Novel tridentate ligands derived from (+)-camphoric acid for enantioselective ethylation of aromatic aldehydes

Article abstract of DOI:10.1016/j.tetasy.2015.09.017

Novel tridentate ligands were prepared from (+)-camphoric acid, using simple synthetic sequences. The synthesized ligands were used in enantioselective ethylations of benzaldehydes, showing enantioselectivities up to 92%, at room temperature. Extending th

Full text of DOI:10.1016/j.tetasy.2015.09.017

Tetrahedron: Asymmetry 26 (2015) 1256–1260
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Novel tridentate ligands derived from (+)-camphoric acid
for enantioselective ethylation of aromatic aldehydes
⇑
Dina Murtinho , Camila H. Ogihara, M. Elisa Silva Serra
Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade de Coimbra, 3004-535 Coimbra, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel tridentate ligands were prepared from (+)-camphoric acid, using simple synthetic sequences. The
synthesized ligands were used in enantioselective ethylations of benzaldehydes, showing enantioselec-
tivities up to 92%, at room temperature. Extending the reaction to other aromatic aldehydes, very good
results (almost quantitative yields and ee up to 97%, for m-anisaldehyde) were obtained. Structural
features such as no substitution in the salicylaldehyde moiety of the Schiff base and an ethyl group in
the nitrogen at the C1 position of the cyclopentane ring seem to be essential for obtaining high
enantioselectivities.
Received 1 September 2015
Accepted 23 September 2015
Available online 21 October 2015
Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
state through the reaction of the (+)-camphoric derived ligands
with diethylzinc.
Asymmetric carbon–carbon bond formation reactions consti-
tute one of the most important and fundamental topics of research.
Among these reactions, the enantioselective ethylation of aromatic
aldehydes assumes special interest since it allows for the synthesis
of chiral secondary alcohols, essential components in the prepara-
tion of pharmaceuticals, agrochemicals, and perfumes, among
others.1–4
Chiral bidentate ligands such as aminoalcohols, diamines, diols,
and their derivatives are the most frequently used in alkylation
reactions. Tridentate ligands have been less explored, although in
recent years several examples have appeared in the
literature.5–16 Tridentate ligands are expected to form a more rigid
zinc chelate in the transition state than bidentate ones, exhibiting a
better discrimination between the two enantiotopic faces of
the substrate and therefore may lead to a more enantioselective
alkylation reaction.10,15,16 In continuation of our studies on the
enantioselective ethylation of aromatic aldehydes with diethylzinc
using chiral ligands derived from (+)-camphoric acid and since
very good ee were obtained with some of our ligands (ee up to
99%),17 we decided to synthesize a new series of N,N,O-tridentate
ligands using this chiral source. Several ligands were obtained from
(1R,3S)-1,3-diamino-1,2,2-trimethylcyclopentane and used in the
enantioselective addition of diethylzinc to aldehydes. In all cases
N,N,O-chelating zinc complexes can be formed in the transition
2. Results and discussion
2.1. Synthesis of chiral tridentate N,N,O-ligands
Diamine 1 [(1R,3S)-1,3-diamino-1,2,2-trimethylcyclopentane]
was prepared from commercial (+)-camphoric acid, according to
a previously described procedure.18 Compounds 2 and 3 have
already been described by Urabe et al. and by us.17,19 Compound
3 can be prepared by the reaction of 1 with benzoyl chloride in
ethanol to give 2, followed by reaction with formaldehyde and for-
mic acid in order to obtain the dimethylated product. Compound 4
was synthesized by hydrolysis of
(Scheme 1).
3
with concentrated HCl
O
PhCHN
i
ii
HO2C
CO2H
NH2
H2N
NH2
2
1
O
iv
iii
H2N
N(CH3)2
PhCHN
N(CH3)2
4
3
Scheme 1. Synthesis of (1R,3S)-3-amino-1-(dimethylamino)-1,2,2-trimethyl-
cyclopentane 4. Reagents and conditions: (i) NaN3, H2SO4, CHCl3, 55–60 °C,
overnight, 85%; (ii), EtOH, rt, overnight, 90%; (iii) HCO2H, HCHO, reflux, 18 h, 96%;
(iv) HCl 37%, H2O, reflux, 24 h, 77%.
⇑
Corresponding author. Tel.: +351 239854478; fax: +351 239827703.
E-mail addresses: dmurtinho@ci.uc.pt (D. Murtinho), camila_ogihara@hotmail.
com.br (C.H. Ogihara), melisa@ci.uc.pt (M.E.S. Serra).
http://dx.doi.org/10.1016/j.tetasy.2015.09.017
0957-4166/Ó 2015 Elsevier Ltd. All rights reserved.

D. Murtinho et al. / Tetrahedron: Asymmetry 26 (2015) 1256–1260
1257
Reaction of 4 with several aldehydes using ultrasound irradia-
tion and activated silica gel as promoter, gave the corresponding
Schiff bases 5a-f in moderate to good yields (Scheme 2).
and since better results are obtained in the alkylation reactions
of aldehydes when a less sterically demanding group is present
in the amine moiety at C1,17,19 we decided to prepare several tri-
dentate ligands using dimethylated compound 4. Also, since salen
ligands are known to be relatively efficient in several asymmetric
reactions, we thought that the combination of these two structural
features could give several tridentate Schiff bases which could be
promising ligands for enantioselective ethylations of aromatic
aldehydes. Therefore, Schiff bases 5a–e were synthesized via reac-
tion of 4 with several salicylaldehydes. For comparative purposes
5f, a bidentate ligand, was also synthesized via reaction of 4 with
benzaldehyde.
Ligands 5a–f were tested in the enantioselective alkylation of
benzaldehyde with diethylzinc, using our previously optimized
conditions (Scheme 5).20 The reactions were carried out in dry
cyclohexane at 0 °C in the presence of 15 mol% of chiral ligand.
Since at 0 °C the substrate conversions were moderate (50–79%
yield), the reaction temperature increased to room temperature.
As can be seen from the results in Table 1, this resulted in a signif-
icant increase in the conversion (85–99%) without a significant
deterioration of the enantiomeric excess.
R4
i
H2N
N(CH3)2
N
N(CH3)2
4
R3
R1
R2
5a R1 = OH, R2 = R3 = R4 = H
5b R1 = OH, R2 = OMe, R3 = R4 = H
5c
5d
5e
R
R
R
1 = OH, R2 = R3= t-Bu, R4 = H
1 = OH, R3 = Br, R2 = R4 = H
1 = OH, R2 = R3 = H, R4 = Me
5f R1 = R2 = R3 = R4 = H
Scheme 2. Synthesis of Schiff bases 5a–f. Reagents and conditions: (i) salicylalde-
hydes 5a–d, acetophenone 5e or benzaldehyde 5f, ultrasound irradiation 30–
60 min, EtOH, rt, 28–78%.
Ligands 5a and 5d were reduced to the respective amines 6a
and 6b using excess sodium borohydride in CHCl3/MeOH (2:1) at
room temperature, in 95% and 55% yields, respectively (Scheme 3).
OH
O
15 mol% ligand
cyclohexane
H
Et2Zn
R4
+
R4
N
N(CH3)2
N
H
N(CH3)2
i
Scheme 5. Asymmetric addition of diethylzinc to benzaldehyde.
R3
R1
R3
R1
R2
R2
Table 1
Enantioselective alkylation of benzaldehyde catalyzed by 5a–fa
6a R1 = OH, R2 = R3 = R4 = H
5a R1 = OH, R2 = R3 = R4 = H
5d
6b R1 = OH, R3 = Br, R2 = R4 = H
R
1 = OH, R3 = Br, R2 = R4 = H
Ligand
Reaction
temperature (°C)
Conversionb
(%)
1-Phenyl-1-
eed (%)
propanolc (%)
Scheme 3. Synthesis of amines 6a–b. Reagents and conditions: NaBH4, CHCl3/
MeOH (2:1), rt, 95% (6a) and 55% (6b).
5a
5a
5b
5b
5c
5c
5d
5d
5e
5e
5f
0
rt
0
rt
0
rt
0
rt
0
79
99
50
98
72
96
69
99
51
98
55
85
90
91
89
98
62
80
82
89
70
95
66
82
42 (S)
40 (S)
18 (S)
16 (S)
3 (R)
Schiff base ligands 9a–b were also prepared, according to the
synthetic sequence shown in Scheme 4. Compound 2 was alkylated
with ethyl iodide, in the presence of potassium carbonate to give 7.
Hydrolysis of the benzoyl group 8, followed by reaction with
salicylaldehyde or 5-bromosalicylaldehyde gave ligands 9a-b in
very good yields. Compounds 7 and 8 have already been prepared
by us and reported previously.17
4 (R)
35 (S)
31 (S)
11 (R)
13 (R)
12 (R)
11 (R)
rt
0
rt
5f
a
Reactions conditions: cyclohexane (4 mL), chiral ligand (0.15 mmol), benzalde-
hyde (1 mmol), diethylzinc solution 1 M in hexane (2 mmol), 24 h reaction.
b
Determined by GC.
Relative to converted benzaldehyde.
Determined by GC on a chiral column; the major enantiomer is indicated in
O
O
c
i
ii
PhCHN
NH2
PhCHN
NHEt
d
7
2
parenthesis.
iii
In addition to the desired chiral alcohol, 1-phenyl-1-propanol,
benzyl alcohol was also formed as a by-product. The formation of
benzyl alcohol has been observed by others and is the result of a
secondary process in which the benzaldehyde is reduced by the
zinc alkoxide of the ethylation product, 1-phenyl-1-propanoxide.21
An increase in the chiral alcohol yields was observed for all of the
ligands at room temperature, when compared with those obtained
at 0 °C.
H2N
NHEt
N
NHEt
8
R
OH
9a
R = H
9b R = Br
Scheme 4. Synthesis of Schiff bases 9a–b. Reagents and conditions: (i) EtI,K2CO3,
EtOH, reflux, 24 h, 67%; (ii) HCl 37%, H2O, reflux, 24 h, 77%; (iii) salicylaldehyde 9a,
5-bromosalicylaldehyde 9b, ultrasound irradiation 30–60 min, EtOH, rt, 92% both
9a and 9b.
Poor to moderate ee were obtained with ligands 5a–f, wherein
the best result was with ligand 5a, [42% (S) at 0 °C]. It is notewor-
thy that ligands 5c, 5e, and 5f gave products with an (R)-configura-
tion, while the other ones gave products with an (S)-configuration.
In an attempt to improve the results, ligand 5a was tested with
other solvents and different catalyst loadings (Table 2).
2.2. Enantioselective addition of diethylzinc to aldehydes
Encouraged by the good results obtained with bidentate ligands
derived from (1R,3S)-1,3-diamino-1,2,2-trimethylcyclopentane

1258
D. Murtinho et al. / Tetrahedron: Asymmetry 26 (2015) 1256–1260
Table 2
Table 4
Enantioselective alkylation of benzaldehyde with 5aa
Enantioselective alkylation aromatic aldehyde catalyzed by 9aa
Ligand Solvent
Catalyst Conversionb 1-Phenyl-1-
eed
Aldehyde
Conversionb (%)
eec (%)
(mol %)
(%)
propanolc (%) (%)
o-Methylbenzaldehyde
m-Methylbenzaldehyde
p-Methylbenzaldehyde
m-Anisaldehyde
o-Chlorobenzaldehyde
p-Chlorobenzaldehyde
1-Naphthaldehyde
>99
>99
>99
>99
>99
>99
98
88 (S)
96 (S)
93 (S)
97 (S)
75 (S)
78 (S)
72 (S)
74 (S)
5a
5a
5a
5a
5a
5a
5a
Cyclohexane
Ethyl ether
Toluene
Dichloromethane 15
Tetrahydrofuran
Cyclohexane
15
15
15
99
71
75
74
29
99
99
91
78
56
69
67
88
87
40 (S)
37 (S)
36 (S)
27 (S)
12 (S)
37 (S)
39 (S)
15
10
20
Cyclohexane
2-Naphthaldehyde
97
a
a
Reactions conditions: solvent (4 mL), benzaldehyde (1 mmol), room tempera-
Reactions conditions: cyclohexane (4 mL), chiral ligand (0.15 mmol), ben-
ture, diethylzinc solution 1 M in hexane (2 mmol), 24 h reaction.
zaldehyde (1 mmol), diethylzinc solution 1 M in hexane (2 mmol), 24 h reaction,
room temperature.
b
Determined by GC.
Relative to converted benzaldehyde.
c
b
Determined by GC.
d
c
Determined by GC on a chiral column; the major enantiomer is indicated in
Determined by GC on a chiral column; the major enantiomer is indicated in
parenthesis.
parenthesis.
As it can be seen from the results in Table 2, the best solvent for
the enantioselective alkylation of benzaldehyde with ligand 5a was
cyclohexane while a variation in the catalyst loading did not
improve the ee of the reaction. Therefore we decide to use our best
ligands 5a and 5d and reduce the imines to the respective amines
in order to see if better results could be obtained with these less
rigid ligands. The presence of an sp3 hybridized nitrogen in ligands
6a–b instead of sp2 could lead to a more flexible complex, with a
different geometry22 and perhaps higher ee could be obtained. As
can be seen from the results in Table 3, contrary to our expecta-
tions, poor ee were obtained with ligands 6a–b.
3. Conclusions
A new series of tridentate ligands was synthesized from
(+)-camphoric acid, using simple synthetic sequences. The ligands
were tested in the enantioselective ethylation of benzaldehyde,
showing enantioselectivities up to 92%, at room temperature.
Structural features such as no substitution in the salicylaldehyde
moiety of the Schiff base (ligands 5a and 9a) and an ethyl group
in the C1 nitrogen of the cyclopentane ring (ligand 9a) are essential
to obtain high enantioselectivities. The best ligand, 9a, was used in
the alkylation of other aromatic aldehydes with diethylzinc, giving
very good results (almost quantitative yields and ee up to 97%, for
m-anisaldehyde). It is our objective to extend the application of
these and other (+)-camphoric acid derived ligands to other
asymmetric transformations.
Table 3
Enantioselective alkylation of benzaldehyde catalyzed by 6a–b and 9a–ba
Ligand
Conversionb (%)
1-Phenyl-1-propanolc (%)
eed (%)
6a
6b
9a
9b
95
86
>99
>99
81
70
99
97
3 (S)
7 (S)
92 (S)
16 (S)
4. Experimental
4.1. General
a
Reactions conditions: cyclohexane (4 mL), chiral ligand (0.15 mmol), ben-
zaldehyde (1 mmol), diethylzinc solution 1 M in hexane (2 mmol), 24 h reaction,
room temperature.
Commercially available compounds were used without further
purification. All solvents were dried prior to use following standard
procedures. Diethylzinc (Aldrich) was used as a 1 M solution in
hexane. Benzaldehyde was distilled prior to use and stored over
4 Å molecular sieves. Melting points were determined using an
Electrothermal melting point apparatus (values are uncorrected).
Optical rotations were measured with an Optical Activity AA-5
polarimeter. NMR spectra were recorded on a Bruker Avance III
400 MHz (100 MHz for 13C). TMS was used as the internal standard
and chemical shifts are given in ppm. Infrared spectra were
recorded on a Thermo Scientific Nicolet 6700 FTIR. Sonication
was performed in a Bandelin Sonorex RK100H cleaning bath with
a frequency of 35 Hz and a nominal power of 80/160 W. High-
resolution mass spectra (HRMS) were obtained on a TOF VG Auto-
spect M spectrometer with electrospray ionization (ESI). Alkylation
reactions were carried out in an inert atmosphere using standard
Schlenk-type techniques. Enantiomeric excesses were determined
b
Determined by GC.
Relative to converted benzaldehyde.
Determined by GC on a chiral column; the major enantiomer is indicated in
c
d
parenthesis.
In our previous paper17 we observed that the presence of an
ethyl group instead of two methyl groups in the nitrogen at C1
of the cyclopentane ring could be beneficial in terms of ee. With
this in mind, we prepared two other ligands 9a–b, with an ethyl
group, according to the synthetic sequence of Scheme 4. These
ligands were tested in the enantioselective alkylation of benzalde-
hyde and very good results were obtained with ligand 9a (Table 3).
1-Phenyl-1-propanol was obtained in quantitative yield and 92%
ee.
The efficiency of ligand 9a was examined with a series of other
aromatic aldehydes, using 15 mol% of catalyst and cyclohexane as
solvent at room temperature. The obtained results are shown in
Table 4.
Very good conversions were obtained with all of the aldehydes.
In all cases, the absolute configuration of the major enantiomer
was assigned as (S) by comparison of the retention times with
reported values or by determining the sign of the specific rotation
of the isolated reaction product.23–25 The best ee was obtained for
m-anisaldehyde (97%). Better ee were obtained when aromatic
aldehydes with electron-donating substituents were used
(88–97%). Bulky substrates, such as 1- and 2-naphthaldehyde gave
moderate ee, 72% and 74%, respectively.
by using a chiral
c-cyclodextrin capillary column (FS-Lipodex-E,
25 m, 0.25 i.d.) from Machery-Nagel using hydrogen as carrier
gas, on an Agilant 7820 instrument. The absolute configuration of
the major enantiomers was determined by comparison of the
retention times with reported values and by determining the sign
of the specific rotation of the isolated reactions.
4.2. Synthesis
Compounds 1, 2, 3, 7, and 8 are already described in the
literature.17–19

D. Murtinho et al. / Tetrahedron: Asymmetry 26 (2015) 1256–1260
1259
4.2.1. (1R,3S)-N1,N1-Dimethyl-1,2,2-trimethylcyclopentane-1,3-
diamine 4
d: 11.36, 17.90, 22.70, 27.25, 29.44, 31.51, 34.12, 35.05, 37.96,
40.31, 48.34, 67.39, 78.60, 117.87, 125.78, 126.74, 136.71, 139.85,
158.30, 164.63. HRMS (ESI) m/z: calcd for C25H43N2O [M+H]+
387.3370, found 387.3365.
To compound 3 (1.83 g, 6.67 mmol), water (10 mL) and conc.
HCl (15 mL) were added and the reaction mixture was refluxed
overnight. After cooling to room temperature, the reaction was
evaporated and water and ethyl acetate were added to the residue.
Next, NaOH 15% was added until basic pH and the aqueous phase
was extracted several times with ethyl acetate. The combined
organic phases were washed with water and brine and dried over
anhydrous Na2SO4. After filtration and evaporation of the solvent
an oil, 4 was obtained and used in the next step without further
purification. Yield: 77%. 1H NMR (400 MHz, CDCl3) d: 0.85 (s, 3H),
0.89 (s, 3H), 0.99 (s, 3H), 1.22–1.39 (m, 3H), 1.48–1.57 (m, 1H),
1.77–2.03 (m, 2H), 2.22 (s, 6H), 2.92 (t, 1H, J = 9.4 Hz).
4.3.4. (1R,3S)-N1,N1-Dimethyl-N3-(5-bromosalicylidene)-1,2,2-
trimethylcyclopentane-1,3-diamine 5d
The product was purified by silica gel column chromatography
using diethyl ether as eluent to give a yellow solid. Yield: 78%; mp:
20
89–91 °C, [
a
]
= +60 (c 1, CH2Cl2). IR (KBr, cmÀ1): 2960, 2871,
D
2821, 2777, 1631, 1572, 1483, 1371, 1277, 1184, 1063, 827. 1H
NMR (400 MHz, CDCl3) d: 0.89 (s, 3H); 0.93 (s, 3H); 0.98 (s, 3H),
1.58–1.64 (m, 1H); 1.75–1.85 (m, 2H); 1.95–2.01 (m, 1H); 2.18 (s,
6H); 3.35 (t, 1H, J = 8.8 Hz); 6.79 (d, 1H, J = 8.4 Hz) 7.29–7.31 (m,
2H); 8.11 (s, 1H); 13.78 (s, 1H). 13C NMR (100 MHz, CDCl3) d:
10.30; 16.87; 21.74; 26.12; 36.91; 39.27; 47.47; 66.33; 77.21;
108.74, 118.13; 119.08; 132.26; 133.79; 159.70; 161.19. HRMS
4.3. General procedure for the synthesis of compounds 5a–f
In a 25 mL erlenmeyer flask, compound 4 (0.51 g, 3 mmol) was
dissolved in 10 mL of ethanol and the aldehyde (3 mmol) and silica
gel (0.5 g, pre-activated at 200 °C during 2 h) were added. The
mixture was placed in an ultrasound bath until the reaction was
complete (usually 1 hour). The silica was filtered off and washed
with dichloromethane. The solvent was evaporated and the crude
products were purified as described below.
(ESI) m/z: calcd for C
17H26BrN2O [M+H]+ 353.1223, found
353.1219.
4.3.5. (1R,3S)-N1,N1-Dimethyl-N3-(2-hydroxyacetophenylidene)-
1,2,2-trimethylcyclopentane-1,3-diamine 5e
The product was recrystallized in diethyl ether/hexane to give a
yellow solid. Yield: 72%; mp: 131–133 °C, [a]
20 = +145 (c 1, CH2Cl2).
D
IR (KBr, cmÀ1): 2974, 2966, 2939, 2814, 2771, 1612, 1577, 1504,
1450, 1439, 1369, 1309, 754, 744. 1H NMR (400 MHz, CDCl3) d:
0.96 (s, 3H); 1.03 (s, 3H); 1.20 (s, 3H), 1.61–1.71 (m, 2H);
1.93–2.10 (m, 2H); 2.25 (s, 6H); 2.36 (s, 3H); 3.97 (t, 1H,
J = 9.0 Hz); 6.74 (t, 1H, J = 7.4 Hz); 6.92 (d, 1H, J = 8.0 Hz); 7.28
(t, 1H, J = 7.2 Hz); 7.50 (d, 1H, J = 8.0 Hz). 13C NMR (100 MHz,
CDCl3) d: 11.50; 14.40; 17.90; 23.18; 26.83; 37.77; 40.24; 48.63;
66.96; 67.35; 116.50, 119.01; 119.21; 128.06; 132.63; 165.25;
170.77. HRMS (ESI) m/z: calcd for C18H29N2O [M+H]+ 289.2274,
found 289.2271.
4.3.1. (1R,3S)-N1,N1-Dimethyl-N3-salicylidene-1,2,2-trimethylcy-
clopentane-1,3-diamine 5a
The product was purified by silica gel column chromatography
using diethyl ether as eluent to give a yellow solid. Yield: 73%; mp:
65–66 °C; [a]
20 = +108 (c 1, CH2Cl2). IR (KBr, cmÀ1): 2979, 2968,
D
2945, 2819, 2779, 1628, 1581, 1504, 1460, 1421, 1371, 1280, 1147,
1117, 1065, 1043, 966, 756. 1H NMR (400 MHz, CDCl3) d: 0.96 (s,
3H); 1.00 (s, 3H); 1.07 (s, 3H), 1.64–1.70 (m, 1H); 1.83–1.97 (m,
2H); 2.03–2.11 (m, 1H); 2.25 (s, 6H); 3.41 (t, 1H, J = 9.0 Hz); 6.97
(t, 1H, J = 7.4 Hz); 6.96 (d, 1H, J = 8.4 Hz); 7.24–7.32(m, 2H); 8.26
(s, 1H); 13.83 (s, 1H). 13C NMR (100 MHz, CDCl3) d: 11.30; 17.92;
22.77; 27.23; 37.99; 40.30; 48.40; 67.32; 78.30; 117.08, 118.39;
118.80; 131.14; 132.14; 161.52; 163.45. HRMS (ESI) m/z: calcd for
4.3.6. (1R,3S)-N1,N1-Dimethyl-N3-(phenylidene)-1,2,2-trimethyl-
cyclopentane-1,3-diamine 5f
The product was purified by silica gel column chromatography
using diethyl ether/triethylamine (80:2) as eluent to give a white
C
17H26N2O [M+H]+ 275.2179, found 275.2115.
solid. Yield: 28%; mp: 57–59 °C; [a]
20 = +85 (c 1, CH2Cl2). IR (KBr,
D
4.3.2. (1R,3S)-N1,N1-Dimethyl-N3-(3-methoxysalicylidene)-1,2,2-
trimethylcyclopentane-1,3-diamine 5b
cmÀ1): 2972, 2873, 2819, 2781, 1641, 1448, 1371, 1060, 1035,
960, 752, 692. 1H NMR (400 MHz, CDCl3) d: 0.94 (s, 3H); 1.00 (s,
3H); 1.11 (s, 3H), 1.64–1.70 (m, 1H); 1.79–1.96 (m, 2H);
2.05–2.15 (m, 1H); 2.27 (s, 6H); 3.39 (t, 1H, J = 9.0 Hz); 7.39–7.41
(m, 3H); 7.74–7.76 (m, 2H); 8.19 (s, 1H). 13C NMR (100 MHz,
CDCl3) d:11.43; 17.98; 22.83; 26.80; 38.25; 40.35; 48.90; 67.60;
79.21; 128.16, 128.51; 130.31; 136.65; 159.23. HRMS (ESI) m/z:
calcd for [M+H]+ C17H26N2 259.2169, found 259.2167.
The product was purified by silica gel column chromatography
using diethyl ether as eluent to give a yellow solid. Yield: 65%; mp:
66–68 °C; [a]
20 = +110 (c 1, CH2Cl2). IR (KBr, cmÀ1): 2974, 2962,
D
2868, 2839, 2821, 2779, 1633, 1475, 1462, 1414, 1369, 1254,
1084, 1063, 970, 850, 781, 724. 1H NMR (400 MHz, CDCl3) d: 0.97
(s, 3H); 0.99 (s, 3H); 1.08 (s, 3H), 1.64–1.70 (m, 1H); 1.79–1.99
(m, 2H); 2.03–2.11 (m, 1H); 2.24 (s, 6H); 3.43 (t, 1H, J = 9.0 Hz);
6.78 (t, 1H, J = 7.8 Hz); 6.86–6.92 (m, 2H); 8.23 (s, 1H); 14.51 (s,
1H). 13C NMR (100 MHz, CDCl3) d: 11.28; 17.87; 22.75; 27.19;
37.94; 40.29; 48.37; 56.01; 67.27; 77.53; 113.61, 117.42; 118.26;
122.69; 148.79; 153.13; 163.38. HRMS (ESI) m/z: calcd for
4.4. General procedure for the synthesis of compounds 6a–b
To a solution of 5a or 5d (1 mmol) in CHCl3/MeOH (2:1, 7.5 mL),
placed in a 25 mL round bottom flask, NaBH4 (0.38 g, 10 mmol)
was added in small portions at 0 °C, with stirring. The reaction
was then stirred at room temperature and the progress of reaction
monitored by TLC. After completion, the reaction mixture was
cooled to 0 °C and quenched with saturated ammonium chloride.
The reaction mixture was extracted three times with dichloro-
methane and the combined organic phases were dried over anhy-
drous Na2SO4 and filtered. The solvent was evaporated and the
crude products were purified as described below.
C
18H29N2O2 [M+H]+ 305.2224, found 305.2220.
4.3.3. (1R,3S)-N1,N1-Dimethyl-N3-(3,5-di-t-butylsalicylidene)-1,
2,2-trimethylcyclopentane-1,3-diamine 5c
The product was purified by silica gel column chromatography
using diethyl ether/triethylamine (80:2) as eluent to give a yellow
solid. Yield: 68%; mp: 185–188 °C; [a]
20 = +75 (c 1, CH2Cl2). IR (KBr,
D
cmÀ1): 3124, 2960, 2871, 2819, 2773, 1630, 1466, 1439, 1392,
1369, 1273, 1252, 1070. 1H NMR (400 MHz, CDCl3) d: 0.96 (s,
3H); 1.00 (s, 3H); 1.08 (s, 3H), 1.31 (s, 9H); 1.45 (s, 9H);
1.63–1.70 (m, 1H); 1.85–1.92 (m, 2H); 2.05–2.10 (m, 1H); 2.25 (s,
6H); 3.38 (t, 1H, J = 9.0 Hz); 7.09 (d, 1H, J = 2.0 Hz); 7.38 (d, 1H,
J = 2.0 Hz); 8.27 (s, 1H); 13.94 (s, 1H). 13C NMR (100 MHz, CDCl3)
4.4.1. (1R,3S)-N1,N1-Dimethyl-N3-(2-hydroxybenzyl)-1,2,2-tri-
methylcyclopentane-1,3-diamine 6a
The product was purified by silica gel column chromatography
using diethyl ether as eluent to give a white solid. Yield: 95%; mp:

1260
D. Murtinho et al. / Tetrahedron: Asymmetry 26 (2015) 1256–1260
85–86 °C; [
a
]
20 = +65 (c 1, CH2Cl2). IR (cmÀ1): 3263, 2993, 2962,
NMR (CDCl3): 16.34; 17.62; 21.70; 22.44; 28.07; 36.47; 37.32;
48.15; 64.22; 109.49; 119.42, 119.92; 133.32; 134.92; 161.35;
161.75. HRMS (ESI) m/z: calcd for [M+H]+ C17H26BrN2O 353.1223,
found 353.1220.
D
2868, 2829, 2790, 1591, 1471, 1408, 1261, 1080, 1038, 964, 750.
1H NMR (CDCl3): 0.89 (s, 3H); 0.94 (s, 3H); 1.10 (s, 3H),
1.35–1.45 (m, 1H); 1.56–1.63 (m, 1H); 1.86–1.94 (m, 1H);
2.05–2.15 (m, 1H); 2.21 (s, 6H); 2.85 (t, 1H, J = 8.8 Hz); 3.82 (d,
1H, J = 13.6 Hz); 4.06 (d, 1H, J = 13.6 Hz); 6.77 (t, 1H, J = 7.4 Hz);
6.84 (d, 1H, J = 8.0 Hz); 6.98 (d, 1H, J = 7.2 Hz); 7.17 (t, 1H,
J = 7.4 Hz). 13C NMR (CDCl3): 11.01; 16.90; 23.34; 26.73; 37.14;
40.23; 46.91; 51.69; 66.67; 66.96; 116.43, 118.94; 122.97;
128.12; 128.78; 158.41. HRMS (ESI) m/z: calcd for [M+H]+
C17H29N2O 277.2274; found 277.2272.
4.6. General procedure for enantioselective alkylation reactions
To the chiral ligand (0.15 mmol) and benzaldehyde (1 mmol) in
an inert atmosphere, 4 mL of solvent was added. The temperature
of the reaction mixture was lowered to 0 °C and diethylzinc
(2 mmol, as a 1 M hexane solution) was added. The reaction was
stirred for 10 min at 0 °C and then for 24 h at 0 °C or room temper-
ature. After this time a saturated ammonium chloride solution
(1 mL) followed by 2 M HCl (1 mL) was added and the reaction
mixture was extracted with diethyl ether. The organic phases were
washed with water and brine and dried over anhydrous sodium
sulfate. The resulting solution was analyzed by GC on a chiral
4.4.2. (1R,3S)-N1,N1-Dimethyl-N3-(5-bromo-2-hydroxybenzyl)-1,
2,2-trimethylcyclopentane-1,3-diamine 6b
The product was purified by silica gel column chromatography
using diethyl ether/triethylamine (80:2) as eluent to give a white
solid. Yield: 55%; mp: 77–79 °C; [a]
20 = +40 (c 1, CH2Cl2). IR
D
(cmÀ1): 3313, 3299, 2964, 2871, 2821, 2781, 1485, 1477, 1444,
1261, 1099, 1082, 1022, 955, 810, 802. 1H NMR (CDCl3): 0.82 (s,
3H); 0.87 (s, 3H); 1.01 (s, 3H), 1.27–1.36 (m, 1H); 1.50–1.57 (m,
1H); 1.80–1.88 (m, 1H); 1.97–2.06 (m, 1H); 2.15 (s, 6H); 2.75 (t,
1H, J = 8.2 Hz); 3.71 (d, 1H, J = 14.0 Hz); 3.96 (d, 1H, J = 14.0 Hz);
6.64 (d, 1H, J = 8.4 Hz); 7.03 (s, 1H); 7.18 (m, 1H). 13C NMR (CDCl3):
9.99, 15.89, 22.33, 25.64, 36.05, 39.22, 45.91, 50.08, 65.57, 65.91,
109.59, 117.20, 123.83, 129.70, 130.41, 156.60. HRMS (ESI) m/z:
calcd for [M+H]+ C17H28BrN2O 355.1380, found 355.1379.
c-cyclodextrin capillary column in order to determine the ee of
the products.17
Acknowledgments
The authors thank the FCT (projects Pest-C/QUI/UI0313/2011
and PEstOE/QUI/UI0313/2014), FEDER, Portugal, COMPETE and
QREN for financial support and the UC-NMR facility for NMR
spectroscopic data (FCT, grant numbers REEQ/481/QUI/2006,
RECI/QEQQFI/0168/2012, CENTRO-07-CT62-FEDER-002012 and
RNRMN, FEDER and COMPETE).
4.5. General procedure for the synthesis of compounds 9a–b
In a 25 mL erlenmeyer flask, compound 8 (0.51 g, 3 mmol) was
dissolved in 10 mL of ethanol and the aldehyde (3 mmol) and silica
gel (0.5 g, pre-activated at 200 °C during 2 h) were added. The
mixture was placed in an ultrasound bath until the reaction was
complete (usually 1 h). The silica was filtered off and washed with
dichloromethane. The solvent was evaporated and the crude
products were purified as described below.
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mp: 127–128 °C; [a]
20 = +72 (c 1, CH2Cl2). IR (cmÀ1): 3446, 3294,
D
2970, 2870, 1651, 1626, 1579, 1498, 1485, 1460, 1281, 1119,
758, 704. 1H NMR (CDCl3): 0.95 (s, 3H); 0.99 (s, 3H); 1.08 (s, 3H),
1.15 (t, 3H, J = 7.0 Hz); 1.51–60 (m, 2H), 1.97–2.06 (m, 1H);
2.25–2.34 (m, 1H); 2.50–2.63 (m, 1H); 2.65–2.73 (m, 1H); 4.30 (t,
1H, J = 8.4 Hz); 7.39–7.46 (m, 3H); 7.77–7.79 (m, 2H); 8.85 (d,
1H, J = 8.4 Hz) 13C NMR (CDCl3): 16.60; 16.65; 19.03; 25.32;
30.11; 31.89; 36.35; 48.58; 59.35; 65.91; 126.81, 128.35; 130.88;
135.43; 165.33. HRMS (ESI) m/z: calcd for [M+H]+ C17H27N2O
275.2118, found 275.2116.
4.5.2. (1R,3S)-N1-Ethyl-N3-(5-bromosalicylidene)-1,2,2-trime-
thylcyclopentane-1,3-diamine 9b
The product was purified by silica gel column chromatography
using diethyl ether/triethylamine (80:2) as eluent to give a yellow
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solid. Yield: 92%; mp: 77–78 °C; [a]
20 = +64 (c 1, CH2Cl2). IR (cmÀ1):
D
3421, 2970, 2870, 1630, 1570, 1477, 1373, 1282, 1182, 1140, 1111,
1074, 1057, 822, 625. 1H NMR (CDCl3): 0.83 (s, 3H); 0.88 (s, 3H);
1.04 (t, 3H, J = 7.0 Hz); 1.09 (s, 3H), 1.67–1.79 (m, 3H), 1.88–1.96
(m, 1H); 2.49–2.58 (m, 1H); 2.63–2.71 (m, 1H); 3.35–3.39 (m,
1H); 6.77 (d, 1H, J = 8.4 Hz); 7.28–7.31 (m, 2H); 8.08 (s, 1H). 13C