Methyltrifluoropyruvate imines possessing N-oxalyl and N-phosphonoformyl groups - Precursors to a variety of α-CF3-α-amino acid derivatives

Article abstract of DOI:10.1039/b607060d

Convenient routes to methyl 2-oxalylimino- and 2-(phosphonoformimido)-3,3,3-trifluoropropanoates have been elaborated, based on the reaction of methyl trifluoropyruvate with ethyl oxamate or diethyl carbamoylphosphonate, respectively, followed by dehydration. The compounds obtained are useful synthetic intermediates toward a variety of novel 3,3,3-trifluoroalanine derivatives that are potential drug candidates. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b607060d

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Methyltrifluoropyruvate imines possessing N-oxalyl and N-phosphonoformyl
groups—precursors to a variety of a-CF3-a-amino acid derivatives
Hanna Skarpos,a Daria V. Vorob’eva,b Sergey N. Osipov,*b Irina L. Odinets,b Eli Breuerc and
Gerd-Volker Ro¨schenthaler*a
Received 18th May 2006, Accepted 3rd August 2006
First published as an Advance Article on the web 17th August 2006
DOI: 10.1039/b607060d
Convenient routes to methyl 2-oxalylimino- and 2-(phosphonoformimido)-3,3,3-trifluoropropanoates
have been elaborated, based on the reaction of methyl trifluoropyruvate with ethyl oxamate or diethyl
carbamoylphosphonate, respectively, followed by dehydration. The compounds obtained are useful
synthetic intermediates toward a variety of novel 3,3,3-trifluoroalanine derivatives that are potential
drug candidates.
tives (including peptides) based on the amidoalkylation of differ-
ent nucleophiles with highly electrophilic imines of methyl 3-halo-
3,3-difluoropyruvates (Scheme 1).10
1. Introduction
Peptides modified by non-proteinogenic amino acids are useful
building blocks for drug discovery. Therefore, the development
of new synthetic pathways to unnatural amino acids containing
different functionalities remains a constant challenge. In this
connection, hydroxamic acid derivatives including N-oxalylamino
acids have attracted considerable attention due to their high
activity in inhibiting medically important metalloenzymes.1 For
example oxaloglycine and its derivatives are known to inhibit
prolyl hydroxylase2 involved in the biosynthesis of collagen. The
hyperactivity of the enzyme leads to the accumulation of large
amounts collagen in different organs and tissues that causes the
life-threatening fibrotic diseases such as pulmonary fibroses, liver
and renal fibrosis etc. Furthermore, phosphonoformate (PFA,
Foscarnet) is an effective antiviral compound clinically used in
the treatment of herpetic diseases and of AIDS.3 Incorporation
of the PFA backbone into amides and amino acids is a promising
strategy used currently for the development of new drug candidates
based on selective inhibition of important enzymes including
MMPs (matrix metalloproteinases).4 The capacity of oxamic
and phosphonoformic acid moieties for bidentate metal binding
presumably plays a role in metalloenzyme inhibition. On the other
hand, a-amino acids containing the trifluoromethyl (Tfm) group5
are of particular interest due to the unique characteristics of
the trifluoromethyl group, such as high electronegativity, electron
density, steric hindrance and hydrophobicity.6 The advantages of
peptides modified by Tfm-amino acid include enhanced prote-
olytic stability, affinity for lipid bilayer membranes, as well as
stabilization of secondary supramolecular structures7 owing to
the ability of the fluorine atom to form hydrogen bonds.8,9
Scheme 1
In this communication, we report the synthesis of novel
imines of methyl trifluoropyruvate bearing oxalyl and phospho-
noformyl groups at the nitrogen atom, and their subsequent
transformations into the corresponding amino acid derivatives
(see Scheme 2). The resulting a-Tfm-a-amino acids possessing
N-oxalyl and N-phosphonoformyl groups are potentially useful
candidate molecules for the design of novel inhibitors of medically
important enzymes.
2. Results and discussion
We found that methyl trifluoropyruvate (MTFP)11 had reacted
readily with ethyl oxamate and diethyl carbamoylphosphonate at
room temperature in the absence of any solvent, to give, in high
yields, the stable adducts 1 which could be dehydrated by standard
procedure10 to afford the corresponding imines 2 (Scheme 2).
Similar to the other acylimines10b of MTFP, the imines 2 can
interact smoothly with organometallic reagents at −78 ◦C in
anhydrous THF or diethyl ether. The nucleophilic addition to
Previously we have developed an effective strategy for the syn-
thesis of a-halodifluoromethyl-substituted a-amino acid deriva-
=
the C N double bond proceeded regiospecifically and resulted in
the alkylation of the a-carbon atom, to give the corresponding
a-amino acid derivatives 3 in moderate to good yields (Scheme 3,
Table 1).
Further examination of the chemistry of imines 2 has revealed
that these compounds are sufficiently powerful electrophiles to
alkylate p-donor aromatic compounds such as furan, pyrrole,
indole, N,N-dimethylaniline, and pyrazolone. Thus, the various
aInstitute for Inorganic and Physical Chemistry, The University of Bremen,
Leobener Str., D-28334, Germany. E-mail: gvr@chemie.uni-bremen.de
bA.N. Nesmeyanov Institut of Organoelement compounds, Russian Academy
of Sciences, 119991, Moscow, Vavilov str. 28, Russia. E-mail: osipov@
ineos.ac.ru; Fax: +7 095 135 5085
cThe Department of Medicinal Chemistry, The School of Pharmacy, The
Hebrew University of Jerusalem, P.O. Box 12065, Jerusalem, 91120, Israel
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Scheme 2
Table 1 Reaction of 2 with Grignard reagents via Scheme 3
The reactions with indoles, 1-phenyl-3-methylpyrazol-5-one, fu-
ran, N-methylpyrrole and N,N-dimethylaniline proceeded under
mild conditions (entries 4–7 and 10,11), or at moderate heating
(entries 3,8,9) to yield the corresponding a-aryl(hetaryl)-b,b,b-
trifluoroalanine derivatives 4–7. In the aromatic rings, the C-
amidoalkylation had been directed consistently and regioselec-
tively to the sites of maximal p-electron density.
Entry
Product
R
X
Yielda (%)
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
Me
Me
Ph
Ph
CH2Ph
CH2Ph
Allyl
Allyl
C
P-OEt
C
P-OEt
C
P-OEt
C
65
58
52
49
59
55
43
48
=
Due to the strong electrophilic nature, the reduction of C N
3g
3h
double-bond of the imines 2 could also be easily accomplished
using 1.5 equivalents of NaBH4 (Scheme 5) in anhydrous ether
at room temperature. Under these conditions the reduction of N-
oxalyl imine 2a lead to the desired trifluoroalanine derivative 8 in
69% yield, while in the case of phosphorus-containing imine 2b,
the unexpected azirine derivative 9 was obtained in preparative
yield. The structure of 9 has been unambiguously confirmed by
the NMR, IR and HRMS data. The formation of azirine 9 is
being tentatively rationalized by assuming the tautomerization of
the initially formed reduction product A to the enol B, followed
by dehydration. However; the actual mechanism of this reaction
is not quite clear.
P-OEt
a Isolated yields after the purification by column chromatography.
Scheme 3
In conclusion, the results reported in this paper offer
a convenient pathway to a variety of novel N-oxalyl and
a-aryl and a-heteroaryl substituted a-Tmf-amino acids could easily
be prepared as indicated (Scheme 4, Table 2).
Scheme 4
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Table 2 Results of reactions with aromatic p-donors shown in Scheme 4
Entry
Product
R
X
Y
Reaction temperature/◦C
Yielda (%)
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
5a
5b
5c
5d
6a
6b
7a
7b
H
H
C
P-OEt
C
P-OEt
C
P-OEt
C
P-OEt
C
P-OEt
C
—
—
—
—
O
O
N-Me
N-Me
—
RT
RT
60
60
0 → RT
0 → RT
0 → RT
0 → RT
60
93
85
62
50
39
40
38
42
76
55
46
43
Me
Me
—
—
—
—
—
—
—
—
10
11
12
—
—
—
60
−40 → RT
P-OEt
−40 → RT
a Isolated yields after purification by column chromatography.
on a Fourier-spectrometer “Magna-IR750” (Nicolet), resolution
2 cm−1, 128 scans. The assignment of the absorption bands in IR
spectra was made according to ref. 12.
General procedure for the preparation of hemiamidals 1
A mixture of MTFP (10 mmol) and ethyl oxamate (or diethyl
carbamoylphosphonate; 10 mmol) was kept at room temperature
for 16 h. The crude solid product was washed with petroleum ether
to give analytically pure hemiamidals 1.
2-(Ethoxyoxalyl-amino)-3,3,3-trifluoro-2-hydroxy-propionic
acid methyl ester (1a). Yield: 98% (white solid), mp 58–61 ◦C. 1H
NMR (CDCl3) d: 8.11 (s, 1H), 5.42 (s, 1H), 4.41 (q, 2H, 3JHH = 7.1
Hz), 3.90 (s, 3H), 1.42 (t, 3H, 3JHH = 7.1 Hz). 19F NMR (CDCl3)
d: −81.7 (s, CF3). 13C NMR (CDCl3) d: 16.6, 55.2, 65.5, 80.5 (q,
2JCF = 29.5 Hz), 121.6 (q, CF3, JCF = 285.0 Hz), 156.1, 158.3,
1
159.1. HRMS calculated for C8H10F3NO6 (M+) 273.0460, found
273.0462.
Scheme 5
N-phosphonoformyl derivatives of a-Tfm-a-amino acids—
potential inhibitors of medically important enzymes. In addition,
the novel amino acid derivatives herein reported could find further
applications as building blocks for the modification of other
biologically active peptides. The new compounds reported in this
study will be examined for MMP inhibitory activity.
2-(Diethylphosphonoformamido)-3,3,3-trifluoro-2-propionic acid
◦
1
methyl ester (1b). Yield: 97% (white solid), mp 69–72 C. H
NMR (CDCl3) d: 8.51 (s, 1H), 5.32 (s, 1H), 4.20 (m, 4H), 3.93
3
(s, 3H), 1.4 (t, 6H, JHH = 7.0 Hz). 19F NMR (CDCl3) d: −75.5
(s, CF3). 31P NMR (CDCl3) d: −1.9 (m). 13C NMR (CDCl3) d:
16.6 and 16.7, 55.3, 65.6 and 65.7, 80.5 and 80.6 (both q, 2JCF
29.0 Hz), 122.5 and 122.6 (both q, CF3, JCF = 286.0 Hz), 165.5
(d, 1JCP = 123.0 Hz), 170.2. HRMS calculated for C9H15F3NO7P
(M+) 337.0538, found 337.0539.
=
1
3. Experimental
General remarks
All solvents used in reactions were freshly distilled from appropri-
ate drying agents before use. All other reagents were recrystallized
or distilled as necessary. Reactions were performed under an
atmosphere of dry nitrogen. Analytical TLCs were performed with
Merck silica gel 60 F254 plates. Visualization was accomplished
by UV light or spraying by Ce(SO4)2 solution in 5% H2SO4.
Flash chromatography was carried out using Merck silica gel 60
(230–400 mesh ASTM). Melting points were determined with an
Electrothermal IA9100 Digital Melting Point Apparatus and are
uncorrected. NMR spectra were obtained on a Bruker DPX-200
spectrometer operating at 200.13 MHz for 1H (TMS), 188.31 MHz
for 19F (CFCl3), 80.99 MHz for 31P (H3PO4) and 50.32 MHz 13C
(TMS). HRMS spectra were obtained on a Varian MAT CH7A
instrument at 70 eV. IR spectra were recorded in a thin layer
General procedure for the preparation of imines 2
Trifluoroacetic anhydride (4.5 mL, 31.9 mmol) was added at 0 ◦C
to a vigorously stirred solution of a hemiamidal (29.0 mmol)
in dry ether (100 mL) over a period of 0.5 h. After stirring
for 0.5 h, pyridine (5.2 mL, 64.0 mmol) was added slowly.
Stirring was continued for additional 2 h. The reaction mixture
was cooled down to −20 ◦C and the precipitated pyridinium
trifluoroacetate was filtered off under an inert gas atmosphere. The
filtrate was concentrated in vacuum and triturated with petroleum
ether (3 × 100 mL) to dissolve the imine and separate it from
residual pyridinium trifluoroacetate. The combined petroleum
ether solutions were evaporated to give 2 which was additionally
purified by distillation in the case of 2a. Imine 2b proved to be
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unstable under distillation conditions; therefore it was used further
as a crude product (purity ca. 90% according the NMR data).
Methyl N-(diethylphosphonoformyl)-3,3,3-trifluoro-2-phenyl-
alaninate (3d). Yield: 49% (pale yellow solid), mp 74–78 ◦C. 1H
NMR (CDCl3) d: 7.92 (s, 1H), 7.61 (s, 5H), 4.30 (m, 4H), 3.91
(s, 3H), 1.23 (m, 6H). 19F NMR (CDCl3) d: −72.1 (s, CF3). 31P
NMR (CDCl3) d: −1.6 (m). 13C NMR (CDCl3) d: 16.1 and 16.3,
54.2, 62.0 and 62.3, 65.0 and 65.2, (both q, 2JCF = 28.2 Hz), 121.1
Methyl 2-[N-(2-ethoxyoxalyl)imino]-3,3,3-trifluoropropanoate
(2a). Yield: 82% (colorless liquid), bp 95–97 ◦C/0.5 Torr. IR
−1
=
(thin layer) m/cm : 1034 (C–O–C), 1638 (C N), 1756, 1760 and
1
3
=
1765 (C O). H NMR (CDCl3) d: 4.41 (q, 2H, JHH = 6.9 Hz), 4.08
1
and 121.3 (both q, CF3, JCF = 281.0 Hz), 127.2, 128.1, 129.3,
(s, 3H), 1.42 (t, 3H, 3JHH = 6.9 Hz). 19F NMR (CDCl3) d: −71.3 (s,
1
133.7, 164.5 (d, JCP = 121.3 Hz), 165.0. HRMS calculated for
CF3). 13C NMR (CDCl3) d: 14.2, 55.6, 64.4, 122.6 (q, CF3, 1JCF
=
C15H19F3NO6P (M+) 397.0902, found 397.0904.
2
=
279.0 Hz), 154.7, 156.3 (q, C N–CF3, JCF = 35.1 Hz), 160.4,
167.3. HRMS calculated for C8H8F3NO5 (M+) 255.0457, found
255.0461.
Methyl
N-(ethoxyoxalyl)-a-(trifluoromethyl)phenylalaninate
(3e). Yield: 59% (oil). 1H NMR (CDCl3) d: 7.92 (s, 1H), 7.22 (m,
4H), 4.33 (q, 2H, 3JHH = 7.2 Hz), 4.24 (d, 1H, JHH = 14.0 Hz), 3.90
(s, 3H), 3.55 (d, 1H, JHH = 14.0 Hz), 1.36 (t, 3H, 3JHH = 7.2 Hz).
19F NMR (CDCl3) d: −73.4 (s, CF3). 13C NMR (CDCl3) d: 14.0,
Methyl 2-[(N-diethylphosphonoformyl)]imino]-3,3,3-trifluoro-
propanoate (2b). Yield: 75% (pale yellow oil). IR (thin layer)
−1
=
=
m/cm : 1022, 1046 (P–O–C, C–O–C), 1270 (P O), 1651 (C N),
2
1
35.9, 53.8, 63.8, 65.1 (q, JCF = 28.5 Hz), 122.9 (q, CF3, JCF
=
1
=
1759 and 1769 (C O). H NMR (CDCl3) d: 4.33 (m, 4H), 4.07
288.2 Hz), 125.4, 127.2, 131.4, 136.5, 155.1, 162.3, 166.2. HRMS
calculated for C15H16F3NO5 (M+) 347.0980, found 347.0981.
(s, 3H), 1.69 (t, 6H, 3JHH = 6.8 Hz). 19F NMR (CDCl3) d: −71.3
(s, CF3). 31P NMR (CDCl3) d: −2.2 (m). 13C NMR (CDCl3) d:
16.0 and 16.3, 55.3, 63.2 and 63.5, 122.9 and 123.2 (both q, CF3,
1JCF = 282.0 Hz), 151.2, 155.1 and 155.4 (both q, 2JCF = 33.0 Hz),
Methyl N-(diethylphosphonoformyl)-a-(trifluoromethyl)phenyl-
alaninate (3f). Yield: 55% (oil) 1H NMR (CDCl3) d: 7.71 (s, 1H),
7.13 (m, 4H), 4.26 (m, 4H), 4.11 (m, 1H), 3.92 (s, 3H), 3.57 (d, 1H,
JHH = 7.0 Hz), 1.32 (m, 6H). 19F NMR (CDCl3) d: −73.4 (s, CF3).
31P NMR (CDCl3) d: −1.3 (m). 13C NMR (CDCl3) d: 15.9 and
16.1, 34.5, 55.3, 61.7 and 62.0, 65.2 and 65.5, (both q, 2JCF = 29.1
Hz), 122.0 and 122.3 (both q, CF3, 1JCF = 284.1 Hz), 127.4, 129.5,
130.3, 134.9, 158.6, 162.7 (d, 1JCP = 120.3 Hz). HRMS calculated
for C16H21F3NO6P (M+) 411.1058, found 411.1059.
1
164.8 (d, JCP = 120.0 Hz), 168.2. An analytically pure sample
was not obtained.
General procedure for the preparation of 3
The Grignard reagent (solution in THF, 10.0 mmol) was added
dropwise to a stirred solution of an imine (10.0 mmol) in dry THF
(25 mL) at −78 ◦C. After 1 h at −78 ◦C the reaction mixture was
allowed to warm up to room temperature within 2 h. The reaction
mixture was quenched with 1 M HCl and extracted with ether
(2 × 25 mL). The combined organic layers were washed with brine
(25 mL), dried over MgSO4 and filtered. The solvent was removed
under reduced pressure and the crude product was purified by
flash chromatography on silica gel (eluent: ethyl acetate–hexanes).
Methyl 2-(ethoxyoxalylamino)-2-(trifluoromethyl)pent-4-enoate
(3g). Yield: 43% (oil). 1H NMR (CDCl3) d: 7.93 (s, 1H), 5.22 (m,
2H), 4.99 (m, 1H), 4.36 (q, 2H, 3JHH = 7.2 Hz), 3.88 (s, 3H), 3.63 (m,
1H), 2.97 (m, 1H), 1.43 (t, 3H, 3JHH = 7.2 Hz). 19F NMR (CDCl3)
d: −73.2 (s, CF3). 13C NMR (CDCl3) d: 13.7, 38.2, 53.3, 62.9,
70.2 (q, 2JCF = 29.8 Hz), 121. 7, 122.3 (q, CF3, 1JCF = 282.2 Hz),
132.4, 153.6, 160.3, 165.8. HRMS calculated for C11H14 F3NO5
(M+) 297.0824, found 297.0826.
Methyl 2-{N-(2-ethoxyoxalyl)amino}-3,3,3-trifluoro-2-methyl-
1
propanoate (3a). Yield: 65% (oil). H NMR (CDCl3) d: 7.70 (s,
Methyl 2-{(diethylphosphonoformyl)amino}-2-(trifluoromethyl)-
1H), 4.44 (m, 2H), 3.81 (s, 3H), 1.82 (s, 3H), 1.43 (t, 3H, 3JHH = 7.2
Hz). 19F NMR (CDCl3) d: −77.3 (s, CF3). 13C NMR (CDCl3) d:
1
pent-4-enoate (3h). Yield: 48% (oil). H NMR (CDCl3) d: 7.75
(s, 1H), 5.19 (m, 2H), 4.87 (m, 1H), 4.23 (m, 4H), 3.92 (s, 3H),
3.51 (m, 1H), 2.98 (m, 2H), 1.35 (t, 6H, 3JHH = 7.0 Hz). 19F NMR
(CDCl3) d: −73.2 (s, CF3). 31P NMR (CDCl3) d: −1.4 (m). 13C
NMR (CDCl3) d: 15.8 and 16.0, 36.9, 53.9, 62.5 and 62.7, 69.0
and 69.2, (both q, 2JCF = 29.7 Hz), 120.9, 122.5 and 122.7 (both
14.2, 15.9, 54.0, 59.3 (q, 2JCF = 30.2 Hz), 64.1, 123.3 (q, CF3, 1JCF
=
281.0 Hz), 158.5, 164.3, 165.4. HRMS calculated for C9H12F3NO5
(M+) 271.0667, found 271.0668.
Methyl 2-(diethylphosphonoformamido)-3,3,3-trifluoro-2-methyl-
1
1
1
propanoate (3b). Yield: 58% (oil). H NMR (CDCl3) d: 7.81 (s,
q, CF3, JCF = 282.1 Hz), 131.5, 156.7, 162.7 (d, JCP = 120.9
Hz). HRMS calculated for C12H19 F3NO6P (M+) 361.0902, found
361.0903.
3
1H), 4.22 (m, 4H), 3.85 (s, 3H), 1.85 (s, 3H), 1.42 (t, 6H, JHH
=
6.8 Hz). 19F NMR (CDCl3) d: −77.2 (s, CF3). 31P NMR (CDCl3) d:
−1.8 (m). 13C NMR (CDCl3) d: 16.0 and 16.2, 16.9, 54.7, 59.9 and
60.1 (both q, 2JCF = 28.8 Hz), 64.0 and 64.2, 121.8 and 122.0 (both
q, CF3, 1JCF = 283.0 Hz), 163.5 (d, 1JCP = 122.0 Hz), 165.4. HRMS
calculated for C10H17F3NO6P (M+) 335.0745, found 335.0747.
Methyl
N-(ethoxyoxalyl)-3,3,3-trifluoro-2-(1H-indol-3-yl)-
alaninate (4a). A mixture of indole (8.0 mmol) and imine
(8.0 mmol) in anhydrous diethyl ether (10 ml) was stirred at RT
overnight. The white precipitate was filtered off, washed with
ether to give analytically pure 4a. Yield: 93%, mp 178–180 ◦C. 1H
Methyl N-(ethoxyoxalyl)-3,3,3-trifluoro-2-phenylalaninate (3c).
Yield: 52% (white solid), mp 64–69 ◦C. 1H NMR (CDCl3) d: 8.21
(s, 1H), 7.53 (s, 5H), 4.40 (q, 2H, 3JHH = 7.0 Hz), 3.93 (s, 3H), 1.42
(t, 3H, CH3, 3JHH = 7.0 Hz). 19F NMR (CDCl3) d: −72.2 (s, CF3).
NMR (CDCl3) d: 8.62 (s, 1H), 8.43 (s, 1H), 7.84 (d, 1H, JHH
=
3
7.8 Hz), 7.33 (m, 4H), 4.44 (q, 2H, JHH = 6.9 Hz), 3.86 (s, 3H),
1.45 (q, 2H, 3JHH = 6.9 Hz). 19F NMR (CDCl3) d: −72.2 (s, CF3).
2
2
13C NMR (CDCl3) d: 14.1, 53.2, 64.0, 66.3 (q, JCF = 29.8 Hz),
13C NMR (CDCl3) d: 13.9, 53.8, 64.1, 75.8 (q, JCF = 30.2 Hz),
122.2 (q, CF3, 1JCF = 285.0 Hz), 127.5, 128.3, 129.5, 136.6, 157.3,
164.3, 165.4. HRMS calculated for C14H14F3NO5 (M+) 333.0824,
found 333.0826.
112.2, 118.4, 118.9, 120.3, 120,4, 125.6 (q, CF3, 1JCF = 280.1 Hz),
128.1, 129.3, 136.4, 155.6, 160.8, 164.3. HRMS calculated for
C16H15F3N2O5 (M+) 372.0933, found 372.0934.
3672 | Org. Biomol. Chem., 2006, 4, 3669–3674
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Methyl
N-(diethylphosphonoformyl)-3,3,3-trifluoro-2-(1H-
Methyl N-(diethylphosphonoformyl)-3,3,3-trifluoro-2-(2-furyl)-
alaninate (5b). Yield: 40% (oil). H NMR (CDCl3) d: 8.07 (s,
1
indol-3-yl)alaninate (4b). Obtained from indole and 2b following
the procedure for 4a. Yield: 85% (white solid), mp 108–110 ◦C.
1H), 7.42 (m, 1H), 6.63 (d, 1H, JHH = 3.4 Hz), 6.42 (m, 1H),
4.25 (m, 4H), 3.88 (s, 3H), 1.43 (t, 6H, 3JHH = 7.1 Hz). 19F NMR
(CDCl3) d: −73.3 (s, CF3). 31P NMR (CDCl3) d: −1.8 (m). 13C
NMR (CDCl3) d: 16.1 and 16.3, 54.3, 62.2 and 62.4, 65.7 and
1H NMR (CDCl3) d: 8.90 (s, 1H), 8.23 (s, 1H), 7.63 (d, 1H, JHH
=
7.8 Hz), 7.43 (m, 4H), 4.21 (m, 4H), 3.82 (s, 3H), 1.3 (m, 6H).
19F NMR (CDCl3) d: −72.2 (s, CF3). 31P NMR (CDCl3) d: −1.2
(m). 13C NMR (CDCl3) d: 16.6 and 16.7, 54.5, 65.4 and 65.5,
65.7 (m), 105.3, 112.5, 119.2, 121.2, 123.2, 124.6, 124.9 (q, CF3,
2
65.9 (both q, JCF = 31.3 Hz), 100.8, 108.5, 121.8 122.1 (both q,
1
1
CF3, JCF = 280.0 Hz), 140.4, 143.2, 164.7 (d, JCP = 122.5 Hz),
166.1. HRMS calculated for C13H17F3NO7P (M+) 387.0695, found
387.0694.
1JCF = 280.1 Hz), 127.0, 129.3, 136.4, 165.6 (d, JCP = 122.3
1
Hz), 168.2. HRMS calculated for C17H20F3N2O6P (M+) 436.1011,
found 436.1010.
Methyl N-(ethoxyoxalyl)-3,3,3-trifluoro-2-(1-methyl-1H-◦pyrrol-
1
2-yl)alaninate (5c). Yield: 38% (white solid), mp 95–97 C. H
General procedure for the preparation of indoles 4c,d
NMR (CDCl3) d: 8.21 (s, 1H), 7.63 (s, 1H), 6.64 (d, 1H, JHH
=
3
2.4 Hz), 6.25 (s, 1H), 4.46 (q, 2H, JHH = 6.8 Hz), 3.82 (s, 3H),
A mixture of 2-methylindole (8.0 mmol) and appropriate imine
(8.0 mmol) in anhydrous CHCl3 was heated at 60–70 ◦C for 6–
8 hours. The solvent was removed under reduced pressure; the
product was isolated by flash chromatography on silica gel (eluent:
ethyl acetate–hexanes).
3
3.75 (s, 3H), 1.42 (t, 3H, JHH = 6.8 Hz). 19F NMR (CDCl3) d:
−73.3 (s, CF3). 13C NMR (CDCl3) d: 14.3, 36.9, 53.8, 64.2, 67.5 (q,
2JCF = 34.0 Hz), 107.5, 114.6, 119.8, 121.5, 123.5 (q, 1JCF = 286.0
Hz), 155.6, 160.3, 165.7. HRMS calculated for C13H15F3N2O5 (M+)
336.0933, found 336.0934.
Methyl N-(ethoxyoxalyl)-3,3,3-trifluoro-2-(2-methyl-1H-indol-
3-yl)alaninate (4c). Yield 62%. (white solid), mp 107–109 ◦C.
1H NMR (CDCl3) d: 8.80 (s, 1H), 8.71 (s, 1H), 7.65 (br. s, 1H),
Methyl
a-(diethylphosphonoformamido)-a-(trifluoromethyl)-
1
1H-pyrrole-3-acetate (5d). Yield: 42% (oil). H NMR (CDCl3)
3
d: 8.52 (s, 1H), 7.54 (s, 1H), 6.63 (d, 1H, JHH = 2.6 Hz), 6.24 (s,
7.38 (m, 1H), 7.26 (m, 2H), 4.42 (q, 2H, JHH = 7.1 Hz), 3.92 (s,
3
3H), 2.46 (s, 3H), 1.43 (t, 3H, 3JHH = 7.1 Hz). 19F NMR (CDCl3) d:
−71.2 (s, CF3). 13C NMR (CDCl3) d: 11.9, 13.8, 54.8, 64.5, 65.1 (q,
2JCF = 28.2 Hz), 111.8, 113.9, 118.5, 120.1, 121.1, 125.6 (q, CF3,
1JCF = 281.1 Hz), 128.6, 136.2, 141.4, 158.5, 164.8, 167.3. HRMS
calculated for C17H17F3N2O5 (M+) 386.1089, found 386.1090.
1H), 4.33 (m, 4H), 3.82 (s, 3H), 3.65 (s, 3H), 1.36 (t, 6H, JHH
=
7.2 Hz). 19F NMR (CDCl3) d: −73.3 (s, CF3). 31P NMR (CDCl3)
d: −1.1 (m). 13C NMR (CDCl3) d: 16.3 and 16.4, 40.1, 53.8, 61.2
2
and 61.4, 62.0 and 62.2 (both q, JCF = 28.1 Hz), 104.4, 105.2,
1
120.3 123.5 (q, CF3, JCF = 279.7 Hz), 135.2, 158.6, 165.8 (d,
1JCP = 122.5 Hz). HRMS calculated for C14H20F3N2O6P (M+)
Methyl N-(diethylphosphonoformyl)-3,3,3-trifluoro-2-(2-methyl-
1H-indol-3-yl)alaninate (4d). Yield 50%. (pale yellow oil). H
400.1011, found 400.1010.
1
NMR (CDCl3) d: 8.69 (s, 1H), 8.55 (s, 1H), 7.35 (br. s, 1H), 7.21
(m, 1H), 7.18 (m, 2H), 4.26 (m, 4H), 3.92 (s, 3H), 2.48 (s, 3H), 1.39
(m, 6H). 19F NMR (CDCl3) d: −71.8 (s, CF3). 31P NMR (CDCl3)
d: −2.4 (m). 13C NMR (CDCl3) d: 13.4, 16.2 and 16.4, 53.9, 62.4
Methyl N-(ethoxyoxalyl)-3,3,3-trifluoro-2-(5-methyl-3-oxo-2-
phenyl-2,3-dihydro-1H-pyrazol-4-yl)alaninate
(6a). Obtained
from 1-phenyl-4 methylpyrazole and 2a following the procedure
for 4a. Yield: 76% (white solid), mp 84–88 ◦C. 1H NMR (DMSO)
d: 12.10 (s, 1H), 7.62 (m, 2H), 7.51–7.37 (m, 3H), 4.35 (q, 2H,
3JHH = 7.2 Hz), 3.78 (s, 3H), 2.24 (s, 3H), 1.41 (t, 3H, 3JHH = 7.2
Hz). 19F NMR (DMSO) d: −76.3 (s, CF3). 13C NMR (DMSO) d:
11.7, 14.6 and 14.7, 54.2, 62.8 (m), 64.2 and 64.3, 119,5, 121.5,
122.6 (q, CF3, 1JCF = 272.0 Hz), 127.3, 135.3, 140.5, 156.2, 158.3,
159.6, 161.2, 165.2. HRMS calculated for C18H18F3N3O6 (M+)
429.1148, found 429.1147.
2
and 62.6, 64.5 and 64.6 (both q, JCF = 30.8 Hz), 106.2, 113.5,
117.4, 121.2, 122.8, 126.6, 127.0 (q, CF3, 1JCF = 283.0 Hz), 135.4,
1
145.5, 165.2 (d, JCP = 123.5 Hz), 167.2. HRMS calculated for
C18H22F3N2O6P (M+) 450.1167, found 450.1168.
General procedure for the preparation of furans 5a,b and pyrroles
5c,d
To a 0 ◦C solution of the corresponding furan or pyrrole
(8.0 mmol) in ether (10 ml) a solution of imine 2a (4.0 mmol)
in 5 ml of ether was added. The mixture was allowed to warm up
to rt and was stirred until 19F NMR spectrum indicated the full
conversion of imine 2a. The solvent was removed under reduced
pressure. The crude residue was purified by flash chromatography
eluting with AcOEt–hexanes.
Methyl N-(diethylphosphonoformyl)-3,3,3-trifluoro-2-(5-methyl-
3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)alaninate
(6b).
Yield: 55% (pale yellow solid), mp 164–168 ◦C. 1H NMR
(DMSO) d: 13.11 (s, 1H), 7.92 (m, 2H), 7.30–7.19 (m, 3H), 4.15
(m, 4H), 3.63 (s, 3H), 1.91 (s, 3H), 1.37 (t, 6H, 3JHH = 7.0 Hz). 19
F
NMR (DMSO) d: −76.3 (s, CF3). 31P NMR (DMSO) d: −0.7 (m).
13C NMR (CDCl3) d: 12.2, 16.3 and 16.5, 53.3, 64.4 and 64.6, 67.8
(q, 2JCF = 29.3 Hz), 107.0, 121.4, 124.8 (q, CF3, 1JCF = 280.0 Hz),
Methyl
N-(ethoxyoxalyl)-3,3,3-trifluoro-2-(2-furyl)alaninate
1
125.1, 129.3, 139.5, 160.7, 162.3, 163.5, 164.7 (d, JCP = 122.5
(5a). Yield: 39% (white solid), mp 74–79 ◦C. 1H NMR (CDCl3)
d: 8.22 (s, 1H), 7.43 (m, 1H), 6.62 (d, 1H, JHH = 3.2 Hz), 6.43 (m,
1H, JHH = 2.8 Hz), 4.45 (q, 2H, 3JHH = 7.2 Hz), 3.83 (s, 3H), 1.47
(t, 3H, 3JHH = 7.2 Hz). 19F NMR (CDCl3) d: −73.3 (s, CF3). 13C
NMR (CDCl3) d: 14.2, 53.9, 63.5, 64.0 (q, 2JCF = 29.0 Hz), 104.8,
109.7, 121.9 (q, CF3, 1JCF = 278.1 Hz), 139.8, 151.5, 157.8, 165.9,
166.3. HRMS calculated for C12H12F3NO6 (M+) 323.0617, found
323.0619.
Hz). HRMS calculated for C19H23F3N3O7P (M+) 493.1226, found
493.1225.
Methyl
2-[4-(dimethylamino)phenyl]-N-(ethoxyoxalyl)3,3,3-
trifluoroalaninate (7a). To a chilled (−40 ◦C) solution of
N,N-dimethylaniline (8.0 mmol) in ether (10 ml) a solution of
imine 2a (8.0 mmol) in 5 ml of ether was added. The mixture was
allowed to warm to RT and stirred until the 19F NMR spectrum
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Org. Biomol. Chem., 2006, 4, 3669–3674 | 3673
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indicated the full conversion of the imine 2a. The solvent was
removed under reduced pressure. The crude residue was purified
by flash chromatography on silica eluting with AcOEt–hexanes.
1H NMR (CDCl3) d: 4.34 (m, 4H), 4.12 (s, 3H), 1.4 (m, 6H). 19
F
NMR (CDCl3) d: −62.7 (s, CF3). 31P NMR (CDCl3) d: −3.2 (m).
13C NMR (CDCl3) d: 16.4 and 16.5, 60.4, 64.9 and 64.8, 105.9
1
2
Yield: 46% (oil). H NMR (CDCl3) d: 7.80 (s, 1H), 7.32 (d, 2H,
and 105.8 (both q, JCF = 40.9 Hz), 120.5 and 120.6 (both q,
JHH = 9.0 Hz), 6.85 (d, 2H, JHH = 9.0 Hz), 4.2 (q, 2H, 3JHH = 7.0
CF3, 1JCF = 267.0 Hz), 146.5 (d, 1JCP = 278.3 Hz), 158.9. HRMS
3
Hz), 4.03 (s, 3H), 2.95 (s, 6H), 1.44 (t, 6H, JHH = 7.0 Hz). 19F
calculated for C9H13F3NO5P (M+) 303.0483, found 303.0482.
NMR (CDCl3) d: −71.3 (s, CF3). 13C NMR (CDCl3) d: 14.1, 40.4,
55.8, 63.6, 70.5 (q, 2JCF = 31.0 Hz), 113.5, 121.5, 121.6, 123.4 (q,
Acknowledgements
1
CF3, JCF = 281.0 Hz), 125.6, 128.8, 128.9, 149.5, 160.1, 161.3,
165.7. HRMS calculated for C16H19F3N2O5 (M+) 376.1246, found
376.1247.
This work was supported by Deutschen Forschungsgemeinschaft
(DFG No. 436 RUS 113/766/0-1) and Russian Foundation of
Basic Research (grant No. 04-03-32644). G.-V.R. is grateful to the
Forchheimer Foundation for a grant as a Visiting Professor at the
Hebrew University of Jerusalem (Israel).
Methyl
N-(diethylphosphonoformyl)-2-[4-(dimethylamino)-
phenyl]-3,3,3-trifluoroalaninate (7b). Obtained from N,N-
dimethylaniline and imine 2b following the procedure for 7a.
Yield: 43% (oil). 1H NMR (CD3CN) d: 7.93 (s, 1H), 7.34 (d, 2H,
JHH = 9.0 Hz), 6.78 (d, 2H, JHH = 9.0 Hz), 4.13 (m, 4H), 3.76 (s,
3H), 2.91 (s, 6H), 1.33 (t, 6H, 3JHH = 7.2 Hz). 19F NMR (CD3CN)
d: −71.3 (s, CF3). 31P NMR (CD3CN) d: 3.8 (m). 13C NMR
(CDCl3) d: 16.1 and 16.3, 39.9, 53.5, 61.2 and 61.3, 64.8 and 64.9
References
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2
(both q, JCF = 28.3 Hz), 111.4, 120.3, 122.9 and 123.0 (both q,
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Hz). HRMS calculated for C17H24F3N2O6P (M+) 440.1324, found
440.1325.
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General procedure for the reactions of 2 with NaBH4
To a 0 ◦C solution of imine 2 (8.0 mmol) in ether (10 ml)
a sodium borohydride (6.0 mmol, powder from Aldrich) was
carefully added. The resulting suspension was stirred overnight
at rt under nitrogen. The reaction mixture was quenched with 1 M
HCl and extracted with ether (2 × 50 mL). The combined organic
layers were washed with brine (25 mL), dried over MgSO4 and
filtered. The solvent was removed under reduced pressure and the
crude product was purified by flash chromatography on silica gel
(eluent: ethyl acetate–hexanes).
Methyl N-(ethoxyoxalyl)-3,3,3-trifluoroalaninate (8). Yield:
69% (oil). 1H NMR (CDCl3) d: 8.23 (s, 1H), 6.15 (m, 1H), 4.35 (m,
2H), 3.79 (s, 3H), 1.36 (t, 3H, 3JHH = 7.2 Hz). 19F NMR (CDCl3)
d: −72.0 (s, CF3). 13C NMR (CDCl3) d: 14.0, 53.5, 59.9 (q, 2JCF
=
1
32.0 Hz), 64.6, 125.4 (q, CF3, JCF = 288.2 Hz), 159.1, 161.4,
167.7. HRMS calculated for C8H10F3NO5 (M+) 257.0511, found
257.0512.
Methyl 3-(diethylphosphonyl)-2-(trifluoromethyl)-2H-azirine-2-
carboxylate (9). Yield: 57% (oil). IR (thin layer) m/cm−1: 1025,
12 (a) A. Hassner, C. S. Bunnel and K. Haltiwanger, J. Org. Chem., 1978,
43, 57; (b) L. J. Bellamy, The infrared spectra of complex molecules,
Wiley, New York, 1975.
=
=
=
1046 (P–O–C, C–O–C), 1271 (P O), 1652 (C O), 1765 (C N).
3674 | Org. Biomol. Chem., 2006, 4, 3669–3674
This journal is
The Royal Society of Chemistry 2006
©