Ugi-Smiles couplings in water

Article abstract of DOI:10.1016/j.tetlet.2010.07.058

The four-component couplings of isocyanides with amines, aldehydes and phenols (Ugi-Smiles reactions) can be performed in water as the solvent instead of methanol or toluene.

Full text of DOI:10.1016/j.tetlet.2010.07.058

Tetrahedron Letters 51 (2010) 4962–4964
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Ugi–Smiles couplings in water
*
*
Laurent El Kaïm , Laurence Grimaud , Srinivas Reddy Purumandla
Laboratoire Chimie et Procédés, DCSO, UMR 7652, Ecole Nationale Supérieure de Techniques Avancées, 32 Bd Victor, Paris 75015, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The four-component couplings of isocyanides with amines, aldehydes and phenols (Ugi–Smiles reactions)
can be performed in water as the solvent instead of methanol or toluene.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 20 May 2010
Revised 24 June 2010
Accepted 9 July 2010
Available online 14 July 2010
Discovered in the late 50s, the Ugi reaction1 has seen its popular-
ity enhanced dramatically by new trends in organic chemistry. Fol-
lowing the emergence of combinatorial chemistry and the need for
efficient library preparation of bioactive compounds, medicinal
chemists have used the Ugi reaction extensively in combination
with post-condensation processes to prepare various heterocyclic
scaffolds.2 More recently, growing environmental concern in chem-
istry has further turned the spotlight on this reaction. Indeed, the Ugi
reaction achieves complex product formation within one step, with-
out any added reagentsand with the sole formationof water as a side
product. As such, this reaction probably embodies perfectly both the
concepts of step and atom economy in chemistry.
in relation to the Smiles rearrangement occurring in the final irre-
versible step of the process (Scheme 1). We have shown in several
studies the utility of this new coupling for the synthesis of com-
plex-fused heterocycles.4 The coupling is usually performed in
methanol or toluene in rather high concentration. In order to fur-
ther comply with the requirements of ‘green chemistry’, we wished
to perform this four-component coupling in water as the solvent.
The reaction was tested using a 2 M aqueous solution of prop-
anal and adding a stoichiometric amount of ortho-nitrophenol,
para-chlorobenzylamine and cyclohexyl isocyanide. The resulting
heterogenous mixture was heated at 90 °C and stirred for 20 h.
After completion of the reaction, the desired adduct was isolated
in 77% yield (Scheme 1). This result can be compared with the
74% yield obtained using methanol at 40 °C and with the 90% yield
in toluene at 60 °C.
We recently proposed an extension of the Ugi reaction by intro-
ducing electron-deficient phenols in place of the traditional car-
boxylic acids.3 This reaction was termed an Ugi–Smiles coupling
Cl
OH
O
CyNC
NO2
N
CyHN
+
Et
NH2
O2N
EtCHO
MeOH, 40 ºC, 20 h
Toluene, 60 ºC, 20 h
H2O, 90 ºC, 20 h
74%
90%
77%
Cl
O2N
R2
R1
H
R2
N
R2
R1
OAr
N
NH
NO2
Smiles
O
O
C
R1
rearrangement
N
R3
HN
N
R3
R3
Scheme 1. Comparison of various solvents in Ugi–Smiles couplings.
* Corresponding authors. Tel.: +33 145525537; fax: +33 145528322.
E-mail addresses: laurent.elkaim@ensta.fr (L.E. Kaïm), laurence.grimaud@ensta.fr (L. Grimaud).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.058

L. E. Kaïm et al. / Tetrahedron Letters 51 (2010) 4962–4964
4963
Table 1
Table 2 (continued)
Ugi–Smiles couplings with nitrophenols in water
Entry ArOH
Product
Time Yield
R3
O
R1NC
(h)
(%)
ArOH
H2O, 90 ºC
N
+
R1HN
R3NH2
Ar
R2CHO
N
OH
R2
O
Entry Ar
R1
R2
R3
Yield
(%)
O2N
4
N
N
14
56
t-BuHN
1
2
2-NO2C6H4
2-NO2C6H4
Cy
Cy
Ph
4-ClC6H4
MeO(CH2)2
4-ClBn
60
NO2
72
(80)a
80
3
2-NO2C6H4
Cy
3,4-MeO2
C6H3CH2
4-NO2C6H4
2-NCC6H4
Et
4-ClBn
Cl
(90)a
39
OH
N
4
5
6
2-NO2C6H4
2-NO2C6H4
2-NO2C6H4
Cy
Cy
Cy
4-ClBn
4-ClBn
MeO(CH2)2
O
30
N
5
40
35
90
N
N
(71)a
81
CyHN
N
7
2-NO2C6H4
Cy
H
Allyl
(72)a
68
8
9
2-NO2C6H4
2-NO2C6H4
Cy
4-Cl
i-Bu
Ph
Furyl
Allyl
58
C6H4CH2
4-Cl
C6H4CH2
4-Cl
C6H4CH2
t-Bu
10
11
12
2-NO2C6H4
2-NO2C6H4
2-NO2C6H4
Et
Allyl
Allyl
77
51
74
Table 3
Ugi–Smiles couplings with mercapto derivatives in water
(CH2)4
Ph
R3
R1NC
S
ArSH
H2O, 90ºC
4-MeO
N
+
R1HN
C6H4CH2
Ar
R3NH2
R2CHO
13
14
15
4-NO2C6H4
4-NO2C6H4
2,4-
Cy
Cy
Cy
Et
H
Et
4-ClC6H4CH2 70
Allyl 68
4-ClC6H4CH2 70
(73)a
4-ClC6H4CH2 92
(98)a
4-ClC6H4CH2 70
(95)a
R2
Entry ArSH
Product
Reaction Yields
time (h) (%)
(NO2)2C6H3
4-MeO-2-
NO2C6H3
2-Cl-4-
NO2C6H3
2-F-4-
NO2C6H3
4-Me-2-
NO2C6H3
16
17
18
19
Cy
Cy
Cy
Cy
Et
Et
Et
Et
N
SH
S
N
N
N
CyHN
1
2
48
36
69
47
4-ClC6H4CH2 58
N
4-ClC6H4CH2 90
Cl
Cl
(96)a
a
Same reaction performed in MeOH at 60 °C.
S
S
N
N
N
N
CyHN
CyHN
Table 2
N
O
Ugi–Smiles couplings with heterocyclic phenols in water
N
O
Entry ArOH
Product
Time Yield
SH
SH
(h)
(%)
3
30
38
O
OH
N
N
N
CyHN
1
48
70
Cl
N
S
O2N
NO2
S
S
4
5
14
40
66
41
N
N
N
N
CyHN
CyHN
S
S
O
OH
N
N
N
CyHN
2
36
47
O2N
NO2
Ph
O
OH
N
Under such conditions, the reaction proved to be quite general
and a wide range of isocyanides, aldehydes and amines were cou-
pled successfully with ortho- and para-nitrophenols (Table 1).5
We further extended the aqueous Ugi–Smiles coupling to het-
erocyclic phenols.6 Hydroxy nitroquinolines reacted in water in
similar yields to those reported with methanol (Table 2, entries
1–3). However, the reactions involving the 2-hydroxypyridine
O
N
3
30
38
O2N
t-BuHN
N
NO2

4964
L. E. Kaïm et al. / Tetrahedron Letters 51 (2010) 4962–4964
4180; (c) El Kaïm, L.; Grimaud, L. Mol. Divers. 2009. doi:10.1007/s11030-009-
9175-3.
(Table 2, entry 4) or 4-hydroxypyrimidines (Table 2, entry 5) were
less efficient in water when compared to the results obtained in
methanol.
4. (a) El Kaïm, L.; Grimaud, L.; Oble, J. J. Org. Chem. 2007, 72, 5835–5838; (b) Oble,
J.; El Kaïm, L.; Gizzi, M.; Grimaud, L. Heterocycles 2007, 73, 503–517; (c) El
Kaim, L.; Gizzi, M.; Grimaud, L. Org. Lett. 2008, 10, 3417–3419; (d) Coffinier, D.;
El Kaim, L.; Grimaud, L. Org. Lett. 2009, 11, 995–997; (e) El Kaïm, L.; Gamez-
Montaño, R.; Grimaud, L.; Ibarra-Rivera, T. Chem. Commun. 2008, 11, 1350–
1352.
We next investigated the behaviour of mercapto derivatives6a,7
in Ugi–Smiles reactions under this new set of conditions in order to
form functionalized thioamides in one step (Table 3). Surprisingly,
2-mercaptopyrimidine which was poorly reactive in various organ-
ic solvents (the best results were obtained without solvent) gave
some good results in water (Table 3, entries 1 and 2). Benzo-fused
mercapto derivatives such as benzoxazol-2-yl and benzothiazol-2-
yl7a reacted under these conditions to afford similar yields to those
previously reported (Table 3, entries 3–5).8
5. Typical procedure for Ugi–Smiles coupling in H2O for 2-[allyl(2-
nitrophenyl)amino]-N-(4-chlorobenzyl)butanamide (Table 1, entry 10). To an
aqueous 1 M solution of propanal (70 mL, 1.0 mmol) was added allylamine
(120 mL, 1.0 mmol) followed by para-chlorobenzyl isocyanide (160 mL,
1.0 mmol) and phenol (140 mg, 1.0 mmol). The reaction mixture was stirred
at 90 °C for 20 h and extracted with EtOAc (2 Â 15 mL). The combined organic
layers were dried (MgSO4), concentrated and the residue was purified by flash
chromatography on silica gel (EtOAc/PE, 1:2) to give the desired adduct
(300 mg, 77%). 1H NMR (CDCl3, 400 MHz) d 7.65 (dd, 1H, J = 1.5, 8.1 Hz), 7.48
(dt, 1H, J = 1.5, 8.1 Hz), 7.38 (t, 1H, J = 5.3 Hz), 7.27–7.22 (m, 3H), 7.18–7.10 (m,
3H), 5.65–5.55 (m, 1H), 5.08–5.01 (m, 2H), 4.44 (dd, 1H, J = 6.1, 14.9 Hz), 4.36
(dd, 1H, J = 6.1, 14.9 Hz), 3.82–3.77 (m, 1H), 3.74 (d, 1H, J = 6.1 Hz), 3.51 (dd,
1H, J = 6.3, 15.4 Hz), 2.05–1.94 (m, 1H), 1.83–1.72 (m, 1H), 0.95 (t, 3H,
J = 7.6 Hz); 13C NMR (CDCl3, 100.6 MHz) d 172.0, 146.3, 143.0, 137.3, 133.4,
133.3, 132.9, 129.5, 129.0, 125.6, 125.5, 124.2, 119.6, 68.5, 53.6, 43.1, 23.4,
Ugi reactions are mostly performed in methanol but good yields
are also observed in aprotic solvents such as dichloromethane or
acetonitrile. The use of water as solvent, as reported by Pirrung
and Das Sarma, leads to an acceleration of the reaction without
any decrease in the yields.9 Further results from Mironov’s group
indicate a more pronounced beneficial effect of water on the Passe-
rini reaction.10 In the case of the Ugi–Smiles reaction, the resulting
reactivity is close to that observed in organic solvents using either
nonpolar solvents such as toluene or polar ones such as methanol
or acetonitrile. These results expand further the range of solvents
that can be employed in Ugi–Smiles couplings. Further work is in
progress in order to examine the analogous Passerini–Smiles cou-
plings in water.
11.5; IR (thin film) 3307, 2925, 1662, 1603, 1520, 1491, 1349, 1276, 1091 cmÀ1
HRMS calcd for C20H22ClN3O3: 387.1350, found 387.1329.
;
6. (a) Oble, J.; El Kaïm, L.; Gizolme, M.; Grimaud, L. Org. Lett. 2006, 8, 4019–4021;
(b) Barthelon, A.; Dos Santos, A.; El Kaim, L.; Grimaud, L. Tetrahedron Lett. 2008,
49, 3208–3211.
7. (a) El Kaïm, L.; Gizolme, M.; Grimaud, L. Synlett 2007, 465–469; (b) Barthelon,
A.; El Kaïm, L.; Gizolme, M.; Grimaud, L. Eur. J. Org. Chem. 2008, 35, 5974–5987.
8. Typical procedure for the synthesis of 2-[allyl(benzo[d]thiazol-2-yl)amino]-N-
cyclohexyl-2-phenyl-ethanethioamide (Table 3, entry 5). To an aqueous 1 M
solution of benzaldehyde (100
lL, 1.0 mmol) was added allylamine (70
lL,
1.0 mmol) followed by cyclohexyl isocyanide (120
l
L, 1.0 mmol) and 2-
mercaptobenzothiazole (150 mg, 1.0 mmol). The reaction mixture was stirred
at 90 °C for 40 h and extracted with EtOAc (2 Â 15 mL). The combined organic
layer was dried (MgSO4), concentrated in vacuo and the residue was purified by
flash chromatography on silica gel (EtOAc/PE, 1:9) to give the desired adduct
(170 mg, 41%). 1H NMR (CDCl3, 400 MHz) d 9.78 (br s, 1H), 7.64 (d, 1H,
J = 7.8 Hz), 7.43 (d, 1H, J = 8.0 Hz), 7.39–7.27 (m, 6H), 7.13 (t, 1H, J = 7.4 Hz),
6.17 (s, 1H), 5.95–5.85 (m, 1H), 5.32 (dd, 1H, J = 1.3, 17.2 Hz), 5.26 (dd, 1H,
J = 1.0, 10.1 Hz), 4.50–4.40 (m, 1H), 4.29 (dd, 1H, J = 5.4, 16.3 Hz), 4.21 (dd, 1H,
J = 5.4, 16.3 Hz), 2.20–2.12 (m, 1H), 2.01–1.93 (m, 1H), 1.79–1.70 (m, 1H), 1.66–
1.57 (m, 2H), 1.52–1.33 (m, 3H), 1.28–1.15 (m, 2H); 13C NMR (CDCl3,
100.6 MHz) d 198.1, 168.1, 151.6, 136.1, 132.5, 131.2, 128.9, 128.6, 128.5,
126.4, 122.3, 121.2, 120.1, 119.5, 77.1, 56.6, 54.7, 31.4, 31.3, 25.9, 24.74, 24.67;
IR (thin film) 2930, 1519, 1445, 1285, 1214, 1123, 1068 cmÀ1; HRMS calcd for
Acknowledgement
Dr. P.S.R. thanks the région Ile de France for a Post-Doctoral
fellowship.
References and notes
1. (a) Ugi, I.; Meyr, R.; Fetzer, U.; Steinbrückner, C. Angew. Chem. 1959, 71, 386; (b)
Ugi, I.; Steinbrückner, C. Angew. Chem. 1960, 72, 267–268.
2. For recent reviews, see: (a) Dömling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39,
3168–3210; (b) Bienaymé, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem. Eur. J.
2000, 6, 3321–3329; (c) Ugi, I.; Werner, B.; Dömling, A. Molecules 2003, 8, 53–
66; (d) Dömling, A. Curr. Opin. Chem. Biol. 2002, 6, 306–313; (e)Multicomponent
Reactions; Zhu, J., Bienaymé, H., Eds.; Wiley-VCH: Weinheim, 2005; (f) Dömling,
A. Chem. Rev. 2006, 106, 17–89.
C
24H27N3S2: 421.1646, found 421.1658.
9. Pirrung, M. C.; Das Sarma, K. J. Am. Chem. Soc. 2004, 126, 444–445.
10. Acceleration of Passerini reactions has been studied by Pirrung et al. (see Ref. 3)
and Mironov et al.: Mironov, M. A.; Ivantsova, M. N.; Tokareva, M. I.;
Mokrushin, V. S. Tetrahedron Lett. 2005, 46, 3957–3960.
3. (a) El Kaim, L.; Grimaud, L.; Oble, J. Angew. Chem., Int. Ed. 2005, 117, 7961–7964;
(b) El Kaim, L.; Gizolme, M.; Grimaud, L.; Oble, J. J. Org. Chem. 2007, 72, 4169–