Enantioselective alkylation of aromatic aldehydes with (+)-camphoric acid derived chiral 1,3-diamine ligands

Article abstract of DOI:10.1016/j.tetasy.2017.01.013

A series of chiral 1,3-diamine ligands derived from (+)-camphoric acid were prepared from the reaction of 1,3-diamino-1,2,2-trimethylcyclopentane with aromatic aldehydes, followed by reduction of the corresponding diimines. These newly synthesized ligands

Full text of DOI:10.1016/j.tetasy.2017.01.013

Tetrahedron: Asymmetry xxx (2017) xxx–xxx
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Tetrahedron: Asymmetry
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Enantioselective alkylation of aromatic aldehydes with
(+)-camphoric acid derived chiral 1,3-diamine ligands
⇑
M. Elisa Silva Serra , Dina Murtinho, Victória Paz
CQC and Department of Chemistry, University of 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:
A series of chiral 1,3-diamine ligands derived from (+)-camphoric acid were prepared from the reaction of
1,3-diamino-1,2,2-trimethylcyclopentane with aromatic aldehydes, followed by reduction of the corre-
sponding diimines. These newly synthesized ligands were tested in the enantioselective alkylation of
benzaldehyde with diethylzinc, giving 1-phenyl-1-propanol with enantiomeric ratios of up to 86:14.
Our most selective ligand, derived from 2-methoxybenzaldehyde, was also tested in the alkylation of sev-
eral aromatic aldehydes and product alcohols with enantiomeric ratios of up to 93.5:6.5 being observed
in 2 h at room temperature in the presence of 5 mol % ligand.
Received 3 January 2017
Revised 12 January 2017
Accepted 19 January 2017
Available online xxxx
Ó 2017 Published by Elsevier Ltd.
1. Introduction
Our continued interest in the use of (+)-camphoric acid derived
(1R,3S)-1,3-diamino-1,2,2-timethylcyclopentane,
a
1,3-diamino
Chiral secondary alcohols have found widespread application in
many areas such as fine chemistry, pharmaceuticals, perfumes,
herbicides and pesticides, among others, because they incorporate
many structures with biological activity. Thus, reactions which
allow the efficient synthesis of these compounds are of major
importance in organic chemistry. The direct synthetic utility of chi-
ral alcohols is no less significant, since the hydroxyl group is an
excellent precursor for many other functional groups. Among the
methods for obtaining optically active secondary alcohols, special
interest has been placed upon the enantioselective alkylation of
aldehydes with organozinc reagents in the presence of chiral
ligands. This reaction allows the creation of a new stereogenic cen-
ter from the carbonyl carbon atom and, simultaneously, a length-
ening of the carbon chain in the alcohol product relatively to the
parent aldehyde.1–9 Additionally, the use of organozinc reagents
with different alkyl or aryl groups allows obtaining a wide variety
of optically active products to be obtained.
chiral backbone,26–29 led us to prepare some new chiral secondary
diamine ligands to test in the enantioselective alkylation of aldehy-
des with diethylzinc.
2. Results and discussion
2.1. Ligand synthesis
Scheme 1 illustrates the synthetic sequence used for obtaining
the camphoric acid derived secondary diamines 3: the reaction of
(1R,3S)-1,3-diamino-1,2,2-trimethylcyclopentane
1,
prepared
according to our previously described procedure,26 with aromatic
aldehydes, originates from diimines 2, which are subsequently
reduced to the chiral secondary diamines.
For the synthesis of diimines 2, we initially carried out the reac-
tion with benzaldehyde, using various reaction conditions (reflux
in ethanol or toluene, acid and base catalysis, the use of water
sponges, ultrasound irradiation, microwave irradiation). Micro-
wave irradiation has been described for the synthesis of imines
under different reaction conditions, so we decided to try this tech-
nique in the synthesis of our diimines.30–33
From the different methods tested, we found that the most
favorable one was using microwave irradiation. Using this method,
the products were formed in short reaction times and tedious
work-up was not necessary, since the products precipitated
directly from the reaction medium upon cooling. Our studies led
to the following optimized conditions: the reaction of the diamine
with 2 equivalents of aldehyde, in ethanol and in the presence of a
While many types of structurally diverse ligands have been
used in enantioselective alkylations,10–15 those with two N-donor
atoms have not received widespread attention, although there
are several examples of efficient ligands of this type. It should also
be noted that 1,3- and 1,4-bidentate ligands have been relatively
less studied than 1,2-bidentate ligands.16–25
⇑
Corresponding author. Tel.: +351 39854480.
E-mail addresses: melisa@ci.uc.pt (M. Elisa Silva Serra), dmurtinho@ci.uc.pt
(D. Murtinho), victoriapatriciopaz@hotmail.com (V. Paz).
http://dx.doi.org/10.1016/j.tetasy.2017.01.013
0957-4166/Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Serra, M. E. S.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.01.013

2
M. Elisa Silva Serra et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
CHO
R1
R2
R5
R4
R2
R3
R5
R1
N
R4
R3
ii)
i)
CO2H
CO2H
NH2
NH2
N
R1
R3
2
1
R5
R2
R2
R3
iii)
R4
R1
R4
H
N
R5
N
H
R5
R1
R3
R2
R4
3
Scheme 1. Synthesis of the chiral diamine ligands. Reagents and conditions: (i) H2SO4, NaN3, CHCl3, 55–65 °C, overnight; (ii) ethanol, microwave radiation, 30 min. (iii)
NaBH4, MeOH/CHCl3 1:1, rt.
catalytic amount of p-toluenesulfonic acid monohydrate. The reac-
tion was irradiated for 15 min. at 250 W (the reaction temperature
reached 85–150 °C and the pressure 1–8 bar). Using these condi-
tions, we synthesized the series of diimines 2a–2h, (Table 1) with
moderate yields.
In order to obtain the diamines, the corresponding diimines 2a–
2h were subjected to reduction with sodium borohydride, in a 1:1
mixture of MeOH/CHCl3, at room temperature. In this way, diami-
nes 3a–3h were isolated, mostly in very good yields (Table 2).
ligand, our previously optimized conditions in Scheme 2.26 The
results obtained are presented in Table 3.
All of ligands tested were very efficient, with almost complete
conversion in the alkylations. Moderate to good selectivity was
observed, and the highest enantiomeric ratio (er), 86:14, was
obtained in the presence of ligand 3b. In order to analyze the
effect of the reaction temperature, the most selective ligands 3b
and 3h were additionally tested at 0 °C and ꢀ10 °C. Only a slight
2.2. Enantioselective alkylation reactions
OH
O
15 mol% ligand
cyclohexane, rt
Using benzaldehyde as the model substrate, diamine ligands
2a–2h were tested in the enantioselective alkylation with diethylz-
inc. The reactions were initially carried out in dry cyclohexane at
room temperature for 24 h, in the presence of 15 mol % of chiral
H
+
Et2Zn
Scheme 2. Asymmetric addition of diethylzinc to benzaldehyde.
Table 1
Diimines derived from camphoric acid
Ligand
R1
R2
R3
R4
R5
Yield (%)
2a
2b
2c
2d
2e
2f
H
H
H
H
H
OCH3
H
H
H
H
H
H
H
OCH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
CH3
52
49
19
49
53
52
52
36
OCH3
CH3
Cl
H
H
2g
2h
Cl
CH3
H
CH3
Table 2
Diamines derived from diimines 2a–2h
Ligand
R1
R2
R3
R4
R5
Yield (%)
3a
3b
3c
3d
3e
3f
H
H
H
H
H
OCH3
H
H
H
H
H
H
H
OCH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
CH3
96
65
97
80
88
99
65
47
OCH3
CH3
Cl
H
H
3g
3h
Cl
CH3
H
CH3
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M. Elisa Silva Serra et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
3
Table 3
Enantioselective alkylation of benzaldehyde catalyzed by 3a–ha
Table 6
Enantioselective alkylation of benzaldehyde in different solvents with 3ba
Ligand
Conversionb (%)
1-Phenyl-1-propanolb,c (%)
er (S):(R)b
Solvent
Conversionb,c (%)
er (S):(R)b
3a
3b
3c
3d
3e
3f
>99
>99
>99
>99
>99
>99
98
97
>99
98
98
99
97
93
88
71:29
86:14
73.5:26.5
71:29
71:29
71:29
Cyclohexane
Diethylether
Toluene
>99
>99
>99
>99
86:14
83.5:16.5
84.5:15.5
83:17
Dichloromethane
a
Reactions were carried out for 2 h at rt, using 5 mol % chiral ligand, 1 mmol of
benzaldehyde and 2 mmol of diethylzinc (1 M in hexane).
3g
3h
73:27
78:22
b
Determined by chiral gc.
No secondary product was observed.
98
c
a
Reactions were carried out for 24 h at rt, in cyclohexane, using 15 mol % of
chiral ligand, 1 mmol of benzaldehyde and 2 mmol of diethylzinc (1 M in hexane).
b
Determined by chiral gc.
Relatively to converted benzaldehyde.
enantioselective alkylation of other aldehyde substrates with
diethylzinc in the presence of 3b in order to evaluate the scope
of the reaction. The results are shown in Table 7.
c
All aldehydes, except for p-methoxybenzaldehyde, showed
complete conversions to the products with er varying from
84.5:15.5 to 93.5:6.5. The best er was obtained for m-methoxyben-
zaldehyde, 93.5:6.5. We also tested an aliphatic aldehyde, cin-
namaldehyde, which was completely converted into the
ethylated alcohol with an er of 78:22, which is a promising result
for this type of substrate.
improvement in selectivity was observed, but this was accompa-
nied by much lower conversions; therefore, additional reactions
were carried out at room temperature. Considering the complete
conversions observed with the diamine ligands in the alkylation
of benzaldehyde, we decided to analyze results after shorter reac-
tion times, namely, conversions and product selectivity, using the
most efficient ligand 3b (Table 4).
Diimines 2a–2h were also tested as ligands in the enantioselec-
tive alkylation of benzaldehyde. However, the conversions were
moderate and the products were almost racemic. It is also note-
worthy that we had previously synthesized structurally analogous
camphoric acid derived salen and salan ligands and also tested
them in the enantioselective alkylation of benzaldehyde with
diethylzinc. In this case, only moderate conversions and very low
selectivities were observed, which may be attributed to the
tetradentate nature of these ligands as opposed to the bidentate
nature of 3a–3h.34 Based on Noyori’s model, a plausible reaction
pathway for the enantioselective alkylation of benzaldehyde in
the presence of 3b, involves bidentate coordination of the ligand
to the zinc, originating a tricyclic 6/4/4 transition state, as pre-
sented in Figure 1.
Complete conversions were obtained, even for the short 2 h
reaction time, while maintaining the selectivity of the alcohol
product. These results reveal that ligand 3b is a strongly active
catalyst for the enantioselective alkylation reaction. Considering
the high activity of 3b, we studied the effect of reducing catalyst
loading (Table 5). Complete conversions were observed in 2 h using
1–15 mol %. Although there was no great variation in the er, a
slightly better result was observed when using 5 mol % of the
ligand, with an er of 86:14 for the product.
Finally, the solvent effect was also studied and results are
shown in Table 6. In all cases there was complete conversion of
the benzaldehyde and no secondary product was formed. The best
er was obtained in cyclohexane (86:14).
Using the optimized conditions, i.e. 2 h reaction time, 5 mol %
ligand and cyclohexane at room temperature, we carried out the
Table 7
Enantioselective alkylation of different aldehydes catalyzed by 3ba
Table 4
Aldehyde
Conversionb (%)
er (S):(R)b
Enantioselective alkylation of benzaldehyde with different reaction times, in the
presence of 3ba
o-Methoxybenzaldehyde
m-Methoxybenzaldehyde
p-Methoxybenzaldehyde
o-Chlorobenzaldehyde
p-Chlorobenzaldehyde
1-Naphthaldehyde
>99
>99
89
>99
>99
>99
>99
>99
91.5:8.5
93.5:6.5
84.5:15.5
85:15
84.5:15.5
90.5:9.5
84.5:15.5
78:22
Reaction time (h)
Conversionb,c (%)
er (S):(R)b
24
8
6
4
2
>99
>99
>99
>99
>99
86:14
85.5:14.5
85.5:14.5
85:15
o-Methylbenzaldehyde
Cinnamaldehyde
85:15
a
a
Reactions were carried out for 2 h at rt, in cyclohexane, using 5 mol % of 3b,
Reactions were carried out at rt, in cyclohexane, using 15 mol % of chiral ligand,
1 mmol of benzaldehyde and 2 mmol of diethylzinc (1 M in hexane).
1 mmol of benzaldehyde and 2 mmol of diethylzinc (1 M in hexane).
b
b
Determined by chiral gc.
Determined by chiral gc.
No secondary product was observed.
c
Table 5
Enantioselective alkylation of benzaldehyde with different catalyst loadings of 3ba
MeO
H
3b (mol %)
Conversionb,c (%)
er (S):(R)b
15
10
5
2
1
>99
>99
>99
>99
>99
85:15
85.5:14.5
86:14
84.5:15.5
83:17
OMe
N
n
Z
N
H
O
Zn
a
Reactions were carried out for 2 h at rt, in cyclohexane, 1 mmol of benzalde-
hyde and 2 mmol of diethylzinc (1 M in hexane).
b
Determined by chiral gc.
No secondary product was observed.
c
Figure 1. Possible 6/4/4 transition state for 3b.
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M. Elisa Silva Serra et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
1119, 1075, 1059, 959, 753, 90, 672. HRMS (ESI): calculated for
22H27N2 [M+H]+: 319.2169; found: 319.2163.
3. Conclusions
C
A new series of 1,3-chiral diamine ligands was prepared in a
simple three-step synthetic sequence from (+)-camphoric acid.
The ligands were tested in the enantioselective alkylation of ben-
zaldehyde with diethylzinc, showing excellent conversions and er
up to 86:14 in only 2 h with 5 mol % chiral ligand. Extending the
reaction to other substrates using our most efficient ligand, 3b,
was also very efficient, giving products with er up to 93.5:6.5. Fur-
ther studies are currently in progress involving the synthesis and
application of similar types of diamine ligands.
4.2.2. (1R,3S)-N,N0-Bis[2-methoxyphenylidene]-1,3-diamino-
1,2,2-trimethylcyclopentane 2b
Yield: 49%. mp: 123–126 °C. ½a D20
ꢁ
= -1.7 (c 6, CH2Cl2). 1H NMR
(CDCl3), d (ppm): 0.92 (s, 3H); 0.96 (s, 3H); 1.22 (s, 3H); 1.75–
1.82 (m, 1H); 2.02–2.08 (m, 2H); 2.28–2.36 (m, 1H); 3.59 (aprox.
t, 1H, J = 8.4); 3.87 (s, 3H); 3.88 (s, 3H); 6.91 (d, 2H, J = 8.0);
6.95–7.00 (m, 2H); 7.33–7.38 (m, 2H); 7.99–8.06 (m, 2H); 8.67 (s,
1H); 8.68 (s, 1H). 13C NMR (CDCl3), d (ppm): 18.7; 20.99; 24.8;
28.0; 34.3; 49.1; 55.5; 71.3; 77.9; 110.9; 120.8; 125.2; 126.01;
127.0; 127.69; 131.1; 131.4; 152.0; 155.1; 158.6. IR (cmꢀ1):
2964, 2941, 2869, 2838, 1631, 1599, 1486, 1459, 1437, 1375,
1286, 1240, 1176, 1160, 1111, 1104, 1043, 1024, 755. HRMS
4. Experimental
4.1. General
(ESI): calculated for
379.2373.
C
24H31N2O2 [M+H]+: 379.2380; found:
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 a FALC
melting point apparatus (open capillary method). Optical rotations
were measured with an Optical Activity AA-5 polarimeter. NMR
spectra were recorded at room temperature on a Bruker Avance
III 400 MHz (100 MHz for 13C). TMS was used as the internal stan-
dard and chemical shifts are given in ppm. Infrared spectra were
recorded on an Agilent Technologies Cary 630 FTIR in the ATR
mode. Microwave reactions were carried out in a CEM Discover
S-Class instrument.
4.2.3. (1R,3S)-N,N0-Bis[2-methylphenylidene]-1,3-diamino-
1,2,2-trimethylcyclopentane 2c
Yield: 19%. mp: 83–85 °C. ½a D20
ꢁ
= +29.7 (c 1, CH2Cl2). 1H NMR
(CDCl3), d (ppm): 0.94 (s, 3H); 0.98 (s, 3H); 1.24 (s, 3H); 1.76–
1.83 (m, 1H); 2.04–2.10 (m, 2H); 2.27–2.35 (m, 1H); 2.53 (s, 3H);
2.54 (s, 3H); 3.57 (aprox. t, 1H, J = 8.6); 7.17–7.30 (m, 6H); 7.85–
7.89 (m, 2H); 8.55 (s, 2H). 13C NMR (CDCl3), d (ppm): 18.9; 19.6;
19.7; 21.0; 25.0; 28.1; 34.2; 49.0; 71.5; 78.3; 126.1; 127.7;
128.1; 129.6; 129.8; 130.7; 130.8; 134.7; 135.4; 137.3; 137.4;
155.2; 158.1. IR (cmꢀ1): 2664, 2929, 2868, 1633, 1601, 1483,
1457, 1457, 1449, 1438, 1369, 1358, 1285, 1062, 1044, 959, 763,
+
734, 716. HRMS (ESI): calculated for
347.2482; found: 347.2475.
C
24H31N2 [M+H]
:
High-resolution mass spectra (HRMS) were obtained on a TOF
VG Autospect M spectrometer with electrospray ionization (ESI).
Elemental analyses were carried out on an Elementar Vario Micro
Cube analyser. Alkylation reactions were carried out in an inert
atmosphere using standard Schlenk-type techniques. Enantiomeric
4.2.4. (1R,3S)-N,N0-Bis[2-chlorophenylidene]-1,3-diamino-1,2,2-
trimethylcyclopentane 2d
Yield: 49%. mp: 91–93 °C. ½a D20
ꢁ
= -7.2 (c 2.1, CH2Cl2.). 1H NMR
ratios and conversions were determined by using a chiral
c-
(CDCl3), d (ppm): 0.92 (s, 3H); 0.99 (s, 3H); 1.25 (s, 3H); 1.81–
1.87 (m, 1H); 2.06–2.17 (m, 2H); 2.29–2.37 (m, 1H); 3.66 (aprox.
t, 1H, J = 8.4); 7.28–7.38 (m, 6H); 8.06–8.13 (m, 2H); 8.68 (s, 2H).
13C NMR (CDCl3), d (ppm): 18.8; 21.1; 24.6; 28.0; 34.4; 49.3;
71.7; 77.8; 126.9; 128.2; 128.7; 129.6; 129.7; 131.0; 131.2;
133.6; 134.3; 134.9; 135.1; 153.3; 156.0. IR (cmꢀ1): 3067, 2964,
2869, 1629, 1466, 1438, 1377, 1366, 1271, 1050, 1028, 963, 756,
709. Elemental analysis: Calcd. for C22H24Cl2N2 (%): C, 68.22; H,
6.25; N, 7.23. Found (%): C, 68.35; H, 6.36; N, 7.14.
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 configuration of the major enantiomers was deter-
mined by comparison of the retention times with reported values
and by determining the sign of the specific rotation of the isolated
products.
4.2. General procedure for the synthesis of the diimine ligands
4.2.5. (1R,3S)-N,N0-Bis[3-methoxyphenylidene]-1,3-diamino-
To 3 ml of ethanol in a microwave reaction tube, 6.00 mmol of
diamine 2.2 (0.85 g), 0.60 mmol (10 mol %) of p-toluenesulfonic
acid monohydrate (0.11 g) and 12.00 mmol of aldehyde were
added. The tube was subjected to microwave irradiation, using a
power control program (250 W) for 15 min. Subsequently, upon
cooling, the product diimine crystallized directly from the reaction
medium. The product was filtered and recrystallized from hot
ethanol. The crystals were filtered and dried in vacuo. Upon con-
centration, a second crop of crystals may be collected.
1,2,2-trimethylcyclopentane 2e
Yield: 53%. mp: 120–123 °C. ½a D20
ꢁ
= +45.0 (c 1, CH2Cl2). 1H NMR
(CDCl3), d (ppm): 0.91 (s, 3H); 0.96 (s, 3H); 1.22 (s, 3H); 1.73–1.81
(m, 1H); 2.00–2.08 (m, 2H); 2.23–2.36 (m, 1H); 3.57 (aprox. t, 1H,
J = 8.4); 3.84 (s, 3H); 3.86 (s, 3H); 6.94–6.97 (m, 2H); 7.30–7.41 (m,
6H); 8.23 (s, 1H); 8.24 (s, 1H). 13C NMR (CDCl3), d (ppm): 18.7;
21.1; 24.6; 27.9; 34.2; 49.1; 55.4; 71.0; 77.6; 111.9; 112.2;
116.3; 116.6; 121.0; 121.2; 129.5; 138.2; 139.1; 155.8; 158.9;
159.9. IV (cm-1): 2998, 2966, 2934, 2871, 2833, 1638, 1596,
1585, 1491, 1458, 1449, 1318, 1291, 1264, 1193, 1169, 1151,
1067, 1033, 959, 857, 795, 787, 690. HRMS (ESI): calculated for
4.2.1. (1R,3S)-N,N0-Bis[phenylidene]-1,3-diamino-1,2,2-
trimethylcyclopentane 2a
24H31N2O2 [M+H]+: 379.2380; found: 379.2374.
Yield: 52%. mp: 102–105 °C. ½a D20
ꢁ
= +36.2 (c 1, CH2Cl2). 1H NMR
C
(CDCl3), d (ppm): 0.92 (s, 3H); 0.97 (s, 3H); 1.23 (s, 3H); 1.75–1.82
(m, 1H); 2.02–2.09 (m, 2H); 2.28–2.36 (m, 1H); 3.58 (aprox. t, 1H,
J = 8.4 Hz); 7.39–7.42 (m, 6H); 7.75–7.80 (m, 4H); 8.27 (s, 1H); 8.28
(s, 1H). 13C NMR (CDCl3), d (ppm): 18.7; 21.0; 24.6; 27.9; 34.1;
49.1; 71.0; 77.7; 127.8; 128.2; 128.5; 128.6; 130.1; 130.3; 136.7;
137.5; 156.0; 159.1. IR (cmꢀ1): 2969, 2943, 2868, 2839, 1639,
1624, 1578, 1492, 1449, 1438, 1369, 1358, 1308, 1216, 1173,
4.2.6. (1R,3S)-N,N0-Bis[4-methoxyphenylidene]-1,3-diamino-
1,2,2-trimethylcyclopentane 2f
Yield: 52%. mp: 139–142 °C. ½a D20
ꢁ
= +45.0 (c 1, CH2Cl2). 1H NMR
(CDCl3), d (ppm): 0.90 (s, 3H); 0.94 (s, 3H); 1.21 (s, 3H); 1.72–1.79
(m, 1H); 1.99–2.06 (m, 2H); 2.25–2.33 (m, 1H); 3.52 (aprox. t, 1H,
J = 8.6); 3.84 (s, 6H); 6.90–6.94 (m, 4H); 7.69–7.74 (m, 4H);
Please cite this article in press as: Serra, M. E. S.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.01.013

M. Elisa Silva Serra et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
5
8.20 (s, 2H). 13C NMR (CDCl3), d (ppm): 18.6; 20.9; 24.7; 28.0; 34.2;
49.0; 55.4; 70.6; 113.9; 129.2; 129.6; 129.8; 130.7; 155.1; 158.3;
161.2; 161.3. IR (cmꢀ1): 2962, 2935, 2870, 2841, 1638, 1603,
1508, 1457, 1443, 1306, 1252, 1166, 1109, 1063, 1032, 837, 823.
HRMS (ESI): calculated for C24H31N2O2 [M+H]+: 379.2380; found:
379.2373.
mp: 68–71 °C. ½a 2D0
ꢁ
= +39.4 (c 1, CH2Cl2). 1H NMR (CDCl3), d (ppm):
0.96 (s, 3H); 0.97 (s, 3H); 1.11 (s, 3H); 1.35–1.45 (m, 1H); 1.55–1.62
(m, 1H); 1.80–1.88 (m, 3H); 1.91–2.00 (m, 1H); 2.77–2.82 (m, 1H);
3.67–3.72 (m, 2H); 3.78–3.83 (m, 2H); 3.80 (s, 3H); 3.81 (s, 3H);
6.81–6.92 (m, 4H); 7.17–7.34 (m, 4H). 13C NMR (CDCl3), d (ppm):
16.8; 20.9; 23.8; 28.2; 34.8; 42.3; 47.2; 48.1; 55.2; 64.5; 66.2;
110.1; 120.4; 120.5; 127.6; 127.8; 129.3; 129.4; 157.4; 157.6. IR
(cmꢀ1): 3277, 2952, 2932, 2878, 2831, 2798, 1599, 1588, 1489,
1459, 1449, 1442, 1438, 1433, 1420, 1374, 1284, 1237, 1192,
1171, 1156, 1091, 1083, 1050, 1027, 749, 716. HRMS (ESI): calcu-
lated for C24H35N2O2 [M+H]+: 383.2693; found: 383.2684.
4.2.7. (1R,3S)-N,N0-Bis[2,6-dichlorophenylidene]-1,3-diamino-
1,2,2-trimethylcyclopentane 2g
Yield: 52%. mp: 117–120 °C. ½a D20
ꢁ
= +4.0 (c 5, CH2Cl2). 1H NMR
(CDCl3), d (ppm): 1.08 (s, 3H); 1.09 (s, 3H); 1.32 (s, 3H); 1.82–
1.88 (m, 1H); 2.10–2.17 (m, 2H); 2.38–2.45 (m, 1H); 3.70 (aprox.
t, 1H, J = 8.0); 7.18–7.23 (m, 2H); 7.32–7.35 (m, 4H); 8.40 (s, 1H);
8.42 (s, 1H). 13C NMR (CDCl3), d (ppm): 18.8; 20.6; 25.0; 27.5;
34.0; 48.9; 73.0; 79.1; 128.5; 129.8; 130.1; 133.7; 134.4; 134.5;
153.9; 155.5. IR (cmꢀ1): 2969, 2869, 1633, 1578, 1559, 1426,
1420, 1401, 1377, 1367, 1266, 1213, 1189, 1116, 1086, 1058,
943, 784, 772, 736, 715. Elemental analysis: Calcd. for C22H22Cl4N2
(%): C, 57.92; H, 4.86; N, 6.14. Found (%): C, 57.76; H, 4.70; N, 6.06.
4.3.3. (1R,3S)-N,N0-Bis(2-methylbenzyl)-1,3-diamino-1,2,2-
trimethylcyclopentane 3c
The product, an oil, was obtained pure. Yield: 97%. ½a D20
ꢁ
= +44.9
(c 1.2, CH2Cl2). 1H NMR (CDCl3), d (ppm): 0.96 (s, 6H); 1.15 (s, 3H);
1.25–1.52 (m, 3H); 1.61–1.69 (m, 1H); 1.91–1.97 (m, 1H); 2.04–
2.13 (m, 1H); 2.30 (s, 3H); 2.34 (s, 3H); 2.87 (dd, 1H, J = 8.0; 6.0);
3.60–3.80 (m, 4H); 7.08–7.16 (m, 6H); 7.23–7.32 (m, 2H). 13C
NMR (CDCl3), d (ppm): 16.9; 19.0; 20.5; 24.3; 28.5; 33.9; 44.9;
47.6; 50.7; 64.6; 67.2; 125.8: 125.9; 126.7; 126.8; 128.2; 128.5;
130.1; 136.5; 136.6. IR (cmꢀ1): 3292, 3064, 3017, 2957, 2868,
2821, 1491, 1458, 1453, 1449, 1438, 1386, 1369, 1104, 1086,
1048, 1034, 739, 703, 696. HRMS (ESI): calculated for C24H35N2
[M+H]+: 351.2795; found: 351.2788.
4.2.8. (1R,3S)-N,N0-Bis[2,4,6-trimethylphenylidene]-1,3-diamino-
1,2,2- trimethylcyclopentane 2h
Yield: 36%. mp: 124–127 °C. ½a D20
ꢁ
= +25.0 (c 1, CH2Cl2). 1H NMR
(CDCl3), d (ppm): 0.99 (s, 3H); 1.01 (s, 3H); 1.26 (s, 3H); 1.79–1.85
(m, 1H); 2.01–2.07 (m, 2H); 2.24–2.32 (m, 1H); 2.28 (s, 6H); 2.39 (s,
6H); 2.41 (s, 6H); 3.55 (aprox. t, 1H, J = 8.6); 6.86 (s, 4H); 8.57 (s,
2H). 13C NMR (CDCl3), d (ppm): 19.2; 20.8; 20.9; 21.0; 21.1; 21.2;
25.9; 28.1; 34.1; 48.2; 72.3; 79.4; 129.3; 131.6; 132.4; 137.0;
137.3; 138.1; 138.4; 157.6; 159.7. IR (cmꢀ1): 2960, 2955, 2917,
2868, 1629, 1609, 1565, 1559, 1457, 1449, 1438, 1429, 1396,
1374, 1364, 1359, 1114, 1067, 1032, 852, 804. HRMS (ESI): calcu-
lated for C28H39N2 [M+H]+: 403.3108; found: 403.3100.
4.3.4. (1R,3S)-N,N0-Bis(2-chlorobenzyl)-1,3-diamino-1,2,2-
trimethylcyclopentane 3d
The product was purified by column chromatography using sil-
ica gel and ethyl ether as eluent to give an oil. Yield: 80%. ½a D20
ꢁ
=
+37.0 (c 1.1, CH2Cl2). 1H NMR (CDCl3), d (ppm): 0.88 (s, 3H); 0.92
(s, 3H); 1.04 (s, 3H); 1.36–1.45 (m, 1H); 1.49–1.59 (m, 3H); 1.81–
1.88 (m, 1H); 1.89–1.99 (m, 1H); 2.74 (dd, 1H, J = 8.0; 6.0); 3.68–
3.83 (m, 4H); 7.05–7.14 (m, 4H); 7.22–7.26 (m, 2H); 7.30–7.33
(m, 1H); 7.37–7.40 (m, 1H). 13C NMR (CDCl3), d (ppm): 16.9;
20.5; 24.3; 28.4; 34.0; 44.6; 47.6; 50.1; 64.7; 66.7; 126.7; 126.8;
127.8; 127.9; 129.2; 129.3; 129.8; 129.9; 133.5; 133.6; 138.5;
139.4. IR (cmꢀ1): 3278, 3063, 2959, 2868, 2376, 2324, 1466,
1441, 1438, 1420, 1371, 1164, 1126, 1092, 1048, 1036, 746, 697,
679. HRMS (ESI): calculated for C22H29Cl2N2 [M+H]+: 391.1702;
found: 391.1694.
4.3. General procedure for the synthesis of the diamine ligands
In a round bottom flask, 2.00 mmol diimine and a mixture of
20 ml of MeOH/CHCl3 (1:1) were stirred for 10 min at room tem-
perature. The mixture was placed in an ice bath and 40.00 mmol
of NaBH4 were slowly added with stirring. The mixture was
allowed to react overnight at room temperature, then placed in
an ice bath and a saturated solution of ammonium chloride was
gradually added until bubbling stopped. The reaction mixture
was extracted with H2O and dichloromethane. The combined
organic extracts were dried over Na2SO4, filtered and the solvent
was evaporated. In some cases, the products were purified by col-
umn chromatography.
4.3.5. (1R,3S)-N,N0-Bis(3-methoxybenzyl)-1,3-diamino-1,2,2-
trimethylcyclopentane 3e
The product was purified by column chromatography using sil-
ica gel and ethyl ether/NEt3 80:2 to give an oil. Yield: 88%. ½a D20
ꢁ
=
+43.5 (c 1.2, CH2Cl2). 1H NMR (CDCl3), d (ppm): 0.95 (s, 3H); 1.00 (s,
3H); 1.11 (s, 3H); 1.42–1.51 (m, 1H); 1.59–1.66 (m, 1H); 1.87–1.94
(m, 1H); 1.99–2.08 (m, 1H); 2.83 (dd, 1H, J = 8.2; 6.2); 3.62–3.85
(m, 4H); 3.76 (s, 3H); 3.77 (s, 3H); 6.74–6.92 (m, 6H); 7.18–7.24
(m, 2H). 13C NMR (CDCl3), d (ppm): 17.0; 20.7; 24.3; 28.5; 34.2;
47.2; 47.5; 52.4; 55.1; 55.2; 64.6; 66.4; 112.0; 112.2; 113.3;
113.6; 120.3; 129.2; 129.3; 142.9; 143.8; 159.7; 159.8. IR (cmꢀ1):
2954, 2870, 2834, 1596, 1585, 1487, 1465, 1457, 1453, 1437,
1434, 1420, 1369, 1261, 1152, 1118, 1087, 1042, 909, 775, 731,
691. HRMS (ESI): calculated for C24H35N2O2 [M+H]+: 383.2693;
found: 383.2685.
4.3.1. (1R,3S)-N,N0-Dibenzyl-1,3-diamino-1,2,2-trimethylcyclo-
pentane 3a
The product, an oil, was obtained pure. Spectroscopic details are
in agreement with those previously described.35 Yield: 96%. ½a D20
ꢁ
=
+47.8 (c 1.2, CH2Cl2). 1H NMR (CDCl3), d (ppm): 0.95 (s, 3H); 0.97 (s,
3H); 1.10 (s, 3H); 1.41–1.51 (m, 1H); 1.52–1.67 (m, 3H); 1.85–1.92
(m, 1H); 2.00–2.09 (m, 1H); 2.83 (dd, 1H, J = 8.2; 5.8); 3.67 (d, 1H,
J = 12.0); 3.71 (d, 1H, J = 12.0); 3.77 (d, 1H, J = 12.0); 3.86 (d, 1H,
J = 12.0); 7.19–7.35 (m, 10H). 13C NMR (CDCl3), d (ppm): 17.0;
20.7; 24.4; 28.4; 34.1; 47.2; 47.5; 52.6; 64.6; 66.6; 126.6; 126.7;
128.0; 128.1; 128.3; 128.4; 141.2; 142.1. IR (cmꢀ1): 3285, 3061,
3026, 2959, 2868, 2824, 2362, 2322, 1494, 1466, 1452, 1438,
1387, 1369, 1166, 1118, 1092, 1073, 1028, 730, 695. HRMS (ESI):
calculated for C22H31N2 [M+H]+: 323.2482; found: 323.2470.
4.3.6. (1R,3S)-N,N0-Bis(4-methoxybenzyl)-1,3-diamino-1,2,2-
trimethylcyclopentane 3f
The product, an oil, was obtained pure. Yield: 99%. ½a D20
ꢁ
= +40.0
(c 1.1, CH2Cl2). 1H NMR (CDCl3), d (ppm): 0.95 (s, 3H); 1.03 (s, 3H);
1.15 (s, 3H); 1.43–1.58 (m, 1H); 1.62–1.70 (m, 1H); 1.93–2.08 (m,
2H); 2.85 (dd, 1H, J = 7.4; 5.4); 3.56–3.69 (m, 2H); 3.73–3.84 (m,
2H); 3.79 (s, 3H); 3.80 (s, 3H); 6.81 (d, 2H, J = 4.2); 6.83 (d, 2H,
J = 4.2); 7.15 (d, 2H, J = 8.4); 7.26 (d, 2H, J = 8.4). 13C NMR (CDCl3),
4.3.2. (1R,3S)-N,N0-Bis(2-methoxybenzyl)-1,3-diamino-1,2,2-
trimethylcyclopentane 3b
The product was purified by column chromatography using sil-
ica gel and ethyl ether/NEt3 80:2 to give a white solid. Yield: 65%.
Please cite this article in press as: Serra, M. E. S.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.01.013

6
M. Elisa Silva Serra et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
d (ppm): 17.1; 20.0; 24.4; 27.7; 33.8; 46.5; 47.6; 51.6; 55.2; 65.5;
66.4; 113.7; 113.8; 129.2; 129.4; 132.3; 132.9; 158.6. IR (cmꢀ1):
2954, 2834, 1610, 1584, 1509, 1491, 1458, 1438, 1420, 1369,
1299, 1242, 1172, 1105, 1032, 1012, 817, 734, 701. HRMS (ESI):
calculated for C24H35N2O2 [M+H]+: 383.2693; found: 383.2685.
Acknowledgements
Thanks are due to Coimbra Chemistry Centre (CQC), supported
by the Portuguese Agency for Scientific Research, Fundação para a
Ciência e a Tecnologia (FCT), through Project N° 007630 UID/
QUI/00313/2013, co-funded by COMPETE2020-UE. We acknowl-
edge the UC-NMR facility for obtaining the NMR data (www.nmr-
ccc.uc.pt).
4.3.7. (1R,3S)-N,N0-Bis(2,6-dichlorobenzyl)-1,3-diamino-1,2,2-
trimethylcyclopentane 3g
The product was purified by column chromatography using sil-
ica gel and CHCl3/MeOH 90:10, giving a white solid. Yield: 65%.
References
mp: 86–89 °C. ½a 2D0
ꢁ
= +30.0 (c 1, CH2Cl2). 1H NMR (CDCl3), d
1. Pu, L.; Yu, H. B. Chem. Rev. 2001, 101, 757–824.
2. Lin, G.; Li, Y.; Chan, A. S. C. Principles and Applications of Asymmetric Synthesis;
John Wiley & Sons Inc: New York, 2001.
3. Naganawa, Y.; Namba, T.; Aoyama, T.; Shoji, K.; Nishiyama, H. Chem. Commun.
2014, 13224–13227.
4. Karabuga, S.; Karakaya, I. Tetrahedron: Asymmetry 2014, 25, 851–855.
5. Zhang, W.; Tang, R.; Yu, H.; Gao, S. Appl. Organomet. Chem. 2014, 28, 545–551.
6. Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. 1991, 30, 49–69.
7. Soai, K.; Niwa, S. Chem. Rev. 1992, 833–856.
8. Binder, C. M.; Singaram, B. Org. Prep. Proced. Int. 2011, 43, 139–208.
9. Łowicki, D.; Bas´, S.; Mlynarski, J. Tetrahedron 2015, 71, 1339–1394.
10. Jarzyn´ ski, S.; Les´niak, S.; Pieczonka, A. M. Tetrahedron: Asymmetry 2015, 26, 35–
40.
(ppm): 0.91 (s, 3H); 0.96 (s, 3H); 1.19 (s, 3H); 1.34–1.43 (m, 1H);
1.51–1.69 (m, 3H); 1.81–1.88 (m, 1H); 1.93–2.02 (m, 1H); 2.83
(aprox. t, 1H, J = 7.8); 3.93–4.10 (m, 4H); 7.07–7.13 (m, 2H);
7.25–7.28 (m, 4H). 13C NMR (CDCl3), d (ppm): 16.5; 20.7; 23.6;
28.7; 34.9; 42.8; 47.3; 48.2; 64.5; 66.9; 128.3; 128.4; 128.5;
128.6; 135.9. IR (cmꢀ1): 2962, 2863, 1561, 1457, 1434, 1420,
1374, 1169, 1111, 1085, 1053, 1019, 771, 760, 735, 693. HRMS
(ESI): calculated for
459.0918.
C
22H27Cl4N2 [M+H]+: 459.0923; found:
11. Wang, Z.; Huang, D.; Xu, P.; Dong, X.; Wang, X.; Dai, Z. Tetrahedron Lett. 2015,
56, 1067–1071.
4.3.8. (1R,3S)-N,N0-Bis(2,4,6-trimethylbenzyl)-1,3-diamino-
1,2,2-trimethylcyclopentane 3h
12. Wu, H.-L.; Wu, P.-Y.; Cheng, Y.-N.; Uang, B.-J. Tetrahedron 2016, 72, 2656–2665.
13. Frensch, G.; Labes, R.; Wosch, C. L.; Munaretto, L. D. S.; Salomé, K. S.; Guerrero,
P. G.; Marques, F. A. Tetrahedron Lett. 2016, 57, 420–422.
14. Lee, D.-S.; Chang, S.-M.; Ho, C.-Y.; Lu, T.-J. Chirality 2016, 28, 65–71.
15. Li, F.; Huang, H.; Zong, H.; Bian, G.; Song, L. Tetrahedron Lett. 2015, 56, 2071–
2076.
16. Martins, J. E. D. Tetrahedron: Asymmetry 2008, 19, 1250–1255.
17. Burguete, M. I.; Escorihuela, S. V. L.; Lledós, A.; Ujaque, G. Tetrahedron 2008, 64,
9717–9724.
18. Cheng, Y. Q.; Bian, Z.; Kang, C. Q.; Guo, H. Q.; Gao, L. X. Tetrahedron: Asymmetry
2008, 19, 1572–1575.
19. Scarpi, D.; Occhiato, E. G. Tetrahedron: Asymmetry 2009, 20, 340–350.
20. Olsson, C.; Helgesson, S. Tetrahedron: Asymmetry 2008, 19, 1484–1493.
21. Martínez, A. G.; Vilar, E. T.; Fraile, A. G.; Cerero, S. M.; Ruiz, P. M.; Morillo, C. D.
Tetrahedron: Asymmetry 2007, 18, 742–749.
22. Zanardi, M. M.; Suárez, A. G. Tetrahedron Lett. 2015, 56, 3762–3765.
23. Asami, M.; Hasome, A.; Yachi, N.; Hosoda, N.; Yamaguchi, Y.; Ito, S. Tetrahedron:
Asymmetry 2016, 27, 322–329.
24. Asami, M.; Miyairi, N.; Sasahara, Y.; Ichikawa, K. I.; Hosoda, N.; Ito, S.
Tetrahedron 2015, 71, 6796–6802.
25. Csillag, K.; Szakonyi, Z. Tetrahedron: Asymmetry 2013, 24, 553–561.
26. Serra, M. E. S.; Murtinho, D.; Goth, A.; Rocha Gonsalves, A. M. d’A.; Abreu, P. E.;
Pais, A. A. C. C. Chirality 2010, 431, 425–431.
27. Serra, M. E. S.; Murtinho, D.; Goth, A. ARKIVOC 2009, 2010, 64–69.
28. Murtinho, D.; Serra, M. E. S. Tetrahedron: Asymmetry 2010, 21, 62–68.
29. Murtinho, D.; Ogihara, C. H.; Serra, M. E. S. Tetrahedron: Asymmetry 2015, 26,
1256–1260.
30. Bekdemir, Y.; Efil, K. Org. Chem. Int. 2014, 2014, 1–5.
31. Gopalakrishnan, M.; Sureshkumar, P.; Kanagarajan, V.; Thanusu, J. Res. Chem.
Intermed. 2007, 33, 541–548.
32. Ramos, N. C.; Echevarria, A.; Valbon, A.; Bortoluzzi, A. J.; Guedes, G. P.;
Rodrigues-Santos, C. E.; Smith, C. Cogent Chem. 2016, 2, 1207863.
33. Das, S.; Das, V. K.; Saikia, L.; Thakur, A. J. Green Chem. Lett. Rev. 2012, 5, 457–
474.
34. Goth, A. Masters Thesis, Coimbra, Portugal, 2007.
35. He, K.; Zhou, Z.; Wang, L.; Li, K.; Zhao, G.; Zhou, Q.; Tang, C. Tetrahedron 2004,
60, 10505–10513.
36. Reddy, P. V. G.; Tabassum, S.; Blanrue, A.; Wilhelm, R. Chem. Commun. 2009,
5910–5912.
The product was purified by column chromatography using sil-
ica gel and CHCl3/MeOH 90:10 as eluent to give an oil. Spectro-
scopic details are in agreement with those previously
described.36 Yield: 47%. ½a 2D0
ꢁ
= +34.1 (c 1, CH2Cl2). 1H NMR (CDCl3),
d (ppm): 0.82 (s, 3H); 0.93 (s, 3H); 1.19 (s, 3H); 1.39–1.49 (m, 1H);
1.64–1.72 (m, 1H); 1.88–1.98 (m, 1H); 2.08–2.19 (m, 1H); 2.24 (s,
6H); 2.31 (s, 6H); 2.34 (s, 6H); 2.85 (dd, 1H, J = 8.2; 7.0); 3.53 (d,
1H, J = 12.0); 3.60 (d, 1H, J = 12.0); 3.71 (d, 1H, J = 12.0); 3.76 (d,
1H, J = 12.0); 6.80 (s, 2H); 6.81 (s, 2H). 13C NMR (CDCl3), d (ppm):
16.7; 19.4; 20.6; 20.9; 23.8; 28.8; 34.1; 40.8; 47.3; 47.4; 64.3;
68.0; 128.8; 128.9; 134.4; 134.7; 136.1; 136.2; 137.0; 137.1. IR
(cmꢀ1): 2949, 2915, 2863, 1613, 1482, 1473, 1466, 1457, 1442,
1438, 1420, 1386, 11369, 1162, 1109, 1085, 1071, 1047, 1032,
1013, 849, 747, 715, 690. HRMS (ESI): calculated for C28H43N2 [M
+H]+: 407.3421; found: 407.3413.
4.4. General procedure for enantioselective alkylations
To the appropriate amount of chiral ligand (0.15–0.01 mmol)
and aldehyde (1 mmol) under an inert atmosphere, 4 mL of dry sol-
vent were added. The temperature of the reaction mixture was
lowered to 0 °C and diethylzinc (2 mmol, 2 mL, as a 1 M hexane
solution) was added. The reaction was stirred for 10 min at 0 °C
and then at the required temperature for the required time. Subse-
quently, a saturated ammonium chloride solution (1 mL) was
added, followed by 2 M HCl (1 mL) and the reaction mixture was
extracted with diethyl ether. The joint organic phases were washed
with water and brine, and dried over anhydrous sodium sulfate.
The resulting solution was analyzed by GC on a chiral
c-cyclodex-
trin capillary column in order to determine the er of the products.
Please cite this article in press as: Serra, M. E. S.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.01.013