Isocyanide-based two- step three-component keteneimine formation

Article abstract of DOI:10.1021/ol9004432

The addition of isocyanides to acyl chlorides (Isocyanide-Nef reaction) leads to imidoyl chlorides which can later be treated with trialkylphosphites to afford new keteneimines in a Perkow- type reaction. The whole sequence may be performed without any so

Full text of DOI:10.1021/ol9004432

ORGANIC
LETTERS
2009
Vol. 11, No. 8
1825-1827
Isocyanide-Based Two-Step
Three-Component Keteneimine
Formation
Didier Coffinier,* Laurent El Kaim,* and Laurence Grimaud*
Laboratoire Chimie et Proce´de´s, Ecole Nationale Supe´rieure de Techniques AVance´es,
32 Bd Victor, 75739 Paris Cedex 15, France
didier.coffinier@laposte.net; laurent.elkaim@ensta.fr; laurence.grimaud@ensta.fr
Received March 3, 2009
ABSTRACT
The addition of isocyanides to acyl chlorides (Isocyanide-Nef reaction) leads to imidoyl chlorides which can later be treated with trialkylphosphites
to afford new keteneimines in a Perkow-type reaction. The whole sequence may be performed without any solvent, and the resulting keteneimine
may easily be converted to phosphorylated tetrazoles and triazoles.
The concept of “ideal synthesis” covers issues of low costs,
good yields, environmental acceptability and easy perfor-
Scheme 1. Passerini/Phospha-Brook Sequence
mance of a synthetic process.1 The development of new
solvent-free, rapid sequences that result in versatile structures
is also an important step on the way to the “ideal synthesis”.
Multiple component reactions (MCRs) fulfill some of these
aims as they lead in a single step to complex structures that
can be further transformed in post condensation reactions.
In the field of multiple component reactions, we recently
disclosed a new 3-component Passerini reaction using acyl
phosphonates as formal aldehyde partners.2 The resulting
phosphonates were directly treated with LiOH to form
R-amido-phosphates in a phospha-Brook type reaction
(Scheme 1).
is generally associated with their interaction with carbonyl
derivatives as disclosed in the Passerini and Ugi reactions.3
First published by Nef,4 the acyl chloride-isocyanide con-
densation has been less studied. It gives imidoyl chloride
intermediates that can be hydrolyzed or trapped to form
various cyclic adducts.5 Acyl bromides6 and highly electro-
philic carboxylic derivatives such as trifluoroacetic anhy-
Starting from the same three components (isocyanides, acyl
chlorides and phosphites), we envisioned that the scope of
this sequence could be extended by altering the order of
addition of the reactants. The synthetic interest of isocyanides
(4) Nef, J. U. Liebigs Ann. Chem. 1892, 270, 267.
(5) (a) Ugi, I.; Fetzer, U. Chem. Ber. 1961, 94, 1116–1121. (b) Westling,
M.; Smith, R.; Livinghouse, T. J. Org. Chem. 1986, 51, 1159–1165. (c)
Lee, C. H.; Westling, M.; Livinghouse, T.; Williams, A. C. J. Am. Chem.
Soc. 1992, 114, 4089–4095. (d) Livinghouse, T. Tetrahedron 1999, 55,
9947–9978. (e) Van Wangenen, B. C.; Cardenilla, J. H. Tetrahedron Lett.
1989, 30, 3605–3608. (f) Adlington, R. M.; Barrett, A. G. M. Tetrahedron
1981, 37, 3935–3942. (g) Chen, J. J.; Deshpande, S. V. Tetrahedron Lett.
2003, 44, 8873–8876.
(1) Wender, P. A.; Handy, S. T.; Wright, D. L. Chem. Ind. 1997, 765.
(2) Coffinier, D.; El Kaim, L.; Grimaud, L. Synlett 2008, 8, 1133–1136.
(3) For recent reviews, see: (a) Banfi, L.; Riva, R. Org. React. 2005,
65, 1–140. (b) Zhu, J. Eur. J. Org. Chem. 2003, 1133–1144. (c) Ugi, I.;
Werner, B.; Do¨mling, A. Molecules 2003, 8, 53–66. (d) Hulme, C.; Gore,
V. Curr. Med. Chem. 2003, 10, 51–80. (e) Bienayme´, H.; Hulme, C.; Oddon,
G.; Schmitt, P. Chem.-Eur. J. 2000, 6, 3321–3329. (f) Do¨mling, A.; Ugi,
I. Angew. Chem., Int. Ed. 2000, 39, 3168–3210. (g) Do¨mling, A. Chem.
ReV. 2006, 106, 17–89.
(6) Westling, M.; Livinghouse, T. Tetrahedron Lett. 1985, 26, 5389–
5392.
10.1021/ol9004432 CCC: $40.75
Published on Web 03/25/2009
2009 American Chemical Society

dride7 were shown to be more efficient than the correspond-
ing chlorides.
Table 1. Isocyanide-Nef-Perkow Sequence Resulting to
Keteneimines
To test the behavior of phosphites with R-keto imidoyl
chlorides, cyclohexyl isocyanide was condensed with para-
fluorobenzoyl chloride in a solvent-free Isocyanide-Nef
reaction. When the corresponding imidoyl chloride, formed
in 1 h at 60 °C, was treated with trimethyl phosphite, the
new keteneimine 1a was formed in a 68% yield after 5 min
at room temperature (Scheme 2).
product
(yield %)a
entry
R1
R2
R3
1
2
3
4
5
6
7
8
p-F-Ph
′′
′′
′′
Ph
′′
m-Me-Ph
COOEt
Cy
′′
′′
(CH2)2Arb
Cy
′′
′′
′′
(CH2)2Arb
t-Bu
(CH2)2OAllyl
Me
Et
i-Pr
′′
Me
i-Pr
′′
′′
′′
′′
Et
1a (68)
1b (59)
1c (75)
1d (62)
1e (41)
1f (64)
1g (59)
1h (100)
1i (88)
1j (100)
1k (54)
Scheme 2. Addition of Phosphites on Imidoyl Chlorides
9
10
11
′′
′′
The formation of this keteneimine may be explained by a
Perkow reaction8 of the Isocyanide-Nef adduct behaving as
an R-halocarbonyl compound.9,10 Different acyl chlorides,
isocyanides and phosphites behave similarly as shown in
Table 1. Simple aliphatic acyl chlorides (propionyl, hydro-
cinnamoyl) failed to undergo this sequence. When reacted
with cyclohexylisocyanide, these acyl chlorides are quanti-
tatively converted into imidoyl chlorides, but the following
step does not give any adduct with phosphites at room
temperature. Raising the temperature leads to the degradation
of the Isocyanide-Nef adducts. Aromatic acyl chlorides
(Table 1, entries 1-7) give the desired keteneimines (1a-1g)
in moderate to good isolated yields. tert-Butyl isocyanide
was only efficiently coupled with ethyl oxalyl chloride (Table
1, entry 10), reaction with aromatic acyl chlorides failed to
give Isocyanide-Nef adducts in our hands. Benzylic isocya-
nides failed to undergo this sequence as the Isocyanide-Nef-
adducts decomposed under these conditions. With the more
reactive ethyl or methyl oxalyl chloride (Table 1, entries
8-11), both steps are efficiently performed within 5 min at
room temperature.
COOMe
a Isolated yields. b Ar ) 3,4-dimethoxyphenyl.
and ethyl ones are probably associated to the increased
stability toward hydrolysis of the bulkier and less polar
resulting keteneimine. The direct hydrolysis of the crude
mixture can be performed using TFA at room temperature;
1i was thus converted to the corresponding amidophosphate
in a 69% isolated yield over three steps. This amidophosphate
is similar to the products obtained by the Arbuzov/Passerini/
saponification/phospha-Brook sequence as disclosed in our
previous study (Scheme 1).2
The keteneimine formation from isocyanides has already
been disclosed and usually involves isocyanide addition to
carbenoid intermediates. Besides few studies involving
couplings with metal-free carbenes12 most studies on kete-
neimine formation from isocyanides have been reported with
Fisher-type carbene complexes.13 We have thus performed
here a formal addition of an O-phosphoryl substituted
carbene onto an isocyanide without any assistance of a metal.
The synthetic scope of this new reaction is highly increased
by the potential of the postcondensations involving ketene-
imines. Besides the obvious hydrolysis, more interesting
heterocycle formations could be reached using these kete-
neimines as reactive intermediates. For instance, under
Keteneimines are usually very sensitive to nucleophilic
attacks and have to be generated in situ.11 The presence of
an electron-donating phosphate group makes these particular
keteneimines less prone to hydrolysis, allowing them to be
purified under a flash column on silica gel. The higher yields
obtained with isopropyl substituted phosphites over methyl
(12) (a) Ciganek, E. J. Org. Chem. 1970, 35, 862. (b) Halleux, A. Angew.
Chem. 1964, 76, 889. (c) Boyer, J. H.; Beverung, W. J. Chem. Soc., Chem.
Commun. 1969, 1377. (d) Green, J. A.; Singer, L. A. Tetrahedron Lett.
1969, 5093. (e) Obata, N.; Mizumo, H.; Koitabashi, T.; Takizawa, T. Bull.
Chem. Soc. Jpn. 1975, 48, 2287.
(7) El Kaim, L.; Pinot-Pe´rigord, E. Tetrahedron 1998, 54, 3799–3806
(8) Perkow, W.; Ullerich, K.; Meyer, F. Naturwissenschaften 1952, 39,
353; Chem. Abstracts, 1953, 47, 8248.
.
.
(9) For review on the Perkow reaction, see: (a) Lichtenhalter, F. W.
Chem. ReV. 1961, 61, 607–649. (b) Krauch, H.; Kunz, W. Reaktionen der
organischen Chemie, 6th ed.; Kunz, W., Nonnenmacher, E., Eds.; Hu¨thig
Verlag: Heidelberg, 1997; pp 634-636, and the literature therein.
(10) For some recent Perkow-type reactions, see: (a) Waszkuc, W.;
Janecki, T. Org. Biomol. Chem. 2003, 1, 2966–2972. (b) Tarasenko, K. V.;
Gerus, I. I.; Kukhar, V. P. J. Fluorine Chem. 2007, 128, 1264–1270. (c)
Coutrot, P.; Dumarc¸ay, S.; Finance, C.; Tabayaoui, M.; Tabayaoui, B.;
Grison, C. Bioorg. Med. Chem. Lett. 1999, 9, 942–952. (d) Paleta, O.;
Pomeisl, K.; Kafka, S.; Klasek, A.; Kubelka, V. Beilstein J. Org. Chem.
(13) For a review on keteneimine complexes from carbene complexes
and isocyanides see: Aumann, R. Angew. Chem., Int. Ed. Engl. 1988, 27,
1456–1467.
(14) (a) Yu, K. L.; Johnson, R. L. J. Org. Chem. 1987, 52, 2051–2059.
(b) Zabrocki, J.; Smith, D.; Dunbar, J. B., Jr.; Iijima, H.; Marshall, G. R.
J. Am. Chem. Soc. 1988, 110, 5875–5880. (c) Zabrocki, J.; Dunbar, J. B.,
Jr.; Marshall, K. W.; Toth, M. V.; Marshall, G. R. J. Org. Chem. 1992, 57,
202–209. (d) Nelson, D. W.; Gregg, R. J.; Kort, M. E.; Perez-Medrano,
A.; Voight, E. A.; Wang, Y.; Grayson, G.; Namovic, M. T.; Donnelly-
Roberts, D. L.; Niforatos, W.; Honore, P.; Jarvis, M. F.; Faltynek, C. R.;
Carroll, W. A. J. Med. Chem. 2006, 49, 3659–3666.
2005, 1, 17
.
(11) Dondoni, A. J. Org. Chem. 1982, 47, 3998–4000.
1826
Org. Lett., Vol. 11, No. 8, 2009

addition of trimethylsilyl azide in tert-butanol, these kete-
neimines give phosphorylated tetrazoles in fair to good yields
(Table 2, entries 1-4). Considering the biological signifi-
cance of tetrazoles,14 the phosphorylated moiety of these
previously unknown tetrazoles will probably increase their
biological interest. Alternatively, [3 + 2] cycloadditions with
trimethylsilyl diazomethane may be achieved with the
formation of new triazoles in moderate to good yields (Table
2, entries 5-8). As far as we know, none of these ꢀ-phos-
phato- tetrazoles or triazoles have already been described.
In summary, we have developed a new, solvent-free, two-
step three-component synthesis of keteneimines. The diver-
sity offered by this process is further enhanced by the
electrophilic nature of keteneimines which allows further
additions of nucleophilic components. This was demonstrated
by the preparation of small libraries of O-phosphorylated
triazoles and tetrazoles.
Table 2. Triazoles and Tetrazoles Formation from Keteneimines
entry
keteneimine
adduct
yield (%)a
1
2
3
4
5
6
7
8
1c
1h
1g
1j
1h
1d
1g
1k
2a (X ) N)
2b (X ) N)
2c (X ) N)
2d (X ) N)
2e (X ) CH)
2f (X ) CH)
2g (X ) CH)
2h (X ) CH)
58
73
61
55
79
50
52
57
Acknowledgment. Financial support was provided by
Glaxo Smith Kline, CNRS and ENSTA. We thank Dr Julien
Sanc¸on from GSK-Les Ulis for the fruitful discussions.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
a Isolated yields.
OL9004432
Org. Lett., Vol. 11, No. 8, 2009
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