Ammonia in Ugi-smiles and ugi couplings

Article abstract of DOI:10.1055/s-0030-1259004

Ammonia may be used in Ugi-type reactions, providing good yields of Ugi-Smiles and Ugi-Mumm adducts under microwave irradiation.

Full text of DOI:10.1055/s-0030-1259004

2784
LETTER
Ammonia in Ugi–Smiles and Ugi Couplings
Ammonia in
U
gi–S
n
miles and U
a
gi
c
oupling
ë
s
lle Barthelon, Laurent El Kaim,* Marion Gizzi, Laurence Grimaud*
Laboratoire Chimie et Procédés, 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: laurence.grimaud@ensta.fr
Received 10 August 2010
yields did not exceed 30%. These disappointing results,
Abstract: Ammonia may be used in Ugi-type reactions, providing
combined with the lack of reproducibility, have led us to
design a sequence involving an Ugi–Smiles coupling
good yields of Ugi–Smiles and Ugi–Mumm adducts under micro-
wave irradiation.
combined with a deprotection, allylamine being used as
Key words: ammonia, Ugi–Smiles, isocyanide, multicomponent
couplings
an ammonia equivalent (Scheme 1).11 However, this pro-
cedure was limited to ortho-nitrophenol as no NH-adducts
could be obtained using other electron-deficient phenols.
Among the tools available to chemists for the efficient
synthesis of biologically relevant scaffolds, multicompo-
nent reactions (MCRs) have been found to occupy a fore-
NO2
HO
CyNC
O
NO2
most position.1 For instance, Ugi couplings have been
widely used by medicinal chemists to synthesize peptidyl
compounds as well as heterocyclic derivatives.2 A few
years ago, we disclosed a new Ugi-type reaction using an
electron-deficient phenol as an acid surrogate, namely the
Ugi–Smiles coupling.3 Starting from primary amines, this
reaction provides tertiary N-aryl amine derivatives that
can be readily transformed into various heterocycles.4
Though hydroxy pyridines and hydroxy pyrimidines are
efficient partners in Ugi–Smiles reactions,4 most of the N-
aryl or N-heteroaryl derivatives of potential pharmacolog-
ical interest include a free NH functionality. Indeed, a
wide range of NH-pyridines and NH-pyrimidines have
been described as potent drugs against asthma, rheuma-
toid arthritis,5 psoriasis,6 osteoporosis7 and cancer.8 An
access to such compounds through an Ugi–Smiles cou-
pling would logically imply the use of ammonia as the
amine partner. Unfortunately, Ugi reactions with ammo-
nia are rarely documented and good yields are only ob-
tained with sterically hindered aldehydes.9 Wishing to
1) MeOH, 60 °C
2) PTSA, Pd/C
+
Cy
NH
i-Bu
N
H
NH2
i-BuCHO
88%
Scheme 1 Allylamine as ammonia equivalent
Inspired by the results of Kazmaier et al. in Ugi couplings
with ammonium salts,9b,c we recently reinvestigated the
feasibility of a Ugi–Smiles coupling with ammonia using
fluorinated solvents. Use of HFIP (hexafluoroisopro-
panol) or 2,2,2-trifluoroethanol did not result in the de-
sired reaction taking place, but 2,2,2-trifluoroethanol
helped to promote the reaction quite efficiently. Indeed,
the coupling between ortho-nitro phenol, cyclohexyliso-
cyanide, isovaleraldehyde and one equivalent of a 30%
aqueous ammonia solution performed in 2,2,2-trifluoro-
ethanol gave the desired adduct 1 in 53% yield, along with
15% of the N-aryl carboxamide 2 as by-product
(Scheme 2).
develop more efficient processes, chemists have chosen to In order to limit the formation of 2, two equivalents of am-
develop alternatives to ammonia by using ‘convertible monia were introduced in the reaction mixture. We were
primary amines’ such as nitrobenzylamine,10 that can be then able to isolate the desired four-component adduct in
deprotected after the Ugi reaction. Herein, we wish to re- a 58% yield after 36 hours at 60 °C. Most noteworthy, the
port new conditions that allow Ugi–Smiles and Ugi cou- reaction time can be dramatically decreased under micro-
plings to be performed with ammonia.
wave irradiation (Scheme 3) at 130 °C (100 W, 90 min),
giving the product in similar yields (65%) even with a de-
creased amount of ammonia (1.5 equiv). Under this new
set of conditions, protic polar solvents were screened
again and methanol gave the best yields.
Since the discovery of the Ugi–Smiles reaction, we have
been trying to perform Ugi–Smiles couplings with ammo-
nia. Indeed, different sets of conditions have been sur-
veyed, by varying both the ammonia sources and the
solvents: ammonium acetate, ammonium chloride with a With these conditions in hand, the reaction proceeded
stoichiometric amount of base as additive, either triethyl- smoothly to completion, as shown in Table 1. The desired
amine, potassium carbonate, DBU or potassium tert- NH-adducts were isolated in good yields with various
butanolate, hexamethyldisilamine, or magnesium nitride, ortho- (entries 1–4, Table 1) and para-nitro phenols (en-
using methanol, acetonitrile or toluene. Unfortunately, the tries 5–7, Table 1) and with several different isocyanides.
However, concerning the carbonyl substrate, this method
failed with aromatic aldehydes and is therefore limited to
aliphatic derivatives for the moment.
SYNLETT 2010, No. 18, pp 2784–2788
Advanced online publication: 22.10.2010
DOI: 10.1055/s-0030-1259004; Art ID: D21810ST
x
x
.x
x
.2
0
1
0
© Georg Thieme Verlag Stuttgart · New York

LETTER
Ammonia in Ugi–Smiles and Ugi couplings
2785
4-Cl(C6H4)CH2NC
i-BuCO
NH3 (1 equiv)
OH
O
NO2
O
NO2
NO2
4-Cl(C6H4)CH2
N
4-Cl(C6H4)CH2
NH
i-Bu
+
N
4CH2[C6H4(4-Cl)]
CF3CH2OH
N
H
H
i-Bu
1
2
53%
15%
Scheme 2 Ammonia couplings in CF3CH2OH
OH
O
NO2
NO2
NH3 (1.5 equiv)
MW (130 °C, 100 W)
CF
4-Cl(C6H4)CH2
NH
i-Bu
4-Cl(C6H4)CH2NC
i-BuCHO
+
N
H
3CH2OH
MeOH
1
65%
90%
Scheme 3 Ammonia couplings under microwave irradiation
Table 1 Ammonia Couplings with Nitro Phenols
Entry
Phenol
RCHO
RNC
Product
Yield (%)
44
OH
NO2
NO2
NO2
NO2
O
NO2
1
i-BuCHO
CyNC
Cy
NH
N
H
i-Bu
OH
OH
OH
O
NO2
2
3
i-BuCHO
4-MeO(C6H4)CH2NC
4-Cl(C6H4)CH2NC
89
55
4-MeO(C6H4)CH2
NH
i-Bu
N
H
O
NO2
EtCHO
4-Cl(C6H4)CH2
NH
N
H
Et
OMe
4
4
i-BuCHO
4-MeO(C6H4)CH2NC
69
23
O
NO2
4-MeO(C6H4)CH2
NH
i-Bu
N
H
OMe
OH
OMe
NO2
Ph(CH2)2CHO
4-MeO(C6H4)CH2NC
O
NO2
4-MeO(C6H4)CH2
NH
N
H
OMe
Ph
Synlett 2010, No. 18, 2784–2788 © Thieme Stuttgart · New York

2786
A. Barthelon et al.
LETTER
Table 1 Ammonia Couplings with Nitro Phenols (continued)
Entry
5
Phenol
RCHO
RNC
Product
Yield (%)
NO2
NH
OH
i-BuCHO
CyNC
42
53
O
Cy
N
NO2
OH
H
i-Bu
NO2
NH
OMe
6
7
i-BuCHO
i-BuCHO
4-MeO(C6H4)CH2NC
O
OMe
4-MeO(C6H4)CH2
NO2
OH
N
H
i-Bu
NO2
Cl
4-MeO(C6H4)CH2NC
68
O
Cl
4-MeO(C6H4)CH2
NH
N
H
NO2
i-Bu
More interestingly, these conditions can be efficiently ap- The possibility to form Ugi–Smiles adducts between am-
plied to 2-hydroxypyridine (Table 2, entry 1) or 4-hydroxy- monia and simple aldehydes such as propionaldehyde
pyrimidines (Table 2, entries 2–4), as these compounds (Table 1, entry 3) is noteworthy when considering the low
yield the expected NH-heteroaryl substrates. As the previ- efficiency of these aldehydes in related Ugi–Mumm reac-
ous MCR-deprotection sequence failed with heteroaro- tions (couplings with carboxylic acids).9 This might be
matic phenols, this procedure is thus far the sole pathway due to the higher temperature used, which allows a revers-
for the synthesis of such products via Ugi–Smiles cou- ible formation of all the aminal side products easily
plings.
formed with ammonia.9b,c Therefore, microwave irradia-
Table 2 Ammonia Couplings with Hydroxy Heteroaromatic
Entry
HetOH
RCHO
RNC
Product
Yield(%)
47
OH
N
N
NO2
O
NO2
1
i-BuCHO
4-MeO(C6H4)CH2NC
4-MeO(C6H4)CH2
NH
i-Bu
N
H
N
i-Pr
OH
N
N
N
2
3
i-BuCHO
i-BuCHO
4-Cl(C6H4)CH2NC
4-Cl(C6H4)CH2NC
42
74
O
N
4-Cl(C6H4)CH2
NH
N
N
i-Pr
H
i-Bu
N
Ph
OH
O
O
N
N
4-Cl(C6H4)CH2
NH
N
H
N
Ph
i-Bu
N
OH
4
i-BuCHO
4-Cl(C6H4)CH2NC
57
4-Cl(C6H4)CH2
NH
N
H
N
i-Bu
Synlett 2010, No. 18, 2784–2788 © Thieme Stuttgart · New York

LETTER
Ammonia in Ugi–Smiles and Ugi couplings
2787
Table 3 Ammonia Couplings in Ugi Reaction
R2
O
H
NH3 (1.5 equiv)
N
R1COOH
Entry
1
+
R2CHO
+
R3NC
HN
R1
R3
MeOH, MW
O
130 °C, 1.5 h
RCO2H
RR¢CO
i-BuCHO
RNC
Product
Yield (%)
O
Ph
COOH
O
4-Cl(C6H4)CH2NC
93
92
4-Cl(C6H4)CH2
NH
N
H
i-Bu
O
O
Ph
COOH
2
3
4
5
i-BuCHO
i-BuCHO
EtCHO
CyNC
Cy
NH
N
H
i-Bu
O
O
O
4-Cl(C6H4)CH2NC
4-Cl(C6H4)CH2NC
4-Cl(C6H4)CH2NC
quant
64
COOH
4-Cl(C6H4)CH2
4-Cl(C6H4)CH2
NH
NH
N
H
i-Bu
O
Ph
COOH
N
H
Et
O
O
O
Ph(CH2)2CHO
45
COOH
4-Cl(C6H4)CH2
4-Cl(C6H4)CH2
NH
NH
N
H
Ph
Ph
O
COOH
O
6
4-Cl(C6H4)CH2NC
60
N
H
tion in Ugi reactions with ammonia should bring similar References and Notes
improvements. Indeed, when various Ugi reactions were
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good yields were obtained with aliphatic aldehydes as
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(d) Jacobi Von Wangelin, A.; Neumann, H.; Gördes, D.;
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To conclude, we have developed a straightforward Ugi–
Smiles access to NH-aryl and NH-heteroaryl derivatives
via a four-component coupling involving ammonia.12
This method allows the direct formation of medicinally
relevant heterocyclic scaffolds. It can be furthermore ap-
plied to Ugi couplings with ammonia and carboxylic ac-
ids.
(2) For reviews concerning Ugi couplings, see: (a) Zhu, J. Eur.
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Acknowledgment
Financial support was provided by the ENSTA and the ANR
(CP2D, Muse project). M.G. thanks the Délégation Générale de
l’Armement for a fellowship. A.B. thanks the MENR for a fel-
lowship.
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Synlett 2010, No. 18, 2784–2788 © Thieme Stuttgart · New York

2788
A. Barthelon et al.
LETTER
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(12) Typical Procedure for 1: In a microwave tube were
introduced MeOH (1.0 mL), 2-nitrophenol (140 mg, 1.0
mmol), a 30% aq solution of NH3 (120 mL, 1.5 equiv),
isovaleraldehyde (108 mL, 1.0 equiv), and p-chlorobenzyl-
isocyanide (150 mL, 1.0 equiv). The reaction mixture was
stirred for 90 min under microwave irradiation (100 W, 130
°C). The solvent was then removed under reduced pressure
to afford the Ugi–Smiles product after purification by flash
column chromatography on silica gel (244 mg, 65% yield);
mp 91–92 °C. 1H NMR (400 MHz, CDCl3): d = 8.22 (dd, 1
H, J = 8.6, 1.4 Hz), 8.07 (d, 1 H, J = 4.5 Hz), 7.48 (ddd, 1 H,
J = 8.4, 7.1, 1.4 Hz), 7.24 (dt, 2 H, J = 8.6, 2.3 Hz), 7.09 (d,
2 H, J = 8.6 Hz), 6.84 (ddd, 1 H, J = 8.6, 7.1, 1.3 Hz), 6.76
(d, 1 H, J = 8.4 Hz), 6.72 (t, 1 H, J = 5.9 Hz), 4.43 (dd, 1 H,
J = 15.3, 5.9 Hz), 4.38 (dd, 1 H, J = 15.3, 5.9 Hz), 4.01 (dt,
1 H, J = 9.3, 4.5 Hz), 1.98–1.75 (m, 3 H), 1.05 (d, 3 H, J =
6.2 Hz), 0.95 (d, 3 H, J = 6.2 Hz). 13C NMR (100.6 MHz,
CDCl3): d = 173.1, 144.3, 137.1, 136.8, 133.8, 133.6, 129.3,
129.2, 127.4, 118.0, 115.0, 58.1, 43.0, 42.7, 25.6, 23.6, 21.8.
HRMS: m/z calcd for C19H22ClN3O3: 375.1350; found:
375.1352.
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Synlett 2010, No. 18, 2784–2788 © Thieme Stuttgart · New York

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