Development of aqueous oxidative Ugi-type reactions by copper-catalyzed surfactant-promoted C(sp3)-H direct functionalization in water

Article abstract of DOI:10.1016/j.tetlet.2013.11.006

Direct assembly of α-amino amides from N-alkyl amines and isocyanides through oxidative Ugi-type reactions in aqueous conditions, has been achieved in a Cu(I)-TBHP-surfactant catalysis system. Various N-alkyl amines and isocyanides could be tolerated in t

Full text of DOI:10.1016/j.tetlet.2013.11.006

Tetrahedron Letters 55 (2014) 240–243
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Development of aqueous oxidative Ugi-type reactions
by copper-catalyzed surfactant-promoted C(sp3)–H direct
functionalization in water
⇑
Chunsong Xie , Laihong Han
College of Material, Chemistry and Chemical Engineering, Hangzhou Normal University, Hangzhou 310036, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 July 2013
Revised 31 October 2013
Accepted 4 November 2013
Available online 13 November 2013
Direct assembly of
a-amino amides from N-alkyl amines and isocyanides through oxidative Ugi-type
reactions in aqueous conditions, has been achieved in a Cu(I)–TBHP–surfactant catalysis system. Various
N-alkyl amines and isocyanides could be tolerated in this reaction and furnish a-amino amides in mod-
erate yields.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Aqueous oxidative Ugi-type reaction
Copper catalysis
C–H functionalization
Surfactant
As a variant of the classic Ugi four-component reaction,1 oxida-
tive Ugi-type reactions have attracted much attention in recent
years,2 mainly due to that they provide strategically novel accesses
gave a very sluggish result (Table 1, entry 1). However, after adding
some surfactants to the reaction system,3 it afforded
a-amino
amide 3aa in 16–24% yields with various surfactants employed
(Table 1, entries 2–9). Among these reactions, the anionic surfac-
tant SDS (sodium dodecyl sulfate) produced the best result. We
thus conducted the following optimization with SDS as the reac-
tion promoter.
to
a-amino amides. A recent Letter indicated that they could be
performed under almost neutral conditions, and avoid the use of
acidic components in traditional Ugi-type reactions.2d However,
from the viewpoint of green chemistry, one of the major draw-
backs associated with these reactions is that they are necessarily
conducted in organic solvents. So, the development of aqueous
oxidative Ugi-type reactions deserves efforts to spend on and will
reveal great significance.
Various copper salts were screened and CuCl was selected be-
cause it provided the desired product 3aa in a higher yield (30%)
than others (Table 1, entries 10–14). The addition of ligands could
benefit the reaction, and PPh3 was finally employed among several
candidates (Table 1, entries 15–20). After careful comparison, the
reaction temperature was set at 70 °C because neither lower tem-
perature nor higher temperature could afford better yields (Table 1,
entries 21–23). Similarly, the reaction required at least 6 h to
achieve its best conversion, and elongation of the reaction time
would not lead to improvement (Table 1, entries 24 and 25). Final-
ly, the best yield was obtained by doubling the loading of the cat-
alyst and ligand, and a moderate yield (52%) was produced
(Table 1, entry 26). Different oxidants had been investigated as
well, and none of them afforded better yields than TBHP (Table 1,
entries 27–31).
During our investigation on the oxidative Ugi-type reactions,
we have developed the Cu(I)–TBHP catalytic system, rendering
the assembly of
a-amino imides from N-alkyl amines in moderate
to good yields.2c,d Further studies indicated that this reaction could
be performed using aqueous TBHP as an oxidant, and still give
a-
amino amides under nearly neutral conditions.2d Regarding that
the Cu(I) salts are water soluble, we envisioned that this copper-
catalyzed oxidative Ugi-type reaction might be able to conduct in
water. In this letter, we will report preliminary results of our
investigation.
We initiated our investigation by performing the reaction of
N,N-dimethylaniline 1a and 1-(isocyanomethylsulfonyl)-4-methyl-
benzene 2a under the promotion of Cu(I)/THBP in aqueous condi-
tions (Table 1). Without any additives, this reaction in water
With the optimal conditions in hand, we next studied the scope
of this reaction (Table 2). Various N-aryl-N-alkyl amines proved to
be compatible with this aqueous condition. Both electron-donating
and electro-withdrawing substituents on the ortho-position of
N,N-dimethylanilines could give desired
moderate yields (Table 2, entries 2–5). In general, electron-donating
a-amino amides in
⇑
Corresponding author. Tel.: +86 57128866142.
E-mail address: chunsongxie@hznu.edu.cn (C. Xie).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.11.006

C. Xie, L. Han / Tetrahedron Letters 55 (2014) 240–243
241
Table 1
The optimizationa
[Cu] 10 mol %, [L] 20 mol %
[O] 2.7 equiv
CN
Ts
N
N
NHCH2Ts
O
+
Surfactants 0.5 equiv
T oC, t h, in Water
1a
2a
3aa
Entry
[Cu]
[L]
[O]
Surfactants
T (°C)
t (h)
Yieldb (%)
1
2
3
4
5
6
7
8
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuCl
CuI
CuBr2
CuCl2
Cu(OAc)2ꢀH2O
No
No
No
No
No
No
No
No
No
No
No
No
No
No
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
No
SDS
60
60
60
60
60
60
60
60
60
60
60
60
60
60
6
6
6
6
6
6
6
6
6
6
6
6
6
6
<5
24
18
22
19
17
16
19
18
30
22
24
26
21
TBAB
CTAB
SS
SDBS
DSASS
PEG400 Monolaurate
PEG400 Dilaurate
9
10
11
12
13
14
SDS
SDS
SDS
SDS
SDS
15c
CuCl
TBHP
SDS
60
6
35
N
N
N
16c
CuCl
TBHP
SDS
60
6
32
N
17c
18c
CuCl
CuCl
TBHP
TBHP
SDS
SDS
60
60
6
6
26
28
H2N
NH2
NH HN
19c
CuCl
N
N
TBHP
SDS
60
6
23
20
21
22
23
24
25
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
H2O2
(t-BuO)2
(PhCOO)2
PhCO3t-Bu
O2
SDS
SDS
SDS
SDS
SDS
SDS
SDS
SDS
SDS
SDS
SDS
SDS
60
40
70
80
70
70
70
70
70
70
70
70
6
6
6
6
3
12
6
6
6
6
6
6
36
25
38
29
21
34
52
22
19
50
42
18
26d
27d
28d
29d
30d
31d
a
Reaction conditions: 1a (2 mmol), 2a (1 mmol), [Cu] (0.1 mmol), [L] (0.2 mmol), [O] (2.7 mmol), surfactants (0.5 mmol), H2O (5 mL), 60 °C, 6 h.
Isolated yield.
[L] (0.1 mmol).
b
c
d
The loading of CuCl was 20 mol %, and the loading of PPh3 was 40 mol %.
groups furnished better yields than electron-withdrawing groups.
The meta-substituted N,N-dimethylanilines having substituents,
whatever electron-donating and electron-withdrawing, provided
In recent years, much progress had been made in understanding
the mechanism of transition metal-catalyzed TBHP-mediated di-
rect functionalization of C(sp3)–H bonds adjacent to nitrogen
atoms.6 Based on these progresses, in combination with our obser-
vation,7 we proposed the following mechanisms as depicted in
Scheme 1. As an initiation of the cascades, Cu(I) could be oxidized
by TBHP to produce the Cu(II) complex A,6d,e thus TBHP was re-
duced to tert-butoxyl radical in this process. Then, two pathways
(i and ii) might be involved. In pathway i, the interaction of the
thus-formed Cu(II) complex A and tert-butoxyl radical with TBHP
could produce the tert-butylperoxide radical species.6e This radical
desired
Table 2, entries 6 and 7). Moreover, the para-substituted N,N-dime-
thylanilines gave better results, furnishing the corresponding
a-amino amides with slightly higher yields (46% and 44%,
a
-
amino amides in up to 72% yields (Table 2, entries 8–10). Once again,
similar trends were observed as the electron-rich anilines provided
higher yields than electron-deficient ones. The halogen atom could
survive in the reaction, offering feasibilities of further manipula-
tions at these sites.4 Besides the N,N-dialkylanilines, the N,N-diary-
lalkylamines 1k was also employed in this reaction, giving the
could oxidize N-alkylamines 1 to give a-nitrogen methylene radi-
a
-diarylamino amide product in a 32% yield (Table 2, entry 11). This
result is of particular significance that the phenyl on the -nitrogen
can be removed more easily than the methyl, which will make the
post modification on the
-nitrogen be more convenient.5 Besides
cals II by a stepwise SET (single electron transfer) and PT (proton
transfer) process.6e After a further SET with tert-butylperoxide rad-
ical, II could be converted to electrophilic iminiums III,6e which
could be stabilized by equilibrating with hemiaminal III00.6b In
a
a
these, other isocyanides such as 1-(isocyanomethyl)benzene 2b,
contrast, in pathway ii, a-nitrogen methylene radicals II might
2-isocyano-1,3-dimethylbenzene 2c, and tert-butyl isocyanide 2d
be directly generated from the oxidation of N-alkylamines 1 by
tert-butoxyl radical. The interaction between Cu(II) complex A
and TBHP might produce a new Cu(II) complex B.6d Then, the SET
could also afford
a-amino amides bearing different substituents
on the amide nitrogens (Table 2, entries 12–14).

242
C. Xie, L. Han / Tetrahedron Letters 55 (2014) 240–243
Table 2
R2
N
R3
O
R3
NH
HO
The scope of the reactiona
N
R2
N
Ar
R2
N
H2O
R3
Ar
N
3
V
IV
CuCl 20 mol %
PPh3 40 mol %
R2
R2
N
Ar
R3-NC
R2
+
R3 NC
NHR3
O
N
2
R1
H
TBHP 2.7 equiv
SDS 50 mol %
70 oC, 6 h, H2O
R1
Ar
R2
Ar
R2
H2O
H
H
Ar
Cu(I)
N
N
N
N
1
2
3
III
III'
III''
t
-BuO2
OH
R2
Entry
1
N-alkyl amines 1
R4
Yield (%)
b
Ar
R2
CuCl
Ar
t
-BuO2
N
R2
Ar
R2
L2
L2CuCl
Ar
II
I
PT
N
N
N
TsCH2 2a
52
44
II
1
t
-BuO
1a
t-BuO2
SET
Ar
N
R2
t
-BuO2H
-BuO
2
3
4
5
6
7
TsCH2 2a
TsCH2 2a
TsCH2 2a
TsCH2 2a
TsCH2 2a
TsCH2 2a
N
L2CuCl(O2t-Bu)
Me
1b
t
B
1
Pathway i Pathway ii
N
32
34
30
46
44
L2CuCl(OH)
t
-BuO2H
Cl
1c
A
N
Scheme 1. Proposed mechanism.
I
1d
improvement on the reaction efficiency, as well as the application
of this reaction is ongoing in our lab.
N
Ph
1e
N
Experimental
Me
1f
Typical procedure for the reaction
N
To an oven-dried flask, N,N-dimethylaniline 1a (2.0 mmol),
1-(isocyanomethylsulfonyl)-4-methylbenzene 2a (1.0 mmol), CuCl
(0.2 mmol), PPh3 (0.4 mmol), SDS (0.5 mmol), and TBHP (70 wt %
aqueous, 2.7 mmol) were added at room temperature. Under air,
water (5 mL) was added and the reaction mixture was allowed to
react at 70 °C for 6 h. The mixture was then filtered through a
pad of Celite and the filtrate was extracted by EA three times.
The combined organic layers were washed by brine and dried by
Na2SO4. After removing of the organic solvents, the residue was
then separated on a silica gel column and the final product was ob-
tained as a yellow powder (174 mg, 52%). 1H NMR (400 MHz,
CDCl3, TMS) d 7.72 (d, J = 8.8 Hz, 2 H), 7.29–7.35 (m, 3 H), 7.27
(m, 1 H), 6.89 (t, J = 7.4 Hz, 1H), 6.68 (d, J = 7.6 Hz, 2 H), 4.69 (d,
J = 7.2 Hz, 2 H), 3.75 (s, 2 H), 2.99 (s, 3 H), 2.46 (s, 3 H); 13C NMR
(100 MHz, CDCl3) d 170.4, 149.0, 145.6, 133.7, 130.0, 129.5,
128.9, 119.3, 113.4, 59.8, 58.6, 40.1, 21.8. HRMS (EI) Calcd for
Cl
1g
Me
Et
N
8
TsCH2 2a
TsCH2 2a
TsCH2 2a
63
72
50
1h
1i
N
9
Br
N
10
1j
Ph
N
11
12
TsCH2 2a
32
39
1k
N
Bn 2b
1a
N
Me
Me
13c
14
46
52
2c
1a
2c
C
17H20N2O3S: [M]+ 332.1195; Found, 332.1186.
Br
N
t-Bu 2d
1j
a
Acknowledgments
Reaction conditions: 1 (2 mmol), 2 (1 mmol), CuCl (0.2 mmol), PPh3 (0.4 mmol),
TBHP (2.7 mmol), SDS (0.5 mmol), H2O (5 mL), 70 °C, 6 h.
b
Isolated yields.
The ligand was 2,20-bipyridyl (0.2 mmol).
The authors gratefully thank the Grant support from the
Zhejiang Provincial Research Program (2012C31026) and PCSIRT
(IRT 1231).
c
Supplementary data
from II to B might happen, leading to the formation of the a-amino
peroxides III0.6d The reduction of III0 by Cu(I) species could afford
the electrophilic iminiums III.6d After their formation, III could be
attacked by the nucleophilic isocyanides 2. The as-generated nitri-
liums IV could be subsequently hydrated to provide the azaenols
V.8 The azaenol-amide tautomerization of V would eventually pro-
Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.
tetlet.2013.11.006.
References and notes
duce the a-amino amides 3.
In summary, by incorporating surfactants as reaction promoters
and employing a soluble catalytic system (CuCl/T-HYDRO), aque-
ous oxidative Ugi-type transformation has been developed. The
reaction conditions have been optimized and the scope of this
reaction has been studied under the optimized conditions. Various
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Ed.; Pergamon: Oxford, 1991; Vol. 2, pp 1083–1109; (b) Domling, A.; Ugi, I.
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a-amino amides could be directly afforded from N-alkylamines in
moderate yields by using water as a reaction media. Further

C. Xie, L. Han / Tetrahedron Letters 55 (2014) 240–243
243
3. The concentration of surfactants was selected around their CMC (Critical Micelle
Concentration). Typical CMC of some surfactants are as follows (in pure water at
25 °C): SDS 0.0082; CTAB 0.0089; SDBS 0.0012.
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7. For example, similar electron effect had been found in our experiment and the
Ref. 6e.
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