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DOI: 10.1055/s-0028-1087529
Efficient Multicomponent Synthesis of α-Trifluoromethyl Proline, Homoproline, and Azepan Carboxylic Acid Dipeptides
Publication History
Publication Date:
21 January 2009 (online)
Abstract
Cyclic imines bearing CF3 and C2F5 group were successfully used for the first Ugi multicomponent synthesis of polyfluoroalkyl-substituted proline, homoproline, and azepan carboxylic acid derivatives. Based on the suggested reaction the first synthesis of dipeptides containing α-CF3 cyclic amino acids residue was described. The scope and limitations of the approach are discussed.
Key words
amino acids - peptides - fluorine - multicomponent reactions - imines
- Supporting Information for this article is available online:
- Supporting Information
-
1a
Renner C.Alefelder S.Bae JH.Budisa N.Huber R.Moroder L. Angew. Chem. Int. Ed. 2001, 40: 923 -
1b
Improta R.Benzi C.Barone V. J. Am. Chem. Soc. 2001, 123: 12568 -
1c
Golbik R.Yu C.Weyher-Stingl E.Huber R.Moroder L.Budisa N.Schiene-Fischer C. Biochemistry 2005, 44: 16026 - 2
Chen L.Kim YM.Kucera DJ.Harrison KE.Bahmanyar S.Scott JM.Yazbeck D. J. Org. Chem. 2006, 71: 5368 - 3
Wu W.-J.Raleigh DP. 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 - 5
Shevchenko NE.Nenajdenko VG.Röschenthaler G.-V. J. Fluorine Chem. 2008, 129: 390 -
6a
Osipov SN.Bruneau C.Picquet M.Kolomiets AF.Dixneuf PH. Chem. Commun. 1998, 2053 -
6b
Osipov SN.Artyushin OI.Kolomiets AF.Bruneau C.Picquet M.Dixneuf PH. Eur. J. Org. Chem. 2001, 3891 -
6c
Eckert M.Monnier F.Thchetnikov GT.Titanyuk ID.Osipov SN.Toupet L.Dérien S.Dixneuf PH. Org. Lett. 2005, 7: 3741 -
7a
Moldeni M.Pesenti C.Sani M.Volonterio A.Zanda M. J. Fluorine Chem. 2004, 125: 1735 -
7b
Koksch B.Sewald N.Hofmann H.-J.Burger K.Jakubke H.-J. J. Pept. Sci. 1997, 3: 157 -
8a
Druzhinin SV.Balenkova ES.Nenajdenko VG. Tetrahedron 2007, 63: 7753 -
8b
Zanda M. New J. Chem. 2004, 28: 1401 -
8c
Jäckel C.Koksch B. Eur. J. Org. Chem. 2005, 4483 -
9a
Hodgson DRW.Sanderson JM. Chem. Soc. Rev. 2004, 33: 422 -
9b
Thust S.Koksch B. Tetrahedron Lett. 2004, 45: 1163 - 10
Kobsev SP.Soloshonok VA.Yagupol’skii YuL.Kukhar’ VP. 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 VG.Gulevich AV.Balenkova ES. Tetrahedron 2006, 62: 5922 - 13
Gulevich AV.Shevchenko NE.Balenkova ES.Röschenthaler G.-V.Nenajdenko VG. Tetrahedron 2008, 64: 11706
References and Notes
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 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): δ = 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): δ = -71.4
(s, 3 F). ¹³C NMR (100 MHz, CDCl3): δ = 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.
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).
Selected Analytical
Data
Compound 2a: yield 80%;
colorless oil; R
f
= 0.8
(hexanes-EtOAc, 3:1). ¹H NMR (200 MHz,
CDCl3): δ = 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 MHz, CDCl3): δ = -73.7
(s, 3 F), -69.1 (s, 3 F) ppm. ¹³C NMR
(100 MHz, CDCl3): δ = 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; R
f
= 0.8
(hexanes-EtOAc, 3:1). ¹H NMR (200 MHz,
CDCl3): δ = 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. ¹9F NMR
(188 MHz, CDCl3): δ = -73.8
(s, 3 F), -80.5 (s, 3 F), -106.2, -107.7, -109.0, -110.5
(AB system, δA = -109.3 ppm, δB = -107.4
ppm, ²
J
AB = 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; R
f
= 0.8
(hexanes-EtOAc, 3:1). ¹H NMR (200 MHz,
CDCl3): δ = 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): δ = -71.2
(s, 3 F), -80.6 (s, 3 F), -106.2, -107.7, -109.6, -111.1
(AB system, δA =
-110.0
ppm, δB = -107.4 ppm, ²
J
AB = 281.1
Hz, 2 F) ppm. HRMS (EI): m/z calcd
for C17H16F8N2O2:
432.1084; found: 432.1102.
Compound 2i:
yield 59%; colorless oil; R
f
= 0.8 (hexanes-EtOAc,
3:1). ¹H NMR (400 MHz, CDCl3): δ = 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): δ = -69.8
(s, 3 F), -70.1 (s, 3 F) ppm. ¹³C
NMR (100 MHz, CDCl3): δ = 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.
Compound 4b (mixture
of diastereomers, ca. 1:1): yield 60%; yellow oil; R
f
= 0.6
(hexanes-EtOAc, 3:1). ¹H NMR (200 MHz,
CDCl3): δ = 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), 4.80-4.95 (m, 1 H) 6.6 (br s, 1 H), 7.00-7.35
(m, 5 H) ppm. ¹9F NMR (188 MHz, CDCl3): δ = -69.2
(s, 3 F), -73.6, -73.7 (ds, 3 F) ppm. ¹³C
NMR (100 MHz, CDCl3): δ = 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; R
f
= 0.6
(hexanes-EtOAc, 3:1). ¹H NMR (200 MHz,
CDCl3): δ = 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): δ = -73.2,
-73.3
(ds, 3 F), -79.8, -80.0 (ds, 3 F), -105.5, -107.0, -107.6, -108.7
(AB system, δA = -108.3 ppm, δB = -106.3 ppm, ²
J
AB = 277.6
Hz), -106.0, -107.4, -109.0, -110.2
(AB system, δA = -109.2 ppm, δB = -107.2
ppm, ²
J
AB = 277.6 Hz)ppm. ¹³C
NMR (100 MHz, CDCl3): δ = 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; R
f
= 0.6
(hexanes-EtOAc, 3:1). ¹H NMR (200 MHz,
CDCl3): δ = 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): δ = -68.05, -68.41
(ds, 3 F), -70.0, -70.1 (ds, 3 F) ppm. ¹³C
NMR (100 MHz, CDCl3): δ = 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.
Compound 4k (mixture
of diastereomers, ca. 1:1): yield 50%; colorless oil; R
f
= 0.6
(hexanes-EtOAc, 3:1). ¹H NMR (200 MHz,
CDCl3): δ = 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. ¹9F NMR (188 MHz, CDCl3): δ = -70.6, -70.5
(ds, 3 F), -79.9, -79.8 (ds, 3 F), -106.2, -107.7, -109.7, -111.2
(AB system, δA = -110.0 ppm, δB = -107.4
ppm, ²
J
AB = 277.6
Hz),
-106.3, -107.8, -109.5, -111.0
(AB system, δA = -109.8 ppm, δB = -107.5
ppm, ²
J
AB = 277.6
Hz)ppm. ¹³C NMR (100 MHz, CDCl3): δ = 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; R
f
= 0.6 (hexanes-EtOAc,
3:1). ¹H NMR (200 MHz, CDCl3): δ = 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): δ = -77.3
(q, J = 9.7 Hz, 3 F), -80.4
(q, J = 9.7 Hz, 3 F) ppm. ¹³C
NMR (100 MHz, CDCl3): δ = 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.