Water enables transimination between hindered ketimines and β-aminoalcohols and selective protection of a vicinal diamine backbone

Article abstract of DOI:10.1016/j.tet.2010.06.013

Water mediates synthesis of novel hindered Schiff bases via transmination protocol. The feature of the procedure is that it allows both tuning of steric and electronic factors of the substituents and mono-imination of vicinal diamines, which potentially facilitates one-pot approach to unsymmetrical metal ligands. Water mediates access to hindered ketimine ligands incorporating one or two benzylidene moieties and 1,2-diaminocyclohexane.

Full text of DOI:10.1016/j.tet.2010.06.013

Tetrahedron 66 (2010) 7028e7034
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journal homepage: www.elsevier.com/locate/tet
Water enables transimination between hindered ketimines and
and selective protection of a vicinal diamine backbone
b-aminoalcohols
*
Hanane Bafqiren, Jamal Jamal Eddine
Département de Chimie, Université Hassan II Ain-Chock, Faculté des Sciences, B.P.5366 Maârif, Casablanca, Morocco
a r t i c l e i n f o
a b s t r a c t
Article history:
Water mediates synthesis of novel hindered Schiff bases via transmination protocol. The feature of
the procedure is that it allows both tuning of steric and electronic factors of the substituents and
mono-imination of vicinal diamines, which potentially facilitates one-pot approach to unsymmetrical
metal ligands.
Received 27 January 2010
Received in revised form 18 May 2010
Accepted 7 June 2010
Available online 17 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Transmination
Diamine selective protection
Unsymmetrical bis-imines
Chiral metal ligands
Atropisomerism
1. Introduction
salen-type Schiff base ligands have also been synthesized via one-
pot or stepwise approaches12 and used in aerobic oxidation of
Asymmetric aldimine ligands have played a significant role in
the development of novel transition-metal catalyzed asymmetric
reactions. The feature of these ligands is their ease of preparation.
There are a variety of reactions in which good enantioselectivity has
been achieved with transition-metal complexes of chiral aldimine
ligands. Aldimine derivatives of simple chiral aminoalcohols and
N-alkylamines have been demonstrated to be effective in asym-
metric cyclopropanation,1 Michael addition,2 Mannich-type,3
nitroaldol4 desymmetrisation,5 and kinetic resolution6 reactions,
to name a few. Transition-metal complexes of salen ligand have
shown, among many other applications, high enantioselctivities in
oxidation catalysis,7 Diels/Alder cyclisation,8,9 oxidative coupling of
binaphthols10 and have been used as chiral phase-transfer catalysts
cyclohexene.13
However, the number of investigation into the catalytic
properties of the more stable chiral ketimines is relatively small
probably due to preparation difficulties. Oguni et al.14 have first
reported hindered chiral ketimine ligands in 1995, transition-metal
complexes of which have shown usefulness as catalysts for the
enantioselective diketene ring opening reactions. We recently
reported15 the synthesis and structure determination of sterically
crowded chiral biaryl ketimines 2 by means of transimination
protocol between a methylenimine 1 and a primary amine16
(Scheme 1). The atropisomerism due to restricted rotation about
the CeC bond adjacent to C]N was evidenced by high field NMR
and X-ray analysis. In some cases, physical separation of stereo-
chemically stable ketimine atropisomers was accomplished.
for the alkylation of a
-alkyl imino esters.11 Unsymmetrical chiral
Scheme 1.
The feasibility of the transimination process seemed of special
interest to us in view of the ready availability of a variety of chiral
primary amines. Nevertheless, the process showed limitations
when electronic interactions and steric hindrance are combined.
* Corresponding author. Tel.: þ212 665101701; fax: þ212 522230674; e-mail
address: e.j.jamal@fsac.ac.ma (J.J. Eddine).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.06.013

H. Bafqiren, J.J. Eddine / Tetrahedron 66 (2010) 7028e7034
7029
transfer agents17 with easily tunable steric and electronic proper-
ties, we report herein the rather unusual usefulness of water/
ethanol solvent-system in the transimination protocol for the
preparation of some challenging hindered ketimines and selective
protection of vicinal diamines.
Table 1
Synthesis of hindered methylenimines 1
Entry
AreBr
Ar0eCN
Imine 1
Yield (%)
1
90
2. Results and discussion
When 1-naphthylmethylenimine derivative 1a (Table 1) was
heated to reflux with (1S,2S)-2-amino-1-phenylpropane-1,3-diol in
chlorinated or high boiling point solvents, no transimination
occurred. Similarly, when the reaction was carried out in a protic
solvent such as ethanol, only starting materials were recovered.
Surprisingly, the addition of water to the ethanolic solutionwas found
to be beneficial to transimination and produced imine 2a with good
yield (Table 2, entry 1) together with small amounts of the corre-
spondingketonedueto hydrolysis of imine 1a. The generallyaccepted
mechanism of transimination is via a nucleophilic attack into the
imino C]N bond by the primary amine as the first step, followed by
the liberation of ammonia. The nucleophilic addition onto the imino
bond becomes difficult when intramolecular dipole/dipole in-
teraction is possible or/and when steric hindrance is important. We
therefore reasoned that in the presence of water, solvatation of the
starting methylenimine competes with the intramolecular hydrogen
bonding and subsequently facilitate condensation of the primary
amine. The steric hindrance brought by the naphthyl group stabilizes
the imines toward hydrolysis in aqueous media.
2
3
56
60
The 13C NMR of a deuteriochloroform solution of pure 2a
4
70
showed two sets of imino 13C]N signals at
d(176.8, 177.2 ppm) and
171.3 ppm with the proportion largely in favor of the two downfield
shifted signals (ca. 95:5). The important chemical shift difference
indicated the presence of both anti and syn-geometric configura-
tions.18 Thus, high field NMR spectroscopy (1H, 13C, HMQC, COSY,
and NOESY) outlined an intense NOESYeffect between the naphthyl
group and the chiral hydroxyalkyl chain protons, which clearly
evidenced the anti-geometric configuration for the major stereo-
Similarly, the corresponding hindered ketones fail to react with
primary amines under catalytic acidic conditions with azeotropic
removal of water.
In continuing our endeavor to develop new multidentate imine
ligands and sterically hindered iminium salts as chiral phase-
isomer. Therefore, the pair of 13C]N signals at
indicated the presence of two inseparable conformers having the
d(176.8, 177.2 ppm)
Table 2
Preparation of hindered ketimines 2 by means of transimination between methylenimines 1 and chiral primary amines in ethanol/water mixture
Entry
Imine 1
R*NH2
Time (h)
Imine 2
Yield (%)
1
1a
24
60
41a
65b
2
1a
24
3
1a
24
10
(continued on next page)

7030
H. Bafqiren, J.J. Eddine / Tetrahedron 66 (2010) 7028e7034
Table 2 (continued)
Entry
Imine 1
R*NH2
Time (h)
Imine 2
Yield (%)
4
1b
24
40c
5
6
7
1c
1c
1d
2
50d
10
9
2
24
8
1d
24
60
9
1a
2e
18
68
10
1b
2e
18
75
11
1d
2d
18
NR
NR¼No reaction.
a
Methylenimine 1a: 1,2-DAC-Tr, 2:1 M ratio.
Methylenimine 1a: 1,2-DAC-Tr, 1:1 M ratio.
Substantial amounts of hydrolysis of 1b were observed.
b
c
d
The medium became dark after 2 h heating.

H. Bafqiren, J.J. Eddine / Tetrahedron 66 (2010) 7028e7034
7031
same geometrical configuration further evidenced by the low
chemical shift difference (Fig. 1).
methylenimine 1a. Excessive heating and prolonged reaction time
proved unsuccessful. The yield and stability of mono-imines such as
2b makes possible a one-pot condensation procedure leading to
unsymmetrical metal ligands. Classical homo- and hetero-nuclear
experiments were undertaken in order to assign the naphthyl and
phenol protons for mono-imine 2b, which have been found to
appear as two sets of well resolved multiplets at
and
(6.33e7.22 ppm), respectively. Moreover, 13C NMR showed
two 13C]N signals at
(174.1 and 174.8 ppm) revealing detection of
d(7.23e8.06 ppm)
d
d
two stable conformers of mono-imine 2b (9:1) on the NMR time
scale. Of particular importance, the intense NOESY correlations
observed between the naphthyl group protons H2 and H8 and the
a-amino proton H16 and the a-imino proton H15, respectively. This
not only evidenced anti-geometric configuration for imine 2b, but
also more information about the naphthyl group orientation of the
major conformer (Fig. 2, a).
In the same manner, the NOESY experiment allowed us to gain
insight into the orientation of the aromatic groups of pure bis-
imine 2c since only two clear sets of correlations were observed
between the naphthyl groups and the chiral auxiliary protons. This
orientation is in favor of anti anti-geometric configurations.
In order to make feasible the isolation of stable hindered
ketimine conformers, we used the more sterically crowded meth-
ylenimine 1b, which was isolated with a moderate yield. Tran-
simination with 1,2-DAC-Tr under the same conditions afforded
exclusively mono-imine 2d (Table 2, entry 4) isolated as a viscous
yellow oil after chromatographic purification. As for mono-imine
Figure 1. (a) 13C NMR and (b) expansion for pure imine 2a showing the presence of
anti and syn stereoisomers and two conformers of the anti-geometric configuration.
2b, two imino 13C]N signals were observed at
d(174.5 and
173.9 ppm) evidencing the presence of more than one stereoiso-
mer. TLC showed two spots with a different intensity, separation of
which could not be achieved because of the very small difference in
Rf. Again, 2D NMR experiments revealed absence of correlations
between the phenol moiety and the chiral auxiliary for both iso-
mers evidencing anti-geometric configuration and atropisomeric
nature of the two stereoisomers (Fig. 2, b).
On the other hand, the 2-naphtylmethylenimino derivative 1c
was found to be more reactive toward 1,2-DAC-Tr and afforded
about 50% of anti mono-imine 2e (Fig. 3, a) and small amounts of
bis-imine 2f (Table 2, entries 5 and 6). Curiously, after two hours
heating, the medium started to become darker with formation of
an unidentified complex mixture of products. However, this
phenomenon did not occur when methylenimine 1d was sub-
jected to transimination with 1,2-DAC-Tr under identical condi-
tions (Table 2, entries 7 and 8). In opposition to all other
methylenimines, 1d double transiminated readily and in a better
yield (Table 2, entry 8).
We demonstrated earlier that the steric environment imposed
by the aromatic groups in similar hindered ketimines results in
slow rotation of the substituents about the CeC bond adjacent to
the imino C]N bond, which allows ambient temperature detection
of atropisomeric structures.15
Interestingly, heating a solution of (R,R)-1,2-diaminocyclohexane-
(þ)-tartrate salt (1,2-DAC-Tr) and 2 M equiv of imine 1a under basic
conditions in ethanol/water (2/1, v/v) yielded mono-imine 2b and
bis-imine 2c in the ratio of 4:1 (Table 2, entries 2 and 3). Both imines
were purified by column chromatography and were isolated as oils.
More importantly, when a 1:1 M ratio of methylenimine 1a to
1,2-DAC-Tr was used, the yield of mono-imine 2b increased to 65%.
The latter is stable and can be stored at room temperature without
decomposition. It is worth emphasizing that the yield of the sym-
metrical bis-imine 2c, which was the initially desired target com-
pound, could not be optimized via a two-pot approach by means of
a second transimination process between the mono-imine 2b and
Figure 2. NOESY chart expansions for conformers of mono-imines 2b (a) and 2d (b) underlying correlations between the cyclohexyl moiety and the naphthyl group protons.

7032
H. Bafqiren, J.J. Eddine / Tetrahedron 66 (2010) 7028e7034
Figure 3. (a) NOESY spectrum of mono-imine 2e; (b) 1H NMR of the unsymmetrical bis-imine 2i.
It is worth mentioning that bis-imine 2h was isolated as the anti
Elmer 240 polarimeter using the sodium D line and concentra-
tions are given in g/100 mL. IR spectra were recorded on a Perkin/
Elmer 16 PC FT instrument (in cmꢁ1). 1H and 13C NMR spectra were
recorded on Bruker AC 300 spectrometer at 300 and 75 MHz, re-
spectively. Chemical shifts are in parts per million referenced to
TMS in CDCl3. Mass spectra were determined on Thermo Finnigan
SSQ 7000 GC/MS. High resolution mass spectra (HRMS) were
recorded on a Micromass Zab Spectrometer at the University of
Rennes (France). Elemental analyses were performed on Thermo
Finnigan Elementary Analyser Flash EA 1112 at the UATRS, Rabat
(Morocco). Analytical thin layer chromatography (TLC) was per-
formed on Merck Kieselgel 60 F254 glass plates (0.25 mm) and
compounds were visualized by UV light (254 nm) or ninhydrine
acid/ethanol (22.1 ge180 mL) spray. Column chromatography was
carried out on Merck Kieselgel. Chemicals were purchased from
either Sigma/Aldrich or Fluka and used as received. Solvents were
distilled according to known procedures.
anti stereoisomer judging from the intense NOESY effect observed
between the naphthyl group and the cyclohexyl moiety protons.
Finally, unsymmetrical bis-imines 2i and 2j could be prepared
with good yield following the same protocol using mono-imine 2e
as the starting primary amine and either methylenimine 1a or 1b
(Table 2, entries 9 and 10). Surprisingly, mono-imine 2e remained
chemically and stereochemically stable under these conditions,
which allowed recovering the amount that did not react after 18 h.
In the same way, structural information on the stereoisomeric
nature of bis-imines 2i and 2j came from the NMR investigation. A
particular point is the chemical shift observed for the two stereo-
genic centers protons and the hydroxy groups, which appeared for
bis-imine 2i as two pairs of singlets at
(12.34, 12.05 ppm), respectively (Fig. 3, b). The same chiral centers
protons appeared at (4.22, and 3.97 ppm) for bis-imine 2j. This
d(4.23, 3.61 ppm) and d
d
helped to simultaneously assign each of these two protons and
anti-geometric configuration for the newly created imino bonds.
However, the more hindered mono-imine 2d failed to transiminate
with methylenimine 1d under a variety of reaction conditions
(Table 2, entry 11).
4.2. General procedure for the preparation of compounds
1aed
In a 25-mL two-necked flask equipped with a dropping funnel
and reflux condenser fitted with a calcium chloride drying tube,
were introduced Magnesium turnings (120 mg, 4.94 mmol), anhy-
drous THF (2 mL), and 100 mg of either 1-bromonaphthalen (for the
preparation of imines 1a and b) or 2-bromonaphthalen (for the
preparation of imines 1c and d). When the reaction started,
a moderate reflux began which was maintained by slow addition
under vigorous stirring of a solution of the remaining amounts of
the aryl bromide (total of 1 g, 4.829 mmol) in THF (4 mL). The
resulting brown solution was heated under reflux for 2 h after
which time it is cooled and a solution of either 2-cyanophenol (for
the preparation of imines 1a and 1c) (287 mg, 2.41 mmol, 0.5 equiv)
or 2-methoxybenzonirile (for the preparation of imines 1b and 1d)
(578.5 mg, 4.34 mmol, 0.9 equiv) in THF (4 mL) was added. The dark
solution was then heated to reflux for 4 h. The stirred mixture was
cooled to room temperature before addition of absolute methanol
(1.5 mL) and the stirring continued for 30 min. The solvents were
removed in vacuo and the residual brown oil taken in ethyl acetate
(20 mL). The solid, which separated was collected by filtration and
the filtrate concentrated to dryness in vacuo. Column chromatog-
raphy on silica gel afforded pure methylenimines 1aed.
3. Conclusion
In conclusion, water/ethanol solvent-system was found to
facilitate the synthesis of hindered schiff bases through a tran-
simination process between hindered methylenimines and primary
amines. In all cases, NMR spectroscopy evidenced the presence of
an inseparable conformers possessing the same ketimine geo-
metric configuration due to hindered rotation of the aryl groups
about the CeC bond adjacent to C]N.
The transimination reaction between sterically crowded meth-
ylenimines and (R,R)-1,2-diaminocyclohexane under the optimized
reaction conditions led to selective mono-imination with moderate
to good yields. This procedure offers flexibility of substituents steric
and electronic tuning, which opens up new perspectives in the
rational design and one-pot approach to the synthesis of
unsymmetrical metal ligands.
4. Experimental section
4.1. General
Uncorrected melting points were determined on a Büchi 510
instrument. Optical rotations were determined at 25 ꢀC on Perkin/
4.2.1. 1-(1-Naphtyl)-1-(2-hydroxyphenyl)methylenimine (1a). Or-
ange oil, (536 mg, 90%), Rf¼0.21 (3:7 EtOAc/hexane), IR (KBr) nmax
:

H. Bafqiren, J.J. Eddine / Tetrahedron 66 (2010) 7028e7034
7033
3548, 1624 cmꢁ1
;
1H NMR
d
¼14.63 (s, 1H), 9.44 (s, 1H), 7.84e6.99
(m, 0.5H), 2.03e1.71 (m, 2H), 1.7e1.29 (m, 4H), 1.28e1.20 (m, 2H);
13C NMR
(m, 8H), 6.83 (m, 1H), 6.8 (m, 1H), 6.53 (m, 1H); 13C NMR
d¼181.7,
d¼174.8, 174.1, 162.7, 162.5, 133.3, 132.6, 132.5, 131.8, 131.7,
163.6,137.0,134.0,133.8,132.6,130.4,130.0,128.8,127.4,126.9,125.7,
125.5, 125.2, 119.8, 118.6, 118.3; m/z (EI) 247 (Mþ), 230, 217, 128, 91,
69; HRMS (ES): Mþ, found 247.0989. C17H13NO requires 247.0997.
131.4, 131.3, 130.5, 130.2, 129.4, 129.3, 129.0, 128.6, 128.5, 128.2,
127.3, 126.8, 126.7, 126.4, 126.3, 125.6, 125.4, 125.3, 125.0, 120.2,
120.1, 118.3, 117.9, 117.8, 117.7, 65.4, 55.8, 55.6, 33.4, 32.8, 32.3, 31.4,
29.7, 24.7, 24.2, 24.1, 23.7; m/z (EI) 344 (Mþ), 308, 248, 154; HRMS
(ES): Mþ, found 344.1887. C23H24N2O requires 344.1889.
4.2.2. 1-(1-Naphtyl)-1-(2-methoxyphenyl)methylenimine (1b). Vis-
cous yellow oil, (634 mg, 56%), Rf¼0.10 (2:8 EtOAc/hexane), IR (KBr)
nmax: 2964, 1623 cmꢁ1; 1H NMR
d¼8.0e7.85 (m, 3H), 7.61e7.38 (m,
4.3.3. (1R,2R,anti,anti)-1,2-N,N0-Bis(2-hydroxyphenyl-1-naph-
thylidene)cyclohexane (2c). Yellow oil, (57 mg, 10%), Rf¼0.45 (2:8
6H), 7.23e7.19 (m, 1H), 7.07e6.94 (m, 1H), 6.91e6.85 (m, 1H), 3.80
(s, 3H); 13C NMR
d¼176.2, 158.1, 132.2, 131.6, 131.1, 130.9, 130.8,
EtOAc/hexane), [
a
]
þ14.5 (c 0.8, CHCl3), IR (KBr) nmax: 3445,
¼14.61 (br, 2H), 8.13e8.04 (m, 2H), 8.02e7.96
D
129.7, 129.2, 127.2, 126.2, 126.1, 125.9, 25.7, 124.9, 120.6, 120.5, 55.7;
m/z (EI) 261 (Mþ), 246; HRMS (ES): Mþ, found 261.1149. C18H15NO
requires 261.1154.
1605 cmꢁ1; 1H NMR
d
(m, 2H), 7.93e7.68 (m, 2H), 7.64e7.53 (m, 2H), 7.5e7.39 (m, 3H),
7.38e7.32 (m, 3H), 7.31e7.25 (m, 2H), 7.24e6.73 (m, 3H), 6.65e6.46
(m, 3H), 3.6e3.4 (m, 2H), 1.92e1.81 (m, 1H), 1.70e1.50 (m, 3H),
4.2.3. 1-(2-Naphtyl)-1-(2-hydroxyphenyl)methylenimine (1c). Yel-
1.46e1.39 (m, 2H), 1.26e1.14 (m, 2H); 13C NMR
d¼176.8, 162.5,
low oil, (357 mg, 60%), Rf¼0.24 (3:7 EtOAc/hexane), IR (KBr) nmax
3168, 1623 cmꢁ1 1H NMR
¼12.05 (s, 1H), 8.21e8.18 (br s, 1H),
8.01e7.86 (m, 3H), 7.82e7.75 (m, 1H), 7.71e7.39 (m, 5H), 7.14e7.09
(m, 1H), 7.01e6.86 (m, 1H); 13C NMR
132.8, 132.2, 130.4, 129.2, 128.3, 128.2, 127.8, 127.0, 125.3, 120.9,
119.4, 118.7, 118.4; m/z (EI) 247 (Mþ), 171; HRMS (ES): Mþ, found
247.0990. C17H13NO requires 247.0997.
:
134.6, 134.4, 134.1, 133.6, 133.4, 133.3, 133.1, 132.8, 132.6, 130.9,
130.4, 130.1, 130.0, 128.8, 128.7, 128.6, 128.1, 127.9, 127.8, 127.6, 127.1,
126.7, 126.5, 126.1, 125.9, 125.3, 125.0, 124.9, 124.7, 124.6, 123.1,
118.6, 118.2, 117.6, 117.1, 64.5, 29.4, 24.6; m/z (EI) 574 (Mþ), 476, 341;
HRMS (ES): Mþ, found 574.2621. C40H34N2O2 requires 574.2620.
;
d
d
¼163.2, 158.5, 136.3, 133.7,
4.3.4. (1R,2R,anti)-1-N-(2-Methoxyphenyl-1-naphthylidene)-2-N0-
aminocyclohexane (2d). Viscous yellow oil, (143 mg, 40%), Rf¼0.29
4.2.4. 1-(2-Naphtyl)-1-(2-methoxyphenyl)methylenimine (1d). Yel-
low solid, (793 mg, 70%), mp 76e78 ꢀC, Rf¼0.34 (2:8 EtOAc/
and 0.31 (two non-separated isomers) (0.5:9.5 MeOH/CH2Cl2), [a]
D
ꢁ19.2 (c 0.6, CHCl3), IR (KBr) nmax: 2925, 1605 cmꢁ1
;
1H NMR
hexane), IR (neat) nmax: 3243, 1623 cmꢁ1
;
1H NMR
d¼8.25 (s, 1H),
d
¼8.03e7.89 (m, 3H), 7.66e7.55 (m, 2H), 7.54e7.5 (m, 2H), 7.49e7.3
8.05e7.95 (m, 2H), 7.92e7.69 (m, 4H), 7.61e7.25 (m, 3H), 7.12e7.01
(m, 2H), 7.27e7.19 (m, 1H), 7.03e6.98 (m, 1H), 6.58e6.49 (m, 2H),
3.15e3.02 (m, 3H), 3.0e2.9 (m, 1H), 2.67e2.58 (m, 1H), 2.0e1.7 (m,
2H), 1.68e1.56 (m, 2H), 1.55e1.45 (m, 2H), 1.40e1.27 (m, 2H); 13C
(m, 2H), 3.72 (s, 3H); 13C NMR
130.7, 129.6, 128.9, 128.3, 128.0, 127.6, 127.1, 126.5, 126.2, 125.1,
124.6, 120.6, 55.7; m/z (EI) 261 (Mþ), 246; Anal. Calcd for C18H15NO:
C, 82.73; H, 5.79; N, 5.36. Found: C, 82.53; H, 5.60; N, 5.16.
d
¼175.9, 157.4, 136.2, 134.4, 132.1,
NMR
d
¼174.5, 173.9, 162.8, 162.6, 133.3, 132.5, 131.8, 131.6, 131.4,
130.5, 130.2, 129.4, 129.2, 128.6, 128.5, 127.8, 127.2, 126.8, 126.7,
126.4, 126.3, 125.6, 125.5, 125.4, 125.3, 125.0, 124.2, 121.6, 120.2,
120.1, 117.9, 117.8, 117.7, 117.3, 68.0, 65.8, 55.8, 55.6, 53.4, 33.4, 33.1,
32.2, 31.8, 29.7, 24.8, 24.3, 24.2, 23.8; m/z (EI) 358 (Mþ); HRMS (ES):
Mþ, found 358.2061. C24H26N2O requires 358.2045.
4.3. General procedure for transimination
Methylenimine 1 (1.0 mmol) and the primary amine (1 equiv),
or the mixture consisting of (R,R)-1,2-diaminocyclohexane-
(þ)-tartrate salt (132 mg, 0.5 mmol) and K2CO3 (138 mg, 1 mmol),
were dissolved in ethanol/water mixture (2/1, v/v) (6 mL) and the
resulting solution heated to reflux for the period of time shown in
Table 2 to complete the reaction (monitored by TLC). Then the
crude product was subjected to column chromatography over silica
gel using EtOAc/hexane to purify and separate the stereoisomers.
4.3.5. (1R,2R,anti)-1-N-(2-Hydroxyphenyl-2-naphthylidene)-2-N0-
aminocyclohexane (2e). Brown oil, (172 mg, 50%), Rf¼0.28 and 0.34
(two non-separated isomers) (0.5:9.5 MeOH/CH2Cl2), [
a
]
D þ15.1 (c
1, CHCl3), IR (KBr) nmax: 3429, 1606 cmꢁ1; 1H NMR
d
¼12.05 (s, 1H),
8.55e8.10 (m, 1H), 8.08e7.71 (m, 4H), 7.69e7.59 (m, 2H), 7.35e7.2
(m, 2H), 7.13e7.1 (m, 1H), 6.95e6.8 (m, 1H), 6.73e6.59 (m, 2H),
3.7e3.5 (m, 1H), 3.3e2.83 (m, 1H), 2.07e1.8 (m, 2H), 1.75e1.42 (m,
4.3.1. N-((1S,2S,anti)-1,3-Dihydroxy-1-phenylprop-2-yl)-1-naphthyl-
1-(20-hydroxyphenyl)methylenimine (2a). Yellow oil, (238 mg, 60%),
4H), 1.4e1.26 (m, 2H); 13C NMR
d
¼175.3, 175.2, 163.0, 162.9, 136.3,
136.1, 135.1, 134.9, 133.7, 133.1, 132.4, 132.1, 130.4, 129.2, 128.6, 128.4,
128.3, 128.2, 127.8, 127.7, 127.6, 127.0, 126.9, 126.4, 125.8, 125.3,
124.9, 124.3, 121.6, 121.1, 118.7, 118.4, 117.9, 117.4, 64.9, 37.1, 32.7,
32.5, 29.7, 29.3, 31.9, 30.0, 27.1, 23.7, 22.7, 20.6; m/z (EI) 344 (Mþ),
246; HRMS (ES): Mþ, found 344.1877. C23H24N2O requires 344.1889.
Rf¼0.13 (3:7 EtOAc/hexane), [
a
]
þ68.1 (c 1, CHCl3), IR (KBr) nmax
:
D
3412, 1605 cmꢁ1 1H NMR
;
d
¼10.02 (s, 1H), 7.99e7.92 (minor) and
7.91e7.85 (major) (m, 2H), 7.62e7.45 (m, 2H), 7.44e7.35 (m, 2H),
7.33e7.26 (m, 2H), 7.25e7.11 (m, 4H), 7.09e6.98 (minor) and
6.97e6.89 (major) (m, 1H), 6.69e6.41(m, 2H), 6.37e6.3 (m, 1H), 5.78
(dd, J¼7.5 and 6 Hz, 1H), 5.26 (dd, J¼7.5 and 6 Hz, 1H), 4.17e3.98
(major) and 3.97e3.87 (minor) (m,1H), 3.84e3.65 (m,1H), 3.52e3.39
4.3.6. (1R,2R,anti,anti)-1,2-N,N0-Bis(2-hydroxyphenyl-2-naph-
thylidene)cyclohexane (2f). Greenish oil, (57 mg, 10%), Rf¼0.46 (2:8
(m, 2H); 13C NMR
133.0, 132.9, 130.7, 129.9, 129.6, 128.7, 127.4, 127.1, 126.9, 125.8, 125.0,
124.7,124.2,121.4,119.8,117.3, 72.3, 63.1, 62.9; m/z (EI) 397 (Mþ), 381,
153; HRMS (ES): Mþ, found 397.1680. C26H23NO3 requires 397.1678.
d
¼177.2,176.8,171.3,166.7,166.6,141.4,135.9,133.4,
EtOAc/hexane), [
a
]
þ11.1 (c 0.7, CHCl3), IR (KBr) nmax: 3436,
D
1606 cmꢁ1
7H), 7.90e7.7 (m, 7H), 7.2e6.98 (m, 4H), 6.9e6.5 (m, 4H), 4.19e3.5
(m, 2H), 2.40e1.54 (m, 6H), 1.53e1.39 (m, 2H); 13C NMR
;
1H NMR
d
¼14.32 (br, 1H), 12.04 (s, 1H), 8.81e7.92 (m,
d¼177.8,
177.6, 163.2, 162.7, 136.2, 135.0, 134.1, 133.7, 133.5, 133.3, 132.9, 132.7,
132.2,130.4,130.3,129.3,129.2,128.9,128.5,128.4,128.2,128.1,127.9,
127.4, 127.0, 126.7, 125.7, 125.3, 124.7, 124.0, 119.9, 118.7, 118.4, 115.6,
58.5, 32.3, 29.7, 24.7, 23.9, 23.5; m/z (EI) 574 (Mþ), 447, 345, 290;
HRMS (ES): Mþ, found 574.2619. C40H34N2O2 requires 574.2620.
4.3.2. (1R,2R,anti)-1-N-(2-Hydroxyphenyl-1-naphthylidene)-2-N0-
aminocyclohexane (2b). Brown oil, (141 mg, 41%), Rf¼0.26 and 0.3
(two non-separated isomers) (0.5:9.5 MeOH/CH2Cl2), [
a
]
þ17.1 (c
D
0.8, CHCl3), IR (KBr) nmax: 3437, 1605 cmꢁ1; 1H NMR
d
¼15.41 (s, 1H),
8.06e7.89 (m, 2H), 7.67 (minor) and 7.57 (major) (m, 1H), 7.55e7.46
(m, 2H), 7.42e7.23 (m, 2H), 7.22e7.15 (m, 1H), 7.04e6.98 (major)
and 6.97e6.89 (minor) (m, 1H), 6.59e6.48 (major) and 6.45e6.33
(minor) (m, 2H), 3.18e3.05 (m, 1H), 3.02e2.91 (m, 0.5H), 2.69e2.58
4.3.7. (1R,2R,anti)-1-N-(2-Methoxyphenyl-2-naphthylidene)-2-N0-
aminocyclohexane (2g). Brown oil, (32 mg, 9%), Rf¼0.29 (0.5:9.5
MeOH/CH2Cl2), [
a]
D þ12.5 (c 0.7, CHCl3), IR (KBr) nmax: 2925, 2854,

7034
H. Bafqiren, J.J. Eddine / Tetrahedron 66 (2010) 7028e7034
1615 cmꢁ1
;
1H NMR
d
¼8.10e8.05 (m, 1H), 7.96e7.71 (m, 4H),
1.48e1.34 (m, 2H); 13C NMR
d
¼178.6, 163.3, 162.4, 154.0, 149.5,
7.64e7.35 (m, 3H), 7.18e6.99 (m, 3H), 3.71 (s, 3H), 3.4e3.16 (m, 2H),
3.15e2.82 (m, 2H), 2.10e1.85 (m, 1H), 1.81e1.5 (m, 4H), 1.4e1.25 (m,
148.3, 136.2, 135.3, 135.0, 134.3, 133.7, 132.7, 132.1, 130.9, 130.4,
129.7, 128.5, 128.4, 128.3, 127.7, 127.5, 127.4, 126.2, 125.7, 125.3,
124.3, 122.2, 121.4, 120.4, 118.7, 118.2, 117.6, 111.9, 111.2, 55.6, 54.1,
53.7, 29.6, 29.3, 22.6, 22.3; m/z (EI) 588 (Mþ), 524, 507, 473, 363,
324; HRMS (ES): Mþ, found 588.2770. C41H36N2O2 requires
588.2777.
3H); 13C NMR
d¼166.8, 166.0, 156.3, 155.4, 137.2, 136.7, 134.3, 134.2,
132.9,132.4,132.1,131.8,130.1,129.8,129.6,128.9,128.7,128.6,128.3,
127.7, 127.6, 126.8, 126.0, 125.5, 125.1, 124.7, 124.5, 120.9, 120.7, 118.1,
117.4, 111.5, 111.3, 110.9, 68.9, 68.4, 55.8, 55.2, 37.1, 32.3, 31.7, 29.7,
27.4, 27.0, 26.7, 24.9, 24.1, 20.1; m/z (EI) 358 (Mþ), 328, 239, 219,135;
HRMS (ES): Mþ, found 358.2050. C24H26N2O requires 358.2045.
Acknowledgements
4.3.8. (1R,2R,anti,anti)-1,2-N,N0-Bis(2-methoxyphenyl-2-naph-
thylidene)cyclohexane (2h). Yellowish oil, (361 mg, 60%), Rf¼0.37 (2:8
We are grateful to the Centre National de la Recherche Scienti-
fique et Technique for financial support.
EtOAc/hexane), [
a
]
þ18 (c 0.9, CHCl3), IR (KBr) nmax: 2964, 1660,
D
1625 cmꢁ1
7.59e7.34 (m, 6H), 7.20e6.70 (m, 5H), 3.75 (s, 6H), 3.49e3.46 (m, 1H),
3.35e3.3 (m,1H),1.9e1.50 (m, 6H), 1.34e1.15 (m, 2H); 13CNMR
;
1H NMR
d
¼8.40e7.93 (m, 3H), 7.91e7.60 (m, 8H),
References and notes
d¼175.1,
1. (a) Aratani, T.; Yoneyoshi, Y.; Nagase, T. Tetrahedron Lett. 1975, 16, 1707e1710;
(b) Aratani, T.; Yoneyoshi, Y.; Nagase, T. Tetrahedron Lett. 1977, 18, 2599e2602;
(c) Aratani, T.; Yoneyoshi, Y.; Nagase, T. Tetrahedron Lett. 1982, 23, 685e688.
2. Desimoni, G.; Quadrelli, P.; Righetti, P. P. Tetrahedron 1990, 46, 2927e2934.
3. Josephsohn, N. S.; Carswell, E. L.; Snapper, M. L.; Hoveyda, A. H. Org. Lett. 2005,
7, 271e274.
161.6, 157.6, 145.5, 144.8, 134.1, 133.3, 132.9, 132.1, 131.9, 129.6, 129.4,
129.1, 128.8, 128.3, 128.0, 127.9, 127.7, 127.5, 126.5, 125.8, 125.1, 123.5,
123.0,122.4, 121.5,120.5,120.1,119.1,118.8, 118.1,111.8,111.5,110.5, 65.8,
64.1, 55.6, 55.3, 29.8, 29.7, 26.9, 24.3; m/z (EI) 602 (Mþ), 503, 477, 265;
HRMS (ES): Mþ, found 602.2938. C42H38N2O2 requires 602.2933.
4. Gan, C.; Lai, G.; Zhang, Z.; Wang, Z.; Zhou, M. M. Tetrahedron: Asymmetry 2007,
17, 725e728.
5. Byunghyuck, J.; Sung, H. K. Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 1471e1475.
6. Radosevich, A. T.; Musich, C.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 1090e1091.
7. (a) Larrow, J. F.; Jacobsen, E. N.; Gao, Y.; Hong, Y.; Nie, X.; Zepp, C. M. J. Org.
Chem. 1994, 59, 1939e1942; (b) Jacobsen, E. N.; Zhang, W.; Muci, A. R.; Ecker,
J. R.; Deng, L. J. Am. Chem. Soc. 1991, 113, 7063e7064; (c) Comprehensive
Asymmetric Catalysis; Katsuki, T., Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: Berlin, 1999; Vol. II, p 621.
8. Miller, S. J.; Lectka, T.; Jacobsen, E. N. J. Am. Chem. Soc. 1993, 115, 6460e6461.
9. Evans, D. A.; Kozolowski, C. M.; Tedrow, J. C. Tetrahedron Lett. 1996, 37,
7481e7484.
4.3.9. (1R,2R,anti,anti)-1-N-(2-Hydroxyphenyl-2-naphthylidene)-2-
N0-(2-hydroxyphenyl-1-naphthylidene)cyclohexane (2i). Yellow oil,
(390 mg, 68%), Rf¼0.45 (2:8 EtOAc/hexane), [
a]
ꢁ16.4 (c 0.5,
D
CHCl3), IR (KBr) nmax: 3057, 1624 cmꢁ1 1H NMR
;
d¼12.34 (s, 1H),
12.05 (s, 1H), 8.25e8.15 (m, 2H), 8.03e7.85 (m, 9H), 7.8e7.5 (m, 3H),
7.45e7.3 (m, 2H), 7.22e7.05 (m, 2H), 6.98e6.84 (m, 2H), 6.8e6.6 (m,
2H), 4.23 (s, 1H), 3.61 (s, 1H), 2.1e1.6 (m, 6H), 1.40e1.20 (m, 2H); 13C
NMR
d
¼176.6, 176.5, 163.4, 163.2, 136.9, 136.7, 136.3, 134.8, 134.0,
10. Sharma, V. B.; Jain, S. L.; Sain, B. J. Mol. Catal. A 2004, 219, 61e64.
11. Belokon, Y. N.; North, M.; Kublitsk, V. S.; Ikonnikov, N. S.; Krasik, P. E.; Maleev,
V. I. Tetrahedron Lett. 1999, 40, 6105e6108.
12. (a) Campbell, E. J.; Nguyen, S. T. Tetrahedron Lett. 2001, 42, 1221e1225; (b)
Holbach, M.; Zheng, X.; Burd, C.; Jones, C. W.; Weck, M. J. Org. Chem. 2006, 71,
2903e2906; (c) Ambroziaka, K.; Szypab, M. Tetrahedron Lett. 2007, 48,
3331e3335.
133.0, 133.7, 132.5, 130.9, 130.4, 129.2, 129.0, 128.5, 128.4, 128.2,
127.8, 127.5, 127.3, 127.0, 126.6, 126.4, 125.4, 125.3, 124.4, 120.2,
119.3, 118.8, 118.7, 118.4, 118.3, 57.0, 56.4, 31.9, 29.7, 29.3, 22.7; m/z
(EI) 574 (Mþ), 445, 335, 158; HRMS (ES): Mþ, found 574.2618.
C40H34N2O2 requires 574.2620.
13. Mohebbi, S.; Boghaei, D. M.; Sarvestani, A. H.; Salimi, A. Appl. Catal., A 2005,
263e267.
14. Hayashi, M.; Tanaka, K.; Oguni, N. Tetrahedron: Asymmetry 1995, 6, 1833e1836.
15. Retmane, A.; Gmouh, S.; Runghen, M.; Valnot, J. Y.; Maddaluno, J.; Toupet, L.;
Oulyadi, H.; Jamal Eddine, J. Tetrahedron: Asymmetry 2008, 19, 1523e1531.
16. O’Donnell, M. J.; Polt, R. L. J. Org. Chem. 1982, 47, 2663e2666.
17. Gmouh, S.; Jamal Eddine, J.; Valnot, J. Y. Tetrahedron 2000, 56, 8361e8366.
18. Earlier studies on the isomerisation of N-alkyl imines derived from aryl alkyl
ketones showed that the syn and anti 13C]N chemical shift difference is about
10 ppm Casarini, D.; Lunazzi, L.; Macciantelli, D. J. Chem. Soc., Perkin Trans. 2
1992, 1363e1370.
4.3.10. (1R,2R,anti,anti)-1-N-(2-Hydroxyphenyl-2-naphthylidene)-2-
N0-(2-methoxyphenyl-1-naphthylidene)cyclohexane (2j). Orange oil,
(441 mg, 75%), Rf¼0.82 (2:8 EtOAc/hexane), [
a]
ꢁ21.1 (c 0.6,
D
CHCl3), IR (KBr) nmax: 3054, 2959, 1602 cmꢁ1; 1H NMR
d
¼10.21 (br,
1H), 8.60 (dd, J¼13.3 Hz, 1H), 8.26e8.16 (m, 1H), 8.10e7.88 (m, 5H),
7.8e7.40 (m, 8H), 7.38e7.18 (m, 2H), 7.16e6.72 (m, 4H), 6.72e6.40
(m, 1H), 4.22 (s, 1H), 3.97 (s, 1H), 3.6 (s, 3H), 1.98e1.49 (m, 6H),