The synthesis of tetradentate salens derived from (3R,4R)-N-substituted-3, 4-diaminopyrrolidines and their application in the enantioselective trimethylsilylcyanation of aromatic aldehydes

Article abstract of DOI:10.1016/j.tetasy.2013.01.015

The in situ formed Ti(IV) complexes of pyrrolidine-based chiral salen ligands derived from natural l-tartaric acid were evaluated as catalysts in the enantioselective trimethylsilylcyanation of aromatic aldehydes. The different activity and selectivity of the catalysts in the formation of the products were found to be dependent on the N-substituent of the pyrrolidine.

Full text of DOI:10.1016/j.tetasy.2013.01.015

Tetrahedron: Asymmetry 24 (2013) 315–319
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
The synthesis of tetradentate salens derived from (3R,4R)-N-substituted-
3,4-diaminopyrrolidines and their application in the enantioselective
trimethylsilylcyanation of aromatic aldehydes
⇑
M. Elisa Silva Serra , Dina Murtinho, Albertino Goth
Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade de Coimbra, P-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:
Received 3 January 2013
Accepted 23 January 2013
The in situ formed Ti(IV) complexes of pyrrolidine-based chiral salen ligands derived from natural L-tar-
taric acid were evaluated as catalysts in the enantioselective trimethylsilylcyanation of aromatic alde-
hydes. The different activity and selectivity of the catalysts in the formation of the products were
found to be dependent on the N-substituent of the pyrrolidine.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
The enantioselective trimethylsilylcyanation of aldehydes cata-
lyzed by titanium complexes is a convenient process for synthesiz-
ing optically active cyanohydrins. These chiral products have great
synthetic interest as precursors of molecules with other important
2.1. Synthesis of chiral salen ligands
The 3,4-diaminopyrrolidines 2a–2c were prepared from natural
L-tartaric acid and a primary amine (benzylamine, cyclohexyl-
functional groups, such as
mary and secondary b-hydroxyamines,
a
-hydroxyacids,
a
-hydroxyketones, pri-
amine and aniline) according to previously described proce-
dures19,20 (Scheme 1). The subsequent reaction of 2a–2c with the
aldehydes under ultrasound irradiation gave 3a–3c and 4a–4c in
very good yields.
a
-aminonitriles, and a-
hydroxyesters. Titanium, vanadium, and aluminum metals have
been successfully used as Lewis acids in these reactions and struc-
turally diverse chiral ligands have proven to be efficient in this
enantioselective process.1–6 Oguni’s pioneering work with Schiff
bases7–9 led to the development of many ligands of this type for
the enantioselective trimethylsilylcyanation of aldehydes.10–16
Our research has focused on various types of enantioselective
catalysis, particularly for the alkylation and cyanation of alde-
hydes.17–19 We have been especially interested in the synthesis
of chiral salens from the condensation of chiral diamines with dif-
ferent backbones with substituted salicylaldehydes. The structural
characteristics of these ligands make them appropriate for both the
alkylation and trimethylsilylcyanation of aldehydes, allowing a
convenient multiple application of these chiral ligands in enantio-
selective transformations. In this sense, we herein report the re-
sults of the trimethylsilylcyanation of several aromatic aldehydes
using chiral salens prepared from the condensation of three differ-
ent N-substituted-3,4-diaminopyrrolidines with 3,5-di-t-butylsal-
ycylaldehdye and 2-hydroxy-1-naphthaldehyde.
2.2. Enantioselective trimethylsilylcyanation
Using benzaldehyde as the model substrate, the titanium(IV)
complexes of chiral salens 3b, 3c and 4b, 4c were evaluated as cat-
alysts in the enantioselective trimethylsilylcyanation reaction and
compared with the results for 3a and 4a, which were previously
prepared and tested in this catalytic process.19
The reactions were carried out in dichloromethane with tita-
nium tetraisopropoxide and trimethylsilylcyanide, in a N2 atmo-
sphere for 24 h at ꢀ30 °C (Scheme 2). The Ti/ligand/aldehyde/
TMSCN ratio used was 1:1.1:5:10.
The catalytic experimental results are summarized in Table 1.
The catalysts were found to be very active, giving almost quantita-
tive conversions under these reaction conditions, with the excep-
tion of 3c and 4c, which gave slightly lower conversions. The ee
of the products varied according to the structure of each particular
ligand, with the most selective being the 3,5-di-t-butylsalicylalde-
hyde derivatives of the N-benzyl and N-cyclohexylpyrrolidines 3a
and 3b, which gave the corresponding cyanosilylethers with ees
of 88% and 82%, respectively. The 2-hydroxynaphthaldehdye de-
rived salens 4a–4c gave conversions similar to their 3,5-di-t-butyl-
salicylaldehyde counterparts, although the product ee were low for
the three N-substituted derivatives.
⇑
Corresponding author. Tel.: +351 239854480; fax: +351 239827703.
E-mail addresses: melisa@ci.uc.pt (M. E. S. Serra), dmurtinho@ci.uc.pt
(D. Murtinho), goth.uc@sapo.pt (A. Goth).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.01.015

316
M. E. S. Serra et al. / Tetrahedron: Asymmetry 24 (2013) 315–319
HO
HO
H2N
H2N
CO2H
CO2H
i-v
2a R= benzyl
2b R= cyclohexyl
2c R= phenyl
NR
1
2
CHO
CHO
OH
OH
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
HO
HO
N
N
NR
HO
HO
N
NR
3a-c
N
4a-c
t-Bu
Scheme 1. Reagents and conditions: (i) RNH2, xylene, reflux; (ii) AcCl, reflux; (iii) LiAlH4, ether, reflux; (iv) DEAD/PPh3, HN3, rt; (v) H2, Pd/C 10%.
CHO
OSiMe3
CN
Ph3P
Ph3P
HO
HO
Ti(OiPr)4,
NPh
NPh
chiral salen
TMSCN, -30ºC
5a
6a
5b
6b
Scheme 2.
Ph3P
Ph3P
HO
HO
NCH2Ph
NCH2Ph
Table 1
Enantioselective trimethylsilylcyanation of benzaldehyde in the presence of titanium
complexes of ligands 3 and 4a
Scheme 3.
Entry
Salen
Conversionb (%)
eec (%)
1
2
3
4
5
6
3a
3b
3c
4a
4b
4c
>99
>99
87
97
>99
79
88 (S)
82 (S)
15 (S)
30 (S)
40 (S)
20 (S)
responsible for the low discrimination observed with this ligand
compared to 6a.
Considering a similar situation in the salen ligands, the Ti(IV)-3c
complex should exhibit a greater planarity than the Ti(IV)-3a and
Ti(IV)-3b complexes, with the different geometries justifying the
ee of the trimethylsilylcyanation products.
In order to determine the best solvent for the trimethysilylcya-
nations with our salen ligands, we tested a set of the most fre-
quently used solvents.3,10 Our study was carried out with our
most efficient ligand 3a using benzaldehyde as the substrate. With
all of the solvents used, except for ethyl ether, conversions greater
than 97%. The ee of the products were slightly lower in chloroform
and acetonitrile, 78% and 77% respectively, than in dichlorometh-
ane. When ethyl ether and toluene were used, the enantiomeric ex-
cesses of the products were very low, 12% and 40% ee, respectively.
We thus concluded that the best solvent for the trimethysilylcya-
nations with our ligands was dichloromethane (Table 2).
Using our most efficient ligands 3a and 3b, we extended our
studies to a wide range of substituted benzaldehydes. The results
are summarized in Tables 3 and 4.
a
Reaction on a 2 mmol scale in 5 mL of dry CH2Cl2 at ꢀ30 °C, 24 h (molar ratio of
Ti/ligand/aldehyde/TMSCN of 1:1.1:5:10).
b
Determined by GC.
Of the silylether, determined by chiral GC.
c
In an attempt to explain our best results with the 3,5-di-t-butyl-
salicylaldehyde derived salens and taking into account the appar-
ent structural similarities of ligands 3a–3c, that is, the steric
properties of the N-substituents, the results observed for 3c might
be considered to be unexpected. However, similar trends in behav-
ior have previously been observed by us with analogous diphos-
phines 5a and 6a and the corresponding diols 5b and 6b
(Scheme 3) when used in enantioselective transfer hydrogenation
and alkylation reactions.21,22
The structure of diphosphine 5a determined by X-ray crystal-
lography and its comparison with the structures of analogous N-
substituted pyrrolidine diphosphines21,23–27 including 6a, resulted
in significant explanatory differences. Crystallography results re-
vealed the coplanarity of the pyrrolidine and N-phenyl rings in
5a due to the sp2 character of the nitrogen atom in this structure,
a unique characteristic compared to other structural analogues
where the nitrogen atom is sp3 hybridized. This is apparently
No significant differences in activity were observed between the
two catalytic systems studied. All substrates, with the exception of
para-bromobenzaldehyde, gave reaction products with conver-
sions greater than 93%.
The structural characteristics of the ligand, as well as the steric
and electronic properties of the aromatic aldehyde substrate, were
determining factors in the enantioselectivity of the trim-
ethylsilylcyanation reaction products.8,10,11

M. E. S. Serra et al. / Tetrahedron: Asymmetry 24 (2013) 315–319
317
Table 2
mobenzaldehyde gave products with slightly lower, albeit identi-
cal, ee.
Enantioselective trimethylsilylcyanation of benzaldehyde with Ti-3a, using different
solventsa
Solvent
Conversionb (%)/eec (%)
3. Conclusion
Dichloromethane
Chloroform
Acetonitrile
Toluene
>99/88 (S)
97/78 (S)
98/77 (S)
98/12 (S)
82/40 (S)
Chiral salens 3a–c and 4a–c were prepared according to previ-
ously established procedures. The Ti(IV) complexes of these ligands
were used in the trimethylsilylcyanation of a series of substituted
benzaldehydes and showed conversions greater than 93% and
selectivities of up to 92% ee, in the presence of 3a and 3b with
two sterically demanding t-butyl substituents on each aldehyde
moiety of the salen ligand. These N-benzyl and N-cyclohexyl deriv-
atives showed greater activity and selectivity than their N-phenyl
counterpart 3c. The differences may be explained by comparing
the geometry of the ligands and their corresponding complexes,
a tendency that has previously been observed and explained when
structurally analogous pyrrolidine diphosphines and diols were
used in other catalytic transformations.
Ethyl ether
a
Reaction on a 2 mmol scale in 5 mL of dry solvent at ꢀ30 °C, 24 h (molar ratio of
Ti/ligand/aldehyde/TMSCN of 1:1.1:5:10).
b
Determined by GC.
Of the silylether, determined by chiral GC.
c
Table 3
Enantioselective trimethylsilylcyanation of various aromatic aldehydes in the pres-
ence of the titanium complex of 3aa
Entry
Aldehyde
Conversionb (%)
eec (%)
1
2
3
4
5
6
7
Benzaldehyde
>99
96
>99
85
94
95
88 (S)
62 (S)
91 (S)
86 (S)
66 (S)
87 (S)
73 (S)
p-Methylbenzaldehyde
p-Chlorobenzaldehyde
p-Bromobenzaldehyde
o-Chlorobenzaldehyde
m-Methylbenzaldehyde
o-Methylbenzaldehyde
4. Experimental
4.1. General procedures
99
All solvents were dried prior to use following standard proce-
dures. Titanium tetraisopropoxide was obtained from Aldrich and
distilled prior to use; trimethylsilylcyanide was obtained from Flu-
ka. Benzaldehyde was distilled prior to use and stored over 4 Å
molecular sieves. Other aldehydes and reagents were used as com-
mercially obtained.
a
Reaction on a 2 mmol scale in 5 mL of dry CH2Cl2 at ꢀ30 °C, 24 h (molar ratio of
Ti/ligand/aldehyde/TMSCN of 1:1.1:5:10).
b
Determined by GC.
Of the silylether, determined by chiral GC.
c
Melting points were determined using a Leitz–Wetzler 799
microscope with a heated plate (values are uncorrected). Optical
rotations were measured with an Optical Activity AA-5 polarime-
ter. NMR spectra were recorded on a Bruker Avance III 400 MHz
spectrometer. TMS was used as the internal standard, chemical
shifts are referred in d and coupling constants, J, in Hz. Infrared
spectra were recorded on a Thermo Scientific Nicolet 6700 FTIR
(solids were processed as KBr pellets). Elemental Analysis was car-
ried out on a Fisons Instruments EA-1108 CHNS-O apparatus.
Sonication was performed in a Bandelin Sonorex RK100H clean-
ing bath with a frequency of 35 Hz and a nominal power of 80/
160 W.
Table 4
Enantioselective trimethylsilylcyanation of various aromatic aldehydes in the pres-
ence of the titanium complex of 3ba
Entry
Aldehyde
Conversionb (%)
ee (%)
1
2
3
4
5
6
7
Benzaldehyde
>99
95
93
88
94
97
97
82 (S)
86 (S)
86 (S)
81 (S)
57 (S)
92 (S)
76 (S)
p-Methylbenzaldehyde
p-Chlorobenzaldehyde
p-Bromobenzaldehyde
o-Chlorobenzaldehyde
m-Methylbenzaldehyde
o-Methylbenzaldehyde
a
Reaction on a 2 mmol scale in 5 mL of dry CH2Cl2 at ꢀ30 °C, 24 h (molar ratio of
Trimethylsilylcyanation reactions were carried out under an in-
ert N2 atmosphere using standard Schlenk-type techniques. Cata-
lytic experiments were repeated in order to confirm the
reproducibility of the results. Enantiomeric excesses were deter-
Ti/ligand/aldehyde/TMSCN of 1:1.1:5:10).
bDetermined by GC.
cOf the silylether, determined by chiral GC.
mined using a chiral
c-cyclodextrin capillary column (FS-Lipo-
dex-E, 25 m, 0.25 i.d.) from Machery-Nagel, on an Agilant 7820A
instrument. The absolute configuration of the major enantiomer
was determined by comparison of the specific rotation with litera-
ture values and by NMR with a derivatizing agent.7,8,28–30 HRMS
spectra were recorded on a Finnigan MAT95 S Instrument.
With our catalytic system, the lowest selectivities (below 76%
ee) were obtained when ortho-substituted substrates were used.
This may be attributed to the steric properties of the substrate.
On the other hand, benzaldehyde as well as meta- and para-substi-
tuted benzaldehydes gave reaction products with higher ee values,
varying from 80% to 92%.
(3R,4R)-N0,N00-Bis[30,50-di-t-butylsalicylidene]-N-benzyl-3,4-dia-
minopyrrolidine 3a and (3R,4R)-N0,N00-bis[20-hydroxynaphthylid-
From the aromatic aldehydes studied, no direct relationship
was observed between the electronic properties of the substrate
and the ee of the reaction products. In the presence of 3a, the high-
est ee was obtained with electron-deficient para-chlorobenzalde-
hyde (91%), while electron-rich para-methylbenzaldehyde gave
the product with the lowest ee. Benzaldehyde, meta-methylbenzal-
dehyde, and para-bromobenzaldehyde gave cyanosilylation prod-
ucts with very similar, intermediate ee values. Conversely, with
3b, the highest ee was observed with electron-rich meta-methyl-
benzaldehyde (92%), with no significant difference being observed
between electron-rich para-methylbenzaldehyde and electron-
deficient para-chlorobenzaldehyde. Benzaldehyde and para-bro-
ene]-N-benzyl-3,4-diaminopyrrolidine
4a
were
prepared
according to our previously described procedure.19,2
4.2. Ligand synthesis
4.2.1. (3R,4R)-N-Cyclohexyl-3,4-diaminopyrrolidine 2b
The compound was prepared from the corresponding diazide,
according to the procedure described in the literature.31 Product
characterization is in agreement with that described in the litera-
ture.32 1H NMR (CDCl3): 1.20–1.28 (m, 5H); 1.62–1.64 (m, 1H);
1.70–1.80 (m, 2H); 1.83–1.96 (m, 2H); 2.38–2.45 (m, 1H); 2.81–

318
M. E. S. Serra et al. / Tetrahedron: Asymmetry 24 (2013) 315–319
2.84 (m, 2H); 3.23 (dd, 2H, J 5.0, 10.6); 3.69 (br s, 4H); 4.11–4.16
(m, 2H).
4.2.7. (3R,4R)-N0,N00-Bis[20-hydroxynaphthylidene]-N-phenyl-
3,4-diaminopyrrolidine 4c
The product was crystallized from ethanol, yield 68%. Mp 225–
227 °C. ½a 2D5
ꢁ
¼ ꢀ620 (c 1.0, CH2Cl2). 1H NMR (CDCl3): 3.75 (dd, 2H, J
4.2.2. (3R,4R)-N-Phenyl-3,4-diaminopyrrolidine 2c
7.4, 9.2); 4.02 (dd, 2H, J 6.8, 9.2); 4.34–4.40 (m, 2H); 7.11 (d, 2H, J
9.0); 7.26–7.35 (m, 2H); 7.40–7.44 (m, 2H); 7.68 (d, 2H, J8.0); 7.78
(d, 2H, J 9.0); 7.94 (d, 2H, J 8.4); 9.20 (s, 2H); 14.79 (br s, 2H). 13C
NMR (CDCl3): 54.01, 73.34, 109.08, 112.65, 117.91, 119.89,
121.62, 124.30, 128.26, 128.84, 130.02, 130.32, 133.58, 136.55,
147.74, 162.67, 167.29. IR (cmꢀ1): 3049, 1628, 1596, 1508, 1477,
1293, 840, 829, 748, 693. HRMS (ESI): calcd for C32H27N3O2 [M]+
485.2103; found [MH]+ 486.2177.
The compound was prepared from the corresponding diazide,
according to the procedure described in the literature.31 Product
characterization is in agreement with that described in the litera-
ture.32 1H NMR (CDCl3): 2.99 (dd, 2H, J 5.4, 8.6); 3.15 (m, 2H);
3.63 (m, 2H); 6.51 (d, 2H, J 8.0); 6.68 (t, 1H, J 7.2); 7.22 (t, 1H, J 8.0).
4.2.3. General procedure for the synthesis of chiral salens
The diamine (1.5 mmol) was dissolved in 5 mL of dry dichloro-
methane in a 25 mL Erlenmeyer flask and the aldehyde (3 mmol)
was added, followed by activated silica (0.900 g). The mixture
was placed in an ultrasound bath until the reaction was complete,
as monitored by TLC (approximately 30 min). The silica was fil-
tered off and washed with dichloromethane. The combined organic
phases were dried over anhydrous sodium sulfate, filtered, and
evaporated. The product was isolated by crystallization from the
appropriate solvent, to give the title compound.
4.3. General procedure for trimethylsilylcyanation
To a solution of the chiral salen ligand (0.44 mmol) in dry
dichloromethane (5 mL), Ti(OiPr)4 (0.40 mmol, 0.12 mL) was added
under an inert atmosphere at room temperature. The resulting
mixture was stirred overnight and subsequently cooled to
ꢀ30 °C. The aldehyde (2 mmol) and trimethylsilylcyanide (4 mmol,
0.54 mL) were added and the reaction stirred for 24 h at ꢀ30 °C.
Next, hexane was added and the precipitated solids were fil-
tered off. Conversions and the ee of the resulting cyanosilylethers
were determined by chiral gc analysis.
4.2.4. (3R,4R)-N0,N00-Bis[30,50-di-t-butylsalicylidene]-N-cyclohexyl-3,
4-diaminopyrrolidine 3b
The product was crystallized from ethanol/water, yield 65%. Mp
Acknowledgments
165–167 °C. ½a 2D5
ꢁ
¼ ꢀ320 (c 1.0, CH2Cl2). 1H NMR (CDCl3): 1.26–
1.34 (m, 23H); 1.47 (s, 18H); 1.61–1.70 (m, 1H); 1.75–1.87 (m,
2H); 1.91–2.04 (m, 2H); 2.18–2.25 (m, 1H); 2.98–3.09 (m, 2H);
3.18–3.29 (m, 2H); 3.95–4.02 (m, 2H); 7.06 (s, 2H); 7.40 (s, 2H);
8.33 (s, 2H); 13.50 (s, 2H). 13C NMR (CDCl3): 25.81, 25.91, 26.90,
30.35, 32.22, 32.36, 35.03, 35.94, 58.76, 64.13, 75.65, 118.51,
127.21, 128.12, 137.52, 141.12, 158.85, 167.54. IR (cmꢀ1): 2954,
1626, 1596, 1469, 1441, 1362, 1251, 1173, 877, 827, 804, 773,
The authors would like to thank the Nuclear Magnetic Reso-
nance Laboratory of the Coimbra Chemistry Centre
(www.nmrccc.uc.pt), University of Coimbra, supported in part by
Grant REEQ/481/QUI/2006 from FCT, POCI-2010 and FEDER, Portu-
gal, for NMR spectra.
645. LC–MS: m/z (ESI+): 616 (M+1)+ Elemental analysis:
References
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The product was crystallized from ethanol/water, yield 64%. Mp
212–214 °C. ½a 2D5
ꢁ
¼ ꢀ350 (c 1.0, CH2Cl2). 1H NMR (CDCl3): 1.27 (s,
18H); 1.44 (s, 18H); 3.65–3.67 (m, 2H); 3.83–3.7 (m, 2H); 4.16–
4.18 (m, 2H); 6.61 (d, 2H, J 8.0); 6.75 (t, 1H, J 7.2); 7.07 (s, 2H);
7.28 (t, 2H, J 8.0); 7.39 (s, 2H); 8.42 (s, 2H); 13.26 (s, 2H). 13C
NMR (CDCl3): 29.46, 31.45, 34.15, 35.06, 53.35, 73.68, 111.68,
116.57, 117.58, 126.50, 127.60, 129.35, 136.73, 140.44, 147.11,
157.95, 167.85. IR (cmꢀ1): 2961, 1629, 1595, 1503, 1477, 1440,
1361, 1250, 804, 773, 750, 729, 693. LC–MS: m/z (ESI+): 610
(M+1)+; Elemental analysis: C40H55N3O2 calcd C, 78.77; H, 9.09;
N, 6.89. Found: C, 78.65; H, 9.09; N, 6.75.
4.2.6. (3R,4R)-N0,N00-Bis[20-hydroxynaphthylidene]-N-cyclohexyl-3,
4-diaminopyrrolidine 4b
The product was crystallized from ethanol, yield 68%. Mp 190–
192 °C. ½a 2D5
ꢁ
¼ ꢀ305 (c 1.0, CH2Cl2). 1H NMR (CDCl3): 1.21–1.39 (m,
5H); 1.60–1.66 (m, 1H); 1.74–1.88 (m, 2H); 1.89–2.02 (m, 2H);
2.23–2.37 (m, 1H); 3.02 (dd, 2H, J 6.0, 9.6); 3.34 (dd, 2H, J 6.8,
9.6); 4.13–4.18 (m, 2H); 7.07 (d, 2H, J 9.2); 7.24–7.28 (m, 2H);
7.39–7.43 (m, 2H); 7.66 (d, 2H, J 8.0); 7.76 (d, 2H, J 9.2); 7.89 (d,
2H, J 8.4); 9.02 (s, 2H); 14.80 (br s, 2H). 13C NMR (CDCl3): 25.61,
25.69, 26.92, 32.17, 58.22, 63.29, 73.26, 108.64, 119.62, 122.95,
124.09, 127.91, 128.84, 130.03, 133.90, 137.00, 160.51, 170.46. IR
(cmꢀ1): 2965, 1626, 1544, 1346, 1314, 863, 834, 753. HRMS
(ESI): calcd for C32H33N3O2 [M]+ 491.2573; found [MH]+ 492.2634.

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