Regioselective synthesis of 3,4,5-trisubstituted 2-aminofurans

Article abstract of DOI:10.1039/c4ob01037j

Three series of methyl 5-substituted 2-aminofuran-4-keto-3-carboxylates have been prepared following a multicomponent reaction strategy by the addition of an isocyanide to 4-oxo-2-butynoate in the presence of an aldehyde. The cycloaddition regioselectivit

Full text of DOI:10.1039/c4ob01037j

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Regioselective synthesis of 3,4,5-trisubstituted
2-aminofurans†
Cite this: Org. Biomol. Chem., 2014,
12, 5098
Thi Ngoc Tram Huynh,a,b Pascal Retailleau,c Clément Denhez,*a
Received 20th May 2014,
Accepted 30th May 2014
Kim Phi Phung Nguyenb and Dom Guillaumea
DOI: 10.1039/c4ob01037j
www.rsc.org/obc
Three series of methyl 5-substituted 2-aminofuran-4-keto-3-car-
boxylates have been prepared following a multicomponent reaction
strategy by the addition of an isocyanide to 4-oxo-2-butynoate in
the presence of an aldehyde. The cycloaddition regioselectivity is
generally high (>95%) but decreases when an electron-rich substi-
tuent is located at the butynoate 4-position.
Furan is an important five membered O-heterocycle frequently
present in biologically important natural products and
pharmaceutical substances.1 2-Aminofurans are powerful
synthetic intermediates2 whose use is somehow hampered by
their limited availability. Such a limitation is particularly
stressed for 3,4,5-trisubstituted 2-aminofurans. Indeed, if
3-cyano-4,5-disubstituted-2-aminofurans can be prepared by
reaction of α-bromoacetophenones with malononitrile,3 or by
a cascade Stetter-γ-keto nitrile cyclization reaction of aromatic
aldehydes and acylidenemalononitriles,4 most of the reported
3,4,5-trisubstituted-2-aminofurans have been prepared by
nucleophilic addition of isocyanides to dimethyl acetylenedi-
carboxylate in the presence of mainly aromatic aldehydes,5 but
also conjugated aldehydes,6 or modified aldehydes,7 acids,8 or
acyl chlorides9 (Scheme 1).
Diaroylacetylenes (1,4-diarylbut-2-yne-1,4-diones) have also
been scarcely but successfully used in place of dimethyl ace-
tylenedicarboxylate10 (Scheme 1). However, despite its chemical
efficiency the isocyanide-based multicomponent approach has
exclusively been applied to symmetrical alkynes, allowing the
preparation of 3,4,5-trisubstituted-2-aminofurans presenting
simultaneously either a diketo- or a diester-functionality at C3
Scheme 1 Known
2-aminofurans.
strategies
to
prepare
3,4,5-trisubstituted
and C4, so far. Recently, a two-step synthesis of three 3,4,5-
trisubstituted-2-aminofurans in which the 3- and 4-positions
are functionalized with an ester and keto group, respectively,
has been reported11 (Scheme 1).
This synthesis necessitates the oxidation of a 2-amino-2,3-
dihydrofuran initially resulting from the reaction of carbe-
noids with enamines. Taking advantage of the high isocyanide
reactivity, we report the regioselective one-step synthesis of
3,4,5-trisubstituted 2-aminofurans in which the 3- and 4-posi-
tions are functionalized with an ester and keto group.
First we screened experimental conditions of the three com-
ponent reaction using benzaldehyde, the known methyl 4-oxo-
2-alkynoate (1),12 and tert-butyl isocyanide (4) in various
solvents (Table 1). Even though [Bmim]BF4, toluene/benzene,
or PEG 400 have been reported to be suitable solvents for such
cycloaddition reactions,5a–f,6 in our hands those solvents failed
to deliver the expected furan (Table 1, entries 1–3). Interest-
ingly, the use of H2O as a solvent led to 2-aminofuran 5a in
around 68% yield, depending on the reaction temperature
(Table 1, entries 4 and 5). Replacement of water with dichloro-
methane afforded the expected 2-aminofuran in 55% yield
when the reaction was performed at room temperature and
72% upon heating at 70 °C (sealed tube) (Table 1, entries 6
and 7). Furthermore and delightedly, the 1H-NMR spectrum of
the crude reaction mixture evidenced that the successful cyclo-
aICMR, UMR7312-CNRS, Université de Reims Champagne Ardenne, UFR Pharmacie,
51 rue Cognacq Jay, 51096 Reims Cedex, France.
E-mail: clement.denhez@univ-reims.fr
bDepartment of Organic Chemistry, University of Science, National University – Ho
Chi Minh City, 227 Nguyen Van Cu Str., Dist. 5, 748355 Ho Chi Minh City, Vietnam
cICSN, UPR2301-CNRS, 1 Avenue de la Terrasse, 91190 Gif sur Yvette, France
†Electronic supplementary information (ESI) available: Synthesis, characteriz-
ation of new compounds, computational details and crystallographic data of 7b
and 8b. CCDC 949882 and 949883. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c4ob01037j
5098 | Org. Biomol. Chem., 2014, 12, 5098–5101
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Table 1 Screening of the reaction conditions for 2-aminofuran
synthesis
Table 3 Cycloaddition yield (%) using methyl 4-oxo-4-(thiophen-2-yl)-
but-2-ynoate (3) and various aromatic aldehydes
Isomer 7a,b
Isomer 8a,b
Entry
Solvent, conditions
Yield (%)
Ar
1
2
3
4
5
6
7
PEG 400,a RT, 24 hours
C6H5CH3, reflux, 24 hours
[Bmim]BF4, RT, 24 hours
H2O, RT, 24 hours
H2O, 110 °C, sealed tube, 24 hours
CH2Cl2, RT, 24 hours
CH2Cl2, 70 °C, sealed tube, 24 hours
0
0
0
69
66
55
72
Ph
7a (40)
7b (62)
7c (61)
7d (23)
7e (32)
7f (42)
7g (47)
7h (35)
7i (41)
7j (40)
7k (26)
8a (10)
8b (30)
8c (25)
8d (9)
8e (8)
8f (8)
8g (–)
8h (12)
8i (12)
8j (13)
8k (8)
p-O2N-C6H4
m-O2N-C6H4
Piperonylc
p-H3C-C6H4
p-F-C6H4
2-(Pivaloyloxy)-C6H4
3-(Pivaloyloxy)-C6H4
4-(Pivaloyloxy)-C6H4
3,5-Dimethoxy-4-(pivaloyloxy)-C6H2
2-(3-Methyl)thiophenyl
a PEG = poly(ethylene glycol).
a Reactions were conducted using 1 eq. of 3 and 1.1 eq. of tert-butyl
isocyanide (4). b Isolated yields. c 5-Benzo[d][1,3]dioxole.
Table 2 Cycloaddition yield (%) using methyl 5,5-dimethyl-4-oxohex-
2-ynoate (1) or methyl 4-phenyl-4-oxo-2-butynoate (2) and various aro-
matic aldehydes
Then, to evaluate the influence of the C4-alkyne substituent
on the regioselectivity, we used methyl 4-phenyl-4-oxo-
2-butynoate (2)12,14 in place of 1. In that case, cycloaddition
again nicely occurred with a higher than 95% regioselectivity
(Table 2). However, it was associated with a slightly lower
chemical yield compared to those observed with 1.
Ar
5a,b
6a,b
More contrasting results were obtained when methyl 4-oxo-
4-(thiophen-2-yl)but-2-ynoate15 (3) was used. In this case, even
though global chemical yields were similar to those observed
with 1 or 2, a minor regioisomer (8) resulting from the nucleo-
philic isocyanide attack at α-position of the keto group was iso-
lated together with 7, the regioisomer resulting from a similar
attack at β-position of the keto group (Table 3).
The structures of 7b and 8b (Ar = p-NO2-C6H4) were un-
ambiguously solved by X-ray crystallography (Fig. 1). A high
reactivity of the α-position of the methoxycarbonyl group of
alkynes such as 1–3 towards nucleophilic attack has generally
been assumed since the pioneering work of Jones et al.13
However, the reactivity of the Michael-acceptor is known to be
Ph
5a (72)
5b (93)
5c (92)
5d (53)
5e (61)
5f (50)
5g (60)
5h (53)
5i (62)
5j (70)
5k (59)
6a (52)
6b (79)
6c (78)
6d (45)
6e (57)
6f (52)
6g (58)
6h (50)
6i (52)
6j (63)
6k (53)
p-O2N-C6H4
m-O2N-C6H4
Piperonylc
p-H3C-C6H4
p-F-C6H4
2-(Pivaloyloxy)-C6H4
3-(Pivaloyloxy)-C6H4
4-(Pivaloyloxy)-C6H4
3,5-Dimethoxy-4-(pivaloyloxy)-C6H2
2-(3-Methyl)thiophenyl
a Reactions were conducted using 1 eq. of 1 (or 2) and 1.1 eq. of tert-
butyl isocyanide (4). b Isolated yields. c 5-Benzo[d][1,3]dioxole.
addition was accompanied by single regioisomer formation. reduced if it is substituted with an electron rich group.16,17 It
Characteristic 13C chemical shift of 2-aminofuran C3- and is very likely that the electron-rich thienyl group modifies the
C4-atoms at δ 91.0 and 123.6, respectively,11 unequivocally alkyne charge distribution, resulting in a lower regioselectivity
indicated the exclusive (above 95%) formation of 5a (Table 1), of the isonitrile attack.
the furan resulting from a nucleophilic attack of the isocyanide
In order to explain the observed regioselectivity, we deter-
at the carbon alpha of the methyl 4-oxo-2-alkynoate ester mined DFT-based reactivity18 and Fukui condensed indices19
+
− 20
group.13
fk and fk
widely used to study 1,3-dipolar cycloadditions.21
−
Then, we focused on the cycloaddition regioselectivity. We As expected, tert-butyl isocyanide (4) featured a fk concen-
observed that aldehydes had no influence on the regioselect- trated on the isocyanide carbon (0.581 unit). Interestingly,
+
ivity since all eleven studied aromatic aldehydes afforded only alkyne 1 featured a fk concentrated on carbon 2 (0.178 unit)
one regioisomer with the yield of 50–95% after cycloaddition associated with a high discrimination between the two reactive
in the presence of 1 or 2 in CH2Cl2 at 70 °C (Table 2). If nitro- alkyne carbons (difference of 0.134 unit in favor of carbon 2).
benzaldehydes and benzaldehyde afforded tetrasubstituted
Conversely, alkynes 2 and 3 displayed a more balanced
furans in high yield, 2-aminofurans 5f or 5h, and 6f or 6h Fukui indices distribution. Indeed, whereas the highest fk+ was
resulting from 4-fluorobenzaldehyde or 4-pivaloyloxybenzalde- again concentrated on carbon 2 (0.051 and 0.105 unit for
+
hyde, respectively, were obtained in only 50% yield (Table 2).
2 and 3, respectively), fk indices on carbon 3 were calculated
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