A facile preparation of trisubstituted amino-furan and -thiophene derivatives

Article abstract of DOI:10.1039/c1ob05216k

β-Alkylation of amino-furan and -thiophene heterocycles is described through metal-, acid- and base-free carbon-carbon bond formation. The ability of both heterocycles to undergo selective β-alkylation is compared by mean of experimental and theoretical data. The presence of chiral amine substituents induced the diastereoselective generation of the newly formed additional stereocenter.

Full text of DOI:10.1039/c1ob05216k

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PAPER
A facile preparation of trisubstituted amino-furan and -thiophene derivatives†
Raouf Medimagh,a,b Sylvain Marque,*a Damien Prim*a and Saber Chattib
Received 9th February 2011, Accepted 6th June 2011
DOI: 10.1039/c1ob05216k
b-Alkylation of amino-furan and -thiophene heterocycles is described through metal-, acid- and
base-free carbon–carbon bond formation. The ability of both heterocycles to undergo selective
b-alkylation is compared by mean of experimental and theoretical data. The presence of chiral amine
substituents induced the diastereoselective generation of the newly formed additional stereocenter.
of expensive metals9 respectively is scarcely reported. In this
Introduction
context, the increase of the electronic density of the furan ring
Furans and thiophenes are among the most versatile five-
induced by the presence of electron-donating groups was shown
to be beneficial to the overall reactivity of furans10–14 allowing the
selective synthesis of complex molecular architectures. Moreover,
the presence of an amino substituent plausibly impacted the
electron density at adjacent carbon atoms. This pseudo “enamine-
type reactivity” was first evidenced by Boyd15 some years ago with
the formation of a C–N bond from aminofurylaryl derivatives
and electrophilic nitrogen atom precursors. In contrast, attempts
to generalise this methodology to the formation of C–C bonds
failed.15 The appealing “enamine-type property” of amino-furans
and -thiophenes has until now been greatly under-exploited. Thus,
the development of methods allowing the selective introduction of
electrophiles at amino furans or thiophenes under mild conditions
may open up new routes to polysubstituted heterocycles and more
complex architectures. In this context we report herein the metal-,
acid- and base-free electrophilic formation of carbon–carbon
bonds on 5-amino-2-carbonylated furans or thiophenes. The
behaviour of both heterocycles towards electrophiles is compared
at experimental and theoretical levels.
membered heterocycles commonly found in natural products
and widely used as building blocks in the synthesis of complex
molecular architectures. Although 2,5-disubstituted furans and
thiophenes are common compounds in these series, installation
of an additional substituent is usually not trivial and often
requires tedious procedures. 2,4,5-Trisubstituted analogues maybe
obtained either through the construction of the heterocycle from
appropriate precursors or through additional substitution of par-
ent 2,5-disubstituted furans.1–15 In addition to traditional routes1
using established Paal–Knorr2 or Feist–Be´nary3 procedures, recent
appealing papers by Li4a and Pirali4b described Pd/Cu-mediated
cascade and multicomponent reaction sequences respectively that
revived the interest for the polysubstituted targets. A phosphino-
assisted cyclisation strategy was also recently described by Lin5
via intramolecular Wittig-type reactions. Although undoubtedly
useful for the construction of furans, these procedures were not
applied to the analogous thiophene series. Although tremendous
work has been done, the direct b-alkylation of preformed hete-
rocycles, under classical metal-induced Friedel–Crafts conditions,
suffers from a lack of generalisation and is strongly dependent
on the substitution pattern.6 Nucleophilic-based alkylation of
electron-withdrawing group-substituted heterocycles such as 2-
nitrofuran or 2-nitrothiophene7 requires harsh conditions (strong
base or acid). In contrast, fewer studies have been directed
towards heterocycles bearing electron-donating substituents. b-
Alkylation of 2-acetamidothiophene or 2-imidazolothiophene
using the Vilsmeier–Haach reagent8 or requiring the presence
Results and discussion
Preparation of starting materials
We first prepared six aminofurans 1a–f and five aminothiophenes
2a–e starting from their parent commercial bromide derivatives.
If furans 1a–b and thiophenes 2a–b were synthesised as already
stated in refluxing water or water–dioxane mixture,11 the previous
conditions were not suitable for obtaining all the furan or
thiophene derivatives (Table 1). In fact, the introduction of
prolinol and proline or pipecolic acid moieties at aminohetero-
cycles required a further optimisation of the reaction conditions
(refluxing water and ethanolic solution respectively)16 Thus, new
aminoheterocycles were obtained in fair to high yields under
metal-free conditions.
aUniversite´ de Versailles-St-Quentin (UVSQ), Institut Lavoisier de
Versailles (ILV) UMR CNRS 8180, 45 Avenue des Etats-Unis,
78035, Versailles Cedex, France. E-mail: prim@chimie.uvsq.fr, sylvain.
marque@chimie.uvsq.fr; Fax: (+33) 1 39 25 44 52; Tel: (+33) 1 39 25
44 54
bInstitut National de Recherche et d’Analyse Physico-chimique (INRAP),
Laboratoire des Substances Naturelles, LR10 INRAP02, Poˆle Tech-
nologique de Sidi Thabet, 2020, Sidi Thabet, Tunisia
† Electronic supplementary information (ESI) available: Cartesian coor-
dinates and energies, copies of 1H NMR and 13C NMR spectra for the
synthesised compounds. See DOI: 10.1039/c1ob05216k
With the aim of investigating the diastereoselective formation of
the C–C bond and the role of the protected-free hydroxyl group,
we further extended the range of reactants to the O-protected
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Table 1 Preparation of 2-carbonylated 5-aminoheterocycles 1a–f & 2a–e
Table 2 C–C bond formations with the furan derivatives 1a–h
Entry
X
Y
R2R1NH
Product
Yield (%)c
1a
O
O
O
O
O
O
S
S
S
S
S
CHO
CHO
CHO
CHO
CHO
CHO
CHO
CHO
CHO
CHO
COMe
Morpholine
Piperidine
(S)-Prolinol
(L)-(-)-Proline
( )-Pipecolic acid
N-Methylallylamine
Morpholine
Piperidine
(S)-Prolinol
1a
1b
1c
1d
1e
1f
2a
2b
2c
2d
2e
98 17
80 17
50
2a
Time
(h)
Yield
(%)
3c
Entry Furan 1 R3
R4
Product 3
drd
4d
73
65
5d
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1b
1d
1e
1f
1g
1g
1h
1h
CF3
CF3
CF3
CO2Me 18
CO2Me 18
3aa
90a
91b
85a
78a
nra
nra
42a
50b
79b
57a
39c
72a
62b
—
—
—
—
—
—
—
—
6: 1
1: 1
—
2: 1
2: 1
5: 1
—
6b
78 11d
73 17
64 18
23
3aa
7a
CF3
18
48
18
3ab
3ac
—
—
8a
CF2Cl CF2Cl
9c
CF3
CH3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CH3
10d
11e
(L)-(-)-Proline
(S)-Prolinol
40
43
CO2Me 18
CF3 24
CO2Me 18
CO2Me 18
3bb
3da
a Amine (2 eq), NEt3 (3 eq) in refluxing water. b Amine (2 eq), NEt3 (3 eq)
in refluxing dioxane : water (9 : 1). c Aminoalcohol (1.5 eq), NEt3 (2 eq)
in refluxing water. d Aminoacid (1.01 eq), NaHCO3 (4 eq) in refluxing
EtOH : H2O (1 : 1). e Amine (2 eq), NEt3 (3 eq) in water under pressure.
9
3ea
10
11
12
13
14
CF3
20
3fb
CO2Me 18
CO2Me 16
CO2Me 16
3ga
3ga
3ha
CF3
16
Degradationa
substrates. Although O-benzylated and O-silylated derivatives
could not be isolated, generating both side products and degra-
dation upon purification, O-mesylated heterocycles 1g, 2g, 2f
could be obtained in very good yields, starting from the parent
prolinol reactants (Fig. 1). On the other hand 3-morpholino-2-
thiophenecarboxaldehyde 2h was synthesised from its 3-bromide
parent in 82% yield.17 Thus, cyclic, acyclic, chiral functionalised
amines were introduced iton 2-carbonylated furans or thiophenes
giving a wide variety of potent nucleophilic heterocycles.
a Experiment conducted in refluxing toluene. b Experiment conducted in
CH2Cl2 at rt. c Experiment conducted in CH2Cl2 at reflux. d dr measured
in 1H NMR spectroscopy on the isolated product mixture.
The use of additional MgSO4 and/or Dean–Stark apparatus
and/or a closed vessel gave similar results. As expected, the use of
the lesser electrophilic dichlorotetrafluoroketone with 1a required
a prolonged reaction time (48 h) for completion. Nevertheless the
corresponding alcohol 3ac was isolated in 78% yield (entry 4).
As a minimum, the presence of the both a-polyfluorinated and
other electron-withdrawing moieties that substituted the ketone
were required to get the corresponding product. In fact, 1,1,1-
trifluoropropanone or methyl pyruvate were revealed to be inactive
with 1a (entries 5 and 6). Thus the enaminic character was
illustrated by methyl trifluoropyruvate with the furans 1d, 1e, 1h
giving the tertiary alcohols 3da, 3ea, 3ha respectively (entries 8,
9, 13).
Fig. 1 Further functionalisation of heterocycles 1g–h and 2f–h.
Interestingly, the C–C bond formation gave a mixture of insepa-
rable diastereomers 3 starting from an unsymmetrical electrophile.
The diastereomeric ratio was determined by NMR spectroscopies
analysis based on the displacements in each diastereomers. The
relative intensity of the singlet signal of the methyl carboxylate
group was compared for the two diastereomers in 1H NMR
spectroscopy and then corroborated in 19F NMR spectroscopy
by the relative intensity of the two signals of the trifluoromethyl
moiety. Low to moderate dr were observed depending on the chiral
amine residue.
The use of the (L)-(-)-proline furan derivative induced the
diastereoselective introduction in a 6 : 1 ratio that could not be
increased by modifications of the reaction conditions (Table 2,
entry 8). In contrast, moving from proline to pipecolic acid or to
mesylated prolinol dramatically affected the diastereoselectivity
of the reaction (entry 9). It is worth noting that the O-Boc
protective group similarly allowed a good 5 : 1 dr to be maintained
(entry 13).
Enaminic behavior in the furan series
We next focused our attention to the formation15 of carbon–carbon
bonds in the furan series (Table 2). We anticipated that strong
electrophilic partners would be able to induce carbon–carbon
bonds with aminoheterocycle substrates. In fact, preliminary
results with 1a and tert-butyl chloride or 2-nitrobenzaldehyde gave
unsatisfactory results. We decided to use methyl trifluoropyruvate
as a better electrophile.19
5-Morpholino-2-furancarboxaldehyde 1a reacted with methyl
trifluoropyruvate at rt in DCM giving 3aa with 91% yield (entry
2). Moving from trifluoropyruvate reactant to hexafluoroacetone
gave a surprising result showing a lesser reactivity (85%) even in
refluxing toluene (entry 3). This difference was more pronounced
with the substrate 1g which reacted with methyl trifluoropyruvate
at rt whereas no reaction occurred with hexafluoroacetone at 110◦
(entry 10). This behavior was likely due to the sesquihydrate form
of hexafluoroacetone decreasing the electrophilicity (vide infra).
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Table 3 C–C bond formation with the thiophene derivatives 2a–g
Table 4 Calculation results for the electrophiles
Entry
Compound
LUMOa
1
2
3
4
5
6
7
1,1,1-Trifluoropropanone
Methyl pyruvate
Hexafluoroacetone·H2O
Hexafluoroacetone·2 H2O
Methyl trifluoropyruvate (a)
1,3-Dichloro-1,3-tetrafluoroacetone (g)
Hexafluoroacetone
-2.10
-2.33
-2.81
-3.07
-3.35
-3.37
-3.48
Entry
Thiophene 2
Time (h)
Product
Yield (%)
drd
1
2
3
4
5
6
7
2a
2a
2b
2d
2d
2f
66
66
18
18
42
18
24
4a
4a
4b
4d
4d
4f
40c
84a
66a
50b
99b
89a
69a
—
—
—
2: 1
2: 1
1: 1
2: 1
a Energy of the Lowest Unoccupied Molecular Orbital (eV).
Table 5 Calculation results for the nucleophiles
2g
4g
Entry Compound
HOMOa
Exp. resultb
Conditions
a Experience conducted in refluxing toluene. b Experience conducted in
CH2Cl2 at rt. c Experience conducted in CH2Cl2 at reflux. d dr measured in
1H NMR spectroscopy on the isolated product mixture.
1
2
3
4
5
6
2-N-(Prolino)furan
-5.11
-5.72
-5.77
-5.78
-6.01
-7.21
—
50
79
50
39
—
1d
DCM, 20 ◦C
1e
DCM, 20 ◦
DCM, 20 ◦
DCM, 40 ◦
C
C
C
2d
1g
2-Furaldehyde
No reaction Tol, 110 ◦
C
Enaminic behavior in the thiophene series
a Energy of the Highest Occupied Molecular Orbital (eV). b Yield obtained
with methyl trifluoropyruvate during 18 h.
The thiophene series was slightly less reactive. Although the
reaction with 2a and methyl trifluoropyruvate took place in DCM
at 40◦, refluxing toluene was required to obtain a good yield
(Table 3, entries 1 and 2). Surprisingly, the C–C bond formation
was easily exemplified with thiophenes 2d and 2g after prolonged
reaction times leading to 4d and 4g in 99 and 69% yield respectively
(entries 5 and 7). This was an expected result since 5-amino-2-
thiophenecarboxaldehydes did not display Diels–Alder reactivity
unlike the furan series.11
The keto substrate 2f yielded 4f in high yield and thus
compared favorably to the carboxaldehyde analogue (entries 6
and 7). The influence of the position of the amino moiety was
next examined. No reaction occurred between 3-morpholino-2-
thiophenecarboxaldehyde 2h and methyl trifluoropyruvate even
under harsh conditions for prolonged reaction time (toluene,
110◦, 66 h) confirming a similar enaminic-type behaviour be-
tween both amino heterocycles vis-a`-vis electrophiles such as a-
polyhalogenated ketones. Moving from the furan to thiophene
series gave a decrease of the stereoinduction (Table 3, entries 4
and 5 compared to Table 2, entry 8). In addition, alkylation of
mesyl protected thiophenes 2g, 2f led to low dr (Table 3, entries 6
and 7) indicating a similar trend in the stereoinduction regardless
of the heterocycle.
Fig. 2 LUMO representation for an isovalue at 95%.
Calculations
In order to gain more information and insight in regard to
the b-alkylation results, calculations have been performed. The
experimental results were compared to calculations, on the one
hand, to verify the reactivity order, and on the other hand to
investigate the enaminic character. The geometry optimisations
and energies of aminoheterocycles 1d, 1e, 1g, 2d, 2g, as well as of
the electrophiles, were performed in the gas phase at a B3LYP/6-
311+G(d,p) level of theory20 with standard parameters for both
reactants using the Gaussian 09 Package software.21 The main
calculations results are gathered in Table 4, Fig. 2 and Table 5,
Fig. 3 for the electrophiles and the heterocycles respectively.
Fig. 3 HOMO representation for an isovalue at 95%.
We have first checked that the shape of the LUMOs of the
electrophiles presented adequate symmetry to interact with the
HOMOs of the substrates (Fig. 2 and 3).
The examination of the calculated LUMO values and the exper-
imental results allowed to distinguish two classes of electrophiles:
i) unreactive electrophiles (1,1,1-trifluoropropanone and methyl
pyruvate), ii) reactive ones a, b and c, associating both halogenated
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moiety and another withdrawing group with the ketone. The latter
combination ensured the closest electrophile LUMO and substrate
HOMO values (Table 4, entries 5, 6 and 7). Interestingly, the
presence of surrounding water molecules in hexafluoroacetone
affected the LUMO energy level ranging from -3.48 to -2.81
eV (entries 3, 4 and 7) and explained the hexafluoroacetone
sesquihydrate poor reactivity observed (vide supra).
Considering the frontier molecular orbital theory, the introduc-
tion of an amino group clearly confirmed the increase of the energy
level of the HOMO compared to the unsubstituted 2-furaldehyde
in which case no reaction occurred (Table 5, entry 6). The HOMO
levels were roughly equal between 1d, 1e, 2d (compare entries
2, 3, 4). In contrast, 1g exhibited a slightly lower HOMO level
(entry 5). This marked difference was in good agreement with the
yields observed and the experimental conditions employed. As
shown in Fig. 3, the increase of the C-4 relative coefficient in 1d,
1e, 2d, 1g highlighted the enaminic character of the N–C5–C4
bond sequence. The latter enaminic character is likely due to the
presence of the amine moiety that induced a strong modification
of the balance symmetry of the p-aromatic orbital system and
thus resulted in an enhanced reactivity toward electrophiles. It is
worth noting that the enaminic character is similar moving from
furan to thiophene (entries 2 and 4). In contrast to the marked
difference of reactivity between amino-furans and -thiophenes as
dienes in Diels–Alder reactions,11 the present study evidenced a
similar behaviour for both heterocycles.
Scheme 1 Access to furan-fused oxazepin(on)es 5 and 6.
tricyclic oxazepine and oxazepinone could be obtained through
intramolecular etherification and lactonisation processes.
Experimental
General methods
Unless otherwise noted, all starting materials were obtained from
commercial suppliers and used without purification. Petroleum
ether was distilled under Argon. Toluene was used without
distillation. All reactions were carried out under an atmosphere of
dry argon. Solutions were evaporated under reduced pressure with
a rotary evaporator and the residue was purified by silica gel flash
chromatography using an ethyl acetate–petroleum ether mixture as
the eluent unless specified otherwise. NMR spectra were recorded
on 300 MHz and 200 MHz spectrometers. Chemical shifts were
reported in ppm relative to the residual solvent peak (7.26 ppm
for CHCl3, 2.05 ppm for acetone-d6, 3.31 ppm for CD3OD) for
1H spectra and (77.0 ppm for CDCl3, 206.0 ppm for acetone-
d6, 49.0 ppm for CD3OD) for 13C spectra. Melting points were
measured on a Melting-Point B-545 device and were uncorrected.
High Resolution Mass spectroscopy data in electronic impact
were recorded with a resolution of 5000 RP at 5%. Electronic
impact (EI) and chemical ionisation (CI) mass spectroscopies were
recorded on a HP5989 B device. Electrospray ionisation (ESI) mass
spectroscopy was recorded on an UPLC Waters device (in positive
mode unless otherwise noted). Infrared spectra were recorded on a
FT IR spectrometer in KBr for liquid and solid compounds. TLC
was carried out on Silica Gel 60 F254 (0.5 mm thickness).
Synthesis of furan-fused oxazepin(on)e
Amino heterocycles bearing adjacent substituents in positions 4
and 5 are of particular interest. Indeed, formation of a fused
seven membered ring may result from intramolecular etherifi-
cation or lactonisation processes of substrates bearing adequate
combination of functional groups. Taking into account that
fused heterocycles based on a 7-membered central ring and/or
a fluorinated moiety such as Chloropramine or Telcagepant
are pharmaceutically-relevant compounds,22 new access to such
architectures from easily accessible building-blocks is of high
interest.23 The joint presence of OMs and OH or COOH and OH
groups in 3ga and 4f or 3da and 4g may generate the formation
of oxazepine or oxazepinone rings respectively. Surprisingly, both
heterocycles did not exhibit similar behaviour. Indeed, extensive
attempts to promote both etherification and lactonisation starting
from thiophenes 4d, 4f, 4g failed. In contrast, etherification
and lactonisation gratifyingly led to the fused tricyclic targets
(Scheme 1). The O-mesylated compound 3ga reacted with sodium
hydride in THF to cleanly afford oxazepine 5 in 52% yield.
In addition, oxazepinone 6 could be obtained under classical
coupling conditions from carboxylic acid 3da in 60% yield.
(S)-5-(2-Hydroxymethyl)pyrrolidin-1-yl-2-furancarboxaldehyde
(1c)
Following the general procedure for amination,11d 5-bromo-2-
furancarboxaldehyde led to 1c as an yellow solid (50%) af-
ter silica gel flash chromatography (petroleum ether : MeOH
Conclusions
9.5 : 0.5). Rf : 0.12 (petroleum ether : EtOAc 2 : 8); 0.22 (petroleum
◦
ether : EtOAc : MeOH 4.5 : 5 : 0.5). Mp: 119.3–120.1 ◦C. [a]D
=
20
C
In conclusion, we succeeded in the selective b-alkylation of
5-amino-2-carbonylated furans or thiophenes by a convenient
atom economical procedure. Both experimental and theoretical
data suggested that furans and thiophenes behave similarly
towards functionalised electrophiles. The presence of chiral
amine substituents induced the diastereoselective formation of
neighbouring carbon–carbon bonds. Unprecedented furan-fused
¥ 153 8 (c = 0.116; CHCl3). IR (KBr, n, cm-1): 3446, 3113,
2950, 2874, 1637, 1584, 1405, 1278, 1246, 1160, 1141, 1048, 1025,
942, 793, 756. 1H NMR (CDCl3, 300 MHz) d 2.01–2.06 (m, 4H,
NCH2C2H4), 3.00 (brs, 1H, OH), 3.39–3.45 (m, 1H, NCH2), 3.54–
3
3.56 (m, 1H, NCH2), 3.69 (d, J = 5.4 Hz, 2H, NCHCH2OH),
4.00–4.04 (m, 1H, NCHCH2OH), 5.29 (d, 3J = 3.9 Hz, 1H,
6058 | Org. Biomol. Chem., 2011, 9, 6055–6065
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3
HC CN), 7.19 (d, J = 3.1 Hz, 1H, HC CCHO), 8.89 (s, 1H,
2.45 (m, 1H, NC2H4CH2CHH), 3.43–3.51 (m, 2H, NCH2), 5.04
CHO). 13C NMR (CDCl3, 75 MHz) d 23.9 (NCH2CH2CH2), 28.4
(NCH2CH2CH2), 48.8 (NCH2CH2CH2), 61.3 (NCHCH2OH),
63.7 (NCHCH2OH), 87.3 (HC CN), 132.1 (HC CCHO), 144.4
(HC CN), 162.6 (HC CCHO), 170.5 (CHO). MS (CI, NH3)
m/z (rel int): 196.1 (50, M + H+), 218.1 (100, M + Na+). MS
(ESI, CH3CN) m/z (rel int): 196.0 (20, M + H+), 218.0 (100, M +
Na+), 279.1 (65). HRMS (ESI, CH3CN) m/z: calcd for (M + Na+)
C10H13NO3Na 218.0793; found 218.0775.
(d, J = 4.2 Hz, 1H, NCHCOOH), 5.41 (d, J = 4.1 Hz, 1H,
3
3
3
HC CN), 7.28 (d, J = 4.2 Hz, 1H, HC CCHO), 8.70 (s, 1H,
CHO), 9.41 (brs, 1H, COOH). 13C NMR (CDCl3, 75 MHz) d 20.0
(NCH2CH2CH2), 24.3 (NCH2CH2CH2), 26.6 (NC2H4CH2CH2),
44.1 (NCH2CH2CH2), 55.3 (NCHCOOH), 88.9 (HC CN), 134.0
(HC CCHO), 143.4 (HC CN), 164.9 (HC CCHO), 170.1
(CHO), 172.7 (CO2H). MS (ESI+, MeOH) m/z (rel int): 178.0
(20), 224.0 (100, M + H+), 246.0 (100, M + Na+), 262.0 (20), 469.1
(20, 2M + Na+). MS (ESI-, MeOH) m/z (rel int): 222.0 (100, M -
H-), 445.1 (15, 2M - H-). HRMS (ESI+, MeOH) m/z: calcd for
(M + H+) C11H14NO4 224.0923; found 224.0889.
(S)-1-(5-Formylfuran-2-yl)pyrrolidine-2-carboxylic acid (1d)
In a 25 mL round-bottom flask were mixed 5-bromo-2-
furancarboxaldehyde (500.0 mg, 2.86 mmol, 1 eq), (-)-(L)-
proline (334.0 mg, 2.89 mmol, 1.1 eq) and NaHCO3 (729.0 mg,
17.13 mmol, 3 eq) in a mixture of water : ethanol 1 : 1 (30 mL).
The mixture was heated at reflux for 6 h. The mixture was allowed
to cool to rt and then a HCl solution (1 N) was added until
pH ª 3 (15 mL). The mixture was extracted with EtOAc (4 ¥
100 mL). The combined organic layers were dried over MgSO4 and
concentrated under reduced pressure. The residue was purified by
silica gel flash chromatography (CH2Cl2 : MeOH 9 : 1) to afford
441.4 mg of 1d as a blue powder (74%). Rf : 0.13 (CH2Cl2 : MeOH
9 : 1). Mp: 171.6–172.2 ◦C. The solution was too dark therefore
the optical rotation could not be measured. IR (KBr, n, cm-1):
3436, 3132, 2957, 2883, 1721, 1644, 1569, 1412, 1345, 1292, 1225,
1152, 1044, 915, 769. 1H NMR (CD3OD, 300 MHz) d 2.03–
2.47 (m, 4H, NCH2C2H4), 3.54–3.72 (m, 2H, NCH2), 4.50 (dd,
(S)-(1-(5-Formylfuran-2-yl)pyrrolidin-2-yl)methylmethanesul
fonate (1g)
To a solution of 1c (217.5 mg, 1.114 mmol, 1 eq) in CH2Cl2
(5 mL) was added triethylamine (185 mL, 1.321 mmol, 1.2 eq).
The reaction was cooled to 0 ◦C and MsCl (100 mL, 1.266 mmol,
1.1 eq) was added dropwise. The mixture was allowed to reach rt
and stirred during 2 h. The reaction was stopped by the addition of
a NaHCO3 saturated solution (10 mL) and organic materials were
extracted with CH2Cl2 (4 ¥ 10 mL). The combined organic layers
were dried over MgSO4, filtered, and concentrated under vacuum.
The residue was purified by silica gel flash chromatography
to afford 292.9 mg of 1g with 96% as a blue oil (petroleum
ether : EtOAc 3 : 7 to 2 : 8). Rf : 0.28 (petroleum ether : EtOAc 2 : 8).
◦
◦
C
20
C
20
[a]D
= -143 10 (c = 0.029; CHCl3); [a]546Hg
= -225 11 (c =
3J = 8.7 and 3.1 Hz, 1H, NCHCOOH), 5.43 (d, J = 4.2 Hz,
0.029; CHCl3). IR (neat, n, cm-1): 3128, 3011, 2975, 2959, 2936,
3
3
1H, HC CN), 7.48 (d, J = 4.1 Hz, 1H, HC CCHO), 8.75
2879, 2084, 1650, 1567, 1545, 1479, 1462, 1409, 1354, 1281, 1174,
(s, 1H, CHO). 1H NMR (CDCl3, 200 MHz) d 2.04–2.19 (m,
2H, NCH2C2H4), 2.23–2.39 (m, 2H, NCH2C2H4), 3.39–3.51 (m,
1H, NCH2), 3.62–3.73 (m, 1H, NCH2), 4.78 (t, 3J = 5.1 Hz, 1H,
NCHCOOH), 4.16 (d, 3J = 4.2 Hz, 1H, HC CCHO), 5.50–6.00
(brm, 1H, OH), 7.28 (d, 3J = 4.3 Hz, 1H, HC CCHO), 8.69 (s,
1H, CHO). 13C NMR (CD3OD, 75 MHz) d 24.8 (NCH2CH2CH2),
31.7 (NCH2CH2CH2), 49.4 (NCH2CH2CH2), 61.9 (NCHCOOH),
89.3 (HC CN), 135.4 (HC CCHO), 146.0 (HC CN), 164.0
(HC CCHO), 171.7 (CHO), 175.3 (COOH). MS (ESI, CH3CN)
m/z (rel int): 210.0 (40, M + H+), 232.0 (100, M + Na+), 441.1
(30, 2M + Na+). HRMS (ESI, CH3CN) m/z: calcd for (M + Na+)
C10H11NO4Na 232.0586; found 232.0562.
1030, 960, 927, 914, 850, 826, 765. H NMR (CDCl3, 300 MHz)
1
d 1.99–2.17 (m, 4H, NCH2C2H4), 2.99 (s, 3H, CH3), 3.33–3.41
(m, 1H, NCH2), 3.52–3.59 (m, 1H, NCH2), 4.15–4.22 (m, 1H,
NCHCH2OMs), 4.26–4.32 (m, 2H, NCHCH2OMs), 5.28 (d, 3J =
4.1 Hz, 1H, HC CN), 7.19 (brs, 1H, HC CCHO), 8.97 (s, 1H,
CHO). 13C NMR (CDCl3, 75 MHz) d 23.5 (NCH2CH2CH2),
28.3 (NCH2CH2CH2), 37.2 (SCH3), 48.6 (NCH2CH2CH2), 57.8
(NCHCH2OMs), 69.1 (NCHCH2OMs), 86.9 (HC CN), 131.3
(HC CCHO), 144.7 (HC CN), 161.3 (HC CCHO), 171.2
(CHO). MS (ESI+, CH3CN) m/z (rel int): 250.5 (25), 273.1 (70),
274.1 (50, M + H+), 501.1 (50), 569.1 (100, 2M + Na+). HRMS
(ESI+, CH3CN) m/z: calcd for (M + H+) C11H16NO5S 274.0749;
found 274.0764.
1-(5-Formylfuran-2-yl)piperidine-2-carboxylic acid (1e)
(S)-tert-Butyl (1-(5-formylfuran-2-yl)pyrrolidin-2-yl)methyl
carbonate (1h)
In a 25 mL round-bottom flask were mixed 5-bromo-2-
furancarboxaldehyde (200.0 mg, 1.149 mmol, 1 eq), pipecolic acid
(149.8 mg, 1.160 mmol, 1 eq) and NaHCO3 (288.0 mg, 3.428 mmol,
3 eq) in a mixture of water : ethanol 1 : 1 (20 mL). The mixture was
heated at reflux for 6 h. The mixture was allowed to cool to rt
and then a HCl solution (1 N) was added until pH ª 3. The
mixture was extracted with EtOAc (2 ¥ 20 mL). The combined
organic layers were dried over MgSO4 and concentrated under
reduced pressure. The residue was purified by silica gel flash
chromatography (CH2Cl2 : MeOH 97.5 : 2.5 to 92 : 8) to afford
165.2 mg of 1e as a green oil (65%). Rf : 0.14 (CH2Cl2 : MeOH
95 : 5). IR (KBr, n, cm-1): 2952, 2861, 1715, 1532, 1331, 1258, 1178,
1030, 982, 888, 776, 749. 1H NMR (CDCl3, 300 MHz) d 1.45–1.62
(m, 2H, NCH2CH2), 1.75–1.86 (m, 3H, NC2H4CH2CHH), 2.38–
To a solution of 1c (196.3 mg, 1.005 mmol, 1 eq) in CH2Cl2
(10 mL) were added triethylamine (190 mL, 1.356 mmol, 1.3 eq),
then Boc2O (837.0 mL, 3.720 mmol, 3.5 eq). The solution was
stirred at reflux for 18 h, then cooled to rt. The reaction was
stopped by addition of a NaHCO3 saturated solution (5 mL) and
the organic layer was extracted with CHCl3 (2 ¥ 10 mL). The
combined organic layers were dried over MgSO4, filtered, and
concentrated under vacuum. The residue was purified by silica
gel flash chromatography (petroleum ether : EtOAc 1 : 1) to afford
245.5 mg of 1h with 83% as a brown oil. Rf: 0.31 (petroleum
◦
20
C
ether : EtOAc 5 : 5); 0.51 (petroleum ether : EtOAc 2 : 8). [a]D
=
-137 12 (c = 0.045; CHCl3). IR (KBr, n, cm-1): 3127, 2977,
Org. Biomol. Chem., 2011, 9, 6055–6065 | 6059
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2875, 2796, 1741, 1657, 1651, 1580, 1538, 1409, 1277, 1254,
1158, 1100, 1027, 859, 768. 1H NMR (CDCl3, 300 MHz) d
1.42 (s, 9H, CH3), 1.95–2.07 (m, 4H, NCH2C2H4), 3.35–3.45
(m, 1H, NCH2), 3.55–3.65 (m, 1H, NCH2), 3.95–4.01 (m, 1H,
NCHCH2OBoc), 4.04–4.07 (m, 1H, NCHCH2OBoc), 4.17 (dd,
2J = 10.2, 3J = 3.7 Hz, 1H, NCHCH2OBoc), 5.30 (d, 3J = 3.9 Hz,
1H, HC CN), 7.10–7.20 (m, 1H, HC CCHO), 8.94 (s, 1H,
CHO). 13C NMR (CDCl3, 75 MHz) d 23.4 (NCH2CH2CH2),
27.6 (COCH3), 28.5 (NCH2CH2CH2), 48.3 (NCH2CH2CH2),
57.8 (NCHCH2OBoc), 66.2 (NCHCH2OBoc), 82.4 (C), 86.7
(HC CN), 131.5 (HC CCHO), 144.6 (C), 153.1 (C), 161.7
(CO2Boc), 170.8 (CHO). MS (ESI+, CH3CN) m/z (rel int): 218.1
(15), 262.1 (35), 318.1 (100, M + Na+), 613.2 (40, 2M + Na+).
HRMS (ESI+, CH3CN) m/z: calcd for (M + Na+) C15H21NO5Na
318.1317; found 318.1303.
3.7 Hz, 1H, HC CCHO), 8.50–9.29 (br, 1H, COOH), 9.29 (s, 1H,
CHO). 13C NMR (acetone-d6, 50 MHz) d 24.7 (NCH2CH2CH2),
31.6 (NCH2CH2CH2), 52.0 (NCH2CH2CH2), 63.8 (NCHCOOH),
104.2 (HC CN), 127.9 (HC CCHO), 140.7 (HC CN), 163.8
(HC CCHO), 172.9 (COOH),180.2 (CHO). MS (ESI+, CH3CN)
m/z (rel int): 182.1 (50), 217.0 (60), 226.0 (20, M + H+), 229.1 (80),
248.0 (50, M + Na+), 251.1 (100), 301.1 (25), 473.1 (20, 2M + Na+).
MS (ESI-, CH3CN) m/z (rel int): 152.0 (100), 162.9 (25), 224.0
(40, M - H-), 471.1 (5, 2M - 2H+Na-). HRMS (ESI+, CH3CN)
m/z: calcd for (M + H+) C10H12NO3S 226.0538; found 226.0545.
(S)-1-(5-(2-(Hydroxymethyl)pyrrolidin-1-yl)thiophen-2-yl)
ethanone (2e)
In
a
reactor tube 5-bromo-2-acetylthiophene (998.0 mg,
eq) was dissolved in mixture of
4.818 mmol,
1
a
(S)-5-(2-(Hydroxymethyl)pyrrolidin-1-yl)thiophene-2-
carboxaldehyde (2c)
water : triethylamine 1 : 1 (8 mL), then (S)-prolinol (0.97 mL,
8.979 mmol, 2 eq) was added. The tube was sealed and the mixture
◦
was stirred at 145 C for 66 h. The reaction was allowed to cool
Following the general procedure for amination,11d 5-bromo-2-
thiophenecarboxaldehyde led to 127.8 mg of 2c as an yellow
solid (23%) after silica gel flash chromatography (petroleum
to rt, then stopped with a NaHCO3 saturated solution (5 mL)
and the organic layer was extracted with CH2Cl2 (3 ¥ 20 mL).
The combined organic layers were dried over MgSO4, filtered,
and concentrated under vacuum. The residue was purified by
silica gel flash chromatography (petroleum ether : EtOAc 1 : 1)
to afford 460.0 mg of 2e with 43% as orange crystals. Rf: 0.14
(petroleum ether : EtOAc 1 : 1); 0.46 (petroleum ether : EtOAc
ether : EtOAc 2 : 8). Rf : 0.40 (petroleum ether : EtOAc 1 : 9); 0.11
◦
(petroleum ether : EtOAc 1 : 1). Mp: 94.2–94.8 ◦C. [a]D
= -119
20
C
8 (c = 0.102; CHCl3). IR (KBr, n, cm-1): 3361, 2979, 2918, 2855,
1607, 1534, 1493, 1455, 1367, 1272, 1052, 1036, 768, 744. 1H NMR
(CDCl3, 300 MHz) d 2.01–2.25 (m, 4H, NCH2C2H4), 2.69 (brs,
1H, OH), 3.25–3.34 (m, 1H, NCH2), 3.48–3.55 (m, 1H, NCH2),
3.73 (dd, 3J = 5.1, 2J = 1.3 Hz, 2H, NCHCH2OH), 3.78–3.86 (m,
1H, NCHCH2OH), 5.98 (d, 3J = 4.4 Hz, 1H, HC CN), 7.44 (d,
3J = 4.4 Hz, 1H, HC CCHO), 9.40 (s, 1H, CHO). 13C NMR
(CDCl3, 75 MHz) d 24.0 (NCH2CH2CH2), 28.8 (NCH2CH2CH2),
52.1 (NCH2CH2CH2), 62.2 (NCHCH2OH), 64.2 (NCHCH2OH),
103.9 (HC CN), 126.1 (HC CN), 140.6 (HC CCHO), 164.9
(HC CCHO), 179.9 (CHO). MS (ESI-, CH3CN) m/z (rel int):
297.1 (20), 311.1 (45), 325.2 (100), 339.2 (25). MS (ESI+, CH3CN)
m/z (rel int): 177.1 (70), 212.1 (100, M + H+), 234.1 (50, M +
Na+), 245.1 (70), 248.2 (20), 445.1 (20, 2M + Na+), 467 (20).
HRMS (ESI+, CH3CN) m/z: calcd for (M + Na+) C10H13NO2SNa
234.0565; found 234.0562.
◦
◦
20
C
2 : 8). Mp: 98.5–99.6 C. [a]D
= -119 8 (c = 0.102; CHCl3).
IR (KBr, n, cm-1): 3321, 2965, 2927, 2874, 2849, 1580, 1534, 1518,
1475, 1359, 1325, 1130, 1097, 1072, 1022, 934, 760. H NMR
1
(CDCl3, 300 MHz) d 2.00–2.20 (m, 4H, NCH2C2H4), 2.38 (s,
3H, CH3), 2.44–2.50 (m, 1H, OH), 3.21–3.30 (m, 1H, NCH2),
3.46–3.53 (m, 1H, NCH2), 3.68–3.75 (m, 2H, NCHCH2OH),
3.75–3.85 (m, 1H, NCHCH2OH), 5.88 (d, 3J = 4.4 Hz, 1H,
3
HC CN), 7.42 (d, J = 4.4 Hz, 1H, HC CCOMe). 13C NMR
(CDCl3, 75 MHz) d 24.0 (Me), 24.1 (NCH2CH2CH2), 28.8
(NCH2CH2CH2), 52.0 (NCH2CH2CH2), 62.3 (NCHCH2OH),
64.1 (NCHCH2OH), 103.0 (HC CN), 126.7 (HC CN), 135.9
(HC CCOMe), 163.8 (HC CCOMe), 188.4 (COMe). MS
(ESI+, CH3CN) m/z (rel int): 226.1 (5, M + H+), 248.1 (80,
M + Na+), 301.1 (100), 473.1 (25), 526.1 (25), 579.1 (100, M +
Na+), 580.2 (50). HRMS (ESI+, CH3CN) m/z: calcd for (M +
H+) C11H16NO2S 226.0902; found 226.0911.
(S)-1-(5-Formylthiophen-2-yl)pyrrolidine-2-carboxylic acid (2d)
In a 25 mL round-bottom flask were mixed 5-bromo-2-
thiophenecarboxaldehyde (246.2 mg, 1.29 mmol, 1 eq), (-)-(L)-
proline (156.7 mg, 1.36 mmol, 1.1 eq) and NaHCO3 (347.7 mg,
4.46 mmol, 3 eq) in a mixture of water : ethanol 1 : 1 (15 mL). The
mixture was heated at reflux for 18 h. The mixture was allowed to
cool to rt and then a HCl solution (2 N) was added until pH ª 3
(1.7 mL). The organic materials were extracted with EtOAc (4 ¥
50 mL). The combined organic layers were dried over MgSO4 and
concentrated under reduced pressure. The residue was purified by
silica gel flash chromatography (petroleum ether : EtOAc 50 : 50
to 20 : 80) to afford 116.3 mg of 2d as a blue powder (40%). Rf :
0.10 (CH2Cl2 : MeOH 9 : 1). Mp: 176.9–180.0 ◦C. The solution was
too dark therefore the optical rotation could not be measured.
IR (KBr, n, cm-1): 3434–2871, 1734, 1629, 1532, 1488, 1473,
(S)-(1-(5-Acetylthiophen-2-yl)pyrrolidin-2-yl)methylmethane
sulfonate (2f)
To a solution of 2e (309.2 mg, 1.372 mmol, 1 eq) in CH2Cl2
(6 mL) was added triethylamine (230 mL, 1.642 mmol, 1.2 eq).
The reaction was cooled to 0 ◦C and MsCl (120 mL, 1.519 mmol,
1 eq) was added dropwise. The mixture was allowed to reach rt
and stirred for 4 h. The reaction was stopped by addition of a
NaHCO3 saturated solution (10 mL) and the organic layer was
extracted with CH2Cl2 (3 ¥ 10 mL). The combined organic layers
were dried over MgSO4, filtered, and concentrated under vacuum.
The residue was purified by silica gel flash chromatography
(petroleum ether : EtOAc 1 : 1) to afford 380.5 mg of 2f with
1
1457, 1209, 1063. H NMR (CDCl3, 200 MHz) d 1.80–2.40 (m,
92% as a green powder. Rf : 0.65 (petroleum ether : EtOAc 2 : 8).
◦
Mp: 87.4–87.8 ◦C. [a]D
= -119 6 (c = 0.146; CHCl3). IR
20
C
4H, NCH2C2H4), 3.30–3.70 (m, 2H, NCH2), 4.10–4.40 (m, 1H,
NCHCOOH), 5.90 (d, 3J = 3.2 Hz, 1H, HC CN), 7.44 (d, 3J =
(KBr, n, cm-1): 3009, 2932, 2913, 2858, 2836, 1620, 1538, 1477,
This journal is The Royal Society of Chemistry 2011
6060 | Org. Biomol. Chem., 2011, 9, 6055–6065
©

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1
1454, 1360, 1310, 1167, 989, 967, 919, 851, 772, 532. H NMR
General procedure for 4-substituted-5-amino-2-carbonylated furan
or thiophene derivatives synthesis
(CDCl3, 300 MHz) d 2.08–2.19 (m, 4H, NCH2C2H4), 2.40 (s, 3H,
COCH3), 2.99 (s, 3H, SCH3), 3.22–3.32 (m, 1H, NCH2), 3.49–
3.55 (m, 1H, NCH2), 3.95–4.00 (m, 1H, NCHCH2OMs), 4.19
In a 10 mL round-bottom flask, 5-amino-2-carbonylated furan or
thiophene derivative 1 or 2 (50 mg, 1 eq) and the electrophile a,
b, or c (2 eq) were stirred in toluene (3 mL) at reflux overnight.
The crude mixture was allowed to cool to rt and concentrated
under reduced pressure. The residue was purified by silica gel flash
chromatography (petroleum ether : EtOAc).
2
3
2
(dd, J = 10.2, J = 6.8 Hz, 1H, NCHCH2OMs), 4.28 (dd, J =
3
3
10.3, J = 4.0 Hz, 1H, NCHCH2OMs), 5.91 (d, J = 4.3 Hz,
1H, HC CN), 7.44 (d, J = 4.3 Hz, 1H, HC CCOMe). 13C
3
NMR (CDCl3, 75 MHz) d 23.7 (NCH2CH2CH2), 25.1 (COCH3),
28.8 (NCH2CH2CH2), 37.5 (SCH3), 51.7 (NCH2CH2CH2), 60.8
(NCHCH2OMs), 67.6 (NCHCH2OMs), 103.2 (HC CN), 128.1
(HC CN), 135.4 (HC CCOMe), 162.4 (HC CCOMe), 188.6
(COMe). MS (ESI+, CH3CN) m/z (rel int): 304.1 (30, M + H+),
326.1 (100, M + Na+), 629.1 (30, 2M + Na+), 753.1 (15). HRMS
(ESI+, CH3CN) m/z: calcd for (M + H+) C12H18NO4S2 304.0677;
found 304.0679 and calcd for (M + Na+) C12H17NO4S2Na
326.0497; found 326.0511.
Methyl 3,3,3-trifluoro-2-(5-formyl-2-morpholinofuran-3-yl)-2-
hydroxypropanoate (3aa). Following the general procedure for
enamine reactivity, 1a (50.0 mg, 0.27 mmol, 1 eq) and methyl
trifluoropyruvate a (42 mL, 0.40 mmol, 1.5 eq) afforded 82.5 mg of
3aa as brown crystals (90%) after silica gel flash chromatography
(petroleum ether : EtOAc 65 : 35 to 6 : 4◦). Rf : 0.28 (petroleum
ether : EtOAc 60 : 40). Mp: 126.5–127.2 C. IR (KBr, n, cm-1):
3172, 2991, 2966, 2894, 2799, 1765, 1731, 1660, 1589, 1542, 1447,
1404, 1372, 1310, 1248, 1224, 1179, 1139, 1068, 1046, 1000, 950,
890, 867, 844, 793, 752, 687, 666. 1H NMR (CDCl3, 300 MHz): d =
3.11–3.22 (m, 2H, NCH2), 3.28–3.38 (m, 2H, NCH2), 3.71–3.77
(m, 4H, OCH2), 3.91 (s, 3H, CO2CH3), 7.34 (s, 1H, CH CCHO),
8.73 (s, 1H, OH), 9.36 (s, 1H, CHO) ppm. 13C NMR (CDCl3,
75 MHz): d = 50.7 (2C, NCH2), 54.6 (CO2CH3), 66.4 (2C,
OCH2), 75.0 (q, 2JC-F = 31 Hz, CCF3), 105.1 (NC CCCF3OH),
(S)-(1-(5-Formylthiophen-2-yl)pyrrolidin-2-yl)methylmethane
sulfonate (2g)
To a solution of 2c (99.8 mg, 0.47 mmol, 1 eq) in CH2Cl2 (6 mL)
was added triethylamine (80 mL, 0.57 mmol, 1.2 eq). The reaction
was cooled to -10 ◦C and MsCl (38 mL, 0.48 mmol, 1 eq) was
added dropwise. The mixture was allowed to reach rt and stirred
during 2 h. The reaction was stopped by addition of a NaHCO3
saturated solution (10 mL), then organic materials were extracted
with CH2Cl2 (2 ¥ 10 mL). The combined organic layers were
dried over MgSO4, filtered, and concentrated under vacuum. The
residue was purified by silica gel flash chromatography (petroleum
ether : EtOAc 1 : 1) to afford 134.4 mg of 2g with 99% as an
1
122.9 (q, JC-F = 285 Hz, CF3), 124.1 (CH CCHO), 146.2
(NC CCCF3OH), 159.7 (CH CCHO), 168.5 (CO2CH3), 176.0
(CHO) ppm. 19F NMR (CDCl3, 188 MHz): d = -76.9 (s, 3F)
ppm. ESI-MS CH3CN m/z (rel int): 338.2 (100, M + H+), 360.0
(50, M + Na+). ESI-MS MeOH m/z (rel int): 338.0 (100, M +
H+), 360.0 (50, M + Na+), 370.1 (60), 382.1 (40), 697.1 (10, 2M +
Na+). ESI-HRMS MeOH m/z: calcd for (M + H+) C13H15NO6F3
338.0851; found 338.0841.
yellow oil. Rf : 0.16 (petroleum ether : EtOAc 1 : 1); 0.63 (EtOAc).
◦
20
C
[a]D
= -159 25 (c = 0.0094; CHCl3). IR (neat, n, cm-1): 2960,
2933, 2876, 2795, 1633, 1533, 1470, 1455, 1353, 1253, 1172, 1142,
1058, 960, 826, 746, 660. 1H NMR (CDCl3, 200 MHz) d 2.05–2.25
(m, 4H, NCH2C2H4), 2.98 (s, 3H, CH3), 3.20–3.35 (m, 1H, NCH2),
3.40–3.60 (m, 1H, NCH2), 3.95–4.10 (m, 1H, NCHCH2OMs),
4.10–4.35 (m, 1H, NCHCH2OMs), 6.00 (d, 3J = 4.4 Hz, 1H,
4-(Hexafluoro-2-hydroxypropan-2-yl)-5-morpholinofurancarbo-
xaldehyde (3ab). Following the general procedure for enam-
ine reactivity, 1a (75 mg, 0.41 mmol, 1 eq) and 1,1,1,3,3,3-
hexafluoroacetone sesquihydrate b (95 mL, 0.83 mmol, 2 eq)
afforded 120.9 mg of 3ab as an yellow solid (85%) after silica gel
flash chromatography (petroleum ether : EtOAc 9 : 1 to 8 : 2). Rf :
0.29 (petroleum ether : EtOAc 8 : 2). Mp: 107.1–108.2 ◦C. IR (KBr,
n, cm-1): 3093, 2918, 2765, 1670, 1627, 1540, 1448, 1391, 1365,
1271, 1259, 1219, 1050, 1172, 1146, 951, 879, 765, 726. 1H NMR
(CDCl3, 300 MHz) d 3.16–3.21 (m, 4H, NCH2), 3.84–3.88 (m, 4H,
OCH2), 7.23 (s, 1H, CH CCHO), 8.30 (s, 1H, OH), 9.58 (s, 1H,
CHO). 13C NMR (CDCl3, 75 MHz) d 51.7 (2C, NCH2), 66.4 (2C,
OCH2), 74.5 (sep, 2JC-F = 31 Hz, CCF3), 106.6 (NC CC(CF3)2),
3
HC CN), 7.47 (d, J = 4.3 Hz, 1H, HC CCHO), 9.47 (s, 1H,
CHO). 13C NMR (CDCl3, 75 MHz) d 23.5 (NCH2CH2CH2),
28.6 (NCH2CH2CH2), 37.3 (SCH3), 51.6 (NCH2CH2CH2), 60.7
(NCHCH2OMs), 67.4 (NCHCH2OMs), 103.9 (HC CN), 127.0
(HC CN), 140.1 (HC CCHO), 163.4 (HC CCHO), 180.1
(CHO). MS (ESI+, CH3CN) m/z (rel int): 290.0 (80, M + H+),
312.0 (100, M + Na+), 533.1 (40), 601.1 (2M + Na+). HRMS
(ESI+, CH3CN) m/z: calcd for (M + Na+) C11H15NO4S2Na
312.0340; found 312.0360.
1
120.0 (CH CCHO), 122.1 (q, JC-F = 337 Hz, 2C, CF3), 148.9
(NC CC(CF3)2), 158.1 (CH CCHO), 177.1 (CHO). 19F NMR
(CDCl3, 188 MHz) d -77.8 (s, 6F). MS (ESI, CH3CN) m/z (rel
int): 348.0 (100, M + H+), 382.1 (30). HRMS (ESI) m/z: calcd for
(M + H+) C12H12NO4F6 348.0671; found 348.0655.
3-Morpholino-2-thiophenecarboxaldehyde (2h)
Following the general procedure for amination,11d 3-bromo-2-
thiophenecarboxaldehyde led to 237.2 mg of 2h as a brown
oil (82%) after silica gel flash chromatography (petroleum
ether : EtOAc 8 : 2 to 7 : 3). Rf : 0.17 (petroleum ether : EtOAc
8 : 2). 1H NMR (CDCl3, 300 MHz) d 3.28 (t, 3J = 4.7 Hz,
4H, NCH2), 3.78 (t, 3J = 4.8 Hz, 4H, OCH2), 6.76 (d, 3J =
5.4 Hz, 1H, SCHCH), 7.55 (dd, J = 5.3 Hz, J = 0.7 Hz, 1H,
SCHCH), 9.79 (s, 1H, CHO). 13C NMR (CDCl3, 75 MHz) d
52.8 (NCH2), 66.3 (OCH2), 120.1 (HC CN), 123.0 (HC CN),
135.4 (HC CCHO), 157.5 (HC CCHO), 180.4 (CHO) ppm.
Full agreement with the literature spectroscopic data.17
4-(1,3-Dichloro-1,1,3,3-tetrafluoro-2-hydroxypropan-2-yl)-5-
morpholinofuran-2-carboxaldehyde (3ac). Following the general
procedure for enamine reactivity, 1a (75.0 mg, 0.41 mmol, 1 eq)
and 1,3-dichloro-1,1,3,3-tetrafluoroacetone c (135 mL, 1.03 mmol,
2.5 eq) afforded 120.2 mg of 3ac as a white solid (78%) after
silica gel flash chromatography (petroleum ether : EtOAc 8 : 2).
Rf : 0.34 (petroleum ether : EtOAc 8 : 2). Mp: 138.8–139.2 ◦C.
IR (KBr, n, cm-1): 3144, 2923, 2860, 2774, 1766, 1658, 1592,
3
4
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1557, 1446, 1397, 1362, 1337, 1311, 1292, 1269, 1235, 1210, 1175,
1143, 1112, 1068, 1005, 942, 922, 874, 840, 785, 757, 705, 687,
654. H NMR (CDCl3, 300 MHz) d 3.19–3.23 (m, 4H, NCH2),
1-(3-(1-Methoxycarbonyl)-(2,2,2-trifluoro-1-hydroxyethyl)-5-
formylfuran-2-yl)piperidine-2-carboxylic acid (3ea). Following
the general synthesis procedure of 1c, 1e (70 mg, 0.31 mmol,
1 eq) and methyl trifluoropyruvate a (42 mL, 0.40 mmol, 1.3 eq)
afforded 41.8 mg of 3ea as a brown oil (79%, 2 diastere-
omers in the ratio 1 : 1) after silica gel flash chromatography
(CH2Cl2 : MeOH 97.5 : 2.5 to 95 : 5). Rf : 0.11 (CH2Cl2 : MeOH
95 : 5). 1H NMR (CDCl3, 300 MHz) d 1.65–1.68 (m, 3H,
NCH2CH2), 1.75–1.86 (m, 3H, NC2H4CH2CHH), 2.38–2.45 (m,
1H, NC2H4CH2CHH), 3.30–3.47 (m, 2H, NCH2), 3.89 (s, 3H,
CO2CH3), 4.38 (t, 3J = 4.8 Hz, 0.5H, NCHCOOH), 4.44 (t,
3J = 4.8 Hz, 0.5H, NCHCOOH), 7.35 (s, 0.5H, HC CCHO),
7.36 (s, 0.5H, HC CCHO), 9.28 (s, 0.5H, CHO), 9.29 (s, 0.5H,
CHO). 13C NMR (CDCl3, 75 MHz) d 21.2 (NCH2CH2CH2), 24.7
(NCH2CH2CH2), 27.8 (NC2H4CH2CH2), 49.2 (NCH2CH2CH2),
54.5 and 54.6 (NCHCOOH), 60.1 and 60.4 (CO2CH3), 75.1–
75.6 (m, CCF3), 103.7 and 104.0 (HC CN), 125.6 and 125.8
(HC CCHO), 145.1 and 145.2 (HC CN), 160.1 and 160.5 (C),
168.3 and 168.7 (CO2CH3), 175.5 and 175.6 (CHO), 175.7 and
175.8 (COOH). 19F NMR (CDCl3, 188 MHz) d -76.7 (s, 3F),
-76.6 (s, 3F). MS (ESI, CH3CN) m/z (rel int): 380.0 (20, M +
H+), 402.0 (100, M + Na+), 781.1 (20, 2M + Na+). HRMS (ESI,
CH3CN) m/z: calcd for (M + H+) C15H17NO7F3380.0957; found
380.0950.
1
3.85–3.89 (m, 4H, OCH2), 7.23 (s, 1H, CH CCHO), 8.73 (s,
1H, OH), 9.56 (s, 1H, CHO). 13C NMR (CDCl3, 75 MHz) d
2
51.5 (2C, NCH2), 66.4 (2C, OCH2), 80.7 (pent, JC-F = 27 Hz,
CCF2Cl), 109.4 (NC CC(CF2Cl)2), 120.4 (CH CCHO), 128.4
1
(t, JC-F = 301 Hz, 2C, CF2Cl), 148.6 (NC CC(CF2Cl)2), 157.9
(CH CCHO), 177.3 (CHO). 19F NMR (CDCl3, 188 MHz) d
-64.2–(-64.1) (m, 1F)), -63.5–(-63.3) (m, 1F), -61.3–(-61.1) (m,
1F)), -60.4–(-60.3) (m, 1F). MS (ESI, CH3CN) m/z (rel int): 380.0
(100, M + H+). MS (ESI, MeOH) m/z (rel int): 380.0 (100, M +
H+), 382.0 (75), 412.0 (50, M + MeOH + H+), 414.0 (40). HRMS
(ESI, MeOH) m/z: calcd for (M + H+) C12H12NO4F4Cl2 380.0080;
found 380.0071.
4-(Hexafluoro-2-hydroxypropan-2-yl)-5-piperidinofuran-2-car-
boxaldehyde (3bb). Following the general procedure for enam-
ine reactivity 1b (40 mg, 0.22 mmol, 1 eq) and 1,1,1,3,3,3-
hexafluoroacetone sesquihydrate b (50 mL, 0.44 mmol, 2 eq)
afforded 32.1 mg of 3bb as an yellow oil (42%) after silica gel
flash chromatography (petroleum ether : EtOAc 70 : 30 to 55 : 45).
1
Rf : 0.30 (petroleum ether : EtOAc 8 : 2). H NMR (acetone-d6,
300 MHz) d 3.16–3.21 (m, 4H, NCH2), 3.84–3.88 (m, 4H, OCH2),
7.23 (s, 1H, CH CCHO), 8.30 (s, 1H, OH), 9.58 (s, 1H, CHO).
13C NMR (acetone-d6, 75 MHz) d 23.8 (NCH2CH2CH2), 26.2
5-(N-Allyl-N-methylamino)-4-(hexafluoro-2-hydroxypropan-2-
yl)furan-2-carboxaldehyde (3fb). Following the general proce-
dure for enamine reactivity, 1f (50.0 mg, 0.30 mmol, 1 eq) and
1,1,1,3,3,3-hexafluoroacetone sesquihydrate b (68 mL, 0.60 mmol,
2 eq) afforded 61.0 mg of 3fb as an yellow oil (57%) after silica
gel flash chromatography (petroleum ether : EtOAc 9 : 1). Rf : 0.45
(2C, NCH2CH2), 53.5 (2C, NCH2), 75.7 (q, 2JC-F = 31 Hz, CCF3),
1
104.7 (NC CC(CF3)2), 121.7 (CH CCHO), 124.2 (q, JC-F
=
327 Hz, 2C, CF3), 149.7 (NC CC(CF3)2), 160.8 (CH CCHO),
178.1 (CHO). MS (ESI, CH3CN) m/z (rel int): 368.2 (95, M +
∑
Na+), 400.3 (100), 593.3 (40). HRMS (EI) m/z: calcd for (M+ )
(petroleum ether : EtOAc 1 : 1). H NMR (CDCl3, 300 MHz) d
1
C13H13NO3F6 345.0800; found 345.0800.
2.82 (s, 3H, NCH3), 3.65 (d, 3J = 6.9 Hz, 2H, NCH2CHCH2), 5.23–
5.30 (m, 2H, NCH2CHCH2), 5.75–5.86 (m, 1H, NCH2CHCH2),
7.22 (s, 1H, HC CCHO), 9.55 (s, 1H, CHO). 13C NMR (CDCl3,
(2S)-1-(3-(1-(Methoxycarbonyl)-2,2,2-trifluoro-1-hydroxyethyl)-
75 MHz) d 40.5 (NCH3), 58.1 (NCH2CH CH2), 73.7 (q, 2JC-F
=
5-formylfuran-2-yl)pyrrolidine-2-carboxylic acid (3da). To
a
31 Hz, CCF3), 106.0 (NC CC(CF3)2), 119.3 (CH CCHO),
120.2 (NCH2CH CH2), 122.9 (q, 1JC-F = 288 Hz, 2C, CF3), 130.2
(NCH2CH CH2), 147.7 (NC CC(CF3)2) 158.3 (CH CCHO),
176.7 (CHO). 19F NMR (CDCl3, 188 MHz) d -78.3 (s, 6F). MS
(CI, CH4) m/z (rel int): 332.0 (100, M + H+), 360.0 (20, M +
solution of 1d (70 mg, 0.320 mmol, 1 eq) in CH2Cl2 (4 mL) was
added methyl trifluoropyruvate a (42 mL, 0.415 mmol, 1.3 eq)
at rt. After 18 h, the solvent was evaporated and the residue
was purified by silica gel flash chromatography (CH2Cl2 : MeOH
97 : 3 to 92 : 8) to afford 56.6 mg of 3da as a red brown oil (50%,
2 diastereomers in the ratio 6 : 1). Rf : 0.09 (CH2Cl2 : MeOH
95 : 5). IR (KBr, n, cm-1): 3154, 2880, 2360, 2325, 1743, 1626,
1538, 1436, 1235, 1149, 1100, 956, 896, 783, 734. 1H NMR
(CDCl3, 200 MHz) d 1.94–2.42 (m, 4H, NCH2C2H4), 3.58–3.85
(m, 2H, NCH2), 3.88 (s, 0.4H, CH3), 3.93 (s, 2.5H, CH3),
4.90 (dd, 3J = 8.2 and 5.2 Hz, 1H, NCHCOOH), 7.40–7.42
(m, 1H, HC CCHO), 8.84 (s, 0.85H, CHO), 8.91 (s, 0.15H,
CHO).13C NMR (CDCl3, 75 MHz) d 23.9 (0.2C, NCH2CH2CH2),
24.8 (1C, NCH2CH2CH2), 29.6 (1C, NCH2CH2CH2), 30.2
(0.2C, NCH2CH2CH2), 50.9 (1C, NCH2CH2CH2), 54.0 (0.2C,
NCHCOOH), 55.0 (1C, NCHCOOH), 62.0 (1C, CO2CH3), 74.9
(1C, CCF3), 97.3 (1C), 132.3 (HC CCHO), 141.7 (1C), 159.9
(1C), 167.5 (1C, CO2CH3), 169.8 (1C), 172.2 (1C, CHO), 174.3
(1C, COOH). 19F NMR (CDCl3, 188 MHz) d -76.6 (s, 0.6F),
-76.2 (s, 3F). MS (ESI, CH3CN) m/z (rel int): 366.0 (20, M +
H+), 388.0 (100, M + Na+), 753.1 (30, 2M + Na+). HRMS (ESI,
CH3CN) m/z: calcd for (M + H+) C14H15NO7F3 366.0801; found
366.0800.
+
+
C2H5 ), 372.0 (10, M + C3H5 ). MS (ESI, CH3CN) m/z (rel
∑
int): 332.0 (100, M + H+). HRMS (EI) m/z: calcd for (MH+ )
C12H11NO3F6 331.0643; found 331.0643.
Methyl 3,3,3-trifluoro-2-(5-formyl-2-((S)-2-((methylsulfony-
loxy)methyl)pyrrolidin - 1 - yl)furan - 3 - yl) - 2 - hydroxypropanoate
(3ga). To a solution of 1g (18.5 mg, 0.068 mmol, 1 eq) in
toluene (0.50 mL) was added methyl trifluoropyruvate a (20
mL, 0.189 mmol, 2.5 eq) at rt. The solution was stirred at
reflux for 16 h, then cooled to rt. The solvent was evaporated
and the residue was purified by silica gel flash chromatography
(petroleum ether : EtOAc 5 : 5) to afford 20.9 mg of 3ga as an
brown oil (72%, 2 diastereomers in the ratio 2 : 1). Rf : 0.34 and
0.40 (petroleum ether : EtOAc 1 : 1); 0.66 (petroleum ether : EtOAc
2 : 8). IR (KBr, n, cm-1): 3434, 3030, 2959, 2853, 1754, 1668,
1595, 1537, 1441, 1354, 1285, 1258, 1174, 949, 904, 847, 798, 784.
1H NMR (CDCl3, 300 MHz) d 1.60–1.70 (m, 2H, NCH2C2H4),
1.93–2.04 (m, 4H, NCH2C2H4), 3.10 (s, 4.5H, SCH3), 3.13–
2
3.36 (m, 3.5H, NCH2 + NCHCH2OMs), 3.45 (dd, J = 12.4,
6062 | Org. Biomol. Chem., 2011, 9, 6055–6065
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3J = 3.0 Hz, 0.5H, NCHCH2OMs), 3.56 (dd, J = 12.6, J =
2.8 Hz, 1H, NCHCH2OMs), 3.58–3.90 (m, 0.5H, NCHCH2OMs),
3.92 (s, 3H, OCH3), 3.93 (s, 1.5H, OCH3), 3.95–3.99 (m, 0.5H,
NCHCH2OMs), 4.85–4.92 (m, 1.5H, NCHCH2OMs), 5.55 (brs,
1H, OH), 5.83 (brs, 0.5H, OH), 7.34–7.36 (m, 1.5H, HC CCHO),
9.41 (s, 1H, CHO), 9.43 (s, 0.5H, CHO). 13C NMR (CDCl3,
50 MHz) d 21.4 (0.5C, NCH2CH2CH2), 21.5 (1C, NCH2CH2CH2),
29.4 (1C, NCH2CH2CH2), 30.9 (0.5C, NCH2CH2CH2), 38.5 (1C,
SCH3), 38.6 (0.5C, SCH3), 50.5 (1C, NCH2CH2CH2), 50.9 (0.5C,
NCH2CH2CH2), 53.4 (0.5C, OCH3), 54.5 (1C, OCH3), 54.6
(0.5C, NCHCH2OMs), 54.9 (1C, NCHCH2OMs), 73.7 (0.5C,
NCHCH2OMs), 74.2 (1C, NCHCH2OMs), 74.9 (q, 2JC-F = 31 Hz,
enamine reactivity, 2a (195.3 mg, 0.990 mmol, 1 eq) and methyl
trifluoropyruvate (320 mL, 3.023 mmol, 3.0 eq) afforded 292.0
mg of 4a as white crystals (84%) after silica gel flash chro-
matography (petroleum ether : EtOAc 80 :◦20). Rf : 0.19 (petroleum
ether : EtOAc 80 : 20). Mp: 138.1–139.4 C. IR (KBr, n, cm-1):
3433, 3112, 2963, 2894, 2858, 1737, 1681, 1464, 1435, 1372, 1283,
2
3
1
1251, 1208, 1161, 1121, 997, 920, 892, 650. H NMR (CDCl3,
300 MHz) d 2.87–2.94 (m, 2H, NCH2), 3.07–3.14 (m, 2H, NCH2),
3.75–3.88 (m, 4H, OCH2), 3.88 (s, 3H, CO2CH3), 7.17 (brs, 1H,
OH), 7.79 (d, 4J = 1.1 Hz, 1H, CH CCHO), 9.78 (s, 1H, CHO).
13C NMR (CDCl3, 75 MHz) d 54.0 (CO2CH3), 55.8 (2C, NCH2),
66.34 (2C, OCH2), 77.2 (q, 2JC-F = 30 Hz, CCF3), 123.0 (q, 1JC-F
=
2
1C, CCF3), 75.0 (q, JC-F = 31 Hz, 0.5C, CCF3), 105.6 (1C,
285 Hz, CF3), 126.1 (NC CCCF3OH), 135.3 (CH CCHO),
137.8 (NC CCCF3OH), 164.9 (CH CCHO), 168.2 (CO2CH3),
182.7 (CHO). 19F NMR (CDCl3, 188 MHz) d -76.7 (s, 3F).
MS (ESI+, CH3CN) m/z (rel int): 217.1 (65), 262.1 (20), 318.1
(30), 376.0 (50, M + Na+), 418.1 (30), 474.1 (100), 729.1 (20,
2M + Na+). HRMS (ESI+, CH3CN) m/z: calcd for (M + Na+)
C13H14NO5F3SNa 376.0442; found 376.0434.
1
C
CN), 106.6 (0.5C, C CN), 122.9 (q, JC-F = 285 Hz, 1.5C,
CF3), 123.5 (0.5C, HC CCHO), 123.8 (1C, HC CCHO), 146.3
(1C, C CN), 146.7 (0.5C, C CN), 159.0 (0.5C, HC CCHO),
159.4 (1C, HC CCHO), 168.0 (0.5C, CO2CH3), 168.3 (1C,
CO2CH3), 176.1 (1C, CHO), 176.3 (0.5C, CHO). 19F NMR
(CDCl3, 188 MHz) d -76.8 (s, 3F), -76.9 (s, 1.5F). MS (ESI+,
CH3CN) m/z (rel int): 242.3 (30), 452.1 (100, M + Na+), 881.1
(100, 2M + Na+). HRMS (ESI+, CH3CN) m/z: calcd for (M +
Na+) C15H18NO8SF3Na 452.0603; found 452.0603.
Methyl 3,3,3-trifluoro-2-(5-formyl-2-(piperidin-1-yl)thiophen-3-
yl)-2-hydroxypropanoate (4b). Following the general procedure
for enamine reactivity, 2b (51.5 mg, 0.264 mmol, 1 eq) and
methyl trifluoropyruvate (32 mL, 0.312 mmol, 1.2 eq) afforded
61.1 mg of 4b as white solid (66%) after silica gel flash chro-
matography (petroleum ether : EtOAc 85 : 15). Rf : 0.41 (petroleum
ether : EtOAc 80 : 20); 0.81 (petroleum ether : EtOAc 60 : 40). Mp:
112.4–113.2 ◦C. IR (KBr, n, cm-1): 3244, 2943, 2854, 2815, 1758,
1659, 1443, 1416, 1374, 1315, 1279, 1245, 1214, 1179, 1152, 1124,
1042, 1028, 1008, 996, 860, 786, 724, 664, 648. 1H NMR (CDCl3,
300 MHz) d 1.58–1.64 (m, 2H, NCH2CH2CH2), 1.72–1.79 (m, 4H,
NCH2CH2), 2.86–2.93 (m, 2H, NCH2), 2.96–3.04 (m, 2H, NCH2),
Methyl 2-(2-((S)-2-((tert-butoxycarbonyloxy)methyl) pyrrolidin-
1-yl)-5-formylfuran-3-yl)-3,3,3-trifluoro-2-hydroxy
propanoate
(3ha). To a solution of 1h (245.0 mg, 0.829 mmol, 1 eq) in
CH2Cl2 (10 mL) was added methyl trifluoropyruvate a (270 mL,
2.551 mmol, 3.0 eq) at rt. The solution was stirred at rt for 16
h, then the solvent was evaporated and the residue was purified
by silica gel flash chromatography (petroleum ether : EtOAc 1 : 1)
to afford 229.4 mg of 3ha as an yellow oil (62%, 2 diastereomers
in the ratio 5 : 1). Rf : 0.69 (petroleum ether : EtOAc 1 : 1). IR (in
CCl4, n, cm-1): 3411–3233, 2980, 2896, 1747, 1660, 1651, 1645,
1583, 1548, 1538, 1455, 1395, 1370, 1281, 1255, 1155, 1103, 1026,
4
3.88 (s, 3H, CO2CH3), 7.79 (d, J = 1.4 Hz, 1H, CH CCHO),
8.60 (brs, 1H, OH), 9.80 (s, 1H, CHO). 13C NMR (CDCl3,
75 MHz) d 23.0 (1C, NCH2CH2CH2), 25.6 (2C, NCH2CH2CH2),
53.8 (CO2CH3), 57.7 (2C, NCH2), 77.7 (q, 2JC-F = 30 Hz, CCF3),
1
998, 957, 911, 861, 796, 786, 733, 679, 648. H NMR (CDCl3,
300 MHz) d 1.39 (s, 3H, OBoc), 1.40 (s, 9H, OBoc), 1.76–1.97
(m, 3.8H, NCH2C2H4), 1.99–2.11 (m, 1.3H, NCH2C2H4),
3.41–3.47 (m, 1H, NCH2), 3.49–3.57 (m, 1.2H, NCH2), 3.86
(s, 0.8H, OCH3), 3.87 (s, 3H, OCH3), 4.05 (d, 3J = 4.6 Hz,
2.5H, NCHCH2OBoc), 4.33–4.42 (m, 1.3H, NCHCH2OBoc),
4.80–5.06 (br, 1H, OH), 5.05–5.20 (br, 0.2H, OH), 7.30–7.32 (m,
1
123.2 (q, JC-F = 283 Hz, CF3), 125.6 (NC CCCF3OH), 135.2
(CH CCHO), 138.0 (NC CCCF3OH), 165.9 (CH CCHO),
168.0 (CO2CH3), 182.7 (CHO). MS (ESI+, CH3CN) m/z (rel int):
352.1 (15, M + H+), 374.1 (100, M + Na+), 725.1 (70, 2M + Na+).
HRMS (ESI+, CH3CN) m/z: calcd for (M + H+) C14H17NO4F3S
352.0830; found 352.0816.
1.2H, HC CCHO), 9.15 (s, 1H, CHO), 9.16 (s, 0.2H, CHO). 13
C
NMR (CDCl3, 75 MHz) d 24.2 (0.2C, NCH2CH2CH2), 24.9 (1C,
NCH2CH2CH2), 27.5 (OCO2CH3), 27.6 (3C, NCH2CH2CH2),
51.7 (0.2C, NCH2CH2CH2), 52.9 (1C, NCH2CH2CH2), 54.3
(0.2C, OCH3), 54.6 (1C, OCH3), 59.0 (1C, NCH), 59.2 (0.2C,
(2S)-1-(3-(1-Methoxycarbonyl)-2,2,2-trifluoro-1-hydroxyethyl -
5-formylthiophen-2-yl)pyrrolidine-2-carboxylic acid (4d). To a
solution of 2d (185.6 mg, 0.824 mmol, 1 eq) in CH2Cl2 (6 mL) was
added methyl trifluoropyruvate (135 mL, 1.275 mmol, 1.5 eq) at rt.
After 42 h, the solvent was evaporated and the residue was purified
by silica gel flash chromatography (petroleum ether : EtOAc 1 : 1 to
0 : 1) to afford 312.5 mg of 4d as an yellow oil (99%, 2 diastereomers
in the ratio 2 : 1). Rf : 0.15 (petroleum ether : EtOAc 1 : 1); 0.04–0.25
(CH2Cl2 : MeOH 95 : 5). IR (KBr, n, cm-1): 3450–2400, 1755, 1747,
1651, 1633, 1470, 1462, 1454, 1416, 1281, 1241, 1159, 1122, 1094,
2
NCH), 66.8 (1C, OCH2), 75.1 (q, JC-F = 30 Hz, 1C, CCF3),
2
75.4 (q, JC-F = 30 Hz, 0.2C, CCF3), 82.2 (1C, C), 82.3 (0.2C,
1
C), 99.2 (1C, C), 99.7 (0.2C, C), 122.9 (q, JC-F = 286 Hz, 1C,
CF3), 126.9 (0.2C, HC CCHO), 127.3 (1C, HC CCHO), 143.5
(1C, C), 143.9 (0.2C, C), 153.2 (0.2C, C), 153.3 (1C, C), 158.1
(0.2C, OCO2), 159.0 (1C, OCO2), 168.8 (0.2C, CO2), 169.5 (1C,
CO2), 173.8 (1C, CHO), 173.9 (0.2C, CHO). 19F NMR (CDCl3,
188 MHz) d -76.8 (s, 3F), -77.4 (s, 0.6F). MS (ESI+, CH3CN)
m/z (rel int): 474.1 (20, M + Na+), 635.2 (10), 925.2 (100, 2M +
Na+), 926.2 (40). HRMS (ESI+, CH3CN) m/z: calcd for (M +
Na+) C19H24NO8F3Na 474.1352; found 474.1351.
1
1027, 996, 937, 730, 675. H NMR (CDCl3, 300 MHz) d 1.93–
2.20 (m, 4.5H, NCH2C2H4), 2.35–2.47 (m, 1.5H, NCH2C2H4),
3.02–3.10 (m, 0.5H, NCH2), 3.18–3.25 (m, 1H, NCH2), 3.58–3.71
(m, 1.5H, NCH2), 3.81 (s, 3H, CH3), 3.84 (s, 1.5H, CH3), 3.88 (s,
3
1.5H, OH), 4.22 (dd, J = 8.6 and 5.0 Hz, 0.5H, NCHCOOH),
Methyl 3,3,3-trifluoro-2-(5-formyl-2-morpholinothiophen-3-yl)-
2-hydroxypropanoate (4a). Following the general procedure for
4.29 (dd, 3J = 8.4 and 5.3 Hz, 1H, NCHCOOH), 6.77–7.60
4
(brs, COOH), 7.73 (d, J = 1.5 Hz, 1H, HC CCHO), 7.76 (d,
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4J = 1.3 Hz, 0.5H, HC CCHO), 9.62 (s, 1H, CHO), 9.65 (s, 0.5H,
CHO). 13C NMR (CDCl3, 50 MHz) d 24.2 (1C, NCH2CH2CH2),
24.4 (0.5C, NCH2CH2CH2), 30.5 (1C, NCH2CH2CH2), 30.7
(0.5C, NCH2CH2CH2), 54.0 (0.5C, OCH3), 54.3 (1C, OCH3),
57.6 (1C, NCH2CH2CH2), 58.1 (0.5C, NCH2CH2CH2), 67.1
(1C, NCHCOOH), 67.6 (0.5C, NCHCOOH), 77.2–78.1 (m,
0.831 mmol, 2.0 eq) at rt. The solution was stirred at reflux for
24 h, then cooled to rt. The solvent was evaporated and the
residue was purified by silica gel flash chromatography (petroleum
ether : EtOAc 7 : 3) to afford 126.9 mg of 4g as an yellow oil
(69%, 2 diastereomers in the ratio 2 : 1). Rf : 0.42 (petroleum
ether : EtOAc 1 : 1). IR (in CCl4, n, cm-1): 2956, 2925, 2854,
1749, 1682, 1581, 1572, 1537, 1461, 1347, 1261, 1178, 1166,
2
CCF3), 90.6 (q, JC-F = 34 Hz, CCF3), 122.8 (1C, C CN),
1
1
123.0 (q, JC-F = 285 Hz, CF3), 123.8 (0.5C, C CN), 133.7
1157, 1099, 1014. H NMR (CDCl3, 300 MHz) d 1.67–1.82 (m,
(1C, C CN), 134.4 (0.5C, C CN), 137.4 (0.5C, HC CCHO),
137.7 (1C, HC CCHO), 162.9 (0.5C, HC CCHO), 163.5 (1C,
HC CCHO), 167.5 (1C, CO2CH3), 167.9 (0.5C, CO2CH3), 176.8
(1C, CO2CH3), 176.9 (0.5C, CO2CH3), 182.9 (1.5C, CHO). 19F
NMR (CDCl3, 188 MHz) d -76.2 (s, 3F), -76.6 (s, 1.5F). MS
(ESI-, CH3CN) m/z (rel int): 234.0 (20), 304.0 (15), 380.0 (100,
M - H-), 783.1 (5, 2M - 2H + Na-). MS (ESI+, CH3CN) m/z (rel
int): 226.0 (30), 279.1 (15), 336.0 (30), 382.0 (100, M + H+), 404.0
(60, M + Na+), 785.1 (15, 2M + Na+). HRMS (ESI-, CH3CN)
m/z: calcd for (M - H-) C14H13NO6SF3380.0416; found 380.0435.
HRMS (ESI+, CH3CN) m/z: calcd for (M + H+) C14H15NO6SF3
382.0572; found 382.0556.
1.5H, NCH2C2H4), 1.89–2.08 (m, 4.5H, NCH2C2H4), 2.84–3.09
(m, 4.5H, NCH2 + NCHCH2OMs), 3.10 (s, 1.5H, SCH3), 3.12
(s, 3H, SCH3), 3.22–3.27 (m, 0.5H, NCHCH2OMs), 3.32–3.37
(m, 1H, NCHCH2OMs), 3.85 (s, 3H, OCH3), 3.88 (s, 1.5H,
OCH3), 4.89–4.97 (m, 1.5H, NCHCH2OMs), 7.76–7.79 (m,
1.5H, HC CCHO), 9.77 (s, 1H, CHO), 9.78 (s, 0.5H, CHO).
13C NMR (CDCl3, 75 MHz) d 21.1 (0.5C, NCH2CH2CH2), 21.6
(1C, NCH2CH2CH2), 28.7 (0.5C, NCH2CH2CH2), 28.9 (1C,
NCH2CH2CH2), 38.4 (1C, SCH3), 38.5 (0.5C, SCH3), 54.0 (1.5C,
OCH3), 55.2 (1C, NCH2CH2CH2), 54.0 (0.5C, NCH2CH2CH2),
59.4 (0.5C, NCHCH2OMs), 59.8 (1C, NCHCH2OMs), 73.3
(0.5C, NCHCH2OMs), 73.6 (1C, NCHCH2OMs), 77.2–77.6
1
(m, 1.5C, CCF3), 123.0 (q, JC-F = 285 Hz, 1.5C, CF3), 126.1
Methyl 2-(5-acetyl-2-((S)-2-((methylsulfonyloxy)methyl)pyrro-
lidin-1-yl)thiophen-3-yl)-3,3,3-trifluoro-2-hydroxy propanoate (4f).
In a 10 mL round bottom flask was introduced 2f (101.5 mg,
0.335 mmol, 1 eq) dissolved in toluene (5 mL). Then methyl
trifluoropyruvate (110 mL, 1.039 mmol, 3 eq) was added and the
solution was stirred at reflux for 18 h, then cooled to rt. The
solvent was evaporated and the residue was purified by silica gel
flash chromatography (petroleum ether : EtOAc 7 : 3 to 6 : 4) to
afford 137.3 mg of 4f as an yellow powder (89%, 2 diastereomers
in the ratio 1 : 1). Rf : 0.47 (petroleum ether : EtOAc 6 : 4); 0.67
(petroleum ether : EtOAc 2 : 8). Mp: 54.1–59.3 ◦C. IR (KBr, n,
cm-1): 3441, 3030, 2959, 2847, 1752, 1669, 1445, 1359, 1279, 1250,
(1C, C CN), 126.8 (0.5C, C CN), 135.1 (0.5C, HC CCHO),
135.3 (1C, HC CCHO), 137.8 (1C, C CN), 138.3 (0.5C,
C
CN), 164.1 (0.5C, HC CCHO), 164.3 (1C, HC CCHO),
167.9 (0.5C, CO2CH3), 168.1 (1C, CO2CH3), 182.6 (1C, CHO),
182.7 (0.5C, CHO). 19F NMR (CDCl3, 188 MHz) d -76.9 (s,
1.5F), -76.8 (s, 3F). MS (ESI-, CH3CN) m/z (rel int): 416.1 (30),
430.0 (100), 460.0 (50), 480.0 (35). MS (ESI+, CH3CN) m/z
(rel int): 446.0 (100, M + H+), 468.0 (75, M + Na+), 913.1 (55,
2M + Na+). HRMS (ESI+, CH3CN) m/z: calcd for (M + H+)
C15H19NO7S2F3446.0555; found 446.0554 and calcd for (M +
Na+) C15H18NO7S2F3Na 468.0375; found 468.0376.
1
1173, 1120, 953, 932, 905, 844. H NMR (CDCl3, 300 MHz) d
1.69–2.12 (m, 8H, NCH2C2H4), 2.53 (s, 3H, COCH3), 2.54 (s,
3H, COCH3), 2.83–3.12 (m, 6H, 4H NCH2 + 1H OH + 2H
NCHCH2OMs), 3.12 (s, 3H, SCH3), 3.15 (s, 3H, SCH3), 3.22–3.29
(m, 2H, NCHCH2OMs), 3.87 (s, 3H, OCH3), 3.90 (s, 3H, OCH3),
3.91–3.92 (m, 1H, OH), 4.94–5.01 (m, 2H, NCHCH2OMs),
7.64–7.67 (m, 2H, HC CCOMe).13C NMR (CDCl3, 50 MHz)
Synthesis of the 1,4-oxazepine (5). The furan derivative 3ga
(423.8 mg, 0.987 mmol, 1 eq) was dissolved in THF (10 mL).
The reaction was stirred and cooled to 0 ◦C. Sodium hydride
(43 mg 60% in oil, 1.075 mmol, 1.1 eq) was added portionwise.
The mixture was allowed to reach rt and stirred during 2 h. The
reaction was stopped by the addition of a NaHCO3 saturated
solution (10 mL) and organic materials were extracted with EtOAc
(3 ¥ 15 mL). The combined organic layers were dried over MgSO4,
filtered, and concentrated under vacuum. The residue was purified
by silica gel flash chromatography to afford 171.0 mg of 5 with
52% as an yellow oil (petroleum ether : EtOAc 75 : 25). Rf: 0.68
(petroleum ether : EtOAc 75 : 25). IR (KBr, n, cm-1): 2957, 2883,
2158, 2030, 1748, 1655, 1553, 1444, 1263, 1101, 987, 888, 776, 683.
1H NMR (CDCl3, 300 MHz) d 1.51–1.55 (m, 1H, NCH2C2H4),
1.92–2.10 (m, 3H, NCH2C2H4), 3.68–3.75 (m, 2H, NCH2C2H4),
3.75 (s, 1H, CO2CH3), 3.81 (s, 3H, CO2CH¢3), 4.05–4.12 (m,
1H, NCHCH2O), 4.18–4.28 (m, 2H, NCHCH2O), 7.34 (s, 1H,
HC CCHO), 9.04 (s, 1H, CHO). 13C NMR (CDCl3, 75 MHz)
d 21.0 (NCH2C2H4), 28.7 (NCH2C2H4), 48.6 (NCH2C2H4), 53.5
(NCHCH2O), 62.1 (CO2CH3), 69.8 + 70.1 (NCHCH2O), 80.2
d
21.0 (NCH2CH2CH2), 21.5 (NCH2CH2CH2), 25.9 (2C,
COCH3), 28.6 (NCH2CH2CH2), 28.8 (NCH2CH2CH2), 38.5 (2C,
SCH3), 53.8 (OCH3), 53.9 (OCH3), 55.4 (NCH2CH2CH2), 56.1
(NCH2CH2CH2), 59.5 (NCHCH2OMs), 59.8 (NCHCH2OMs),
73.3 (NCHCH2OMs), 73.6 (NCHCH2OMs), 76.6–78.6 (m, 2C,
CCF3), 123.0 (2q, JC-F = 288 Hz, 2C, CF3), 125.9 (C CN),
126.5 (C CN), 130.5 (2q, JC-F = 2 Hz, 2C, HC CCOMe),
1
3
138.9 (C CN), 139.4 (C CN), 162.5 (HC CCOMe), 162.6
(HC CCOMe), 167.9 (CO2CH3), 168.1 (CO2CH3), 190.1 (2C,
COMe). 19F NMR (CDCl3, 188 MHz) d -76.9 (s, 3F), -76.3
(s, 3F). MS (ESI+, CH3CN) m/z (rel int): 460.1 (5, M + H+),
482.0 (100, M + Na+), 638.1 (15), 941.1 (15, 2M + Na+),
1097.1 (10). HRMS (ESI+, CH3CN) m/z: calcd for (M + H+)
C16H21NO7F3S2 460.0712; found 460.0733 and calcd for (M +
Na+) C16H20NO7F3S2Na 482.0531; found 482.0533.
(q, 2JC-F = 29 Hz, CCF3CO2Me), 90.0 (NC C), 123.6 (q, 1JC-F
=
Methyl 3,3,3-trifluoro-2-(5-formyl-2-((S)-2-((methylsulfonylo-
xy)methyl)pyrrolidin-1-yl)thiophen-3-yl)-2-hydroxypropanoate
(4g). To a solution of 2g (119.9 mg, 0.414 mmol, 1 eq) in
toluene (5 mL) was added methyl trifluoropyruvate (88 mL,
288 Hz, CCF3CO2Me), 130.5 (HC CCHO), 143.7 (C), 156.8 (C),
166.5 + 167.2 (CO2), 171.1 + 172.1 (CHO). 19F NMR (CDCl3,
188 MHz) d -77.6 (s, 1F, CF3), -77.4(s, 3F, CF¢3). MS (ESI,
CH3CN) m/z (rel int): 334.3 (25, M + H+), 356.2 (100, M + Na+).
6064 | Org. Biomol. Chem., 2011, 9, 6055–6065
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HRMS (ESI, CH3CN) m/z (rel int): calcd for (MH+) C14H15NO5F3
334.0902; found 334.0898.
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Rapid synthesis of the 1,4-oxazepine (5). To a solution of
1c (75 mg, 0.385 mmol, 1 eq) in CH2Cl2 (5 mL) was added
triethylamine (65 mL, 0.460 mmol, 1.2 eq). The reaction was cooled
to -10 ◦C and MsCl (30 mL, 0.385 mmol, 1 eq) was added dropwise.
After completion to give 1g, the mixture was allowed to reach
rt and methyl trifluoropyruvate a (59 mL, 0.577 mmol, 1.5 eq)
was added. After 20 h the reaction was stopped by addition of
NaHCO3 saturated solution (3 mL) followed by 7 mL of H2O
and extracted by CH2Cl2 (2 ¥ 10 mL). The combined organic
layers were dried over MgSO4 and evaporated under reduced
pressure to afford the crude 3ga which was engaged without
purification. The latter was dissolved in THF (4 mL) and cooled
to 0 ◦C prior to addition of NaH (16.9 mg, 0.423 mmol, 1.1 eq).
After 2 h the reaction was quenched with 5 mL of NaHCO3
saturated solution and the organic phase extracted by EtOAc and
concentrated under vacuum. The residue was purified by silica gel
flash chromatography to afford 5 as a yellow oil, with 36% global
yield (mixture 1 : 3 of diastereomers) starting from 1c.
1,4-Oxazepinone (6). To a 0 ◦C cooled solution of 3da (35 mg,
0.11 mmol, 1 eq) in CH2Cl2 (2 mL) was added triethylamine (23.5
mL, 0.16 mmol, 1.5 eq) followed by EDC (21.5 mg, 0.11 mmol,
1 eq). Then the solution was warmed at rt and stirred overnight.
The reaction was stopped by adding water (10 mL) and a saturated
solution of NaHCO3 (1 mL) and extracted with CH2Cl2 (3 ¥
10 mL). The combined organic layers were dried over MgSO4 and
concentrated under vacuum. The residue was purified by silica gel
flash chromatography to afford 19.9 mg of 6 with 60% as a green oil
(petroleum ether : EtOAc 6 : 4). Rf: 0.25 (Petroleum ether : EtOAc
6 : 4). IR (KBr, n, cm-1): 2976, 2897, 2158, 2023, 1753, 1652, 1602,
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Migianu, D. Prim and G. Kirsch, Synlett, 2000, 459.
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Biomol. Chem., 2011, 9, 497.
1
1459, 1300, 1049, 931, 790, 677. H NMR (CDCl3, 300 MHz) d
¢
1.98–2.30 (m, 3H, NCH2C2H4), 2.65–2.75 (m, 1H, NCH2C2H4 ),
3.67–3.72 (m, 2H, NCH2C2H4), 3.93 (s, 1.3 H, CO2CH3), 4.29–4.34
(m, 1H, NCHCH2O), 4.18–4.28 (m, 2H, NCHCH2O), 7.36 (s, 1H,
HC CCHO), 9.21 (s, 1H, CHO). 13C NMR (CDCl3, 75 MHz)
d 23.9 (NCH2C2H4), 28.5 (NCH2C2H4), 48.6 (NCH2C2H4), 55.0
2
(NCHCO2), 60.8 (CO2CH3), 63.1 (CO2C¢H3), 80.7 (q, JC-F
=
1
31 Hz, CCF3CO2Me), 90.0 (NC C), 121.4 (q, JC-F = 285 Hz,
CCF3CO2Me), 127.1 (HC CCHO), 144.4 (C), 157.7 (C), 165.4
(CO2Me) + 167.2 (NCCO2), 173.2 (CHO). 19F NMR (CDCl3,
188 MHz) d -77.1 (s, 1F), -75.2 (s, 9F). MS (ESI, CH3CN) m/z
(rel int): 348.0 (20, M + H+), 380.0 (30, M + Na+), 402.0 (50),
491.1 (100), 713.1 (10). HRMS (ESI, CH3CN) m/z (rel int): calcd
for (M + H+) C14H13NO6F3 348.0695; found 348.0688.
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Acknowledgements
Authors are highly grateful to the Universite´ de Versailles-Saint-
Quentin for material support and ANR program (ANR–07–
CP2D–14–01). R. M. acknowledges CNRS for a grant.
22 C. A. Salvatore, J. C. Hershey, H. A. Corcoran, J. F. Fay, V. K. Johnston,
E. L. Moore, S. D. Mosser, C. S. Burgey, D. V. Paone, A. W. Shaw, S.
L. Graham, J. P. Vacca, T. M. Williams, K. S. Koblan and S. A. Kane,
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Notes and references
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Kirsch, D. Prim, F. Leising and G. Mignani, J. Heterocycl. Chem., 1994,
31, 1005; (c) D. Prim, A. Fuss, G. Kirsch and A. M. S. Silva, J. Chem.
Soc., Perkin Trans. 2, 1999, 1175.
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 6055–6065 | 6065
©