Organocatalysis with chiral formamides: Asymmetric allylation and reduction of imines

Article abstract of DOI:10.1002/ejoc.200700058

Simple aldimine, derived from p-nitrobenzaldehyde and 2-aminophenol, reacts with allyltrichlorosilane in the presence of chiral N-formylproline activator 5 and an L-proline additive to afford the corresponding homoallylic amine in good yield (84 %) and with moderate enantioselectivity (43 % ee). The role of the second formamide moiety in the activator is crucial to bring about the enhancement in the reaction rate and enantioselectivity, as C₂-chiral bisformamide 1 promotes for the same allylation reaction in higher yield (94%) and enantioselectivity (83 % ee). Chiral monoformamide 5 (10 mol-%), with the assistance of HMPA as an additive, also catalyses the asymmetric reduction of ketimine 13 in the presence of trichlorosilane in good yield and enantioselectivity (75 %, 81 % ee). Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200700058

FULL PAPER
DOI: 10.1002/ejoc.200700058
Organocatalysis with Chiral Formamides: Asymmetric Allylation and
Reduction of Imines
Christine Baudequin,[a] Devdutt Chaturvedi,[a] and Svetlana B. Tsogoeva*[a][‡]
Keywords: Chirality / Formamides / Organocatalysis / Allylation / Reduction
Simple aldimine, derived from p-nitrobenzaldehyde and 2-
aminophenol, reacts with allyltrichlorosilane in the presence
for the same allylation reaction in higher yield (94%) and
enantioselectivity (83%ee). Chiral monoformamide
5
of chiral N-formylproline activator 5 and an
L
-proline addi-
(10 mol-%), with the assistance of HMPA as an additive, also
catalyses the asymmetric reduction of ketimine 13 in the
presence of trichlorosilane in good yield and enantio-
selectivity (75%, 81%ee).
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
tive to afford the corresponding homoallylic amine in good
yield (84%) and with moderate enantioselectivity (43%ee).
The role of the second formamide moiety in the activator is
crucial to bring about the enhancement in the reaction rate
and enantioselectivity, as C2-chiral bisformamide 1 promotes
bution, we also demonstrate the potential of these chiral
formamides as organocatalysts for the reduction reaction of
ketimines.
Introduction
The allylation of aldehydes and aldimines with allyltri-
chlorosilane is among the most useful C–C bond-forming
reaction as it can provide valuable intermediates for the
synthesis of bioactive natural products and pharmaceuti-
cally important compounds.[1]
Whereas a broad variety of chiral organocatalysts has
been found to catalyse the enantioselective allylation of al-
dehydes,[2] as well as of N-acylhydrazones,[3] and fruitful re-
sults have been reported, enantioselective allylation of sim-
ple aldimines with allyltrichlorosilane was an unsolved
task[4] until 2006.[5,6]
Quite recently, our group reported the first example of
an organocatalytic enantioselective allylation of simple 2-
aminophenol-derived aldimines utilising novel C2-chiral
bisformamide 1 (Figure 1) and an in situ generated -pro-
line-derived allylsilane reagent.[5] We proposed a plausible
transition state model and, for simplicity, considered only
one formamide group of the C2-chiral bisformamide; we
speculated that the second formamide moiety might coordi-
nate in a similar manner to the silicon atom of the second
molecule of the -proline-derived allylsilane reagent.[5] To
test this hypothesis and to elucidate the role of the second
formamide moiety in reactivity and enantioselectivity, we
decided to synthesise and use chiral monoformamides 2–6
(Figure 1) for the same allylation reactions. In this contri-
Figure 1. Structures of C2-chiral bisformamide 1, monoformamides
2–6 and proline-derived N-oxide 7.
[a] Institut für Organische und Biomolekulare Chemie der Georg-
August-Universität Göttingen,
Results and Discussion
Tammannstrasse 2, 37077 Göttingen, Germany
[‡] Present address: Institut für Organische Chemie der Friedrich-
Alexander Universität Erlangen-Nürnberg,
Henkestrasse 42, 91054 Erlangen, Germany
Fax: +49-9131-85-26865
The syntheses of chiral formamide compounds 2–6 were
accomplished by known methods[7] as summarised in
Scheme 1. - and -proline were converted into their N-
formyl derivatives by treatment with formic acid in the pres-
E-mail: tsogoeva@chemie.uni-erlangen.de
Eur. J. Org. Chem. 2007, 2623–2629
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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C. Baudequin, D. Chaturvedi, S. B. Tsogoeva
FULL PAPER
ence of acetic anhydride. The subsequent treatment of chi- yields (45 and 42%, respectively) than with 20 mol-% load-
ral N-formylprolines with (R)- or (S)-1-(1-naphthyl)ethyl- ing (Table 1, Entries 1, 3 vs. 2, 4).
amine and (R)- or (S)-1-phenylethylamine in the presence
of HOBt and DCC gave target chiral formamides 2–6 (Fig-
ure 1).
Similarly, moderate yields (48–52%) and enantio-
selectivities (47–57%ee) were observed with chiral for-
mamides 4–6 under the same reaction conditions (Table 1,
Entries 5–7). Notably, the (S) product was obtained with
formamides 2–5, which contained the N-formylproline moi-
ety with the (R) configuration, independent of the absolute
configuration of the arylethyl moiety [(R) or (S), respec-
tively]. This shows that the absolute configuration of the
product depends only on the configuration of the chiral
centre in the proline moiety. Indeed, formamide 6, which
contains the N-formylproline unit in the (S) configuration,
gave the (R) product (Table 1, Entry 7).
Scheme 1.
Chiral formamide 5 was found to be the best activator
with respect to both the yield and the enantioselectivity
(50%, 57%ee, Table 1, Entry 7) and was selected for further
experiments with aldimine 8b containing an electron-with-
drawing group on the aromatic ring.
Whereas the yields are noticeably influenced by the load-
ing of the formamide, the enantioselectivity appears to be
rather insensitive to it (cf. Table 1, Entries 1, 3 vs. 2, 4).
Furthermore, yields are slightly dependent on the substrate
concentration and decrease when the concentration is in-
creased from 0.05 to 0.5 and then up to 1.0 molL–1 (cf.
Table 1, Entry 8 vs. 9 vs. 10). Higher levels of asymmetric
induction are observed at higher substrate concentrations
(cf. Table 1, Entry 8 vs. 9 vs. 10).
Allylation of Aldimines with Allyltrichlorosilane
The formamide derivatives were then examined for their
ability to mediate the enantioselective allylation of simple
aldimines derived from aldehydes and 2-aminophenols. As
a first model, we studied the addition of allyltrichlorosilane
to 8a, which contains an electron-donating group on the
aromatic ring, in the presence of the formamide derivatives
at room temperature. The results obtained are summarised
in Table 1 (Entries 1–7).
The use of 2 and 3 at 20 mol-% resulted in the formation
of (S) product 9a in low yields and moderate enantio-
selectivities (15%, 37%ee and 13%, 41%ee for Entries 1
and 3, respectively). Interestingly, formamides 2 and 3 in
stoichiometric amounts showed approximately the same
The presence of electron-donating (8a) or electron-with-
enantioselectivities (40 and 48%ee, respectively), but better drawing (8b) groups on the aromatic ring of the aldimine
Table 1. Screening of chiral formamides 2–6 for asymmetric allylation of aldimines 8a and 8b.
Entry
X
Activator
(equiv.)
t
[h]
Concentration
[molL–1]
Additive
(equiv.)
Yield
[%][a]
ee
Configuration
[%][b]
1
2
3
4
5
6
7
8
OMe
OMe
OMe
OMe
OMe
OMe
OMe
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
2 (0.2)
2 (1)
3 (0.2)
3 (1)
4 (1)
5 (1)
6 (1)
5 (1)
5 (1)
5 (1)
7 (1)
1 (2)
1 (2)
5 (1)
5 (2)
5 (2)
5 (1)
55
72
51
72
72
72
72
72
72
72
72
48
4
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.05
0.5
1
0.05
0.5
0.5
1
–
–
–
–
–
–
–
–
–
–
–
–
15
45
13
42
48
50
52
60
54
43
44
93
94
65
78
84
50
37
40
41
48
47
57
54
28
42
50
0
54
83
36
42
43
36
(S)
(S)
(S)
(S)
(S)
(S)
(R)
(S)
(S)
(S)
–
(S)
(S)
(S)
(S)
(S)
(S)
9
10
11
12[5]
13[5]
14
15
16
17
-proline (2)
-proline (1)
-proline (2)
-proline (2)
(+)-CSA (1)
72
26
72
72
1
0.5
0.5
[a] Yield of isolated product after column chromatography on SiO2. [b] Enantioselectivities were determined by chiral HPLC analysis
(Daicel Chiralpak AD) by comparison with an authentic racemic material.
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Asymmetric Allylation and Reduction of Imines
FULL PAPER
did not affect the yields significantly; however, the enantio-
Comparison of the optical rotation value of 1-(4-ni-
selectivities were influenced and a higher enantiomeric ex- trophenyl)-but-3-enylamine (12) with that of the literature
cess was obtained with 8a (cf. Table 1, Entry 6 vs. 9) at the data[8] allowed us to determine that the absolute configura-
same substrate concentration (0.5 molL–1).
tion of the major enantiomer was (R). By a similar analogy,
Furthermore, we prepared a chiral proline-derived N-ox- it was possible to determine that the absolute configuration
ide 7 as an analogue of a known organocatalyst[2i] (iden- of the allylated product that was obtained from aldimine 8
tified as an effective catalyst for the reaction of allyltrichlo- with formamides 2–5 was (S).
rosilane with aldehydes[2i]) and employed it in the allylation
reaction of aldimine 8b. However, N-oxide 7 gave the prod-
uct only in racemic form and in moderate yield (44%, Reduction of Ketimine with Trichlorosilane
Table 1, Entry 11).
The asymmetric hydrogenation of imines represents one
As demonstrated in our previous communication,[5] the
of the most important methods for the preparation of chiral
reaction rate and the enantioselectivity could be signifi-
amines;[9] nevertheless, this process is associated with metal-
leaching and high pressure. Recently, some attention was
turned to the development of chiral organocatalysts. In fact,
cantly improved by combination of the chiral bisformamide
activator with an -proline additive (Table 1, Entry 12 vs.
13). Hence, we decided to examine this reaction by using
monoformamide 5 with the -proline additive. The reaction
conditions (activator, substrate and additive concentration)
were further varied to study and compare their effects on
the allylation reaction of bis- and monoformamides
(Table 1, Entries 12, 13 vs. 14–16).
several groups reported the use of chiral Lewis bases for the
reduction of imines with trichlorosilane[10] and Brønsted ac-
ids for the transfer hydrogenation with Hantzch ester.[11]
Also, chiral N-formylproline derivatives were reported as
organocatalysts for the reduction of imines.[10a] We there-
fore decided to examine the catalytic efficiency of for-
Although the yield improved to 84% (Table 1, Entry 16),
mamides 2–6 in the reduction reaction of ketimines in the
as expected,[5] by using -proline (2 equiv.) as an additive in
presence of Cl3SiH.
the presence of 5 (2 equiv.), no improvement in the enantio-
In the trial reduction reaction of imine 13 in CH2Cl2 at
selectivity and reaction times (43%ee, 72 h) with monofor-
room temperature for 24 h, chiral formamide 5 (10 mol-%)
mamide 5, relative to those with C2-chiral bisformamide 1
afforded the highest ee value (64%ee, Table 2, Entry 5). The
(83%ee, 4 h) was observed (Table 1, Entry 13 vs. 16).
alternative catalyst, diastereomer 4, promoted a signifi-
Evidently, the second formamide group of 1, as reported
cantly less-selective transformation to afford the product
recently,[5] acts in a similar way to the first formamide moi-
ety by coordination to a silicon atom of -proline-derived
allylsilane reagent and by steric hindrance, which provides
Table 2. Screening of chiral catalysts 1–5 and 7 for the asymmetric
reduction of ketimine 13.
higher reaction rates and enantioselectivities for the al-
lylation reaction of aldimines (Table 1, Entry 13 vs. 16).
Exchange of the -proline additive for (+)-CSA gave the
(S) product in lower yield and enantioselectivity (Table 1,
Entry 17).
To determine the absolute configuration of the allylated
product, it was necessary to remove the N-hydroxyphenyl
group. The Kobayashi group examined deprotection condi-
tions and it was found that a 2-amino-p-cresol derivative
gave better yields than 2-aminophenol-derived aldimine by
using PhI(OAc)2 for the deprotection.[4]
Aldimine 10 was also a suitable substrate for the asym-
metric allylation reaction and gave compound 11 in 79%
yield and 51%ee (Scheme 2). The absolute configuration of
the allylated product was determined after converting 11
into useful homoallylamine 12. Methylation of the phenolic
OH group followed by deprotection using PhI(OAc)2 gave
allylated amine 12.
Entry
Catalyst
Yield[a]
[%]
69[c]
48
53
48
ee (S)[b]
[%]
1
2
3
4
5
6
1
2
3
4
5
7
33
20
44
19
64
0
47
34
[a] Yield of isolated product after column chromatography on SiO2.
[b] Enantioselectivities were determined by chiral HPLC analysis
(Daicel Chiralpak OD) by comparison with an authentic racemic
material. [c] Reaction was carried out for 70 h.
Scheme 2.
Eur. J. Org. Chem. 2007, 2623–2629
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2625

C. Baudequin, D. Chaturvedi, S. B. Tsogoeva
FULL PAPER
with the same absolute configuration (19%ee, Table 2, En-
Further development of new formamide-derived chiral
try 4). Replacement of the phenyl group with a naphthyl bifunctional organocatalysts and new applications in cataly-
moiety (catalyst 5 vs. 3, Figure 1) led to a reduction in the sis are currently underway in our laboratory.
enantioselectivity of the imine from 64 to 44%ee (Table 2,
Entry 5 vs. 3). As in the case of the allylation reaction, chi-
ral N-oxide 7 gave no induction, and the amine was ob-
tained in a racemic form (Table 2, Entry 6).
We then studied the solvent effects on the chemical yield
and enantioselectivity. Some results, with the use of 30 mol-
% of selected catalyst 5, are shown in Table 3. Reactions
performed in chloroform, toluene and 1,2-dichloroethane
showed a small difference in terms of enantioselectivity,
compared to the results obtained in CH2Cl2.
Experimental Section
General: All solvents were purified by standard procedures and dis-
tilled prior to use. Reagents obtained from commercial sources
were used without further purification. TLC chromatography was
performed on precoated aluminium silica gel SIL G/UV254 plates
(Marcherey, Nagel & Co.) or silica gel 60-F254 precoated glass
plates (Merck). 1H NMR spectra were recorded with a Varian
Unity 300 spectrometer. ESI mass spectra were recorded with a
LCQ Finnigan spectrometer. High-resolution mass spectra were
measured with a Bruker APEX IV 7T FT-ICR instrument. A Per-
kin–Elmer 241 polarimeter was used for optical rotation measure-
ments.
Table 3. Optimisation of reaction conditions with selected catalyst
5.
N-Formyl-D-proline: -Proline (3 g, 26.05 mmol) was dissolved in
85% formic acid (55 mL) and cooled to 0 °C. Acetic anhydride
(18 mL) was added, and the reaction mixture was stirred at room
temperature for 2 h. Ice cold water (21 mL) was then added, and
the solvent was removed under reduced pressure. The residual pale
yellow oil was dissolved in methanol, and the solvent was removed
under reduced pressure to give the product as a white solid in 91%
Entry
Additive
(equiv.)
Solvent
T
[°C]
t
Yield ee (S)
[h] [%][a] [%][b]
yield (3.4 g). [α]2D0 = +121.5 (c = 1.2, EtOH). H NMR (300 MHz,
1
CDCl3): δ = 11.32 (s, 1 H, COOH), 8.26 and 8.22 (2ϫs, 1 H,
CHO), 4.45–4.39 (m, 1 H), 3.68–3.47 (m, 2 H), 2.30–1.95 (m, 4 H)
ppm. MS (ESI+): m/z = 143.9 [M + H]+, 166.0 [M + Na]+, 308.8
[2M + Na]+.
1
2
3
4
5
6
–
–
–
CH2Cl2
CHCl3
Toluene
ClCH2CH2Cl r.t.
CH2Cl2
CH2Cl2
r.t.
r.t.
r.t.
24
24
24
24
24
24
52
38
66
58
64
63
67
61
58
64
74
62
–
HMPA (0.3)
p-nitrobenzoic
acid (0.3)
HMPA (0.3)
r.t.
r.t.
N-Formyl-L-proline: This compound was prepared from -proline
by the same procedure as described above as to give the product
as a white solid in 93%. [α]2D0 = –118.4 (c = 0.8, EtOH). H NMR
1
7
CH2Cl2
–20
72
75
81
(300 MHz, CDCl3): δ = 8.81 (s, 1 H, COOH), 8.29 and 8.26 (2ϫs,
1 H, CHO), 4.51–4.41 (m, 1 H), 3.67–3.51 (m, 2 H), 2.29–2.20 (m,
2 H), 2.08–1.87 (m, 2 H) ppm. MS (ESI+): m/z = 144.0 [M + H]+,
166.0 [M + Na]+, 308.8 [2M + Na]+.
[a] Yield of isolated product after column chromatography on SiO2.
[b] Enantioselectivities were determined by chiral HPLC analysis
(Daicel Chiralpak OD) in comparison with authentic racemic ma-
terial.
Compound 2: A solution of DCC (2.16 g, 10 mmol) in DMF
(10 mL) at 0 °C was added dropwise to a mixture of N-formyl--
proline (1 g, 6.98 mmol), anhydrous CuCl2 (1.41 g, 10 mmol) and
HOBt (1.6 g, 10 mmol) in dry DMF (20 mL), and the reaction mix-
ture was stirred for 30 min. (R)-1-(1-naphthyl)ethylamine (2.24 g,
13 mmol) was added and the stirring was continued for 24 h (0 °C,
room temp.). The reaction mixture was diluted with EtOAc
(50 mL) and washed with cold 0.1  HCl, saturated NaHCO3 and
brine. The organic layer was dried with anhydrous sodium sulfate,
and the solvent was removed under reduced pressure. The crude
material was purified by column chromatography on silica gel (hex-
ane/EtOAc) to give pure amide 2 as a white solid in 35% yield
(0.7 g). [α]2D0 = +123.0 (c = 0.7, EtOH). 1H NMR (300 MHz,
Finally, we examined two additives, HMPA and p-nitro-
benzoic acid (Table 3, Entries 5–7). The most effective of
these was found to be HMPA, which provided in combina-
tion with formamide 5 the best yield and enantioselectivity
at –20 °C (75%, 81%ee, Table 3, Entry 7).
Conclusions
Chiral monoformamide 5 in combination with -proline
as an additive was shown to promote the enantioselective
allylation of simple aldimines with allyltrichlorosilane with
up to 84% yield and 43%ee within 72 h. The study pre- CDCl3, cis and trans forms): δ = 8.31 (s, 1 H, CHO), 8.09–8.06 and
8.01–7.98 (m, 1 H), 7.87–7.74 (m, 2 H), 7.54–7.41 (m, 4 H), 7.38
and 6.19 (2ϫd, J = 8.7 and 8.6 Hz, 1 H, NH), 5.91 and 5.84
(2ϫquintet, J = 6.9 and 7.0 Hz, 1 H), 4.42 and 4.30 (2ϫdd, J =
8.3 and 4.1 Hz; J = 8.1 and 3.3 Hz, 1 H), 3.58 (m, 2 H), 2.51–2.40
(m, 1 H), 2.21–2.01 (m, 1 H), 1.97–1.79 (m, 2 H), 1.64 and 1.59
(2ϫd, J = 6.3 and 6.9 Hz, 3 H, Me) ppm. 13C NMR (75.5 MHz,
CDCl3, major isomer): δ = 169.22, 162.17, 138.68, 133.84, 130.79,
128.75, 127.98, 126.25, 125.63, 125.35, 123.16, 122.42, 57.87, 46.91,
45.03, 27.04, 24.18, 21.30 ppm. 13C NMR (75.5 MHz, CDCl3,
minor isomer): δ = 170.17, 162.05, 137.44, 133.89, 130.94, 128.87,
128.55, 126.54, 125.91, 125.12, 122.96, 122.60, 60.67, 44.82, 44.31,
sented undoubtedly suggests the importance of the second
formamide moiety for higher rates and stereoselectivities in
the allylation reaction, as C2-chiral bisformamide 1 pro-
motes the same reaction with higher yield (94%) and
enantioselectivity (83%ee) within 4 h.
The use of chiral formamides 1–6 in the reduction of
ketimine 13 and in the presence of trichlorosilane was also
demonstrated. The reaction gave good results (75%,
81%ee) with monoformamide 5 in the presence of an
HMPA additive.
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Asymmetric Allylation and Reduction of Imines
FULL PAPER
30.36, 22.85, 20.53 ppm. IR (KBr): ν = 3297, 3257, 3106, 3070,
2350, 2167, 1961, 1896, 1823, 1681, 1574, 1495, 1448, 1424, 1385,
1353, 1306, 1284, 1270, 1242, 1230, 1182, 1144, 1101, 1090, 1077,
˜
2978, 2933, 2878, 1666, 1597, 1571, 1552, 1508, 1448, 1416, 1383,
1336, 1310, 1286, 1250, 1197, 1116, 978, 921, 805, 781, 448 cm–1. 1024, 1017, 974, 956, 924, 900, 874, 841, 802, 761, 749, 738, 700,
MS (ESI+): m/z = 319.2 [M + Na]+, 614.9 [2M + Na]+.
C18H20N2O2 (296.36): calcd. C 72.95, H 6.80, N 9.45; found C
73.12, H 7.06, N 9.24.
628, 611, 544, 525, 480, 428 cm–1. MS (ESI+): m/z = 269.2 [M +
Na]+, 514.8 [2M + Na]+. C14H18N2O2 (246.30): calcd. C 68.27, H
7.37, N 11.37; found C 68.16, H 7.45, N 11.30.
Compound 6: This compound was prepared from N-formyl--pro-
line and (R)-phenylethylamine by the same procedure as described
above for 2 to give 6 as a white solid in 85% yield. [α]2D0 = –100.2
Compound 3: This compound was prepared from N-formyl--pro-
line and (S)-1-(1-naphthyl)ethylamine in a manner analogous to 2
and was obtained as a white solid. [α]2D0 = +155.0 (c = 0.5, CHCl3).
1H NMR (300 MHz, CDCl3, cis and trans forms): δ = 8.19 and
8.14(2ϫs, 1 H, CHO), 8.02–7.94 (m, 1 H), 7.86–7.70 (m, 2 H),
7.54–7.38 (m, 4 H), 6.35 (d, J = 8.4 Hz, 1 H, NH), 5.90 and 5.80
(2ϫquintet, J = 7.5 and 7.2 Hz, 1 H), 4.54 and 4.30 (2ϫdd, J =
6.9 and 3.6 Hz; J = 8.1 and 3.3 Hz, 1 H), 3.52–3.31 (m, 2 H), 2.55–
2.43 and 2.22–2.04 (m, 1 H), 2.02–1.71 (m, 3 H), 1.64 and 1.60
(2ϫd, J = 6.9 Hz, 3 H, Me) ppm. 13C NMR (75.5 MHz, CDCl3,
major isomer): δ = 169.11, 162.27, 138.81, 133.81, 130.73, 128.74,
127.91, 126.10, 125.60, 125.34, 123.13, 122.28, 57.90, 46.74, 45.15,
26.90, 24.02, 21.57 ppm. 13C NMR (75.5 MHz, CDCl3, minor iso-
mer): δ = 170.15, 162.17, 137.28, 133.89, 130.98, 128.90, 128.64,
126.53, 125.93, 125.15, 122.94, 122.70, 60.89, 44.72, 44.17, 30.34,
1
(c = 1, CHCl3). H NMR (300 MHz, CDCl3, cis and trans forms):
δ = 8.29 and 8.26(2ϫs, 1 H, CHO), 7.45 and 6.15 (2ϫd, J = 7.2
and 8.7 Hz, 1 H, NH), 7.36–7.16 (m, 5 H), 5.12 and 5.02 (2ϫquin-
tets, J = 7.2 Hz, 1 H), 4.53 and 4.35 (2ϫdd, J = 6.9 and 4.2 Hz
and J = 7.5 and 3.9 Hz, 1 H), 3.61–3.38 (m, 2 H), 2.53–2.47 and
2.20–2.12 (m, 1 H), 2.06–1.76 (m, 3 H), 1.48 and 1.45 (2ϫd, J =
7.2 Hz, 3 H, Me) ppm. 13C NMR (75.5 MHz, CDCl3, major iso-
mer): δ = 169.21, 162.09, 143.30, 128.34, 126.82, 125.66, 57.69,
48.88, 46.71, 26.90, 23.92, 22.41 ppm. 13C NMR (75.5 MHz,
CDCl3, minor isomer): δ = 170.38, 161.95, 142.83, 128.45, 127.15,
125.79, 60.51, 48.63, 44.10, 30.23, 22.69, 21.39 ppm. IR (KBr): ν =
˜
3293, 3061, 2978, 2969, 2927, 2885, 2866, 1681, 1638, 1547, 1496,
1463, 1448, 1424, 1386, 1306, 1270, 1230, 1182, 1143, 1100, 1098,
1017, 974, 924, 900, 875, 841, 801, 760, 738, 699, 627, 611, 545,
525, 480, 426 cm–1. MS (ESI+): m/z = 247.0 [M + H]+, 269.1 [M
+ Na]+, 514.8 [2M + Na]+. C14H18N2O2 (246.30): calcd. C 68.27,
H 7.37, N 11.37; found C 67.94, H 7.65, N 11.15.
22.65, 20.21 ppm. IR (KBr): ν = 3288, 3051, 2976, 2875, 1657,
˜
1535, 1448, 1379, 1238, 1182, 1043, 802, 779, 443 cm–1. MS (ESI+):
m/z = 319.2 [M + Na]+, 614.9 [2M + Na]+. C18H20N2O2 (296.36):
calcd. C 72.95, H 6.80, N 9.45; found C 72.80, H 6.52, N 9.22.
Compound 4: This compound was prepared from N-formyl--pro-
line and (R)-phenylethylamine by the same procedure as described
above for 2 to give 4 as a white solid in 88% yield. [α]2D0 = +194.5
Compound 7: This compound was prepared from (R)-1-(1-naph-
thyl)ethylamine and -proline by the same procedures as described
in the literature for its derivative.[2i] The crude material was purified
by flash chromatography on silica gel (CH2Cl2/MeOH, 95:5) to give
pure 7 as a white solid (478 mg, 70% yield). [α]2D0 = –34.0 (c =
1.152, CHCl3). 1H NMR (600 MHz, CDCl3): δ = 11.79 (d, J =
9.0 Hz, 1 H, NH), 8.07 (d, J = 7.8 Hz, 1 H), 7.81 (d, J = 8.4 Hz, 1
H), 7.71 (d, J = 8.4 Hz, 1 H), 7.50 (d, J = 7.2 Hz, 1 H), 7.49–7.46
(m, 1 H), 7.44–7.39 (m, 2 H), 5.89 (quintet, J = 7.2 Hz, 1 H), 3.65
(br. s, 1 H), 3.37–3.33 (m, 1 H), 3.22–3.17 (m, 1 H), 3.11 (m, 1 H),
2.36–2.23 (m, 4 H), 2.11–2.09 (m, 1 H), 1.91–1.88 (m, 2 H), 1.84–
1.79 (m, 1 H), 1.68–1.59 (m, 3 H), 1.61 (d, J = 7.2 Hz, 3 H), 1.31–
1.23 (m, 2 H), 1.18–1.11 (m, 1 H) ppm. 13C NMR (75.5 MHz,
CDCl3): δ = 167.92, 139.12, 133.82, 130.74, 128.71, 127.65, 126.00,
125.45, 125.43, 123.27, 122.54, 76.23, 72.59, 66.51, 44.22, 28.39,
27.61, 27.48, 25.38, 25.26, 24.97, 21.66, 20.06 ppm. MS (ESI+):
m/z = 367.3 [M + H]+, 389.3 [M + Na]+, 733.1 [2M + H]+, 755.2
[2M + Na]+. HRMS (ESI): calcd. for C23H30N2O2 [M + H]+
367.23800; found 367.23798. C23H30N2O2 (366.50): calcd. C 75.37,
H 8.25, N 7.64; found C 75.67, H 8.08, N 7.40.
1
(c = 1, EtOH). H NMR (300 MHz, CDCl3, cis and trans forms):
δ = 8.31 and 8.22(2ϫs, 1 H, CHO), 7.41 and 6.18 (2ϫd, J =
6.6 Hz, 1 H, NH), 7.38–7.19 (m, 5 H), 5.11 and 5.00 (2ϫquintets,
J = 7.5 and 7.1 Hz, 1 H), 4.46 and 4.32 (2ϫdd, J = 8.1 and 3.9 Hz,
1 H), 3.62–3.46 (m, 2 H), 2.52–2.41 and 2.23–2.17 (m, 1 H), 2.08–
1.76 (m, 3 H), 1.47 and 1.42 (2ϫd, J = 6.3 and 7.2 Hz, 3 H, Me)
ppm. 13C NMR (75.5 MHz, CDCl3, major isomer): δ = 169.32,
162.15, 143.30, 128.45, 127.01, 125.90, 57.78, 49.02, 46.85, 27.00,
24.04, 22.09 ppm. 13C NMR (75.5 MHz, CDCl3, minor isomer): δ
= 170.40, 162.07, 142.62, 128.54, 127.30, 126.00, 60.61, 48.63,
44.25, 30.27, 22.78, 21.31 ppm. IR (KBr): ν = 3296, 3065, 2969,
˜
2946, 2925, 2889, 2870, 2783, 2657, 2600, 2468, 2339, 2166, 2048,
1963, 1897, 1882, 1823, 1602, 1493, 1474, 1463, 1353, 1305, 1284,
1268, 1210, 1145, 1134, 1099, 1091, 1075, 1030, 1014, 976, 954,
923, 912, 900, 874, 842, 736, 648 cm–1. MS (ESI+): m/z = 247.0 [M
+ H]+, 269.1 [M + Na]+, 514.8 [2M + Na]+. HRMS (ESI): calcd.
for C14H18N2O2 [M
+
H]+ 247.14410; found 247.14405.
C14H18N2O2 (246.30): calcd. C 68.27, H 7.37, N 11.37; found C
68.11, H 7.52, N 11.18.
General Procedure for the Allylation of Aldimines with Allyltrichlo-
rosilane in the Presence of a Chiral Formamide: Allyltrichlorosilane
(0.33 mmol, 1.5 equiv.) was added dropwise to a solution of aldim-
ine (0.22 mmol) and formamide (0.22 mmol, 1 equiv.) in dry
CH2Cl2 (0.44 mL). After stirring at room temperature for 72 h, tri-
ethylamine (0.15 mL) in methanol (0.8 mL) was added to quench
the reaction. The mixture was diluted with CH2Cl2 and water. The
organic layer was separated, dried with anhydrous Na2SO4, filtered
and concentrated under reduced pressure. The crude product was
purified by column chromatography on silica gel (CH2Cl2) to give
the pure product.
Compound 5: This compound was prepared from N-formyl--pro-
line and (S)-phenylethylamine by the same procedure as described
above for 2 to give 5 as a white solid in 93% yield. [α]2D0 = +89.8
1
(c = 1, CHCl3). H NMR (300 MHz, CDCl3, cis and trans forms):
δ = 8.21 and 8.18(2ϫs, 1 H, CHO), 7.46 and 6.76 (2ϫd, J = 7.2
and 7.5 Hz, 1 H, NH), 7.29–7.17 (m, 5 H), 5.09 and 4.99 (2ϫquin-
tets, J = 7.5 and 7.1 Hz, 1 H), 4.48 and 4.29 (2ϫdd, J = 7.7 and
4.1 Hz; J = 7.7 and 3.8 Hz, 1 H), 3.52–3.39 (m, 2 H), 2.46–2.40
and 2.15–2.07 (m, 1 H), 1.97–1.72 (m, 3 H), 1.43 and 1.41 (2ϫd,
J = 7.2 and 6.6 Hz, 3 H, Me) ppm. 13C NMR (75.5 MHz, CDCl3,
major isomer): δ = 169.20, 162.21, 143.36, 128.44, 126.92, 125.73,
57.79, 49.02, 46.81, 26.82, 24.01, 22.55 ppm. 13C NMR (75.5 MHz,
CDCl3, minor isomer): δ = 170.40, 162.10, 142.75, 128.60, 127.33,
9a: 1H NMR (300 MHz, CDCl3): δ = 7.27 (d, J = 8.9 Hz, 2 H),
6.85 (d, J = 8.9 Hz, 2 H), 6.69–6.67 (m, 2 H), 6.58–6.53 (m, 1 H),
6.41 (d, J = 7.2 Hz, 1 H), 5.84–5.70 (m, 1 H), 5.21–5.10 (m, 2 H),
4.32 (t, J = 6.5 Hz, 1 H), 3.77 (s, 3 H), 2.59–2.53 (m, 2 H) ppm.
13C NMR (75.5 MHz, CDCl3): δ = 158.38, 143.65, 135.96, 135.50,
125.84, 60.69, 48.74, 44.22, 30.31, 22.76, 21.45 ppm. IR (KBr): ν =
˜
3290, 3062, 2968, 2927, 2916, 2893, 2866, 2851, 2782, 2656, 2599,
Eur. J. Org. Chem. 2007, 2623–2629
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2627

C. Baudequin, D. Chaturvedi, S. B. Tsogoeva
FULL PAPER
134.69, 127.41, 121.36, 118.09, 117.64, 114.09, 113.88, 113.69,
57.15, 55.20, 43.14 ppm. The enantiomeric excess of the product
was determined by chiral HPLC analysis (Daicel Chiralpak AD)
by comparison with an authentic racemic material: n-hexane/2-pro-
panol = 90:10, flow rate 1 mLmin–1, λ = 254 nm: tR = 10.74 min,
tR = 16.43 min.
Acknowledgments
The authors gratefully acknowledge the Deutsche Forschungsge-
meinschaft (Schwerpunktprogramm 1179 “Organokatalyse”) for
generous financial support.
9b: 1H NMR (300 MHz, CDCl3): δ = 8.16 (d, J = 8.6 Hz, 2 H),
7.52 (d, J = 8.6 Hz, 2 H), 6.71–6.53 (m, 3 H), 6.20 (d, J = 7.8 Hz,
1 H), 5.81–5.67 (m, 1 H), 5.23–5.15 (m, 2 H), 4.48–4.44 (m, 1 H),
2.67–2.52 (m, 2 H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 151.54,
146.96, 143.18, 135.33, 133.33, 127.25, 123.88, 121.39, 119.19,
117.88, 114.28, 112.71, 57.10, 42.68 ppm. The enantiomeric excess
of the product was determined by chiral HPLC analysis (Daicel
Chiralpak AD) by comparison with an authentic racemic material:
n-hexane/2-propanol = 90:10, flow rate 1 mLmin–1, λ = 254 nm: tR
= 18.00 min, tR = 27.12 min.
[1] a) E. F. Kleinmann, R. A. Volkmann in: Comprehensive Or-
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Asymmetry 1997, 8, 1895–1946; c) R. Bloch, Chem. Rev. 1998,
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[2] For recent reports on asymmetric organocatalytic allylation of
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Scettri, Tetrahedron Lett. 2003, 44, 7179–7181; b) A. V. Malkov,
M. Bell, M. Orsini, D. Pernazza, A. Massa, P. Herrmann, P.
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Compound 11: This compound was prepared by the same pro-
cedures as described in the literature for a similar compound[4] by
using chiral formamide 6 as an activator. The crude product was
purified by flash chromatography on silica gel (CH2Cl2) to give
pure enantioenriched homoallylic amine 11 as a white solid in 79%
yield and 51%ee (R). [α]2D0 = +39.1 (c = 0.672, CHCl3). H NMR
1
(300 MHz, CDCl3): δ = 8.17 (d, J = 8.4 Hz, 2 H), 7.53 (d, J =
8.4 Hz, 2 H), 6.58 (d, J = 7.2 Hz, 1 H), 6.35 (d, J = 7.2 Hz, 1 H),
6.01 (s, 1 H), 5.80–5.66 (m, 1 H), 5.22–5.14 (m, 2 H), 4.77 (br. s, 1
H), 4.55 (br. s, 1 H), 4.45 (m, 1 H), 2.64–2.50 (m, 2 H), 2.05 (s, 3
H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 151.61, 147.09, 140.93,
135.23, 133.41, 130.96, 127.23, 123.92, 119.19, 118.04, 114.14,
113.54, 57.08, 42.83, 21.02 ppm. The enantiomeric excess of the
product was determined by chiral HPLC analysis (Daicel Chi-
ralpak AD) by comparison with an authentic racemic material: n-
hexane/2-propanol = 90:10, flow rate 1 mLmin–1, λ = 254 nm: tR
= 22.37 min, tR = 25.49 min.
(1R)-1-(4-Nitrophenyl)but-3-en-1-amine (12): This compound was
prepared from 11 by the same procedures as described in the litera-
ture.[4] [α]2D0 = +4.3 (c = 0.463, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 8.17 (d, J = 8.7 Hz, 2 H), 7.51 (d, J = 8.7 Hz, 2 H),
5.76–5.62 (m, 1 H), 5.13–5.07 (m, 2 H), 4.12 (dd, J = 8.0 and
5.3 Hz, 1 H), 2.49–2.28 (m, 2 H), 1.79 (br. s, 2 H) ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 153.24, 146.95, 134.20, 127.24, 123.63,
118.62, 54.82, 44.02 ppm.
[7] a) E. Leete, J. A. Bjorklund, M. M. Couladis, S. H. Kim, J. Am.
Chem. Soc. 1991, 113, 9286–9292; b) P. Saravanan, A. Bisai,
S. Baktharaman, M. Chandrasekhar, V. K. Singh, Tetrahedron
2002, 58, 4693–4706.
General Procedure for the Reduction of Imine with Trichlorosilane:
Trichlorosilane (29 µL, 0.29 mmol) was added dropwise to a stirred
solution of imine 13 (37.33 mg, 0.19 mmol), chiral formamide (0.1
or 0.3 equiv.) and additive (0.3 equiv.) in anhydrous solvent (1 mL)
at 0 °C (or at –20 °C). The reaction mixture was stirred 10 min at
0 °C and then at room temperature under an argon atmosphere
for 24 h. The reaction was quenched with a saturated solution of
NaHCO3, and the product was extracted with CH2Cl2. The organic
layer was dried with Na2SO4 and filtered, and the solvent was evap-
orated. The residue was purified by column chromatography on
silica gel (CH2Cl2) to afford desired product 14. The yields and
enantioselectivities are given in Tables 2 and 3. 1H NMR
(300 MHz, CDCl3): δ = 7.40–7.29 (m, 4 H), 7.26–7.20 (m, 1 H),
7.13–7.07 (m, 2 H), 6.68–6.63 (m, 1 H), 6.55–6.51 (m, 2 H), 4.49
(q, J = 6.9 Hz, 1 H), 1.52 (d, J = 6.9 Hz, 3 H) ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 147.14, 145.12, 129.07, 128.60, 126.84,
125.81, 117.23, 113.28, 53.45, 24.99 ppm. The enantiomeric excess
of the product was determined by chiral HPLC analysis (Daicel
Chiralpak OD) by comparison with an authentic racemic material:
n-hexane/2-propanol = 94:6, flow rate 0.5 mLmin–1, λ = 254 or
210 nm: tR = 15.66 min, tR = 19.20 min.
[8] P. V. Ramachandran, T. E. Burghardt, Chem. Eur. J. 2005, 11,
4387–4395.
[9] a) H.-U. Blaser, F. Spindler in: Comprehensive Asymmetric Ca-
talysis (Ed.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto),
Springer, Berlin, 1999, vol. 1, p. 247; b) T. Ohkuma, R. Noyori
in: Comprehensive Asymmetric Catalysis (Ed.: E. N. Jacobsen,
A. Pfaltz, H. Yamamoto), Springer, New York, 2004, suppl. 1,
p. 43.
[10] For recent reports on asymmetric organocatalytic hydro-
silylation with trichlorosilane, see: a) F. Iwasaki, O. Onomura,
K. Mishima, T. Kanematsu, T. Maki, Y. Matsumura, Tetrahe-
dron Lett. 2001, 42, 2525–2527; b) A. V. Malkov, A. Mariani,
K. N. Mac Dougall, P. Kocˇovský, Org. Lett. 2004, 6, 2253–
2256; c) A. V. Malkov, S. Stoncˇius, K. N. Mac Dougall, A.
Mariani, G. D. McGeoch, P. Kocˇovský, Tetrahedron 2006, 62,
264–284; d) A. V. Malkov, A. J. P. Stewart Liddon, P. Ramírez-
López, L. Bendová, D. Haigh, P. Kocˇovský, Angew. Chem. Int.
Ed. 2006, 45, 1432–1435; e) Z. Wang, X. Ye, S. Wei, P. Wu, A.
Zhang, J. Sun, Org. Lett. 2006, 8, 999–1001; f) Z. Wang, M.
Cheng, P. Wu, S. Wei, J. Sun, Org. Lett. 2006, 8, 3045–3048; g)
O. Onomura, Y. Kouchi, F. Iwasaki, Y. Matsumura, Tetrahe-
dron Lett. 2006, 47, 3751–3754.
2628
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2623–2629

Asymmetric Allylation and Reduction of Imines
FULL PAPER
[11] a) M. Rueping, E. Sugiono, C. Azap, T. Theissmann, M. Bolte,
Org. Lett. 2005, 7, 3781–3783; b) S. Hoffmann, A. M. Seayad,
B. List, Angew. Chem. Int. Ed. 2005, 44, 7424–7427; c) R. I.
Storer, D. E. Carrera, Y. Ni, D. W. C. MacMillan, J. Am. Chem.
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gew. Chem. Int. Ed. 2006, 45, 3909–3912.
Received: January 23, 2007
Published Online: April 18, 2007
Eur. J. Org. Chem. 2007, 2623–2629
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2629