Efficient multicomponent synthesis of α-trifluoromethyl proline, homoproline, and azepan carboxylic acid dipeptides

Article abstract of DOI:10.1055/s-0028-1087529

Cyclic imines bearing CF₃ and C₂F₅ group were successfully used for the first Ugi multicomponent synthesis of polyfluoro-alkyl-substituted proline, homoproline, and azepan carboxylic acid derivatives. Based on the suggeste

Full text of DOI:10.1055/s-0028-1087529

LETTER
403
Efficient Multicomponent Synthesis of a-Trifluoromethyl Proline,
Homoproline, and Azepan Carboxylic Acid Dipeptides
Multicomponent
S
n
ynthesis of
a
t
-Triflu
o
oromethyl Pr
n
oline V. Gulevich,a Nikolay E. Shevchenko,a Elisabeth S. Balenkova,a Gerd-V. Röschenthaler,*b
Valentine G. Nenajdenko*a
a
Department of Chemistry, Moscow State University, Leninskije Gory, 119992 Moscow, Russian Federation
Fax +7(495)9328846; E-mail: nen@acylium.chem.msu.ru
Institute of Inorganic and Physical Chemistry, University of Bremen, Leobener Str., 28334 Bremen, Germany
b
Fax +49(421)2184267; E-mail: gvr@chemie.uni-bremen.de
Received 22 August 2008
same approach can be ineffective in case of CF3-amino
acids due to low nucleophilicity of the amino group10 and
sterical hindrance of carboxy group by CF3.11 Therefore,
the development of noncondensation approaches to
Abstract: Cyclic imines bearing CF3 and C2F5 group were success-
fully used for the first Ugi multicomponent synthesis of polyfluoro-
alkyl-substituted proline, homoproline, and azepan carboxylic acid
derivatives. Based on the suggested reaction the first synthesis of
dipeptides containing a-CF3 cyclic amino acids residue was de- dipeptides of a-CF3 amino acids is a significant problem.
scribed. The scope and limitations of the approach are discussed.
Substituted cyclic imines have been used for the Ugi syn-
Key words: amino acids, peptides, fluorine, multicomponent reac-
tions, imines
thesis of substituted proline and homoproline and their
dipeptides.12 Recently, we have developed the Ugi reac-
tion with CF3-carbonyl compounds and their imines.13 We
propose that the Ugi reaction can be used as an effective
Fluorinated analogues of proline were found to be very ef-
fective to control the cis-trans isomerisation of the prolyl
bonds1 and for the design of enzyme inhibitors.2 Pipe-
colinic acid (homoproline) is abundant in many drugs and
natural products such as immunosuppresants or cyclic
peptides with antifungal activity.3 Recently, the synthesis
alternative of the condensative method for the synthesis of
the target structures.
In this paper we report the first synthesis of a-CF3 cyclic
amino acids derivatives and dipeptides by Ugi reaction
with polyfluoroalkylated cyclic imines (Scheme 1).
4
5
Polyfluoroalkyl-substituted cyclic imines 1a–e can be
easily prepared from commercially available compounds
and very cheap fluorinated starting materials (CF3COOEt
or C2F5Li, prepared from C2F5H) in good yields
(Scheme 1).5,14 We decided to explore the synthetic poten-
tial of the Ugi multicomponent reaction with imines 1a–e.
of a-trifluoromethyl (a-CF3) proline and C2F5-proline
have been described. CF3-Imino acids derivatives (with
five-, six-, or seven-membered cycle) have been also ob-
tained by ring-closing metathesis.6
Modification of peptides and proteins by incorporation of
a-CF3 amino acids is a modern strategy in drug discovery7
due to the unique stereoelectronic properties of the tri-
fluormethyl group.8 However, peptides containing a-CF3
proline and its homologues are, to the best of our knowl-
edge, still unexplored.
Using a model experiment for the Ugi reaction (entry 1,
Table 1), we found the following optimal conditions:
CH2Cl2, 0.1 M, –20 °C to r.t., 12 h (Scheme 2). The CF3-
substituted cyclic imines 1a–e react only with strong
acids, such as CCl3COOH or CF3COOH, and trifluoro-
acetic acid was the reagent of choice. It is important that
A conventional protocol for the peptide synthesis is based
on condensation of protected amino acids.9 However, the
(n)
(n)
a
O
CF3
ref. 13
N
N
O
R
(n)
Ugi
1a: n = 1
1b: n = 2
1c: n = 3
N
COOPG2
H
N
RF
(n)
PG1
(n)
N
b
OMe
C2F5
ref. 5
N
1c: n = 1
1d: n = 2
Scheme 1 MCR approach to dipeptides of a-CF3 cyclic amino acids. Reagents and conditions: (a) CF3COOEt, NaH then HCl (concd), reflux;
(b) C2F5Li, BF3·OEt2.
SYNLETT 2009, No. 3, pp 0403–0406
x
x.
x
x.
2
0
0
9
Advanced online publication: 21.01.2009
DOI: 10.1055/s-0028-1087529; Art ID: D30208ST
© Georg Thieme Verlag Stuttgart · New York

404
A. V. Gulevich et al.
LETTER
O
imines 1 and isocyanoacetic acid derivatives 3 opens a
new effective one-step approach to earlier unknown
dipeptides 4a–k (Scheme 4) containing CF3- and C2F5-
substituted proline and its homologues and natural amino
acid residues (Table 2). All compounds were isolated in
good yields as a mixture of diastereomers (ca. 1:1, accord-
ing to GC–MS of reaction mixtures), that is usual for the
Ugi reaction.12
(n)
(n)
R1
CF3COOH
+
N
RF
R1NC
a
N
H
N
RF
F3C
O
1a–e
2a–j
Scheme 2 Reagents and conditions: (a) CH2Cl2, –20 °C to r.t., 12 h.
Table 1 The Ugi Reaction with Polyfluorosubstituted Cyclic
Imines15,16
O
R1
CF3COOH
(n)
(n)
Entry
n
1
1
1
2
2
2
2
2
3
3
RF
R1
Product Yield (%)
+
N
COOEt
RF
R1
a
H
N
N
RF
1
2
CF3
CF3
C2F5
CF3
CF3
CF3
C2F5
C2F5
CF3
CF3
t-Bu
2a
2b
2c
2d
2e
2f
80
81
61
63
75
89
70
71
59
70
CN
COOEt
F3C
O
1a–e
3
4a–m
Bn
Scheme 4 Reagents and conditions: (a) CH2Cl2, 0.1 M, –20 °C to
r.t., 12 h.
3
t-Bu
4
t-Bu
Table 2 Synthesis of Polyfluoroalkylated Dipeptides
5
Et
Entry
1
n
1
1
1
1
1
1
2
2
2
2
2
3
3
RF
R1
Product Yield (%)
6
4-MeOBn
Bn
CF3
CF3
CF3
CF3
CF3
C2F5
CF3
CF3
CF3
CF3
C2F5
CF3
CF3
Me
4a
4b
4c
4d
4e
4f
61
60
67
51
59
53
79
56
44
50
50
54
59
7
2g
2h
2i
2
Bn
8
4-EtOBn
t-Bu
3
MeSCH2CH2
9
4
EtOOCCH2CH2
10
4-MeOBn
2j
5
3-indolylCH2
the trifluoroacetyl group can be easily removed subse-
quently from products in mild conditions.12
6
Me
7
H
4g
4h
4i
The CF3-substituted five- and six-membered cyclic im-
ines 1a,c react smoothly, and the corresponding proline
and homoproline derivatives were isolated in high yields
(Table 1). Imines 1b,d containing the C2F5 group also
react similarly and give fluorinated products 2c,g in good
yields. Previously, we have observed the formation of
exocyclic double-bond product A in the Ugi reaction with
seven-membered Me-imine (Scheme 3). In the case of 1e
it is not possible, and target products 2i,j are formed in
good yields.
8
Me
9
MeSCH2CH2
10
11
12
13
EtOOCCH2CH2
4j
Me
H
4k
4l
i-Pr
4m
In general, polyfluorosubstituted cyclic imines react
smoothly and appear to be cheap and very effective start- In conclusion the first example of the Ugi reaction with 2-
ing materials for one-step, multicomponent preparation of polyfluoroalkyl-substituted pyrroline, piperideine, and
2-polyfluorosubstituted proline, homoproline, and azepan tetrahydroazepine was described. The reaction opens a
carboxylic acid derivatives.
new straightforward route to polyfluorosubstituted pro-
line, homoproline, and azepan carboxylic acid deriva-
tives. The reaction represents a general one-step approach
to construct a broad variety of earlier unknown orthogo-
Several times, isocyanoacetic acid derivatives were used
for the multicomponent synthesis of substituted amino
acid dipeptides. The combination of polyfluoroalkylated
O
a
a
N
N
NHR1
N
R = Me
1e, R = CF3
R
CH2
CF3
F3C
O
F3C
O
ref. 12
this work
59–70%
71%
A
2i,j
Scheme 3 Seven-membered imines in the Ugi reaction. Reagents and conditions: (a) Ugi conditions: TFA, R1NC, CH2Cl2, 0.1 M, –20 °C
to r.t.
Synlett 2009, No. 3, 403–406 © Thieme Stuttgart · New York

LETTER
Multicomponent Synthesis of a-Trifluoromethyl Proline
405
mixture was cooled to r.t. and carefully diluted with solution
of AcOH (40 g) in H2O (100 mL). The organic layer was
separated and the solution of crude keto lactam product was
slowly added to 6 N HCl (0.5 L) under stirring and heating
at reflux. THF was removed during the addition by use of the
distilling head. After heating at reflux for 60 h the reaction
mixture was cooled to 0 °C, made basic to pH 12 by using
50% KOH aq and extracted with Et2O (4 × 100 mL). The
combined organic layers were dried over K2CO3 and
concentrated under atmospheric pressure to give 73 g of
crude cyclic hemi-aminal product as an oil that solidified
under cooling. To remove H2O the cyclic hemi-aminal was
distilled at atmospheric pressure to the receiving flask
charged with anhyd Na2SO4 (20 g). The drying agent was
removed by filtration to afford 54.0 g (79% yield) of product
as a clear, colorless liquid. 1H NMR (200 MHz, CDCl3): d =
1.97–2.12 (m, 2 H), 2.70–2.78 (m, 2 H), 3.98–4.08 (m, 2 H).
19F NMR (188 MHz, CDCl3): d = –71.4 (s, 3 F). 13C NMR
(100 MHz, CDCl3): d = 124.9 (q, J = 285.4 Hz, CF3), 115.9
(q, J = 35.4 Hz), 62.2, 33.7, 22.6. HRMS (EI): m/z calcd for
C5H6F3N: 137.0452; found: 137.0462.
nally protected dipeptides, containing polyfluorosubsti-
tuted cyclic amino acid residues from very cheap
fluorinated starting materials.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
The authors thank the Deutsche Forschungsgemeinschaft (436 RUS
113/812/0-1) for financial support of this work.
References and Notes
(1) (a) Renner, C.; Alefelder, S.; Bae, J. H.; Budisa, N.; Huber,
R.; Moroder, L. Angew. Chem. Int. Ed. 2001, 40, 923.
(b) Improta, R.; Benzi, C.; Barone, V. J. Am. Chem. Soc.
2001, 123, 12568. (c) Golbik, R.; Yu, C.; Weyher-Stingl, E.;
Huber, R.; Moroder, L.; Budisa, N.; Schiene-Fischer, C.
Biochemistry 2005, 44, 16026.
(2) Chen, L.; Kim, Y. M.; Kucera, D. J.; Harrison, K. E.;
Bahmanyar, S.; Scott, J. M.; Yazbeck, D. J. Org. Chem.
2006, 71, 5368.
(15) General Procedure for the Ugi Reaction
The imine (1 mmol) was dissolved in CH2Cl2 (10 mL) and
TFA (1 mmol), then isocyanide was added at –20 °C. The
mixture was stirred for 12 h and treated with a mixture of
EtOH–HCl aq (10:1, 0.5 mL) to remove any remaining
isocyanide. The solvent was evaporated, and the residue was
purified by column chromatography (hexane–EtOAc,4:1).
(16) Selected Analytical Data
(3) Wu, W.-J.; Raleigh, D. P. J. Org. Chem. 1998, 63, 6689; and
references therein.
(4) Chaume, G.; Van Severen, M.-C.; Marinkovic, S.; Brigaud,
T. Org. Lett. 2006, 8, 6123.
Compound 2a: yield 80%; colorless oil; Rf = 0.8 (hexanes–
EtOAc, 3:1). 1H NMR (200 MHz, CDCl3): d = 1.36 (s, 9 H),
1.97–2.63 (m, 2 H), 2.25–2.60 (m, 2 H), 3.67–3.85 (m, 1 H),
3.90–4.07 (m, 1 H), 6.00 (br s, 1 H) ppm. 19F NMR (188
(5) Shevchenko, N. E.; Nenajdenko, V. G.; Röschenthaler,
G.-V. J. Fluorine Chem. 2008, 129, 390.
(6) (a) Osipov, S. N.; Bruneau, C.; Picquet, M.; Kolomiets,
A. F.; Dixneuf, P. H. Chem. Commun. 1998, 2053.
(b) Osipov, S. N.; Artyushin, O. I.; Kolomiets, A. F.;
Bruneau, C.; Picquet, M.; Dixneuf, P. H. Eur. J. Org. Chem.
2001, 3891. (c) Eckert, M.; Monnier, F.; Thchetnikov, G. T.;
Titanyuk, I. D.; Osipov, S. N.; Toupet, L.; Dérien, S.;
Dixneuf, P. H. Org. Lett. 2005, 7, 3741.
(7) (a) Moldeni, M.; Pesenti, C.; Sani, M.; Volonterio, A.;
Zanda, M. J. Fluorine Chem. 2004, 125, 1735. (b) Koksch,
B.; Sewald, N.; Hofmann, H.-J.; Burger, K.; Jakubke, H.-J.
J. Pept. Sci. 1997, 3, 157.
(8) (a) Druzhinin, S. V.; Balenkova, E. S.; Nenajdenko, V. G.
Tetrahedron 2007, 63, 7753. (b) Zanda, M. New J. Chem.
2004, 28, 1401. (c) Jäckel, C.; Koksch, B. Eur. J. Org.
Chem. 2005, 4483.
(9) (a) Hodgson, D. R. W.; Sanderson, J. M. Chem. Soc. Rev.
2004, 33, 422. (b) Thust, S.; Koksch, B. Tetrahedron Lett.
2004, 45, 1163.
(10) Kobsev, S. P.; Soloshonok, V. A.; Yagupol’skii, Y. u. L.;
Kukhar’, V. P. J. Gen. Chem. USSR 1989, 59, 801.
(11) Nagai, T.; Nishioka, G.; Koyama, M.; Ando, A.; Mild, T.;
Kumadaki, I. J. Fluorine Chem. 1992, 57, 229.
(12) Nenajdenko, V. G.; Gulevich, A. V.; Balenkova, E. S.
Tetrahedron 2006, 62, 5922.
(13) Gulevich, A. V.; Shevchenko, N. E.; Balenkova, E. S.;
Röschenthaler, G.-V.; Nenajdenko, V. G. Tetrahedron 2008,
64, 11706.
MHz, CDCl3): d = –73.7 (s, 3 F), –69.1 (s, 3 F) ppm. 13
C
NMR (100 MHz, CDCl3): d = 163.4, 156.1 (m), 124.9 (q,
J = 285.4 Hz, CF3), 115.9 (q, J = 288.4 Hz, CF3), 52.4, 49.6
(m), 33.8, 28.3, 23.8 ppm. HRMS (EI): m/z calcd for
C12H16F6N2O2: 334.1116; found: 334.1112.
Compound 2c: yield 61%; white solid, mp 55–57 °C; Rf =
0.8 (hexanes–EtOAc, 3:1). 1H NMR (200 MHz, CDCl3): d =
1.35 (s, 9 H), 2.00–2.19 (m, 2 H), 2.38–2.55 (m, 2 H), 3.50–
3.75 (m, 1 H), 3.90–4.20 (m, 1 H), 6.1 (br s, 1 H) ppm. 19
F
NMR (188 MHz, CDCl3): d = –73.8 (s, 3 F), –80.5 (s, 3 F),
–106.2, –107.7, –109.0, –110.5 (AB system, dA = –109.3
ppm, dB = –107.4 ppm, 2JAB = 275.9 Hz, 2 F) ppm. HRMS
(EI): m/z calcd for C13H16F8N2O2: 384.1084; found:
384.1080.
Compound 2g: yield 70%; white solid; mp 121–123 °C; Rf =
0.8 (hexanes–EtOAc, 3:1). 1H NMR (200 MHz, CDCl3): d =
1.68–1.87 (m, 3 H), 1.94–2.17 (m, 2 H), 2.31–2.55 (m, 1 H),
3.38 (t, J = 14.7 Hz, 1 H), 3.82–4.11 (m, 1 H), 4.40–4.68 (m,
2 H), 6.0 (br s, 1 H), 6.86 (d, J = 8.6 Hz), 7.19–7.43 (m, 5 H)
ppm. 19F NMR (188 MHz, CDCl3): d = –71.2 (s, 3 F), –80.6
(s, 3 F), –106.2, –107.7, –109.6, –111.1 (AB system, dA =
–110.0 ppm, dB = –107.4 ppm, 2JAB = 281.1 Hz, 2 F) ppm.
HRMS (EI): m/z calcd for C17H16F8N2O2: 432.1084; found:
432.1102.
Compound 2i: yield 59%; colorless oil; Rf = 0.8 (hexanes–
EtOAc, 3:1). 1H NMR (400 MHz, CDCl3): d = 1.25–1.30 (m,
1 H), 1.36 (s, 9 H), 1.66–1.90 (m, 3 H), 1.90–2.00 (m, 1 H),
2.05–2.17 (m, 2 H), 2.23–2.33 (m, 1 H), 3.20–3.30 (m, 1 H),
3.90–4.00 (m, 1 H), 5.40 (br s)ppm. 19F NMR (188 MHz,
CDCl3): d = –69.8 (s, 3 F), –70.1 (s, 3 F) ppm. 13C NMR (100
MHz, CDCl3): d = 162.1, 157.4 (q, J = 35.9 Hz), 125.9 (q,
J = 289.8 Hz), 116.3 (q, J = 288.3 Hz), 70.2 (q, J = 24.9 Hz),
52.0, 46.2, 33.0, 30.5, 28.6, 22.3, 28.3 ppm. HRMS (EI):
m/z calcd for C14H20F6N2O2: 362.1429; found: 362.1433.
(14) The CF3-imines 1a,c,e were prepared using a standard
Claisen condensation and subsequent decarboxylation,
details will be published in due course.
Synthesis of 2-CF3 Pyrroline (1a)
The stirred suspension of 60% NaH (26.7 g 0.665 mol) in
anhyd THF (250 mL) was heated at reflux while a mixture
of freshly distilled N-vinylpyrrolidin-2-one (55.0 g, 0.50
mol) and ethyl trifluoroacetate (78.0 g, 0.55 mol) was slowly
added. After refluxing for an additional hour the reaction
Synlett 2009, No. 3, 403–406 © Thieme Stuttgart · New York

406
A. V. Gulevich et al.
LETTER
Compound 4b (mixture of diastereomers, ca. 1:1): yield
60%; yellow oil; Rf = 0.6 (hexanes–EtOAc, 3:1). 1H NMR
(200 MHz, CDCl3): d = 1.24, 1.25 (dt, J = 6.9 Hz, 3 H), 1.90–
2.15 (m, 2 H), 2.26–2.50 (m, 2 H), 3.10–3.22 (m, 2 H), 3.65–
3.85 (m, 1 H), 3.89–4.04 (m, 1 H), 4.09–4.30 (m, 2 H), 4.80–
ppm. 13C NMR (100 MHz, CDCl3): d = 171.4, 171.3, 164.5,
164.0, 157.0 (m), 125.3, 125.1 (dq, J = 289.8 Hz), 115.9 (q,
J = 287.6 Hz), 66.3 (m), 61.8, 52.2, 42.0, 41.7, 30.9, 30.6,
29.7, 29.5, 28.2, 27.7, 21.5, 21.3, 15.2, 15.2, 15.1, 15.0, 13.9
ppm. HRMS (EI): m/z calcd for C16H22F6N2O4S: 452.1205;
found: 452.1220.
4.95 (m, 1 H) 6.6 (br s, 1 H), 7.00–7.35 (m, 5 H) ppm. 19
F
NMR (188 MHz, CDCl3): d = –69.2 (s, 3 F), –73.6, –73.7
(ds, 3 F) ppm. 13C NMR (100 MHz, CDCl3): d = 170.6,
170.5, 164.1, 163.9, 155.4 (q, J = 34.4 Hz), 135.3, 135.2,
129.3, 129.2, 128.4, 127.1, 121.7, 121.6 (dq, J = 286.6 Hz),
118.8 (q, J = 277.6 Hz), 72.7 (m), 61.7, 61.6, 53.7, 53.5,
49.5, 37.5, 37.3, 33.8, 33.7, 23.6, 13.8 ppm. HRMS (EI):
m/z calcd for C19H20F6N2O4: 454.1327; found: 454.1333.
Compound 4f (mixture of diastereomers, ca. 1:1): yield
53%; yellow oil; Rf = 0.6 (hexanes–EtOAc, 3:1). 1H NMR
(200 MHz, CDCl3): d = 1.27 (t, J = 7.3 Hz, 3 H), 1.40–1.55
(m, 3 H), 1.97–2.25 (m, 2 H), 2.45–2.70 (m, 2 H), 3.60–3.81
(m, 1 H), 4.00–4.40 (m, 3 H), 4.45–4.70 (m, 1 H), 6.00, 7.50
(br ds, 1 H) ppm. 19F NMR (188 MHz, CDCl3): d = –73.2,
–73.3 (ds, 3 F), –79.8, –80.0 (ds, 3 F), –105.5, –107.0, –
107.6, –108.7 (AB system, dA = –108.3 ppm, dB = –106.3
ppm, 2JAB = 277.6 Hz), –106.0, –107.4, –109.0, –110.2 (AB
system, dA = –109.2 ppm, dB = –107.2 ppm, 2JAB = 277.6
Hz)ppm. 13C NMR (100 MHz, CDCl3): d = 172.3, 172.1,
163.9, 163.8, 156.8, 115.9 (q, J = 286.9 Hz), 108.0–126.0
(unresolved signals, C2F5 group), 72.7 (m), 61.8, 61.7, 49.7
(m), 49.1, 34.1, 23.1, 17.8, 17.7, 14.0 ppm. HRMS (EI): m/z
calcd for C14H16F8N2O4: 428.0982; found: 428.0978.
Compound 4i (mixture of diastereomers, ca. 1:1): yield 44%;
colorless oil; Rf = 0.6 (hexanes–EtOAc, 3:1). 1H NMR (200
MHz, CDCl3): d = 1.28 (t, J = 7.3 Hz, 3 H), 1.70–1.95 (m, 4
H), 2.05–2.40 (m, 6 H), 2.40–2.55 (m, 2 H), 3.35–3.60 (m, 1
H), 3.85–4.10 (m, 1 H), 4.21 (q, J = 7.3 Hz, 2 H), 4.53–4.70
(m, 1 H), 6.55–6.80 (m, 1 H) ppm. 19F NMR (188 MHz,
CDCl3): d = –68.05, –68.41 (ds, 3 F), –70.0, –70.1 (ds, 3 F)
Compound 4k (mixture of diastereomers, ca. 1:1): yield
50%; colorless oil; Rf = 0.6 (hexanes–EtOAc, 3:1). 1H NMR
(200 MHz, CDCl3): d = 1.20–1.35 9m, 3 H), 1.44 (t, J = 7.3
Hz, 3 H), 1.70–1.87 (m, 3 H), 1.90–1.25 (m, 2 H), 2.30–2.50
(m, 1 H), 3.20–3.50 (m, 1 H), 3.80–4.00 (m, 1 H), 4.10–4.30
(m, 2 H), 4.45–4.68 (m, 1 H), 6.6, 6.2 (br ds, 1 H) ppm. 19
F
NMR (188 MHz, CDCl3): d = –70.6, –70.5 (ds, 3 F), –79.9,
–79.8 (ds, 3 F), –106.2, –107.7, –109.7, –111.2 (AB system,
dA = –110.0 ppm, dB = –107.4 ppm, 2JAB = 277.6 Hz),
–106.3, –107.8, –109.5, –111.0 (AB system, dA = –109.8
ppm, dB = –107.5 ppm, 2JAB = 277.6 Hz)ppm. 13C NMR (100
MHz, CDCl3): d = 172.5, 172.3, 162.7, 162.6, 157.5 (q, J =
36.6 Hz), 116.0 (q, J = 287.6 Hz), 111.0–124.0 (unresolved
signals, C2F5 group), 67.9 (m), 61.8, 61.7, 49.0, 48.9, 48.8
(m), 26.8, 26.3, 20.3, 30.2, 18.0, 17.7, 14.3, 14.2, 13.9, 13.8
ppm. HRMS (EI): m/z calcd for C15H18F8N2O4: 442.1139;
found: 442.1133.
Compound 4l·H2O: yield 54%; colorless oil; Rf = 0.6
(hexanes–EtOAc, 3:1). 1H NMR (200 MHz, CDCl3): d =
1.30 (t, J = 7.1 Hz), 1.55–1.65 (m, 1 H), 1.80–2.05 (m, 4 H),
2.50–2.70 (m, 1 H), 3.00–3.15 (m, 1 H), 3.60–3.70 (m, 1 H),
4.02 (d, J = 18.0 Hz, 1 H), 4.25 (q, J = 7.1 Hz, 2 H), 4.54 (q,
J = 18.0 Hz, 1 H), 4.9 (br s, 1 H) ppm. 19F NMR (188 MHz,
CDCl3): d = –77.3 (q, J = 9.7 Hz, 3 F), –80.4 (q, J = 9.7 Hz,
3 F) ppm. 13C NMR (100 MHz, CDCl3): d = 172.0, 169.6,
169.1, 124.6 (q, J = 288.4 Hz), 122.4 (q, J = 291.3 Hz), 96.5
(q, J = 34.4 Hz), 70.2 (m), 60.3, 44.0, 42.7 (m), 32.6, 30.0,
29.9, 22.5, 13.9 ppm. HRMS (EI): m/z calcd for
C13H16F6N2O4: 378.1014; found: 378.1000.
Synlett 2009, No. 3, 403–406 © Thieme Stuttgart · New York

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