Homocoupling of aldimines mediated by zirconocene: Synthesis of vicinal diamines and imidazolidines

Article abstract of DOI:10.1016/j.tetlet.2011.01.075

The reductive coupling of imines in the presence of the lanthanide-originated zirconocene equivalent allows the synthesis of vicinal diamines or imidazolidines under mild conditions in good yields with high diastereoselectivity.

Full text of DOI:10.1016/j.tetlet.2011.01.075

Tetrahedron Letters 52 (2011) 1348–1350
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Tetrahedron Letters
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Homocoupling of aldimines mediated by zirconocene: synthesis of vicinal
diamines and imidazolidines
Mohamad Soueidan a, Florence Hélion a, , Jean-Louis Namy a, Jan Szymoniak b
⇑
a Equipe de Catalyse Moléculaire, CNRS (UMR 8182), ICMMO, Bât 420, Université Paris-Sud, 91405 Orsay, France
b Institut de Chimie Moléculaire de Reims, CNRS (UMR 6229), Université de Reims, 51687 Reims Cedex 2, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The reductive coupling of imines in the presence of the lanthanide-originated zirconocene equivalent
allows the synthesis of vicinal diamines or imidazolidines under mild conditions in good yields with high
diastereoselectivity.
Received 4 October 2010
Revised 12 January 2011
Accepted 14 January 2011
Available online 20 January 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Lanthanides
Zirconocene
Aldimine coupling
Imidazolidine
The pinacol coupling of imines to vicinal diamines is an impor-
tant reaction in organic synthesis because vicinal diamines1 consti-
tute a class of compounds that have found widespread applications
as medicinal products.2 Furthermore, some vicinal diamines are
used as chiral ligands in asymmetric synthesis3 and as chiral
resolving agents.4 A variety of reductants5 including active metals
have been developed for this purpose: for example, samarium(II)
iodide,5a–c indium,5d Pb/Al bimetal redox system,5e Zn–Cu couple,5f
niobium,5g LVT (low valent titanium).5h In all cases, the diastere-
oselectivity of the reaction (dl and meso) was moderate.
graphic purification of the crude product afforded vicinal diamines
1.
Results are presented in Table 1. 1,2-Diamines 1 were obtained
in good yields (70–95%) and with excellent to total diastereoselec-
tivity: (dl)-isomers were obtained as major products (dl/meso: 91/
9–100/0). In no case was the reduction of aldimines to amines
(R2CH2–NHR1) observed. In contrast, coupling of a N-aryl ketimine
such as phenyl-(1-phenyl-ethylidene)-amine (Table 1, entry 6) un-
der the same conditions was not observed. Only N-phenyl-1-phen-
ylethanamine 2f was obtained in 30% yield. Unfortunately,
attempts to have a procedure catalytic in zirconium failed.11
To explain these results, we propose a mechanistic rationale
involving the initial formation of the zirconaaziridine A and the
successive aldimine (R3 = H) insertion into A affording the azazirc-
onacycle B stereoselectively. Subsequently, the hydrolysis of B
gives diamine (d,l)-1. With ketimines (Table 1, entry 6), the steric
Recently we have explored the potential of Cp2Zr(II),6–8 gener-
ated under mild conditions by reduction of Cp2ZrCl2 with a pure
lanthanide metal (La) or Mischmetall (an alloy of Ce, La, Nd and
Pr), to induce coupling reactions (Scheme 1).9
Herein, we report that the La-generated Cp2Zr(II) can be applied
to the synthesis of vicinal diamines1 and imidazolidines.10 These
products were obtained in good yields with high diastereoselectiv-
ity by reductive couplings of imines under mild conditions.
The optimized procedure for intermolecular reductive coupling
of N-aryl or N-alkyl imines is as follows: a mixture of Cp2ZrCl2
(0.5 mmol) and the powdered La (0.66 mmol) was stirred at
50 °C in 4 mL of THF until a deep red colour appeared (10 min). A
solution of the imine (1 mmol) in 1 mL of THF was then added,
and the reaction was carried out at 50 °C for 12 h. The mixture
was then cooled to room temperature, hydrolysed under argon
by HCl 0.1 M and extracted with dichloromethane. The chromato-
R
R
R
R
R
R
R = Ph, 86%
R = n-Pr, 93%
THF
3 Cp2Zr + 2 LnCl3
3 Cp2ZrCl2 + 2 Ln
N
Ph
R
Ln = La, Ce, Mischmetall
PMP
NHPMP
R
Ph
R = Ph, 81%
R = n-C5H11, 83%
⇑
Corresponding author. Tel.: +33 1 69 15 47 43; fax: +33 1 69 15 46 80.
E-mail address: florence.helion@u-psud.fr (F. Hélion).
Scheme 1. Coupling reactions induced by Cp2Zr/LnCl3.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.075

M. Soueidan et al. / Tetrahedron Letters 52 (2011) 1348–1350
1349
Table 1
Bu
Ph
Coupling of N-aryl imines: formation of vicinal diamines 1
H
N
BuN
Ph
NBu
Ph
Ph
H
1) La, THF, 10 min, 50°C
R1HN
R2
NHR1
R2
+
Cp2ZrCl2
1) La, THF, 10 min, 50°C
Cp2ZrCl2
N
H
Bu
H
H
Ph
R1
N
N
Bu
3g
R3 R3
2)
, THF, 0.5-12h, 50°C
1g
2)
, THF, 12h, 50°C
Ph
H
R2
R3
1
3) HCl 0.1 M
Scheme 3. Reaction of benzylidene–butylamine.
3) HCl 0.1 M
Entry
R1
R2
R3
Products, yielda (%) (dl/meso)b
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
n-C4H9
n-C5H11
n-C3H7
n-C3H7
Ph
H
H
H
H
H
Me
H
H
H
H
1a, 70 (91/9)
1b, 76 (94/6)
1c, 95 (94/6)
1d, 94 (95/5)
1e, 70 (100/0)
1f, 0c
1g, 90 (100/0)
1h, 85 (90/10)
1i, 90 (100/0)
1j, 85 (100/0)
Table 2
Formation of imidazolidines 3
p-MeO–C6H4
p-Me2N–C6H4
p-Me–C6H4
Naphthyl
Ph
R1
R2
R2
R2
1) La, THF, 10 min, 50°C
H
H
N
Cp2ZrCl2
R1
Ph
Ph
H
N
R1
N
2)
, THF, 1.5-12h, 50°C
p-Me–C6H4
p-MeO–C6H4
R2
H
3
10
3) HCl 0.1 M
a
Isolated yields: entries 1–6: purification by chromatography, entries 7–10:
purification by CeliteÒ filtration.
Entry
R1
R2
T (h)
Products, yield (%)
b
Ratio determined by 1H NMR.
Only 50% of phenyl-(1-phenyl-ethylidene)-amine was converted to N-phenyl-
1
2
3
4
5
6
7
n-C4H9
n-C5H11
n-C3H7
n-C3H7
n-C3H7
n-C3H7
n-C3H7
Ph
Ph
1.5
1.5
1.5
1.5
1.5
1.5
3g, 83
3h, 82
3i, 85a
3j, 75
3m, 80
3n, 78
3o, 70
c
1-phenylethanamine 2f (isolated yield 30%).
p-Me–Ph
p-MeO–Ph
Ph
Furanyl
Pyridinyl
bulk would prevent the formation of B12 from A. Interestingly, the
formation of A is supported by a partial (50%) incorporation of deu-
terium into 2f after deuterolysis. Besides, the reaction of a N-trim-
ethylsilylzirconaaziridine with an N-trimethylsilylimine gives the
expected (d,l)-diamine as a major product (isolated yield 78%, dl/
meso: 98/2).13 Moreover, it is generally admitted that radical cou-
pling of imines gives meso-diamines as major products.5k,o,14
Therefore, the formation of the (d,l)-vicinal diamine 1 with an
excellent stereoselectivity gives support to the mechanistic
Scheme 2.
The monitoring of the benzylidene–phenylamine coupling reac-
tion showed a rapid conversion to diamine 1a (after 20 min, 80%
conversion was observed, based on 1H NMR analysis of the crude
product). Nevertheless, the total conversion was obtained after
12 h. Unexpectedly, a similar monitoring with N-alkyl aldimines
such as benzylidene–butyl-amine showed that imidazolidine 3g
was obtained together with diamine 1g (Scheme 3). The ratio dia-
mine 1g/imidazolidine 3g gradually increased, 1g being the major
product after the 4 h-reaction time. Analogous observations have
been reported recently.15
12
5% of the diamine 1i was observed in the crude product (determined by 1H
NMR).
a
isomers were obtained.16 It would be noticed that diazazircona-
cyclopentanes B do not react directly with additional equivalent
of imines since imidazolidines 3 are obtained in very low yields
when reactions are performed for a long period but with a short-
time hydrolysis. Besides, it is known that acidic hydrolysis condi-
tions are compatible with the hydrolysis of N-alkylimines to alde-
hydes and the formation of imidazolidines.15b,17 Consequently, the
formation of imidazolidines 3 can be rationalized as follows: imi-
nes are partly converted (1.5 mmol of imine for 0.5 mmol of zirco-
nocene) to diazazirconacyclopentanes B. During hydrolysis, B gives
corresponding diamines 1 and residual N-alkyl aldimines are
hydrolysed to aldehydes, thus diamines 1 react slowly (12 h) with
aldehydes to give corresponding imidazolidines 3 (Scheme 4).
An additional experiment showed that under hydrolysis condi-
tions applied, metallic species (from Zr or La) were not involved in
the reaction of diamines with aldehydes to give imidazolidines 3.
Since a mixture of diamine 1g, benzaldehyde, HCl 0.1 M in THF,
yields in a 12 h-reaction time the imidazolidine 3g.
Synthesis of imidazolidines 3 was optimized by using 1.5 mmol
of alkyl-imines instead of 1 mmol as described above. Hydrolysis
was completed after 12 h. Results are collected in Table 2. It should
be mentioned that N-alkyl aldimines were converted to imidazoli-
dines 3 in good yields (70–85%) except for 3o. In all cases only dl
It can be noticed that during monitoring the formation of five-
membered ring aminals 3 from N-aryl aldimines was not observed,
Cp2
R1
Cp Cp
Zr
R1
R1
Zr
R1
N
N
R1HN
R2
NHR1
R2
N
N
R1
R2
R1
R1
R3
Cp2Zr/LaCl3
N
N
H
+
R3
R3= H
R2
N
R2 R3
R2 R3
Cp2Zr(II)
ZrCp2
R3
R2
H
R3 R3
R2
R2
B
A
B
H3O
R3= Alk
H3O+
THF or H3O+
R1
R2
R3
R1HN
NHR1
R2
R2
N
R1HN
R2
NHR1
R2
NHR1
O
R3
R1NH3
+
+
H
R2
R3
R2
N
R1
R2 R3
R2
R3 R3
Alk
H
2
(dl)-1
3
1
Scheme 2. Mechanistic proposal for the synthesis of amines 1 and 2.
Scheme 4. Mechanistic proposal for synthesis of imidazolidines 3.

1350
M. Soueidan et al. / Tetrahedron Letters 52 (2011) 1348–1350
Takahashi, T., Ed.; Springer: Berlin, 2005; Vol. 8, Negishi, T. Bull. Chem. Soc.
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7. Earlier works employed Na or Mg as reductants typically in the presence of
alkynes or bipyridine, see for example: (a) Watt, G. W.; Drummond, F. O., Jr. J.
Am. Chem. Soc. 1970, 92, 826–828; (b) Wailes, P. C.; Weigold, H. J. Organomet.
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10. (a) Viso, A.; Fernandez de la Pradilla, R.; Garcia, A.; Guerrero-Strachan, C.;
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probably due to the lesser sensitivity to hydrolysis. When reactions
with N-aryl aldimines were stopped at an early stage, N-aryl aldi-
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N-alkyl aldimines were not recovered.
In conclusion, dimerization of aromatic imines was carried out
by using Cp2Zr(II) to afford the corresponding vicinal diamines 1
in excellent yields and high diastereoselectivity. In addition, we
found a simple method to prepare only dl-isomer five-membered
ring aminals 3 in good yields. These products are interesting in
synthesis as precursors of chiral imidazolinium salts.18 Besides
they constitute important parts of biologically active compounds.17
11. Soueidan, M.; Hélion, F.; Namy, J.-L.; Szymoniak, J. Tetrahedron Lett. 2010, 51,
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Acknowledgements
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We thank the CNRS and the Ministère de l’Enseignement Supé-
rieur et de la Recherche for their financial support.
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16. Materials and methods. All reactions were performed under an atmosphere of
argon using standard Schlenk techniques. Prior to use tetrahydrofuran was
distilled under argon from sodium benzophenone ketyl. 1H NMR spectra were
recorded in CDCl3 on a Brucker 360 AVANCE. Chemical shifts are reported in
delta (d) units, expressed in parts per million (ppm). 13C NMR spectra were
recorded in CDCl3 on a Brucker 250 DPX. Chemical shifts are reported in delta
(d) units, expressed in parts per million (ppm). Coupling constants are
expressed in hertz (Hz). High-resolution mass spectra (HRMS) were obtained
with a MAT-95-S Finnigan. GC–MS were obtained with a DSQ-Thermo electron
instrument. 2,4-(Di-furane-2-yl)-5-(furane-3-yl)-1,3-dipropylimidazolidine (3n):
Purification: eluent pentane/EtOAc (90:10). Yellow oil. Yield (78%). 1H NMR
(CDCl3): d 0.70 (t, J = 7.4, 3H), 0.72 (t, J = 7.4, 3H), 1.20–1.50 (m, 4H), 1.90 (m,
1H), 2.21 (m, 1H), 2.76 (m, 2H), 4.18 (d, J = 7.4, 1H), 4,29 (d, J = 7.4, 1H), 4.89 (s,
1H), 6.20–6.50 (m, 6H), 7.35 (d, J = 1.7, 1H), 7.41 (d, J = 2.1, 1H), 7.43 (d, J = 1.9,
1H). 13C NMR (CDCl3): d 155.7, 155.2, 152.5, 142.3, 142.0, 141.8, 110.0, 109.8,
109.2, 107,1, 78.1, 65.5, 63.5, 56.2, 49.2, 21.8, 20.9, 11.7, 11.5. HRMS: [M+] calcd
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C
21H26N2O3+[Na+] 377.1836; found, 377.1846. 1,3-Dipropyl-2,4,5-
dipyridinylimidazolidine (3o): Purification: eluent pentane/EtOAc (90:10).
Incolored oil. Yield (70%). 1H NMR (CDCl3): d 0.56 (t, J = 7.4, 3H), 0.61 (t,
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