Optimized conditions for Passerini-Smiles reactions and applications to benzoxazinone syntheses

Article abstract of DOI:10.3390/molecules21091257

Initial conditions disclosed for the Passerini-Smiles reaction are associated with a lack of efficiency that has prevented chemists from using it since its discovery. We wish to report herein our thorough study in the development of new experimental conditions for this coupling between electron-poor phenols, isocyanides, and carbonyl derivatives. These new conditions have been applied to several synthetic strategies towards benzoxazinones.

Full text of DOI:10.3390/molecules21091257

molecules
Article
Optimized Conditions for Passerini-Smiles Reactions
and Applications to Benzoxazinone Syntheses
Elodie Martinand-Lurin 1,2, Aurélie Dos Santos 3, Emmanuelle Robineau 2, Pascal Retailleau 1,
Philippe Dauban 1, Laurence Grimaud 2,* and Laurent El Kaïm 3,
*
1
Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Univ. Paris-Sud, Université Paris-Saclay,
Avenue de la Terrasse, 91198 Gif-sur-Yvette CEDEX, France;
Elodie.MARTINAND-LURIN@cnrs.fr (E.M.-L.); pascal.retailleau@icsn.cnrs-gif.fr (P.R.);
Philippe.DAUBAN@cnrs.fr (P.D.)
2
1 Ecole Normale Supérieure, PSL Research University, UPMC Univ. Paris 06, CNRS,
Département de Chimie, PASTEUR, 24, rue Lhomond, 75005 Paris, France; 2 Sorbonne Universités,
UPMC Univ. Paris 06, ENS, CNRS, PASTEUR, 75005 Paris, France; Emmanuelle.robineau@ens.fr
Laboratoire de Synthèse Organique, CNRS, Ecole Polytechnique, ENSTA ParisTech–UMR 7652,
Université Paris-Saclay, 91128 Palaiseau, France; aurelie.dossantos@ensta-paristech.fr
Correspondence: laurence.grimaud@ens.fr (L.G.); laurent.elkaim@ensta-paristech.fr (L.E.K.);
Tel.: +33-144-323-872 (L.G.)
3
*
Academic Editor: Philippe Belmont
Received: 27 July 2016; Accepted: 13 September 2016; Published: 21 September 2016
Abstract: Initial conditions disclosed for the Passerini-Smiles reaction are associated with a lack of
efficiency that has prevented chemists from using it since its discovery. We wish to report herein
our thorough study in the development of new experimental conditions for this coupling between
electron-poor phenols, isocyanides, and carbonyl derivatives. These new conditions have been
applied to several synthetic strategies towards benzoxazinones.
Keywords: isocyanide; Passerini-Smiles; multicomponent reaction; heterocycles; benzoxazinones
1. Introduction
In the last decade, we developed a variant of Ugi couplings in which the carboxylic acid is
replaced with an electron-deficient phenol. Due to the nature of the final rearrangement involved in
the process, we named this extension Ugi-Smiles coupling [1–4]. The potential of this new reaction was
thoroughly studied by exploring the scope of the various phenols and related hydroxy heterocycles
prone to react in this coupling and by developing efficient and rapid heterocyclic syntheses through
the development of post-condensation transformations of the adducts. Soon after our first report on
Ugi-Smiles coupling, we reported its three-component version, which involves a carbonyl derivative,
an isocyanide and an electron-deficient phenol. In analogy with the previous four-component reaction,
the term Passerini-Smiles reaction was used to coin these couplings [5]. However, the latter turned
out to be of rather limited scope and its potential was, thus, neglected in favor of the more efficient
Ugi-Smiles transformation. Herein, we wish to report all our results on improved conditions for the
Passerini-Smiles coupling and their use in new heterocyclic syntheses.
2. Results
We recently reinvestigated the Passerini-Smiles reaction in order to study possible transformations
of the three-component adducts [
cyclohexylisocyanide, and 2-nitrophenol was stirred in methanol at 60 C for three days, as previously
settled, we were surprised to be unable to reproduce our previous results (80% of isolated yields),
6
]. Actually, when a stoichiometric amount of propanal,
◦
Molecules 2016, 21, 1257; doi:10.3390/molecules21091257
www.mdpi.com/journal/molecules

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whatever the conditions of time and temperature (Scheme 1). We surmised that these divergent results
could be due to an uncontrolled evaporation of the solvent during the reaction time and decided to
investigate this reaction under neat conditions.
Scheme 1. Passerini-Smiles couplings of ortho-nitrophenol according to previous conditions.
When performed with an activated ketone, the neat Passerini-Smiles proceeded smoothly giving
the desired product in good yields. Indeed, cyclobutanone, trifluoromethylacetone, and methoxy
acetone gave the desired product within 72 h in good yields whereas no adduct could be formed when
using pentan-3-one and cyclohexanone under the same conditions (Scheme 2).
Scheme 2. Neat Passerini-Smiles for ketones.
However when an aldehyde, such as propanal, was chosen as the electrophilic partner, no
improvement was observed for the reaction and the isolation of 2a turned out to be difficult as an
impurity is formed along with the product. This byproduct turned out to be the ketal 3a formed by the
incorporation of a second aldehyde and from the nitrophenol which triggered ring-opening of a cyclic
imidate (Scheme 3). Probably due to higher steric hindrance, the ketal byproduct was never observed
for ketones, even when used in excess.
Scheme 3. Neat Passerini-Smiles for aldehydes and byproduct formation.

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These first results encouraged us to further optimize the Passerini-Smiles reaction with aldehydes.
During our former studies, we have observed that low yields of products were isolated in the case of
4-nitrophenol, probably due to the impossibility to activate the hydroxy group through a hydrogen
bond occuring during the Smiles rearrangement (as demonstrated for Ugi-Smiles coupling) [7].
Nevertheless, a modified 4-nitrophenol was prepared via a Mannich reaction and showed a particular
efficiency in the three-component (Scheme 4). Indeed, the piperazinyl-modified 4-nitrophenol afforded
the desired adduct in 65% isolated yield after three days in MeOH.
Scheme 4. Mannich-modified para-nitrophenol in Passerini-Smiles couplings.
We, thus, decided to test the Passerini-Smiles in the presence of additives such as tertiary
amines [8]. Various amines were tested for this purpose in the reaction of a stoichiometric amount of
propanal, cyclohexylisocyanide and 2-nitrophenol (Scheme 5). The formation of the Passerini-Smiles
adduct 2a was not improved when adding tertiary amines such as the Hunig0s base. However, the
use of more nucleophilic tertiary amines dramatically impacted the reaction rate and yields. The
best results were obtained with DABCO (1,4-diazabicyclo[2.2.2]octane). Indeed, the addition of 1
equivalent of DABCO afforded 2a in 65% isolated yield with no traces of byproduct.
Scheme 5. Additives in Passerini-Smiles reaction.
3. Discussion
In order to prove the effect of additives, we then performed kinetic studies (See Supplementary
Materials) with 1 and 2 equivalents of propanal (Figure 1). The above reaction was done at 55 ◦C and
the conversion was determined and plotted against time. This study confirmed that piperazine and
DABCO both accelerated the reaction as the half-reaction time is under one hour in their presence.
However, whatever the additives are, the conversion seemed to be limited to 70% after one day.
We decided, thus, to use an excess of aldehyde and, under these optimized conditions, we were
pleased to observe a very high level of conversion within a few hours with no trace of ketal 3a as a
byproduct. The role of the additive is still unexplained at the moment but in order to rationalize the
inhibition of the by-path towards 3a, we proposed that the aldehyde could be momentaneously stored
as a hemiaminal intermediate. This would lower the concentration of the aldehyde in the medium and
avoid the addition of a second aldehyde before the Smiles process.

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Figure 1. Formation of 2a with time under various conditions.
Under these new optimized conditions, the scope of the Passerini-Smiles coupling was further
investigated by varying the three reagents. The reaction was first tested using 2-nitrophenol and
cyclohexylisocyanide, and varying the aldehyde partner. The reaction is highly efficient with aliphatic
aldehydes, but aromatic aldehydes give only moderate yields (Scheme 6). As previously observed for
Ugi-Smiles couplings, no adduct could be isolated from α,β-unsaturated aldehydes.
Scheme 6. Passerini-Smiles couplings of aldehyde in the presence of DABCO.
The scope was next tested using substituted 2-nitrophenols. The nature of the substituent did not
affect the efficiency of the reaction as electron-donating groups such as methyl, methoxy, or allyl and
electron-withdrawing groups—halogen atom, cyano or trifluoromethyl—gave the desired adducts

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2
in good yields (Scheme 7). It is worth noting that different isocyanides—cyclohexyl, tert-butyl,
benzylic, etc.—can be used in this reaction with constant efficiency. These optimized conditions
were also successfully applied to heterocyclic compounds such as hydroxyl nitropyridines and the
corresponding Passerini-Smiles adducts 2x and 2y were isolated in good yields (Scheme 7).
O
NO2
O
NO2
O
NO2
O
NO2
O
O
O
Ph
O
N
H
N
H
CyHN
N
H
i-Bu
t-Bu
MeO
Me
Me
Cl
Me
OMe
NO2
2g
2j
78%
2h
2i
83%
72%
40%
OMe
O
O
NO2
O
NO2
O
NO2
NO2
O
O
O
O
Ph
O
CyHN
CyHN
O
N
H
CyHN
N
H
i-Pr
i-Pr
t-Bu
t-Bu
OMe
i-Pr
Br
Br
OMe
2o
96%
2m
2n
2k
2l
MeO
59%
78%
68%
68%
OMe
O
NO2
O
NO2
O
NO2
O
NO2
O
O
O
O
t-BuHN
t-BuHN
N
H
N
H
Et
i-Pr
t-Bu
Et
Cl
Cl
Cl
Cl
MeO
Cl
2q
2p
2r
86%
2s
79%
68%
83%
F3C
O
NO2
NO2
O
NO2
O
NO2
O
i-Bu
O
N
H
Ph
O
O
O
N
H
N
H
Et
i-Bu
CN
MeO
CN
NH
CF3
2u
61%
2v
2w
MeO
2t
74%
82%
OMe
67%
NO2
MeO
OMe
O
NO2
N
O
O
NO2
O
NO2
N
O
O
O
O
CyHN
CyHN
CyHN
CyHN
i-Pr
N
Et
Et
2ya
43%
N
i-Pr
2xb
77%
2xa
2yb
74%
57%
Scheme 7. Passerini-Smiles couplings of substituted 2-nitro phenol and hydroxyl heterocycles.
Surprisingly, using this new set of experimental conditions, the 4-nitrophenol was successfully
coupled with isobutyraldehyde and cyclohexylisocyanide to give the desired adduct 2z in 40% yield
after two days along with about 15% of the corresponding acetal (Scheme 8).
Scheme 8. Passerini-Smiles couplings of 4-nitrophenol.
Due to our theoretical studies concerning the mechanism of the Ugi-Smiles coupling [
9], we
assumed that 2-substituted 4-nitrophenol could behave more efficiently due to the possibility for the

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substituent to interact with the hydroxy group through an intramolecular hydrogen bond. This
interaction should stabilize the spiro intermediate along the Smiles rearrangement. Therefore,
we started to investigate 2-heterosubstituted-4-nitrophenols in this coupling. 2,4-dinitrophenol
and 2-chloro or 2-bromo substituted 4-nitrophenols gave the desired
4 with good yields, but
2-fluoro-4-nitrophenol gave lower conversions after 12 h as the isolated yield of 4a did not exceed 50%
(Scheme 9).
Scheme 9. Passerini-Smiles couplings of substituted 4-nitrophenols.
After 12 h of heating at 80 ◦C—instead of 60 ◦C—various isocyanides and aliphatic aldehydes
were coupled with 2-fluoro-4-nitrophenol to form the three-component adducts in yields ranging from
31% to 81% (Scheme 10).
Scheme 10. Passerini-Smiles couplings of substituted 2-fluoro-4-nitrophenol.

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Considering the high potential of Passerini and Ugi adducts in heterocyclic synthesis, we decided
to investigate further post-condensation transformations of Passerini-Smiles adducts. The presence
of the nitro group affords easy access to the corresponding anilines by direct reduction. Indeed, we
recently reported a two step sequence involving a hydrogenolysis and an acidic cyclization towards
the synthesis of NH-benzoxazinones as already done with Ugi-Smiles adducts a few years ago [10].
However, in contrast to our previous results, in this case, the whole sequence turned out to be difficult
and required harsh conditions to proceed. Indeed, the reduction towards aniline was achieved using
Pd/C (10%) at 60 ◦C in a H-cube apparatus under high pressure conditions (50 bars) and then the
crude aniline was treated with two equivalents of trifluoroacetic acid in toluene at 80 ◦C overnight
(Scheme 11).
Scheme 11. Reduction and acidic cyclization towards benzoxazinones.
Under these experimental conditions, the desired benzoxazinones 5 were synthesized in moderate
to excellent yields (Scheme 12). However, in this synthesis, the loss of the former isocyanide moiety
reduces the molecular diversity traditionally associated with Passerini couplings.
Scheme 12. Benzoxazinone synthesis through a two-step cascade from Passerini-Smiles adducts.
When considering the literature upon Smiles rearrangements, an impressive number of reactions
involves the transfer of the aromatic moiety from an oxygen atom to the nitrogen atom of an amide
under basic conditions [11
it could be possible to perform a second Smiles rearrangement in order to obtain N-aryl
carboxamides. The Passerini-Smiles product 2b was, thus, treated with sodium hydride in DMF.
–
13]. Due to the structure of Passerini-Smiles adducts, we surmised that
α
-hydroxy

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At room temperature, no evolution occurred. However, after 1 h at 100 ◦C, a new cyclized product
was formed. The latter turned out to a N-alkyl benzoxazinone 6a. The reaction was further optimized
by varying both the solvent and the base. Potassium tert-butoxide in DMF (at a concentration of 0.2 M)
at 100 ◦C turned out to be the best set of experimental conditions (Scheme 13).
Conditions a
Yields (%)
Cs2CO3 (1 equiv.), DMF, 100 ◦C, 3 h
DBU (1.5 equiv.), DMF, 100 ◦C, 3 h
NaH (2 equiv.), DMF, 100 ◦C, 3 h
KH (1.5 equiv.), DMF, 100 ◦C, 3 h
t-BuOK (1.5 equiv.), DMF, 100 ◦C, 2 h
t-BuOK (1.5 equiv.), MeCN, 75 ◦C, 3 h
t-BuOK (1.5 equiv.), THF, 65 ◦C, 2 h
0
0
54
69
82 (89) b
28
36
All reactions were done at [2b] = 0.4 M. b at [2b] = 0.2 M, for 1 h.
a
Scheme 13. Optimization for the second Smiles rearrangement.
This method constitutes an alternative to the former NH-benzoxazinone formation as in the
present case, the benzoxazinone presents all three points of diversity of the Passerini-Smiles reaction.
In order to precisely determine the mechanism of this cyclization, compound 1b was then submitted
to the cyclization conditions. The structure of the resulting product 6b was undoubtfully assigned
through X-ray analyses (Scheme 14).
Scheme 14. Smiles rearrangement for substrate 1b.
As the chlorine atom was located at the para-position of the amide, a second Smiles rearrangement
was involved and the spiro ring-opening probably occurred with concomittant substitution of the nitro
by the released alkoxide (Scheme 15) [11–14]. Similar concerted processes have been clearly evidenced
by theoretical calculations [15].
Scheme 15. Plausible Mechanism for the Smiles rearrangement.

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Various benzoxazinones
6
were formed under these conditions as most of the Passerini-Smiles
substrates and 2 derived from 2-nitrophenols were successfully transformed under basic conditions
1
with good to excellent yields (Scheme 16). Similarly, Passerini-adducts derived from hydroxy
heterocycles were cyclized to form the corresponding benzofused systems 6x and 6y in good yields
(Scheme 16). Noteworthy is the special behavior of the dinitro compound 4c that decomposed under
these conditions. Unfortunately, the reaction failed for Passerini-adducts derived from an aromatic
aldehyde. Indeed, compound 2f treated under basic conditions gave the pyruvamide
7
through an
oxidative process of the benzylic anion (Scheme 17).
R2
NO2
O
R3
O
t-BuOK
R1
O
O
NHR4
DMF
N
R1 R2
R3
100 °C, 1 h
R4
6
1
Br
O
N
i-Pr
O
N
NC
O
N
F3C
O
N
i-Bu
CF3
O
O
O
O
Cy
71%
81%
6d
74%
70%
6c
6e
6f
Ph
OMe
OMe
F3C
O
N
OMe
O
O
Cl
O
N
i-Pr
O
N
MeO
t-Bu
O
N
i-Bu
O
O
N
O
O
t-Bu
94%
6h
86%
6g
71%
6i
67%
6j
96%
6k
OMe
Ph
OMe
Br
Cl
OMe
Br
O
N
O
t-Bu
O
O
O
t-Bu
O
N
O
N
O
N
O
N
O
Cy
Cy
80%
95%
93%
71%
86%
6l
6m
6n
6o
6p
Ph
OMe
OMe
OMe
O
Ph
NC
O
i-Bu
Cl
O
N
O
Cl
O
N
O
N
O
O
N
O
Cy
t-Bu
83%
84%
95%
6s
74%
Ph
6q
6r
6t
OMe
OMe
O
Cl
t-Bu
N
O
N
O
O
N
O
i-Pr
OMe
O
N
O
O
N
N
O
N
O
Cy
Cy
Cy
Cy
95%
6u
63%
89%
56%
71%
6y
6v
6w
6x
Cl
Scheme 16. Scope for the second Smiles rearrangement and benzoxazinone formation.
Scheme 17. Oxidative cleavage for Passerini-Smiles adducts with aromatic substituent under
anionic conditions.

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A similar cascade towards substituted benzoxazinones could be done starting with
2-fluoro-4-nitrophenol as a partner of the Passerini-Smiles reaction. Under similar experimental
conditions, the reaction proceeded smoothly with the release of a fluoride ion in place of the
previous nitro group elimination (Scheme 18). Indeed, X-ray analyses of 8j confirmed that a Smiles
rearrangement occurred prior to cyclization.
Scheme 18. Smiles rearrangement of Passerini-Smiles adducts from 2-fluoro-4-nitrophenols.
Due to the simple experimental procedure settled for the three-component coupling, the whole
sequence Passerini-double Smiles could be performed in the same pot. Indeed after 12 h of stirring at
◦
55 C, DMF was added to dilute the reaction mixture and the desired amount of potassium tert-butoxide
was added at once. This one-pot sequential procedure affords a very convenient and straightforward
access to benzoxazinones in moderate to high yields with three points of molecular diversity. In all
cases, the products are isolated in similar or even better yields (Table 1).

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Table 1. Comparison of sequential and one-pot benzoxazinone synthesis.
Entry
1
Phenol
Product
Yield over 2 Steps (%)
Yield One-Pot (%) 1
63 2
75
89 2
2
3
82
67
65 2
48 2
4
5
49
63
71 3
61 3
68 2
66 2
6
7
8
54
66
50
53 2
9
39
1
2
Isolated Yields. The first step was performed using 2 equiv. of aldehyde and adding 1 equiv. of DABCO.
The first step was performed using a stoichiometric ratio of the three starting materials.
3

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4. Materials and Methods
4.1. General Procedure A for Passerini-Smiles Reaction with 2-Nitrophenol Derivatives
4.1.1. Aldehydes
To 1.0 equiv. of phenol were added successively 1.0 equiv. of DABCO, 2.0 equiv. of aldehyde and
1.0 equiv. of isocyanide. The resulting mixture was stirred neat at 55 ◦C for 12 h. The crude product
was purified by flash chromatography on silica gel.
4.1.2. Ketones
To 1.0 equiv. of phenol were added successively 1.0 equiv. of ketone and 1.0 equiv. of isocyanide
under an inert atmosphere. The resulting mixture was stirred neat at 55 ◦C for three days. The crude
product was purified by flash chromatography on silica gel.
4.2. General Procedure B for Passerini-Smiles Reaction with 2-Fluoro-4-nitrophenol Derivatives
To 1.0 equiv. of phenol were added successively 1.0 equiv. of DABCO, 2.0 equiv. of aldehyde, and
1.0 equiv. of isocyanide. The resulting mixture was stirred neat at 80 ◦C for 12 h. The crude product
was dissolved in dichloromethane. The organic layer was washed with 1 M NaOH, water, dried over
MgSO4 and then concentrated. The crude product was purified by flash chromatography on silica gel.
4.3. General Procedure C for Reduction-Cyclization Sequence
The reduction of nitro compounds was carried out using a H-cube® system (Thalesnano, Budapest,
Hungary) with a 10% Pd/C as a catalyst. The Passerini-Smiles adduct (0.5 mmol) was dissolved in
◦
methanol (0.06 M) and was then passed through the H-cube® system at 60 C, 50 bars pressure with a
H2 constant flow rate of 0.5 mL/min. The methanol was then removed under reduced pressure and
the 1H-NMR analysis showed total conversion.
The crude product was dissolved in toluene (0.1 M) and TFA (2.5 mmol, 5 equiv.) was added.
After 12 h of stirring at 85 ◦C, the reaction mixture was diluted with dichloromethane. The content
was transferred to a separatory funnel and the organic phase was washed with a saturated aqueous
solution of NaHCO3. The aqueous layer was extracted with CH2Cl2. The combined organic layers
were washed with water, dried over MgSO4 and concentrated under reduced pressure. The crude
product was purified by flash chromatography on silica gel.
4.4. General Procedure D for Smiles Cyclization
To a 0.2 M solution of Passerini-Smiles adduct in DMF were added 1.5 equiv. (aldehyde) or 2.0
equiv. (ketone) of potassium tert-butoxide. The resulting mixture was stirred for 1 h at 100 ◦C. The
resulting mixture was diluted with 1 M HCl. The aqueous layer was extracted three times with CH2Cl2.
Organic layers were combined, washed with water, dried over MgSO4, and concentrated. The crude
product was purified by flash chromatography on silica gel.
4.5. General Procedure E for Passerini-Double-Smiles Reaction (One-Pot)
To 1.0 equiv. of phenol were added successively 1.0 equiv. of DABCO (only for aldehydes), 2.0
equiv. of aldehyde (1.0 equiv. of ketone), and 1.0 equiv. of isocyanide under an inert atmosphere.
The resulting mixture was stirred neat at 55 ◦C (or 80 ◦C for 2-fluoro-4-nitrophenol derivatives) for
12 h for aldehyde (three days for ketone). Then, DMF (0.2 M) and 1.5 equiv. (aldehyde) or 2.0 equiv.
(ketone) of potassium tert-butoxide were added. The resulting mixture was stirred for 1 h at 100 ◦C.
The resulting mixture was diluted with CH2Cl2 then washed with H2O and 1 M HCl. The aqueous
layer was extracted three times with CH2Cl2. Organic layers were combined, washed with water, dried
over MgSO4, and concentrated. The crude product was purified by flash chromatography on silica gel.

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5. Conclusions
In conclusion, we have settled new conditions for efficient Passerini-Smiles reactions. The
dramatic improvement of this reaction is strongly associated to the use of a tertiary nucleophilic amine
as additive together with solvent free conditions. This new procedure has allowed us to propose
various syntheses of functionalized 1,4-benzoxazin-3-ones through post-condensation transformations
of the resulting adducts. The most interesting transformations are based on a Smiles cyclization cascade
taking full advantage of the phenoxy group introduced during the first Passerini-Smiles process. The
whole sequence could be performed according to a very convenient one-pot procedure affording
one of the most straightforward access to 1,4-benzoxazin-3-ones, heterocycles of interest for both
agrochemical [16] and pharmaceutical [17–19] applications.
Supplementary Materials: Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/21/
9/1257/s1.
Acknowledgments: We thank ENSTA, ENS, ICSN and CNRS for financial support.
Author Contributions: L.E.K. and L.G. conceived and designed the experiments with some useful advices from
P.D.; E.M.-L., A.D.S. and E.R. performed the experiments; P.R. analyzed the crystal structures; P.D. contributed
reagents/materials/analysis tools; L.G. and L.E.K. wrote the paper.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds 1b–8j are available from the authors.
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