Diastereoselective silver-catalyzed 1,3-dipolar cycloaddition of azomethine ylides with fluorinated imine

Article abstract of DOI:10.1021/jo101447n

We described hereby an instance of diastereoselective silver-catalyzed 1,3-dipolar cycloaddition of azomethine ylides with imine compounds. This new method provided synthetically useful, highly substituted tetrahydroimidazole derivatives with efficiency a

Full text of DOI:10.1021/jo101447n

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imparting properties. As a matter of fact, extensive studies
Diastereoselective Silver-Catalyzed 1,3-Dipolar
Cycloaddition of Azomethine Ylides with
Fluorinated Imine
have been carried out in seeking new synthetic fluorination
methodologies during the last 30 years.2
The catalytic asymmetric 1,3-dipolar cycloaddition of
azomethine ylides to electron-deficient alkenes has become
one of the most convenient and diversity-oriented syntheses
for the construction of highly substituted pyrrolidines with
up to four stereogenic centers.3 Although various methods
have been developed for this transformation, most of the
electron-deficient alkenes applied in the 1,3-dipolar cycload-
ditions of azomethine ylides are limited to maleates, fuma-
rates, maleimides, acrylates, nitroalkenes, and vinyl phenyl
sulfones in the synthesis of multisubstituted pyrrolidines. On
the contrary, Mannich reaction of azomethine ylides with
imine was documented,4 while 1,3-dipolar cycloaddition of
azomethine ylides to imine is rarely reported.5
Haibo Xie,† Jiangtao Zhu,† Zixian Chen,†,‡ Shan Li,† and
Yongming Wu*,†
†Key Laboratory of Organofluorine Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032, China, and
‡Department of Chemistry, Huazhong University of Science
and Technology, Wuhan, Hubei 430074, China
ymwu@sioc.ac.cn
Received August 9, 2010
Herein, we wish to report the synthesis of fluorinated
tetrahydroimidazole by 1,3-dipolar cycloaddition of azo-
methine ylides with fluorinated imine catalyzed by silver(I)
acetate. To begin our study, we selected azomethine ylides
and N-aryl bromodifluoroethylimine, which was obtained
by condensation of bromodifluoroacetaldehyde ethyl hemi-
acetal with arylamine, as the model reaction to optimize the
reaction conditions. We found that AgOAc, AgOTf, Ag2SO4,
AgNO3, and Ag2CO3 catalyzed the 1,3-dipolar cycloaddition
reaction (12 h, rt) affording the desired fluorinated tetrahy-
droimidazole in 70%, 60%, 64%, 20%, and 72% yield,
respectively (Table 1, entries 1-5), in toluene. Then using
We described hereby an instance of diastereoselective
silver-catalyzed 1,3-dipolar cycloaddition of azomethine
ylides with imine compounds. This new method provided
synthetically useful, highly substituted tetrahydroimida-
zole derivatives with efficiency and high diastereoselec-
tivity. We can conveniently obtain fluorinated dihydro-
imidazole, imidazole, and diamino esters through simple
modification.
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Published on Web 10/11/2010
DOI: 10.1021/jo101447n
r
2010 American Chemical Society

Xie et al.
JOCNote
TABLE 1. Optimization of the Reaction Conditionsa
entry
catalyst (5 mol %)
solvent
yield (%)b
1
2
3
4
5
6
7
8
9
AgOAc
AgOTf
Ag2SO4
AgNO3
Ag2CO3
AgOAc
Ag2CO3
AgOAc
Ag2CO3
toluene
toluene
toluene
toluene
toluene
THF
THF
CH2Cl2
CH2Cl2
70
60
64
20
72
94
87
42
63
FIGURE 2. The conformational analysis of the stepwise mecha-
nism.
aThe reactions all proceeded away from light. bYields are of isolated
products after column chromatography.
TABLE 2. AgOAc-Catalyzed Synthesis of Fluorinated Tetrahydroimid-
azolea
entry
Rf
Ar
drb
product/yield (%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
CF2Br
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
Ph
Ph
>20:1
>20:1
>20:1
>20:1
>20:1
11:2:1:1
>20:1
>20:1
>20:1
>20:1
14:1:1:1
12:1:1:1
>20:1
11:1:1:1
14:1:1:1
>20:1
3a/94
3b/91
3c/87
3d/84
3e/42
3f/65
3g/96
3h/94
3i/96
3j/97
3k/95
3l/96
3m/94
3n/80
3o/92
3p/93
p-CH3C6H4
p-CH3OC6H4
3,5-CH3OC6H3
o-CH3OC6H4
p-PhC6H4
p-BrC6H4
p-ClC6H4
p-FC6H4
o-ClC6H4
o-FC6H4
m-BrC6H4
2-furyl
2-thienyl
2-naphthyl
aThe reactions all proceeded away from light. bDetermined by 19F
NMR signals in the crude precipitate. Yields are of isolated products
after column chromatography.
FIGURE 1. The stereochemistry of the cycloaddition.
c
AgOAc and Ag2CO3 as catalyst, various solvents were
screened, and it was found that THF was the most desirable
solvent for this reaction. Eventually, we determined the opti-
mization condition was AgOAc (5 mol %) in THF at rt.
The stereochemistry of the cycloaddition of azomethine
ylides is dependent on the geometries of the dipoles as well as
dipolarophiles. The 2,5-stereochemistry of the resultant
pyrrolidine ring is determined by the geometry of the ylide.
The 2,5-cis-disubstituted pyrrolidine formed by intermediary
W- and U-shaped dipole, while 2,5-trans-disubstituted prod-
uct emerges from two possible S-shaped ylides (Figure 1).6
However, the most catalytic 1,3-dipolar cycloaddition of
azomethine ylides to electron-deficient alkenes formed
2,5-cis-disubstitutedpyrrolidine, while2,5-trans-disubstituted
product is rare. From the X-ray of the product 3a,7 we found
out that the 2 position phenyl group is trans to the 5 position
ester group. There are two possible mechanisms for this
reaction, concerted cycloaddition mechanism and stepwise
mechanism, but we have not found a suitable experiment to
distinguish these possibilities. We invoke an unusual S-shaped
azomethine ylide to explain the unusual trans arrangement of
the ylidearylandestersubstituents. We supposed thisreaction
is stepwise, but conformational analysis (Figure 2) indicated
that the arrangement of the major product aryl and ester
substituents should be cis, which is inconsistent with our
experiment. In view of this indirect inference, we incline
toward the concerted cycloaddition mechanism. However,
the possibility of the stepwise mechanism cannot be excluded
without direct experiment evidence.
Having established suitable reaction conditions, we explored
the scope and generality of this methodology (Table 2). As
shown in Table 2, most substrates examined provided excellent
yields and high stereoselectivity under the standard reaction
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Tetrahedron 2007, 63, 3235.
(7) See the Supporting Information.
J. Org. Chem. Vol. 75, No. 21, 2010 7469

Xie et al.
JOCNote
Experimental Section
General Procedure for 3a-p. A Schlenk tube was charged
with AgOAc (83 mg, 0.5 mmol), evacuated, and backfilled with
nitrogen. THF (10 mL), azomethine ylide (1.772 g, 10 mmol),
and 4-methoxy-N-(2-bromo-2,2-difluoroethylidene)aniline (2.641 g,
10 mmol) were successively added. Then the reaction mixture was
stirred at rt and away from light for 24 h. The mixture was
partitioned between ethyl acetate and water, then the organic layer
was washed with brine, dried over MgSO4, and concentrated in
vacuo. The residue was purified by column chromatography on
silica and then recrystallized from methanol to provide 3a. White
solid, mp 99-100 °C; 1HNMR (300 MHz, CDCl3) δ 7.58-7.56
(m, 2H), 7.38-7.36 (m, 3H), 6.74 (s, 4H), 5.43 (s, 1H), 4.79
(dd, J1 = 16.3 Hz, J2 = 4.2 Hz, 1H), 4.41 (s, 1H), 3.81 (s, 3H),
3.71 (s, 3H), 2.77 (br, 1H); 19F NMR (282 MHz, CDCl3) δ -52.1
(dd, J1 = 160.5 Hz, J2 = 4.2 Hz, 1F), -57.8 (dd, J1 = 160.5 Hz,
J2 = 16.3 Hz, 1F); 13C NMR (100 MHz, CDCl3) δ 170.8, 154.4,
139.9, 139.0, 129.0, 127.0, 124.6 (t, J = 312.3 Hz), 118.4, 114.6,
83.3, 72.9 (t, J = 22.3 Hz), 62.1, 55.5, 53.0; IR (KBr) 3261, 2953,
2840, 1755, 1739, 1512, 1458, 1373, 1337, 1289, 1250, 1116,
1044, 936, 824, 698, 588; MS (EI) m/z (rel intensity) 440 (24)
[Mþ], 185 (67), 177 (100), 146 (37), 117 (88). Anal. Calcd for
C19H19BrF2N2O3: C, 51.72; H, 4.34; N, 6.35. Found: C, 51.62; H,
4.27; N, 6.25
FIGURE 3. The derivatization of product 3.
General Procedure for 4h, 4o, and 4p. A Schlenk tube was
charged with 3h (459 mg, 1 mmol) and THF (3 mL). Then DDQ
(227 mg, 1 mmol) was added. The reaction mixture was stirred at
rt for 10 min. The mixture was partitioned between ethyl acetate
and water, then the organic layer was washed with brine, dried
over MgSO4, and concentrated in vacuo. The residue was
purified by column chromatography on silica and then recrys-
tallized from methanol to provide 4h. 1H NMR (300 MHz,
CDCl3) δ 7.50-7.36 (m, 4H), 7.10-6.77 (m, 4H), 4.93 (d, J =
5.3 Hz, 1H), 4.60 (qd, J1 = 7.8 Hz, J2 = 5.3 Hz, 1H), 3.88 (s,
3H), 3.75 (s, 3H); 19F NMR (282 MHz, CDCl3) δ -76.7 (d, J =
7.8 Hz, 3F); 13C NMR (100 MHz, CDCl3) δ 170.4, 166.0, 158.8,
135.4, 131.4, 131.1, 128.9, 128.0, 125.5, 124.8 (q, J = 278.7 Hz),
114.8, 69.0 (q, J = 30.9 Hz), 69.0, 55.4, 53.1; IR (KBr) 2955,
2839, 1745, 1620, 1511, 1401, 1337, 1237, 1167, 1133, 1037, 926,
835, 740; MS (EI) m/z (rel intensity) 456 (9) [Mþ], 396 (100), 216
(80), 147 (53); HRMS calcd for C19H16BrF3N2O3 456.0294,
found 456.0296.
condition. In an effort to understand the limitation of the
reaction, the effect of various substituents on the arene ring
of the azomethine ylides was investigated. Generally, electron-
donating substitutions on the benzene ring of the azomethine
ylides, such as methoxy (Table 2, entries 4, 5, and 6) and methyl
(Table 2, entry 3), would reduce the yield, while electron-
withdrawing substitutions like the phenyl group (Table 2,
entry 7), bromo (Table 2, entries 8 and 13), chloro (Table 2,
entries 9 and 11), and fluoro (Table 2, entries 10 and 12)
enhance the yield. Moreover, stereoselectivity is high except
when the ortho position of the arene ring was substituted
(Table 2, entries 6, 11, and 12) or the ortho position of the
arene was a heteroatom (Table 2, entries 14 and 15). It is
worthwhile to note that when the arene ring of the azomethine
ylides is 2-furyl (Table 2, entry 14), 2-thienyl (Table 2, entry 15),
or 2-naphthyl (Table 2, entry 16), they could also afford 3 in
excellent yield.
The highly substituted tetrahydroimidazole products can
be converted into a variety of other useful compounds and
intermediates without erosion in dr (Figure 3). 1,2-Dihy-
droimidazole can be obtained in 90% yield with DDQ
oxidation. Imidazole can be generated via treatment of 1,2-
dihydroimidazole with BrCCl3 and DBU.8 Furthermore,
acidic hydrolysis of tetrahydroimidazole products 3 with
TsOH in methanol affords diamino esters 6 without erosion
in dr.
General Procedure for 5h, 5o, and 5p. A Schlenk tube was
charged with 3h (229 mg, 0.5 mmol) and THF (4 mL). BrCCl3
(109 mg, 0.55 mmol) and DBU (76 mg, 0.5 mmol) were
successively added. Then the reaction mixture was stirred at rt
for 4 h. The mixture was partitioned between ethyl acetate and
water, then the organic layer was washed with brine, dried over
MgSO4, and concentrated in vacuo. The residue was purified by
column chromatography on silica and then recrystallized from
methanol to provide 5h. 1H NMR (300 MHz, CDCl3) δ 7.39-
7.37 (m, 2H), 7.26-7.19 (m, 4H), 6.97-6.94 (m, 2H), 3.98 (s,
3H), 3.84 (s, 3H); 19F NMR (282 MHz, CDCl3) δ -55.4 (s); 13
C
NMR (100 MHz, CDCl3) δ 162.0, 160.7, 148.9, 134.1, 131.5,
130.6, 128.9, 127.7, 127.3, 125.6 (q, J = 39.1 Hz), 124.3, 119.6 (q,
J = 270.5 Hz), 114.8, 55.5, 52.6; IR (KBr) 2954, 2841, 1736,
1608, 1568, 1512, 1466, 1421, 1350, 1300, 1225, 1132, 1036, 911,
843, 738, 645; MS (EI) m/z (rel intensity) 454 (100) [Mþ], 369
(54), 288 (29), 183 (23), 77 (29); HRMS calcd for C19H14BrF3-
N2O3 454.0140, found 454.0139
In conclusion, we described here an instance of diaste-
reoselective silver-catalyzed 1,3-dipolar cycloaddition of azo-
methine ylides with imine compounds. This new method
provided synthetically useful, highly substituted tetrahydroi-
midazole derivatives with efficiency and high diastereo-
selectivity. We can conveniently obtain fluorinated dihydroi-
midazole, imidazole, and diamino esters through simple
modification. Additional studies of asymmetric silver-catalyzed
reactions of azomethine ylides with imine compounds are
underway.
General Procedure for 6a and 6b. A Schlenk tube was charged
with 3a (441 mg, 1 mmol) and methanol (5 mL). Next
TsOH H2O (760 mg, 4 mmol) was added. Then the reaction
3
mixture was stirred at rt over light. We neutralized the mixture
by Na2CO3. Then the mixture was partitioned between ethyl
acetate and water, then the organic layer was washed with brine,
dried over MgSO4, and concentrated in vacuo. The residue was
(8) Williams, D. R.; Lowder, P. D.; Gu, Y. G.; Brooks, D. A. Tetrahedron
Lett. 1997, 38, 331.
7470 J. Org. Chem. Vol. 75, No. 21, 2010

Xie et al.
JOCNote
purified by column chromatography on silica to provide 6a. 1H
NMR (300 MHz, CDCl3) δ 6.78-6.67 (m, 4H), 4.72 (d, J = 10.1
Hz, 1H), 4.55-4.44 (m, 1H), 4.32 (s, 1H), 3.74 (s, 3H), 3.58 (s,
3H), 1.74 (br, 2H); 19F NMR (282 MHz, CDCl3) δ -51.5 to
-53.3(m, 2F); 13C NMR (100 MHz, CDCl3) δ 171.6, 152.9,
139.8, 124.3 (t, J = 313.7 Hz), 115.7, 114.5, 65.0 (q, J = 21.þ3
Hz), 55.4, 53.1, 52.5; HRMS calcd for C12H16BrF2N2O3
353.0307, found 353.0316
Acknowledgment. The authors gratefully acknowledge
generous financial support from National Science Founda-
tion of China (Nos. 20532040 and 20772145).
Supporting Information Available: Experimental details,
characterization data, and the 1H and 13C NMR spectra for all
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 21, 2010 7471