"isocyanide-free" Ugi reactions

Article abstract of DOI:10.1039/b908541f

High-yielding Ugi reactions have been carried out with in situ-prepared isocyanides, derived from the reaction of bromide derivatives with silver and potassium cyanide, thus alleviating the burden of the preparation, purification and subsequent use of iso

Full text of DOI:10.1039/b908541f

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www.rsc.org/obc | Organic & Biomolecular Chemistry
“Isocyanide-free” Ugi reactions†
Laurent El Ka¨ım,* Laurence Grimaud* and Aure´lie Schiltz
Received 30th April 2009, Accepted 5th June 2009
First published as an Advance Article on the web 17th June 2009
DOI: 10.1039/b908541f
High-yielding Ugi reactions have been carried out with in situ-
prepared isocyanides, derived from the reaction of bromide
derivatives with silver and potassium cyanide, thus alleviating
the burden of the preparation, purification and subsequent
use of isocyanides in multicomponent reactions.
and co-workers, based on the Scho¨llkopf reaction, and subsequent
Ugi coupling, but the starting point of the reaction remains an
isocyanide.8 We wish to report herein the first (to the best of
our knowledge) four-component Ugi reaction using a halogenated
compound as an isocyanide substitute.
The alkylation reaction was performed in acetonitrile at 80 ◦C,
using a stoichiometric mixture of silver cyanide and potassium
cyanide in the presence of a catalytic amount of an ammonium
salt (20% of triethylbenzyl ammonium chloride—TEBAC). We
presume that the reactive metal species might be the complex
Considered as the most famous coupling among multicomponent
reactions, the Ugi reaction1 has seduced many organic chemists,
especially in the middle of the 1990s, when the demand for
molecular diversity and for huge libraries of pharmaceutical
scaffolds grew considerably. For the scientists who are unfamiliar
with this chemistry, the main issue rests with the isocyanide
synthesis, because of their (wrongly) suspected toxicity and the
strongly unpleasant smell associated with the most representative
ones.
Above all, very few compounds are commercially available, and
among the various preparative methods reported in the literature2,
the preferred processes are either the carbylamine reaction3, or the
dehydration of formamides.4 Both syntheses are impaired by the
use of chlorinated agents in excess and by the harsh experimental
conditions that are not always compatible with functionalized
substrates.
Inspired by Songstad and co-workers’ modified procedure5 of
the Lieke synthesis of isocyanides6, we have recently devised a
process that involves the reaction of bromide derivatives with silver
cyanide and potassium cyanide in the same pot, thereby allowing
the formation of several benzylic and allylic isocyanides. We
showed that these conditions were compatible with the Ugi–Smiles
coupling and we have reported the first one-pot four-component
reaction without any manipulation of isocyanide (Scheme 1).7
-
+
Ag(CN)2 NBn(Et)3 . According to the previous work of the
Songstad group, the counter ion should be a bulky ammonium salt
to perform the bromide exchange; this explains the beneficial effect
of the phase-transfer agent. However, in contrast to Songstad’s
work, we have been able to reduce the amount of such a salt in the
medium from a stoichiometric to a catalytic amount of 20 mol%,
preventing the formation of a slurry that would slow down the
subsequent reaction.
The brominated compound 1a in solution in acetonitrile
was treated with stoichiometric amounts of silver cyanide and
potassium cyanide in the presence of 20 mol% of TEBAC. The
resulting mixture was next heated at 80 ◦C until completion of
1
the reaction (which could be checked by H NMR analysis of
an aliquot). Allylamine, para-chlorobenzaldehyde and acetic acid
were then successively added. We observed that an excess of the
reactants—imine and carboxylic acid—as well as preformation of
the imine noticeably increased the yields (Table 1).
However, quite surprisingly, when performed at room
temperature—the usual procedure for this reaction—the Ugi
coupling was not complete and isocyanide was still recovered
unreacted. Nevertheless, the reaction proceeded smoothly at 40 ◦C
in acetonitrile (2 M) for three days to provide the desired adduct
2a in 82% yield.
Table 1 Influence of the imine on the yield of the reaction
Scheme
1 One-pot sequence: isonitrile synthesis and Ugi–Smiles
reaction.
Considering the importance of the Ugi adducts towards organic
chemistry, we were eager to test the feasibility of the four-
component reaction using an in situ-generated isocyanide. An
in situ alkylation of isocyanide has been reported by Armstrong
entry
amount of imine
formation of imine
yield (%)
Laboratoire Chimie et Proce´de´s, Ecole Nationale Supe´rieure de Techniques
Avance´es, 32 Bd Victor, 75739 Paris Cedex 15, France. E-mail: laurent.
elkaim@ensta.fr, laurence.grimaud@ensta.fr; Fax: 0033145528322;
Tel: 0033145525537
1
2
3
4
1.2 equiv.
1.5 equiv.
1.5 equiv.
2.0 equiv.
in situ
in situ
preformed
preformed
11
50
57
82
† Electronic supplementary information (ESI) available: Experimental
details, 1H and 13C NMR spectra. See DOI: 10.1039/b908541f
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Table 2 Ugi reactions with in situ-prepared isocyanides
entry
1
R1
R2
R3
R4
product
yield (%)
82
p-tBuBn
p-ClPh
All
Me
2
3
p-tBuBn
p-tBuBn
iBu
p-ClBn
Me
84
44
p-ClPh
All
4
p-tBuBn
p-ClPh
All
i-Pr
48
5
6
7
Bn
Bn
Bn
p-ClPh
p-ClPh
iPr
All
Me
97
67
75
All
Furfuryl
8
9
Bn
iBu
iBu
iBu
p-ClBn
p-ClBn
p-ClBn
Me
Me
Me
96
64
60
o-BrBn
=
10
PhCH CH–CH2
11
All
p-ClPh
All
Me
47
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The high yield and simple experimental protocol of this new
tandem process prompted us to explore this reaction more widely
(Table 2).‡ Various benzyl isocyanides were synthesized and
coupled in situ with different aliphatic or aromatic aldehydes and
amines (Table 2, entries 1–9). In all the cases, the Ugi adducts
were isolated in fair to excellent yields. In order to compare the
efficiency of the sequence, we prepared the compound 2g already
reported by Pirrung and Sarma9, and obtained a similar yield (75%
instead of 85% yield) (Table 2, entry 7).
(CN). dH (400 MHz; CDCl3) 1.31 (9H, s, Me3), 2.10 (3H, s, COMe), 4.05–
=
3.95 (2H, m, NCH2CH CH2), 4.39 (1H, dd, J 14.7 and 5.2, ArCH2), 4.47
=
(1H, dd, J 14.7 and 5.2, ArCH2), 4.98 (1H, d, J 17.4, NCH2CH CH2),
4.99 (1H, d, J 11.4, NCH2CH CH2), 5.48–5.38 (1H, m, NCH2CH=CH2),
=
6.13 (1H, s, pClArCH), 6.57 (1H, br t, J 5.2, NH), 7.19 (2H, d, J 8.1,
2H, HAr), 7.36–7.28 (6H, m, HAr). dC (100.6 MHz; CDCl3) 22.4 (COMe),
=
31.7 (Me3), 34.9 (CMe3), 43.7 (CArCH2), 49.8 (NCH2CH CH2), 60.8
=
(pClArCH), 117.1 (NCH2CH CH2), 126.0 (CHAr), 127.9 (CHAr), 129.3
=
(CHAr), 131.4 (CHAr), 134.2 (NCH2CH CH2 and CAr), 134.9 (CArCl),
135.1 (CArCH2), 150.9 (CArtBu), 169.7 (NHCO), 172.7 (COCH3). HRMS
(EI) Found: 412.1900, Calc. for C24H29ClN2O2: 412.1918.
When taking into account the yield of the preparation of the
isocyanide, the interest of such a process becomes obvious. Even if
allyl isocyanides seem to be less efficient in this sequence (Table 2,
entries 10 and 11), this procedure constitutes an attractive way of
forming the corresponding adducts, considering the high volatility
and strong odour of allyl isocyanide.
To conclude, the burden of isocyanide synthesis has been consid-
erably lightened with the disclosure of this new strategy featuring
their synthesis from bromide derivatives, silver and potassium
cyanide, followed by their in situ use in a multicomponent reaction.
This approach has been successfully applied to the Ugi reaction,
allowing us to report herein an efficient and time-saving method for
preparing peptidic derivatives bearing an allyl or a benzyl amide.
This sequence avoids the isolation of volatile and foul-smelling
intermediates, providing the desired adduct in yields comparable
to those obtained using classical conditions. Further studies to
extend such easy-to-handle methods are still in progress in our
laboratory.
1 (a) I. Ugi, R. Meyr, U. Fetzer and C. Steinbru¨ckner, Angew. Chem.,
1959, 71, 386; (b) I. Ugi and C. Steinbru¨ckner, Angew. Chem., 1960,
72, 267–268. For recent reviews, see: A. Do¨mling and I. Ugi, Angew.
Chem., Int. Ed., 2000, 39, 3168–3210; H. Bienayme´, C. Hulme, G.
Oddon and P. Schmitt, Chem.–Eur. J., 2000, 6, 3321–3329; I. Ugi, B.
Werner and A. Do¨mling, Molecules, 2003, 8, 53–66; A. Do¨mling, Curr.
Opin. Chem. Bio., 2002, 6, 306–313; “Multicomponent reactions”, J. Zhu,
H. Bienayme´, Eds Wiley-VCH, Weinheim, 2005; A. Do¨mling, Chem.
Rev., 2006, 106, 17–89.
2 I. A. O’Neil, in Comprehensive Organic Functional Group Transformaion,
Vol 3, (Eds.: A. R. Katrizky, D. Meth-Cohn, C. W. Rees,), Pergamon,
Oxford, 1995, pp. 693–726. P. Hoffman, G. Gokel, D. Marquading, I.
Ugi, in Isonitrile Chemistry (Ed.: I. Ugi,), Academic Press, New York,
1971, p. 9; M. P. Periasamy and H. M. Walborsky, Organic preparations
and procedures int., 1979, 11, 293–311 and references cited herein.;
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I. Hoppe, Justus Liebigs Ann. Chem., 1975, 533–546; S. E. Whitney
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J. Am. Chem. Soc., 2006, 128, 11772–11773; P. G. Gassman and T. L.
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Acknowledgements
3 A. W. Hoffmann, Ann. Chem. Pharm., 1867, 144, 114–120; W. P. Weber,
G. W. Gokel and I. Ugi, Angew. Chem., Int. Ed. Engl., 1972, 11, 530–531;
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VI, 232–235.
A.S. thanks the De´le´gation Ge´ne´rale de l’Armement for a
fellowship. Financial support was provided by the ENSTA.
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Notes and references
‡ Typical procedure for 2b: To a 2 M solution of para-tert-butylbenzyl
bromide (184 mL, 1.0 mmol) in acetonitrile were added silver cyanide
(134 mg, 1.0 mmol), potassium cyanide (65 mg, 1.0 mmol) and TEBAC
(46 mg, 0.20 mmol). The mixture was then heated at 80 ◦C for one day.
Meanwhile, the imine was preformed by stirring para-chlorobenzaldehyde
(280 mg, 2.0 mmol) and allylamine (150 mL, 2.0 mmol) at 40 ◦C for 2 hours.
The imine and the acetic acid (120 mL, 2.0 mmol) were added to the mixture
and left to react at 40 ◦C for 3 days. The reaction was quenched by the
addition of water and then extracted with dichloromethane (3 ¥ 50 mL).
The combined extracts were dried and evaporated under reduced pressure
to leave a yellow oil, which was purified by flash column chromatography
on silica gel using a 4:6 mixture of petroleum ether and diethyl ether as
eluent to give the Ugi adduct (340 mg, 85%) as a yellow solid. m.p. 159–
160 ◦C; nmax/cm-1 (thin film) 3272 (NH), 3054 (conj. CH), 2964 (CH), 1674
(CO), 1626 (CO), 1515 (conj. CC), 1491 (conj. CC), 1411 (conj. CC), 1265
7 L. El Ka¨ım, L. Grimaud and A. Schiltz, Synlett, 2009, 9, 1401–1404.
8 P. A. Tempest, S. D. Brown and R. W. Armstrong, Angew. Chem., 1996,
108, 689–691; P. A. Tempest, S. D. Brown and R. W. Armstrong, Angew.
Chem., Int. Ed. Engl., 1996, 35, 640–642.
9 M. C. Pirrung and K. D. Sarma, Tetrahedron, 2005, 61, 11456–11472.
3026 | Org. Biomol. Chem., 2009, 7, 3024–3026
This journal is
The Royal Society of Chemistry 2009
©