Allyl and benzyl dance under basic conditions

Article abstract of DOI:10.1055/s-0030-1260964

Ugi-Smiles adducts formed from allyl (propargyl or benzyl) amine rearrange under basic condition with an allyl migration between two nitrogen atoms. The shift is reversible and may be controlled by the strength of the base used in the reaction. Georg Thie

Full text of DOI:10.1055/s-0030-1260964

1816
LETTER
Allyl and Benzyl Dance under Basic Conditions
A
llyl and Benzy
a
l
Dance un
u
de
r
Basic Co
r
nditionsent El Kaim,* Laurence Grimaud,* Srinivas Reddy Purumandla
Laboratoire Chimie et Procédés, UMR 7652, Ecole Polytechnique-ENSTA-CNRS, Ecole Nationale Supérieure de Techniques Avancées,
32 Bd Victor, 75739 Paris Cedex 15, France
Fax +33(1)45528322; E-mail: laurent.elkaim@ensta.fr; E-mail: grimaud@dcso.polytechnique.fr
Received 9 May 2011
With such an easy rearrangement, we surmised that new
Abstract: Ugi–Smiles adducts formed from allyl (propargyl or
heterocyclic systems could be prepared from 2a through
benzyl) amine rearrange under basic condition with an allyl migra-
N-alkylation. However, when treating 2a with various
alkylating agents in methanol with potassium carbonate as
a base, we unexpectedly recovered 1a within a few hours
at room temperature. The same result was obtained in the
absence of alkylating agent, and 1a was isolated in quan-
titative yield. To our surprise, such a shift was also ob-
served in acetonitrile as solvent with potassium carbonate
or using a catalytic amount of sodium hydride
(Scheme 2). The nature of this ‘allyl dance’5 was very
puzzling, and we decided to study its scope and mecha-
nism.
tion between two nitrogen atoms. The shift is reversible and may be
controlled by the strength of the base used in the reaction.
Key words: Ugi–Smiles, isocyanide, multicomponent couplings,
allyl, benzyl, propargyl, migration
A few years ago, we disclosed a new Ugi-type coupling
involving electron-deficient phenols.1 This transforma-
tion was coined as the Ugi–Smiles coupling in relation
with the rerrangement involved in the process. It converts
the isocyanide component into a secondary carboxamide
as observed in most Ugi couplings (Scheme 1). We wish
to disclose herein a novel base-induced rearrangement in-
volving the amide functionality of Ugi–Smiles adducts.
NaH
CH3CN, r.t.
6 h, 80%
O
NO2
O
NO2
Following our initial report on these couplings, we ex-
plored the reactivity of the new Ugi–Smiles adducts and
disclosed various syntheses of fused heterocycles.2 Dur-
ing these studies, we became particularly interested by the
trapping of the potential anions resulting from a basic
treatment of the products. Indeed, two positions may be
subject to deprotonation, the N–H amide and the peptidyl
C–H. With aromatic aldehydes, the peptidyl position be-
comes more acidic and the anion, formed under DBU
treatment, may be trapped intramolecularly.3 With ali-
phatic aldehydes, the functionalization of the peptidyl po-
sition requires the use of a strong base in excess due to the
higher acidity of the amide moiety.4 While working on
these topics, we observed with the N-allyl Ugi–Smiles
product 1a a shift of the allyl group forming 2a under
treatment with a slight excess of sodium hydride in aceto-
nitrile at room temperature (Scheme 1). Such migration,
rather unusual for Ugi-type adducts, could be explained
by the formation of a highly stabilized aniline anion.
NH
N
K2CO3,MeOH
or K2CO3, CH3CN
or NaH (cat.), CH3CN
CyN
CyHN
Et
Et
quant.
Scheme 2 ‘Allyl dance’ under basic conditions
Using various amine partners in the Ugi–Smiles process,
we first confirmed that, with a simple alkyl chain such as
a methoxy ethyl group, nothing happened under basic
conditions (Table 1, entry 1). However, the allyl group
migrates for a set of different partners in the four-compo-
nent reaction (Table 1, entries 2–4). The propargyl and
benzyl groups demonstrated migratory abilities as well
(Table 1, entries 5–7).
Surprisingly, no migration was observed when treating
compound 1i under the same conditions (Table 2, entry
1). In general, Ugi–Smiles adducts resulting from the con-
densation of a p-nitrophenol failed to rearrange in a simi-
lar way. Nevertheless, when substituted with a heteroatom
OH
O
NO2
O
NO2
EtCHO
NaH
NO2
MeOH
N
NH
+
CyHN
CyN
CH3CN, r.t.
6 h, 80%
60 °C
75%
CyNC
Et
Et
H2N
1a
2a
Scheme 1 Allyl shift in Ugi–Smiles adducts under basic conditions
SYNLETT 2011, No. 13, pp 1816–1820
x
x
.x
x
.2
0
1
1
Advanced online publication: 21.07.2011
DOI: 10.1055/s-0030-1260964; Art ID: D14211ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Allyl and Benzyl Dance under Basic Conditions
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Table 1 Scope of the Alkyl Shift with o-Nitro Derivatives
Entry
1
Starting material
Product
Yield (%)
O
NO2
OMe
–
–
N
N
H
Ph
Cl
1b
O
O
O
NO2
NO2
NO2
O
NO2
NH
NH
NH
2
81
N
N
N
N
N
H
Et
Et
Cl
Cl
1c
2c
O
NO2
3
77
N
N
H
Ph
Ph
Cl
Cl
1d
2d
O
NO2
4
86
N
N
H
Cl
Cl
1e
2e
O
NO2
O
NO2
5
88
NH
N
N
N
H
Cl
Cl
1f
2f
O
NO2
NH
O
NO2
N
6
64
N
N
H
Cl
Cl
Cl
1g
Cl
2g
OMe
OMe
O
NO2
O
NO2
Cy
NH
7
71
N
Cy
N
N
Cl
H
Cl
1h
2h
Synlett 2011, No. 13, 1816–1820 © Thieme Stuttgart · New York

1818
L. El Kaim et al.
LETTER
at the ortho position, they behave as o-nitroaryl carbox- cross adduct could be detected, and the corresponding 2f
amides do (Table 2, entries 2–4). We imagine that these and 2l were isolated in good yields. These results are con-
ortho substituents may stabilize further the salt after mi- sistent with an intramolecular rearrangement.
gration through chelation of the metal cation. Finally, het-
eroaryl-substituted Ugi–Smiles adducts behave quite
differently as no rearranged product could be isolated;
only, on lengthening the reaction time with allyl deriva-
tives, an isomerization of the double bond to give the
more stable heteroaryl enamine was observed (Table 2,
entry 5).
The reverse migration is more difficult to explain. This
behavior was confirmed for benzylic derivatives as 2g,
left for few hours at room temperature in acetonitrile with
potassium carbonate, reverts quantitatively to 1g. The re-
spective migratory properties of allyl and benzyl groups
may be illustrated by the reaction of compound 2e which
may transfer either the allyl or the benzyl residue under
These rearrangements raise several questions concerning treatment with potassium carbonate in acetonitrile. Al-
their mechanism. To assess the intra- or intermolecular though the configuration of the amide has to be examined
nature of the process, an equimolar mixture of compound more carefully in relation in this instance, the exclusive
1f and 1l was submitted to the NaH/MeCN conditions. No
Table 2 Influence of the Aryl Moiety on the Shift
Entry
Starting material
Product
Yield (%)
NO2
O
1
–
–
N
N
H
Cl
1i
NO2
NH
NO2
O
Cl
O
Cl
2
78
N
N
N
H
Cl
Cl
1j
2j
NO2
NO2
O
Cl
O
Cl
3
66
Cy
NH
Cy
N
N
N
H
Cl
Cl
1k
2k
NO2
NH
NO2
O
OMe
4
78
O
OMe
Cy
N
Cy
N
i-Bu
N
H
i-Bu
1l
2l
N
N
N
N
N
O
O
5
–
N
N
N
H
H
Cl
Cl
2m
1m
Synlett 2011, No. 13, 1816–1820 © Thieme Stuttgart · New York

LETTER
Allyl and Benzyl Dance under Basic Conditions
1819
J = 8.3 Hz), 7.12 (d, 1 H, J = 8.3 Hz), 6.90–6.85 (m, 1 H), 5.81–5.67
(m, 1 H), 5.75 (d, 0.4 H, J = 14.6 Hz, H-A1), 5.66 (d, 0.6 H, J = 14.6
Hz, H-A), 5.11 (d, 0.6 H, J = 14.6 Hz), 5.07 (d, 0.4 H, J = 14.6 Hz),
4.98 (d, 1 H, J = 10.4 Hz), 4.11 (d, 0.6 H, J = 14.6 Hz), 4.02 (d, 0.4,
J = 14.6 Hz), 3.20 (dd, 0.6 H, J = 5.8, 13.9 Hz), 3.12 (dd, 0.4 H,
J = 5.8, 13.9 Hz), 2.98 (dd, 0.4 H, J = 5.8, 13.9 Hz), 2.92 (dd, 0.6 H,
J = 5.8, 13.9 Hz), 2.83 (dd, 0.4 H, J = 5.3, 7.3 Hz), 2.75 (dd, 0.6 H,
J = 4.3, 7.3 Hz), 1.79 (br s, 1 H), 1.56–1.47 (m, 0.8 H), 1.44–1.33
(m, 1.2 H), 0.80 (t, 1.2 H, J = 7.6 Hz), 0.78 (t, 1.8 H, J = 7.6 Hz).
13C NMR of A (100.6 MHz, CDCl3): d = 174.4, 146.6, 136.7, 135.3,
134.4, 133.7, 132.5, 130.6, 129.8, 128.7, 126.0, 115.5, 59.8, 52.2,
49.9, 26.8, 10.3. 13C NMR of A1 (100.6 MHz, CDCl3): d = 174.3,
146.8, 136.7, 135.3, 134.4, 133.7, 132.5, 130.7, 129.7, 128.6, 125.9,
115.8, 59.4, 52.2, 50.2, 25.6, 10.1. IR (thin film): 2970, 2857, 1662,
1601, 1531, 1488, 1352, 1277, 1263, 1093, 1018 cm–1. HRMS: m/z
calcd for C20H22ClN3O3: 387.1350; found: 387.1354.
formation of allyl aniline 1e is consistent with a lower mi-
gratory ability of the benzyl group.
The recovery of starting allyl or benzyl derivatives under
treatment with potassium carbonate is certainly associated
with an equilibrium between the aniline and amide anions.
Under strongly basic conditions, the amide anion further
evolves to give the more thermodynamically stable N-aryl
anion which is quenched at the end of the reaction giving
the NH-aryl adduct 2 (Scheme 3). However, in the pres-
ence of traces of a base, 2 gives the N-aryl anion in equi-
librium with the more basic secondary amide anion which
may be protonated by starting 2. Once the amide is proto-
nated, potassium carbonate is not basic enough to reform
the amide causing a shift of the equilibrium towards 1.
This was confirmed when 2a was treated by a catalytic
amount of sodium hydride in acetonitrile, 1a could be then
quantitatively recovered after leaving the reaction over-
night at room temperature.
N-(4-Chlorobenzyl)-2-(2-nitrophenylamino)-N-(prop-2-ynyl)
Butanamide (2f)
Prepared from 1f in a 1 mmol scale and isolated as 0.55:0.45 mix-
ture of two rotamers (A/A1). 1H NMR (400 MHz, CDCl3): d = 8.13–
8.06 (m, 1 H), 7.58–7.52 (m, 2 H), 7.22 (d, 1 H, J = 4.5 Hz), 7.20
(d, 1 H, J = 4.5 Hz), 7.13 (d, 1 H, J = 8.3 Hz), 7.09 (d, 1 H, J = 8.3
Hz), 7.04–6.99 (m, 0.45 H), 6.92–6.87 (m, 0.55 H), 5.69 (d, 0.45 H,
J = 14.6 Hz), 5.55 (d, 0.55 H, J = 14.6 Hz), 4.10 (d, 0.55 H, J = 14.6
Hz), 4.00 (d, 0.45 H, J = 14.6 Hz), 3.39 (dd, 0.45 H, J = 2.3, 16.4
Hz), 3.25 (t, 1 H, J = 3.0 Hz), 3.18 (dd, 0.55 H, J = 2.5, 16.4 Hz),
2.97 (dd, 0.45 H, J = 4.5, 7.6 Hz), 2.90 (dd, 0.55 H, J = 4.5, 7.6 Hz),
2.01 (t, 0.45 H, J = 2.5 Hz), 1.96 (br s, 1 H), 1.92 (t, 0.55 H, J = 2.5
Hz), 1.57–1.45 (m, 0.9 H), 1.45–1.30 (m, 1.1 H), 0.76 (t, 3 H,
J = 7.6 Hz). 13C NMR of A (100.6 MHz, CDCl3): d = 173.9, 146.2,
134.8, 134.3, 133.9, 133.8, 133.4, 130.5, 129.9, 128.7, 126.2, 81.7,
71.0, 59.1, 52.2, 36.5, 26.7, 10.1. 13C NMR of A1 (100.6 MHz,
CDCl3): d = 173.8, 146.6, 135.0, 134.1, 133.9, 133.7, 132.5, 130.9,
129.7, 128.6, 126.0, 82.0, 71.6, 59.2, 52.4, 36.7, 25.7, 10.0. IR (thin
film): 2928, 2857, 1662, 1606, 1531, 1493, 1394, 1347, 1272, 1089,
1013 cm–1. HRMS: m/z calcd for C20H20ClN3O3: 385.1193; found:
385.1195.
O
NO2
NH
O
NO2
R2N
NaH, CH3CN
N
R1
R2HN
R1
1
2
then
hydrolysis
NaH
K2CO3
O
NO2
O
NO2
N
N
R2N
R2N
R1
R1
Acknowledgment
S.R.P. thanks the ANR-CP2D Program (ANR MUSE) for a post-
doctoral fellowship.
Scheme 3 Base-promoted equilibria
References and Notes
In conclusion, we have disclosed a new rearrangement of
Ugi-type adducts under basic conditions. The reaction is
reversible and controlled by the amount of base used in
the reaction medium. We are currently studying synthetic
applications involving potential trapping of the aniline an-
ion generated in the process.
(1) (a) El Kaïm, L.; Grimaud, L.; Oble, J. Angew. Chem. Int. Ed.
2005, 117, 7961. (b) El Kaïm, L.; Gizolme, M.; Grimaud,
L.; Oble, J. J. Org. Chem. 2007, 72, 4169. (c) Barthelon,
A.; El Kaim, L.; Gizolme, M. Eur. J. Org. Chem. 2008,
5974.
(2) (a) El Kaim, L.; Gizolme, M.; Grimaud, L.; Oble, J. J. Org.
Chem. 2007, 72, 5835. (b) Oble, J.; El Kaim, L.; Gizzi, M.;
Grimaud, L. Heterocycles 2007, 73, 503. (c) El Kaim, L.;
Grimaud, L.; Gizzi, M. Org. Lett. 2008, 10, 3417.
(d) Coffinier, D.; El Kaim, L.; Grimaud, L. Org. Lett. 2009,
11, 995. (e) Barthelon, A.; Legoff, X.-F.; El Kaim, L.;
Grimaud, L. Synlett 2010, 153. (f) El Kaïm, L.; Grimaud, L.
Mol. Diversity 2010, 14, 855. (g) El Kaim, L.; Grimaud, L.;
Wagschal, S. J. Org. Chem. 2010, 75, 5343. (h) El Kaim,
L.; Grimaud, L.; Wagschal, S. Chem. Commun. 2011, 47,
1887.
General Procedure for the Synthesis of Migrated Products
To a 0.5 M solution of Ugi–Smiles adduct in MeCN was added NaH
(95%, 1.5 equiv) at 0 °C. The resulting mixture was stirred at r.t. un-
til completion, then quenched with a sat. aq solution of NH4Cl, and
extracted with EtOAc. The organic phases were collected and con-
centrated in vacuo to afford migrated products after purification by
flash column chromatography on silica gel.
N-Allyl-N-(4-chlorobenzyl)-2-(2-nitrophenylamino) Butan-
amide (2c)
Prepared from 1c in a 0.5 mmol scale and isolated as 0.6:0.4 mixture
of two rotamers (A/A1). 1H NMR (400 MHz, CDCl3): d = 8.10–8.06
(m, 1 H), 7.58–7.48 (m, 2 H), 7.29–7.23 (m, 2 H), 7.15 (d, 1 H,
(3) (a) El Kaim, L.; Gamez-Montaño, R.; Grimaud, L.; Ibarra-
Rivera, T. Chem. Commun. 2008, 1350. (b) El Kaim, L.;
Grimaud, L.; Legoff, X.-F.; Schiltz, A. Org. Lett. 2011, 13,
534.
Synlett 2011, No. 13, 1816–1820 © Thieme Stuttgart · New York

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L. El Kaim et al.
LETTER
(5) This term has been mainly used for the ‘halogen-dance
(4) (a) El Kaim, L.; Grimaud, L.; Wagschal, S. J. Org. Chem.
2010, 75, 5343. For similar synthetic strategies with
classical Ugi adducts, see: (b) Marcaccini, S.; Pepino, R.;
Pozo, M. C. Tetrahedron Lett. 2001, 42, 2727. (c) Bossio,
R.; Marcos, C. F.; Marcaccini, S.; Pepino, R. Heterocycles
1997, 45, 1589. (d) Bossio, R.; Marcos, C. F.; Marcaccini,
S.; Pepino, R. Synthesis 1997, 1389.
reaction’. It involves migration of halogen atoms when aryl
derivatives are treated under basic conditions. See: Bunnett,
J. F. Acc. Chem. Res. 1972, 5, 139. For a more recent use,
see: Stanetty, P.; Schnürch, M.; Mereiter, K.; Mihovilovic,
M. D. J. Org. Chem. 2005, 70, 567.
Synlett 2011, No. 13, 1816–1820 © Thieme Stuttgart · New York