Formation of 3-aminofuran-2-(5 H)-ones and 3-amino-1 H -pyrrole-2,5-diones by rearrangement of isoxazolidines

Article abstract of DOI:10.1055/s-0030-1259308

A novel rearrangement pathway of 3-alkoxycarbonyl-4- carbamoylisoxazolidines, leading to 1H-pyrrole-2,5-diones by treatment with TBAF, is reported. DFT quantum chemical calculations support the reaction route, controlled by ring strain, which proceeds thr

Full text of DOI:10.1055/s-0030-1259308

LETTER
245
Formation of 3-Aminofuran-2-(5H)-ones and 3-Amino-1H-pyrrole-2,5-diones
by Rearrangement of Isoxazolidines
Rearrangement of
a
I
soxazolidi
n
nes iela Iannazzo,*a Caterina Carnovale,a Salvatore V. Giofrè,a Roberta Ettari,a Giovanni Romeo,a Roberto Romeo,a
Giuseppe Lanza,b Ugo Chiacchiob
a
Dipartimento Farmaco-Chimico, Università di Messina, Viale SS. Annunziata, 98168 Messina, Italy
Fax +39(090)6766562; E-mail: diannazzo@unime.it
Dipartimento di Scienze Chimiche, Università di Catania, Viale Andrea Doria 6, 95125 Catania, Italy
b
Received 16 December 2010
Dedicated to Prof. Alberto Brandi on the occasion of his 60th birthday
O
N
Abstract: A novel rearrangement pathway of 3-alkoxycarbonyl-4-
carbamoylisoxazolidines, leading to 1H-pyrrole-2,5-diones by
treatment with TBAF, is reported. DFT quantum chemical calcula-
tions support the reaction route, controlled by ring strain, which
proceeds through the opening of a bicyclic intermediate, with alde-
hyde extrusion.
OH
O
Me
R1HN
COR2
R3
N
N
N
H
H
N
N
O
O
O
O
3-amino 2(5H)-furanones
Raltegravir
O
Key words: 1,3-dipolar cycloaddition, isoxazolidines, furan-
2(5H)-ones, 1H-pyrrole-2,5-diones, density function calculations
1
F
O
MeHN
OH
O
NH
Diketo acids (DKA) have been described as effective in-
hibitors of human retroviruses: in 2007, the FDA ap-
proved for the first time a DKA analogue, raltegravir
(Figure 1), for the treatment of human immunodeficiency
virus (HIV-1) infection in combination with other antiret-
roviral agents.1 Some DKA analogues have also been
shown to inhibit the hepatitis C virus (HCV) replication
by the block of NS5B polymerase.2
O
O
OH
phenyl-DKA
2
Figure 1 General structure of 3-aminofuran-2(5H)-one and some
DKA analogues
may be predicted by considering the electronic and steric
features of substituents on the isoxazolidine ring.5
In this context, we have synthesized a series of 3-amino-
furan-2(5H)-ones 1 containing a carbonyl group at the C4
position; these derivatives may be regarded as DKA cy-
clic analogues where the 1,3-diketone functionality is re-
placed by the 1-keto-3-imino group, enolized into the
corresponding 1-keto-enamino functionality, while the
acid moiety is masked in the furanose structure. In partic-
ular, N-phenyl carboxamide 2, featured by a 3-aminofu-
ran-2(5H)-one skeleton, recently emerged as a good HCV
inhibitor, with EC50 = 19 mM in the replicon assay.3
We report in this paper a novel rearrangement pathway of
isoxazolidines which possess an amido group at C4: treat-
ment of 4-carbamoylisoxazolidines with TBAF leads to
the formation of 1H-pyrrole-2,5-diones 6 (Scheme 1, path
C) as main products, together with lactones 4.
R1
O
O
path A
R2
MeHN
O
4
B
Compounds 1 have been prepared by exploiting the basic
rearrangement of 3-carboxyalkyl isoxazolidines 3 using a
mild base such as tetrabutylammonium fluoride
(TBAF).4,5 Recently, we have reported that the nature of
the substituents at C4 and C5 of the isoxazolidine nucleus
determines two different rearrangement routes, which
may lead to 3-aminofuran-2(5H)-ones 4 (Scheme 1, path
A) or b-enaminones 5 (Scheme 1, path B). Two alterna-
tive mechanisms (lactonization and retroaldolization)
have been rationalized by DFT quantum chemical meth-
ods and the relative importance of two reaction channels
EtO
H
R2
N
R1
path B
Me
O
OEt
3
O
path C
R2
R1 = Me
MeHN
R2 = C(O)NHR3
5
R3
N
O
O
MeHN
6
SYNLETT 2011, No. 2, pp 0245–0248
Advanced online publication: 10.01.2011
DOI: 10.1055/s-0030-1259308; Art ID: G34710ST
x
x.
x
x.
2
0
1
1
Scheme 1 Rearrangement pathways of the isoxazolidine nucleus by
TBAF treatment
© Georg Thieme Verlag Stuttgart · New York

246
D. Iannazzo et al.
LETTER
The 1,3-dipolar cycloaddition of C-ethoxycarbonyl N- For the trisubstituted dipolarophile 8d higher regiochem-
methyl nitrone 7 with a,b-unsaturated amides 8a–d, per- ical control was observed with compound 10d represent-
formed in dry toluene under microwave irradiation (100 ing only the 16% of the reaction mixture. The observed
W, 120 °C, 30 min), affords a mixture of three cycload- stereochemical results are in good agreement with the data
ducts 9, 10, and 12, which were separated by MPLC reported for cycloadditions of nitrones bearing an elec-
(Scheme 2, Table 1).
tron-withdrawing group at the carbon atom.7
The adducts 9a–c and 10a–c are featured by an E-stereo-
chemistry at the C3–C4 bond, arising from a transition
state where the ethoxycarbonyl group and the amide moi-
ety or the methyl group are anti with respect to the rising
pentatomic ring, in order to minimize the Van der Waals
interactions. In the case of the trisubstituted dipolarophile
8d, the main cycloadduct 11d, precursor of bicyclic 12d,
originates from a transition state stabilized by an hydro-
gen bond between the amido and esteral groups which
overcomes the destabilizing effect caused by the proxim-
ity of methyl and ester functionalities in a cis relationship.
O
R1
EtO2C
R2HN
+
N
Me
O
8a–d
7
O
O
R1
R1
EtO2C
+
EtO2C
EtO2C
NHR2
NHR2
R1
O
+
N
N
N
NHR2
Me
Me
Me
O
O
O
Treatment of isoxazolidines 9a–c with TBAF, in a 1:1 ra-
tio, led to the formation of a mixture of 3-aminofuran-
2(5H)-ones 4a–c (13–15% yield) and 1H-pyrrole-2,5-di-
ones 6a–c (41–44% yield) in a 1:3 ratio, respectively
(Scheme 3).
9a–d
10a–d
11a–d
R2
N
O
O
H
R1
O
O
C
N
EtO
O
O
EtO
NHR2
O
Me
O
O
12a–d
NHR2
N
MeHN
NHR2
Me
O
C
MeN
Scheme 2 Cycloaddition reaction of nitrone 7 with a,b-unsaturated
amides 8a–d
O
O
13a–c
4a–c
Table 1 Cycloaddition between Nitrone 7 and a,b-Unsaturated
Amides 8a–d
path a
F
O
R1
H
R2
Yield (%)a 9/10/12b
O
H
Alkene
8a
H
O
EtO2C
EtO2C
NHR2
NHR2
Ph
70
72
68
55
1.4:1.6:1
1.4:1.9:1
1.5:1.8:1
1:1:4
N
N
Me
O
Me
8b
H
Bn
n-Bu
Bn
9a–c
11a–c
8c
H
path b
8d
Me
R2
R2
N
R2
N
a Global yield.
b The relative ratio has been determined by 1H NMR spectroscopy of
the crude reaction mixture.
N
O
O
O
O
O
O
H
F
H
O
N
N
MeHN
Me
Me
H
O
The product ratios were determined by 1H NMR spectros-
copy of the crude reaction mixture. In all the examined re-
actions, besides the regioisomers 9 and 10, a consistent
amount of the bicyclic compounds 12 was recovered.
Compounds 12 originate from the not isolated cycload-
ducts 11 which undergo a subsequent transamidification
reaction between the two functionalities present at C3 and
C4, in a cis relationship. The regiochemistry of the adducts
6a–c
12a–c
Scheme 3 Rearrangement pathways of 9a–c
The formation of these compounds can be rationalized ac-
cording to two different pathways (Scheme 3). In path a,
in analogy with previous reports,5 the fluoride anion re-
moves from isoxazolidines 9a–c the more acidic proton at
C3. Then, the alkoxy anion intermediate 13, formed by the
ring opening of the isoxazolidine nucleus, evolves to-
wards compounds 4a–c by intramolecular lactonization.
In path b, the base promotes an epimerization reaction at
C3 producing the not-isolated intermediates 11a–c; the
subsequent intramolecular amidation leads to the bicyclic
1
was readily deduced from H NMR data. In agreement
with other literature reports for disubstituted electron-
poor dipolarophiles,6 the adducts 9 and 11, which contain
an electron-withdrawing group at C4 position of the isox-
azolidine ring, are predominant (56–67%).
Synlett 2011, No. 2, 245–248 © Thieme Stuttgart · New York

LETTER
Rearrangement of Isoxazolidines
247
derivatives 12a–c.8 These bicyclic compounds, according
to our previous results on furoisoxazolidinones,4b undergo
the fragmentation of the isoxazolidine nucleus (because of
high ring strain), releasing the acetaldehyde and the 1H-
pyrrole-2,5-diones 6a–c.
Bn
N
Bn
N(Me)4
F
O
N
O
O
H
O
(Me)4N
R1
R1
N
N
Me
F–H
Me
O
O
As confirmation, in the reaction of bicyclic compounds
12a–c with TBAF, 1H-pyrrole-2,5-diones 6a–c were ob-
served and collected as exclusive products.
12b
I
Treatment of compound 12d, substituted at C4 position of
the N,O-ring, with TBAF failed and only the unreacted
substrate was recovered. The use of the more basic MeO-
Na (in MeOH) proceeds easily leading to the formation, as
exclusive product, of 1,3-dimethyl-4-(methylamino)-1H-
pyrrole-2,5-dione 6d (Scheme 4).
Bn
N
Bn
O
N
O
O
O
R1
R1
(Me)4N
+ HF
+ N(Me)4
N
N
Me
Me
O
O
R1 = H, Me
III
II
Ph
Ph
Scheme 5 Active species generated from 12b and 12d
N
N
O
O
O
O
MeONa
MeOH
Optimized structures of compound 12b and the plausible
intermediates 12b-I, 12b-II, and 12b-III are reported in
Figure 2, while Table 2 reports the stability of intermedi-
ates I–III relative to compounds 12b and 12d. All of these
structures lie at high energy; therefore, their generation is
hardly reached and actually they are the rate-limiting step
for retroaldolization. We found that the next step, which
involves the aldehyde extrusion, occurs with a negligible
energy (<1 kcal/mol) and in fact, during the search for in-
termediate structures in the geometry optimization, ace-
taldehyde is often pushed out spontaneously, depending
on the starting geometry. Nevertheless, reported struc-
tures I–III are stable on the Born–Oppenheimer surface
and their stability gives a reasonable estimation of the eas-
iness or difficulty of the reaction to occur.
H
N
MeHN
Me
O
12d
6d
Scheme 4 Reaction of 12d with MeONa
From a thermodynamic point of view, the conversion of
bicyclic compounds 12 to 1H-pyrrole-2,5-diones 6 and
acetaldehyde is largely exergonic because of the energy
released in the fragmentation of the sterically hindered
rings and of the large increase of entropy. Nevertheless,
retroaldolization does not occur until a suitable base acti-
vates the process; hence, the generation of the carbanion
represents the reaction driving force.
To understand which factors control the reaction route, we
have investigated the active species for 12b and 12d em-
ploying quantum chemical methods B3PW91/6-31+G**,
(see computational detail section). To improve computa-
tional performance, (n-Bu)4N+F– was modeled by tetra-
methylammonium fluoride Me4N+F–.
The energies required for the formation of intermediates
related to 12d are about 1 kcal/mol greater than those
computed for 12b. Thus, in agreement with experiments,
the reaction of 12d with TBAF does not occur, while
when a stronger base is used (like MeONa) the reaction
takes place. The lower stability of 12d intermediates is
due to the electron-release character of the Me substituent
group at the C4 ring position and also to its sterically hin-
drance that in some degree destabilizes the anionic spe-
cies. Structural data of intermediate I (Figure 2) clearly
Because of the involvement of neutral and charged spe-
cies in the reactions, different stabilization effects occur
due to the solvent. Therefore, it becomes mandatory to in-
clude solvent effects in geometry optimization (B3PW91/
6-31+G**/PCM = THF).9 Schematic elementary reac-
tions involved in the active species generation are report-
ed in Scheme 5.
+
show the close contact between NMe4 cation and the car-
bonyl adjacent to the C3 isoxazolidine ring that largely
stabilizes the negative charge of the molecule. The anion
is also stabilized by the withdrawing of the electron den-
sity and the hydrogen-bond formation with HF. In the in-
Hydrogen abstraction from 12b and 12d leads to the for-
mation of a first intermediate I in which the Me4N+ cation
coordinates the oxygen atom adjacent to C3 of the isox-
azolidine unit and the formed HF coordinates, through hy-
drogen bonding, the isoxazolidine nitrogen atom. The HF
can be easily released because of the large entropy change
and/or hydrogen-bond formation with the solvent, leading
to the generation of the contact-ion-pair intermediate II.
The next step is the heterolytic ion-pair separation of the
contact-ion pair II caused by the large entropy increase
and by the large stabilization of anion III and NMe4+ cat-
ion due to the solvent.
+
termediate II the NMe4 cation moves close to the
isoxazolidine nitrogen indicating a larger charge delocal-
ization as reported in Scheme 5. For free anion III, the
negative charge is largely on the entire bicyclic system.
In conclusion, a novel reaction pathway of 3-alkoxycarbo-
nyl-4-carbamoylisoxazolidines leading to 1H-pyrrole-
2,5-diones by treatment with TBAF is reported. Due to the
presence of an amide group at C4 position of the isoxazo-
lidine ring, this reaction channel competes with the route
Synlett 2011, No. 2, 245–248 © Thieme Stuttgart · New York

248
D. Iannazzo et al.
LETTER
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Table 2 Relative Gibbs Free Energy (kcal/mol) for the Intermedi-
ates I, II, and III Generated from 12b and 12d at the B3PW91/6-
31+G**/PCM = THF levela
R1
H
Me
Acknowledgment
12b
12d
This work was partially supported by M.I.U.R and C.I.N.M.P.I.S.
I
20.1
25.1
25.6
20.7
26.9
26.4
References and Notes
II
(1) Anderson, M. S.; Kakuda, T. N.; Hanley, W.; Miller, J.;
Kost, J. T.; Stoltz, R.; Wenning, L. A.; Stone, J. A.;
Hoetelmans, R. M. W.; Wagner, J. A.; Iwamoto, M.
Antimicrob. Agents Chemother. 2008, 52, 4228.
III
a The energy of isolated reagents was taken as reference.
(2) Koch, U.; Atenni, B.; Malancona, S.; Colarusso, S.; Conte,
I.; Di Filippo, M.; Harper, S.; Pacini, B.; Giovini, C.; Tomas,
S.; Incitti, I.; Tomei, L.; De Francesco, R.; Altamura, S.;
Matassa, V. G.; Narjes, F. J. Med. Chem. 2006, 49, 1693.
(3) Iannazzo, D.; Piperno, A.; Romeo, G.; Romeo, R.;
Chiacchio, U.; Rescifina, A.; Balestrieri, E.; Macchi, B.;
Mastino, A.; Cortese, R. Bioorg. Med. Chem. 2008, 16,
9610.
(4) (a) Chiacchio, U.; Iannazzo, D.; Piperno, A.; Pistarà, V.;
Rescifina, A.; Romeo, G.; Romeo, R. Tetrahedron 2004, 60,
6593. (b) Chiacchio, U.; Corsaro, A.; Iannazzo, D.; Piperno,
A.; Procopio, A.; Rescifina, A.; Romeo, G.; Romeo, R.
J. Org. Chem. 2002, 67, 4380. (c) Casuscelli, F.; Chiacchio,
U.; Di Bella, M. R.; Rescifina, A.; Romeo, G.; Romeo, R.;
Uccella, N. Tetrahedron 1995, 51, 8605.
(5) Iannazzo, D.; Brunaccini, E.; Giofrè, S. V.; Piperno, A.;
Romeo, G.; Ronsisvalle, S.; Chiacchio, M. A.; Lanza, G.;
Chiacchio, U. Eur. J. Org. Chem. 2010, 5897.
(6) (a) Rescifina, A.; Chiacchio, M. A.; Corsaro, A.; De Clercq,
E.; Iannazzo, D.; Mastino, A.; Piperno, A.; Romeo, G.;
Romeo, R.; Valveri, V. J. Med. Chem. 2006, 49, 709.
(b) Desimoni, G.; Faita, G.; Mella, M.; Righetti, P.; Zema,
M. Tetrahedron 1999, 55, 8509.
(7) (a) Chiacchio, U.; Corsaro, A.; Gumina, G.; Rescifina, A.;
Iannazzo, D.; Piperno, A.; Romeo, G.; Romeo, R. J. Org.
Chem. 1999, 64, 9321. (b) Romeo, G.; Iannazzo, D.;
Piperno, A.; Romeo, R.; Corsaro, A.; Rescifina, A.;
Chiacchio, U. Mini-Rev. Org. Chem. 2005, 2, 59.
(8) Quenching the reaction of 9a with TBAF at 30 min, we have
observed by TLC analysis traces of 12a.
(9) (a) Lanza, G.; Fragalà, I. L.; Marks, T. J. J. Am. Chem. Soc.
1998, 120, 8257. (b) Lanza, G.; Fragalà, I. L.; Marks, T. J.
J. Am. Chem. Soc. 2000, 122, 12764. (c) Lan, Y.; Houk, K.
N. J. J. Am. Chem. Soc. 2010, 132, 17921. (d) Liu, P.;
Sirois, L. E.; Cheong, P. H. Y.; Yu, Z. X.; Hartung, I. V.;
Rieck, H.; Wender, P. A.; Houk, K. N. J. Am. Chem. Soc.
2000, 132, 10127. (e) Paton, R. S.; Mackey, J. L.; Kim, W.
H.; Lee, J. H.; Danishefsky, S. J.; Houk, K. N. J. Am. Chem.
Soc. 2000, 132, 9335.
Figure 2 B3PW91/6-31+G**/PCM = THF computed structure of
12b and intermediates 12b-I, 12b-II and 12b-III
leading to 3-(methylamino)furan-2(5H)-ones. 1H-Pyr-
role-2,5-diones originate from bicyclic compounds
which, following the abstraction of the H3 proton of the
isoxazolidine ring by TBAF attack, undergo a rearrange-
ment controlled the by the ring strain. DFT quantum
chemical calculations have shown that the early stage of
the hydrogen abstraction is modulated by the base
strength and, hence, by the stability of the formed various
ionic intermediates.
Synlett 2011, No. 2, 245–248 © Thieme Stuttgart · New York

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