Diastereoselective addition of organometallic reagents to diimines derived from (R,R)-1,2-diaminocyclohexane and aromatic aldehydes

Article abstract of DOI:10.2174/157017809789124948

The double addition of organolithium compounds and allylzinc bromide to the imines prepared from (R,R)-1,2-diaminocyclohexane by condensation with aromatic and heteroaromatic aldehydes gave secondary diamines with high yields and diastereoselectivities ap

Full text of DOI:10.2174/157017809789124948

434
Letters in Organic Chemistry, 2009, 6, 434-438
Diastereoselective Addition of Organometallic Reagents to Diimines
Derived from (R,R)-1,2-Diaminocyclohexane and Aromatic Aldehydes
Diego Savoia*, Andrea Gualandi and Marco Bandini
Dipartimento di Chimica “G. Ciamician”, Universita’ di Bologna, via Selmi 2, 40126 Bologna, Italy
Received March 17, 2009: Revised June 24, 2009: Accepted June 26, 2009
Abstract: The double addition of organolithium compounds and allylzinc bromide to the imines prepared from (R,R)-1,2-
diaminocyclohexane by condensation with aromatic and heteroaromatic aldehydes gave secondary diamines with high
yields and diastereoselectivities apart for the reaction of 2-pyridinealdehyde derivative which occurred with low to
moderate stereocontrol.
Keywords: Amine, 1,2-diaminocyclohexane, diastereoselectivity, imine, organometallic reagents.
Optically pure trans-1,2-diaminocyclohexane and its
N,N’-functionalized derivatives are widely used as chiral
auxiliaries, bases, ligands and catalysts in asymmetric
synthesis and molecular recognition [1]. Moreover, platinum
complexes of trans-1,2-diaminocyclohexanes are also used
in antitumor chemotherapy [2] and several C- and N-
substituted derivatives have diverse pharmacological
properties [3].
As we have been interested for a long time in the auxiliary-
induced diastereoselective synthesis of amines by addition of
organometallic reagents to chiral imines and diimines, we
observed with surprise the lack of reports on the
organometallic addition to the diimines derived from
enantiopure 1,2-diaminocyclohexane, and decided to fill the
gap. The reactions performed on selected compounds 1-5
lead to the secondary diamines 6-10 with increased
complexity and concomitant formation of two novel
stereocenters (Scheme 1).
Diimines such as 1-5 can been easily prepared by
condensation of trans-1,2-diaminocyclohexane with arom-
RM
R
R
R
R
R
R
R
R
NH HN
NH HN
NH HN
N
N
THF, -78 to 0 °C
S
S
R
R
S
R
Ar
Ar
Ar
Ar
Ar
Ar
Ar
Ar
(R,R)
(S,S)
(R,S)
(R,R)-1
1: Ar = Phenyl
6: Ar = Phenyl
a: R = Methyl
b: R = Allyl
c: R = Phenyl
2: Ar = 2,2'-Dithiophene-5-yl
3: Ar = 2-Pyrrolyl
7: Ar = 2,2'-Dithiophene-5-yl
8: Ar = 2-Pyrrolyl
4: Ar = 2-Pyridyl
9: Ar = 2-Pyridyl
5: Ar = 4-Pyridyl
10: Ar = 4-Pyridyl
Scheme 1.
atic and heteroaromatic aldehydes (Scheme 1). Particularly,
the analogues once prepared from o-phenolic aldehydes
serve to prepare the corresponding salen-metal complexes
which are powerful catalysts in a number of asymmetric
transformations [4]. trans-1,2-Diaminocyclohexane has also
been used as a building block for the preparation of chiral
perazamacrocycles, including macrocyclic di- and
polyimines, e.g. trianglimines [5].
The double addition of the organometallic reagent can
afford in principle three diastereomers: two of them have C2
symmetry and either R or S configuration of both the newly
formed stereocenters, the other one has the opposite
configuration of the adjacent stereocenters. We are aware of
a report where it was described that addition of di(neopentyl)
manganese(II) to rac-trans-N,N’-bis(benzylidene)-1,2-diami-
nocyclohexane (rac-1a) unexpectedly gave in 20% yield an
amino-imine manganese complex derived from the attack of
the neopentyl group on one imine function [6]. Other known
C-C bond forming reactions of enantiopure diimines 1 are
the Staudinger reaction with ketenes, which lead to bis-ꢀ-
lactams with poor diastereoselectivity favoring the meso
*Address correspondence to this author at the Dipartimento di Chimica “G.
Ciamician”, Universita’ di Bologna, via Selmi 2, 40126 Bologna, Italy;
E-mail: diego.savoia@unibo.it
1570-1786/09 $55.00+.00
© 2009 Bentham Science Publishers Ltd.

Diastereoselective Addition of Organometallic Reagents
Letters in Organic Chemistry, 2009, Vol. 6, No. 6
435
products [7, 8] and the low valent titanium-mediated
intramolecular reductive coupling which gave 3,4-
disubstituted-2,5-diazabicyclo[4.4.0]decanes with complete
stereocontrol [9]. Moreover, it has been reported that
deuteride addition to all the six azomethine groups of the
trianglimine derived from (R,R)-1,2-diaminocyclohexane
and phthalaldehyde gave a quasi-enantiomer with apparently
complete diastereoselectivity [10]. In this case, attack of the
deuteride nucleophile exclusively occurred on the less
hindered faces of all the imine groups, i.e. from outside of
the macrocycle, as a single diastereomer was observed by 1H
and 2H NMR spectroscopy.
centers in the products 7a, 7c and 8a was assumed by
analogy with the previously determined configuration of
compound (R,R)-6a.
The organometallic reactions of the imine 4 derived from
2-pyridinecarboxyaldehyde were less satisfactory. Using
methyllithium, two diastereomers of 9a were obtained with
moderate diastereoselectivity (d.r. 86:14), whereas the
reactions with allylmagnesium chloride and allylzinc
bromide gave the corresponding diamines 9b as mixture of
three diastereomers with poor diastereoselectivity, although
the zinc reagent gave a better performance (d.r. 8:72:20. in
order of GC elution). In these cases, no attempt was made to
separate the diastereomers. We considered the inferior
stereocontrol obtained with the diimine 4 to be due to the
electronic-withdrawing effect of the pyridine nucleus. Hence
we examined the behaviour of the bis(4-pyridineimine) 5
towards the addition of methyllithium and observed an
excellent diastereoselectivity in the formation of the product
10a (d.r. >97:3). The similarity of the results obtained with
the 2-pyrrole and 4-pyridine derivatives indicated that the
opposite mesomeric effects of the two aromatic rings did not
significantly affect the stereocontrol in the corresponding
organometallic additions. Instead, probably, the stereocontrol
was negatively influenced by the stronger chelating ability of
the 2-pyridineimine group, which acted in competition with
the 1,2-diiminocyclohexane moiety to form a complex with
the organometallic reagent.
RESULTS AND DISCUSSION
The starting diimines 1-5 were prepared in almost
quantitative yields from the requisite aldehyde and the L-
tartrate salt of (R,R)-1,2-diaminocyclohexane according to a
reported procedure [11] and were purified by crystallization.
First we studied the behavior of the diimine 1a derived from
benzaldehyde and observed that the addition of
methyllithium gave the diamine 6a with excellent yield and
almost complete diastereoselectivity (Table 1), as determined
by GC-MS analysis. A single diastereomer was also
1
observed in the H NMR spectrum which gave evidence of
its C2 symmetry. Then the R configuration of the two newly
formed benzylic stereocenters was determined by
1
comparison with the H NMR spectrum and optical rotation
The sense of asymmetric induction observed in the
addition to the diimines 1-3 and 5 can be tentatively
explained by the following considerations. At first, one
should consider the relative stabilities of the diimine
conformers which display different orientations of the
cyclohexane substituents as a consequence of rotation along
the two C*-N bonds. The syn,syn conformer I (Fig. 1), where
both pairs of the H-C=N and adjacent hydrogens are
eclipsed, is more stable than the syn,anti conformer II (Fig.
1, the less stable anti,anti conformer is not depicted) [7]. The
formation of (R,R)-diamines is consistent with the
occurrence of two consecutive attacks of the organometallic
reagent on the Re-faces of the imine groups, as shown in
power of its known enantiomer (S,S)-6a’ (Scheme 1) [12].
Similarly, the reaction of the diimine 1a with allylzinc
bromide gave the bis-adduct 6b with excellent yield and only
slightly lower diastereoselectivity (d.r. 98:2).
The reactions of the analogous diimine 2 derived from
2,2’-dithiophene-5-carboxaldehyde with methyllithium and
phenyllithium gave the products 7a and 7c with almost
complete stereocontrol. On the other hand, the imine 2 was
unreactive towards phenylmagnesium bromide. An excellent
result was also obtained by the reaction of the 2-pyrrolimine
3 with methyllithium which gave the corresponding diamine
8a. The (R,R) configuration of the newly formed stereo-
Table 1. Addition of Organometallic Reagents to the Diimines 1-5
Diimine
Ar
RMa
T (°C)
Product
D.r. (%)b
Yield (%)
1
1
2
2
2
3
4
4
4
5
Phenyl
Phenyl
MeLi
AllylMgCl
MeLi
ꢀ78 to 0
ꢀ78 to 0
ꢀ78 to ꢀ20
ꢀ78 to ꢀ20
ꢀ78 to ꢀ20
0 to 20
6a
6b
7a
7c
>99:1
98:2
99 (92)c
99 (91)c
92 (82)c
98 (91)c
2,2’-Dithiophene-5-yl
2,2’-Dithiophene-5-yl
2,2’-Dithiophene-5-yl
2-Pyrrolyl
>99:1
>99:1
-
PhLi
d
PhMgBr
MeLie
-
8a
9a
>99:1
86:14
9:44:47
8:72:20
>97:3
96 (89)c
98
2-Pyridyl
MeLi
ꢀ78 to 0
ꢀ78 to 0
ꢀ78 to 0
ꢀ78
2-Pyridyl
AllylMgCl
AllylZnBr
MeLi
9b
98
2-Pyridyl
9b
97
4-Pyridyl
10a
96 (90)c
aThe organometallic reagent (2.5 equiv.) was slowly added to the diimine dissolved in THF at -78 °C and the mixture was stirred during 3-4 h meanwhile the temperature was
allowed to reach 0 or ±20 °C. bDetermined by GC-MS analysis and reported according to the order of elution. cYield of pure (R,R)-diastereomers isolated by column chromatography
(SiO2). dNo reaction occurred. e3.5 Equivalents of methyllithium was used.

436 Letters in Organic Chemistry, 2009, Vol. 6, No. 6
Savoia et al.
model III. However, it should be observed that the external
attack of the nucleophile on the imine Si faces in the
identical syn,syn conformation should be more favourable
because it obeys the Felkin-Anh-type model of 1,3-
asymmetric induction [13], as depicted in model IV.
The observed sense of asymmetric induction is in
agreement with previous reports [6, 10] but not with the
sodium borohydride reduction of the manganese dichloride
complex of a macrocyclic diketimine derived from (R,R)-
diaminocyclohexane, where the newly formed stereocenters
were formed with the R configurations (Si face attack) [14].
Apparently, further studies are necessary to make clear the
origin of diastereoselectivity in the organometallic reactions
of diimines derived from 1,2-diaminocyclohexane.
syn
syn
H
Ph
H
H
H
H
Ph
N
N
N
N
H
H
anti
Ph
Ph
The described stereoselective synthesis of 1,2-diamino-
cyclohexanes carrying 1-arylalkyl substituents at the
nitrogen atoms constitutes an improvement with respect to
previously described routes. We have previously reported the
synthesis of (S,S)-6a through the double allylation of the
glyoxal diimine 11 and the ring closing metathesis of the
alkene functions of the intermediate compound 12 (Scheme
2) [15]. On the other hand, the three step route described by
Juaristi involves the ring-opening of cyclohexene oxide by
attack of optically pure 1-phenylethylamine and separation
of the diastereomeric compounds (S,S)-6a’ and (S,S)-6a
which were formed in a 2:1 ratio [16].
H
syn
I
II
H
H
H
N
Ph
N
N
H
N
Ph
R-M
H
Ph
H
Ph
R-M
M-R
III
IV
internal Re-face attack to
the syn,syn-(R,R)-diimine
external Si-face attack to
the syn,syn-(R,R)-diimine
(Felkin-Anh-type)
AllylZnBr
N
N
Ph
NH HN
Ph
Ph
N
N
M
Ph
Ph
11
Ph
12
R
V
2) H2, cat.
1) RCM
O
O
Si-face attack / Re-face attack
H
N
Ph
Ph
NH2
N
R
R
Ph
N
N
H
Ph
NH HN
H
H
S
S
Ph
Ph
VI
VII
Ph
3 steps
(S,S)-6a
internal Si-face attack to
the syn,syn-(R,R)-diimine
internal Re-face attack to
the syn,syn-(R,R)-diimine
O
Fig. (1).
The poorer stereochemical outcomes obtained with the 2-
pyridineimine 4 suggest the importance of the preliminary
formation of the N,N’-metal chelation involving the C2-
symmetric diiminocyclohexane metal complex V involving
the 1,2-cyclohexanediimine moiety. In this case, the C-C
bond forming step should take place by attack of the
nucleophilic R group to the one or the other imine groups.
The corresponding models VI and VII describe the
alternative attacks to the Si and Re faces of the azomethine
functions, respectively. It can be observed that the model
VII is favored by stereoelectronic effects, since the
nucleophile attacks anti to the orthogonally disposed allylic
carbon substituent (the methylene carbon of the cyclohexane
ring) rather than the hydrogen atom in the former model. On
the other hand, the attack on the imine Si face is perhaps
hindered by the equatorial hydrogen of the cyclohexane
methine carbon.
R
R
+
S
S
NH HN
NH HN
S
S
S
S
Ph
Ph
Ph
Ph
(S,S)-6a'
2 : 1
(S,S)-6a
Scheme 2.
The enantiomers (R,R)-6a and (S,S)-6a’ can be used in
diverse asymmetrically catalyzed reactions. For example,
(S,S)-6a’ has found application as a catalyst in the
enantioselective hydrosilylation of ketones, where it
provided better enantioselectivities (up to 89% ee) than the
diastereomer (S,S)-6a [16]. We have carried out preliminary
investigations into the activity of the diamines (R,R)-7a,c as
ligands in the enantioselective Henry reaction, where the
unsubstituted dithiophene derivative 14 produced excellent
enantioselectivity in the formation of the ꢀ-nitroalcohol 13
[17] (Scheme 3 and Table 2). Unfortunately, the results we

Diastereoselective Addition of Organometallic Reagents
Letters in Organic Chemistry, 2009, Vol. 6, No. 6
437
have obtained demonstrated that introduction of any
substituents at the benzylic positions with R configuration of
those stereocenters have a negative effect. In fact, using the
methyl-substituted ligand (R,R)-7a loss of enantioselectivity
was observed, whereas no reaction occurred using the
phenyl-substituted ligand (R,R)-7c, probably due to adverse
steric effects. Future studies might be addressed to improve
the enantioselectivity in the reduction of carbonyl
compounds, which was previously accomplished using (S,S)-
6a’, [12] by thoroughly defining the role of the aromatic ring
present in the N-substituents. This can be easily achieved by
varying the nature of starting aldehyde.
Typical Procedure for the Double Addition of
Organometallic Reagents to Diimines. Preparation of
(R,R)-6a
Methyllithium (1.6 M in Et2O, 6.1 mmol, 3.8 mL) was
added to a magnetically stirred solution of the imine (R,R)-1
(1.5 mmol, 0.440 g) in THF (15 mL) which was previously
cooled at -78 °C. After 30 min, the reaction mixture was
slowly warmed to 0 °C, stirred for a further 4 h, then quen-
ched by saturated aq. NaHCO3 (10 mL). The organic phase
was extracted with EtOAc (3 ꢀ 20 mL) and the organic
layers were collected, dried over Na2SO4 and concentrated to
leave the crude product. The d.r. was determined by GC-MS
analysis (using HP-5 column, 30 m, ID 0.25 mm). Flash
column chromatography (SiO2), eluting with cyclohexane/
EtOAc (1:1), gave the product (R,R)-6a [12] as a yellow oil:
0.444 g, 92 %.
CHO
OH
Cu(OAc)2, L
NO2
+
EtOH, 0 °C, 18 h
13
1
CH3NO2
(R,R)-6b: yellowish oil. H NMR (300 MHz, CDCl3): ꢀ
7.20-7.40 (m, 5 H), 5.62-5.80 (m, 2 H), 5.01-5.18 (m, 4 H),
3.72 (q, J = 4.7, 2 H), 2.38-2.56 (m, 4 H), 2.16 (bs, 2 H),
2.01 (bs, 2 H), 1.71(d, J = 6.4, 2 H), 1.48-1.54 (m, 2 H), 0.8-
1.2 (m, 4 H). 13C NMR (75 MHz, CDCl3): ꢀ: 145.8, 135.6,
128.1, 127.2, 126.7, 117.0, 61.5, 60.9, 42.6, 32.8, 24.7; MS
m/z 333 (100), 131 (97), 91 (68), 106 (56), 146 (41), 203
(17), 228 (12), 186 (11).
NH HN
S
S
1
S
S
(R,R)-7a: yellowish oil. H NMR (300 MHz, CDCl3): ꢀ
14
7.16-7.20 (m, 2 H), 7.11-7.14 (m, 2 H), 6.94-7.03 (m, 4 H),
6.82-6.87 (m, 2 H), 4.16 (q, J = 6.2, 2 H), 2.31-2.35 (m, 2
H), 1.91-2.01 (d, J = 26.5, 2 H), 1.8 (bs, 2 H), 1.60-1.72 (m,
2 H), 1.46 (d, J = 6.1, 6 H), 1.0-1.24 (m, 4 H). 13C NMR (75
MHz, CDCl3): ꢀ 152.2, 138.0, 135.3, 127.7, 123.8, 123.1,
123.0, 60.1, 51.7, 32.5, 24.9, 24.3. MS m/z 499.2 [M + H]+.
Scheme 3.
CONCLUSIONS
The results obtained demonstrate that alkyl- and aryl-
lithiums and allylzinc compounds are the preferred reagents
as compared to Grignard reagents to achieve high level of
stereocontrol in the double addition to N,N’-arylidene-1,2-
diaminocyclohexanes 1-5. In this way a large variety of C2-
symmetric 1,2-diaminocyclohexanes 6-10 carrying chiral
nitrogen substituents can be prepared in only two steps from
both enantiomers of 1,2-diaminocyclohexane by varying
either the nature of the starting aldehyde or the
organometallic reagent. Only in the case of the bis(2-
1
(R,R)-7c: yellowish oil. H NMR (300 MHz, CDCl3): ꢀ
1H NMR (300 MHz, CDCl3): ꢀ 7.50-7.58 (m, 4 H), 7.40-7.46
(m, 4 H), 7.29-7.37 (m, 3 H), 7.18-7.24 (m, 3 H), 6.98-7.60
(m, 4 H), 6.91 (dd, J = 1.2, J = 6.3, 2 H), 5.21 (s, 2 H), 2.14-
2.28 (m, 6 H), 1.68 (d , J = 6.1, 4 H), 0.90-1.10 (m, 6 H). 13C
NMR (75 MHz, CDCl3): ꢀ 149.8, 142.9, 137.9, 136.1, 128.7,
127.7, 127.6, 124.3, 123.9, 123.1, 123.0, 59.6, 28.1, 31.1,
29.7. MS m/z 623.5 [M + H]+.
1
(R,R)-8a: yellowish oil. H NMR (200 MHz, CDCl3): ꢀ
pyridineimine)
4
were low to moderate levels of
8.82 (bs, 2 H), 6.71 (m, 2 H), 6.18 (m, 2 H), 6.01 (m, 2 H),
3.98 (q, J = 6.3, 2 H), 2.29-2.35 (m, 2 H), 1.98 (d , J = 17.8,
2 H), 1.63-1.79 (m, 2 H), 1.38 (d , J = 6.3, 6 H), 1.17-1.29
(m, 2 H), 0.83-1.04 (m, 4 H). MS m/z 301.4 [M + H]+.
stereocontrol achieved. Unsatisfactory results were obtained
when two of the diamines prepared were used as ligands in
the enantioselective Cu(II)-catalyzed Henry reaction.
1
(R,R)-10a: yellowish oil. H NMR (200 MHz, CDCl3): ꢀ
EXPERIMENTAL SECTION
8.55 (dd, J = 1.8, J = 4.8, 2 H), 7.31 (dd, J = 1.4, J = 4.4, 2
H), 3.84 (q, J = 6.2, 2 H), 2.31 (dd, J = 3.6, J = 5.2, 2 H),
2.01 (bs, 2 H), 1.79 (d , J = 13.6, 2 H), 1.50-1.62 (m, 2 H),
1.35 (d, J = 6.2, 6 H), 0.89-1.18 (m, 4 H). 13C NMR (50
All the diimines were prepared by the same general
procedure [11] and have been previously described: 1, [12]
2, [18] 3, [19] 4, [20] 5, [21].
Table 2. Enantioselective Copper-Catalyzed Henry Reactions to Give Compound 13a
L (6 mol%)
R
Cu(OAc)2 (mol%)
Conversion (%)a
e.e. (%)b
14
H
5
5
5
90
39
96 (S)
56 (S)
-
(R,R)-7a
(R,R)-7c
Me
Ph
traces
aDetermined by 1H NMR analysis. bDetermined by chiral HPLC analysis.

438 Letters in Organic Chemistry, 2009, Vol. 6, No. 6
Savoia et al.
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ACKNOWLEDGEMENTS
[7]
This work was carried out in the field of the Prin Project:
“Sintesi e stereocontrollo di molecole organiche per lo
sviluppo di metodologie innovative" and with the
fundamental contribution by Fondazione del Monte di
Bologna e Ravenna.
[8]
[9]
[10]
[11]
[12]
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