Low Valent Titanium Mediated Imino-Pinacol Coupling: An Improved and Expeditious Route to Vicinal Diamino-Based Ligands

Full text of DOI:10.1021/jo9716892

3468
J . Org. Chem. 1998, 63, 3468-3470
indirect and multistep protocols, use of substrates such
Low Va len t Tita n iu m Med ia ted
as olefins8 or 1,2-dicarbonyls9a,b or amino acid esters10 was
reported.
Im in o-P in a col Cou p lin g: An Im p r oved
a n d Exp ed itiou s Rou te to Vicin a l
Dia m in o-Ba sed Liga n d s
Our experience with LVT reagents3,4a-f for the reduc-
tive coupling of carbonyls prompted us to explore the
scope of this reagent toward the reduction of the corre-
sponding nitrogen analogues (imino-pinacol coupling).
We envisaged that analogous to carbonyl coupling
reaction,5a-e the imino-pinacol coupling probably would
also proceed through a single electron transfer (SET)
mechanism via a radical anion intermediate (2, Scheme
1). In principle, the intermediate 2 can undergo dimer-
ization to diamines 3 by bimolecular process (path a) or
can be quenched by hydrogen from the medium to give
unimolecularly reduced amines 4 (path b). In fact, the
serious shortcoming of the earlier report7h on the syn-
thesis of vicinal diamines via reductive dimerization of
imines using LVT reagent (generated in situ from TiCl4-
Mg/Hg-THF, stoichiometrically TiII) is the low yields due
to concomitant formation of amines as a result of
competitive7k unimolecular reduction of imines, in addi-
tion to extended reaction time. In the present investiga-
tion, this point has been addressed. The rationale for
the present approach is to direct the reaction to follow
path a (bimolecular process) in preference to path b
(unimolecular process).
Sanjay Talukdar and Asoke Banerji*
Bio-Organic Division, Bhabha Atomic Research Centre,
Mumbai (Bombay)-400 085, India
Received September 9, 1997
Vicinal diamines find extensive applications in radio-
pharmaceuticals1a-c and as complexing agents and chiral
auxiliaries.2a,b In connection with our ongoing program
on nuclear medicine, an efficient route to vicinal diamino-
based ligands was needed. Recently, we have been
exploring the potential of low valent titanium (LVT)
induced carbonyl-olefin McMurry coupling reaction in
a multitude of synthetic endeavors.3,4a-f Although reduc-
tive coupling of carbonyls to vicinal diols using different
LVT reagents5a-e has been extensively studied, analogous
reactions involving carbon-nitrogen functions to the
corresponding 1,2-diamino compounds are less common.6
Although vicinal diamino units occur frequently in
natural products and medicinal agents, not many general
routes for their preparation are reported. Reductive
dimerization of imines offers attractive possibilities for
the direct access to vicinal diamines. A variety of
reductants7a-m including active metals have been devel-
oped for this purpose, viz., samarium(II) iodide,7a-c
indium,7d Pb/Al bimetal redox system,7e Zn-Cu couple,7f
niobium,7g LVT,7h and electrochemical reduction.7i In the
Resu lts a n d Discu ssion
Transformation of N-benzylideneaniline (1a ) to N,N′-
diphenyl-1,2-diphenyl-1,2-ethanediamine (3a ) was chosen
as a model reaction (Scheme 1). To optimize the reaction
conditions, different sources5a-e of LVT were tried. Use
of TiCl3-Mg-DME (reagent A) as the source of LVT
species gave 3a in 52% yield at 25 °C (Table 1, entry 1).
When Li was used as the reducing metal instead of Mg
as in TiCl3-Li-DME (reagent B) (Table 1, entry 2), the
yield of 3a showed slight improvement, though the
coupling proceeded slowly (5.5 h). Change of the solvent
from DME to THF, i.e., use of TiCl3-Mg-THF (reagent
C) improved the yield of 3a to 62%, requiring 3.5 h (Table
1, entry 3). However, best results were obtained using
TiCl3-Li-THF (reagent D) when 3a was obtained in 78%
yield within only 2.5 h (Table 1, entry 4). Therefore, the
reagent D was used for subsequent studies. It is impor-
tant to note that the diamine 3a was the only product in
all the experiments described above. However, when the
reaction was carried out at reflux temperature using
reagent D, a mixture of three different products was
obtained. These were characterized as 3a (26%), N-
benzylaniline (4a , 25%), and bibenzyl (5, 30%) (Table 1,
entry 5). Formation of 3a , 4a , and 5 from 1a under
refluxing conditions is conceivable through the interme-
diacy of a ketyl-like radical (2a ). The dimerization of the
radical 2a followed by aqueous workup results in the
formation of vicinal diamine 3a . However, the facile
(1) (a) J urisson, S.; Berning, D.; J ia, W.; Ma, D. Chem. Rev. 1993,
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1990, 20, 981. (b) Liao, P.; Huang, Y.; Zhang, Y. Synth. Commun. 1997,
27, 1483 and references therein. (c) Aurrecoechea, J . M.; Ferna´ndez-
Acebes, A. Tetrahedron Lett. 1992, 33, 4763. (d) Kalyanam, N.;
Venkateswara Rao, G. Tetrahedron Lett. 1993, 34, 1647. (e) Tanaka,
H.; Dhimane, H.; Fujita, H.; Ikemoto, Y.; Torii, S. Tetrahedron Lett.
1988, 29, 3811. (f) Shimizu, M.; Iida, T.; Fujisawa, T. Chem. Lett. 1995,
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J . Synthesis 1988, 255. (i) Tanaka, H.; Nakahara, T.; Dhimane, H.;
Torii, S. Synlett. 1989, 51. (j) von Betschart, C.; Seebach, D. Helv. Chim.
Acta 1987, 70, 2215. (k) Eisch, J . J .; Kaska, D. D.; Peterson, C. J . J .
Org. Chem. 1966, 31, 453. (l) J ones, D. S.; Srinivasan, A.; Kasina, S.;
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S0022-3263(97)01689-7 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/28/1998

Notes
J . Org. Chem., Vol. 63, No. 10, 1998 3469
Sch em e 1
Ta ble 1. Red u ctive Dim er iza tion of
N-Ben zylid en ea n ilin e (1a ) Usin g Differ en t LVT Rea gen ts
underwent reactions to give diamines 3 (Table 2, entries
1-9). The method holds good for aldimines where either
of the aldehyde or amine component is nonaromatic.
Thus, it is applicable to aldimines containing alkyl
amines (Table 2, entries 8 and 9) as well as alkyl
aldehyde (Table 2, entry 7) residue. As is seen from the
Table 2 the electronic factors have little influence on the
reactivity of imines. Thus, strongly electron donating
(+R) groups, e.g., 2-OMe, 4-Me2N, and 4-Me (Table 2,
entries 3, 5, and 6) do not have significant influence on
the reaction time or on the yield. Similarly, the electron-
attracting inductive (-I) effect of chlorine (where -I >
+R) also have marginal influences (Table 2, entries 2 and
4). The compatibility of methoxy,4c chloro,12c and
N-benzyl12a,b functionalities (Table 2, entries 2-4 and 8)
which remain unaffected under the present experimental
condition is noteworthy.
The vicinal diamines (3a -i) were obtained as diaster-
eomeric (dl:meso) mixtures. The stereochemical assign-
ments of the vicinal diamines were made by comparing7
the resonances of the benzylic (C1-C2 methine) protons
for the dl (upfield signals) and meso (downfield signals)
isomers (except for the compound 3g) as reported7m by
Smith et al. A chromatographically pure diastereomeric
mixture was used for the analysis.
time (h),
temp (°C)
product(s)
(% yield)
entry
reagent
1
2
3
4
5
TiCl3-Mg-DME (A)
TiCl3-Li-DME (B)
TiCl3-Mg-THF (C)
TiCl3-Li-THF (D)
TiCl3-Li-THF (D)
3.5, 25
5.5, 25
3.5, 25
2.5, 25
5, reflux
3a (52)
3a (58)
3a (62)
3a (78)
3a (26), 4a (25),
5 (30)
Ta ble 2. Dim er iza tion of Ald im in es (R3 ) H, 1) a t 25 °C:
Gen er a tion of Vicin a l Dia m in es (3)
% yielda
(dl:meso)b
entry
R1
R2
compd time (h)
of 3
ref
1
2
3
4
5
6
7
8
9
Ph
Ph
1a , 3a
1b, 3b
2.5
3
3.5
2.5
3
3
5
3
2.5
78 (75:25) 7k
76 (57:43) 7d
72 (29:71) 7m
65 (60:40) 7m
79 (73:27) 7b
83 (70:30) 7m
2′-ClC6H4 Ph
Ph
Ph
Ph
Ph
Ph
PhCH2
c-C6H11
2′-MeOC6H4 1c, 3c
4′-ClC6H4 1d , 3d
4′-Me2NC6H4 1e, 3e
4′-MeC6H4
c-C6H11
Ph
1f, 3f
1g, 3g
1h , 3h
1i, 3i
62
7a
72 (67:33) 7a
70 (27:73) 7a
Ph
a
All yields refer to isolated products (purity > 95%, analyzed
by 1H NMR); no significant amounts of other products were
detected. The products were fully characterized by IR and 1H
b
NMR. dl:meso ratio was obtained from 1H NMR.
The present LVT reagent (TiCl3-Li-THF, mostly in
zerovalent state5d) offers significant improvements over
the earlier method7h (generated in situ from TiCl4-Mg/
Hg-THF, stoichiometrically bivalent Ti), by reducing the
reaction time considerably (2.5-5 h compared to ∼12 h),
simplifying the workup procedure, and, above all, aug-
menting the yield of the desired diamines; the most
marked examples are 1a and 1h , where the yields of the
diamines 3a and 3h increased from 41% and 51% to 78%
and 72%, respectively. In the earlier case,7h the forma-
tion of unimolecularly reduced amines 4a and 4h (50%
and 30% respectively) actually decreases the yields of 3a
and 3h .
delivery of H• radical by THF5c,11 serves to quench a
proportion of the intermediate radical generating the
corresponding unimolecularly reduced N-benzylaniline
(4a ). Formation of 5 can be explained by the cleavage of
the C-N bonds (N-debenzylation) of 3a . This is in
accordance with our earlier observation12a,b of N-benzyl
bond cleavage at reflux temperature using TiCl3-Li-
THF. The generation of bibenzyl from 1,2-diphenyl-1,2-
ethanediamine is in sharp contrast to the fact that olefins
(or stilbenes) are formed from the analogous LVT-
mediated cleavage of 1,2-diols. The reaction at room
temperature did not favor N-benzyl bond cleavage or
unimolecular reduction. Thus, the reaction could be
biased toward the preferential formation of the desirable
products by carrying out it at room temperature (25 °C)
using judiciously selected reagents.
Unlike aldimines, the reactions of ketimines (R3
)
alkyl, aryl, 1j-n ) with reagent D did not yield the dimer
3 (Table 3, entries 1-5), but amines 4 were obtained. The
steric bulk offered by the alkyl/aryl groups in ketimines
biased the unimolecular quenching of the intermediate
ketyl-like radical 2 by THF in preference to dimerization
(path a). The steric effects therefore govern and direct
the course of imine reduction. In addition, aldimines
react faster (2.5-5 h) compared to ketimines (6-12 h).
The C-N double bond can be chemoselectively reduced
in the presence of alkyl acid functionality, thus giving
access to useful amino acid-based ligands. In fact, when
4-phenyl-4-(phenylimino)butanoic acid (1m ) was sub-
jected to LVT reagent, smooth reduction of the imino
group took place, leading to the formation (62%) of the
biochemically important N-substituted γ-amino acid
To explore the scope of the protocol, experiments were
carried out using a variety of imines which were prepared
according to the literature procedures.13 Table 2 presents
examples which illustrate the generality and selectivity
of the transformation. Aldimines obtained from ali-
phatic, alicyclic, or aromatic amines and aldehydes
(11) J ung, J . C.; Choi, H. C.; Kim, Y. H. Tetrahedron Lett. 1993, 34,
3581.
(12) (a) Talukdar, S.; Banerji, A. Synth. Commun. 1995, 25, 813.
(b) Talukdar, S.; Banerji, A. Synth. Commun. 1996, 26, 1051. (c) Tyrlik,
S.; Wolochowicz, I. J . Chem. Soc., Chem. Commun. 1975, 781.
(13) Layer, R. W. Chem. Rev. 1963, 63, 489 and references therein.

3470 J . Org. Chem., Vol. 63, No. 10, 1998
Ta ble 3. Un im olecu la r Red u ction of Ketim in es a t 25 °C: Gen er a tion of Am in es (4)
Notes
ref
entry
R1
Ph
R2
R3
compd
time (h)
% yielda of 4
1
2
3
4
5
Ph
Ph
Me
Et
1j, 4j
6
8
71
65
66
62
58
14a
12b
12b
12b
14b
Ph
Ph
2-naphthyl
2-(1′-OH-naphthyl)
1k , 4k
1l, 4l
12
8
10
Ph
PhCH2
Ph
(CH2)2CO2H
1m , 4m
1n , 4n
b
b
a
b
All yields refer to pure isolated products, fully characterized by IR and 1H NMR. R2R3 ) c-C6H10; i.e., ketone component is
cyclohexanone.
completion (monitored by TLC), the reaction mixture was diluted
with petroleum ether-ethyl acetate mixture (60:40) and passed
through Celite; the organic layer was washed with water and
brine and dried (Na2SO4). Concentration gave the crude product
which was purified by preparative TLC (SiO2) to furnish the
desired product. The yields are reported in Tables 2 and 3.
The vicinal diamines (3a -i) were obtained as diastereomeric
(dl:meso) mixtures. Assignments were made by comparing7 the
C1-C2 methine (benzylic) proton signals for the dl and meso
isomers. The dl and meso ratio was determined by 1H NMR
spectroscopy.
All the vicinal diamines, viz., N,N′-diphenyl-1,2-diphenyl-1,2-
ethanediamine (3a ), N,N′-bis(2′-chlorophenyl)-1,2-diphenyl-1,2-
ethanediamine (3b), N,N′-diphenyl-1,2-bis(2′-methoxyphenyl)-
1,2-ethanediamine (3c), N,N′-diphenyl-1,2-bis(4′-chlorophenyl)-
1,2-ethanediamine (3d ), N,N′-diphenyl-1,2-bis(4′-N,N-dimethyl-
aminophenyl)-1,2-ethanediamine (3e), N,N′-diphenyl-1,2-bis(4′-
methylphenyl)-1,2-ethanediamine (3f), N,N′-diphenyl-1,2-dicy-
clohexyl-1,2-ethanediamine (3g), N,N′-dibenzyl-1,2-diphenyl-1,2-
ethanediamine (3h ), and N,N′-dicyclohexyl-1,2-diphenyl-1,2-
ethanediamine (3i), and the amines, viz., anilinodiphenylmethane
(4j), 1-anilino-1-(2′-naphthyl)ethane (4k ), 1-anilino-1-(1′-hydroxy-
2′-naphthyl)propane (4l), 4-anilino-4-phenylbutanoic acid (4m ),
and N-benzyl cyclohexylamine (4n ), are known compounds and
were characterized by comparison7,12b,14 (mp, 1H NMR, IR) with
authentic samples (Supplementary Information available).
derivative 4-anilino-4-phenylbutanoic acid (4m ) (Table
3, entry 4). Imines obtained from cyclic ketones can also
be reduced successfully to generate amines. Thus, N-
benzylcyclohexylamine (4n ) was obtained in 58% yield
from N-cyclohexylidinebenzylamine (1n ) (Table 3, entry
5).
In conclusion, an efficient one-step synthesis of vicinal
diamines from easily accessible aldimines has been
developed which essentially involves a carbon-carbon
bond formation step. The reaction is operationally simple
and can be performed chemoselectively in the presence
of a number of otherwise easily reducible functionalities
and is general for aldimines obtained from both aliphatic
and aromatic precursors. The protocol holds considerable
promise for the synthesis of nitrogen-containing macro-
cycles of contemporary interest via reductive intramo-
lecular coupling of dialdimines. Work in this direction
leading to the synthesis of medicinally important pip-
erazine derivatives and aza-crown ethers are currently
under progress in this laboratory.
Exp er im en ta l Section
Gen er a l Meth od s. General information regarding instru-
ments and techniques used are the same as mentioned in our
previous publication.4a
Sta r tin g Ma ter ia ls. All imines were prepared from the
respective carbonyls and amines by known methods.13 Lithium
rods cut into small pieces were used for the reduction of TiCl3.
Su p p or tin g In for m a tion Ava ila ble: Experimental data
for 3a -i and 4j-n (2 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
Gen er a l P r oced u r e for th e Red u ction of Im in es.
A
J O9716892
mixture of TiCl3 (964 mg, 6.25 mmol) and lithium (144 mg, 20.6
mmol) was refluxed (3 h, argon) in dry THF (70 mL). To the
LVT reagent thus prepared was added an appropriate imine (2.5
mmol, 5 mL THF) and the reaction mixture was stirred at 25
°C for a specified period of time (Table 2, Table 3). After the
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