Practical and efficient synthesis of C2 symmetrical diamines with Zn / Me3SiCl

Article abstract of DOI:10.1055/s-1998-1790

C₂ symmetrical diamines are efficiently obtained by reductive coupling of imines with the couple Zn/Me₃SiCl. This high yielding method is very practical and cheap for large scale preparation.

Full text of DOI:10.1055/s-1998-1790

August 1998
SYNLETT
873
Practical and Efficient Synthesis of C Symmetrical Diamines with Zn / Me SiCl
2
3
Alexandre Alexakis*, Isabelle Aujard, Pierre Mangeney
Department of Organic Chemistry, Université P. et M. Curie, T44-45, case 183, 4 place Jussieu, Paris 75005, France
Fax (int.) 33 1 44 27 75 67; e-mail alexakis@moka.ccr.jussieu.fr
Received 7 May 1998
Abstract : C symmetrical diamines are efficiently obtained by
2
reductive coupling of imines with the couple Zn/Me SiCl. This high
3
yielding method is very practical and cheap for large scale preparation.
Chiral C symmetrical diamines are among the most promising chiral
2
1
auxiliaries in asymmetric synthesis. Our group is strongly involved in
2
this field, and new practical methods are needed to prepare, in bulk, a
variety of such diamines. Among the various ways of preparation, the
pinacol-type coupling of imines seems the most attractive. The use of a
3
low valent metal for such a reductive coupling is known since 1908,
4
and several metals have since been used. Most of them, however, suffer
from high cost or practical problems in scaling up, such as filtration and
isolation of the desired diamine.
4f
filtration problems encountered in our previous Ti procedure, or in
many other methods. Thus, from a practical point of view, there was no
problem in scaling up the reaction up to 1 mole.
Scheme 1
The coupling reaction usually affords the useful racemic d,l diamine, the
useless meso diamine and variable amounts of reduction material. We
present herein a very practical and high yielding method, which is even
more efficient when associated with the isomerization of the meso
diamine into the d,l one, as described in the following article.
The reductive properties of the cheap metal Zn(0) have been known for
5
a long time, and the combination of Zn and Me SiCl (TMSCl) has been
3
6
used previously for the coupling of carbonyl compounds. The reductive
dimerization of isoquinoline has also been observed in the presence of
7
Li or Mg and TMSCl.
The optimization of the experimental conditions was undertaken for the
synthesis of N,N'-dimethyl-1,2-diphenylethane-1,2-diamine (R=Ph,
2
R'=Me, 2a), the most employed in our group. As shown in Table 1,
several metals were tried, first in THF, and Mg/TMSCl or Zn/TMSCl
emerged as the best ones. Mg was too reactive, particularly on large
scale and high concentration conditions. Zn was preferred for its
Scheme 2
8
mildness and low cost. Li and Na gave several by-products arising from
reduction of the aromatic ring. No reaction occurred with Mn or Fe.
Although this procedure affords an equal amount of the d,l and meso
isomers, the separation was trivial : the meso diamine 2’a is completely
Concerning the solvent, Et O was not suitable, whereas the best results
2
were obtained in acetonitrile (entry 8). Finally, no reaction occurred in
the absence of TMSCl (entry 9). These results were compared to our
first-generation coupling method, with low valent Ti as reducing agent
insoluble in pentane and slightly soluble in Et O, whereas the d,l
2
diamine 2a is fully soluble in pentane. This trend is also followed by
most the other diamines synthesized in this way (see Table 2). Another
way to isolate pure d,l diamine is to treat the crude mixture with racemic
tartaric acid in EtOH. Only the salt formed with the d,l diamine
precipitates out of solution. This is our preferred procedure.
4f
(entry 10).
Mechanistically, we believe that the acceleration of the reaction is due to
the trapping of the radical anion by TMSCl, generating a radical species
6
which is very prone to coupling. The reduction product is probably
As shown in Table 2 several diamines were prepared according to our
optimized conditions. In almost all cases the reaction went to
generated by hydrogen abstraction from the solvent, a result which is
compatible with the fact that a lesser amount of 3a is obtained in
acetonitrile instead of THF (see Scheme 2). The silylated diamines are
decomposed to the free diamine during the hydrolytic work up. In this
process, no zinc alkoxides or amides are generated, thus avoiding the
1
completion and the crude H NMR spectra showed essentially the d,l
and meso diamines (2 and 2’, respectively) and the reduction compound
3. The isolated yields of pure d,l diamine range from 33 to 47%, after
crystallization or treatment with d,l tartaric acid. However, in most

874
LETTERS
SYNLETT
463, 281-322. Chem. Abstr. 1928, 22, 4499. q) Jaunin, R. Helv.
Chim. Acta 1956, 39, 111-116. r) Bachmann, E. J. Am. Chem. Soc.
1931, 53, 2672-2676. s) Kalyanam, N.; Venkateswara Rao, G.
Tetrahedron Lett. 1993, 34, 1647-1648. t) Roskamp, E.J.,
Pedersen, S.F. J. Am. Chem. Soc. 1987, 109, 3152-3154.
u) Takaki, K.; Tsubaki, Y.; Tanaka, S.; Beppu, F.; Fujiwara, Y.
Chem. Lett. 1990, 203-204. v) Imamoto, T.; Nishimura, S. Chem.
Lett. 1990, 1141-1142. w) Enholm, E.J.; Forbes, D.C.; Holub, D.P.
Synth. Comm. 1990, 20, 981-987. x) Shono, T.; Kise, N.; Oike, H.;
Yoshimoto, M.; Okazaki, E. Tetrahedron Lett. 1992, 33, 5559-
5562. y) Buchwald, S.L.; Watson, B.T.; Wannamaker, M.W.;
Dewan, J.C. J. Am. Chem. Soc. 1989, 111, 4486-4494.
(5) For a review see J. Boersma in Comprehensive Organometallic
Chemistry, Ed. G. Wilkinson, 1982, Vol 2, p. 823-851.
(6) Banerjee, A.K.; Sulbaran de Carrasco, M.C.; Frydrych-Houge, C.,
Motherwell, W.B., J. Chem. Soc., Chem. Comm. 1986, 1803-1805.
(7) Grignon-Dubois, M., Fialeix, M., Can. J. Chem. 1993, 71, 754.
(8) Zinc dust was purchased from Aldrich. Other sources of Zn work
equally well.
cases, the crude mixture was directly submitted to the isomerization
procedure described in the next article, in order to increase the amount
of the useful d,l diamine.
(9) The synthesis optically pure of N,N'-dimethyl-1,2-diphenyl-
ethane-1,2-diamine 2a, by this coupling procedure, isomerization
and resolution was submitted (and accepted) to Organic Syntheses
(procedure n° 2778).
Some interesting points should be commented on. An aromatic R
substituent should be preferred, since a cyclohexyl group gives rise to
extensive formation of reduction product (entry 10). The same is true
when a bulky isopropyl group is placed on the nitrogen (entry 9).
Although the usual trend gave an almost 1/1 ratio of the two
diastereomers, in two cases (entries 6 and 7) we observed an excess of
the d,l diamine and, with R = naphthyl, only the d,l isomer was detected.
(10 Typical procedure for 2d : A three necked round bottomed flask
(500 ml), was charged with Zn dust (325 mesh, 13.1 g, 0.2 mole)
and anhydrous acetonitrile (50 mL) under a nitrogen atmosphere.
The zinc was activated by the addition of dibromo-1,2-ethane
(~1.5 mL, 3.5 g, half a Pasteur pipette) and the mixture was
brought to reflux for 1 min, then allowed to cool to room
temperature. Then, a small amount of TMSCl (~3.2 mL, 2.5 g,
two Pasteur pipettes) was added, whereupon an evolution of
ethylene gas was observed. The mixture was stirred for 45 min
The above examples show that this method is relatively general. Despite
the formation of a 1/1 mixture of diastereomers, the ease of this
procedure is such that it is the preferred one in our laboratories for large
9, 10
scale preparations.
11
and then imine 1d (37.6 g, 0.2 mole) dissolved in acetonitrile
References and Notes
(100 mL) was added in one portion. Pure TMSCl (38 mL, 0.3
mole) was slowly added (30 min). The temperature increased so as
to maintain the internal temperature below +35-40°C. After 1h,
the mixture was cooled to 0°C and cautiously (very exothermic at
(1) Bennani Y.L., Hanessian S. Chem. Rev. 1997, 97, 3161-3195.
(2) Alexakis A., Mangeney P. in Advanced Asymmetric Synthesis, Ed.
G.R. Stephenson, Chapman & Hall, London, Chap. 5, 1996, 93-
110.
the beginning) hydrolyzed with a mixture of aq. NH OH (60 mL)
4
and of saturated aqueous solution of NH Cl (140 mL). The excess
4
(3) Anselmino, O. Chem. Ber. 1908, 41, 621-623.
Zn was removed by filtration, the organic layer was separated and
(4) a) Neumann, W.P.; Werner, F. Chem. Ber. 1978, 111, 3904-3911.
b) Thies, H.; Schönenberger, H.; Bauer, K.H. Arch. Pharm. 1958,
291/63, 373-375. Chem. Abstr. 1959, 53, 2127h. c) Baruah, B.;
Prajapati, D.; Sandhu, J.S. Tetrahedron Lett. 1995, 36, 6747-6750.
d) Nosek, J. Coll. Czech. Chem. Comm. 1967, 32, 2025-2028.
e) Betschart, C.; Seebach, D. Helv. Chim. Acta 1987, 70, 2215-
2231. f) Mangeney, P.; Tejero, T.; Alexakis, A.; Grosjean, F.;
Normant, J. Synthesis 1988, 255-257. g) Stühmer, W.; Messwrb,
G. Arch. Pharmaz. 1953, 286, 221-231. Chem. Abstr. 1955, 49,
6192b. h) Tanaka, H.; Dhimane, H.; Fujita, H.; Ikemoto, Y.; Torii,
S. Tetrahedron Lett. 1988, 29, 3811-3814. i) Khan, N.H.; Zuberi,
R.H.; Siddiqui, A.A. Synth. Comm. 1980, 10, 363-371. j) Smith,
J.G.; Boettger, T.J. Synth. Comm. 1981, 11, 61-64. k) Shimizu, M.;
Iida, T.; Fujisawa, T. Chem. Lett. 1995, 609-610. l) Smith, J.G.;
Veach, C.D. Can. J. Chem. 1966, 44, 2497-2502. m) Smith, J.G.;
Ho, I. J. Org. Chem. 1972, 37, 653-656. n) Eisch, J.J.; Kaska,
D.D.; Peterson, C.J. J. Org. Chem. 1966, 31, 453-456. o) Schlenk,
W.; Appenrodt, J.; Michael, A.; Thal, A.. Chem. Ber 1914, 47,
473-490. p) Schlenk, W.; Bergmann, E. Liebigs Ann. Chem. 1928,
the aqueous phase washed once with Et O (200 mL) and twice
2
with CH Cl (2x200 mL). The combined organic extracts were
2
2
dried over K CO . The salts were removed by filtration, washed
2
3
with Et O (50 ml) and the solvents removed on a rotatory
2
evaporator to afford a semi-solid residue (35-37 g, yield >95%).
This crude diamine is dissolved in absolute EtOH (700mL),
racemic tartaric acid (0.096 mol, 14.2 g) was added, and the
heterogeneous mixture is brought to reflux for 30 min. After
cooling to +20°C, the precipitate is collected by filtration and
washed twice with EtOH (2x50 mL). This salt was poured to a
mixture of 35% NaOH (60 mL), water (200 mL) and Et O (200
2
mL). After stirring for 30 min., the layers were separated, the
aqueous phase extracted twice with Et O (2x200 mL), and the
2
combined organic phases were dried over K CO . The solvents
2
3
11
are evaporated and the pure d,l diamine 2d is obtained in 44%
yield (16.5 g)
(11) Cuvinot, D.; Mangeney, P.; Alexakis, A.; Normant, J.F. J. Org.
Chem. 1989, 54, 2420-2425.