An efficient method for the preparation of vicinal tertiary diamines by reductive coupling of aminoacetals mediated by low valent titanium iodide species

Article abstract of DOI:10.1246/cl.2001.1334

Aminoacetals, easily prepared by condensation of aromatic aldehydes, secondary amines and alcohols, are reductively coupled by using low valent titanium iodide species to afford the corresponding coupling products, vicinal tertiary diamines, in good to hi

Full text of DOI:10.1246/cl.2001.1334

1334
Chemistry Letters 2001
An Efficient Method for the Preparation of Vicinal Tertiary Diamines by Reductive Coupling of
Aminoacetals Mediated by Low Valent Titanium Iodide Species
Naritoshi Yoshimura and Teruaki Mukaiyama*
Department of Applied Chemistry, Faculty of Science, Science University of Tokyo, Kagurazaka, Shinjuku-ku, Tokyo 162-8601
(Received October 3, 2001; CL-010972)
Aminoacetals, easily prepared by condensation of aromatic
aldehydes, secondary amines and alcohols, are reductively cou-
pled by using low valent titanium iodide species to afford the
corresponding coupling products, vicinal tertiary diamines, in
good to high yields under mild reaction conditions.
There are many natural products containing vicinal diamine
function and some of which have interesting biological proper-
ties and are used synthetic precursors in medicinal chemistry.1
Further, vicinal diamines are frequently employed in organic
synthesis, especially in the field of catalytic asymmetric synthe-
sis. Various synthetic methods were studied intensively for the
preparation of vicinal diamines and one of the most popular pro-
cedures was the coupling of two nitrogen-containing substrates
by carbon–carbon bond forming reaction. Concerning reductive
coupling of imines affording the corresponding vicinal second-
ary diamines, for example, various effective reducing reagents
were reported,1 among which low valent titanium (LVT) com-
pounds proved to be particularly effective.2 Also, some direct
methods for the formation of vicinal tertiary diamines, that is,
reductive coupling of iminium salts3,4 or aminals4 and deoxy-
genative coupling of amides5 and so on were reported. Further,
it was reported by Seebach and co-workers3,4 that reductive cou-
pling of the substrates which were synthetically equivalent to
iminium salts by using excess amounts of LVT derived from
titanium(IV) chloride (TiCl4) and potassium or magnesium
afforded the corresponding vicinal tertiary diamines. In the
above reactions, the substrates were prepared by initial forma-
zinc8 in tetrahydrofuran (THF) (Table 1). Similar to the case of
coupling of dithioacetal,6b addition of copper was not effective
for the present reaction. On the other hand, desirable reaction
was promoted moderately by addition of zinc which afforded
the corresponding vicinal tertiary diamine, 1,2-bis(diethyl-
amino)-1,2-diphenylethane, in good yield at the temperatures
ranging from room temperature to 55 °C (entries 1–5). When
zinc was further added to the supernatant solution of zinc-treat-
ed LVTI,9 the coupling proceeded smoothly to afford the
desired vicinal tertiary diamine in excellent yield at the temper-
atures ranging from 0 °C to room temperature. When the reac-
tions were carried out at lower temperature, this coupling also
afforded the diamines after a prolonged reaction time (entries 6
– 9). Concerning the amounts of zinc, double molar amounts of
the respective initial and additional zinc to TiI4 gave a most
effective reductant, which promoted the reaction smoothly10
(entries 7 and 10–17). Incidentally, in the absence of TiI4, that
is, when the reaction was carried out by using only zinc, it did
not proceed at all,11 which indicated that LVTI was essential for
this reaction (entry 18).
tion of adducts from aromatic aldehydes and lithium dialkyl-
amides and the subsequent treatment with TiCl4.
Recently, it was reported from our laboratory that a newly
utilized low valent titanium iodide (LVTI) species generated by
treating titanium(IV) iodide (TiI4) with copper or zinc was an
effective reducing reagent in coupling reactions of aldehydes
and dithioacetals to afford various vicinal diols and vicinal
bis(alkylthio) derivatives, respectively, in good to high yields
under mild reaction conditions.6 Therefore, it was expected
that treatment of aminoacetals, which were easily prepared
from aromatic aldehydes, secondary amines and alcohols,7 with
LVTI would afford vicinal tertiary diamines; the reduction was
considered to proceed by selective abstraction of alkoxy group
of aminoacetal because titanium has stronger affinity for oxy-
gen and thus the resulted two radical intermediates coupled to
give the vicinal tertiary diamine. In this communication, we
would like to report an efficient method for the direct prepara-
tion of various vicinal tertiary diamines by reductive coupling
of aminoacetals with LVTI.
In the first place, α-(diethylamino)benzyl ethyl ether was
used as a substrate in reductive coupling by using supernatant
solution of LVTI generated by treating with TiI4 and copper or
Based on the above results, reductive coupling reaction of
various other aminoacetals using the above LVTI was next
Copyright © 2001 The Chemical Society of Japan

Chemistry Letters 2001
1335
lead to the formation of a mixture of dl- and meso-diastere-
omers of vicinal tertiary diamine.
Then, reactivities of acetal, dithioacetal and aminoacetal in
reductive coupling by using LVTI in dichloromethane–pivalo-
nitrile (CH2Cl2–tBuCN)6 or THF were compared (Table 3). In
the cases of using CH2Cl2–tBuCN as a solvent, dithioacetal
smoothly reacted within 1 h and acetal also coupled in a pro-
longed reaction time while complex mixtures resulted on treat-
ing highly reactive aminoacetal (entries 1–3). When THF was
used, on the other hand, aminoacetal successfully gave the cou-
pling product while neither acetal nor dithioacetal reacted at all
(entries 4–6). These results suggested that THF solvated the
LVTI to decrease its reactivity appropriately, and thus the cou-
pling of reactive aminoacetal proceeded smoothly.
Thus, an efficient method for direct preparation of vicinal
tertiary diamines by reductive coupling of aminoacetals was
established by using reactive LVTI in THF under mild reaction
conditions.
References and Notes
1
For a review, see: D. Lucet, T. Le Gall, and C. Mioskowski, Angew.
Chem. Int. Ed., 37, 2580 (1998) and references cited therein.
For reviews, see: a) G. M. Robertson, in “Comprehensive Organic
Synthesis,” ed. by B. M. Trost and I. Fleming, Pergamon Press,
Oxford (1991), Vol. 3, p 563. b) T. Wirth, Angew. Chem., Int. Ed.
Engl., 35, 61 (1996). c) A. Fürstner and B Bogdanovic, Angew.
Chem., Int. Ed. Engl., 35, 2442 (1996). Recent reports of preparation
of vicinal diamines by reductive coupling of aldimines mediated by
LVT, see: d) S. Talukdar and A. Banerji, J. Org. Chem., 63, 3468
(1998). e) S. Rele, S. Talukdar, A. Banerji, and S. Chattopadhyay, J.
Org. Chem., 66, 2990 (2001).
2
examined (Table 2). Concerning the amino group in aminoac-
etals, both acyclic and cyclic derivatives were applicable
(entries 1–3). With regard to the substituents on phenyl groups,
various electron-donating and electron-withdrawing sub-
stituents gave nearly equal influence on reactivities (entries 4–
7). Furthermore, other substrates which had hetero-aromatic
ring reacted similarly to give the coupling products in good
yields although the yields of these diamines were previously
reported3 to be rather low (entries 8–10). In addition, various
alkoxy groups and an alkylthio group behaved nearly the same
as leaving group (entries 11–13). Incidentally, diastereoselec-
tivities of this coupling reaction gave nearly the same results in
all cases (dl / meso ~ 1).
This reaction is thought to proceed as follows; that is, reac-
tive LVTI preferentially abstracts an alkoxy (or alkylthio)
group over an amino group of an aminoacetal because of the
stronger affinity of titanium for oxygen. And the resulted
naked α-(dialkylamino)benzyl radical intermediates are not
sterically controlled and couple at random conformations to
3
4
5
6
C. Betschart and D. Seebach, Helv. Chim. Acta, 70, 2215 (1987) and
references cited therein.
C. Betschart, B. Schmidt, and D. Seebach, Helv. Chim. Acta, 71, 1999
(1988).
K. Selvakumar and J. F. Harrod,. Angew. Chem. Int. Ed., 40, 2129
(2001).
a) T. Mukaiyama, N. Yoshimura, K. Igarashi, and A. Kagayama,
Tetrahedron, 57, 2499 (2001). b) N. Yoshimura, K. Igarashi, S.
Funasaka, and T. Mukaiyama, Chem. Lett., 2001, 640.
a) J.-P. Quintard, B. Elissondo, and B. Jousseaume, Synthesis, 1984,
495. b) P. J. Smith and M. Amin, Can. J. Chem., 67, 1457 (1989).
Copper powder was used after drying under vacuum at 100 °C. Zinc
powder was activated before use with 1 M aqueous hydrochloric acid
and washed with water and ether, then dried under vacuum at 100 °C.
A typical reaction procedure for the reductive coupling of α-(diethy-
lamino)benzyl ethyl ether corresponding to Table 1, entry 7: to TiI4
(1.11 g, 2.0 mmol) and zinc powder (0.26 g, 4.0 mmol) was added
THF (10 mL) under argon atmosphere. The color was changed
immediately to dark brown and the mixture was further stirred for 3 h
at room temperature. Resulted dark brown supernatant solution (6.5
mL, 1.3 mmol Ti) was added to additional zinc powder (0.170 g, 2.6
mmol) and the mixture was stirred for another 30 min. Resulted dark
brown suspension was cooled to 0 °C and α-(diethylamino)benzyl
ethyl ether (0.207 g, 1.0 mmol) was added. The reaction mixture was
further stirred for 3 h, and then saturated aqueous sodium hydrogen-
carbonate was added. The mixture was filtered and extracted with
dichloromethane, and the organic layer was washed with saturated
aqueous sodium chloride, dried over sodium sulfate. After filtration
and concentration, the crude product was purified by thin layer chro-
matography to afford the desired vicinal tertiary diamine (dl-isomer
0.070 g, 43% yield, meso-isomer 0.084 g, 52% yield).
7
8
9
10 When TiCl4 and TiBr4 were employed in place of TiI4 using double
molar amounts of the respective initial and additional zinc, the yields
of diamine decreased (72% yield [ dl / meso = 48 / 52 ] and 69% yield
[ dl / meso = 40 / 60 ], respectively).
11 In the case of reductive coupling of aldimine, it was reported that the
reaction was effectively promoted by only zinc in aqueous basic
media, see: a) M. P. Dutta, B. Baruah, A. Boruah, D. Prajapati, and J.
S. Sandhu, Synlett, 1998, 857. b) T. Tsukinoki, S. Nagashima, Y.
Mitoma, and M. Tashiro, Green Chem., 2, 117 (2000).