Three-component Ugi-Smiles couplings of cyclic imines

Article abstract of DOI:10.1016/j.tetlet.2009.01.145

Cyclic imines react with isocyanides and electron-deficient phenols to afford N-aryl piperidines and pyrrolidines in good yields (Ugi-Smiles couplings of cyclic imines). The starting imines were formed by oxidation with N-chlorosuccinimide followed by a b

Full text of DOI:10.1016/j.tetlet.2009.01.145

Tetrahedron Letters 50 (2009) 1741–1743
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Three-component Ugi–Smiles couplings of cyclic imines
*
*
Laurent El Kaïm , Laurence Grimaud , Julie Oble, Simon Wagschal
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:
Cyclic imines react with isocyanides and electron-deficient phenols to afford N-aryl piperidines and pyr-
rolidines in good yields (Ugi–Smiles couplings of cyclic imines). The starting imines were formed by oxi-
dation with N-chlorosuccinimide followed by a base-induced dehydrochlorination.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 12 November 2008
Revised 19 January 2009
Accepted 28 January 2009
Available online 1 February 2009
The synthetic utility of the Ugi reaction has led to the use of iso-
cyanide-based multicomponent reactions (IMCRs) to generate bio-
logically relevant scaffolds with a high level of diversity.1 Recent
efforts in this field have mostly focused on the formation of hetero-
cyclic derivatives through post-condensation transformations.2
Alternatively, straightforward formation of heterocycles can be
achieved when Ugi reactions are performed on difunctional start-
ing components.
imine at such a temperature led us to perform the reaction with
a two-fold excess of imine, and we were pleased to isolate the cor-
responding piperidine in 77% yield (Scheme 2).8
As reported in Table 1, various phenols and isocyanides behaved
similarly. Indeed, ortho-nitrophenol gave the desired piperidines in
good yields with different isocyanides (Table 1, entries 1 and 2). Hy-
For example, the oxidation of cyclic amines to their related imi-
nes affords suitable substrates for a three-component Ugi reaction.
This was first reported by Joullié two decades ago. This approach
was later adopted by several groups to form pyrrolidine and piper-
idine derivatives.3
We recently reported a new Ugi-type coupling between an alde-
hyde, an amine, an isocyanide and an electron-deficient phenol
leading to N-arylamino carboxamides (Scheme 1).4 This coupling
was further extended to different hydroxy- and mercapto-hetero-
cycles, such as pyridines and pyrimidines.5
R2CHO
R3NH2
R1NC
HO
O2N
R1
HN
O
methanol
60 °C
+
N
NO2
R3
R2
Scheme 1.
Ugi reactions involving carboxylic acids are traditionally per-
formed at room temperature. The higher temperature required
for phenol couplings, associated with the instability of cyclic imi-
nes,6 may become an issue in obtaining N-aryl pyrrolidine or piper-
idine adducts in good yields.
Ph
OH
Ph
Ph
NO2
CyHN
1. NCS, Et2O
2. DBU, THF
Herein, we present our results on the behavior of cyclic imines
in Ugi–Smiles couplings.
N
CyNC
MeOH, 60 °C
O
NO2
77%
N
N
H
We first started working with six-membered rings. Starting
from 4-benzylpiperidine, oxidation with N-chlorosuccinimide
(NCS) followed by treatment with diazabicycloundecene afforded,
after filtration, the crude imine,7 which was employed in the fol-
lowing Ugi–Smiles step. Upon addition of stoichiometric amounts
of para-nitrophenol and cyclohexylisocyanide, the reaction did
not reach completion under heating at 60 °C. However, the desired
adduct was obtained in a moderate 34% yield. Degradation of the
O2N
O2N
O
O
Smiles
H
H
Cy
Cy
N
N
N
N
PhH2C
PhH2C
Scheme 2.
* Corresponding authors. Tel.: +33 145525537; fax: +33 145528322 (L.E.K.).
E-mail addresses: laurent.elkaim@ensta.fr (L.E. Kaïm), laurence.grimaud@
ensta.fr (L. Grimaud).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.145

1742
L. El Kaïm et al. / Tetrahedron Letters 50 (2009) 1741–1743
Table 1
Ugi–Smiles reaction of 4-benzylpiperidine
1. NCS, Et2O
2. DBU, THF
Ph
RHN
X
Ph
HN
N
3. RNC, ArXH
MeOH
Ar
X=O,S
Entry
ArXH
RNC
Product
Yield (%)
Ph
NC
p-ClC6H4CH2NH
O
OH
NO2
1
88
N
NO2
Cl
Ph
t-BuNH
OH
NO2
2
50
NC
O
N
NO2
Ph
NC
p-ClC6H4CH2NH
O
OH
N
NO2
3
48
N
N
NO2
Cl
Ph
CyNH
OH
NC
N
O
N
N
4
45
CF3
F3C
Ph
NC
p-ClC6H4CH2NH
O
OH
N
5
67
N
N
N
Cl
N
Ph
CyNH
SH
NC
6
65
N
N
S
N
N
N
droxy-containing heterocycles, such as hydroxy-pyridines and
pyrimidines (Table 1, entries 3–5) reacted efficiently, as did 2-mer-
captopyrimidine (Table 1, entry 6). In all these reactions, a single dia-
stereomer was isolated (>95:5 by 1H NMR), which is probably due to
an axial attack of the nucleophilic isocyanide on the cyclic iminium.
In order to investigate five-membered ring imines, L-tartaric
acid was condensed with benzylamine. Then reduction, protection
of the two hydroxy groups, and debenzylation gave the starting
pyrrolidine which was utilized in the same oxidation–dehydro-
chlorination sequence.9
The results summarized in Table 210 show that this imine be-
haved just as efficiently toward phenols (Table 2, entries 1 and
2), hydroxy and mercapto-heterocycles (Table 2, entries 3–6). In
contrast to six-membered ring imines, poor diastereoselectivity
was observed (1:1 to 1.2:1), probably due to the higher conforma-
tional flexibility of these imines.11

L. El Kaïm et al. / Tetrahedron Letters 50 (2009) 1741–1743
1743
Table 2
References and notes
Ugi–Smiles reaction of five-membered ring imines
1. For
a recent review of isocyanide-based multicomponent reactions, see:
Dömling, A. Chem. Rev. 2006, 106, 17.
1.NCS,Et2O
PO
PO
OP
2. Zhu, J.; Bienaymé, H. Multicomponent Reactions; Wiley-VCH: Weinheim, 2005.
3. Examples of Ugi-3CRs using pyrroline-type cyclic imines: (a) Banfi, L.; Basso, A.;
Guanti, G.; Merlo, S.; Repetto, C.; Riva, R. Tetrahedron 2008, 64, 1114; (b)
Nenajdenko, V. G.; Gulevich, A. V.; Balenkova, E. S. Tetrahedron 2006, 62, 5922;
(c) Chapman, T. M.; Davies, I. G.; Gu, B.; Block, T. M.; Scopes, D. I. C.; Hay, P. A.;
Courtney, S. M.; McNeill, L. A.; Schofield, C. J.; Davis, B. G. J. Am. Chem. Soc. 2005,
127, 506–507; (d) Banfi, L.; Basso, A.; Guanti, G.; Riva, R. Tetrahedron Lett. 2004,
45, 6637; (e) Flanagan, D. M.; Joullié, M. M. Synth. Commun. 1989, 19, 1; (f)
Bowers, M. M.; Carroll, P.; Joullié, M. M. J. Chem. Soc., Perkin Trans. 1 1989, 857;
(g) Nutt, R. F.; Joullié, M. M. J. Am. Chem. Soc. 1982, 104, 5852; Examples of Ugi-
3CRs using piperidine-type cyclic imines: (h) Maison, W.; Lutzen, A.; Kosten,
M.; Schlemminger, I.; Westerhoff, O.; Martens, J. J. Chem. Soc., Perkin Trans. 1
1999, 3515; (i) Maison, W.; Lutzen, A.; Kosten, M.; Schlemminger, I.;
Westerhoff, O.; Saak, W.; Martens, J. J. Chem. Soc., Perkin Trans. 1 2000, 1867;
For the oxidative Ugi reaction using IBX see: (j) Ngouansavanh, T.; Zhu, J.
Angew. Chem., Int. Ed. 2007, 46, 5775.
4. El Ka, L.; Grimaud, L.; Oble, J. Angew. Chem., Int. Ed. 2005, 44, 7961.
5. (a) El Ka, L.; Grimaud, L.; Gizolme, M.; Oble, J. Org. Lett. 2006, 8, 4019; (b) El Ka,
L.; Gizolme, M.; Grimaud, L.; Oble, J. J. Org. Chem. 2007, 72, 4169.
6. Cyclic imines usually form oligomers when heated above room temperature.
For a six-membered ring example, see: Stevens, C.; De Kimpe, N. J. Org. Chem.
1993, 1971.
7. Davis, B.; Maughan, M.; Chapman, T.; Villard, R.; Courtney, S. Org. Lett. 2002, 4, 103.
8. Typical procedure for six-membered ring Joullié-Ugi adducts: To a 2 M solution of
imine (1.6 mmol) in methanol were added successively 0.5 equiv of o-
nitrophenol (111 mg, 0.8 mmol) and 0.5 equiv of cyclohexyl isocyanide
2.DBU,toluene
OP
RHN
X
3.RNC,ArXH
MeOH
N
Ar
N
H
X=O,S
P=TBS
Entry
ArXH
Isocyanide
Product
Yield (%)
O2N
N
PO
PO
OH
OH
NC
NO2
1
78
O
HN
Cy
O2N
N
PO
O
NC
NO2
2
82
PO
O
O
HN
(100
lL, 0.8 mmol). The resulting mixture was stirred at 60 °C overnight. The
solvent was then removed under reduced pressure and the crude reaction
mixture was purified by flash column chromatography on silica gel (petroleum
ether–diethyl ether, 90:10) to give 260 mg of 4-benzyl-1-(2-nitrophenyl)-
piperidine-2-carboxylic acid cyclohexylamide (77%). 1H NMR (CDCl3, 400 MHz)
d 7.84 (dd, J = 8.2, 1.6 Hz, 1H), 7.63 (d, J = 7.4 Hz, 1H), 7.50 (ddd, J = 8.5, 7.3,
1.6 Hz, 1H), 7.29 (t, J = 8.5 Hz, 2H), 7.23–7.13 (m, 4H), 7.02 (ddd, J = 8.2, 7.3,
1.1 Hz, 1H), 4.38–4.34 (m, 1H), 3.82–3.71 (m, 1H), 3.15 (ddd, J = 13.8, 12.7,
2.9 Hz, 1H), 2.80 (d, J = 13.8 Hz, 1H), 2.75 (dd, J = 13.6, 5.8 Hz, 1H), 2.67 (br d,
J = 13.1 Hz, 1H), 2.45 (dd, J = 13.6, 8.5 Hz, 1H), 1.88–1.56 (m, 5H), 1.55–1.09 (m,
9H). 13C NMR (CDCl3, 100.6 MHz) d 169.7, 146.1, 141.6, 139.8, 134.5, 129.6,
128.7, 127.4, 126.5, 122.1, 121.2, 60.5, 51.0, 48.9, 43.4, 33.8, 33.7, 33.2, 32.2,
30.6, 25.9, 25.4, 22.8. IR (thin film) 3363, 3027, 2929, 1668, 1602, 1513, 1481,
1447, 1340 cmÀ1. HRMS: Calcd for C25H31N3O3 421.2365. Found: 421.2369.
9. For the use of this imine in an Ugi reaction see: Chapman, T. M.; Davies, I. G.;
Gu, B.; Block, T. M.; Scopes, D. I. C.; Hay, P. A.; Courtney, S. M.; McNeill, L. A.;
Schofield, C. J.; Davis, B. G. J. Am. Chem. Soc. 2005, 127, 506.
PO
OH
N
N
CF3
NC
NC
NC
NC
N
PO
3
4
5
6
53
77
65
63
O
HN
Cy
CF3
PO
PO
OH
N
N
N
N
O
S
HN
N
10. Typical procedure for five-membered ring Joullié-Ugi adducts: To 1.6 mmol of
imine were added successively 0.5 equiv of 2-mercaptopyrimidine (90 mg,
Cy
0.8 mmol) and 0.5 equiv of cyclohexylisocyanide (100 lL, 0.8 mmol). The
PO
PO
SH
resulting mixture was stirred at 80 °C for 2 d without any solvent. The crude
reaction mixture was purified by flash column chromatography on silica gel
(cyclohexane–diethyl ether, 90:10) to give 278 mg of 4-bis-(tert-butyl-
N
CF3
N
N
dimethyl-silyloxy)-1-pyrimidin-2-yl-pyrrolidine-2-carbothioic
acid
cyclohexylamide (63%) as 1:1.2 mixture of two diastereomers. Major
a
HN
diastereomer: 1H NMR (CDCl3, 400 MHz) d 8.37 (d, J = 4.8 Hz, 2H), 7.68 (br d,
J = 8.2 Hz, 1H), 6.64 (t, J = 4.8 Hz, 1H), 5.08 (d, J = 4.0 Hz, 1H), 4.49 (d, J = 4.0 Hz,
1H), 4.43–4.35 (m, 1H), 4.14 (d, J = 11.3 Hz, 1H), 4.03 (s, 1H), 3.86 (dd, J = 11.3,
2.8 Hz, 1H), 2.01–1.89 (m, 2H), 1.70–1.49 (m, 4H), 1.39–1.23 (m, 2H), 0.93–0.85
(m, 2H), 0.87 (s, 9H), 0.73 (s, 9H), 0.13 (s, 3H), 0.12 (s, 3H), 0.05 (s, 3H), 0.00 (s,
3H). 13C NMR (CDCl3, 100.6 MHz) d 196.7, 163.2, 158.1, 112.2, 79.9, 75.8, 75.7,
56.1, 53.6, 32.2, 31.2, 26.2, 25.9, 25.1, 24.8, 18.4, 18.2, À4.0, À4.2, À4.5, À4.6.
Minor diastereomer: 1H NMR (CDCl3, 400 MHz) d 8.38 (d, J = 4.8 Hz, 2H), 7.84 (br
d, J = 7.7 Hz, 1H), 6.67 (t, J = 4.8 Hz, 1H), 4.80 (s, 1H), 4.71 (s, 1H), 4.35–4.27 (m,
1H), 4.07 (d, J = 3.8 Hz, 1H), 3.88 (dd, J = 8.0, 3.8 Hz, 1H), 3.70 (d, J = 11.3 Hz,
1H), 2.01–1.89 (m, 2H), 1.70–1.49 (m, 4H), 1.39–1.23 (m, 2H), 1.21–1.00 (m,
2H), 0.87 (s, 9H), 0.82 (s, 9H), 0.22 (s, 3H), 0.19 (s, 3H), 0.09 (s, 3H), 0.07 (s, 3H).
13C NMR (CDCl3, 100.6 MHz) d 197.3, 162.4, 158.3, 112.3, 83.4, 79.1, 77.7, 56.3,
53.5, 31.7, 31.2, 26.3, 26.1, 25.9, 24.8, 24.7, 18.8, 18.4, À3.8, À4.3, À4.4, À4.5. IR
(thin film) 2931, 2857, 1584, 1555, 1527, 1471, 1452, 1104 cmÀ1. HRMS: Calcd
for C27H50N4O2SSi2 Calcd: 550.3193. Found: 550.3181.
CF3
Cy
PO
PO
N
N
SH
N
N
N
S
HN
Cy
In conclusion, we have developed a new route to N-aryl pyrrol-
idines and piperidines. This constitutes the first example of a
three-component Ugi–Smiles coupling involving cyclic imines.
These couplings will be further studied with aromatic imines such
as pyridines and quinolines.12
11. Bonger, K. M.; Wennekes, T.; Filippov, D. V.; Lodder, G.; Van der Marel, G. A.;
Overkleeft, H. S. Eur. J. Org. Chem. 2008, 3678.
12. (a) Williams, N. A. O.; Masdeu, C.; Diaz, J. L.; Lavilla, R. Org. Lett. 2006, 8, 5789;
(b) Diaz, J. L.; Miguel, M.; Lavilla, R. J. Org. Chem. 2004, 69, 3550.