
of the electronic nature of the aromatic rings (R1 and R2, Table
3). The substrates with electron-donating (e.g., 4-methy, 2-
methoxy) or electron-withdrawing (e.g., 4-bromo) group were
applicable, furnishing 3b−d in 78−85% yields. Moreover,
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10.1002/ejoc.201701323
European Journal of Organic Chemistry
FULL PAPER
COOH
electron-rich (e.g., 6,7-dimethoxy, 5-methoxy) and electron-poor
(e.g., 7-nitro) substituents on the 1,2,3,4-tetrahydroisoquinoline
moiety were both tolerable and gave 3e−g in good yields. The
protocol scope was further explored by varying the R3 group of
the isocyanides (Table 3, entries 8−11). Similar results were
observed when isocyanide derivatives were examined, giving 3h,
3j and 3k in 62−72% yields. When tert-butyl isocyanide was
employed, however, the desired product 3l was obtained only in
43% yield.
To highlight the utility of this method, we further employed
non-cyclic anilines 4 as substrates (Table 4). Based on the
conditions determined, toluene was selected as the solvent. The
non-cyclic substrates 4a-c gave the desired product 5a-f in
moderate yield (47−61%), with lengthened reaction time and
increased temperature. In addition, electron-donating and
electron-withdrawing substituents on the phenyl ring were found
to be well-tolerated in this process. The N-ethyl-N-methylaniline
4d provided the N-methyl-derivatives 5g and 5h in 15% and 11%
yields, respectively. The steric effect of N-ethyl may be
responsible for the dramatic decrease of yields.[12] N,N-
dimethylcyclohexylamine and N-benzoyl 1,2,3,4-tetrahydro
isoquinoline were also employed, however, no desired product
was observed.[13] Furthermore, gram-scale preparation was
carried out with increased concentrations of reactants, providing
2a, 3a, 5a and 5d in desired yields (for more details, see SI).
Since IBX was a representative organic oxidant for oxidative
Ugi-type reaction, the comparison between IBX and DEAD as
oxidants was also carried out, indicating our protocol more
suitable and effective for the oxidative Ugi-type reactions of
tertiary amines (for more details, see SI).
N
COOH,
(1.1 equiv)
DEAD
N
N
(1.1 equiv),
TosMIC
(1.1 equiv),
Ts
Ts
Ts
N
H
O
(1)
(2)
1a
1a
3a
3a
, 70%
DCM
8 h
rt,
(0.1 M),
COOH
,
N
(1.1 equiv)
HOOC
DEAD
(1.1 equiv),
TosMIC
N
H
O
(1.1 equiv),
, 0%
DCM
16 h
rt,
(0.1 M),
O
18
H
O
H18
O
N
O
N
N
DEAD
(1.1 equiv),
O18
TosMIC
N
H
(1.1 equiv),
(3)
(4)
1a
1a
3a
+
, 31%
DCM
12 h
rt,
(0.1 M),
AcOH
DEAD
(1/5/10 equiv)
(1.1 equiv),
TosMIC
(1.1 equiv)
2a
3a
DCM
8 h
rt,
(0.1 M),
Scheme 5. Control Experiments.
Figure 1. The yield of 2a and 3a with different equiv of AcOH.
To confirm the reaction pathway further, several control
experiments were performed (Scheme 5). Phthalic acid was well
tolerated, providing 3a in 70% yields (eq 1). Terephthalic acid,
by contrast, did not lead to the production of 3a (eq 2). Therefore,
the dicarboxylic acids capable of transforming into the
corresponding cyclic anhydride are essential for the introduction
of carbonyl oxygen. Subsequently, we used 18O-labeled succinic
acid to probe the origin of the oxygen in 3a. As we expected,
18O-labeled 3a was obtained in 31% yields (eq 3).[14]
Furthermore, based on the proposed behavior of intermediate B',
we speculated that even intermolecular nucleophilic attack could
compete with the Mumm rearrangement at carbonyl. Therefore,
competitive experiments were designed with the addition of
excessive AcOH (5 equiv and 10 equiv, eq 4). Finally, we
isolated 3a in 16% and 25% yields, respectively (Figure 1).[15]
Together, the control experiments verified that dicarboxylic acids
could deliver one oxygen atom to 3a via self-annulation during
the amidation.
N
N
Ar
Ar
imino
intermediate
anhydride
R
R
H
O
B'
N
O
N
O
H
3
O
O
O
O
O
Scheme 4. Proposed Dicarboxylic Acid-based Mechanism
In the light of the above experiment results, a dicarboxylic
acid-based mechanism was proposed (Scheme 4). When the
imino anhydride intermediate B' was formed (see Scheme 1, eq
6), out of the ordinary, an intramolecular annulation occured at
the carbonyl, instead of the Mumm rearrangement, affording the
amide 3 with one molecule of succinic anhydride released.
.
A
.
B
intramolecular
water-mediated amidation
amidation
nucleophile-mediated
endogenous
R2 R3
N
R1
R2 R3
N
R2 R3
N
N
R2 R3
N
R4
A
B
H
N
N
R1
R4
R1
R4
O
H
H
R1
O
O
O
intramolecular
nucleophiles
endogenous
water
Nu
R5
imino
intermediate
O
R2 R3
imine
formation
anhydride
N
H
+
R1
H
Scheme 6. Insertion of the Amide Carbonyl Oxygen in Ugi-amidation.
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10.1002/ejoc.201701323
European Journal of Organic Chemistry
FULL PAPER
J = 8.1 Hz, 2H), 6.31 (s, 1H), 5.55 (AB, J = 15.0 Hz, 1H), 4.86 (AB, J =
15.1 Hz, 1H), 3.75 (d, J = 11.4 Hz, 1H), 3.47 – 3.35 (m, 1H), 2.97 – 2.83
(m, 1H), 2.73 – 2.61 (m, 1H), 2.46 (s, 3H), 2.37 (s, 3H), 2.32 (s, 3H). 13C
NMR (125 MHz, CDCl3) δ 174.58, 172.31, 145.67, 145.53, 135.30,
134.11, 131.03, 130.43, 130.15, 129.89, 128.97, 128.87, 128.63, 127.81,
126.20, 117.38, 62.81, 61.44, 45.38, 25.89, 25.10, 21.71, 20.45. HRMS
(ESI) calcd. for C27H29N2O4S [M+H]+ 477.1843, found 477.1858.
Based on the above mechanism, our method could be
considered as a representative Ugi-MCR concisely providing α-
amino amides without water as a nucleophile.[16,17] Unlike the
typical Ugi-amidation utilizing endogenous water generated
during the imine or iminium ion formation [3g-h, 5, 16], the amide
carbonyl oxygen in this protocol was introduced through an
intramolecular nucleophilic attack on the imino anhydride
intermediate (Scheme 6) [17]. Notably, dicarboxylic acid was
served as a readily accessible and highly reactive alternative to
water for the insertion of the amide carbonyl oxygen, especially
when the water added could not facilitate amide formation
(Table 2, entry 9). Studies are in progress to boarden the
application of the dicarboxylic acid-assisted Ugi-MCRs in our
group.
N-acetyl-2-(2-methoxyphenyl)-N-(tosylmethyl)-1,2,3,4-
tetrahydroisoquinoline-1-carboxamide (2c), white solid, 117 mg, 79%
yield. m.p. 204–206oC. 1H NMR (500 MHz, CDCl3) δ 7.64 (d, J = 8.1 Hz,
2H), 7.41 – 7.34 (m, 1H), 7.34 – 7.26 (m, 4H), 7.21 – 7.15 (m, 1H), 7.14 –
7.08 (m, 1H), 6.93 (d, J = 8.2 Hz, 1H), 6.90 – 6.80 (m, 2H), 6.10 (s, 1H),
5.49 (AB, J = 15.0 Hz, 1H), 4.74 (AB, J = 15.1 Hz, 1H), 3.87 (s, 3H), 3.57
(dd, J = 14.0, 5.6 Hz, 1H), 3.42 – 3.29 (m, 1H), 2.95 – 2.83 (m, 1H), 2.73
– 2.62 (m, 1H), 2.44 (s, 3H), 2.27 (s, 3H). 13C NMR (126 MHz, CDCl3) δ
173.90, 172.31, 152.80, 145.41, 137.76, 135.20, 134.09, 131.66, 129.84,
129.08, 128.88, 128.25, 127.51, 126.00, 124.70, 121.82, 121.17, 111.77,
62.67, 62.22, 55.41, 44.42, 26.17, 25.60, 21.71. HRMS (ESI) calcd. for
C27H29N2O5S [M+H]+ 493.1792, found 493.1803.
Conclusions
In conclusion, we herein report a DEAD-promoted oxidative Ugi-
type reaction of tertiary amines, furnishing α-amino amides and
imides with diverse substitutes. Notably, an unprecedented
amidation assisted by dicarboxylic acids has been disclosed,
which provide a solution for poor reactivity of water in some Ugi
reaction. Dicarboxylic acids are supposed to be cost effective
and operationally simple alternatives to water. Moreover, the
reaction proceeded with broad substrate scope under mild and
practical conditions, affording the target compounds in good
yields. Further exploration of DEAD-promoted oxidation is now
ongoing in our laboratory.
N-acetyl-2-(4-bromophenyl)-N-(tosylmethyl)-1,2,3,4-
tetrahydroisoquinoline-1-carboxamide (2d), white solid, 143 mg, 88%
1
yield. m.p. 144–146oC H NMR (500 MHz, CDCl3) δ 7.61 (d, J = 7.9 Hz,
2H), 7.44 – 7.36 (m, 3H), 7.35 – 7.30 (m, 2H), 7.28 (d, J = 8.1 Hz, 2H),
7.22 – 7.15 (m, 1H), 6.81 (d, J = 8.7 Hz, 2H), 6.48 (s, 1H), 5.44 (AB, J =
15.1 Hz, 1H), 4.87 (AB, J = 15.1 Hz, 1H), 3.71 – 3.62 (m, 1H), 3.56 –
3.46 (m, 1H), 2.93 – 2.84 (m, 1H), 2.80 (dt, J = 16.1, 5.5 Hz, 1H), 2.44 (s,
3H), 2.43 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 174.34, 172.79, 147.10,
145.66, 135.57, 134.01, 132.33, 131.09, 129.97, 128.79, 128.25, 126.55,
117.29, 112.06, 63.26, 61.35, 44.96, 25.92, 25.76, 21.71. HRMS (ESI)
calcd. for C26H26N2O4SBr [M+H]+ 541.0791, found 541.0808.
N-acetyl-6,7-dimethoxy-2-phenyl-N-(tosylmethyl)-1,2,3,4-
tetrahydroisoquinoline-1-carboxamide (2e), light yellow solid, 107 mg,
68% yield. m.p. 176–178oC. 1H NMR (500 MHz, CDCl3) δ 7.66 (d, J = 7.9
Hz, 2H), 7.36 – 7.25 (m, 4H), 7.03 – 6.93 (m, 4H), 6.64 (s, 1H), 6.29 (s,
1H), 5.52 (AB, J = 15.0 Hz, 1H), 4.85 (AB, J = 15.2 Hz, 1H), 3.97 (s, 3H),
3.90 (s, 3H), 3.77 (d, J = 13.6 Hz, 1H), 3.49 – 3.37 (m, 1H), 2.92 – 2.75
(m, 1H), 2.62 (dt, J = 16.3, 4.0 Hz, 1H), 2.44 (s, 3H), 2.40 (s, 3H). 13C
NMR (126 MHz, CDCl3) δ 174.63, 172.42, 148.88, 148.08, 147.71,
145.60, 134.18, 129.91, 129.60, 128.79, 127.63, 122.78, 120.76, 116.99,
111.53, 111.19, 62.92, 61.09, 56.13, 55.85, 45.19, 25.87, 24.99, 21.71.
HRMS (ESI) calcd. for C28H31N2O6S [M+H]+ 523.1897, found 523.1909.
Experimental Section
General procedure for synthesis of compound 2:
A 10 mL flask was charged with 1a-e (0.3 mmol), isocyanides (0.33
mmol) and acid (0.33 mmol) in DCM (3.0 mL). To the flask was added
DEAD (52 μL, 58 mg, 0.33 mmol, 1.1 equiv) and the resulting mixture
stirred at room temperature. The reaction was monitored by TLC until
complete consumption. The solvent was directly removed under reduced
pressure. The residue was purified by flash chromatography (petroleum
ether/ethyl acetate = 50:1-5:1) to give the desired products 2a-q, which
was further purified by trituration in ether or ether/hexane.
N-acetyl-N-cyclohexyl-2-phenyl-1,2,3,4-tetrahydroisoquinoline-1-
carboxamide (2f), colorless glass, 87 mg, 77% yield. 1H NMR (300 MHz,
CDCl3) δ 7.34 – 7.27 (m, 1H), 7.25 – 7.14 (m, 4H), 7.14 – 7.05 (m, 1H),
6.92 (d, J = 8.2 Hz, 2H), 6.77 (t, J = 7.2 Hz, 1H), 6.10 (s, 1H), 3.68 – 3.57
(m, 1H), 3.56 – 3.42 (m, 2H), 3.03 – 2.75 (m, 2H), 2.12 (s, 3H), 2.00 –
1.81 (m, 1H), 1.81 – 1.59 (m, 3H), 1.53 – 1.34 (m, 2H), 1.15 – 0.91 (m,
4H). 13C NMR (75 MHz, CDCl3) δ 177.13, 174.51, 148.65, 135.46,
132.53, 129.23, 128.39, 127.70, 126.34, 119.11, 115.42, 63.33, 59.17,
44.78, 30.67, 29.49, 27.44, 26.44, 25.56, 25.07. HRMS (ESI) calcd. for
C24H29N2O2 [M+H]+ 377.2224, found 377.2239.
N-acetyl-2-phenyl-N-(tosylmethyl)-1,2,3,4-tetrahydroisoquinoline-1-
carboxamide (2a), white solid, 118 mg, 85% yield. m.p. 148–150oC. 1H
NMR (300 MHz, CDCl3) δ 7.60 – 7.50 (m, 2H), 7.38 – 7.29 (m, 1H), 7.28
– 7.13 (m, 6H), 7.11 – 7.01 (m, 1H), 6.97 – 6.79 (m, 3H), 6.34 (s, 1H),
5.41 (AB, J = 15.0 Hz, 1H), 4.75 (AB, J = 15.0 Hz, 1H), 3.79 – 3.56 (m,
1H), 3.47 – 3.26 (m, 1H), 2.90 – 2.71 (m, 1H), 2.71 – 2.51 (m, 1H), 2.34
(s, 3H), 2.29 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 174.54, 172.45, 147.93,
145.53, 135.42, 133.97, 131.10, 129.88, 129.57, 128.85, 128.80, 128.46,
127.91, 126.27, 120.48, 116.52, 62.91, 61.26, 44.98, 25.82, 25.53, 21.69.
HRMS (ESI) calcd. for C26H27N2O4S [M+H]+ 463.1686, found 463.1698.
N-acetyl-N-benzyl-2-phenyl-1,2,3,4-tetrahydroisoquinoline-1-
carboxamide (2g), colorless glass, 69 mg, 60% yield. 1H NMR (300 MHz,
CDCl3) δ 7.29 – 7.19 (m, 4H), 7.19 – 7.08 (m, 5H), 6.87 (d, J = 8.0 Hz,
2H), 6.84 – 6.70 (m, 3H), 6.59 (s, 1H), 4.99 (d, J = 16.8 Hz, 1H), 4.57 (d,
J = 16.8 Hz, 1H), 3.80 – 3.67 (m, 1H), 3.62 – 3.49 (m, 1H), 3.04 – 2.90
(m, 1H), 2.90 – 2.77 (m, 1H), 2.23 (s, 3H). 13C NMR (75 MHz, CDCl3) δ
176.53, 174.49, 148.89, 136.76, 136.20, 132.62, 129.32, 128.74, 128.56,
127.86, 127.32, 127.24, 126.42, 126.06, 118.94, 115.14, 62.16, 48.07,
N-acetyl-2-(p-tolyl)-N-(tosylmethyl)-1,2,3,4-tetrahydroisoquinoline-1-
carboxamide (2b), white solid, 119 mg, 83% yield. m.p. 150–152oC. H
NMR (500 MHz, CDCl3) δ 7.68 (d, J = 7.9 Hz, 2H), 7.47 – 7.39 (m, 1H),
7.36 – 7.26 (m, 4H), 7.19 – 7.14 (m, 1H), 7.12 (d, J = 8.0 Hz, 2H), 6.90 (d,
1
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701323
European Journal of Organic Chemistry
FULL PAPER
44.29, 27.31, 25.69. HRMS (ESI) calcd. for C25H25N2O2 [M+H]+ 385.1911,
found 385.1924.
128.51, 127.80, 126.05, 120.54, 116.61, 65.75, 60.60, 44.96, 25.74,
21.66. HRMS (ESI) calcd. for C31H29N2O4S [M+H]+ 525.1843, found
525.1853.
Ethyl N-acetyl-N-(2-phenyl-1,2,3,4-tetrahydroisoquinoline-1-carbonyl)
glycinate (2h), colorless glass, 70 mg, 61% yield. 1H NMR (300 MHz,
CDCl3) δ 7.33 – 7.23 (m, 1H), 7.24 – 7.13 (m, 4H), 7.13 – 7.04 (m, 1H),
6.93 – 6.75 (m, 3H), 5.99 (s, 1H), 4.38 (AB, J = 17.9 Hz, 1H), 4.26 (AB, J
= 17.9 Hz, 1H), 4.14 – 3.90 (m, 2H), 3.59 (t, J = 6.1 Hz, 2H), 2.99 – 2.73
(m, 2H), 1.09 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 174.98,
173.57, 168.34, 148.45, 135.46, 131.54, 129.36, 128.85, 127.86, 127.82,
126.31, 120.24, 116.49, 62.88, 61.46, 46.04, 45.53, 26.63, 26.01, 13.96.
HRMS (ESI) calcd. for C22H25N2O4 [M+H]+ 381.1809, found 381.1825.
N-(4-chlorobenzoyl)-2-phenyl-N-(tosylmethyl)-1,2,3,4-
tetrahydroisoquinoline-1-carboxamide (2m), off-white solid, 139 mg,
83% yield. m.p. 132–134oC. 1H NMR (500 MHz, CDCl3) δ 7.80 (d, J = 7.9
Hz, 2H), 7.50 (d, J = 8.1 Hz, 2H), 7.37 – 7.27 (m, 4H), 7.27 – 7.17 (m,
3H), 7.12 (t, J = 7.8 Hz, 2H), 7.07 (d, J = 7.0 Hz, 1H), 6.88 (t, J = 7.3 Hz,
1H), 6.58 (d, J = 8.0 Hz, 2H), 5.53 (s, 1H), 5.25 (AB, J = 14.2 Hz, 1H),
5.08 (AB, J = 14.1 Hz, 1H), 3.69 – 3.58 (m, 1H), 3.38 – 3.24 (m, 1H),
2.83 – 2.71 (m, 1H), 2.66 (d, J = 16.4 Hz, 1H), 2.45 (s, 3H). 13C NMR
(126 MHz, CDCl3) δ 173.63, 169.98, 147.05, 145.44, 139.43, 134.77,
134.51, 131.24, 130.63, 130.46, 129.92, 129.09, 128.94, 128.84, 128.70,
127.87, 126.06, 120.94, 116.68, 65.73, 60.61, 44.92, 25.51, 21.66.
HRMS (ESI) calcd. for C31H28N2O4SCl [M+H]+ 559.1453, found 559.1467.
N-(2-ethylbutanoyl)-2-phenyl-N-(tosylmethyl)-1,2,3,4-
tetrahydroisoquinoline-1-carboxamide (2i), white solid, 128 mg, 82%
yield. m.p. 118–120oC. 1H NMR (500 MHz, CDCl3) δ 7.69 (d, J = 7.9 Hz,
2H), 7.52 – 7.46 (m, 1H), 7.36 – 7.26 (m, 6H), 7.20 – 7.13 (m, 1H), 7.01
(d, J = 8.1 Hz, 2H), 6.95 (t, J = 7.3 Hz, 1H), 6.44 (s, 1H), 5.62 (AB, J =
15.2 Hz, 1H), 4.90 (AB, J = 15.2 Hz, 1H), 3.85 (d, J = 13.3 Hz, 1H), 3.54
– 3.43 (m, 1H), 3.07 – 2.98 (m, 1H), 2.97 – 2.87 (m, 1H), 2.69 (d, J =
16.2 Hz, 1H), 2.45 (s, 3H), 1.69 – 1.59 (m, 2H), 1.55 – 1.45 (m, 1H), 1.45
– 1.36 (m, 1H), 0.88 (t, J = 7.4 Hz, 3H), 0.81 (t, J = 7.5 Hz, 3H). 13C NMR
(126 MHz, CDCl3) δ 178.51, 175.39, 147.89, 145.45, 135.36, 134.21,
131.09, 129.85, 129.68, 129.02, 128.99, 128.93, 127.92, 126.28, 120.57,
116.60, 62.73, 61.54, 47.84, 45.40, 24.67, 21.68, 11.67, 11.09. HRMS
(ESI) calcd. for C30H35N2O4S [M+H]+ 519.2312, found 519.2327.
N-(4-methoxybenzoyl)-2-phenyl-N-(tosylmethyl)-1,2,3,4-
tetrahydroisoquinoline-1-carboxamide (2n), white solid, 100 mg, 60%
yield. m.p. 164–166oC. 1H NMR (300 MHz, CDCl3) δ 7.78 (d, J = 8.2 Hz,
2H), 7.49 (d, J = 8.8 Hz, 2H), 7.28 (d, J = 6.0 Hz, 3H), 7.23 – 6.97 (m,
5H), 6.81 (t, J = 8.0 Hz, 3H), 6.52 (d, J = 8.1 Hz, 2H), 5.53 (s, 1H), 5.23
(AB, J = 14.1 Hz, 1H), 5.03 (AB, J = 14.1 Hz, 1H), 3.85 (s, 3H), 3.63 –
3.48 (m, 1H), 3.40 – 3.23 (m, 1H), 2.80 – 2.55 (m, 2H), 2.40 (s, 3H). 13C
NMR (75 MHz, CDCl3) δ 173.78, 170.42, 163.59, 147.49, 145.16, 134.99,
134.62, 131.63, 131.12, 129.77, 129.00, 128.91, 128.67, 127.66, 125.93,
124.95, 120.37, 116.59, 113.78, 65.93, 60.56, 55.50, 44.95, 25.71, 21.60.
HRMS (ESI) calcd. for C32H31N2O5S [M+H]+ 555.1948, found 555.1961.
N-(cyclobutanecarbonyl)-2-phenyl-N-(tosylmethyl)-1,2,3,4-
tetrahydroisoquinoline-1-carboxamide (2j), white solid, 113 mg, 75%
yield. m.p. 104–106oC. 1H NMR (500 MHz, CDCl3) δ 7.66 (d, J = 8.0 Hz,
2H), 7.46 – 7.38 (m, 1H), 7.33 – 7.29 (m, 4H), 7.27 (d, J = 8.1 Hz, 2H),
7.19 – 7.13 (m, 1H), 6.97 (d, J = 8.1 Hz, 2H), 6.93 (t, J = 7.3 Hz, 1H),
6.48 (s, 1H), 5.44 (AB, J = 15.1 Hz, 1H), 4.84 (AB, J = 15.1 Hz, 1H), 3.81
– 3.68 (m, 2H), 3.49 (ddd, J = 13.5, 9.4, 4.9 Hz, 1H), 2.89 (ddd, J = 15.6,
9.5, 5.6 Hz, 1H), 2.74 (dt, J = 16.2, 4.6 Hz, 1H), 2.43 (s, 3H), 2.33 – 2.09
(m, 4H), 2.02 – 1.89 (m, 1H), 1.88 – 1.77 (m, 1H). 13C NMR (126 MHz,
CDCl3) δ 177.34, 174.35, 148.02, 145.45, 135.61, 134.14, 131.42,
129.87, 129.55, 128.92, 128.82, 128.49, 127.93, 126.25, 120.16, 116.22,
62.76, 61.04, 44.83, 40.60, 25.64, 24.99, 21.67, 17.55. HRMS (ESI)
calcd. for C29H31N2O4S [M+H]+ 503.1999, found 503.2010.
N-cinnamoyl-2-phenyl-N-(tosylmethyl)-1,2,3,4-
tetrahydroisoquinoline-1-carboxamide (2o), yellow solid, 102 mg, 62%
yield. m.p. 128–130oC. 1H NMR (300 MHz, CDCl3) δ 7.69 (d, J = 15.4 Hz,
1H), 7.63 (d, J = 8.1 Hz, 2H), 7.52 – 7.37 (m, 6H), 7.35 – 7.22 (m, 6H),
7.21 – 7.12 (m, 1H), 7.03 – 6.79 (m, 4H), 6.39 (s, 1H), 5.51 (AB, J = 14.9
Hz, 1H), 4.99 (AB, J = 14.9 Hz, 1H), 3.80 – 3.64 (m, 1H), 3.62 – 3.45 (m,
1H), 2.98 – 2.67 (m, 2H), 2.42 (s, 3H). 13C NMR (75 MHz, CDCl3) δ
177.30, 171.04, 150.60, 149.39, 147.99, 138.35, 137.04, 136.72, 134.08,
133.49, 132.53, 132.04, 131.49, 131.36, 131.16, 131.04, 130.56, 128.95,
122.64, 121.77, 118.71, 66.38, 63.97, 47.55, 28.62, 24.27. HRMS (ESI)
calcd. for C33H31N2O4S [M+H]+ 551.1999, found 551.2018.
tert-Butyl
(2-oxo-2-(2-phenyl-N-(tosylmethyl)-1,2,3,4-tetrahydro
2-((2-phenyl-1,2,3,4-tetrahydroisoquinoline-1-
isoquinoline-1-carboxamido)ethyl)carbamate (2k), white solid, 123
carbonyl)(tosylmethyl)carbamoyl)phenyl acetate (2p), white solid,
131 mg, 75% yield. m.p. 118–120oC. 1H NMR (500 MHz, CDCl3) δ 7.65
(d, J = 8.0 Hz, 2H), 7.54 (t, J = 7.8 Hz, 1H), 7.44 (d, J = 7.9 Hz, 1H), 7.35
(d, J = 7.6 Hz, 1H), 7.30 (d, J = 8.7 Hz, 1H), 7.26 (d, J = 8.7 Hz, 1H), 7.22
(t, J = 7.9 Hz, 6H), 7.16 (d, J = 7.4 Hz, 1H), 6.87 (t, J = 7.3 Hz, 1H), 6.82
(d, J = 8.1 Hz, 2H), 6.34 (s, 1H), 5.17 – 5.06 (m, 2H), 3.73 – 3.65 (m, 1H),
3.65 – 3.58 (m, 1H), 2.98 – 2.89 (m, 1H), 2.89 – 2.80 (m, 1H), 2.40 (s,
3H), 2.13 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 174.20, 169.49, 168.69,
148.18, 148.04, 145.23, 136.05, 134.91, 133.12, 131.73, 130.54, 129.87,
129.25, 128.75, 128.54, 128.38, 128.08, 126.44, 126.29, 125.99, 123.54,
119.35, 115.34, 65.33, 60.85, 44.71, 26.44, 21.64, 20.77. HRMS (ESI)
calcd. for C33H31N2O6S [M+H]+ 583.1897, found 583.1917.
1
mg, 71% yield. m.p. 138–140oC. H NMR (500 MHz, CDCl3) δ 7.68 (d, J
= 8.0 Hz, 2H), 7.46 – 7.40 (m, 1H), 7.37 – 7.28 (m, 6H), 7.21 – 7.12 (m,
1H), 7.03 (d, J = 8.1 Hz, 2H), 6.98 (t, J = 7.3 Hz, 1H), 6.35 (s, 1H), 5.57
(AB, J = 15.2 Hz, 1H), 5.00 (s, 1H), 4.95 (AB, J = 15.2 Hz, 1H), 4.37 (d, J
= 18.9 Hz, 1H), 4.27 (dd, J = 18.7, 5.0 Hz, 1H), 3.91 – 3.82 (m, 1H), 3.52
– 3.37 (m, 1H), 2.95 – 2.84 (m, 1H), 2.66 (d, J = 16.7 Hz, 1H), 2.46 (s,
3H), 1.48 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 174.38, 172.65, 155.62,
147.75, 145.74, 135.34, 134.03, 130.50, 130.05, 129.73, 129.07, 128.79,
128.77, 128.04, 126.35, 121.13, 117.24, 79.93, 62.45, 61.22, 46.86,
45.50, 28.33, 24.79, 21.72. HRMS (ESI) calcd. for C31H36N3O6S [M+H]+
578.2319, found 578.2334.
N-benzoyl-2-phenyl-N-(tosylmethyl)-1,2,3,4-tetrahydroisoquinoline-
1-carboxamide (2l), white solid, 105 mg, 67% yield. m.p. 144–146oC. 1H
NMR (500 MHz, CDCl3) δ 7.80 (d, J = 7.9 Hz, 2H), 7.55 (t, J = 7.1 Hz,
3H), 7.37 (t, J = 7.6 Hz, 2H), 7.30 (d, J = 7.4 Hz, 2H), 7.26 – 7.17 (m, 3H),
7.15 – 7.04 (m, 3H), 6.85 (t, J = 7.3 Hz, 1H), 6.59 (d, J = 8.0 Hz, 2H),
5.67 (s, 1H), 5.26 (AB, J = 14.2 Hz, 1H), 5.08 (AB, J = 14.2 Hz, 1H), 3.66
– 3.55 (m, 1H), 3.46 – 3.34 (m, 1H), 2.83 – 2.65 (m, 2H), 2.43 (s, 3H).
13C NMR (126 MHz, CDCl3) δ 173.84, 171.25, 147.41, 145.32, 135.03,
134.52, 133.03, 132.72, 131.04, 129.87, 129.28, 129.04, 128.94, 128.75,
N-(2-(4-chlorophenoxy)-2-methylpropanoyl)-2-phenyl-N-
(tosylmethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide
(2q),
light-yellow solid, 126 mg, 68% yield. m.p. 136–138oC. 1H NMR (500
MHz, CDCl3) δ 7.76 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.30 (d,
J = 8.6 Hz, 2H), 7.22 (t, J = 7.7 Hz, 3H), 7.16 (t, J = 7.4 Hz, 1H), 7.11 (d,
J = 7.7 Hz, 1H), 7.05 (d, J = 7.5 Hz, 1H), 6.95 (d, J = 8.1 Hz, 2H), 6.92 (t,
J = 7.3 Hz, 1H), 6.84 (d, J = 8.3 Hz, 2H), 6.10 (s, 1H), 5.58 – 5.44 (m,
2H), 3.75 (d, J = 13.2 Hz, 1H), 3.57 – 3.46 (m, 1H), 2.92 – 2.81 (m, 1H),
2.62 – 2.54 (m, 1H), 2.48 (s, 3H), 1.68 (s, 3H), 1.48 (s, 3H). 13C NMR
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701323
European Journal of Organic Chemistry
FULL PAPER
(126 MHz, CDCl3) δ 179.50, 174.06, 151.76, 147.78, 145.27, 135.30,
134.79, 131.18, 129.77, 129.66, 129.42, 129.25, 129.20, 128.99, 128.89,
127.77, 125.85, 124.45, 120.31, 116.51, 84.71, 64.91, 60.93, 44.46,
27.06, 26.59, 24.73, 21.69. HRMS (ESI) calcd. for C34H34N2O5SCl [M+H]+
617.1871, found 617.1886. General procedure for synthesis of
compound 3:
6,7-dimethoxy-2-phenyl-N-(tosylmethyl)-1,2,3,4-
tetrahydroisoquinoline-1-carboxamide (3e), white solid, 94 mg, 65%
yield. m.p. 152–154oC. 1H NMR (500 MHz, CDCl3) δ 7.69 (dd, J = 8.5,
5.5 Hz, 1H), 7.40 (d, J = 8.1 Hz, 2H), 7.34 (t, J = 7.9 Hz, 2H), 7.06 (d, J =
8.0 Hz, 2H), 6.97 (t, J = 7.2 Hz, 1H), 6.88 (d, J = 8.2 Hz, 2H), 6.85 (s, 1H),
6.74 (s, 1H), 4.93 (ABX, J = 14.2, 8.5 Hz, 1H), 4.81 (s, 1H), 4.29 (ABX, J
= 14.3, 5.5 Hz, 1H), 3.98 (s, 3H), 3.96 – 3.90 (m, 1H), 3.82 (s, 3H), 3.26
(td, J = 10.9, 3.2 Hz, 1H), 3.21 – 3.11 (m, 1H), 2.96 (dt, J = 15.6, 3.5 Hz,
1H), 2.40 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 172.57, 149.19, 148.65,
147.84, 144.92, 133.84, 129.56, 129.46, 128.33, 126.89, 123.45, 120.16,
114.86, 111.24, 110.39, 65.04, 59.80, 56.00, 55.85, 45.00, 28.64, 21.50.
HRMS (ESI) calcd. for C26H29N2O5S [M+H]+ 481.1792, found 481.1803.
A 10 mL flask was charged with 1a-g (0.3 mmol), isocyanides (0.33
mmol) and succinic acid (39 mg, 0.33 mmol) in DCM (3.0 mL). To the
flask was added DEAD (52 μL, 58 mg, 0.33 mmol, 1.1 equiv) and the
resulting mixture stirred at room temperature. The reaction was
monitored by TLC until complete consumption. The solvent was directly
removed under reduced pressure. The residue was purified by flash
chromatography (petroleum ether/ethyl acetate = 30:1-2:1) to give the
desired products 3a-k, which was further purified by trituration in ether or
ether/hexane.
5-methoxy-2-phenyl-N-(tosylmethyl)-1,2,3,4-tetrahydroisoquinoline-
1-carboxamide (3f), white solid, 97 mg, 72% yield. m.p. 144–146oC. H
1
NMR (300 MHz, CDCl3) δ 7.70 (t, J = 7.0 Hz, 1H), 7.46 (d, J = 7.9 Hz,
2H), 7.40 – 7.28 (m, 2H), 7.26 (d, J = 8.2 Hz, 1H), 7.07 (d, J = 7.9 Hz,
2H), 6.96 (t, J = 7.3 Hz, 1H), 6.84 (d, J = 8.1 Hz, 2H), 6.76 (d, J = 8.6 Hz,
2H), 4.92 (ABX, J = 14.2, 8.4 Hz, 1H), 4.84 (s, 1H), 4.34 (ABX, J = 14.2,
5.6 Hz, 1H), 4.05 – 3.76 (m, 4H), 3.35 – 3.09 (m, 2H), 3.00 (d, J = 16.3
Hz, 1H), 2.38 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 173.92, 160.55,
150.54, 146.25, 137.51, 131.32, 131.05, 130.87, 129.75, 125.35, 121.40,
115.99, 114.12, 114.01, 66.37, 61.29, 56.71, 46.11, 30.66, 22.98. HRMS
(ESI) calcd. for C25H27N2O4S [M+H]+ 451.1686, found 451.1699.
2-phenyl-N-(tosylmethyl)-1,2,3,4-tetrahydroisoquinoline-1-
carboxamide (3a), white solid, 103 mg, 82% yield. m.p. 110–112oC. 1H
NMR (300 MHz, CDCl3) δ 7.76 (t, J = 7.0 Hz, 1H), 7.43 (d, J = 7.9 Hz,
2H), 7.41 – 7.13 (m, 5H), 7.03 (d, J = 8.0 Hz, 2H), 6.95 (t, J = 7.3 Hz, 1H),
6.84 (d, J = 8.2 Hz, 2H), 5.11 – 4.77 (m, 2H), 4.32 (ABX, J = 14.2, 5.7 Hz,
1H), 4.09 – 3.88 (m, 1H), 3.39 – 3.11 (m, 2H), 3.11 – 2.94 (m, 1H), 2.35
(s, 3H). 13C NMR (75 MHz, CDCl3) δ 173.63, 150.49, 146.25, 136.23,
135.15, 133.25, 131.09, 130.89, 130.26, 129.70, 129.08, 129.04, 128.15,
121.43, 116.01, 66.89, 61.38, 46.23, 30.41, 23.04. HRMS (ESI) calcd. for
7-nitro-2-phenyl-N-(tosylmethyl)-1,2,3,4-tetrahydroisoquinoline-1-
carboxamide (3g), white solid, 77 mg, 55% yield. m.p. 215–218oC. 1H
NMR (300 MHz, DMSO) δ 9.40 (t, J = 6.5 Hz, 1H), 8.34 (d, J = 2.4 Hz,
1H), 8.23 – 8.09 (m, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 7.9 Hz,
2H), 7.34 – 7.10 (m, 4H), 6.93 – 6.68 (m, 3H), 5.40 (s, 1H), 4.81 – 4.60
(m, 2H), 3.87 – 3.66 (m, 1H), 3.50 – 3.34 (m, 1H), 3.20 – 2.94 (m, 2H),
2.33 (s, 3H). 13C NMR (75 MHz, DMSO) δ 173.13, 150.09, 147.66,
146.18, 145.95, 136.60, 136.54, 131.26, 131.10, 130.94, 129.97, 124.86,
124.23, 119.77, 115.17, 63.22, 62.06, 44.50, 29.40, 22.87. HRMS (ESI)
calcd. for C24H23N3O5SNa [M+Na]+ 488.1251, found 488.1263.
C
24H25N2O3S [M+Na]+ 421.1580, found 421.1593.
2-(p-tolyl)-N-(tosylmethyl)-1,2,3,4-tetrahydroisoquinoline-1-
carboxamide (3b), white solid, 103 mg, 79% yield. m.p. 118–120oC. H
NMR (500 MHz, CDCl3) δ 7.80 (t, J = 7.0 Hz, 1H), 7.45 (d, J = 7.9 Hz,
2H), 7.37 (d, J = 7.7 Hz, 1H), 7.34 – 7.27 (m, 1H), 7.27 – 7.19 (m, 2H),
7.15 (d, J = 8.1 Hz, 2H), 7.05 (d, J = 7.9 Hz, 2H), 6.80 (d, J = 8.1 Hz, 2H),
4.95 – 4.84 (m, 2H), 4.35 (ABX, J = 14.3, 5.7 Hz, 1H), 3.97 – 3.84 (m,
1H), 3.33 – 3.11 (m, 2H), 3.03 (dt, J = 15.5, 3.4 Hz, 1H), 2.38 (s, 3H),
2.35 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 172.37, 146.95, 144.82,
134.81, 133.71, 131.84, 130.01, 129.67, 128.80, 128.31, 127.70, 127.58,
126.68, 115.10, 65.58, 59.96, 45.33, 29.07, 21.64, 20.35. HRMS (ESI)
calcd. for C25H27N2O3S [M+H]+ 435.1737, found 435.1751.
1
N-cyclohexyl-2-phenyl-1,2,3,4-tetrahydroisoquinoline-1-
carboxamide (3h), white solid, 70 mg, 70% yield. m.p. 128–130oC. 1H
NMR (300 MHz, CDCl3) δ 7.31 – 7.21 (m, 2H), 7.21 – 7.12 (m, 2H), 7.08
(d, J = 6.2 Hz, 1H), 6.92 – 6.78 (m, 3H), 6.69 (d, J = 8.7 Hz, 1H), 4.89 (s,
1H), 3.84 – 3.72 (m, 1H), 3.72 – 3.54 (m, 1H), 3.33 – 3.20 (m, 1H), 3.07 –
2.82 (m, 2H), 1.83 – 1.72 (m, 1H), 1.72 – 1.61 (m, 1H), 1.60 – 1.41 (m,
3H), 1.35 – 1.13 (m, 2H), 1.13 – 0.87 (m, 3H). 13C NMR (75 MHz, CDCl3)
δ 171.04, 149.50, 134.44, 132.86, 129.29, 128.95, 127.42, 127.31,
126.63, 119.50, 114.64, 114.56, 65.73, 48.12, 44.97, 32.94, 32.72, 28.88,
25.43, 24.75, 24.64. HRMS (ESI) calcd. for C22H27N2O [M+H]+ 335.2118,
found 335.2134.
2-(2-methoxyphenyl)-N-(tosylmethyl)-1,2,3,4-tetrahydroisoquinoline-
1-carboxamide (3c), white solid, 105 mg, 78% yield. m.p. 104–106oC.
1H NMR (500 MHz, CDCl3) δ 8.71 (t, J = 6.9 Hz, 1H), 7.44 (d, J = 7.6 Hz,
1H), 7.31 (d, J = 8.4 Hz, 2H), 7.30 – 7.21 (m, 2H), 7.22 – 7.13 (m, 3H),
7.11 – 7.04 (m, 3H), 7.00 (t, J = 7.6 Hz, 1H), 4.97 (s, 1H), 4.60 (ABX, J =
14.2, 7.2 Hz, 1H), 4.52 (ABX, J = 14.2, 6.6 Hz, 1H), 4.04 (s, 3H), 3.46 –
3.35 (m, 1H), 3.24 – 3.16 (m, 1H), 3.16 – 3.06 (m, 1H), 2.86 (dt, J = 15.8,
4.1 Hz, 1H), 2.39 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 172.38, 154.37,
144.66, 138.98, 134.80, 133.77, 131.89, 129.63, 128.54, 128.44, 128.40,
127.11, 126.12, 126.03, 123.61, 121.10, 111.82, 64.27, 60.53, 55.69,
48.32, 29.20, 21.67. HRMS (ESI) calcd. for C25H27N2O4S [M+H]+
451.1686, found 451.1696.
N-(tert-butyl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline-1-carboxamide
(3i), white solid, 40 mg, 43% yield. m.p. 94–96oC. 1H NMR (300 MHz,
CDCl3) δ 7.65 – 7.53 (m, 1H), 7.47 – 7.10 (m, 5H), 7.09 – 6.88 (m, 3H),
6.78 (s, 1H), 4.90 (s, 1H), 3.94 – 3.73 (m, 1H), 3.46 – 3.29 (m, 1H), 3.17
– 2.92 (m, 2H), 1.29 (s, 9H). 13C NMR (75 MHz, CDCl3) δ 172.68, 150.97,
135.76, 134.38, 130.72, 130.37, 128.95, 128.67, 128.00, 121.10, 116.46,
67.58, 52.35, 46.64, 30.16, 30.02. HRMS (ESI) calcd. for C20H25N2O
[M+H]+ 309.1961, found 309.1972.
2-(4-bromophenyl)-N-(tosylmethyl)-1,2,3,4-tetrahydroisoquinoline-1-
1
carboxamide (3d), white solid, 130 mg, 85% yield. m.p. 144–146oC. H
NMR (300 MHz, CDCl3) δ 7.63 (t, J = 7.0 Hz, 1H), 7.52 – 7.16 (m, 8H),
7.06 (d, J = 7.9 Hz, 2H), 6.70 (d, J = 8.5 Hz, 2H), 4.95 – 4.74 (m, 2H),
4.40 (ABX, J = 14.2, 5.9 Hz, 1H), 4.04 – 3.79 (m, 1H), 3.39 – 3.12 (m,
2H), 3.12 – 2.91 (m, 1H), 2.38 (s, 3H). 13C NMR (75 MHz, CDCl3) δ
173.26, 149.46, 146.40, 135.98, 135.06, 133.60, 132.92, 131.13, 130.14,
129.65, 129.28, 129.11, 128.28, 117.49, 113.63, 66.73, 61.36, 46.25,
30.29, 23.06. HRMS (ESI) calcd. for C24H24N2O3SBr [M+H]+ 499.0686,
found 499.0703.
N-benzyl-2-phenyl-1,2,3,4-tetrahydroisoquinoline-1-carboxamide (3j),
white solid, 64 mg, 62% yield. m.p. 144–146oC. 1H NMR (300 MHz,
CDCl3) δ 7.65 – 7.53 (m, 1H), 7.29 – 7.18 (m, 4H), 7.19 – 7.07 (m, 4H),
7.03 – 6.92 (m, 2H), 6.93 – 6.81 (m, 3H), 5.02 (s, 1H), 4.42 – 4.24 (m,
2H), 3.86 – 3.69 (m, 1H), 3.34 – 3.18 (m, 1H), 3.11 – 2.80 (m, 2H). 13C
NMR (75 MHz, CDCl3) δ 172.31, 149.36, 138.14, 134.49, 132.61, 129.37,
128.86, 128.53, 127.63, 127.47, 127.37, 127.27, 126.74, 119.74, 114.90,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701323
European Journal of Organic Chemistry
FULL PAPER
65.54, 45.20, 43.41, 28.97. HRMS (ESI) calcd. for C23H23N2O [M+H]+
343.1805, found 343.1818.
2-(methyl(p-tolyl)amino)-N-(tosylmethyl)acetamide (5e), white solid,
51 mg, 49% yield. m.p. 132–134oC. 1H NMR (300 MHz, CDCl3) δ 7.76 (d,
J = 7.8 Hz, 2H), 7.42 (s, 1H), 7.37 (d, J = 8.1 Hz, 2H), 7.12 (d, J = 7.6 Hz,
2H), 6.63 (d, J = 8.8 Hz, 2H), 4.72 (d, J = 6.7 Hz, 2H), 3.73 (s, 2H), 2.98
(s, 3H), 2.49 (s, 3H), 2.33 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 171.84,
148.43, 146.85, 135.40, 131.35, 131.31, 130.24, 130.15, 115.27, 61.34,
60.27, 41.76, 23.14, 21.69. HRMS (ESI) calcd. for C18H23N2O3S [M+H]+
347.1424, found 347.1437.
ethyl (2-phenyl-1,2,3,4-tetrahydroisoquinoline-1-carbonyl)glycinate
(3k), white solid, 73 mg, 72% yield. m.p. 92–94oC. 1H NMR (300 MHz,
CDCl3) δ 7.53 – 7.44 (m, 1H), 7.35 (t, J = 5.7 Hz, 1H), 7.30 – 7.21 (m,
2H), 7.21 – 7.15 (m, 2H), 7.14 – 7.05 (m, 1H), 6.94 – 6.78 (m, 3H), 4.99
(s, 1H), 4.15 – 3.96 (m, 3H), 3.89 – 3.76 (m, 2H), 3.37 – 3.24 (m, 1H),
3.18 – 3.02 (m, 1H), 3.00 – 2.86 (m, 1H), 1.15 (t, J = 7.2 Hz, 3H). 13C
NMR (75 MHz, CDCl3) δ 172.50, 169.58, 149.30, 134.90, 132.45, 129.35,
129.04, 127.57, 127.53, 126.64, 119.48, 114.56, 114.48, 65.37, 61.38,
44.79, 41.32, 28.53, 14.05. HRMS (ESI) calcd. for C20H23N2O3 [M+H]+
339.1703, found 339.1718.
2-((4-bromophenyl)(methyl)amino)-N-(tosylmethyl)acetamide
(5f),
white solid, 68 mg, 55% yield. m.p. 148–150oC. 1H NMR (300 MHz,
CDCl3) δ 7.73 (d, J = 8.4 Hz, 2H), 7.45 – 7.31 (m, 4H), 7.29 – 7.20 (m,
1H), 6.55 (d, J = 8.8 Hz, 1H), 4.71 (d, J = 6.9 Hz, 2H), 3.77 (s, 2H), 3.00
(s, 3H), 2.50 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 171.18, 149.40, 147.00,
135.28, 133.56, 131.36, 130.13, 116.42, 112.79, 61.32, 59.65, 41.57,
23.16. HRMS (ESI) calcd. for C17H20N2O3SBr [M+H]+ 411.0373, found
411.0385.
General procedure for synthesis of compound 5:
A 10 mL two-neck flask was charged with 4 (0.3 mmol), TosMIC (65 mg,
0.33 mmol) and acid (0.33 mmol) in toluene (3.0 mL). After the two-neck
flask was evacuated and back filled with nitrogen, DEAD (52 μL, 58 mg,
0.33 mmol, 1.1 equiv) was added and the resulting mixture was heated at
80 °C for 24 h. The reaction was monitored by TLC until complete
consumption. The solvent was directly removed under reduced pressure.
The residue was purified by flash chromatography (petroleum ether/ethyl
acetate = 15:1-2:1) to give the desired products 5a-h, which was further
purified by trituration in ether.
N-acetyl-2-(ethyl(phenyl)amino)-N-(tosylmethyl)acetamide (5g), white
solid, 17 mg, 15% yield. m.p. 98–100oC. 1H NMR (300 MHz, CDCl3) δ
7.75 (d, J = 7.9 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.20 (t, J = 7.7 Hz, 2H),
6.73 (t, J = 7.3 Hz, 1H), 6.59 (d, J = 8.1 Hz, 2H), 5.24 (s, 2H), 4.54 (s,
2H), 3.30 (q, J = 7.1 Hz, 2H), 2.50 (s, 3H), 2.45 (s, 3H), 1.15 (t, J = 7.1
Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 170.15, 169.55, 144.89, 143.06,
131.57, 127.29, 126.51, 126.18, 114.62, 109.79, 60.68, 53.58, 43.35,
22.79, 19.02, 9.70. HRMS (ESI) calcd. for C20H25N2O4S [M+H]+ 389.1530,
found 389.1544.
N-acetyl-2-(methyl(phenyl)amino)-N-(tosylmethyl)acetamide
(5a),
white solid, 53 mg, 47% yield. m.p. 104–106oC 1H NMR (500 MHz, CDCl3)
δ 7.76 (d, J = 8.1 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 7.24 (t, J = 7.8 Hz,
2H), 6.78 (t, J = 7.3 Hz, 1H), 6.65 (d, J = 8.2 Hz, 2H), 5.22 (s, 2H), 4.61
(s, 2H), 2.92 (s, 3H), 2.54 (s, 3H), 2.46 (s, 3H). 13C NMR (126 MHz,
CDCl3) δ 172.34, 172.31, 148.71, 145.78, 134.31, 130.02, 129.17,
128.88, 117.48, 112.36, 63.39, 58.52, 39.06, 25.52, 21.70. HRMS (ESI)
calcd. for C19H23N2O4S [M+H]+ 375.1373, found 375.1388.
2-(ethyl(phenyl)amino)-N-(tosylmethyl)acetamide (5h), white solid, 11
mg, 11% yield. m.p. 106–108oC. 1H NMR (300 MHz, CDCl3) δ 7.72 (d, J
= 8.0 Hz, 2H), 7.46 – 7.28 (m, 5H), 6.90 (t, J = 7.3 Hz, 1H), 6.70 (d, J =
8.1 Hz, 2H), 4.69 (d, J = 6.9 Hz, 2H), 3.78 (s, 2H), 3.45 (q, J = 7.0 Hz,
2H), 2.49 (s, 3H), 1.21 (t, J = 7.0 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ
170.42, 147.38, 145.39, 133.90, 129.88, 129.52, 128.75, 118.92, 113.71,
59.87, 55.36, 46.45, 21.72, 11.49.HRMS (ESI) calcd. for C18H23N2O3S
[M+H]+ 347.1424, found 347.1436.
N-acetyl-2-(methyl(p-tolyl)amino)-N-(tosylmethyl)acetamide
(5b),
white solid, 69 mg, 59% yield. m.p. 130–132oC. 1H NMR (300 MHz,
CDCl3) δ 7.65 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.1 Hz, 2H), 6.94 (d, J =
8.2 Hz, 2H), 6.48 (d, J = 8.3 Hz, 2H), 5.12 (s, 2H), 4.46 (s, 2H), 2.79 (s,
3H), 2.42 (s, 3H), 2.36 (s, 3H), 2.17 (s, 3H). 13C NMR (75 MHz, CDCl3) δ
172.44, 172.23, 146.59, 145.72, 134.23, 129.97, 129.70, 128.88, 126.74,
112.65, 63.26, 58.73, 39.27, 25.52, 21.68, 20.21. HRMS (ESI) calcd. for
C20H25N2O4S [M+H]+ 389.1530, found 389.1539.
Acknowledgements
This project is supported by the National Natural Science
Foundation of China (grants 81602966, 81530098) and the
Province Natural Science Foundation of Jiangsu (BK20160759),
the National Major Scientific and Technological Special Project
for “Significant New Drugs Development” (2015ZX09501001)
and the Fundamental Research Funds for the Central
Universities (2016ZPY013).
N-acetyl-2-((4-bromophenyl)(methyl)amino)-N-(tosylmethyl)
acetamide (5c), white solid, 71 mg, 52% yield. m.p. 126–128oC. 1H NMR
(300 MHz, CDCl3) δ 7.74 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H),
7.30 (d, J = 8.8 Hz, 2H), 6.49 (d, J = 8.6 Hz, 2H), 5.20 (s, 2H), 4.59 (s,
2H), 2.88 (s, 3H), 2.56 (s, 3H), 2.46 (s, 3H). 13C NMR (75 MHz, CDCl3) δ
173.75, 173.29, 149.23, 147.30, 135.75, 133.22, 131.47, 130.24, 115.38,
110.83, 64.88, 59.95, 40.53, 26.91, 23.13. HRMS (ESI) calcd. for
C19H22N2O4SBr [M+H]+ 453.0478, found 453.0490.
Keywords: MCRs • Oxidative Ugi reaction• DEAD • Metal-free •
Oxidation
[1]
[2]
a) I. Ugi, R. Meyr, U. Fetzer, C. Steinbrückner, Angew. Chem. 1959,
71, 386. b) I. Ugi, C. Steinbrückner, Angew. Chem. 1960, 72, 267. c) R.
F. Nutt, M. M. Joullié, J. Am. Chem. Soc. 1982, 104, 5852.
2-(methyl(phenyl)amino)-N-(tosylmethyl)acetamide (5d), white solid,
61 mg, 61% yield. m.p. 114–116oC. 1H NMR (300 MHz, CDCl3) δ 7.75 (d,
J = 7.9 Hz, 2H), 7.44 – 7.17 (m, 5H), 6.92 (t, J = 7.3 Hz, 1H), 6.71 (d, J =
8.1 Hz, 2H), 4.71 (d, J = 6.9 Hz, 2H), 3.78 (s, 2H), 3.02 (s, 3H), 2.49 (s,
3H). 13C NMR (75 MHz, CDCl3) δ 171.66, 150.45, 146.88, 135.38,
131.33, 130.86, 130.22, 121.00, 120.67, 114.91, 61.34, 59.92, 41.45,
23.14. HRMS (ESI) calcd. for C17H21N2O3S [M+H]+ 333.1267, found
333.1279.
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Tetrahedron 2009, 65, 2153. f) A. Dömling, W. Wang, K. Wang, Chem.
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Synthesis and Material Science (Eds.: V. G. Nenajdenko), Wiley-VCH,
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10.1002/ejoc.201701323
European Journal of Organic Chemistry
FULL PAPER
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5i
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This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701323
European Journal of Organic Chemistry
FULL PAPER
Table of Contents
FULL PAPER
Ugi-type reaction *
Jiankun Wang, Yilin Sun, Guangji
Wang,* and Le Zhen*
Page No. – Page No.
Novel DEAD-Promoted Oxidative Ugi-
Type Reaction Including an
Unprecedented Ugi-Amidation
Assisted by Dicarboxylic Acids
Utilize mono- or dicarboxylic acids? α-Amino imides or amides could be
respectively obtained through this novel DEAD-promoted oxidative Ugi-type
reaction. This metal-free transformation features high efficiency and good tolerance
with diverse functional groups. Mechanistic studies indicated the dicarboxylic acids
may readily undergo an intramolecular annulation, instead of the Mumm
rearrangement, affording the amides with one molecule of anhydride released.
This article is protected by copyright. All rights reserved.