A new (S)-prolinamide modified by an ionic liquid moiety-a high performance recoverable catalyst for asymmetric aldol reactions in aqueous media

Article abstract of DOI:10.1016/j.tet.2009.11.033

New prolinamide derivatives modified with ionic liquid moieties were synthesized and studied as organocatalysts in asymmetric aldol reactions in water. Aldol reactions between cycloalkanones or methylketones and aromatic aldehydes proceeded under studied

Full text of DOI:10.1016/j.tet.2009.11.033

Tetrahedron 66 (2010) 513–518
Contents lists available at ScienceDirect
Tetrahedron
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A new (S)-prolinamide modified by an ionic liquid moietyda high performance
recoverable catalyst for asymmetric aldol reactions in aqueous media
*
Dmitry E. Siyutkin, Alexander S. Kucherenko, Sergei G. Zlotin
Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47, Leninsky Prosp., 119991, Moscow, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 July 2009
Received in revised form 19 October 2009
Accepted 5 November 2009
Available online 10 November 2009
New prolinamide derivatives modified with ionic liquid moieties were synthesized and studied as or-
ganocatalysts in asymmetric aldol reactions in water. Aldol reactions between cycloalkanones or
methylketones and aromatic aldehydes proceeded under studied conditions with high conversions
(yields), diastereo- and enantioselectivities in the presence of a hydrophobic catalyst bearing a PF6 anion
(1–5 mol %). The procedure is scalable and the catalyst retained its diastereo- and enantioselectivity over
at least four reaction cycles and its activity over at least three reaction cycles.
Keywords:
Asymmetric catalysis
Aldol reaction
Ó 2009 Elsevier Ltd. All rights reserved.
Chiral ionic liquid
Recoverable organocatalyst
Prolinamide
Water
1. Introduction
thousands of catalytic cycles whereas the majority of organo-
catalysts are ‘washed out’ during the reaction workup and their
Asymmetric organocatalysis is an intensively developing area of
modern organic chemistry.1
-Aminoacid, imidazolidin-4-one or
regeneration is challenging.9e
a
Recently, some organocatalysts that repeatedly catalyze aldol
reactions in aqueous media and can be regenerated have been
synthesized. Normally, these organocatalysts contain an a-amino-
cinchona derivatives as well as some other small chiral molecules
used as catalysts allow the synthesis of complex polyfunctional
compounds of high enantiomeric purity from simple achiral pre-
cursors.2 The asymmetric aldol reaction is one of the most impor-
tant organocatalytic reactions and an irreplaceable instrument in
organic chemists and Nature’s toolboxes for forming a C–C bond in
organic compounds, in particular in saccharides.3 In living systems,
aldol reactions are catalyzed by aldolases, which have a peptide
structure.4 In the laboratory, these are normally performed in the
acid moiety linked to a polymer group (polystyrene)10 or to an ionic
fragment comprising an organic cation and hydrophobic fluori-
nated anion (PF6, NTf2).11 The polymeric or specific ionic group
presence makes it possible to recover catalysts due to their low
solubility in organic solvents and water. Furthermore, they create
the hydrophobic environment of the enamine-type transition state,
which resembles a hydrophobic pocket of aldolases,10e, which is
essential for efficient reaction stereocontrol.
presence of
a
-aminoacids (proline first of all)5 and their de-
rivatives.6 Lower peptides7 and proline amides bearing a
b
-ami-
Most of recoverable proline derivatives prepared so far contain
a free carboxylic group. Only a few immobilized prolinamide de-
rivatives have been reported to be capable of catalyzing the aldol
reaction in an aqueous medium, in particular compounds 1,12a 212b,c
and 312d (Fig. 1). However, to attain high catalytic performance
poorly water-soluble polymer-supported catalysts 1 and 2 should
be used in water/organic solvent mixtures (THF or CHCl3). The or-
ganic additive is needed for partial dissolution or swelling of
polymeric molecules. The synthesis of dendritic catalyst 3 is rather
tedious.
noalcohol moiety8 are among the most active and enantioselective
organocatalysts.
Apart from the structural similarity, there are some differences
in the behaviour of aldolases and organocatalysts. As a rule, re-
actions in the presence of organocatalysts are performed in organic
solvents or under solvent-free conditions9a–d whereas enzymatic
reactions are run in an aqueous environment. Another distinction is
that aldolases retain their extremely high catalytic activity in
It might be expected that recovery of prolinamide catalysts,
which retain their activity and selectivity in an aqueous medium
might be achieved by an ionic liquid (IL) tag insertion in the catalyst
* Corresponding author. Tel.: þ7 499 137 13 53; fax: þ7 499 135 53 28.
E-mail address: zlotin@ioc.ac.ru (S.G. Zlotin).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.11.033

514
D.E. Siyutkin et al. / Tetrahedron 66 (2010) 513–518
R
O
S
O
S
O
OBn
OBn
H
N
N
H
O
H
N
N
O
*
H
O
PEG - PS
N
H
N
H
O
O
OBn
OBn
NH
O
Ph
O
PS
3
O
1a, R = H, * - (S)
1b, R = OH, * - (R)
N
H
R
HN
HO
2a, R = i-Bu
2b, R = Ph
Ph
Ph
Figure 1. Prolinamide catalysts, immobilized on polymers or by a dendritic group.
structure. This combination may allow tuning the catalyst hydro-
phobic/hydrophilic properties to attain maximum catalytic effi-
ciency in an aqueous environment.
Table 1
Activity and selectivity of catalysts 9, 10 in the model reaction
O
O
O
OH
Catalyst
+
2. Results and discussion
H2O (100 eq.), rt
NO2
NO2
11a
12a
13a
To verify this hypothesis we synthesized new IL-immobilized
chiral catalysts 9 and 10, bearing a (S)-diphenylvalinol (4) fragment.
The respective prolinamide efficiently catalyzes the aldol reaction
both in organic solvents8b and in water,13 presumably due to
a strong coordination between the catalyst NH– and OH–groups
and the aldehyde acceptor in the transition state, which minimizes
the unfavourable impact of hydrogen bonding between aldehyde
and water molecules in the aqueous environment. As far as we
know, IL-tagged prolinamide derivatives bearing more that one
chiral centre have not been reported so far.
Cbz-protected 4-hydroxy-(S)-proline (5) was transformed to
amide 6 by a reaction with (S)-diphenylvalinol (4) in the presence of
Et3N/ClCO2Et. Alkylation of amide 6 by bromovaleric acid in the
presence of the DCC/DMAP system afforded bromoester 7 The latter
was converted to imidazolium salt 8 by a reaction with methyl-
imidazole. The deprotection of bromide 8 followed by the anion
exchange in amide 9 yielded hexafluorophosphate 10 (Scheme 1).
Compounds 9 and 10 have mps 103–105 and 98–100 ꢀC, re-
spectively and therefore can be considered as chiral ionic liquids.14
Their solubility in water depended on the anion. Bromide 9 pro-
duced a clear 7% aqueous solution at room temperature whereas
the hexafluorophosphate 10/H2O mixture was a suspension under
the same conditions.
Entry
Catalyst (mol %)
t, h
Conv., %
dr (anti/syn)
ee (anti), %
1
2
3
10 (10)
10 (5)
10 (1)
10 (1)
10 (1)
9 (5)
4
>99
>99
>99
99 (97)b
98
88/12
94/6
97/3
96/4
99/1
84
89
97
98
99
81
89
4.5
4.5
8
18
15
20
4a
5c
6d
7
>99
>99
81/19
85/15
9 (5)
a
Scaling: 7 mmol of aldehyde was used.
Isolated yield in brackets.
The reaction was run at þ3 ꢀC.
25 equiv of water was used.
b
c
d
excess (100 equiv relative to aldehyde) at 3–25 ꢀC. The ketone/
aldehyde ratio was 3/1.
In the presence of both catalysts the reaction proceeded with
a high conversion yielding aldol 13a. Its rate and selectivity were
higher in the presence of hydrophobic catalyst 10 than under the
action of hydrophilic catalyst 9. For that, the very fact of the
available pronounced catalytic activity of water-soluble amide 9
differentiates prolinamide-type catalysts from their respective hy-
drophilic amino acids derivatives bearing free carboxylic group that
did not catalyze aldol reactions in aqueous solutions.11a,c
The reaction diastereo- and enantioselectivity increased with
reduction of the loading of compound 10 and a lower reaction
At first we studied compounds 9 and 10 in a model reaction
between cyclohexanone (11a) and 4-nitrobenzaldehyde (12a) in an
aqueous medium (Table 1). The reactions were run in a large water
Ph
O
O
Ph
4
HO
HO
H2N
OH
Br
N
4
N
O
O
Et3N/ClCO2Et
Br(CH2)4CO2H, DCC/DMAP
CO2H
N
N
N
THF, 0 °C→ RT
CH2Cl2 , 5 °C
74%
heating
91%
Cbz
Cbz
Cbz
HN
HO
HN
91%
5
7
Ph
Ph
Ph
Ph
6
HO
O
O
O
O
O
4
O
N
N
N
N
N
N
4
4
O
O
O
H
2 , Pd/C
KPF6
H2O
93%
Br
N
Br
N
H
PF6
N
H
MeOH
95%
Cbz
HN
HO
HN
HO
HN
8
9
10
Ph
Ph
Ph
Ph
Ph
Ph
HO
Scheme 1. Synthesis of prolinamide derivatives 9 and 10 bearing IL moieties.

D.E. Siyutkin et al. / Tetrahedron 66 (2010) 513–518
515
temperature. The best results were attained in the presence of
12d (R]3–PhO–C6H4) was less active under the studied condi-
tions: as high as 5 mol % of catalyst 10 should be added to achieve
high conversion. Cyclopentanone (11d) reacted with aromatic
aldehydes yielding mixtures of anti- and syn-diastereomers of the
corresponding aldols 13h,i in similar amounts. Ees of major
anti-isomers were close to that obtained for six-membered
cycloalkanones 11a–c. As a rule, conversions, diastereo- and
enantioselectivities of aldol reactions, catalyzed by compound 10,
were comparable to those reported for other organocatalysts
bearing a prolinamide unit.
1 mol % of 10 at 3 ꢀC. A lower loading is another advantage of
prolinamide-type catalysts as compared with modified a-amino-
acids with free carboxylic group, which should be taken in amounts
as high as 10–15 mol % to attain high process efficacy. The pro-
cedure is scalable: yield as well as diastereo- and enantiomeric
excess of product 13a remained the same when the reaction was
run on a 7 mmol scale. Furthermore, the scaling-up procedure
makes the reaction more attractive from green-chemistry point of
view because it allows a significantly reduced amount of organic
solvent (Et2O) for product isolation (see Experimental section).
Next, we examined catalyst 10 in aldol reactions between
cycloalkanones 11a–d and aromatic aldehydes 12a–h (Table 2).
Furthermore, unlike IL-modified proline derivatives with a free
carboxylic group,11 prolinamide 10 catalyzed reactions of aromatic
aldehydes with methylketones 14a–e, in particular those contain-
Table 2
Aldol reactions between cycloalkanones 11a–d and aromatic aldehydes 12a–h in the presence of 10
O
O
O
OH
O
X
OH
10
R
R
R
+
+
H2O (100 eq.),
+3 °C
X
11a-d
X
12a-h
anti-13b-i
syn-13b-i
Conv.,a
>95
Entry
1
11,12
Aldol
13
10 (mol %)
t, ha
%
dr (anti/syn)a
ee (anti),a
%
O
OH
36
98/2
99
11a, 12b
b
c
2
2
(4815a
)
(2315a
)
(95/515a
)
(68–8315a
)
O
OH
40
(7212d
69/64b
97/3
99
2
3
4
11a, 12c
11a, 12d
11a, 12e
)
(85b,12d
)
(98/212d
96/4
)
(9512d
)
F
O
OH
45
77/71b
94
d
e
5
1
OPh
(9011c
)
(8711c
)
(96/411c
)
(>9911c
)
O
OH
F
F
15
>99/97b
(8615a
99/1
99
F
F
(1615a
)
)
(95/515a
)
(9715a
)
F
O
O
OH
48
97
99/1
97
5
6
11b, 12f
11c, 12g
11d, 12a
f
2
2
2
(nd15b
)
)
(81b,15b
)
)
(97/315b
)
)
(9915b
)
)
CN
O
OH NO2
48
88
93/7
92
g
h
(nd15b
(93b,15b
(98/215b
(9915b
S
O
OH
7
16
16
88
12
62/38
44/56
94; 9c
8d
88; 57c
(1812d
)
(9612d
)
(79/2112d
)
(9812d
)
NO2
O
OH
9
11d, 12h
i
2
16
>99
64/36
97; 32c
CO2Me
a
Reported data for other catalysts are given in brackets.
Isolated yield.
Ee of syn–aldol.
b
c
d
Reaction under neat conditions.
The corresponding aldols 13b–i were obtained in all cases, al-
though the required catalyst feed depended on the reagent’s
structure. Reactions of cycloalkanones 11a–d with 2-naph-
thylbenzaldehyde (12b) and aromatic aldehydes 12a,c,e–i bearing
electron-withdrawing groups (F, CN, NO2, CO2Me, entries 1,2,4–9)
proceeded in the presence of 1–2 mol % of catalyst 10. Aldehyde
ing alkyl, alkenyl, benzyl or cyclopropyl groups. The reactions ran
regioselectively at the methyl group of ketones 14a–e under the
studied conditions affording chiral aldols 15a–e (Table 3) in mod-
erate to high yields. The enantioselectivities of these reactions were
comparable to those obtained under the action of most efficient
reported organocatalysts.

516
D.E. Siyutkin et al. / Tetrahedron 66 (2010) 513–518
Table 3
Aldol reactions between methylketones 14a–e and 4-nitrobezaldehyde (12a) in the presence of 10
O
O
O
OH
10, 5 mol %
R
R
+
H2O (100 eq.), rt
NO2
NO2
14a-e
12a
15a-e
Entry
R
14,15
t, ha
Yield,a
%
ee,a
%
1
cyclopropyl
a
47
47
48
38
97
82
2b
(5015c
38
)
(5415c
95
)
(4515c
82
)
3
n-propyl
n-hexyl
b
4b
38
92
75
(3515d
25
)
(7515d
94
)
)
(8515d
86
)
)
5
6
c
(2415d
72
)
(8015d
65
(8515d
89
Me2C]CH(CH2)2-
d
e
(6015c
40
)
(3815c
77
)
(5215c
91
)
7
Bn
a
Reported data for other catalysts are given in brackets.
Reaction under neat conditions.
b
The recoverability of catalyst 10 was examined in the reaction
aldols in high yields and with excellent regio-, diastereo- and
enantioselectivities. The prepared IL-immobilized catalyst is supe-
rior to IL-immobilized proline derivatives having a free carboxylic
group in the activity and catalytic scope in the aqueous environ-
ment. It can be used in the aldol reaction four times and display the
same selectivity and slightly lowered activity.
between cyclohexanone (11a) and 4-nitrobenzaldehyde (12a). Af-
ter the reaction completion, aldol 13a was extracted with Et2O and
replaced with fresh portions of reagents. Catalyst 10 retained its
activity and selectivity over three reaction cycles. In the fourth
cycle, conversion dropped to 72% but dr and ee of the product 13a
remained at the same level (Table 4).
4. Experimental section
Table 4
Multiple use of catalyst 10
4.1. Typical procedure for the aldol reaction
O
O
O
OH
A mixture of the appropriate organocatalyst (1–10
mmol), ketone
10, 2 mol %
+
11/14 (0.30 mmol), aldehyde 12 (0.1 mmol), and distilled water
(0.045–0.18 mL) (for reactions in aqueous media) was stirred at
mentioned temperature for the period given in Tables 1–4. Aldol 13/
15 and remained starting compounds were extracted with Et2O
(2ꢁ3 mL), combined extracts were filtered through a silica gel pad
(1 g) and evaporated in vacuo (15 Torr). In case of reusing of the
catalyst 10, new portions of reagents were added to remaining
suspension of 10 in water and the process ran again. Conversion and
dr values of aldols 13a–i were measured by 1H NMR spectroscopy.
Aldols 13c, 15a–e were isolated by column chromatography (silica
gel Acros, 0.035–0.070 mm, 60A, eluent: n-hexane/EtOAc¼4/1). Ee
values of 13 and 15 were determined by HPLC, chiral phase: Chiralcel
OD-H, OJ-H, Chiralpak AD-H. NMR spectra and HPLC data for aldols
13 and 15 are available in articles, cited in Tables 2 and 3.
18 h, +3 °C
NO2
NO2
11a
12a
13a
Run
Conv., %
dr (anti/syn)
ee (anti), %
1
2
3
4
98
97
95
72
99/1
99/1
>99/1
>99/1
99
99
99
>99
The studied reactions were carried out in a heterogeneous or-
ganic phase (reagent phase)/water systems. Presumably, ionic
catalysts 9 and 10 are partly located in the interfacial region where
the catalytic transformation occurs. The concentration of the cat-
alyst 10, which is poorly soluble both in water and in organic
phases within the reaction area should be higher than of the cat-
alyst 9, which explains its better catalytic performance. Water
plays an important role being unclear so far: a noticeable dr and ee
decrease in aldols 15a,b obtained from methylketones 14a,b in the
presence of 10 was recorded under the water-free conditions
(Table 3, entries 1–4). The aqueous phase impact was even more
sizable in the reaction of 4-nitrobenzaldehyde (12a) with cyclo-
pentanone (11d), which proceeded under neat conditions with
extremely low conversion (12%) and inversion of diaster-
eoselectivity (Table 2, entries 7, 8).
4.2. Scaling-up procedure for the aldol reaction
A mixture of catalyst 10 (47.5 mg, 0.07 mmol), cyclohexanone
(11a, 2.15 mL, 21 mmol), 4-nitrobenzaldehyde (12a, 1.06 g,
7 mmol), and distilled water (6.3 mL, 0.35 mol) was stirred at room
temperature for 8 h. Aldol 13a and excess of cyclohexanone (11a)
were extracted with Et2O (2ꢁ3 mL). Combined extracts were
evaporated in vacuo (15 Torr). The product was isolated by column
chromatography on silica gel (Acros, 0.035–0.070 mm, 60A, eluent:
n-hexane/EtOAc¼3/1) and dried in vacuo (0.5 Torr) for 30 min to
afford 13a (1.7 g, 97%), light-yellow solid, mp 99–100 ꢀC.
3. Conclusion
In summary, new hydrophilic and hydrophobic chiral ionic liq-
uids bearing a prolinamide motif have been synthesized and
studied as organocatalysts in asymmetric aldol reaction between
unmodified ketones and aldehydes. In the presence of a hydro-
phobic organocatalyst, cyclic ketones and methylketones react with
aromatic aldehydes in the aqueous medium affording respective
4.3. Benzyl (4R)-hydroxy-(2S)-((1S)-(hydroxy-diphenyl-
methyl)-2-methyl-propylcarbamoyl)-pyrrolidine-1-
carboxylate 6
A solution of ethyl chloroformate (0.34 mL, 3.50 mmol) in THF
(10 mL) was added dropwise during 10 min to a stirred mixture of

D.E. Siyutkin et al. / Tetrahedron 66 (2010) 513–518
517
Cbz-protected 4-hydroxy-(S)-proline (0.93 g, 3.50 mmol) and Et3N
(0.49 g, 3.50 mmol) in THF (20 mL) at 0–5 ꢀC. After 20 min a solu-
tion of (S)-diphenylvalinole (0.89 g, 3.50 mmol) in THF (10 mL) was
added dropwise during 10 min. The resulting mixture was stirred
for 2 h at 0–5 ꢀC and for 1 h at ambient temperature, then it was
filtrated off and washed with THF (15 mL). The combined organic
extracts were evaporated, and the residue was washed with Et2O
59.0, 58.8, 52.6, 49.3, 36.3, 35.2, 33.3, 29.3, 28.4, 22.8, 21.2, 18.6; IR
(KBr, cmꢂ1): 3350, 3148, 3064, 2956, 2872, 1732, 1704, 1560, 1448,
1420, 1356, 1168, 1120, 1064, 1004, 912; Elemental analysis calcd for
C39H47BrN4O6: C, 62.65; H, 6.34; Br,10.69; N, 7.49; O,12.84; found C,
62.83; H, 6.22; Br, 10.60; N, 7.54.
4.6. (4R)-(5-(1-Methyl-1H-imidazol-3-ium-3-yl))
pentanoyloxy)-(2S)-((1S)-(hydroxy-diphenyl-methyl)-2-
methyl-propylcarbamoyl]-pyrrolidine bromide 9
(2ꢁ10 mL) to afford 6 (1.60 g, 91%) as white solid, mp 219–221 ꢀC;
23
[
a]
ꢂ59.9 (c 0.67, i-PrOH); 1H NMR (300 MHz, CD3COCD3)
d: 7.61
D
(4H, d, J¼7.7 Hz, 2H2H6(Ph)), 7.09–7.43 (11H, m, 2H3–5(Ph),
C6H5(Cbz)), 5.10–5.29 (2H, m, CH2Ph), 4.88–4.98 (1H, m, CHNHCO),
4.16–4.36 (2H, m, CHO, CHCONH), 3.39–3.55 (2H, m, CH2N), 1.61–
2.01 (2H, m, CH2CHN), 1.25–1.58 (1H, m, CH(CH3)2), 0.70–1.07 (6H,
A mixture of 8 (0.90 g, 1.20 mmol) and Pd/C (5%, 0.09 g) in dry
CH3OH (25 mL) was stirred under H2 (760 Torr) at ambient temper-
ature for 3 h. The resulting precipitate was filtered off and washed
with CH3OH (10 mL). The combined organic phases were evaporated,
m, CH(CH3)2); 13C NMR (75.5 MHz, DMSO-d6)
d: 171.6, 154.0, 147.4,
146.0, 136.9, 128.2, 127.9, 127.4, 126.0, 125.8, 125.0, 81.1, 68.4, 65.7,
59.0, 57.8, 55.3, 37.7, 28.0, 22.7, 18.0; IR (KBr, cmꢂ1): 3364, 3292,
2956, 2944, 2872, 1660, 1524, 1432, 1352, 1304, 1180, 1124, 1156,
968, 912; Elemental analysis calcd for C30H34N2O5: C, 71.69; H, 6.82;
N, 5.57; O, 15.92; found C, 71.96; H, 6.75; N, 5.51.
and the residuewasdried invacuo (0.5 Torr) for 2 h to afford 9 (0.70 g,
22
95%) as white solid, mp 103–105 ꢀC; [
a]
D
ꢂ40.6 (c 1, CHCl3); 1H NMR
(300 MHz, CDCl3)
d
: 10.49 (1H, s, NCHN), 8.27 (1H, d, J¼10.3 Hz,
NCHCHN), 7.57 (4H, d, J¼7.3 Hz, 2H2H6(Ph)), 7.06–7.37 (7H, m, 2H3–
5(Ph), NCHCHN), 5.05–5.11 (1H, m, CHO), 4.77 (1H, dd, J1¼9.5 Hz,
J2¼2.6 Hz, CHNHCO), 4.37 (2H, t, J¼7.3 Hz, NCH2CH2), 4.05 (3H, s,
NCH3), 3.88 (2H, t, J¼8.4 Hz, CHCONH), 3.05 (1H, d, J¼12.8 Hz,
CHCHHN), 2.91 (1H, dd, J1¼13.0 Hz, J2¼3.8 Hz, CHCHHN), 2.37 (2H, t,
J¼7.0 Hz, CH2CO), 1.89–2.52 (2H, m, CH2CHN), 1.88–2.05 (2H, m,
CH2CH2N),1.60–1.74 (2H, m, CH2CH2CO),1.25–1.49 (1H, m, CH(CH3)2),
0.98 (3H, d, J¼6.6 Hz, CHCH3), 0.81 (3H, d, J¼7.0 Hz, CHCH3); 13C NMR
4.4. Benzyl (4R)-(5-Bromo-pentanoyloxy)-(2S)-((1S)-
(hydroxy-diphenyl-methyl)-2-methyl-propylcarbamoyl)-
pyrrolidine-1-carboxylate 7
A mixture of amide 6 (1.52 g, 3.03 mmol), 5-bromovaleric acid
(0.56 g, 3.09 mmol), DCC (0.63 g, 3.06 mmol) and DMAP (0.025 g,
0.20 mmol) in CH2Cl2 (20 mL) was stirred at 5 ꢀC for 8 h. The
resulting precipitate was filtered off and washed with CH2Cl2
(3ꢁ10 mL). The combined organic extracts were evaporated, and
the residue was purified by column chromatography on silica gel
(Acros, 0.035–0.070 mm, 60A, eluent: n-hexane/EtOAc¼4/1) and
(75.5 MHz, CDCl3) d: 173.4,172.1,147.2,145.6,136.8,128.9,127.9,127.7,
126.2, 125.6, 125.3, 123.3, 122.3, 81.5, 75.9, 59.6, 52.5, 49.3, 36.4, 33.2,
29.2, 28.5, 24.7, 22.8, 21.0,18.5;IR (KBr, cmꢂ1):3384, 3148, 2956, 2872,
1728, 1660, 1564, 1524, 1448, 1368, 1250, 1168, 1064, 1032; Elemental
analysis calcd for C31H41BrN4O4: C, 60.68; H, 6.74; Br, 13.02; N, 9.13;
O, 10.43; found C, 60.89; H, 6.68; Br, 13.00; N, 9.14.
dried in vacuo (0.5 Torr) for 2 h to afford bromoester 7 (1.49 g, 74%)
21
as white solid, mp 166–168 ꢀC; [
a]
ꢂ59.5 (c 1, CHCl3); 1H NMR
4.7. (4R)-(5-(1-Methyl-1H-imidazol-3-ium-3-yl))
pentanoyloxy)-(2S)-((1S)-(hydroxy-diphenyl-methyl)-2-
methyl-propylcarbamoyl]-pyrrolidine hexafluorophosphate 10
D
(300 MHz, CDCl3)
d
: 7.47 (4H, d, J¼5.1 Hz, 2H2H6(Ph)), 7.11–7.39
(11H, m, 2H3–5(Ph), C6H5(Cbz)), 5.11–5.23 (2H, m, CH2Ph), 4.83 (1H,
d, J¼10.3 Hz, CHNHCO), 4.25 (1H, t, J¼7.5 Hz, CHCONH), 4.07 (1H, d,
J¼7.7 Hz, CHO), 3.41–3.62 (2H, m, CH2N), 3.37 (2H, t, J¼6.4 Hz,
CH2Br), 3.17 (1H, s, OH), 2.26 (2H, t, J¼7.2 Hz, CH2CO),1.56–2.00 (6H,
m, (CH2)2CH2Br, CH2CHN), 1.26–1.45 (1H, m, CH(CH3)2), 0.76–0.97
A solution of KPF6 (0.10 g, 0.54 mmol) in water (5 mL) was added
to a solution of 9 (0.30 g, 0.49 mmol) in water (10 mL). The resulting
precipitate washed with distilled water (2ꢁ5 mL) and dried in vacuo
(6H, m, CH(CH3)2); 13C NMR (75.5 MHz, CDCl3)
d: 172.3, 171.1, 155.4,
(0.5 Torr) for 2 h to afford 10 (0.31 g, 93%) as while solid, mp 98–
22
146.5, 145.4, 136.3, 128.5, 128.4, 128.2, 128.0, 126.8, 125.4, 81.9, 72.8,
67.4, 59.2, 59.0, 52.3, 33.9, 33.1, 32.7, 31.8, 28.8, 23.3, 22.8, 18.0; IR
(KBr, cmꢂ1): 3400, 2960, 2928, 2872, 1732, 1700, 1660, 1532, 1420,
1356,1172,1128, 1064,1000, 972, 920, 892; Elemental analysis calcd
for C35H41BrN2O6: C, 63.16; H, 6.21; Br, 12.00; N, 4.21; O, 14.42;
found C, 63.40; H, 6.15; Br, 12.03; N, 4.17.
100 ꢀC; [
a
]
ꢂ30.6 (c 1, CHCl3); 1H NMR (300 MHz, CDCl3)
d: 8.46
D
(1H, s, NCHN), 7.98 (1H, d, J¼9.5 Hz, NCHCHN), 7.53 (4H, t, J¼8.2 Hz,
2H2H6(Ph)), 7.06–7.38 (7H, m, 2H3–5(Ph), NCHCHN), 5.01–5.08 (1H,
m, CHO), 4.69 (1H, d, J¼8.1 Hz, CHNHCO), 4.11 (2H, t, J¼7.3 Hz,
NCH2CH2), 3.82 (3H, s, NCH3), 3.78 (2H, t, J¼7.7 Hz, CHCONH), 3.05
(1H, d, J¼12.5 Hz, CHCHHN), 2.76 (1H, d, J¼11.8 Hz, CHCHHN), 2.30
(2H, t, J¼5.9 Hz, CH2CO), 1.95–2.38 (2H, m, CH2CHN), 1.79–1.92 (2H,
m, CH2CH2N), 1.49–1.64 (3H, m, CH2CH2CO, CH(CH3)2), 0.93 (3H, d,
J¼6.2 Hz, CHCH3), 0.83 (3H, d, J¼6.6 Hz, CHCH3); 13C NMR
4.5. Benzyl (4R)-(5-(1-Methyl-1H-imidazol-3-ium-3-yl))
pentanoyloxy)-(2S)-((1S)-(hydroxy-diphenyl-methyl)-2-
methyl-propylcarbamoyl]-pyrrolidine-1-carboxylate bromide 8
(75.5 MHz, CDCl3) d: 173.8, 172.2, 146.6, 145.2, 127.8, 127.5, 126.2,
125.2, 125.0, 123.1, 121.7, 81.0, 75.7, 59.3, 52.3, 48.9, 36.4, 35.5, 32.6,
28.4, 28.3, 22.5, 20.5, 17.9; IR (KBr, cmꢂ1): 3370, 3148, 2956, 2872,
1730,1664,1564,1524,1448,1368,1252,1168,1064,1032; Elemental
analysis calcd for C31H41F6N4O4P: C, 54.86; H, 6.09; F, 16.80; N, 8.26;
O, 9.43; P, 4.56; found C, 55.01; H, 6.03; F, 1659; N, 8.22.
A mixture of 7 (1.00 g, 1.50 mmol) and 1-methylimidazole
(0.30 g, 3.66 mmol) was heated at 100 ꢀC for 20 min with contin-
uous stirring and then cooled to ambient temperature. The
resulting viscous yellow oil became white solid as washed with
Et2O (6ꢁ10 mL). The precipitate was dried in vacuo (0.5 Torr) for 2 h
21
to afford 8 (1.02 g, 91%) as white solid, mp 131–133 ꢀC; [
a
]
ꢂ62.5
4.8. 4-Hydroxy-4-(4-nitrophenyl)-1-phenylbutan-2-one 15e
D
(c 1, CHCl3); 1H NMR (300 MHz, CDCl3)
d: 10.09 (1H, s, NCHN), 8.21
(1H, d, J¼10.3 Hz, NCHCHN), 7.54–7.66 (4H, m, 2H2H6(Ph)), 7.02–
7.40 (12H, m, 2H3–5(Ph), C6H5(Cbz), NCHCHN), 4.92–5.27 (4H, m,
CH2Ph, CHNHCO, CHO), 4.57 (1H, t, J¼8.3 Hz, CHCONH), 4.31–4.40
(2H, m, CH2CH2N), 3.96 (3H, s, CH3N), 3.56–3.79 (2H, m, CHCH2N),
2.24–2.42 (2H, m, CH2CO), 1.49–2.09 (6H, m, (CH2)2CH2N, CH2CHN),
1.30–1.45 (1H, m, CH(CH3)2), 0.69–1.14 (6H, m, (CH3)2CH); 13C NMR
Ee: 91%; mp 92–94 ꢀC; [ 21 36.2 (c 1, CHCl3); 1H NMR (300 MHz,
a]
D
CDCl3)
d
: 8.17 (2H, d, J¼8.4 Hz, H3H5(4-NO2-Ph)), 7.46 (2H, d,
J¼8.8 Hz, H2H6(4-NO2-Ph)), 7.11–7.39 (5H, m, C6H5), 5.22 (1H, t,
J¼5.7 Hz, CHOH), 3.74 (2H, s, PhCH2), 3.54 (1H, br, OH), 2.87 (2H, d,
J¼4.7 Hz, CH2CH); 13C NMR (75 MHz, CDCl3)
d: 208.1, 150.1, 147.2,
133.1,129.4,128.9,127.4,126.4,123.6, 69.0, 50.7, 49.8; IR (KBr, cmꢂ1):
3464, 1708, 1604, 1512, 1348, 1080, 1060, 852, 824; Rf¼0.66 (n-
hexane/EtOAc¼2/1); HPLC (Chiralcel OJ-H, n-hexane/i-PrOH¼7/3,
(75.5 MHz, CDCl3)
d: 171.9, 171.6, 154.6, 147.4, 145.7, 136.7, 128.3,
127.9, 127.5, 126.1, 125.6, 125.2, 123.2, 122.2, 120.3, 81.9, 73.2, 66.8,

518
D.E. Siyutkin et al. / Tetrahedron 66 (2010) 513–518
Ibrahem, I.; Reyes, E.; Xu, Y. Chem.dEur. J. 2006, 12, 5383–5397; (d) Revell, J. D.;
flow rate¼0.8 mL/min, ¼254 nm, t1 (major)¼30.3 min, t2 (minor)¼
l
Wennemers, H. Adv. Synth. Catal. 2008, 350, 1046–1052.
32.2 min); Elemental analysis calcd for C16H15NO4: C, 67.36; H, 5.30;
N, 4.91; O, 22.43; found C, 67.61; H, 5.19; N, 4.94.
8. (a) Tang, Z.; Jiang, F.; Yu, L.-T.; Cui, X.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z.; Wu, Y.-D.
J. Am. Chem. Soc. 2003,125, 5262–5263; (b) Raj, M.; Maya, V.; Ginotra, S. K.; Singh,
V. K. Org. Lett. 2006, 8, 4097–4099.
9. (a) Rodriguez, B.; Rantanen, T.;Bolm, C. Angew. Chem., Int. Ed. 2006, 45, 6924–6926;
(b) Guillena, G.; Hita, M.; del, C.; Najera, C.; Viozquez, S. F. Tetrahedron: Asymmetry
2007,18, 2149–2152; (c) Almasi, D.; Alonso, D. A.; Najera, C. Adv. Synth. Catal. 2008,
350, 2467–2472; (d) Almasi, D.; Alonso, D. A.; Balaguer, A.-N.; Najera, C. Adv. Synth.
Catal. 2009, 351, 1123–1131; (e) Gruttadauria, M.; Giacalone, F.; Noto, R. Chem. Soc.
Rev. 2008, 37, 1666–1688.
10. (a) Font, D.; Jimeno, C.; Pericas, M. A. Org. Lett. 2006, 8, 4653–4655; (b)
Giacalone, F.; Gruttadauria, M.; Marculescu, A. M.; Noto, R. Tetrahedron Lett.
2007, 48, 255–259; (c) Gruttadauria, M.; Giacalone, F.; Marculescu, A. M.;
Meo, P. L.; Riela, S.; Noto, R. Eut. J. Org. Chem. 2007, 4688–4698; (d) Liu,
Y.-X.; Sun, Y.-N.; Tan, H.-H.; Tao, J.-C. Catal. Lett. 2008, 120, 281–287; (e)
Font, D.; Sayalero, S.; Bastero, A.; Jimeno, C.; Pericas, M. A. Org. Lett. 2008, 10,
337–340.
11. (a) Siyutkin, D. E.; Kucherenko, A. S.; Struchkova, M. I.; Zlotin, S. G. Tetrahedron
Lett. 2008, 49, 1212–1216; (b) Lombardo, M.; Easwar, S.; Pasi, F.; Trombini, C.
Adv. Synth. Catal. 2009, 351, 276–282; (c) Siyutkin, D. E.; Kucherenko, A. S.;
Zlotin, S. G. Tetrahedron 2009, 65, 1366–1372.
12. (a) Akagawa, K.; Sakamoto, S.; Kudo, K. Tetrahedron Lett. 2005, 46, 8185–8187;
(b) Gruttadauria, M.; Giacalone, F.; Marculescu, A. M.; Noto, R. Adv. Synth. Catal.
2008, 350, 1397–1405; (c) Gruttadauria, M.; Giacalone, F.; Marculescu, A. M.;
Salvo, A. M. P.; Noto, R. Arkivoc 2009, viii, 5–15; (d) Wu, Y.; Zhang, Y.; Yu, M.;
Zhao, G.; Wang, S. Org. Lett. 2006, 8, 4417–4420.
Acknowledgements
The work was partially supported by the Russian Foundation of
Basic Research (Grants 09-03-00384 and 09-03-12164) and the
Russian Academy of Sciences.
References and notes
1. (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2001, 40, 3726–3748; (b) Dalko,
P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138–5175; (c) Mukherjee, S.;
Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471–5569.
2. Figueiredo, R. M.; Christmann, M. Eur. J. Org. Chem. 2007, 2575–2600.
3. Guillena, G.; Najera, C.; Ramon, D. J. Tetrahedron: Asymmetry 2007,18, 2249–2293.
4. (a) Hoffmann, T.; Zhong, G.; List, B.; Shabat, D.; Anderson, J.; Gramatikova, S.;
Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc.1998,120, 2768–2779; (b) Heine, A.;
DeSantis, G.; Luz, J. G.; Mitchell, M.; Wong, C.-H.; Wilson, I. A. Science 2001, 294,
369–374; (c) Maggiotti, V.; Bahmanyar, S.; Reiter, M.; Resmini, M.; Houk, K. N.;
Gouverneur, V. Tetrahedron 2004, 60, 619–632.
5. (a) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000, 122, 2395–2396;
(b) Suri, J. T.; Ramachary, D. B.; Barbas, C. F., III. Org. Lett. 2005, 7, 1383–1385.
6. (a) Torii, H.; Hakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H. Angew. Chem., Int.
Ed. 2004, 43, 1983–1986; (b) Tang, Z.; Jiang, F.; Cui, X.; Gong, L.-Z.; Mi, A.-Q.;
Jiang, Y.-Z.; Wu, Y.-D. Proc. Nac. Acad. Sci. U.S.A. 2004, 101, 5755–5760; (c)
Hartikka, A.; Arvidsson, P. I. Eur. J. Org. Chem. 2005, 4287–4295.
7. (a) Krattiger, P.; Kovasy, R.; Revell, J. D.; Ivan, S.; Wennemers, H. Org. Lett. 2005,
7, 1101–1103; (b) Zou, W.; Ibrahem, I.; Dziedzic, P.; Sunden, H.; Cordova, A.
Chem. Commun. 2004, 4946–4948; (c) Cordova, A.; Zou, W.; Dziedzic, P.;
13. Maya, V.; Raj, M.; Singh, V. K. Org. Lett. 2007, 9, 2593–2595.
14. Ngo, H. L.; LeCompte, K.; Hargens, L.; McEwen, A. B. Thermochim. Acta 2000,
357–358, 97–102.
15. (a) Gryko, D.; Saletra, W. J. Org. Biomol. Chem. 2007, 5, 2148–2153; (b) Chen,
J.-R.; Li, X.-Y.; Xing, X.-N.; Xiao, W.-J. J. Org. Chem. 2006, 71, 8198–8202;
(c) Kucherenko, A. S.; Siyutkin, D. E.; Muraviev, V. O.; Struchkova, M. I.; Zlotin,
S. G. Mendeleev Commun. 2007, 17, 277–278; (d) Zhao, J.-F.; He, L.; Jiang, J.;
Tang, Z.; Cun, L.-F.; Gong, L.-Z. Tetrahedron Lett. 2008, 49, 3372–3375.