Mono alkylation of α-isocyano acetamide to its higher homologues

Article abstract of DOI:10.1055/s-2006-944224

Alkylation of α-isocyano acetamide (2) with alkyl halide in MeCN at 0 °C in the presence of cesium hydroxide afforded the mono-alkylated product 1 in good to excellent yield. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-944224

LETTER
1777
Mono Alkylation of a-Isocyano Acetamide to its Higher Homologues
Mono
A
lkylation
h
of
a
-Isocyan
r
oAceta
i
mide stopher Housseman, Jieping Zhu*
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette Cedex, France
Fax +33(1)69077247; E-mail: zhu@icsn.cnrs-gif.fr
Received 18 April 2006
R
Abstract: Alkylation of a-isocyano acetamide (2) with alkyl halide
in MeCN at 0 °C in the presence of cesium hydroxide afforded the
mono-alkylated product 1 in good to excellent yield.
NR1R2
NR1R2
CsOH·H2O, RX
CN
CN
O
O
MeCN, 0 °C
2
1
Key words: cesium hydroxide, isonitrile, isocyano acetamide,
monoalkylation
Scheme 1 Monoalkylation of a-isocyano acetamide to its higher
homologue
Functionalized isonitriles have found wide application in
the syntheses of heterocycles.1–3 Although less popular
than a-isocyano acetate4 and tosylmethyl isocyanide
(TosMIC),5 a-substituted a-isocyano acetamides (1)6
have recently been developed into a powerful bifunctional
substrate for the multicomponent syntheses of
heterocycles7,8 and macrocycles.9 Indeed, the reactivity
profile of a-isocyano acetamide (1) was found to be rather
different from that of a-isocyano acetate under mild basic
or acidic conditions. Compound 1 has previously been
synthesized from the corresponding amino acid in three
conventional steps via a sequence of N-formylation,
amidation of carboxylic acid and dehydration.10 Although
the sequence is high-yielding for the synthesis of each
individual compound, its limitation in the high-through-
put synthesis of a diverse collection of this class of iso-
nitriles is self-evident. Consequently, we were interested
in developing a more efficient synthesis of 1 in order to
fully exploit its synthetic potential.
(a)
OMe
NR1R2
MeOH
CN
HNR1R2
+
CN
O
r.t., 18 h
O
3
4
2
2a NR1R2
=
=
85%
77%
N
O
2b NR1R2
N
(b)
OK
NR1R2
EDCI, TEA
CH2Cl2, r.t.
CN
HNR1R2
+
CN
O
O
2
5
4
2c NR1R2
2d NR1R2
=
=
49%
69%
NEt2
NMeOMe
Scheme 2 Synthesis of isocyano acetamides
EDCI mediated coupling of the potassium salt of a-iso-
cyano acetic acid14 with diethylamine provided the amide
2c in 49% yield. The Weinreb amide 2d was similarly
prepared in 69% yield (Scheme 2, b).15
Benzylation of a-isocyano acetamide (2) providing the
corresponding a,a-bisalkylated derivative has been devel-
oped by Matsumoto in 1977.11 To the best of our knowl-
edge, this is the only report found in the open literature
dealing with the alkylation of 2 and indeed conditions
allowing the monoalkylation of (2) remained unknown.
Similarly, alkylation of methyl a-isocyano acetate (3)
afforded the corresponding bisalkylated product even
with a substoichiometric amount of alkylating agent.12,13
We report herein that monoalkylation of (2) can be real-
ized under appropriate conditions to afford a-substituted
a-isocyano acetamides (1) in good to excellent yield
(Scheme 1).
The benzylation of morpholino a-isocyano acetamide 2a
with benzyl bromide (6a) was examined as a model reac-
tion by varying the bases, the reaction temperatures, and
the solvents (Table 1). As is seen, no reaction occurred
when NaOH, DBU and Cs2CO3 were used as bases re-
gardless of the nature of solvents used (THF, CH2Cl2, bi-
phasic solution, entries 1–4). In accord with Mastumoto’s
observation, performing the alkylation in THF in the
presence of sodium hydride afforded 1a in only 10% yield
(entry 5). The dibenzylated compound was produced in
30% yield under these conditions. Gratifyingly, cesium
hydroxide was found to be able to promote the desired
monoalkylation in a variety of solvents including dichlo-
romethane, THF, diethyl ether, toluene and acetonitrile.
The optimal conditions for the alkylation of 2a consisted
of performing the reaction in acetonitrile at 0 °C with 1.05
equivalents of BnBr and 1.5 equivalents of CsOH·H2O.
Under these conditions, compound 1a was isolated in
94% yield without the concurrent formation of dibenzyl-
ated compound. It has nevertheless to be emphasized that
a-Isocyano acetamides (2) were synthesized as shown in
Scheme 2. Stirring a methanol solution of a-isocyano
acetate (3) with morpholine and pyrrolidine afforded the
corresponding amides 2a and 2b in yields of 85% and
77%, respectively (Scheme 2, a). On the other hand,
SYNLETT 2006, No. 11, pp 1777–1779
1
2
.0
7
.2
0
0
6
Advanced online publication: 04.07.2006
DOI: 10.1055/s-2006-944224; Art ID: G12906ST
© Georg Thieme Verlag Stuttgart · New York

1778
C. Housseman, J. Zhu
LETTER
dibenzylated compound was produced as a major product
if an excess of base and benzyl bromide (2.5 equiv each)
were used under otherwise identical conditions.16
6h
Br
Br
Br
R
6i
6a R = H
The generality of this protocol was next examined using
4 isocyano acetamides 2a–d and 12 electrophiles
(Figure 1). Compounds synthesized by the standard pro-
cedure (1.5 equiv of CsOH·H2O, 1.05 equiv of alkylating
agent, MeCN, 0 °C) were listed in Figure 2. As it is seen,
the reaction turned out to be quite general. The mono-
alkylation took place smoothly not only with the activated
halides such as benzyl bromide, allyl bromide, propargyl
bromide and methyl iodide, but also with less reactive
alkyl halides such as ethyl iodide (6k) and 1-bromobutane
(6l). Alkylation of 4-nitrobenzylbromide (6d) is known to
be low-yielding due to the competitive dimerization and
degradation process via a radical anion mechanism,17 it is
thus interesting to note that alkylation of 2a with 6d pro-
ceeded smoothly to provide 1h in 61% yield. The amide
structures exerted only minor effect on the alkylation pro-
cess and amide derived from cyclic amine (morpholine,
pyrrolidine), acyclic amine (diethylamine) as well as the
Weinreb amide can be effectively converted to the
monoalkylated product.
6b R = 4-Br
6c R = 2-Br
MeI
EtI
6j
6d R = 4-NO2
6k
6e R = 3-NO2
6f R = 4-tBu
6l
n-C4H9Br
6g R = 3,4,5-trimethoxy
Figure 1 Structure of alkyl halides
O
N
N
N
CN
CN
CN
O
O
O
1c 57%
1b 82%
1a 94%
Br
Br
Br
O
N
N
N
CN
CN
CN
O
N
O
O
1e 82%
1d 81%
1f 75%
NO2
Br
O2N
O
Table 1 Survey of Conditions for Alkylation of Morpholino a-Iso-
cyano Acetamide (2a) with Benzyl Bromide (6a)a
O
O
N
N
CN
Entry Base
Solvent
Temp
(°C)
Yield of 1a
CN
CN
(%)b
O
O
O
1g 73%
1h 61%
1i 28%
OMe
1
2
NaOH
CH2Cl2–H2O
CH2Cl2
CH2Cl2
THF
0
–30
r.t.
r.t.
r.t.
–25
0
0
0
MeO
MeO
DBU
O
3
DBU
0
N
N
O
CN
CN
O
4
Cs2CO3
0
1j 81%
1k 80%
5
NaH
THF
10c
21
71
76
14
76
56
58
94
73
O
6
CsOH·H2O
CsOH·H2O
CsOH·H2O
CsOH·H2O
CsOH·H2O
CsOH·H2O
CsOH·H2O
CsOH·H2O
CsOH·H2O
CH2Cl2
CH2Cl2
CH2Cl2
THF
N
O
N
N
O
CN
CN
CN
7
O
1n 63%
1m 88%
8
r.t.
r.t.
0
1l 75%
9
O
O
O
N
N
N
10
11
12
13
14
Et2O
CN
CN
CN
O
O
O
Et2O
r.t.
r.t.
0
1p 82%
1q 47%
1o 80%
MeCN
MeCN
Toluene
N
N
CN
OMe
CN
OMe
O
O
r.t.
1s 62%
1r 57%
a General conditions: 1.5 equiv of base, 1.05 equiv of benzyl bromide,
concentration 0.2 M.
Figure 2 a-Substituted a-isocyano acetamide
bYield referred to pure isolated product.
c Dialkylated product was isolated in 30% yield.
the previously reported three-step synthesis especially if
the starting amino acid is not commercially available. The
present protocol should thus facilitate the further exploita-
tion of this unique class of isonitrile and enhance its appli-
cation scope in heterocycle synthesis.
In summary, conditions for the efficient monoalkylation
of a-isocyano acetamide to its higher homologues have
been developed. This synthesis has clear advantages over
Synlett 2006, No. 11, 1777–1779 © Thieme Stuttgart · New York

LETTER
Mono Alkylation of a-Isocyano Acetamide
1779
(12) (a) Hoppe, D. Angew. Chem., Int. Ed. Engl. 1974, 13, 789.
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(13) Schöllkopf reported that it is possible to perform
monoalkylation of tert-butyl a-isocyano acetate, see:
(a) Schöllkopf, U.; Hoppe, D.; Jentsch, R. Angew. Chem.,
Int. Ed. Engl. 1971, 10, 331. (b) Schöllkopf, U.; Hoppe, D.;
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Acknowledgment
We thank CNRS and this institute for financial support. C.H. thanks
‘Ministère de l’Enseignement Supérieur et de la Recherche’ for a
doctoral fellowship.
References and Notes
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(15) Synthesis of Compound 2a.
To a solution of methyl a-isocyanoacetate (4.4 mmol) in dry
MeOH (3.0 mL) was added morpholine (10.3 mmol, 2.3
equiv) and the reaction mixture was stirred at r.t. for 18 h.
The volatile was removed under reduced pressure and the
crude material was purified by flash chromatography (SiO2,
EtOAc–heptane = 2:1) to afford 2a in 85% yield, mp 77–
78 °C. IR (CHCl3): 2163, 1658, 1462, 1422, 1274, 1236,
1111, 992 cm–1. 1H NMR (300 MHz, CDCl3): d = 4.31 (s, 2
H), 3.63 (m, 4 H), 3.54 (m, 2 H), 3.30 (m, 2 H). 13C NMR (75
MHz, CDCl3): d = 161.3, 160.7, 66.5, 66.1, 45.6, 44.3, 42.6.
MS (ES, positive mode): m/z = 177.1 [M + Na]+.
Synthesis of Compound 2d.
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To a suspension of potassium salt of a-isocyano acetic acid
(4.4 mmol) in dry CH2Cl2 (22 mL) were added Et3N (5.7
mmol), EDCI (5.3 mmol) and hydrochloride salt of
MeNH(OMe) (4.8 mmol). After being stirred at r.t. for 20 h,
the reaction mixture was quenched with H2O (2 mL) and
extracted with CH2Cl2. The combined organic layers were
washed with brine, dried and evaporated under reduced
pressure. The crude material was purified by flash
chromatography (Al2O3, EtOAc–heptane = 2:1) to afford 2d
as a brown solid (69%), mp 72–73 °C. IR (CHCl3): 2162,
1681, 1410, 1317, 1179, 963 cm–1. 1H NMR (300 MHz,
(5) Van Leusen, D.; Van Leusen, A. M. Organic Reactions, Vol.
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York, 2001, 417–666.
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Chem. Soc. 1986, 108, 6405. (d) Bossio, R.; Marcaccini, S.;
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Tetrahedron 1990, 46, 7587. (f) Zhou, X. T.; Lin, Y. R.;
Dai, L. X.; Sun, J. Tetrahedron 1998, 54, 12445.
CDCl3): d = 4.39 (s, 2 H), 3.69 (s, 3 H), 3.19 (s, 3 H). 13
C
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Lett. 2001, 3, 877. (b) González-Zamora, E.; Fayol, A.;
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NMR (75 MHz, CDCl3): d = 163.9, 160.7 (141.9), (62.3)
61.7, (52.3) 43.8, (40.7) 32.7. MS (ES, positive mode):
m/z = 151.1 [M + Na]+.
(16) Monoalkylation of a-Isocyanoacetamide – A General
Procedure.
To a dry test tube containing CsOH·H2O (0.34 mmol, 1.7
equiv) were added, under argon atmosphere, a solution of
isocyano acetamide (0.20 mmol) in MeCN (1.0 mL) and
alkylating agent (0.21 mmol) at 0 °C. The resulting reaction
mixture was stirred at 0 °C. When the reaction was deemed
complete by TLC analysis (typically 24 h), the volatile was
removed under reduced pressure. Purification of the crude
product by either preparative TLC (silica gel) or flash
chromatography (silica gel) afforded the desired product.
Compound 1a: yield 94%. IR (CHCl3): 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 (62.5 MHz, CDCl3): 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]+. Anal. Calcd
for C14H16N2O2 (%): C, 68.83; H, 6.60; N, 11.47. Found: C,
68.71; H, 6.60; N, 11.47.
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Synlett 2006, No. 11, 1777–1779 © Thieme Stuttgart · New York