Ugi post-condensation copper-triggered oxidative cascade towards pyrazoles

Article abstract of DOI:10.3762/bjoc.7.153

Pyrazolidinones were prepared in a two-step sequence starting from α-hydrazonocarboxylic acids. After a four-component Ugi coupling, the resulting hydrazone was engaged in a copper triggered [3 + 2] cycloaddition/aerobic oxidation cascade.

Full text of DOI:10.3762/bjoc.7.153

Ugi post-condensation copper-triggered oxidative
cascade towards pyrazoles
Aurélie Dos Santos, Laurent El Kaim*, Laurence Grimaud*
and Caroline Ronsseray
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 1310–1314.
Laboratoire Chimie et Procédés, Laboratoire Chimie et procédés,
UMR 7652-DCSO-CNRS- ENSTA-École Polytechnique, École
Nationale Supérieure de Techniques Avancées, 32 Bd Victor, Paris
75015, France
doi:10.3762/bjoc.7.153
Received: 20 June 2011
Accepted: 26 August 2011
Published: 21 September 2011
Email:
Aurélie Dos Santos - aurelie.dossantos@ensta.fr; Laurent El Kaim* -
laurent.elkaim@ensta.fr; Laurence Grimaud* -
laurence.grimaud@ensta.fr; Caroline Ronsseray -
caroline.ronsseray@ensta.fr
This article is part of the Thematic Series "Multicomponent reactions".
Guest Editor: T. J. J. Müller
© 2011 Santos et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
aerobic oxidation; copper(II); [3 + 2] cycloaddition; hydrazone;
isocyanide; pyrazolidinone
Abstract
Pyrazolidinones were prepared in a two-step sequence starting from α-hydrazonocarboxylic acids. After a four-component Ugi
coupling, the resulting hydrazone was engaged in a copper triggered [3 + 2] cycloaddition/aerobic oxidation cascade.
Introduction
In the last twenty years, the Ugi reaction coupled with its adducts. Thus, we decided to undertake various studies using
various post-condensations towards heterocyclic libraries has xanthate transfer [8-10], Mn(III) or copper(II) triggered oxida-
established the success of isocyanide-based multicomponent tive couplings [11,12].
reactions [1-7]. Chemists in both academia and industry have
taken advantage of the functional group tolerance of the Ugi We recently reported a new synthesis of fused pyrazolidinone
coupling to apply to these adducts the various cyclizations under oxidative conditions from simple hydrazone derivatives
offered by the chemists toolkit. We became involved in the Ugi- (Scheme 1) [13]. The cascade features a [3 + 2] cycloaddition
post-condensation field through our initial interest in radical coupled with an aerobic oxidation of the resulting pyrazolidine.
processes. We found that, compared with classical cycloaddi- A further oxidative coupling may be observed according to the
tions, cyclocondensations and organometalic couplings, there substitution pattern of the starting acyl chloride. Considering
was no existing description of radical processes on such our interest in IMCR, we envisioned that a similar cascade
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Beilstein J. Org. Chem. 2011, 7, 1310–1314.
could be performed on a properly functionalized Ugi adduct argon. We believe that under these conditions a slow uptake of
allowing us to reach a new 4-component access to pyrazole oxygen helps to control the selective oxidation process. Reac-
derivatives. The present letter summarizes our efforts in this tions performed under air were faster but led to intractable
direction.
mixtures.
Scheme 2: Pyrazolidinone 3a from Ugi adduct 2a.
Scheme 1: Copper-catalyzed oxidative cyclization of alkenyl hydra-
zone.
Analogous hydrazones prepared from pyruvic acid and benzoyl-
formic acid with hydrazine derivatives were tested in this Ugi/
oxidative cyclization sequence under these optimized condi-
tions. Results are reported in Table 1. Surprisingly, the reaction
appears to be only efficient with Ugi adducts prepared with
formaldehyde as the carbonyl component (Table 1, entries 1–5).
With other aldehydes and ketones, even if the Ugi reaction was
performed easily, the following cyclization failed to give the
expected pyrazolidinones and resulted in complex mixture for-
mation. Intermediate Ugi adduct 3g (Table 1, entry 6) only
resulted in a small amount of ring-opened product 4g. The reac-
tion is also limited to N-aryl hydrazones due to the lower effi-
ciency of the Ugi reaction with N-alkyl hydrazones: An attempt
of Ugi coupling with hydrazone 1d, formaldehyde, allylamine
and tert-butylisocyanide failed to give any isolable adduct
(Scheme 3). This may be explained by an enhanced nucleo-
philicity of the N-monoalkyl hydrazone leading to a competi-
tion between the hydrazone and the amine component in the
Ugi steps.
Results and Discussion
Among the possible Ugi pathways to introduce an alkene
moiety that is prone to undergo an intramolecular [3 + 2] cyclo-
addition with a hydrazone, we selected the Ugi coupling
between α-hydrazonocarboxylic acids and allylamine as the
most straightforward path. There are several reports on the use
of hydrazones in Ugi reactions [14-23], however, to the best of
our knowledge, there is no report involving α-hydrazonocar-
boxylic acids.
Hydrazone 1a was prepared through condensation of pyruvic
acid with phenylhydrazine. Adding 1a to aqueous formalde-
hyde, allylamine and tert-butylisocyanide in MeOH under
standard Ugi conditions, led to the formation of the amide
2a in 64% isolated yield. The compatibility of the hydrazone
with this coupling is certainly due to the higher electrophilicity
of the intermediate iminium. The latter traps the isocyanide
before any interaction with the hydrazone. The first
attempted oxidative cyclization of 2a was made with one In order to gain further insight into the reactivity of N-alkyl
equivalent of copper acetate in acetic acid as solvent and gave derivatives, we decided to synthesize an initial hydrazone by a
the expected pyrazolidinone 3a in a 57% isolated yield more conventional route. Benzoylformic acid was converted
(Scheme 2, condition A). Based on our previous study, the yield into its N-diallyl amide derivative. The latter failed to produce a
was improved to reach 84% with a mixture of acetic acid and hydrazone with methylhydrazine under standard conditions
water (80/20). A combination of DMF, acetic acid and water (EtOH, toluene, rt to reflux, with or without added acetic acid).
allowed us to optimize this reaction working with a reduced However, we were able to trigger the addition under microwave
20 mol % of copper (84% isolated yield, Scheme 2, condition conditions (in EtOH with 1.5 equiv of AcOH). The expected
D). The reaction was performed at 80 °C, overnight, and under hydrazone was still not synthesized, however, the cycloadduct 6
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Beilstein J. Org. Chem. 2011, 7, 1310–1314.
Table 1: Cycloaddition/oxidation cascade from Ugi hydrazone adducts.
Entry Ugi Product
Cycloadduct
1
3b, 68%
3c, 76%
2b, 79%
2c, 78%
2
3
4
3d, 90%
3e, 72%
2d, 71%
2e, 94%
5
3f, 49%
2f, 37%
6
3g, 58%
4g, 12%
7
8
–
3h, 52%
3i, 50%
–
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Beilstein J. Org. Chem. 2011, 7, 1310–1314.
addition triggered either by copper acetate or acetic acid [24-
29]. The resulting pyrazoline A may be oxidized by copper(II)
salts forming intermediate D after addition of water [30,31].
Two alternative paths may then be observed from D: Ring-
opening leading to azo or hydrazono derivatives such as 4g,
further oxidation without ring-opening giving the fused pyrazo-
lidinone 3.
Conclusion
In conclusion, we have disclosed a new Ugi coupling with
α-hydrazonocarboxylic acids. These Ugi adducts have been
used in an Ugi post-condensation involving a [3 + 2] cyclo-
addition followed by an oxidative cascade. Among potential
Ugi post-condensations, radical and oxidative processes repre-
sent a very promising route towards the formation of complex
scaffolds. We are currently exploring the reactivity of the N-aryl
Ugi–Smiles adducts using similar strategies.
Scheme 3: Attempted reactions of N-methyl hydrazones.
Experimental
Typical procedure for the first step: (E)-N-allyl-N-(2-(tert-
butylamino)-2-oxoethyl)-2-(2-phenylhydrazono)propan-
amide (2a): To a solution of formaldehyde (210 μL, 2.8 mmol)
in methanol (1 M) were added successively allylamine (210 μL,
2.8 mmol), 2-(2-phenylhydrazono)propanoic acid (500 mg,
2.8 mmol), and tert-butylisocyanide (230 mg, 2.8 mmol). The
resulting mixture was stirred at 40 °C until completion of the
reaction (TLC). The solvent was removed under reduced pres-
sure. The product was isolated by flash chromatography on
silica gel (PE/Et2O) with a yield of 64%. 1H NMR (CDCl3,
400 MHz) δ 7.52 (br s, 1H), 7.29 (dd, J = 7.8, 7.3 Hz, 2H), 7.09
(d, J = 7.8 Hz, 2H), 6.95 (t, J = 7.3 Hz, 1H), 6.16 (br s, 1H),
5.96–5.88 (m, 1H), 5.28–5.23 (m, 2H), 4.34–4.00 (m, 4H), 2.14
(s, 3H), 1.35 (s, 9H); 13C NMR (CDCl3, 100.6 MHz) δ 168.7,
168.6, 143.9, 136.9, 132.8, 129.8, 122.0, 119.0, 114.0, 53.9,
51.7, 51.3, 29.1, 12.6.
Typical procedure for the oxidative cyclization: N-tert-
butyl-2-(6a-methyl-3,6-dioxo-2-phenylhexahydropyrrolo-
[3,4-c]pyrazol-5(1H)-yl)acetamide (3a): To a solution of
hydrazone 2a (100 mg, 0.3 mmol) in a 10/70/20 DMF/
CH3COOH/H2O mixture (0.06 M) was added Cu(OAc)2
(20 mol %). The resulting mixture was heated at 80 °C under
argon. The pH was adjusted to 6 with an aqueous sodium
hydrogencarbonate solution, and the aqueous phase was
extracted with AcOEt. Then the organic layers were washed ten
Scheme 4: Proposed mechanism.
was obtained, probably through a [3 + 2] cycloaddition trig- times with water, dried over anhydrous MgSO4, filtered and
gered by acetic acid. The attempted oxidation of 6 with copper concentrated in vacuo. The product was isolated by flash chro-
acetate in DMF/AcOH/H2O gave only complex mixtures.
matography on silica gel (PE/Et2O with 1% of TEA) with a
yield of 84%. 1H NMR (CDCl3, 400 MHz) δ 7.83 (d, J =
The oxidation sequence may be explained by the mechanism 8.3 Hz, 2H), 7.37 (dd, J = 8.3, 7.3 Hz, 2H), 7.17 (t, J = 7.3 Hz,
depicted in Scheme 4. The process starts with a [3 + 2] cyclo- 1H), 5.52 (br s, 1H, NH), 4.89 (br s, 1H), 3.93 (d, J = 16.2 Hz,
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Beilstein J. Org. Chem. 2011, 7, 1310–1314.
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Supporting Information File 1
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