New bifunctional organocatalysts based on (R,R)-cyclohexane-1,2-diamine for the asymmetric addition of nucleophiles to aldehydes

Article abstract of DOI:10.1007/s11172-012-0008-7

The amide and sulfamide derivatives of (1R,2R)-N,N-diethylcyclohexane-1,2- diamine can serve as organocatalysts for addition of Me₃SiCN and Et₂Zn to aldehydes.

Full text of DOI:10.1007/s11172-012-0008-7

Russian Chemical Bulletin, International Edition, Vol. 61, No. 1, pp. 51—58, January, 2012
51
New bifunctional organocatalysts based on (R,R)ꢀcyclohexaneꢀ1,2ꢀdiamine
for the asymmetric addition of nucleophiles to aldehydes
V. I. Maleev, Z. T. Gugkaeva, A. T. Tsaloev, M. A. Moskalenko, and V. N. Khrustalev
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5085. Eꢀmail: vim@ineos.ac.ru
The amide and sulfamide derivatives of (1R,2R)ꢀN,Nꢀdiethylcyclohexaneꢀ1,2ꢀdiamine can
serve as organocatalysts for addition of Me3SiCN and Et2Zn to aldehydes.
Key words: organocatalysis, asymmetric synthesis, aldehydes, trimethylsilyl cyanide,
diethylzinc, (R,R)ꢀcyclohexaneꢀ1,2ꢀdiamine.
Bifunctional catalysts containing basic and acidic fragꢀ
ments evoke increasing interest in the recent time.1,2 This
is primarily related to their universal character, viz., the
ability to simultaneously activate the nucleophile and elecꢀ
trophile, and high potential of their use.3—5 The scope of
the main, most accessible and used compounds of this
type bearing the chiral function is rather restricted and
includes natural amino acids,6,7 quinine and cinchonidine
derivatives,8,9 TADDOLs,10—13 BINOL,14—16 and cycloꢀ
hexaneꢀ1,2ꢀdiamine derivatives.17 The compounds comꢀ
bining the thiourea and cyclohexanediamine fragments,
where the thiourea moiety is responsible for the acidic
function and the free (or alkylated) amino group provides
basicity, turned out to be most promising (and, hence,
studied18,19). These chiral thioureas found wide use as orꢀ
ganocatalysts in various reactions of С—С bond formaꢀ
tion, for instance, in the dynamic kinetic cleavage of azaꢀ
lactones,20 the reduction of ketones,21 and the Michael
reaction.22
Results and Discussion
There are few examples for the trimethylsilylcyanation
of carbonyl compounds using organocatalysts. One work
can be emphasized, where the 97% ee of the product was
attained in the reaction involving the bifunctional catalyst
based on the thiourea derivative and cyclohexanediamine27
in an amount of 5 mol.% at –78 С. Many works28 are
devoted to the use of amino alcohols and amino amides as
catalysts for diethylzinc addition to aldehydes. When the
cyclohexanediamine derivative was used as a ligand in the
titanium complex,29 the reaction product was isolated in
a yield of 78% and ее 99% at –20 С.
Intramolecular activation by the Brønsted acid of the
Brønsted acid ("Brønsted Acid Assisted Brønsted Acid
Catalysts" (BBA)) is observed in salicylamides (A).23 Due
to hydrogen bonding of the phenolic proton with the oxygen
atom of the amide residue, the acidity of the NH proton is
enhanced (B—D, the H atoms with the increased acidity
are underlined).
In this work, we synthesized the new monoamide deꢀ
rivatives of cyclohexaneꢀ1,2ꢀdiamine (Schemes 1 and 2)
and studied their catalytic activity in the addition of nuꢀ
cleophiles to aldehydes, namely, trimethylsilylcyanation
and the addition of diethylzinc to aromatic aldehydes.
The products of these reactions are important intermediꢀ
ates for the preparation of diverse chiral derivatives.24—26
(1R,2R)ꢀN,NꢀDiethylcyclohexanediamine (6) syntheꢀ
sized by the modified procedure30 (see Scheme 1) was
chosen as the starting compound for the preparation of
the catalysts.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 50—57, January, 2012.
1066ꢀ5285/12/6101ꢀ51 © 2012 Springer Science+Business Media, Inc.

52
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 1, January, 2012
Maleev et al.
Scheme 1
O(2)
C(4)
C(3)
O(1)
C(1)
N(1)
C(12)
C(11)
C(13)
C(2)
C(8)
C(16)
C(5)
C(6)
C(9)
C(10)
C(7)
C(17)
N(2)
C(14)
C(15)
Fig. 1. Molecular structure of compound 7 (one of the two crysꢀ
tallographically independent molecules is shown). Dashed line
is the intramolecular hydrogen bond.
The reaction of diamine 6 (2 equiv.) with oxalyl chlorꢀ
ide in the presence of triethylamine affords oxalic acid
derivative 11 in 70% yield (Scheme 3).
The structures and compositions of synthesized comꢀ
pounds 7—11 were confirmed by the elemental analysis and
1Н and 13С spectroscopy data. The Xꢀray structure study
was also carried out (Fig. 1, Tables 1 and 2).
Monoamide derivatives 7—10 based on compound 6
were synthesized according to Scheme 2 from the correꢀ
sponding acids.
Compound 7 crystallizes in the chiral space group P21
with two crystallographically independent molecules of
similar geometry in the unit cell (Fig. 2).
Scheme 2
Conditions: i. DCC, CH2Cl2.

(R,R)ꢀCyclohexaneꢀ1,2ꢀdiamine organocatalysts
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 1, January, 2012
53
Table 1. Parameters of hydrogen bonds in structure 7
d/Å
Table 2. Selected crystallographic data and refinement
parameters for compound 7
Angle
D—H—A
/deg
Parameter
Value
D—H...A*
D—H H...A D...A
Empirical formula
Molecular weight
T/K
Crystal size/mm
Crystal system
Space group
a/Å
b/Å
C17H26N2O2
290.40
N(1)—H(1)N...O(1)
[–x, y + 1/2, –z + 1]
O(2)—H(2)O...O(1)
N(3)—H(3)N...O(3)
[–x + 2, y + 1/2, –z + 2]
O(4)—H(4)O...O(3)
0.90
2.28 3.123(3)
156
100
0.21×0.18×0.15
Monoclinic
P21
10.6662(5)
9.5798(4)
16.7038(8)
108.391(1)
1619.62(13)
4
0.92
0.91
1.79 2.612(3)
2.25 3.112(3)
146
158
0.94
1.79 2.638(3)
148
c/Å
* D is proton donor, and A is proton acceptor.
/deg
V/Å3
Z
Scheme 3
dcalc/g cm–3
1.191
F(000)
/mm–1
632
0.078
2max/deg
56
Number of measured reflections
Number of independent reflections
Number of observed reflections
with I > 2(I)
18190
4107
2746
Number of refined parameters
R1 (I > 2(I))
383
0.038
The structure of molecule 7 is determined to a subꢀ
stantial extent by both intraꢀ and intermolecular hydrogen
bonds (see Table 1). The angle between the amide and
phenol fragments is 27.8 and 29.0, respectively, for two
crystallographically independent molecules. The nitrogen
atom of the diethylamino group has a pyramidal coordiꢀ
nation (the sum of the bond angles at the N(2) and N(4)
nitrogen atom is 341.2 and 339.4, respectively, for two
crystallographically independent molecules).
In crystal the molecules of compound 7 are localized
on the 21 axes and form the corresponding screw chains
along the b axis due to the intermolecular hydrogen bonds
N—H...O (Fig. 3, see Table 1). The chains are shifted
relative to each other along the monoclinicity axis at
wR2 (all data)
0.095
1.001
0.988; 0.984
Goodnessꢀofꢀfit for F2
Tmax; Tmin
a distance of ~0.25b according to the principle of closest
packing, i.e., "ledgeꢀtoꢀhollow." Similar shift of the chain
along with the close geometry of two independent moleꢀ
cules determines the presence in the crystal structure
of nonꢀcrystallographic symmetry pseudoꢀelements:
the pseudoꢀcenter of inversion and the pseudoꢀplane
of sliding reflection c, which are manifested, particularly,
in systematic pseudoꢀquenchings of the corresponding
reflections.
A molecule of compound 7 contains two asymmetric
carbon atoms C(8) and C(9). Since structure 7 contains
no atoms with Z > 14 (Si), the objective determination of
the absolute configuration of these atoms is not possible.
The relative configuration of these centers is 8R*, 9R*.
We assumed that compounds 7—11 would act as chiral
bifunctional catalysts in the addition of trimethylsilyl cyaꢀ
nide (TMSCN) and Et2Zn to benzaldehyde and, thus,
would simultaneously activate the electrophilic and nuꢀ
cleophilic components.
O(2)/O(4)
O(1)/O(3)
N(1)/N(3)
In the trimethylsilylcyanation of benzaldehyde
(Scheme 4), the use of catalysts 8 and 10 results in the
formation of racemic products in quantitative yields. In
the presence of catalysts 7 and 11, the yield of the product
was 99 and 63%, respectively, and enantiomeric enrichment
was observed: 6% of the Rꢀisomer in the case of catalyst 7
and 5% of the Sꢀisomer in the case of catalyst 11. Among
N(2)/N(4)
Fig. 2. Comparative geometry of two crystallographically indeꢀ
pendent molecules of compound 7.

54
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 1, January, 2012
Maleev et al.
a
0
c
b
Fig. 3. Crystal structure of compound 7 in projection along the a axis. Dashed lines show hydrogen bonds.
all synthesized compounds, compound 9 exhibited the
highest catalytic activity and, being taken in an amount of
5 mol.%, within 24 h in toluene provided the quantitative
yield and enantiomeric enrichment of the reaction prodꢀ
uct with 20% of the Sꢀisomer (Table 3). The reaction in
dichloromethane decreased the yield of the product to
65%, and the enantioselectivity of the reaction to 16%.
6 and 5%, respectively. The further decrease in the cataꢀ
lyst amount to 0.1 mol.% results in a slight decrease in the
reaction rate and enantiomeric excess of the product. Thus,
it can be assumed that it is the presence of the bulky
tertꢀbutyl groups in compound 9 which restricts the numꢀ
ber of possible positions of the substrate (TMSCN) relaꢀ
tive to the catalyst and is responsible for enantioselectivity
of the reaction.
For the addition of diethylzinc to benzaldehyde
(Scheme 5, Table 4), the amounts of diethylzinc and the
solvent were optimized using catalyst 9. It was found that
the yield of the product increases from 55 to 99% (see
Table 4, entries 15—17) with an increase in the amount of
diethylzinc from 1.5 to 3 equiv. in toluene. In this case,
the enantiomeric purity of the product ((R)ꢀconfiguraꢀ
tion) increases from 31 to 37%. When toluene and hexane
are used as solvents, the reaction product is formed in
quantitative yield; however, the enantiomeric excess of
the product is considerably higher in the first case (37%
Scheme 4
i. TMSCN, catalyst,* ~20 C, PhCH3, 24 h.
When the amount of catalyst 9 is decreased to 1 and
0.5 mol.%, Оꢀsilylmandelonitrile 12 is formed in quantiꢀ
tative yield, and the enantioselectivity of the process is

(R,R)ꢀCyclohexaneꢀ1,2ꢀdiamine organocatalysts
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 1, January, 2012
55
Table 3. Dependence of the yield and ее of product on the solꢀ
vent and amount of the catalyst (m)*
Scheme 5
Entry Cataꢀ
lyst
m
Solꢀ
vent
Product
eе (%)
(mol.%)
Yield
(%)
(confiꢀ
guration)
i. Et2Zn, catalyst,* ~20 C, PhCH3, 24 h, then H3O+.
1
2
3
4
5
6
7
8
7
7
8
0.5
5
5
5
5
5
1
0.5
0.1
5
Toluene
СH2Cl2
СH2Cl2
СH2Cl2
СH2Cl2
СH2Cl2
СH2Cl2
СH2Cl2
СH2Cl2
Toluene
Hexane
MeCN
THF
82
99
99
65
83
63
99
99
55
80
82
98
59
6 (R)
5 (R)
0
16 (S)
0
5 (S)
5 (S)
6 (S)
5 (S)
20 (S)
10 (S)
15 (S)
10 (S)
The substrate specificity was studied under the optiꢀ
mum conditions using the most efficient catalysts 9 and
11. As can be seen from Table 5, for catalyst 9 the introꢀ
duction of halogen substituents into the orthoꢀposition to
the carbonyl group in the aldehyde molecule decreases the
yield of the product. When using oꢀfluoroꢀ and oꢀchloꢀ
robenzaldehydes, the enantiomeric excess of the product
remains unchanged and is equal to 23%, whereas it is 19%
ее for оꢀbromobenzaldehyde.
Probably, substituents in the orthoꢀposition of benzꢀ
aldehyde create steric hindrances for the interaction. The
reaction with 2ꢀnaphthaldehyde occurs with the 88% yield
and 30% enantioselectivity.
In summary, we synthesized new organocatalysts,
which in an amount of 5 mol.% catalyze the addition
of TMSCN and Et2Zn to benzaldehydes. Although
the maximum enantiomeric enrichment of Оꢀtrimethylꢀ
silylmandelonitrile was 20% and that of 1ꢀphenylpropanꢀ
1ꢀol was 62%, it can be expected that the further modiꢀ
fication of the catalyst structure (introduction of more
bulky substituents in the benzene ring; in the case of
catalyst 11, the replacement of the oxalic acid residue
by residues of other dicarboxylic acids) can substantialꢀ
9
10
11
9
9
9
9
9
9
9
9
10
11
12
13
5
5
5
* Reaction conditions: benzaldehyde (0.05 mL, 0.47 mmol), triꢀ
methylsilyl cyanide (0.1 mL, 0.74 mmol), solvent (0.25 mL),
argon, 25 C, reaction time 24 h.
compared to 9%). When the reaction is carried out using
catalysts 7, 8, and 10, the reaction in toluene proceeds
quantitatively; however, the products are racemic (entries
18 or 19) or an insignificant enantiomeric enrichment of
the product of 7% is observed (entry 14). The use of cataꢀ
lyst 11 results in the predomination of (S)ꢀconfigured
enantiomer (entry 20), and the maximum ее value of 62%
was achieved during the reaction at –15 С (entry 21).
Table 5. Dependence of the yield and ее of the reaction product
on the substituent in an aldehyde molecules using catalysts 9
and 11a
Table 4. Dependence of the yield and ее of the reaction prodꢀ
uct of diethylzinc addition to benzaldehyde on the catalyst
typea
Entry
Aldehyde
Cataꢀ
lyst
Product
Yield
(%)
ее (%)
(configuration)b
Entry
Cataꢀ
Amount
lyst of Et2Zn (equiv.)
Product
Yield
(%)
eе (%)
(confiꢀ
guration)
22
23c
24
25
26
27
28
29
30
31
PhCHO
PhCHO
PhCHO
9
11
11
9
9
11
9
11
9
11
99
55
99
88
65
42
75
93
93
46
37 (R)
62 (S)
34 (S)
30 (N.D.)
19 (N.D.)
13 (N.D.)
23 (N.D.)
35 (N.D.)
23 (N.D.)
10 (N.D.)
14
15
16b
17c
18
19
20
21b
7
9
9
9
8
10
11
11
3
3
1.5
3
3
3
3
1.5
99
99
55
99
77
90
99
55
7 (R)
37 (R)
31 (R)
9 (R)
0
2ꢀC10H7CHO
2ꢀBrC6H4CHO
2ꢀBrC6H4CHO
2ꢀClC6H4CHO
2ꢀClC6H4CHO
2ꢀFC6H4CHO
2ꢀFC6H4CHO
0
34 (S)
62 (S)
a
Reaction conditions:: catalyst (0.012 mmol), Et2Zn
(0.48 mmol), aldehyde (0.24 mmol), toluene (0.25 mL), 20 C,
nitrogen.
a
Reaction conditions: catalyst (0.012 mmol), Et2Zn
(0.48 mmol), benzaldehyde (0.24 mmol), toluene (0.25 mL),
20 C, argon, solvent toluene.
b N.D. means that the absolute configuration of the predominant
isomer was not determined.
b Reaction temperature –15 С, reaction time 72 h.
c Solvent hexane.
c Reaction temperature –15 С, reaction time 3 days.

56
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 1, January, 2012
Maleev et al.
(s, 3 H); 1.78—1.76 (m, 2 H); 1.44—1.38 (m, 2 H); 1.31—1.25
(m, 2 H).
ly enhance their catalytic activity and stereodifferenꢀ
tiating ability.
Nꢀ((1R,2R)ꢀ2ꢀAminocyclohexyl)acetamide (4). Compound 3
(1.3 g, 8.3 mmol) was heated for 12 h in an ethanol—water (1 : 1)
mixture, and then the solvent was removed on a rotary evaporaꢀ
Experimental
1
tor. The yield was 40%, []25D +10.2 (c 1.0, CHC13). H NMR
1
Н NMR spectra were recorded on Bruker Avance 300
(300 MHz, CDC13), : 1.05—1.28 (m, 4 H); 1.60—1.63 (m, 2 H);
1.74 (s, 3 H); 1.91—1.94 (m, 3 H); 3.38—3.47 (m, 1 H); 6.29
(m, 1 H). 13C NMR (CDCI3, 75 MHz), : 23.5, 25.0, 32.6, 35.5,
55.4, 56.0, 57.8, 170.6.
(working frequency 300.13 MHz) and Bruker Avance 400
(working frequency 400.13 MHz) spectrometers. Chemical shifts
were determined relative to the residual signal of the undeuterꢀ
ated solvent (CDCl3 or DMSOꢀd6); optical rotation was meaꢀ
sured on a Perkin—Elmer 241 polarimeter in 0.1ꢀ or 0.5ꢀdm
cells temperatureꢀmaintained at 25 С. Silica gel Kieselgel 60
(Merck) was used for column chromatography. Elemental analꢀ
ysis was carried out at the Laboratory of Elemental Analysis of
the A. N. Nesmeyanov Institute of Organoelement Compounds,
Russian Academy of Sciences. All solvents were purified acꢀ
cording to standard procedures. Freshly distilled benzaldehyde
and trimethylsilyl cyanide were used for the reactions.
Unit cell parameters and reflection intensities were meaꢀ
sured on a Bruker SMART APEXꢀII CCD automated threeꢀ
circle diffractometer (T = 100 K, (MoꢀK) radiation, graphite
monochromator,  and  scan modes). An Xꢀray absorption
correction was applied by the SADABS program.31 Selected crysꢀ
tallographic data are given in Table 2. The structure was solved
by a direct method and refined by the leastꢀsquares fullꢀmatrix
method in the anisotropic approximation for nonꢀhydrogen atꢀ
oms. The hydrogen atoms of the hydroxy and amino groups were
objectively localized in difference Fourier syntheses and refined
with fixed positional and thermal parameters. Positions of other
hydrogen atoms were calculated geometrically and included into
refinement with fixed positional (riding model) and thermal
(Uiso(H) = 1.5Ueq(C) for CH3 groups and Uiso(H) = 1.2Ueq(C)
for all other groups) parameters. All calculations were performed
using the SHELXTL program package.32 The tables of atomic
coordinates, bond lengths, bond angles, and anisotropic temperꢀ
ature parameters for compound 7 were deposited with the Camꢀ
bridge Crystallographic Data Centre.
Enantiomeric analysis of the reaction products was carried
out on a gas chromatograph using a PPꢀTFAꢀꢀCD capillary
column (25×0.23 mm, film thickness 0.12 m, column temperaꢀ
ture 50 С, gas N2 (1.80 bar)). To carry out this analysis for
1ꢀphenylpropanꢀ1ꢀol, its trifluoroacetyl derivative was synthesized.
(1R,2R)ꢀCyclohexaneꢀ1,2ꢀdiamine was synthesized by the
cleavage of the racemic sample to form the diastereomeric salt
with (1R,2R)ꢀtartaric acid33 followed by the isolation of the free
base by a known procedure.34
(3aR,7aR)ꢀ2ꢀMethylꢀ3a,4,5,6,7,7aꢀhexahydroꢀ1Hꢀbenz[d]ꢀ
imidazole (3). Gaseous HCl was bubbled through a solution of
anhydrous acetonitrile (1 mL, 19 mmol, 2.0 equiv.) and anhyꢀ
drous ethanol (6 mL) for 1.5 h, after which the solution was
evaporated. (1R,2R)ꢀCyclohexaneꢀ1,2ꢀdiamine (1.1 g, 9.6 mmol,
1 equiv.) was added as one portion to unpurified ethyl acetimidꢀ
ate hydrochloride dissolved in anhydrous ethanol, and the mixꢀ
ture was stirred for 8—10 h at ~20 C. Then 1 М NaOH (aqueꢀ
ous, 75 mL) was added, and the product was extracted with 5%
MeOH in CH2Cl2 (3×50 mL). The combined extracts were dried
over Na2SO4 and concentrated on a rotary evaporator. Comꢀ
pound 3 without additional purification was used at the next
stage. The yield was 55%. 1H NMR (400 MHz, CDC13), : 4.31
(s, 1 H); 2.94—2.92 (m, 2 H); 2.16 (d, 2 H, J = 11.6 Hz); 1.95
(1R,2R)ꢀN,NꢀDiethylcyclohexaneꢀ1,2ꢀdiamine (6). A mixture
of compound 4 (1.6 g, 10 mmol, 1 equiv.), acetaldehyde (2.85 mL,
50 mmol, 5 equiv.), water (3 mL), and acetonitrile (60 mL)
was stirred for 15 min, then sodium cyanoborohydride (1.35 g,
21 mmol, 2.1 equiv.) was added, the mixture was stirred for
15 min, then acetic acid (4 mL) was added, and the mixture was
stirred for 2 h. The solvent was removed on a rotary evaporator,
and the residue was placed in a separating funnel with ethyl
acetate (100 mL) and 1 M NaOH (50 mL). The organic layer
was washed with 1 M NaOH (2×50 mL) and a solution of NaCl
(50 mL), dried over Na2SO4, and then concentrated on a rotary
evaporator. The residue was refluxed for 12 h with 4 M HCl
(50 mL). The solution was cooled to ~20 C and treated with 4 M
NaOH to pH = 13. The aqueous layer was extracted with СH2Cl2
(3×50 mL) and dried with Na2SO4. The solvent was removed on
a rotary evaporator. The reaction product was obtained in 60%
yield, []25 –110.9 (c 1.0, CHC13). 1H NMR (400 MHz,
D
CDC13), : 0.98 (t, 6 H, J = 5.4 Hz); 1.21—1.05 (m, 4 H);
1.65—1.62 (m, 2 H); 1.75—1.71 (m, 2 H); 1.99—2.06 (m, 2 H);
2.35—2.27 (m, 2 H); 2.61—2.50 (m, 2 H).
Nꢀ((1R,2R)ꢀ2ꢀDiethylaminocyclohexyl)ꢀ2ꢀhydroxybenzamide
(7). A solution of salicylic acid (0.244 g, 1.76 mmol, 1 equiv.)
in СH2Cl2 (1 mL) and dicyclohexylcarbodiimide (0.436 g,
2.11 mmol, 1.2 equiv.) was added to a solution of compound 6
(0.3 g, 1.76 mmol, 1 equiv.) in a minimum amount of СH2Cl2.
The reaction mixture was stirred for 24 h at ~20 C, and the
formed precipitate of dicyclohexylurea was filtered off. The
mother liquor was concentrated on a rotary evaporator and puriꢀ
fied by column chromatography (eluent ethyl acetate, Rf = 0.2).
1
M.p. 82 С, []25 –125.7 (c 1, CHCl3). H NMR (CDCl3), :
D
1.07 (t, 6 H, J = 7.2 Hz); 1.34—1.21 (m, 5 H); 1.75—1.70 (m, 1 H);
1.91—1.82 (m, 2 H); 2.45—2.33 (m, 2 H); 2.70—2.63 (m, 4 H);
3.59—3.53 (m, 1 H); 6.82 (t, 1 H, J = 7.8 Hz); 6.95 (dd, 1 H,
J1 = 0.9 Hz, J2 = 7.2 Hz); 7.42—7.31 (m, 2 H); 7.74 (br.s, 1 H).
1H NMR (400 MHz, DMSOꢀd6), : 0.93 (t, 6 H, J = 7.2 Hz);
1.36—1.22 (m, 4 H); 1.70—1.67 (m, 1 H); 1.88—1.77 (m, 2 H);
2.06—2.03 (m, 1 H); 2.35—2.31 (m, 2 H); 2.58—2.49 (m, 4 Н);
3.82 (br.s, 1 Н); 6.84—6.80 (m, 2 H); 7.34—7.29 (m, 1 Н); 7.77
(d, 1 H, J = 7.6 Hz); 8.24 (br.s, 1 H). Found (%): С, 70.18;
Н, 9.04; N, 9.41. C17H26N2O2. Calculated (%): С, 70.31;
Н, 9.02; N, 9.65.
3,5ꢀDiꢀtertꢀbutylꢀNꢀ((1R,2R)ꢀ2ꢀdiethylaminocyclohexyl)ꢀ2ꢀ
hydroxybenzamide (9). A solution of 3,5ꢀdiꢀtertꢀbutylsalicylic acid
(0.399 g, 1.76 mmol, 1 equiv.) in СH2Cl2 (1 mL) and dicycloꢀ
hexylcarbodiimide (0.436 g, 2.11 mmol, 1.2 equiv.) was added to
a solution of compound 6 (0.3 g, 1.76 mmol, 1 equiv.) in
a minimum amount of СH2Cl2. The reaction mixture was stirred
for 24 h at ~20 C, and the precipitate of dicyclohexylurea that
formed was filtered off. The mother liquor was concentrated on
a rotary evaporator and purified by column chromatography
(eluent toluene—ethyl acetate (1 : 4), Rf = 0.7). M.p. 152 С,

(R,R)ꢀCyclohexaneꢀ1,2ꢀdiamine organocatalysts
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 1, January, 2012
57
[]25 –57.3 (c 1, CHCl3). 1H NMR (300 MHz, CDC13), :
chromatography (eluent toluene—ethyl acetate (3 : 1), Rf = 0.3).
D
1.07 (t, 6 H, J = 6.9 Hz); 1.29 (s, 9 Н); 1.42 (s, 9 H); 1.74—1.67
(m, 3 H); 1.97—1.83 (m, 4 H); 2.42—2.31 (m, 2 H); 2.64—2.53
(m, 3 H); 2.85—2.81 (d, 1 H, J = 11.4 Hz); 3.48—3.43 (m, 2 H);
7.26 (s, 1 H); 7.42 (d, 1 H, J = 2.4 Hz). 1H NMR (300 MHz,
DMSOꢀd6), : 1.26 (с, 9 H); 1.31—1.30 (m, 3 Н); 1.35 (с, 9 H);
1.73—1.58 (m, 9 H); 1.95—1.91 (m, 1 H); 2.31—2.28 (m, 2 H);
2.56—2.53 (m, 3 H); 3.90 (br.s, 1 Н); 5.59 (d, 1 H, J = 8.1 Hz);
7.33 (d, 1 Н, J = 2.1 Hz); 7.55 (d, 1 H, J = 2.1 Hz); 8.25 (br.s, 1 H).
13C NMR (75 MHz, CDCl3), : 23.46, 24.56, 24.97, 25.62, 25.82,
29.39, 31.36, 32.16, 33.97, 34.27, 35.16, 42.99, 49.10, 51.54,
63.12, 113.79, 119.63, 128.27, 137.82, 139.51, 158.84, 171.82.
Found (%): С, 74.48; Н, 10.49; N, 7.00. C25H42N2O2. Calculatꢀ
ed (%): С, 74.58; Н, 10.51; N, 6.96.
M.p. 83 С, []25 –36.3 (c 1, CHCl3). 1H NMR (300 MHz,
D
CDC13), : 0.82 (d, 3 H, J = 6.6 Hz); 0.88 (d, 3 H, J = 6.6 Hz);
0.97 (br.s, 6 H); 1.24—1.14 (m, 5 H); 1.65—1.61 (m, 2 H);
1.82—1.76 (m, 3 H); 2.08—2.02 (m, 1 H); 2.38 (s, 3 Н);
2.34—2.32 (m, 2 Н); 2.46—2.45 (m, 1 Н); 2.59—2.54 (m, 2 Н);
3.31 (br.s, 1 Н); 3.53 (d, 1 H, J = 4.2 Hz); 7.23 (d, 2 Н,
J = 7.7 Hz); 7.74 (d, 2 Н, J = 7.8 Hz). 13C NMR (75 MHz,
CDCl3), : 14.15, 17.30, 18.93, 21.52, 23.45, 24.40, 24.97, 25.51,
31.96, 43.14, 50.15, 50.79, 61.73, 62.55, 127.25, 129.61, 136.90,
143.35, 169.97, 178.36.
Addition of TMSCN to benzaldehyde. A 5ꢀmL twoꢀnecked
flask was heated to 200 С, evacuated, filled with argon, and
then cooled to ~20 C. The flask was loaded under argon with
a catalyst (5 mol.%), СH2Cl2, (0.25 mL), benzaldehyde (0.05 mL,
0.47 mmol), and TMSCN (0.1 mL, 0.74 mmol). The reaction
mixture was stirred for 24 h under argon at ~20 C and passed
through a small layer (d = 0.5 cm, h = 2 cm) of silica gel to
separate the catalyst, and the filtrate was concentrated on a rotary
evaporator. The residue was dissolved in CDCl3 and analyzed by
1H NMR spectroscopy (no signals of other products were obꢀ
served in the spectrum). 1Н NMR (CDCl3) for trimethylsilyl
mandelonitrile ether (12), : 7.49—7.39 (m, 5 Н); 5.36 (s, 1 Н);
0.24 (s, 9 Н) (cf. Ref. 35).
Nꢀ((1R,2R)ꢀ2ꢀDiethylaminocyclohexyl)ꢀ2ꢀethoxybenzamide
(8). A solution of 2ꢀethoxybenzoic acid (0.292 g, 1.76 mmol,
1 equiv.) in CH2Cl2 (1 mL) and dicyclohexylcarbodiimide
(0.436 g, 2.11 mmol, 1.2 equiv.) was added to a solution of diꢀ
amine 6 (0.3 g, 1.76 mmol, 1 equiv.) in a minimum amount of
СH2Cl2. The reaction mixture was stirred for 24 h at ~20 C, and
the precipitate of dicyclohexylurea that formed was filtered off.
The mother liquor was concentrated on a rotary evaporator and
purified by column chromatography (eluent toluene—ethyl aceꢀ
tate (1 : 3), Rf = 0.3), []25 –72.5 (c 1, MeOH). 1H NMR
D
(300 MHz, CDC13), : 1.00 (t, 6 Н, J = 7.8 Hz); 1.24—1.09
(m, 6 Н); 1.50 (t, 3 Н, J = 6.9 Hz); 1.70—1.66 (m, 1 Н); 1.82—1.79
(m, 1 Н); 1.89—1.86 (m, 1 Н); 2.38—2.31 (m, 2 Н); 2.70—2.56
(m, 2 Н); 3.89—3.79 (m, 2 Н); 6.95 (d, 1 Н, J = 8.4 Hz); 7.06
(t, 1 Н, J = 7.8 Hz); 7.41—7.35 (m, 1 Н); 8.20—8.17 (m, 1 Н); 8.30
(s, 1 Н). 13C NMR (75 MHz, CDCl3), : 14.49, 14.77, 23.98,
24.95, 25.76, 33.26, 43.21, 48.63, 48.76, 51.63, 55.06, 62.69,
64.15, 64.43, 66.11, 112.32, 120.92, 132.17. Found (%): С, 71.59;
Н, 9.49; N, 8.78. C19H30N2O2. Calculated (%): С, 71.66;
Н, 9.50; N, 8.80.
Addition of diethylzinc to aldehydes. Diethylzinc (2 equiv.,
0.48 mmol, 0.3 mL) was slowly added at 0 C under argon to
a solution of the catalyst (0.012 mmol) in toluene (0.25 mL). The
reaction mixture was stirred, bringing the temperature to ~20 C
for 30 min, and then aldehyde (0.24 mmol) was added at the
temperature indicated in Table 5. The mixture was stirred for
24 h. Then 1 M HCl was added, and the organics were extracted
with dichloromethane (3×15 mL). The organic layer was concenꢀ
trated on a rotary evaporator. 1ꢀArylpropanꢀ1ꢀol that formed
was purified by TLC on SiO2 (eluent dichloromethane) (cf. Ref. 36).
N,N´ꢀBis((R,R)ꢀ2ꢀdiethylaminocyclohexyl)oxalylamide (11).
Diamine 6 (0.2 g, 1.17 mmol, 2 equiv.) was dissolved in a miniꢀ
mum amount of СH2Cl2, the solution was cooled to 0 С, and
triethylamine (0.163 mL, 1.17 mmol, 1 equiv.) was added.
A solution of oxalyl chloride (0.069 g, 0.59 mmol, 1 equiv.) in
CH2Cl2 (12 mL) was slowly added dropwise to the reaction mixꢀ
ture on stirring, and the mixture was stirred for 16 h at 0 С. The
solvent was removed on a rotary evaporator, water was added,
and the organics was extracted with CHCl3. The organic layer
was dried with Na2SO4 and purified by column chromatography
(eluent toluene—ethyl acetate (1 : 2), Rf = 0.4). M.p. 144 С,
[]25D –89 (c 1, CHСl3). 1H NMR (400 MHz, CDC13), : 0.97
(t, 12 H, J = 6.9 Hz); 1.21—1.15 (m, 8 H); 1.67—1.63 (m, 2 H);
1.82—1.73 (m, 4 Н); 2.38—2.22 (m, 5 H); 2.58—2.41 (m, 7 H);
3.45—3.38 (m, 2 H); 7.98 (br.s, 2 H). 13C NMR (75 MHz,
CDCl3), : 14.81, 23.86, 24.69, 25.61, 29.71, 31.97, 43.21, 51.29,
62.80, 70.55, 160.17. Found (%): С, 66.90; Н, 10.69; N, 14,12.
C22H42N4O2. Calculated (%): С, 66.96; Н, 10.73; N, 14.20.
(S)ꢀNꢀ((1R,2R)ꢀ2ꢀDiethylaminocyclohexyl)ꢀ4ꢀmethylꢀ2ꢀ
(4ꢀmethylphenylsulfonamino)pentanamide (10). A solution of Nꢀtoꢀ
sylvaline (0.477 g, 1.76 mmol, 1 equiv.) in dichoromethane
(1 mL) and dicyclohexylcarbodiimide (0.436 g, 2.11 mmol,
1.2 equiv.) was added to a solution of diamine 6 (0.3 g, 1.76 mmol,
1 equiv.) in a minimum amount of dichloromethane. The reacꢀ
tion mixture was stirred for 24 h at ~20 C, and the precipitate of
dicyclohexylurea that formed was filtered off. The mother liquor
was concentrated on a rotary evaporator and purified by column
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Received April 21, 2011;
in revised form October 27, 2011