Zn-mediated catalytic photoreduction of aldimines. One-pot synthesis and separation of meso and d,l C2 symmetrical diamines

Article abstract of DOI:10.1016/j.tet.2004.06.029

A new one-pot method for the synthesis and selective separation of 1,2-diamines is reported. The methodology, which involves the photoreduction of imines using catalytic amounts of zinc as a photosensitizer, allows the direct preparation and separation of meso and d,l compounds on a multigram scale.

Full text of DOI:10.1016/j.tet.2004.06.029

Tetrahedron 60 (2004) 6475–6478
Zn-mediated catalytic photoreduction of aldimines. One-pot
synthesis and separation of meso and d,l C symmetrical diamines
2
Mar ´ı a Ortega, Miguel A. Rodr ´ı guez and Pedro J. Campos
*
Departamento de Qu ´ı mica, Universidad de La Rioja, Grupo de S ´ı ntesis Qu ´ı mica de La Rioja, Unidad Asociada al C.S.I.C.,
Madre de Dios, 51, 26006 Logro n˜ o, Spain
Received 3 May 2004; revised 31 May 2004; accepted 7 June 2004
Abstract—A new one-pot method for the synthesis and selective separation of 1,2-diamines is reported. The methodology, which involves
the photoreduction of imines using catalytic amounts of zinc as a photosensitizer, allows the direct preparation and separation of meso and d,l
compounds on a multigram scale.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
The reductive coupling of imines is a useful method for the
1
synthesis of vicinal 1,2-diamines, which are important
2
1
compounds in medicinal and analytical chemistry, as well
as in the field of organic synthesis as chiral catalysts or as
1
,3
metal ligands in asymmetric reactions.
In recent years, investigations have focused on the
4
stereoselective synthesis of 1,2-diamines but, unfortu-
nately, the stereoselectivity of this process has not been
sufficiently improved. Another area of great interest
involves the metal-promoted coupling reaction of imines,
which generally requires stoichiometric amounts or an
Scheme 1.
1
,4
excess of metal complexes. Furthermore, in some cases,
these processes involve a combination of different metal
of aldimines in the presence of different metal complexes
with the expectation that the reaction would take place with
diastereoselectivity. Herein, we report our results from this
investigation.
5
systems.
6
Our experience in the photochemistry of azadienes and
7
imines prompted us to study the photoreduction of
heterocyclic aldimines. As a result, we have previously
reported the acetone-sensitized photoreductive coupling of
2. Results and discussion
8
aldimines (Scheme 1), where the reaction involves the
9
Initially, a set of metal complexes of zinc, cadmium, copper
and cobalt with different non-chiral and chiral ligands were
formation of triplet species which progress giving radical
0
species by hydrogen abstraction of the isopropyl alcohol.
1
1
1
synthesized and tested in the photocoupling reaction of
N-tert-butylbenzaldimine (1a) (Table 1). To test this
methodology, an isopropyl alcohol/acetone solution of
imine 1a was irradiated, through Pyrex glass, in the
presence of increasing amounts of complex derivatives
until total consumption of the starting material had been
achieved.
These radical species are coupled to give a mixture of meso/
d,l symmetrical vicinal diamines in good to excellent yields.
However, in most cases the isolation of each diastereomeric
pair from the crude reaction mixture is particularly difficult.
This fact motivated us to study the photoreductive coupling
Keywords: 1,2-Diamines; Imines; Photoreductive coupling; Zinc-
complexes.
*
Corresponding author. Tel.: þ34-941-299650; fax: þ34-941-299621;
The preliminary results showed that only zinc derivatives
gave the corresponding 1,2-diamines, whereas the rest of the
e-mail address: pedro.campos@dq.unirioja.es
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.06.029

6476
M. Ortega et al. / Tetrahedron 60 (2004) 6475–6478
Table 1.
that a chiral environment was not a prerequisite to obtain
excellent diastereoselectivity (entries 3–6) and, conse-
quently, another factor must be involved in the reaction.
Interestingly, the finding that the ratio of free diamines
3a/2a (Table 2, entries 6–8) was reduced upon increasing
the amount of metal indicates that meso and d,l diamines
interact in a different way with the metal. Indeed, while the
d,l diamines 3a form a Zn–diamine complex, the meso
compound 2a remains free and can be easily isolated by
crystallisation. Subsequent treatment of the Zn–diamine
complex solution with a sulfide salt liberates the d,l
diamines 3a. It can also be seen from entries 5–10 that
catalytic amounts of metal precursor were able to promote
the photoreduction reaction of aldimines.
a
b
Entry
Metal complex
Ratio 2a/3a
c
1
2
3
4
5
6
7
Zn(CH
Zn(Et
Zn(PhCOO)
Cd(CH COO)
3
)
2
L
55/45
85/15
$95/5
c
2
CHCOO)
2
L
c
2
L
c
3
2
L
No reaction
No reaction
No reaction
No reaction
d
Cd(Et
Co(Et
Cu(Et
2
2
2
CHCOO)
CHCOO)
CHCOO)
2
L
2
L
2
L
c
c
a
0.5 equiv. of metal complex for 1.8 mmol of imine 1a.
Free diamines determined by H NMR analysis of the crude mixture.
(R,R)-N,N -ethylenebis(1-phenylmethylamine) was used as the chiral
ligand L.
Cinchonidine was used as the chiral ligand L.
On the other hand, we observed that the combination of
acetone and zinc clearly increases the reaction rate. In this
sense, we studied the effect of the metal complex in the
reaction by performing the irradiation of imine 1a in
isopropyl alcohol with catalytic amounts of Zn complex, but
without acetone (Table 2, entries 9 and 10). Under these
conditions 1,2-diamines could be obtained, which proves
that acetone is not essential in the photocoupling reaction
b
c
1
0
d
complexes did not give any reaction (Table 1, entries 4–7).
We therefore decided to focus our attention on the zinc
complexes. Furthermore, the best selectivity in favour of the
meso form was observed with zinc carboxylate derivatives
1
2
and the zinc complex is able to act as a photosensitizer.
(
Table 1, entries 2 and 3). Diamine 2a could be easily
isolated from the crude reaction mixture by removing the
solvent and then crystallising the residue from isopropyl
alcohol at 0 8C.
Moreover, the use of zinc as a photosensitizer in the
photoreaction allowed us to carry out the reaction on a
multigram scale, as can be seen in Table 3.
Table 3.
The results obtained for different zinc complexes and
reaction conditions are summarised in Table 2. A number of
points warrant particular attention. As shown in entries 1
and 2, the addition of 0.25 equiv. of zinc complex bearing
cinchonidine as a chiral ligand lead to a 2a/3a ratio greater
than 95/5. In an attempt to account for this ligand effect, we
0
carried out the irradiation in the presence of N,N -
ethylenebis(benzylamine) or without ligand. It was found
a
Entry
Photosensitizer
Time
Yield (%)
2
a
3a
Table 2.
b
1
2
3
Acetone
0.05 equiv. of Zn
0.25 equiv. of Zn
14
8
9
84
75
b
c
d
40
35
a
Reaction carried out with 10 mmol of imine 1a.
b
c
d
Isolated yield of isomer mixture after column chromatography.
Isolated yield after crystallisation.
Isolated yield after treatment with sulfide salt and purification.
a
b
Entry
Zn complex
Equiv. Ratio 2a/3a Yield 2a Yield 3a
c d
(
%)
(%)
Table 4.
e
f
1
2
3
4
5
6
7
8
9
Zn(Et
Zn(PhCOO)
Zn(Et CHCOO)
2
CHCOO)
2
L
0.25
0.25
0.25
0.25
0.20
0.20
0.14
0.05
0.20
0.20
$95/5
$95/5
86/14
$95/5
$95/5
$95/5
80/20
60/40
$95/5
$95/5
33
30
31
35
32
36
35
38
40
38
27
24
26
28
26
29
28
31
35
30
e
2
L
2
2
L
f
Zn(PhCOO)
Zn(PhCOO)
2
L
2
Zn(Et
Zn(Et
Zn(Et
Zn(Et
2
2
2
2
CHCOO)
CHCOO)
CHCOO)
2
2
2
2
a
b
Imine
Ar
R
Time
Yield (%)
g
CHCOO)
g
2
a
3a
10
Zn(PhCOO)
2
a
b
c
d
t
Equiv. of Zn complex for 1.8 mmol of imine 1a.
1
1
1
a
b
c
Ph
Ph
p-Tol
Bu
Cy
Bu
9
25
29
40
36
34
35
34
31
1
Free diamines determined by H NMR analysis of the crude mixture.
Yield of isolated diamine 2a after crystallisation.
Yield of isolated diamine 3a after treatment with sulfide salt and
purification.
t
a
Reaction carried out with 10 mmol of imine 1.
e
f
b
Cinchonidine was used as the chiral ligand L.
0
Isolated yield of pure diamines after crystallisation (which gives the meso
compound) followed by treatment with sulfide salt (which leads to the d,l
derivatives).
N,N -ethylenebis(benzylamine) was used as a non-chiral ligand L.
In the absence of acetone.
g

M. Ortega et al. / Tetrahedron 60 (2004) 6475–6478
6477
1
Finally, we extended this methodology to other aryl-
aldimines, which were synthesized by condensation of the
corresponding aldehyde with different primary amines. As
shown in Table 4, irradiation of benzaldimines 1a–c under
catalytic conditions, and without acetone as a photo-
sensitizer, gave similar results to those reported above for
by H NMR spectroscopy). The solvent was then removed
under reduced pressure and a minimum amount of hot
isopropyl alcohol was added to the crude reaction mixture.
The resulting solution was cooled to 0 8C and the
corresponding meso diamine 2a crystallised as white
crystals (650 mg, 2.01 mmol). The meso derivative was
removed and the residue was treated with a 0.65 M solution
1
a.
of Na S until total precipitation of zinc metal as ZnS was
2
observed. The solid was filtered off and the layers separated.
The aqueous layer was extracted with a mixture of isopropyl
alcohol/chloroform 1:3 (3£20 mL). The organic layer was
dried (Na SO ), filtered and the solvent removed under
2 4
3
. Conclusions
In summary, we have developed a new one-pot method for
the synthesis of 1,2-diamines. This methodology, which
involves the photoreduction of imines using catalytic
amounts of zinc as a photosensitizer, allows the easy
synthesis and selective separation of meso and d,l
compounds on a multigram scale.
reduced pressure to give a white solid, which was crystal-
lised from isopropyl alcohol to give the d,l diamines 3a
(570 mg, 1.76 mmol). All diamines used in this work were
obtained as described above and the physical data were
1
3
identical to those reported in the literature.
4
. Experimental
Acknowledgements
4
.1. General procedures
We thank the Ministerio de Ciencia y Tecnolog ´ı a
project BQU2001-1625), the Comunidad Aut o´ noma de
La Rioja (project ANGI2001/29) and the Universidad de La
Rioja (project API-03/08). M. O. thanks the Comunidad
Aut o´ noma de La Rioja for her fellowship.
(
1
13
H and C NMR spectra were recorded on a Bruker ARX-
00 spectrometer in CDCl with TMS as internal standard.
3
3
Electrospray mass spectra were obtained on an HP 5989 B
apparatus with an HP 59987 A interface, in positive-ion
mode with methanol/water/acetic acid (60:35:5) as the
mobile phase. IR spectra were obtained on a Perkin–Elmer
1
000 spectrophotometer. Elemental analyses were obtained
References and notes
using a CE Instrument Model 1110. All solvents were
purified by standard procedures and freshly distilled prior to
use. Reagents were of commercial grade (Aldrich).
Aldimines were prepared by condensation of the corre-
sponding aldehyde with the amine according to a literature
procedure.
1. Lucet, D.; Le Gall, T.; Mioskowski, C. Angew. Chem., Int. Ed.
Engl. 1998, 37, 2581.
2. Michalson, E. T.; Szmuskovicz, J. Prog. Drug. Res. 1989, 33,
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3. Bennani, Y. L.; Hanessian, S. Chem. Rev. 1997, 97, 3161.
4
. (a) Annunziata, R.; Benaglia, M.; Cinquini, M.; Caporale, M.;
Raimondi, L. Tetrahedron: Asymmetry 2002, 13, 2727.
4
4
.2. Metal complex preparation
(
b) Hirao, T.; Hatano, B.; Imamoto, Y.; Ogawa, A. J. Org.
.2.1. Ligand preparation. Chiral and non-chiral diamines
Chem. 1999, 64, 7665. (c) Talukdar, S.; Banerji, A. J. Org.
Chem. 1998, 63, 3468. (d) Taniguchi, N.; Uemura, M. Synlett
1997, 51. (e) Shimizu, M.; Iida, T.; Fujisawa, T. Chem. Lett.
1995, 609, and references quoted therein.
1
1
were prepared according to the literature from 1,2-
dibromomethane and the corresponding amine. The chiral
amino alcohol cinchonidine is commercially available.
5
. Machrouhi, F.; Namy, J.-L.; Nief, F. Tetrahedron Lett. 1999,
40, 1315.
4.2.2. Zinc complex preparation. The synthesis and
spectroscopic data are identical to those reported in the
literature.
6. (a) Campos, P. J.; Caro, M.; Rodr ´ı guez, M. A. Tetrahedron
Lett. 2001, 42, 3575. (b) Campos, P. J.; A n˜ o´ n, E.; Malo, M. C.;
Rodr ´ı guez, M. A. Tetrahedron 1999, 55, 14079. (c) Campos,
P. J.; A n˜ o´ n, E.; Malo, M. C.; Rodr ´ı guez, M. A. Tetrahedron
1998, 54, 14113. (d) Campos, P. J.; A n˜ o´ n, E.; Malo, M. C.;
Rodr ´ı guez, M. A. Tetrahedron 1998, 54, 6929. (e) Campos,
P. J.; Tan, C.-Q.; A n˜ o´ n, E.; Rodr ´ı guez, M. A. J. Org. Chem.
1996, 61, 7195.
1
1
Zinc carboxylates were prepared by reaction of ZnO with
the corresponding carboxylic acid in toluene at 120 8C with
azeotropic distillation of water. To a solution of zinc
carboxylates was added the appropriate ligand to give the
different zinc complexes.
7
. (a) Campos, P. J.; Soldevilla, A.; Sampedro, D.; Rodr ´ı guez,
M. A. Org. Lett. 2001, 3, 4087. (b) Campos, P. J.; Soldevilla,
A.; Sampedro, D.; Rodr ´ı guez, M. A. Tetrahedron Lett. 2002,
4.3. Typical procedure for the irradiation and selective
separation of benzaldimines
4
3, 8811.
A solution of benzaldimine 1a (1.610 g, 10 mmol) and
Zn(Et CHCOO) (600 mg, 1 mmol) in isopropyl alcohol
8. Campos, P. J.; Arranz, J.; Rodr ´ı guez, M. A. Tetrahedron 2000,
56, 7285.
2
2
(
50 mL) was bubbled with argon and irradiated through
9. The presence of triplet quenchers as oxygen inhibited the
formation of diamine. In contrast, the presence of a triplet
photosensitizer as acetone increased the reaction rate. See
Ref. 8.
Pyrex, at room temperature under an Ar atmosphere, using a
medium-pressure mercury lamp (400 W) until complete
consumption of starting material was observed (monitored

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M. Ortega et al. / Tetrahedron 60 (2004) 6475–6478
1
0. In the photoreduction process the solvent act as a source of
hydrogen. Solvents without hydrogen donor capability, as tert-
butyl alcohol or n-hexane, are ineffective in the photoreaction
coupling. See Ref. 8.
transferring energy to a second molecular entity, which is
thereby raised to a higher energy state. See Braslavsky, S. E.;
Houk, K. N. Handbook of Organic Photochemistry; Scaiano,
J. C., Ed.; CRC: Boca Raton, USA, 1989; Vol. 2, p 425,
Chapter 23.
1
1
1. Mimoun, H.; Yves de Saint Laumer, J.; Giannini, L.;
Scopelliti, R.; Floriani, C. J. Am. Chem. Soc. 1999, 121, 6158.
2. Photosensitization is a process in which an excited state with
the appropriate energy (e.g., a triplet) of one molecular entity
13. Mangeney, P.; Tejero, T.; Alexakis, A.; Grosjean, F.;
Normant, J. Synthesis 1988, 255. Enholm, E. J.; Forbes,
D. C.; Holub, D. P. Synth. Commun. 1990, 20, 981.
(
photosensitizer) is deactivated to a lower-lying state by