Studies on the interaction of isocyanides with imines: Reaction scope and mechanistic variations

Article abstract of DOI:10.3762/bjoc.10.3

The interaction of imines with isocyanides has been studied. The main product results from a sequential process involving the attack of two units of isocyanide, under Lewis acid catalysis, upon the carbon-nitrogen double bond of the imine to form the 4-me

Full text of DOI:10.3762/bjoc.10.3

Studies on the interaction of isocyanides with
imines: reaction scope and mechanistic variations
Ouldouz Ghashghaei1, Consiglia Annamaria Manna1,
Esther Vicente-García1, Marc Revés1 and Rodolfo Lavilla*1,2
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 12–17.
1Barcelona Science Park, University of Barcelona, Baldiri Reixac
doi:10.3762/bjoc.10.3
10–12, 08028 Barcelona, Spain and 2Laboratory of Organic
Chemistry, Faculty of Pharmacy, University of Barcelona, Av. Joan
XXIII sn, 08028 Barcelona, Spain
Received: 30 September 2013
Accepted: 29 November 2013
Published: 06 January 2014
Email:
Rodolfo Lavilla* - rlavilla@pcb.ub.es
This article is part of the Thematic Series "Multicomponent reactions II".
Guest Editor: T. J. J. Müller
*
Corresponding author
Keywords:
© 2014 Ghashghaei et al; licensee Beilstein-Institut.
License and terms: see end of document.
azetidines; heterocycles; imines; isocyanides; multicomponent
reactions
Abstract
The interaction of imines with isocyanides has been studied. The main product results from a sequential process involving the
attack of two units of isocyanide, under Lewis acid catalysis, upon the carbon–nitrogen double bond of the imine to form the
4
-membered ring system. The scope of the reaction regarding the imine and isocyanide ranges has been determined, and also some
mechanistic variations and structural features have been described.
Introduction
The interaction of imines with isocyanides is mainly focused on imine, leads to α-aminoamidines, resulting from the trapping of
to the well-known Ugi multicomponent reaction (MCR) [1]. the nitrilium cation by the remaining amine [5-8]. Taking into
This fundamental process features the participation of a account the intrinsic interest in the azetidine scaffold in
carboxylic acid group which attacks the intermediate nitrilium medicinal chemistry [9], we decided to study in detail the for-
ion thus leading, after the Mumm rearrangement, to mation of bis(imino)azetidines 3 from the interaction of imines
α-amidoamides. However, the direct reaction of imines and 1 and isocyanides 2 (Scheme 1), including the scope of the reac-
isocyanides has been considerably less studied and, in the tion and mechanistic features of this interesting ABB’ process
absence of a carboxylate, the mechanistic outcome is consider- [10].
ably modified [2]. A relevant precedent was described by
Results and Discussion
Deyrup in the late sixties, demonstrating the double incorpor-
ation of an isocyanide moiety to an imine [3,4]. Interestingly, Reaction scope
the 3CR between a carbonyl, an amine and an isocyanide, In this section we analyze the reaction conditions, the structural
taking place through the intermediacy of the in situ generated features of the products and the scope of the reactants.
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Beilstein J. Org. Chem. 2014, 10, 12–17.
Structural elucidation
Although we could confirm the constitution of the azetidine 3a
by spectroscopic methods (NMR, MS), the stereochemistry of
the C=N bonds present in the structure remained unsolved.
Furthermore, no conclusive nOe’s were observed to assign
these stereogenic centers, and there were no reports in the litera-
ture regarding this point. A monocrystal of the bis(imino)azeti-
dine 3a was subjected to X-ray diffraction analysis and the solid
state structure is depicted in Figure 1 [11].
Scheme 1: Azetidine formation from the interaction of imines with
isocyanides.
Reaction conditions
We began our studies with the experimental screening of the
solvents, catalysts and temperatures suitable for this transforma-
tion. In this respect, taking imine 1a (R1 = p-MeOC6H4;
R2 = p-ClC6H4) and isocyanide 2a (R3 = t-Bu), we tested the
standard reaction in THF, MeCN, and CH2Cl2 as solvents using
a variety of Lewis and Brønsted acid activating agents
(
20–100 mol %) including: InCl3, Sc(OTf)3, AuCl3, AgOTf,
GaCl3, NbCl5, camphorsulfonic acid, I2, Br2·SMe2 and
BF3·OEt2, at temperatures ranging from rt to 80 °C. The trans-
formations were tested under standard heating or microwave ir-
radiation, with reaction times lasting form 30 min to 48 h. The
imine 1a was generated in situ, using MS 4 Å, or previously
Figure 1: X-ray diffraction analysis of azetidine 3a.
prepared by condensation of the corresponding aldehyde and This result confirms the structural features associated to this
aniline. It was found that the best conditions were obtained scaffold, and also raises some questions on the origin of the
using BF3·Et2O as the activating agent in stoichiometric stereochemistry associated to the C=N moieties. First of all, the
amounts in THF, at rt for 24 hours or under MW irradiation for process can be explained by an attack of one isocyanide equiva-
3
0 min at 65 °C, allowing the formation of the expected azeti- lent to the Lewis acid (LA)-activated imine, leading to a first
dine 3a in 43% and 48%, respectively. Compounds 4 and 5 nitrilium intermediate (Scheme 3), then a subsequent attack
could not be detected (Scheme 2). When the process was run as would give raise to a second nitrilium ion [12-15], which is
a true MCR (mixing the amine, the aldehyde and two equiva- trapped by the nucleophilic nitrogen of the imine. This last step
lents of isocyanide 2a), the adduct 3a was produced in trace is formally a disfavoured nucleophilic 4-exo-dig process [16],
amounts and the main product was the α-amino-amidine 4, in although recent results and calculations show that it should be
good agreement with previous reports [5-8]. In a different feasible and some examples have been disclosed [17]. Interest-
experiment, the addition of a 9-fold excess of isocyanide 2a to ingly, the expected anti-addition mode towards the
the imine 1a under the usual conditions led to detection of carbon–nitrogen triple bonds should generate Z configurations
tris(imino)pyrrolidine 5 (9%) as the minor product, and azeti- [18,19], which are not observed in the solid-sate, thus
dine 3a as the major component (24%, Scheme 2).
suggesting isomerization processes affecting the C=N moieties,
Scheme 2: Reaction conditions.
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Beilstein J. Org. Chem. 2014, 10, 12–17.
Scheme 3: Stepwise mechanism for the formation of azetidine 3a.
likely mediated by acid-catalyzed prototropy or other tautomer- tions (Table 1, entries 5, 6 and 8). In general, imines containing
ization steps. Computational calculations (MMFF, AM1 and electron-rich N-aryl moieties showed higher reactivities, and we
BL3YP/6-31G* performed in a Spartan suite) suggest that the were not able to isolate azetidine adducts 3 from the reaction of
differences in the heat of formation among some geometrical arylimines containing strong electron-withdrawing groups at the
isomers are small. Furthermore, NMR spectra nearly always aniline moiety (p-CF3, p-F and p-COOEt), likely because of
display a single set of signals, thus discarding further isomeriza- their low conversions. However, the presence of such groups
tion events once the compounds are detected or isolated.
linked to the carbon of the imine did not seem to disturb their
reactivity (Table 1, entries 1–8). Interestingly, the reaction of
glyoxylate imine (Table 1, entry 9) with tert-butyl isocyanide
Reactant scope
Next, the scope of the reaction was investigated, and a variety led to the formation of minor amounts of the azetidine adduct 3i
of imines was subjected to the interaction with a range of (9%) whereas the α-aminoamide 7 (34%) was the major compo-
isocyanides under the optimized conditions to determine the nent. The formation of amidoamides has been reported in the
generality of the process and to detect possible restrictions. p-toluenesulfonic acid-catalyzed interaction of anilines, amines
Results are depicted in Table 1.
and isocyanides [8]. On the other hand, the reaction of the same
imine with cyclohexyl isocyanide gave azetidine 3j (34%) in a
The scan of isocyanides shows that their nucleophilicity plays a selective manner (Table 1, entry 10), without traces of the
determining role in the reactivity, since tert-butyl, cyclohexyl corresponding α-aminoamide. Different types of activated
and benzyl isocyanides (Table 1, entries 1–3, 5–12) show a rela- substrates displaying C=N bonds (N-sulfinylimines, oximes and
tively high conversion, whereas the aromatic isocyanide was hydrazones) were studied, but none of them reacted produc-
less reactive (entry 4) and the weaker nucleophiles TOSMIC tively with isocyanides under the described conditions. Finally,
and methyl isocyanoacetate were not productive (Table 1, the reaction with isatinimines led to the formation of the spiro-
entries 13 and 14) [20]. Additionally, with respect to imines, the azetidines 3k (14%) and 3l (28%, Table 1, entries 11 and 12).
reaction works well for substrates generated from aromatic Remarkably, in the former case an intramolecular cyclization of
aldehydes and anilines displaying o-, m- and p-substituents the nitrilium ion upon the electron rich p-methoxyphenyl group
(
Table 1, entries 1–7). Moreover, in one case the 3-aminoin- took place and led to the formation of the bis(imino)tetrahydro-
dole 6 was detected (27%), in agreement with a recent report quinoline 8 (17%, Table 1, entry 11).
Table 1, entry 5) [21].
(
Mechanistic analysis
N-Alkylimines seem to react appropriately (Table 1, entry 8). Taking into account the structural variety observed in this
Furthermore, we have observed some tert-butyl eliminations, family of reactions, a rational explanation is needed to under-
probably due to competing reactions under the acidic condi- stand the formation of such products. Here we describe a
14

Beilstein J. Org. Chem. 2014, 10, 12–17.
Table 1: Scope of the imine and isocyanide starting materials.
entry
R1
R2
R3
yield
1
2
3
4
5
6
7
8
9
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeC6H4
3-MeOC6H4
4-MeOC6H4
2-MeC6H4
n-C3H7
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
2-ClC6H4
4-ClC6H4
4-ClC6H4
EtOCO
t-Bu
3a (48%)
c-C6H11
Bn
3b (41%)a
3c (63%)a
4-MeOC6H4
t-Bu
3d (19%)b
3e (19%) + 6 (27%)
3f (12%) + 3f' (15%)
3g (31%)
t-Bu
t-Bu
t-Bu
3h' (32%)
4-MeOC6H4
4-MeOC6H4
t-Bu
3i (9%)a + 7 (34%)
3j (34%)a
10
EtOCO
c-C6H11
1
1
4-MeOC6H4
4-MeC6H4
t-Bu
t-Bu
3k (14%)b + 8 (17%)
12
3l (28%)
1
3
4
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
4-ClC6H4
Ts-CH2
–
–
1
MeO2C-CH2
aThe reaction was performed at rt. 20% of catalyst was used. bThe adduct could not be isolated in pure form.
simplified hypothesis based on the well-known nucleophilic further addition events and leading to the aminoamides 7 after
addition of isocyanides to Lewis acid-activated imines the final aqueous treatment.
(
Scheme 3). The first nitrilium intermediate can evolve through
a second addition and ring-closure to yield the azetidine adduct Furthermore, we have detected indole 6 arising from the
(Scheme 4, route i), or can also be trapped by water or amine/ cyclization of electron-rich aromatic rings linked to the imine
3
imine nucleophiles leading to α-aminoamides 7 and α-amino- nitrogen upon the electrophilic nitrilium intermediate, in agree-
amidines 4, respectively (Scheme 4, route ii). The formation of ment with a Sorensen report (Scheme 4, route iii) [21]. Finally,
aminoamide 7 was restricted to the use of glyoxylate imines, the imino-nitrilium cation can be trapped by an aromatic ring
and happens only with tert-butyl isocyanide, but not with cyclo- when using isatin imines, leading to bis(imino)tetrahydroquino-
hexyl isocyanide. On the other hand, the aminoamidines 4, the line 8, (Scheme 4, route iv). In a reaction using a large
standard adducts from the amine–aldehyde–isocyanide 3CR isocyanide excess, a triple insertion of the isocyanide moiety
were observed in some occasions [5-7] under our conditions has been observed, the adduct being the tris(imino)pyrrolidine 5
presumably by attack of the unreacted imine upon the nitrilium (Scheme 4, route v).
cation. These facts suggest that either a good nucleophile
(
amines, imines) may act intermolecularly to undergo fast add- Conclusion
ition to this intermediate or, when an alkyl carboxylate group is As a summary, we have described structural and mechanistic
present it may stabilize the nitrilium intermediate precluding features for the bis(imino)azetidines arising from the
15

Beilstein J. Org. Chem. 2014, 10, 12–17.
Scheme 4: Manifold reaction mechanism.
imine–isocyanide interaction, finding that the process involves a Acknowledgements
sequential double isocyanide incorporation into the C=N bond. This work was supported by DGICYT (Spain, project BQU-
The final step is a nucleophilic 4-exo-dig cyclization, and the CTQ2012-30930), and Generalitat de Catalunya (project 2009
anti addition modes likely lead to less stable stereoisomers SGR 1024). C.M. thanks the Leonardo da Vinci Project
which spontaneously isomerize to the observed compounds. Unipharma-Graduates 8 for a fellowship.
Furthermore, we have determined the scope of the reaction,
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