New ortho-quinone methide formation: Application to three-component coupling of isocyanides, aldehydes and phenols

Article abstract of DOI:10.1039/b610229h

A new three - component formation method of heterocyclic scaffolds based on a one - pot process from simple phenols is reported. The important step involved in the process is the formation of ortho - quinon ( o - quinon ) methide under alkyative condition

Full text of DOI:10.1039/b610229h

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New ortho-quinone methide formation: application to three-component
coupling of isocyanides, aldehydes and phenols
Laurent El Ka¨ım,* Laurence Grimaud* and Julie Oble
Received 17th July 2006, Accepted 27th July 2006
First published as an Advance Article on the web 8th August 2006
DOI: 10.1039/b610229h
Herein, we wish to report a new three-component formation
of heterocyclic scaffolds based on a one-pot process from
simple phenols. The key step of this procedure involves an
ortho-quinone methide formation from Mannich adducts
under alkylative conditions. The transient o-quinone methide
has been trapped in situ with indole and diketone using
lithium perchlorate as catalyst. The interest of this proce-
dure has been furthermore demonstrated by a new three-
component aminobenzofuran formation from phenols,
aldehydes and isocyanides.
behaves similarly to form the new indoles 5a and 5b in moderate
to good overall yields (Scheme 1).
ortho-Quinone methides, highly reactive species, are key inter-
mediates in many biological systems as well as natural product
synthesis.1,2 These compounds are mainly involved in Michael-
type additions with nucleophiles as well as [4 + 2] cycloadditions
with a wide range of dienophiles.1 Fast dimerization of o-quinone
methides has, however, constrained the synthetic potential of these
ephemeral species, which must be generated and trapped in situ.
The ortho aldolisation of phenols with aldehydes followed by Lewis
acid-assisted water elimination is probably the most convenient
path available up to now.3 It suffers from the poor reactivity
of electron withdrawing group-substituted phenols and is often
limited to the reaction of formaldehyde. Herein, we wish to report
a convenient formation of o-quinone methides from Mannich
adducts of phenols with N-benzylpiperazine and application to
new couplings with isocyanides.
The Mannich addition of phenols 1a and 1b has been performed
with stoichiometric amounts of aldehydes 2a and 2b, either in
refluxing toluene (1a) or neat at 140 ◦C (1b, which was surprisingly
unreactive in toluene) (Scheme 1). The intermediate Mannich
adducts 3a and 3b were not isolated but directly treated in
refluxing toluene with 1,2-dibromoethane (2 equiv.) and 5,5-
dimethylcyclohexane-1,3-dione (2 equiv.) to trap the expected
o-quinone methide. However, no reaction occurred under these
conditions. Being aware of the catalytic effect of lithium per-
chlorate in [4 + 2] cycloadditions of o-quinone methides with
non activated alkenes,4 we surmised that the lithium salt could
catalyse both generation and trapping of the o-quinone methide.
Indeed, we were pleased to find that in the presence of lithium
perchlorate (10 mol%) the alkylation–elimination–nucleophilic
addition sequence proceeds efficiently in toluene to afford products
4a and 4b in 40 and 51% yields, respectively. 1-Methyl-1H-indole
Scheme 1
If several Mannich-type couplings of aldehydes with phenols
have been already described in the presence of secondary and
primary amines,5 the synthetic potential of these Mannich bases
for o-quinone methide formation has remained largely underesti-
mated in relation to the high temperature needed for the thermal
elimination of the amine. If the problematic reverse addition of the
amine can be addressed by the choice of low boiling point amines,
it often implies the use of sealed tube conditions in the Mannich
coupling.6
The formation of quaternary ammonium salts by alkylation
of the Mannich adducts is a way to induce easier removal
of the amino residue and, therefore, trapping of the transient
electrophilic species at lower temperature.7 In this matter, the
choice of the piperazine core presents interesting features:
the two tertiary amines have different nucleophilic behaviors due
to potential intramolecular hydrogen bonding with the hydroxy
group; easy formation of dialkylated ammonium salts with 1,2-
dibromoethane can thus be observed on these Mannich adducts.
Furthermore, elimination of the piperazine as an insoluble am-
monium salt makes the process irreversible. We recently disclosed
a new Mannich coupling of hydrazones with N-benzylpiperazine
followed by a similar alkylative elimination of the piperazine under
dibromoethane treatment.8 The intermediate azoalkenes were then
trapped with nucleophiles such as enamines or isocyanides to give
new access to pyrazole and pyridazine derivatives. The new results
Laboratoire de Chimie Organique, UMR CNRS 7652, Ecole Nationale
Supe´rieure des Techniques Avance´es, 32, Bd Victor, 75015, Paris, France.
E-mail: laurent.elkaim@ensta.fr; Fax: +33 (0)145 528322; Tel: +33 (0)145
525537
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obtained with phenols show that this strategy can now be applied
to projects of broader synthetic concern.
addition of isocyanides with transient o-quinone methide bring a
further demonstration of the synthetic interest of isocyanide based
multicomponent reactions.
The [4 + 1] cycloadditions of isocyanides with a,b-unsaturated
carbonyl derivatives have been studied by different research
groups.9 Reported formations of aminofurans10 deal mainly either
with simple commercial a,b-unsaturated ketones or stable deriva-
tives formed under aldol or Knoevenagel type condensations. To
our knowledge, similar additions to simple o-quinone methides
have not been yet documented, we were thus eager to examine
whether our procedure could be applied to [4 + 1] cycloadditions
of isocyanides with these instable intermediates (Scheme 2).
Notes and references
† Typical procedure for the one-pot synthesis of aminobenzofuran 6a:
to a solution 2 M of methyl p-hydroxybenzoate in toluene was added
benzaldehyde (1 equiv.) and N-benzylpiperazine (1 equiv.). The resulting
mixture was stirred at 110 ◦C under an inert atmosphere for 3 d, and to this
crude was then added 1,2-dibromoethane (2 equiv.), cyclohexyl isocyanide
(2 equiv.), toluene (1 M) and a catalytic amount (10 mol%) of LiClO4.
The reaction was stirred at 110 ◦C for 6 h and concentrated in vacuo. The
residue was then purified by flash chromatography on silica gel to give
1
41% of the desired adduct. H NMR (CDCl3, 400 MHz) d 8.16 (d, 1H,
J = 1.8 Hz), 7.81 (dd, 1H, J = 7.8,1.7 Hz), 7.66–7.56 (m, 4H), 7.30–7.20
(m, 2H), 4.44 (d, 1H, J = 8.3 Hz), 3.93 (s, 3H), 3.75–3.61 (m, 1H), 2.14–
2.05 (m, 2H), 1.84–1.73 (m, 2H), 1.72–1.58 (m, 2H), 1.49–1.14 (m, 4H).
13C NMR (CDCl3, 100.6 MHz) d 168.1, 156.2, 153.2, 133.5, 130.9, 129.9,
127.9, 125.5, 125.5, 122.6, 118.7, 109.8, 93.1, 53.4, 53.1, 34.7, 26.0, 25.4.
MS (DI, CI NH3) m/z 365. I.R. (thin film) 3364, 2924, 2856, 1762, 1729,
1535, 1219 cm−1. HRMS. Calcd for C22H23NO3: 3491678; found: 3491693.
Scheme 2
1 For a recent review, see: R. W. van de Water and T. R. R. Pettus,
Tetrahedron, 2002, 58, 5367–5405.
We first examined this coupling with isolated Mannich adduct
3d as starting material. When treated with 1,2-dibromoethane
(2 equiv.), cyclohexyl isocyanide (2 equiv.) and lithium perchlorate
(10 mol%) in toluene at 110 ◦C, the desired aminobenzofuran 6a
was obtained in 47% yields (Table 1, entry 1).†
Various Mannich adducts behaved similarly with different
isocyanides as shown in Table 1. The aminobenzofuran formation
could also be obtained in a one-pot procedure directly from
the aldehyde and phenol (entries 1, 2 and 6) without significant
decrease in yields.
Mannich adduct 3h was prepared in an attempt to observe
intramolecular [4 + 2] cycloaddition. Surprisingly, 3h failed to
react when treated with dibromoethane and lithium perchlorate,
even though this latter has been claimed to promote inter-
molecular coupling of o-quinone methide with simple alkenes
at room temperature.4 When cyclohexyl isocyanide is added, the
aminobenzufuran 6g is, however, obtained in 53% yields (Table 1,
entry 8). Aminobenzofuran was still formed with highly hindered
tert-octyl isocyanide without any trace of [4 + 2] cycloaddition
product (Table 1, entry 9).
2 For example, see: P. E. Harrington, I. A. Stergiades, J. Erickson, A.
Makriyannis and M. A. Tius, J. Org. Chem., 2000, 65, 6576–6582; R.
Rodriguez, R. M. Adlington, J. E. Moses, A. Cowley and J. E. Baldwin,
Org. Lett., 2004, 6, 3617–3619.
3 S. M. Stokes, F. Ding, P. L. Smith, J. M. Keane, M. E. Kopach, R. Jervis,
M. Sabat and W. D. Harman, Organometallics, 2003, 22, 4170–4171.
4 K. Chiba, T. Hirano, Y. Kitano and M. Tada, Chem. Commun., 1999,
691–692.
5 S. Tramontini, Synthesis, 1973, 703–775; A. Sharifi, M. Mirzaei and
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J. Zhu, Org. Lett., 2005, 7, 1641–1644.
6 M. Gerster and R. Wicki, Synthesis, 2004, 249–254.
7 P. D. Gardner, H. S. Rafsanjani and L. Rand, J. Am. Chem. Soc., 1959,
81, 3364–3367; E. Breuer and D. Melumad, Tetrahedron Lett., 1969,
10, 1875–1877.
8 V. Atlan, H. Bienayme´, L. El. Ka¨ım and A. Majee, Chem. Commun.,
2000, 1585–1586; V. Atlan, L. El. Ka¨ım, L. Grimaud, A. Majee and
N. K. Nirmal, SYNLETT, 2002, 2, 352.
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2295.
In conclusion, we have settled a new general efficient three-
component coupling of phenols with aldehydes and various
nucleophiles. The application of this process to formal [4 + 1] cyclo-
10 For a related aminofuran formation from isocyanides and salicaldehyde
see: R. Bossio, S. Marcaccini, P. Paoli, R. Pepino and C. Polo, Synthesis,
1991, 999–1000.
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