A practical one-pot synthesis of enantiopure unsymmetrical salen ligands

Article abstract of DOI:10.1021/jo052614y

A practical, one-pot synthesis of enantiopure unsymmetrical salen ligands is described, using a 1:1:1 molar ratio of a chiral diamine and two different salicylaldehydes. The new synthetic protocol can be readily performed in good yields (60-85%) on a mult

Full text of DOI:10.1021/jo052614y

A Practical One-Pot Synthesis of Enantiopure
Unsymmetrical Salen Ligands
Michael Holbach,† Xiaolai Zheng,†,‡ Caroline Burd,†
Christopher W. Jones,†,‡ and Marcus Weck*,†
School of Chemistry and Biochemistry and School of Chemical
& Biomolecular Engineering, Georgia Institute of Technology,
Atlanta, Georgia 30332-0400
FIGURE 1. Jacobsen’s salen ligand 1.
SCHEME 1. Retrosynthetic Analysis of Unsymmetrical
Salen Ligands
marcus.weck@chemistry.gatech.edu
ReceiVed December 20, 2005
salicylidene moieties to supports.13 The use of symmetrical
salens would lead to a bigrafted, bridged geometry.14 This often
restricts the accessibility to catalytic centers and, hence, results
in reduced activities and enantioselectivities. In contrast, studies
from several groups have shown that the immobilization of
monofunctionalized unsymmetrical salen ligands can generate
the supported metal complexes in a more flexible fashion, often
resulting in more desirable catalytic properties.7-10
Moreover, the desymmetrization of the salen core would
introduce more structural variations that allows a deliberate
optimization of both steric and electronic properties of the
ligands. Finally, it has been reported that metal complexes
derived from unsymmetrical salen ligands could exhibit better
enantioselectivities for several reactions in comparison with their
symmetrical counterparts.11,12
A practical, one-pot synthesis of enantiopure unsymmetrical
salen ligands is described, using a 1:1:1 molar ratio of a chiral
diamine and two different salicylaldehydes. The new syn-
thetic protocol can be readily performed in good yields (60-
85%) on a multigram scale with good tolerance toward
various functional groups.
The condensation of a diamine and 2 equiv of a salicylalde-
hyde has been generally practiced as the standard method for
the preparation of symmetrical salen ligands in high yields.4,15
However, the synthesis of unsymmetrical salens has proven to
be challenging (Scheme 1).11,16-18 Although the direct conden-
sation of an unprotected diamine with two different salicyl-
Metal complexes of chiral salen ligands (e.g., 1, Figure 1)
are among the most versatile asymmetric catalysts that have
been applied successfully in a wide range of highly reactive
and enatioselective catalytic reactions.1-5 Whereas the vast
majority of preparative and catalytic studies on this family of
compounds has been dedicated to salen ligands with C2
symmetry, recent studies have demonstrated that unsymmetrical
salen ligands, in terms of two distinct substituents on the two
aromatic rings,6 hold important advantages.7-12 For instance,
immobilized salen catalysts are usually prepared by attaching
aldehydes has been reported to work in several cases,19-21
a
number of research groups have reported problems associated
with this methodology.11,22,23 Since the condensations of the two
amino groups often proceed with comparable rates, the reaction
(13) Sherrington, D. C. Catal. Today 2000, 57, 87.
(14) Sellner, H.; Karjalainen, J. K.; Seebach, D. Chem. Eur. J. 2001, 7,
2873.
(15) Larrow, J. F.; Jacobsen, E. N.; Cao, Y.; Hong, Y.; Nie, X.; Zepp,
C. M. J. Org. Chem. 1994, 59, 1939.
(16) Campbell, E. J.; Nguyen, S. T. Tetrahedron Lett. 2001, 42, 1221.
(17) Lopez, J.; Mintz, E. A.; Hsu, F.-L.; Bu, X. R. Tetrahedron:
Asymmetry 1998, 3741.
(18) Xia, Q.-H.; Ge, H.-Q.; Ye, C.-P.; Liu, Z.-M.; Su, K.-X. Chem. ReV.
2005, 105, 1603.
(19) Daly, A. M.; Dalton, C. T.; Renehan, M. F.; Gilheany, D. G.
Tetrahedron Lett. 1999, 40, 3617.
(20) Kureshy, R. I.; Khan, N.-u. H.; Abdi, S. H. R.; Patel, S. T.; Jasra,
R. V. Tetrahedron: Asymmetry 2001, 12, 433.
(21) Kureshy, R. I.; Khan, N.-u. H.; Abdi, S. H. R.; Singh, S.; Ahmad,
I.; Jasra, R. V.; Vyas, A. P. J. Catal. 2004, 224, 229.
(22) Nielsen, M.; Gothelf, K. V. J. Chem. Soc., Perkin Trans. 1 2001,
2440.
† School of Chemistry and Biochemistry.
‡ School of Chemical & Biomolecular Engineering.
(1) Canali, L.; Sherrington, D. C. Chem. Soc. ReV. 1999, 28, 85.
(2) Katsuki, T. AdV. Synth. Catal. 2002, 344, 131.
(3) Larrow, J. F.; Jacobsen, E. N. Top. Organomet. Chem. 2004, 6, 123.
(4) Cozzi, P. G. Chem. Soc. ReV. 2004, 33, 410.
(5) McMarrigle, E. M.; Gilheany, D. G. Chem. ReV. 2005, 105, 1563.
(6) Salen ligands can also be made unsymmetrical by using diamines
without C2 symmetry. For an example, see: Pfeiffer, W.; Christeleit, W.;
Hesse, T.; Pfitzinger, H.; Theilert, H. J. Prakt. Chem. 1938, 150, 261.
(7) Annis, D. A.; Jacobsen, E. N. J. Am. Chem. Soc. 1999, 121, 4147.
(8) Canali, L.; Cowan, E.; Deleuze, H.; Gibson, C. L.; Sherrington, D.
C. J. Chem. Soc., Perkin Trans. 1 2000, 2055.
(9) Breinbauer, R.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2000, 39,
3604.
(10) Zheng, X.; Jones, C. W.; Weck, M. Chem. Eur. J. 2006, 12, 576.
(11) Renehan, M. F.; Schanz, H.-J.; MvGarrigle, E. M.; Dalton, C. T.;
Daly, A. M.; Gilheany, D. G. J. Mol. Catal. A: Chem. 2005, 231, 205.
(12) Kim, G.-J.; Shin, J.-H. Catal. Lett. 1999, 63, 83.
(23) Kureshy, R. I.; Khan, N. H.; Abdi, S. H. R.; Patel, S. T.; Jasra, R.
V. J. Mol. Catal. A: Chem. 2002, 179, 73.
10.1021/jo052614y CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/10/2006
J. Org. Chem. 2006, 71, 2903-2906
2903

SCHEME 2. Synthesis of the Salicylaldehydes 2
SCHEME 3. One-Pot Synthesis of Unsymmetrical Salen
Ligands
of hydroxy, acetylsulfanyl, vinyl, and/or formyl functional
groups. Second, salicylaldehydes 2d and 2e were produced by
nucleophilic substitutions of 3-tert-butyl-5-chloromethylsalicy-
laldehyde8,25 with RONa (R ) -H, -CH2CH2OH) (path B).
Last, the Friedel-Crafts alkylation of 2-tert-butylphenol with
7-methyl-7-octenoic acid, followed by the reduction of the
carboxylic acid with LiAlH4 and the acid-catalyzed formylation
reaction, produced 2f with a long alkyl chain (path C).
At the outset of this project, it became clear that a one-pot
condensation reaction would be superior to the known stepwise
route11,16 for the preparation of enantiopure unsymmetrical salen
ligands (Scheme 3). A one-pot approach would avoid the
isolation step of the monoimine intermediate that is prone to
the undesired disproportionation reaction.
We chose hydrogen chloride as the acid to protect one amine
group of the diamine. The monoammonium salt 3 was prepared
in almost quantitative yield from a 1:1 molar ratio of (R,R)-
diaminocyclohexane and 2.0 M hydrogen chloride in ether.16
The first condensation between 3 and 3,5-di-tert-butylsalicyla-
ldehyde was carried out in a 1:1 (v/v) mixture of anhydrous
methanol and ethanol at ambient temperature. It is crucial to
use activated 4 Å molecular sieves to remove the water that is
formed during the reaction. This significantly reduced the
reaction time to 4 h and, more importantly, depressed the
exchange of the salicylidene moieties. After the first condensa-
tion was complete, a solution of the functionalized salicylal-
dehyde 2 in dichloromethane was added to the reaction system,
followed by the slow addition of an excess of anhydrous
triethylamine as a deprotective base. The TLC analysis and 1H
NMR spectra showed that the second condensation was
completed within 4 h and only traces of symmetrical salens were
detected.
produces, inevitably, a statistical mixture of an aimed unsym-
metrical salen and two undesired symmetrical salens.7,24
A more efficient approach is to protect one amino group of
the employed diamine and to isolate the monoimine intermediate
after the first condensation step. Acids including hydrogen
chloride,16 (+)-tartaric acid,11 and O,O′-dibenzoyl-D-tartaric acid
(DBTA)11 have been applied to generate diamine monoammo-
nium salts that can undergo stepwise condensations. Unfortu-
nately, while this method has been reported with reasonably
good yields for the synthesis of racemic unsymmetrical salens,
poor yields were obtained when enantiopure diamines were used
as a result of the disproportionation of the salicylidene moi-
eties.11 The origin for this difference between enantiopure and
racemic compounds is still not understood. In this context, the
development of a general and reliable preparative protocol for
this important family of ligands, especially in nonracemic forms,
is needed. Herein, we describe such a protocol by introducing
a straightforward one-pot synthesis of enantiopure unsym-
metrical salen ligands that can be performed in high yields on
multigram scales.
Our efforts are focused on the preparation of nonracemic
unsymmetrical salen ligands that can be attached to a variety
of supports such as organic polymers, silica, and metallic
nanoparticles. For this purpose, we have synthesized several
salicylaldehydes functionalized with an immobilizing group
(-OH, -SAc, or -CHdCH2) and either a rigid (phenylacety-
lene or phenylene) or a flexible spacer (alkyl or ethylene glycol)
as building blocks for the synthesis of unsymmetrical salen
ligands. The synthetic pathway towards these building blocks
is outlined in Scheme 2. First, for the syntheses of the rigid
linker-based compounds, we employed Pd-catalyzed Sono-
gashira or Suzuki coupling reactions to yield 2a-c (path A).14
Both coupling reactions showed good tolerance to the presence
The target unsymmetrical salen ligands 4 were isolated in
60-85% yields as light yellow solids by means of column
chromatography on silica gel pretreated with methanol or
(24) Konsler, R. G.; Karl, J.; Jacobsen, E. N. J. Am. Chem. Soc. 1998,
120, 10780.
(25) Minutolo, F.; Pini, D.; Salvadori, P. Tetrahedron Lett. 1996, 37,
3375.
2904 J. Org. Chem., Vol. 71, No. 7, 2006

SCHEME 4. Disproportionation of the Monoimine
Intermediate
purified by column chromatography on silica gel (ethyl acetate/
hexanes ) 1:5) to afford 4a (323 mg, 75%) as a yellow-orange
powder. Rf (SiO2, ethyl acetate/hexanes ) 1:5) ) 0.13. [R]20
:
D
-136 (c 0.5, DCM). 1H NMR (500 MHz, CDCl3): δ ) 1.26 (s, 9
H), 1.44 (s, 9 H), 1.46 (s, 9 H), 1.40-1.53 (m, 2 H), 1.82-1.93
(m, 2 H), 1.66-1.81 (m, 2 H), 1.93-2.05 (m, 2 H), 3.25-3.77
(m, 4H), 6.81 (d, J ) 8.7 Hz), 7.00 (d, J ) 2.5 Hz), 7.19 (d, J )
2.0 Hz, 1 H), 7.35 (d, J ) 2.5 Hz, 1 H), 7.40 (d, J ) 8.7 Hz, 2 H),
7.41 (d, J ) 2.0 Hz, 1 H), 8.22 (s, 1 H), 8.28 (s, 1 H). 13C NMR
(125 MHz, CDCl3): δ ) 24.4, 29.4, 29.6, 31.5, 33.1, 33.2, 35.0,
34.2, 35.1, 72.0, 2.2, 87.2, 88.3, 112.5, 115.7, 115.6, 117.7, 118.4,
126.1, 127.3, 132.7, 133.1, 133.2, 136.7, 137.9, 140.1, 155.7, 158.4,
161.5, 165.2, 166.2. MS (ESI): m/z (Irel) ) 607 (56, [M + 1]+),
291 (84, C25H31N2O2+). HRMS (ESI): calcd for C40H51N2O3 ([M
+ 1]+) 607.3899, found 607.3888. Anal. Calcd for C40H50N2O3
(606.38): C, 79.17; H, 8.30; N, 4.62; O, 7.91. Found: C, 78.61;
H, 8.26; N, 4.63; O, 8.03.
(R,R)-N-(3,5-Di-tert-butylsalicylidene)-N′-[5-(4′-acetylsul-
fanylphenylethynyl)-3-tert-butylsalicylidene]-1,2-cyclohexane-
diamine (4b). (R,R)-1,2-Diaminocyclohexane mono(hydrogen chlo-
ride) (128 mg, 0.85 mmol), 3,5-di-tert-butyl-2-hydroxybenzaldehyde
(199 mg, 0.85 mmol,), and 4 Å molecular sieves (100 mg) were
charged into a 25 mL flask equipped with a magnetic stir bar and
a septum. Anhydrous ethanol (3 mL) and anhydrous methanol (3
mL) were added, and the bright yellow solution was stirred at room
temperature for 4 h. A solution of 3-tert-butyl-5-(4′-acetylsulfa-
nylphenylethynyl)-2-hydroxybenzaldehyde (300 mg, 0.85 mmol)
in anhydrous CH2Cl2 (6 mL) and anhydrous NEt3 (0.27 mL, 1.9
mmol) were added. The red solution was stirred at room temperature
for an additional 4 h. The reaction mixture was filtered through a
short pad of dry silica gel, and the silica gel was flushed with CH2-
Cl2. The solvent was removed under reduced pressure. The residue
was purified by column chromatography on silica gel (ethyl acetate/
hexanes ) 1:10) to afford 4b (339 mg, 60%) as a yellow powder.
Rf (SiO2, ethyl acetate/hexanes ) 1:5) ) 0.47. [R]20D: -144 (c
0.5, DCM). 1H NMR (300 MHz, CDCl3): δ ) 1.24 (s, 9 H), 1.42
(s, 9 H), 1.43 (s, 9 H), 1.43-1.60 (m, 2 H), 1.84-1.94 (m, 2 H),
1.66-1.83 (m, 2 H), 1.94-2.08 (m, 2 H), 2.43 (s, 3 H), 3.24-
3.44 (m, 2 H), 6.96 (d, J ) 2.4 Hz, 1 H), 7.21 (d, J ) 2.0 Hz, 1
H), 7.32 (d, J ) 2.4 Hz, 1 H), 7.37 (d, J ) 8.4 Hz, 2 H), 7.40 (d,
J ) 2.4 Hz, 1 H), 7.51 (d, J ) 8.4 Hz, 1 H), 8.26 (s, 4 H), 8.28 (s,
4H), 13.60 (br s, 1 H), 14.33 (br s, 1H). 13C{1H} NMR (75 MHz,
CDCl3): δ ) 24.4, 29.3, 29.6, 30.4, 31.6, 33.1, 33.3, 34.2, 35.0,
35.1, 72.4, 72.5, 86.7, 91.6, 111.9, 117.8, 118.6, 125.2, 126.0, 127.1,
127.5, 132.1, 134.3, 132.7, 133.5, 136.6, 137.9, 140.2, 158.0, 161.5,
165.0, 166.2, 193.8. MS (ESI): m/z (Irel) ) 665 (59, [M + 1]+),
449 (69, C27H33N2O2S+), 331 (100, C21H35N2O). Anal. Calcd for
C42H52N2O3S (664.37): C, 75.86; H, 7.88; N, 4.21; O, 7.22.
Found: C, 75.79; H, 7.93; N, 4.06; O, 7.19.
methanol/triethylamine. The reaction is very efficient in terms
of time and reproducibility and can easily be scaled up and
carried out on a multigram scale. For instance, we prepared and
isolated 5 g of the styryl-substituted salen 4c within 2 days.
To compare our one-pot protocol to the stepwise synthesis
developed by other groups,11,16 we attempted to synthesize and
separate the monoimine intermediate 5. Unfortunately, we were
unable to obtain 5 in reasonable yields (typical yields were less
than 30%). It was found that a considerable amount of
symmetrical salen 1 was formed during the workup (Scheme
4). A similar phenomenon was observed by Gilheany and co-
workers, who employed (+)-tartaric acid instead of hydrogen
chloride as the protective acid.11 In addition, a 1H NMR
spectroscopic study revealed that 5 was unstable in solution and
disproportionated quantitatively into 1 and 6 in acetone-d6 at
ambient temperature within 24 h. This observation clearly
demonstrates the advantages of the one-pot strategy over the
previously employed stepwise approach for the preparation of
enantiopure unsymmetrical salen ligands.
In conclusion, we have developed a straightforward one-pot
protocol for the synthesis of monofunctionalized enantiopure
unsymmetrical salen ligands, using a 1:1:1 molar ratio of a
hydrogen chloride-protected chiral diamine and two different
salicylaldehydes. This new synthetic method allows for the
synthesis of unsymmetrical salen ligands in good to excellent
yields and can be readily performed on the large scale. While
we have successfully tested this methodology in the synthesis
of monofunctionalized unsymmetrical salens suitable for im-
mobilization, this one-pot methodology can also be applied as
a general and practical method for the preparation of other
unsymmetrical salens.
(R,R)-N-(3,5-Di-tert-butylsalicylidene)-N′-[3-tert-butyl-5-(4′-
vinylbenzene)salicylidene]-1,2-cyclohexanedediamine (4c). A 250
mL flask was charged with (1R,2R)-1,2-diaminocyclohexane mono-
hydrochloride salt (1.51 g, 10 mmol), activated 4 Å molecular sieves
(4.0 g), anhydrous methanol (40 mL), and anhydrous ethanol (40
mL). 3,5-Di-tert-butyl-2-hydroxybenzaldehyde (2.34 g, 10 mmol)
was added in one portion, and the reaction mixture was stirred at
room temperature for 4 h. After complete consumption of the
aldehyde as monitored by TLC, a solution of 3-tert-butyl-2-hydroxy-
5-(4′-vinylphenyl)benzaldehyde (2.74 g, 10 mmol) in dichlo-
romethane (80 mL) was added to the reaction system, followed by
the slow addition of triethylamine (2.8 mL, 20 mmol). The reaction
mixture was stirred at room temperature for an additional 4 h
followed by the removal of the solvents. The residue was dissolved
in dichloromethane (100 mL), washed with aqueous hydrochloric
acid (1 M, 50 mL) and water (2 × 50 mL), and dried with
magnesium sulfate. Flash chromatography of the crude product with
(ether/hexanes ) 1:50) afforded 4c (5.05 g, 85%) as a yellow solid.
Experimental Section
(R,R)-N-(3,5-Di-tert-butylsalicylidene)-N′-[3-tert-butyl-5-(4′-
hydroxyphenylethynyl)salicylidene]-1,2-cyclohexanediamine (4a).
(R,R)-1,2-Diaminocyclohexane mono(hydrogen chloride) (108 mg,
0.72 mmol), 3,5-di-tert-butyl-2-hydroxybenzaldehyde (168 mg, 0.72
mmol), and 4 Å molecular sieves (100 mg) were charged into a 25
mL flask equipped with a magnetic stir bar and a septum.
Anhydrous ethanol (3 mL) and anhydrous methanol (3 mL) were
added, and the bright yellow solution was stirred at room temper-
ature for 4 h. A solution of 5-(4′-hydroxyphenylethynyl)-3-tert-
butyl-2-hydroxybenzaldehyde (211 mg, 0.72 mmol) in anhydrous
CH2Cl2 (6 mL) and anhydrous NEt3 (0.20 mL, 1.44 mmol) was
added. The red solution was stirred at room temperature for an
additional 4 h. The reaction mixture was filtered through a short
pad of dry silica gel, and the silica gel was flushed with CH2Cl2.
The solvent was removed under reduced pressure. The residue was
1
Mp: 177-178 °C. [R]20D: -156 (c 0.5, DCM). H NMR (400
J. Org. Chem, Vol. 71, No. 7, 2006 2905

MHz, CDCl3): δ ) 1.22 (s, 9 H), 1.42 (s, 9 H), 1.44-1.51 (m, 2
H), 1.46 (s, 9 H), 1.70-1.84 (m, 2 H), 1.88-1.91 (m, 2 H), 1.97-
2.02 (m, 2 H), 3.30-3.38 (m, 2 H), 5.25 (d, J ) 11.0 Hz, 1 H),
5.77 (d, J ) 17.6 Hz, 1 H), 6.74 (dd, J ) 11.0, 17.6 Hz, 1 H), 6.97
(d, J ) 2.5 Hz, 1 H), 7.21 (d, J ) 2.5 Hz, 1 H), 7.31 (d, J ) 2.5
Hz, 1 H), 7.40-7.45 (m, 4 H), 7.49 (d, J ) 2.5 Hz, 1 H), 8.30 (s,
1 H), 8.35 (s, 1 H), 13.69 (s, br, 1 H), 14.01 (s, br, 1 H). 13C{1H}
NMR (100 MHz, CDCl3): δ ) 24.5, 24.6, 29.5, 29.6, 31.6, 33.3,
33.4, 34.2, 35.1, 35.2, 72.6, 113.6, 118.0, 119.0, 126.2, 126.7, 126.9,
127.1, 128.2, 128.3, 130.5, 136.0, 136.6, 136.7, 137.8, 140.2, 140.7,
158.2, 160.2, 165.8, 166.2. IR: ν ) 3082, 2999, 2952, 2933, 2860,
1628, 1467, 1440, 1390, 1271, 1252, 1171, 840 cm-1. UV-vis
(THF): λ ) 262, 300, 340 nm. MS (FAB): m/z (Irel) ) 592 (100,
M+). Anal. Calcd for C40H52N2O2 (592.85): C, 81.04; H, 8.84; N,
4.73. Found: C, 81.06; H, 8.95; N, 4.72.
(R,R)-N-(3,5-Di-tert-butylsalicylidene)-N′-[3-tert-butyl-5-(hy-
droxymethyl)salicylidene]-1,2-cyclohexanedediamine (4d). A 100
mL flask was charged with (1R,2R)-1,2-diaminocyclohexane mono-
hydrochloride salt (151 mg, 1.0 mmol), activated 4 Å molecular
sieves (200 mg), and anhydrous methanol (10 mL). 3,5-Di-tert-
butyl-2-hydroxybenzaldehyde (234 mg, 1.0 mmol) was added in
one portion, and the reaction mixture was stirred at room temper-
ature for 4 h. A solution of 3-tert-butyl-2-hydroxy-5-(hydroxym-
ethyl)benzaldehyde (208 mg, 1.0 mmol) in dichloromethane (10
mL) was added to the reaction mixture, followed by the slow
addition of triethylamine (0.27 mL, 2.0 mmol). The reaction mixture
was stirred at room temperature for an additional 4 h followed by
the removal of the solvents. The residue was dissolved in di-
chloromethane (20 mL), washed with water (2 × 20 mL), and dried
with magnesium sulfate. Flash chromatography of the crude product
on silica gel (ether/hexanes ) 1:4 to 1:1) afforded 4d (0.39 g, 75%)
as a light yellow solid. [R]20D: -318 (c 0.5, DCM). 1H NMR (400
MHz, CDCl3): δ ) 1.23 (s, 9 H), 1.41 (s, 9 H), 1.42 (s, 9 H),
1.43-1.51 (m, 2 H), 1.70-1.80 (m, 2 H), 1.88-1.92 (m, 2 H),
1.96-2.02 (m, 2 H), 3.29-3.38 (m, 2 H), 4.52 (s, 2 H), 6.96 (d, J
) 2.2 Hz, 1 H), 7.01 (d, J ) 2.0 Hz, 1 H), 7.25 (d, J ) 2.0 Hz, 1
H), 7.31 (d, J ) 2.4 Hz, 1 H), 8.28 (s, 1 H), 8.29 (s, 1 H), 13.68
(s br, 1 H), 13.97 (s br, 1 H). 13C{1H} NMR (100 MHz, CDCl3):
δ ) 24.5, 24.6, 29.5, 29.6, 31.6, 33.3, 33.4, 34.2, 35.0, 35.2, 65.6,
72.60, 72.61, 118.0, 118.5, 126.2, 127.0, 129.0 (2 overlapping lines),
130.1, 136.6, 137.7, 140.1, 158.1, 160.3, 165.5, 166.1. MS (EI):
m/z (Irel) ) 520 (100, M+). Anal. Calcd for C33H48N2O3: C, 76.11;
H, 9.29; N, 5.38. Found: C, 76.19; H, 9.51; N, 5.07.
9 H), 1.42 (s, 9 H), 1.43-1.55 (m, 2 H), 1.83-1.92 (m, 2 H), 1.61-
1.81 (m, 2 H), 1.93-2.08 (m, 2 H), 2.01 (br s), 3.28-3.38 (m, 2
H), 3.54 (m, 2 H), 3.72 (br s, 2 H), 4.40 (s, 2 H), 6.98 (d, J ) 2.3
Hz, 1 H), 7.01 (d, J ) 1.6 Hz, 1 H), 7.22 (d, J ) 1.6 Hz, 1 H),
7.31 (d, J ) 2.3 Hz, 1 H), 8.29 (s, 1 H), 8.30 (s, 1 H), 13.70, (br
s, 1 H), 14.00 (br s,1 H). 13C{1H} NMR (125 MHz, CDCl3): δ )
24.3, 29.4, 29.5, 31.5, 33.3, 34.2, 34.9, 35.1, 63.0, 71.2, 72.5, 72.6,
73.4, 117.9, 118.4, 126.1, 126.8, 126.9, 129.6, 129.8, 136.5, 137.4,
140.0, 158.1, 160.3, 165.3, 166.0. MS (ESI): m/z (Irel) ) 565 (13,
[M + 1]+), 349 (48, C20H33N2O3+), 331 (100, C21H35N2O+). HRMS
(ESI): calcd for C35H53N2O4 ([M + 1]+) 565.4005, found 565.4001.
Anal. Calcd for C35H52N2O4 (564.39): C, 74.43; H, 9.28; N, 4.96.
Found: C, 74.38; H, 9.30; N, 4.85.
(R,R)-N-(3,5-Di-tert-butylsalicylidene)-N′-[3-tert-butyl-5-(7′-
hydroxy-1′,1′-dimethylheptyl)salicylidene]-1,2-cyclohexanededi-
amine (4f). (R,R)-1,2-Diaminocyclohexane mono(hydrogen chlo-
ride) (59 mg, 0.39 mmol), 3,5-di-tert-butyl-2-hydroxybenzaldehyde
(92 mg, 0.39 mmol), and 4 Å molecular sieves (200 mg) were
charged into a 25 mL flask equipped with a magnetic stir bar and
a septum. Anhydrous methanol (5 mL) was added, and the bright
yellow solution was stirred at room temperature for 4 h. A solution
of 3-tert-butyl-2-hydroxy-5-(7′-hydroxy-1′,1′-dimethylheptyl)ben-
zaldehyde (125 mg, 0.39 mmol) in anhydrous CH2Cl2 (10 mL) and
anhydrous NEt3 (0.15 mL, 0.90 mmol) were added. The red solution
was stirred at room temperature for an additional 4 h. The reaction
mixture was filtered through a short pad of dry silica gel, and the
silica gel was flushed with ethyl acetate. The solvent was removed
under reduced pressure. The residue was purified by column
chromatography on silica gel (ethyl acetate/hexanes ) 1:3) to afford
4f (208 mg, 84%) as a bright yellow powder. [R]20D: -200 (c 0.5,
1
DCM). H NMR (300 MHz, CDCl3): δ )1.00-1.15 (m, 2 H),
1.16-1.31 (m, 2 H), 1.25 (s, 6 H), 1.23 (s, 9 H), 1.28 (s, 9 H),
1.42 (s, 9 H), 1.43-1.59 (m, 6 H), 1.70-1.80 (m, 2 H), 1.88-
1.92 (m, 2 H), 1.93-2.08 (m, 4 H), 2.01 (s, 1H), 3.29-3.38 (m, 2
H), 3.54 (t, 2 H), 6.98 (d, J ) 2.2 Hz, 1 H), 7.01 (d, J ) 1.8 Hz,
1 H), 7.25 (d, J ) 2.0 Hz, 1 H), 7.31 (d, J ) 2.4 Hz, 1 H), 8.29 (s,
1 H), 8.31 (s, 1 H), 13.71 (s br, 2 H). 13C{1H} NMR (125 MHz,
CDCl3): δ ) 24.6, 24.8, 25.7, 29.1, 29.2, 29.3, 29.6, 29.7, 30.3,
31.6, 31.7, 33.0, 33.4, 33.5, 33.6, 34.3, 35.2, 37.2, 44.6, 63.2,72.6,
76.8, 77.3, 77.7, 118.1, 126.2, 126.9, 127.0, 136.5, 136.6, 138.7,
140.1, 158.1, 158.2, 165.9, 166.0, 166.1, 220.2. MS (ESI): m/z (Irel)
) 635.6 (13, [M + 1]+). HRMS (ESI): calcd for C41H64N2O3 ([M
+ 1]+) 633.4996, found 633.4995. Anal. Calcd for C41H64N2O3
(633.49): C, 77.80; H, 10.19; N, 4.43. Found: C, 77.88; H, 10.20;
N, 4.39.
(R,R)-N-(3,5-Di-tert-butylsalicylidene)-N′-[3-tert-butyl-5-(2′-
hydroxyethoxymethyl)salicylidene]-1,2-cyclohexanediamine (4e).
(R,R)-1,2-Diaminocyclohexane mono(hydrogen chloride) (276 mg,
1.83 mmol), 3,5-di-tert-butyl-2-hydroxybenzaldehyde (460 mg, 1.83
mmol), and 4 Å molecular sieves (200 mg) were charged into a 50
mL flask equipped with a magnetic stir bar and a septum.
Anhydrous ethanol (5 mL) and anhydrous methanol (5 mL) were
added, and the bright yellow solution was stirred at room temper-
ature for 4 h. A solution of 3-tert-butyl-2-hydroxy-5-(2′-hydroxy-
ethoxymethyl)benzaldehyde (460 mg, 1.83 mmol) in anhydrous
CH2Cl2 (10 mL) and anhydrous NEt3 (0.51 mL, 3.66 mmol) were
added. The red solution was stirred at room temperature for an
additional 4 h. The reaction mixture was filtered through a short
pad of dry silica gel, and the silica gel was flushed with CH2Cl2.
The solvent was removed under reduced pressure. The residue was
purified by column chromatography on silica gel (ethyl acetate/
hexanes ) 1:3) to afford 4e (725 mg, 70%) as a yellow powder. Rf
(SiO2, ethyl acetate/hexanes ) 1:3) ) 0.23. [R]20D: -262 (c 0.5,
Acknowledgment. This work was supported by the Depart-
ment of Energy (Grant No. DE-FG02-02ER15459). M.H. thanks
the Deutsche Forschungsgemeinschaft for a postdoctoral fel-
lowship. C.W.J. thanks DuPont for a Young Professor Award
and GT for the J. Carl & Sheila Pirkle Faculty Fellowship. M.W.
gratefully acknowledges a 3M Untenured Faculty Award, a
DuPont Young Professor Award, an Alfred P. Sloan Fellowship,
a Camille Dreyfus Teacher-Scholar Award, and a Blanchard
Assistant Professorship.
Supporting Information Available: Detailed experimental
procedures and characterization data are presented. This material
is available free of charge via the Internet at http://pubs.acs.org.
1
DCM). H NMR (500 MHz, CDCl3): δ ) 1.24 (s, 9 H), 1.41 (s,
JO052614Y
2906 J. Org. Chem., Vol. 71, No. 7, 2006