Synthesis of α-isocyano-α-alkyl(aryl)acetamides and their use in the multicomponent synthesis of 5-aminooxazole, pyrrolo[3,4-a]pyridin-5-one and 4,5,6,7-tetrahydrofuro[2,3-c]pyridine

Article abstract of DOI:10.1055/s-2004-831225

α-Isocyano-β-phenylpropionamide 1 is synthesized from the corresponding amino acid in excellent yield. The unique reactivity of this bifunctional compound is exploited for the development of novel multicomponent synthesis of 5-aminooxazole 6, pyrrolo[3,4-

Full text of DOI:10.1055/s-2004-831225

PRACTICAL SYNTHETIC PROCEDURES
161
Synthesis of a-Isocyano-a-alkyl(aryl)acetamides and their Use in the
Multicomponent Synthesis of 5-Aminooxazole, Pyrrolo[3,4-b]pyridin-5-one
and 4,5,6,7-Tetrahydrofuro[2,3-c]pyridine
S
ynthesis and App
u
lications of
a
d
-Isocyano-
a
e
-alkyl(aryl)acetam
F
ide
s
ayol,a Christopher Housseman,a Xiaowen Sun,a Pierre Janvier,a Hugues Bienaymé,b Jieping Zhu*a
a
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette Cedex, France
Fax +33(1)69077247; E-mail: zhu@icsn.cnrs-gif.fr
Urogene-Chrysalon, 11, Avenue A. Einstein, 69100 Villeurbanne, France
b
PSP
Received 26 May 2004
No37
Abstract: a-Isocyano-b-phenylpropionamide 1 is synthesized from the corresponding amino acid in excellent yield. The unique reactivity
of this bifunctional compound is exploited for the development of novel multicomponent synthesis of 5-aminooxazole 6, pyrrolo[3,4-b]py-
ridin-5-one 10 and 4,5,6,7-tetrahydrofuro[2,3-c]pyridine 13.
Key words: domino process, multicomponent reaction, heterocycles, isonitrile, oxazole, pyrrolopyridinone, tetrahydrofuropyridine
O
O
O
H2N
OHCHN
OH
CN
1) HCOOH, Ac2O
POCl3
Et3N
N
Procedure 1
N
O
O
2) EDC, HOBt
morpholine
2
3
1: 87%
O
N
O
O
N
MeOH
60 °C
C6H13
Procedure 2
N
O
C6H13CHO
+
+
1
N
H
4
5
6: 90%
NO2
CHO
+
O
NH4Cl, 60 °C
then
C4H9N
Procedure 3
1
7
OH
ClOC
N
NO2
C4H9NH2
9
8
10: 70%
COOEt
N
CHO
1
+
NH4Cl
toluene, reflux
Procedure 4
O
COOEt
N
11
O
N
H
13: 80%
12
Scheme 1
portions of all starting materials. By saving synthetic op-
erations while maximizing the buildup of structural and
functional complexity, these highly step-economic reac-
tions are particularly appealing in the context of diversity
as well as target-oriented syntheses.1 Isonitrile is one of
the key components of the well-known Passerini three-
component reaction (P-3CR) and Ugi four-component re-
action (U-4CR).2 A number of isonitriles bearing addi-
tional functionalities are known. Among them, a-
isocyano acetate3 and tosylmethyl isocyanide (TosMIC),
developed by Schöllkopf3 and Van Leusen,4 respectively,
Introduction
Multicomponent reaction (MCR) is a process in which
three or more reactants are combined in a single reaction
flask to produce a product that incorporates substantial
SYNTHESIS 2005, No. 1, pp 0161–0165
Advanced online publication: 16.09.2004
DOI: 10.1055/s-2004-831225; Art ID: Z10304SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
4

162
A. Fayol et al.
PRACTICAL SYNTHETIC PROCEDURES
are notable examples and have found wide applications in isonitrile, rather than the a-carbon leading to the nitrilium
the synthesis of diverse class of heterocycles. In contrast, intermediate 15 that was trapped intramolecularly by the
the chemistry of a-isocyano acetamide has been relatively amide oxygen to afford ultimately the 5-aminooxazole 6.6
underdeveloped.5 Here we describe a convenient prepara-
This three-component reaction took place smoothly in
MeOH without any activator. It was subsequently discov-
ered that the same transformation took place in non-polar
aprotic solvent like toluene, in the presence of a suitable
additive. The following Lewis acids: BF3·OEt2, Cu(OTf)2,
Cu(OTf), Zn(OTf)2, CuBr, LiBr, SiCl4 and Brönsted ac-
tion of a-isocyano-b-phenylpropionamide 1 and its use in
the development of novel multicomponent reactions for
the synthesis of 5-aminooxazole 6,6 pyrrolo[3,4-b]pyri-
din-5-one 107 and 4,5,6,7-tetrahydrofuro[2,3-c]pyridine
13 (Scheme 1).8
ids: NH4Cl, Et3N·HCl, Bu4NCl, pyridine·HCl, luti-
dine·HCl, camphorsulfonic acid have been examined. The
cheapest and the readily available NH4Cl turned out to be
Scope and Limitations
the promoter of choice. Although a stoichiometric amount
of NH4Cl was generally used, the reaction might be cata-
lytic in nature since NH4Cl was scarcely soluble in tolu-
The (D,L)-a-isocyano-b-phenylpropionamide 1 is synthe-
sized from phenylalanine (2) in three conventional steps.
N-formylation of 2 (HCOOH, Ac2O) followed by a EDC-
ene. It is worth noting that the same reaction occurred
mediated amidation with morpholine provided the amide
sluggishly in toluene in the absence of NH4Cl.
3 that is dehydrated (POCl3, Et3N, –20 °C) to afford the
desired isocyanide 1 in 87% yield. This transformation is
Aldehyde
Isonitrile
highly reliable and a range of amino acids and dipeptides
has been converted to the corresponding isocyano deriva-
tives.9,10 The dehydration step is racemization-free and the
optically pure L-a-isocyano-b-phenylpropionamide 1 has
been prepared from L-phenylalanine following the same
synthetic sequence. These a-isocyano-a-alkylacetamides
are generally odorless and are purified by flash chroma-
tography. They are stable in pure form, but are gradually
hydrolyzed back to the N-formyl derivatives in a CH2Cl2
solution.
O
N
C
n-C6H13CHO
n-C3H7CHO
cyclooctyl aldehyde
NR1R2
R
R = H, Bn, i-Pr, Ph
NR1R2 = morpholinyl, piperidinyl
pyrrolidinyl, diethylamino,
N-alkyl amino ester
benzaldehyde
4-chlorobenzaldehyde
4-methoxybenzaldehyde
Amine
MeOOC
HO
NH3Cl
O2N
NH2
The presence of both isocyano and carbonyl (or tosyl)
groups rendered the a-methylene proton of TosMIC, a-
isocyano acetate and a-isocyano acetamide acidic. There-
fore, both the divalent isonitrile carbon and the a-methyl-
ene carbon are potentially nucleophilic. It follows that
different reaction sequences can be envisaged if the rela-
tive reactivity of these two nucleophilic sites can be mod-
ulated. Indeed, the rich chemistry of a-isocyano acetate
and TOSMIC is mainly based on the nucleophilicity of the
a-methylene carbon and several multicomponent reac-
tions have been developed based on this reactivity.11,12 In
contrast, a-isocyano-b-phenylpropionamide 1 displayed
different reactivity profile presumably due to the reduced
acidity of the a-CH. As shown in Scheme 2, when a solu-
tion of an equimolar amount of heptanal, morpholine and
1 was heated to 60 °C for 4 hours, the 5-aminooxazole 6
was obtained in 90% isolated yield. In this transformation,
the in situ generated iminium species was attacked by the
N
Bn
NH2
N
NHBn
O
O
H2N
MeO
NH2
NH2
Me
R
OMe
R = F, OMe
NH2
MeO
MeO
COOMe
NH2
R
NH2
R = H, Br
O
R
COOMe
NH3+Cl-
N
N
H
MeOOC
H
R = Ph, COOMe
Figure 1
The scope of this reaction has been examined. As shown
in the Figure 1, a large set of aldehydes, amines and isoni-
triles having different functionalities are tolerated. When
a hydrochloride salt of an amine was used as an input, in
situ neutralization with Et3N in toluene followed by addi-
tion of aldehyde and isonitrile produced the correspond-
ing 5-aminooxazole. Apparently, the stoichiometric
amount of Et3N·HCl, generated in situ, promoted effi-
ciently the subsequent multicomponent assembly process.
O
O
4
+
1
N
+
N
MeOH
60 °C
6
O
+
N
C6H13
5
C6H13
N
14
O
15
Scheme 2
The 5-aminooxazole possesses several potentially reac-
tive functions. Consequently, a domino process could be
Synthesis 2005, No. 1, 161–165 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Synthesis and Applications a-Isocyano-a-alkyl(aryl)acetamides
163
COOEt
expected if it were combined with another polyfunctional-
ized substrate. One such example is illustrated in the
Scheme 3. Thus, simply heating a solution of oxazole 6
and acyl chloride 9 in toluene in the presence of five
equivalent of Et3N led to the formation of medicinally rel-
evant pyrrolo[3,4-b]pyridin-5-one (10) in excellent yield
(Scheme 3). From results of control experiments, a se-
quence of reaction involving intermolecular acylation-in-
tramolecular Diels–Alder (D–A) cycloaddition-retro-
Michael cycloreversion was proposed to explain the for-
mation of compound 10.
O
Bn
N
12 + 11 + 1
N
O
N
Bn
19
COOEt
O
N
13
O
N
N
Bn
Bn
BnCN
20
NO2
NHC4H9
Scheme 4
toluene, Et3N
O
Cl
Ph
isocyanoacetate and TosMIC. By judicious selection of
reaction partners, several multicomponent reactions have
been developed for the synthesis of a range of heterocy-
cles.13
+
N
O
N
16
O
reflux
O
Bn
9
Ph
C4H9
O
O
N
NO2
N
c
C4H9N
Ph
Melting points were determined with a Kofler apparatus and are un-
corrected. IR spectra were recorded on a Nicolet-205 FT-IR spec-
trometer. 1H NMR spectra were measured on Bruker AC-250 (250
MHz), AC-300 (300 MHz) and AC-400 (400 MHz) spectrometers
with tetramethylsilane as internal standard (d ppm). Solvents were
of ACS grade and were distilled prior to use. Reagents were purified
according to standard laboratory techniques. All reactions requiring
anhydrous conditions or an inert atmosphere were conducted under
an atmosphere of argon.
Ha
Hb
10
Bn
O
N
O
N
O
N
Bn
NO2
17
18
Scheme 3
By combining this bimolecular domino process with the
three-component synthesis of 5-aminooxazole, a one-pot
four-component assembly of pyrrolopyridinone is subse-
quently developed.7 Thus a solution of benzaldehyde (7),
n-butylamine (8) and an isonitrile (1) in the presence of
1.5 equivalents of NH4Cl was stirred at 60 °C. Once the
oxazole formation deemed complete by TLC analysis, p-
nitro cinnamoyl chloride (9) and Et3N were added at 0 °C.
Heating to reflux produced pyrrolopyridinone 10 in good
to excellent yield (Scheme 1, procedure 3). It is interest-
ing to note that six different functionalities participate in
this one-pot process, leading to the formation of a bicyclic
ring system with the creation of five chemical bonds. The
efficiency of this MCR is thus truly remarkable if one
looks at the yield per chemical bond formation.
Procedures
We described in this article four procedures. Procedure 1 concerns
the synthesis of a-isocyano-b-phenylpropionamide 1, while Proce-
dures 2–4 deal with the multicomponent synthesis of heterocycles
based on the unique reactivity of isocyanide 1. Specifically, three-
component synthesis of 5-aminooxazole 6 is described in Proce-
dure 2, a four component assembly of pyrrolo[3,4-b]pyridin-5-one
10 in procedure 3 and a three-component synthesis of 4,5,6,7-tet-
rahydrofuro[2,3-c]pyridine 13 in Procedure 4.
Procedure 1: N-(1-Benzyl-2-morpholin-4-yl-2-oxo-ethyl) For-
mamide (3); Typical Procedure
Acetic anhydride (17.0 mL, 180.2 mmol, 7.2 equiv) was added
dropwise to a solution of phenylalanine (4.13 g, 25.0 mmol, 1.0
equiv) in HCOOH (50.0 mL) at 5 °C. After the addition was com-
plete, the reaction mixture was stirred at r.t. for an additional 1 h.
Ice-water (20.0 mL) was added and the mixture was concentrated at
reduced pressure to give the analytically pure white crystalline N-
formylphenylalanine (quant. yield; mp 163–165 °C).
Using funtionalized amine input such as 5-aminopen-
tynoate 12, a three-component synthesis of 4,5,6,7-tet-
rahydrofuro[2,3-c]pyridine 13 has been developed.8 Thus
refluxing a toluene solution of iso-butyraldehyde (11),
amine 12 and isocyanide 1 furnished 13 in 80% yield. The
outcome of this reaction can be explained by the follow-
ing reaction sequence. The oxazole 19, assembled by a
three-component process, underwent intramolecular D–A
cycloaddition leading to the oxa-bridged tricycle 20. Frag-
mentation of 20 by a retro D–A reaction provided then the
bicycle 13. Five chemical bonds are formed in this exper-
imentally simple multicomponent reaction, thus creating a
significant molecular complexity (Scheme 4).
To a solution of N-formylphenylalanine (3.66 g, 19.0 mmol, 1.0
equiv) and morpholine (2.0 mL, 22.9 mmol, 1.2 equiv) in anhyd
CH2Cl2 (50.0 mL) were added Et3N (3.2 mL, 23.2 mmol, 1.2 equiv),
HOBt (3.11 g, 23.0 mmol, 1.2 equiv) and EDC (4.41 g, 23.0 mmol,
1.2 equiv) successively and the reaction mixture was stirred for 24
h at r.t. The reaction mixture was diluted with sat. NH4Cl and ex-
tracted with CH2Cl2. The organic layer was washed with brine,
dried over anhyd Na2SO4 and concentrated. The residue was puri-
fied by flash column chromatography on silica gel (eluent: heptane–
EtOAc, 1:1 then EtOAc or CH2Cl2–MeOH, 30:1) to give the amide
3 (yield 97%; colorless oil).
N-Formylphenylalanine
1H NMR (250 MHz, MeOD): d = 8.03 (s, 1 H), 7.25 (m, 5 H), 4.77
(dd, J = 8.2, 5.2 Hz, 1 H), 3.24 (dd, J = 14.0, 5.2 Hz, 1 H), 3.01 (dd,
J = 14.0, 8.2 Hz, 1 H).
In summary, readily accessible a-isocyano-a-alkyl-aceta-
mide 1 displayed different reactivity profile relative to a-
Synthesis 2005, No. 1, 161–165 © Thieme Stuttgart · New York

164
A. Fayol et al.
PRACTICAL SYNTHETIC PROCEDURES
13C NMR (75 MHz, MeOD): d = 174.1, 163.5, 138.0, 130.3 (2 C),
1H NMR (250 MHz, CDCl3): d = 7.24 (m, 5 H), 3.83 (s, 2 H), 3.70
(m, 8 H), 3.57 (dd, J = 8.4, 6.8 Hz, 1 H), 2.96 (m, 4 H), 2.57 (ddd,
J = 11.6, 5.6, 3.7 Hz, 2 H), 2.48 (ddd, J = 11.6, 5.6, 3.7 Hz, 2 H),
1.86 (m, 2 H), 1.25 (m, 8 H), 0.86 (t, J = 6.6 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 158.0, 151.9, 139.6, 128.3 (3 C),
126.1 (2 C), 124.1, 67.3, 66.8 (3 C), 63.2, 51.0 (3 C), 50.1, 31.8,
31.6, 29.8, 28.9, 26.2, 22.5, 14.0.
129.5 (2 C), 127.9, 53.6, 38.4.
N-(1-Benzyl-2-morpholin-4-yl-2-oxo-ethyl) Formamide (3)
IR (CDCl3): 3414, 3004, 2864, 1683, 1637, 1445, 1116 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.17 (s, 1 H), 7.19–7.31 (m, 5 H),
6.68 (br s, 1 H), 5.23 (m, 1 H), 3.60–3.24 (m, 6 H), 3.08 (dd, J =
13.0, 5.3 Hz, 1 H), 2.98 (dd, J = 13.0, 9.3 Hz, 1 H), 2.94–2.88 (m, 2
H).
13C NMR (62.5 MHz, CDCl3): d = 169.6, 160.5, 135.8, 129.5,
128.6, 127.3, 66.3, 66.0, 48.1, 46.0, 42.3, 39.8.
MS (ESI): m/z = 450.2 [M]+.
HRMS: m/z [M + Na]+ calcd for C25H37N3O3: 450.2733; found:
450.2733.
Anal. Calcd for C25H37N3O3: C, 70.22; H, 8.72; N, 9.83. Found: C,
69.89; H, 8.76; N, 9.78.
MS (EI): m/z = 262 [M]+.
2-Isocyano-1-morpholin-4-yl-3-phenyl-propan-1-one (1)
Procedure 3: Four-Component Synthesis of Pyrrolo[3,4-b]pyri-
din-5-one (10); Typical Procedure
A stirred solution of morpholinyl amide of N-formyl phenylalanine
(4.85 g, 18.5 mmol, 1.0 equiv) and Et3N (12.8 mL, 92.0 mmol, 5.0
equiv) in anhyd CH2Cl2 (90.0 mL) was cooled to –20 °C to –30 °C.
Phosphorus oxychloride (2.6 mL, 27.5 mmol, 1.5 equiv) was added
dropwise and the reaction mixture was stirred for 3 h at –20 °C to
–30 °C. An aq sat solution of Na2CO3 was introduced dropwise so
that the temperature of mixture was maintained at –20 °C to –30 °C.
The mixture was stirred for 0.5 h and raised to r.t. The aqueous layer
was separated and extracted with CH2Cl2. The organic extracts were
combined, washed with brine, dried over anhyd Na2SO4 and evap-
orated under reduced pressure. The residue was purified by flash
column chromatography on silica gel (eluent: heptane–EtOAc, 2:1)
to provide the isocyanide 1 (yield: 87%; white solid; mp 74–78 °C).
IR (CDCl3): 2928, 2863, 2142, 1668, 1496, 1456, 1116 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.26–7.36 (m, 5 H), 4.54 (dd, J =
7.7, 7.0 Hz, 1 H), 3.20–3.69 (m, 10 H).
13C NMR (CDCl3, 62.5 MHz): d = 163.5, 159.8, 135.0, 129.4 (2 C),
128.8 (2 C), 127.7, 66.4, 65.9, 55.0, 46.2, 42.9, 39.1.
MS (EI): m/z = 244 [M]+.
To a solution of n-butylamine (19.0 mL, 19.7 mmol, 1.3 equiv) in an-
hyd toluene (1.0 mL), was added benzaldehyde (18.0 mL, 17.7
mmol, 1.2 equiv). After being stirred at r.t. for 30 min, isocyanide
(36.0 mg, 14.7 mmol, 1.0 equiv), NH4Cl (12.0 mg, 22.4 mmol, 1.5
equiv) were added, successively. The reaction mixture was stirred
at 60 °C until the disappearance of isonitrile 1. The reaction mixture
was cooled to 0 °C and diluted with toluene (1.0 mL). Et3N (104.0
mL, 74.8 mmol, 5.0 equiv) was added followed by acid chloride 9
(80.0 mg, 37.8 mmol, 2.5 equiv) in small portion. Stirring was con-
tinued at r.t. for 30 min and at reflux for 12 h. After cooling the mix-
ture to r.t., the reaction mixture was diluted with water and extracted
with EtOAc. The combined organic extracts were washed with
brine, dried (Na2SO4) and evaporated under reduced pressure. The
residue was purified by flash chromatography (silica gel, eluent:
CH2Cl2–acetone, 99:1) to give the corresponding pyrrolopyridine
10 (yield 70%; yellow oil).
IR (CDCl3): 3550, 3009, 2962, 2932, 2874, 1682, 1603, 1523, 1494,
1455, 1381, 1349, 1314, 1237, 1120, 1064, 854 cm–1.
1H NMR (250 MHz, CDCl3): d = 8.34 (d, J = 8.3 Hz, 2 H), 7.65 (d,
J = 8.3 Hz, 2 H), 7.43–7.21 (m, 10 H), 5.46 (s, 1 H), 5.18 (br s, 1
H), 4.23 (d, J = 14.1 Hz, 1 H), 4.19 (d, J = 14.1 Hz, 1 H), 3.84 (ddd,
J = 14.0, 7.7, 7.7 Hz, 1 H), 3.29 (ddd, J = 14.0, 8.1, 6.0 Hz, 1 H),
1.48 (m, 2 H), 1.26 (sext, J = 7.3 Hz, 2 H), 0.85 (t, J = 7.3 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 165.9, 157.8, 153.3, 148.1, 146.9,
137.5, 136.5, 135.6, 131.3, 130.3, 129.1, 129.0, 128.9, 128.7, 127.8,
126.8, 123.6, 120.6, 64.5, 40.1, 30.2, 20.1, 13.6.
Anal. Calcd for C14H16N2O2: C, 68.83; H, 6.60; N, 11.47. Found: C,
68.71; H, 6.54; N, 11.47.
Procedure 2: Three-Component Synthesis of 5-Aminooxazole
(6) in MeOH; Typical Procedure
A solution of morpholine (17.0 mL, 19.5 mmol, 1.3 equiv) and hep-
tanal (24.0 mL, 17.9 mmol, 1.2 equiv) in anhyd MeOH (1.0 mL) was
stirred at r.t. for 30 min. Isocyanoacetamide 1 (36.0 mg, 14.7 mmol,
1.0 equiv) was then added. The reaction mixture was stirred at 60
°C and the reaction course was followed by TLC. After the disap-
pearance of isonitrile 1 (typically 4 h), the reaction mixture was
cooled to r.t. and the solvent was evaporated. The residue was puri-
fied by flash chromatography (silica gel, eluent: EtOAc–heptane,
2:1) to give the corresponding oxazole (yield 90%, colorless oil).
MS (CI): m/z = 494 [M + H]+.
Procedure 4: Ammonium Chloride-Promoted Three Compo-
nent Synthesis of 4,5,6,7-Tetrahydrofuro[2,3-c]pyridine (13);
Typical Procedure
A solution of amine 12 (100.0 mg, 43.3 mmol, 1.2 equiv) and iso-
butyraldehyde (39.0 mL, 42.8 mmol, 1.2 equiv) in anhyd toluene (3.6
mL) was stirred at r.t. in the presence of NH4Cl (19.2 mg, 36.0
mmol, 1.0 equiv) for 1 h. a-Isocyanoacetamide 1 (88.0 mg, 36.0
mmol, 1.0 equiv) was added and the reaction mixture was heated to
reflux. The reaction was monitored by TLC (15 h). The reaction
mixture was cooled to r.t. and toluene was removed under reduced
pressure. After dilution with water, the product was extracted with
CH2Cl2. The combined organic extracts were washed with brine,
dried over anhyd Na2SO4 and the solvent was removed under re-
duced pressure. The residue was purified by flash chromatography
(silica gel, eluent: heptane–EtOAc, 3:1) to give the corresponding
furopyridine 13 (yield 80%; yellow oil).
Ammonium chloride-promoted three-component synthesis of
5-amino oxazole (6) in toluene
A solution of morpholine (57.0 mL, 65.4 mmol, 1.3 equiv) and hep-
tanal (81 mL, 60.3 mmol, 1.2 equiv) in anhyd toluene (3.3 mL) was
stirred at r.t. for 30 min. Isocyanoacetamide 1 (122 mg, 50.0 mmol,
1 equiv) and NH4Cl (40 mg, 74.8 mmol, 1.5 equiv) were added, suc-
cessively. The reaction mixture was stirred at 60 °C and followed
by TLC (typically 4 h). After the disappearance of isonitrile, the re-
action mixture was cooled to r.t., diluted with aq Na2CO3 and was
extracted with EtOAc. The combined organic phase was washed by
brine, dried (Na2SO4) and evaporated under reduced pressure. The
residue was purified by flash chromatography (silica gel, eluent:
EtOAc–heptane, 2:1) to give the corresponding oxazole (6) (yield
81%, colorless oil).
IR (CHCl3): 2960, 2867, 1686, 1573, 1494, 1448, 1367, 1296, 1271,
1171, 1115, 1087 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.17–7.31 (m, 5 H), 4.15 (q, J =
7.2 Hz, 2 H), 3.75 (t, J = 4.7 Hz, 4 H), 3.57 (s, 2 H), 3.32–3.47 (m,
IR (CHCl3): 3622, 2967, 2401, 1663, 1495, 1453, 1376, 1231, 1114
cm–1.
Synthesis 2005, No. 1, 161–165 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Synthesis and Applications a-Isocyano-a-alkyl(aryl)acetamides
165
4 H), 2.92 (m, 1 H), 2.87 (d, J = 8.2 Hz, 1 H), 2.63–2.73 (m, 2 H),
2.40 (m, 1 H), 1.81 (m, 1 H), 1.24 (t, J = 7.2 Hz, 3 H), 0.93 (d, J =
6.7 Hz, 3 H), 0.81 (d, J = 6.7 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 164.4, 161.3, 143.2, 139.9, 128.9
(2 C), 128.2 (2 C), 127.0, 116.6, 94.4, 66.8 (2 C), 63.1, 59.8, 57.9,
48.9 (2 C), 44.3, 32.7, 20.9, 20.7, 19.5, 14.6.
MS (ESI): m/z = 413.2 [M + H]+.
HRMS: m/z [M + Na]+ calcd for C24H32N2O4: 435.2260; found:
(4) Van Leusen, D.; Van Leusen, A. M. Org. React. 2001, 57,
417.
(5) Marcaccini, S.; Torroba, T. Org. Prep. Proced. Int. 1993, 25,
141.
(6) Sun, X.; Janvier, P.; Zhao, G.; Bienaymé, H.; Zhu, J. Org.
Lett. 2001, 3, 877.
(7) Janvier, P.; Sun, X.; Bienaymé, H.; Zhu, J. J. Am. Chem. Soc.
2002, 124, 2560.
(8) Fayol, A.; Zhu, J. Org. Lett. 2004, 6, 115.
(9) Zhao, G.; Bughin, C.; Bienaymé, H.; Zhu, J. Synlett 2003,
1153.
(10) (a) Urban, R.; Marquarding, D.; Seidel, P.; Ugi, I.; Weinelt,
A. Chem. Ber. 1977, 110, 2012. (b) Nunami, K. I.; Suzuki,
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435.2259.
Anal. Calcd for C24H32N2O4: C, 69.88; H, 7.82; N, 6.79. Found: C,
69.77; H, 8.04; N, 6.61.
Acknowledgment
Financial support from CNRS, ‘Ministère de l’Enseignement Su-
périeur et de la Recherche’ (doctoral fellowship to A. Fayol and C.
Housseman) and Rhodia (doctoral fellowship to P. Janvier, post-
doctoral fellowship to X. Sun) are gratefully acknowledged.
(11) (a) Suzuki, M.; Nunami, K. I.; Moriya, T.; Matsumoto, K.;
Yoneda, N. J. Org. Chem. 1978, 43, 4933. (b) Bon, R. S.;
Hong, C.; Bouma, M. J.; Schmitz, R. F.; De Kanter, F. J. J.;
Lutz, M.; Spek, A. L.; Orru, R. V. A. Org. Lett. 2003, 5,
3759.
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5633. (b) Sisko, J.; Kassick, A. J.; Mellinger, M.; Filan, J. J.;
Allen, A.; Olsen, M. A. J. Org. Chem. 2000, 65, 1516; and
references cited therein.
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Synthesis 2005, No. 1, 161–165 © Thieme Stuttgart · New York