Lanthanide-promoted ethylation of schiff bases by triethylaluminum

Article abstract of DOI:10.1021/ol049420+

Equation presented. Schiff bases of aromatic aldehydes and anilines that fail to react with triethylaluminum are smoothly alkylated at room temperature in the presence of lanthanide catalysts. The alkylation takes place selectively at the vinylic carbon a

Full text of DOI:10.1021/ol049420+

ORGANIC
LETTERS
2004
Vol. 6, No. 12
1995-1997
Lanthanide-Promoted Ethylation of
Schiff Bases by Triethylaluminum
,‡
Dmitry Tsvelikhovsky,† Dmitri Gelman,† Gary A. Molander,* and
,†
Jochanan Blum*
Department of Organic Chemistry, The Hebrew UniVersity, Jerusalem 91904, Israel,
and Roy and Diana Vagelos Laboratories, Department of Chemistry,
UniVersity of PennsylVania, Philadelphia, PennsylVania 19104-6323
jblum@chem.ch.huji.ac.il; gmolandr@sas.upenn.edu
Received March 29, 2004
ABSTRACT
Schiff bases of aromatic aldehydes and anilines that fail to react with triethylaluminum are smoothly alkylated at room temperature in the
presence of lanthanide catalysts. The alkylation takes place selectively at the vinylic carbon atom.
Recently, we reported1 that the inefficient and nonselective
palladium-catalyzed cross-ethylation of bromoarenes with
Et3Al can be transformed into an efficient and highly
selective process upon addition of a stoichiometric amount
of CeCl3. We now report on another alkylation process in
which lanthanide derivatives have an even more pronounced
stimulating effect. Schiff bases of aromatic aldehydes and
anilines proved to be completely refractory toward Et3Al.2
In the presence of catalytic quantities of europium, praseo-
dymium, or ytterbium complexes, however, smooth and
selective C-alkylation takes place at room temperature.
When, for example, a solution of N-(phenylmethylene)aniline
(C6H5CHdNC6H5, 33.5 mmol) and the NMR shift reagent,
(O,C-6-11)-tris(2,2,6,6-tetramethyl-3,5-heptanedionato-O,O′)-
europium [europium tris-(dipivaloylmethane, Eu(dpm)3,
1.7 mmol], in 30 mL of dry benzene is treated for 24 h
under an Ar atmosphere at 25 °C with Et3Al (33.5 mmol),
followed by quenching of the reaction mixture with MeOH
and NaOH, 73% of C6H5CH(C2H5)NHC6H5 and 25% of
unreacted starting material are isolated.3 Under similar re-
action conditions, C6H5CHdNC6H4-4-CH3, 4-CH3C6H5CHd
NC6H5, 4-ClC6H4CHdNC6H5, 4-NCC6H4CHdNC6H5, and
(2-C5H4N)CHdNC6H5 have been ethylated.4 The results are
summarized in Table 1.
All the Schiff bases listed in Table 1 proved to undergo
alkylation exclusively at the vinylic carbon atoms, and no
detectable amounts of side products were formed. Despite
Table 1. Lanthanide-Catalyzed Alkylation of Schiff Bases by
Trialkylaluminum Reagents under Comparable Conditionsa
entry
Schiff base
R
catalyst
yield, %b
c
1
2
3
4
5
6
7
8
9
C6H5CHdNC6H5
C6H5CHdNC6H5
C6H5CHdNC6H5
C6H5CHdNC6H5
C6H5CHdNC6H5
CH3
Eu(dpm)3
53
73
55
29
11
33
41
82
70
99
C2H5 Eu(dpm)3
C2H5 Eu(tfc)3
C2H5 Yb(OTf)3
C2H5 Pr(tfc)3
C6H5CHdNC6H4-4-CH3 C2H5 Eu(dpm)3
4-CH3C6H4CHdNC6H5
4-ClC6H4CHdNC6H5
4-NCC6H4CHdNC6H5
(2-C5H4N)CHdNC6H5
C2H5 Eu(dpm)3
C2H5 Eu(dpm)3
C2H5 Eu(dpm)3
C2H5 Eu(dpm)3
† The Hebrew University.
‡ University of Pennsylvania.
(1) Shenglof, M.; Gelman, D.; Molander, G. A.; Blum, J. Tetrahedron
Lett. 2003, 44, 8593.
(2) (a) Alberola, A.; Cermen˜o, F. A.; Anton, A. An. Quim. 1977, 73,
886. Allylaluminums add readily to imines. (b) Schumann, H.; Kaufmann,
J.; Dechert, S.; Schmalz, H.-G. Tetrahedron Lett. 2002, 43, 3507.
(3) A detailed general procedure for the alkylation of the Schiff bases is
given in Supporting Information.
10
a Reaction conditions: 33.5 mmol of Schiff base, 33.5 mmol of R3Al in
30 mL of hexane, 1.7 mmol of lanthanide catalyst, 30 mL of dry benzene;
Ar atmosphere; 25 °C; 24 h. b Unreacted Schiff base makes up the remainder
of the material. c Performed with 67.0 mmol of Me3Al.
10.1021/ol049420+ CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/13/2004

the fact that triethylaluminum disproportionates in the
presence of various metals into ethylene and the highly
reactive diethylaluminum hydride,5 no reduction products of
the amines (i.e., nonalkylated saturated amines) could be
detected. The experiment listed as entry 1 indicates that the
lanthanide-promoted alkylation is applicable also to Schiff
base methylations. The application of a chiral catalyst [(+)-
Eu(tfc)3] in this experiment led to the formation of the
optically active (R)-(+)-C6H5CH(CH3)NHC6H5 of 82% opti-
cal purity.6
effect on the process was studied between 2 and 78 °C and
was found to give the best results at 22-28 °C.
The clean ethylation of 4-[(phenylimino)methyl]benzo-
nitrile, 4-NCC6H4CHdNC6H5 to give solely 4-(1-anilino-
propyl)benzonitrile is rather surprising, because Eu(dpm)3
also catalyzes the slow ethylation of aromatic nitriles to form
ethylimines that are hydrolyzed during the workup to the
corresponding ketones. For example, benzo- and 1-naphtho-
nitrile are converted under the conditions of Table 1 within
24 h into 47 and 4% of 1-phenylpropanone and 1-(1-
naphthyl)propanone, respectively.10 The selective alkylation
of 4-NCC6H4CHdNC6H5 at the double bond may thus be
rationalized by the significant difference between the rate
of ethylation of the imine and the nitrile functions.
Two possible mechanisms for the lanthanide-assisted
alkylation of Schiff bases by Et3Al are considered. The fact
that the catalytic activity of various lanthanide compounds
is often assigned to their Lewis acidity,11 and the observation
that the addition of some metal alkyls to imines is promoted
by acids12 could suggest Lewis acid alkylation for our
process. However, experiments to replace the lanthanide
catalysts in the ethylation of C6H5CHdNC6H5 by Me3SiCl,
BF3, InCl3, or ZnCl2 (which enhance the ethylation of the
Schiff base by Et2Zn12) gave negative results. Only a large
molar excess of either the silicon or the zinc compound
afforded traces of C6H5CH(C6H5)NHC6H5 at room temper-
ature. Thus, we assume that it is more likely that our
ethylation proceeds via the intermediacy of an alkyl lan-
thanide formed from Et3Al by transmetalation. The ability
of such lanthanide compounds to alkylate unsaturated
substrates,13 including carbon-nitrogen multiple bonds, has
already been demonstrated.11
Both the nature of the lanthanide metal and the ligands
on the catalysts were found to affect the reaction rate. Among
the four catalysts studied, Eu(dpm)3, (O,C-6-22)-tris[1,7,7-
trimethyl-3-(trifluoroacetyl)bicyclo[2.2.1]heptan-2-onato-
O,O′]europium [Eu(tfc)3], (O,C-6-22)-tris-[1,7,7-trimethyl-
3-(trifluoroacetyl)bicyclo[2.2.1]heptan-2-onato-O,O′]praseo-
dymium [Pr(tfc)3], and ytterbium(+3) trifluoromethane-
sulfonate [Yb(OTf)3] (see entries 2-5), the Eu(dpm)3 was
found to be the most efficient. The alkylation proved to
depend on the electronic nature of the unsaturated substrate.
While electron-withdrawing groups (Cl, CN) seem to en-
hance the rate, the electron-donating methyl group located
on either the benzylidene or the benzeneamine moiety causes
the ethylation to slow as compared with the reaction rate of
the unsubstituted N-(1-phenylmethylene)aniline. This de-
pendence is opposite to that observed in the ethylation of
Schiff bases by Et2Zn and by Et2Cd.7 N-(2-Pyridylmethyl-
ene)aniline (entry 10) is the only Schiff base studied that, at
room-temperature, undergoes slow alkylation in the absence
of the lanthanide catalyst. However, under such conditions,
a variety of undesired side products are formed. In the
presence of Eu(dpm)3, pure N-[(1-pyridin-2-yl)propyl]aniline
is obtained in quantitative yield. It is notable that, under the
conditions of Table 1, optimum results are obtained when a
1:1 molar ratio of the substrate and Et3Al is employed.
Additional reagent has no effect on the yield. The methylation
of the Schiff bases requires, however, the presence of excess
Me3Al.8 The rate dependence of the ethylation of N-(1-
phenylmethylene)aniline by Eu(dpm)3 on the nature of the
solvent was shown to decrease in the order benzene >
benzene-hexane > hexane > dichloromethane > dimethyl-
formamide. No reaction takes place in THF, which strongly
coordinates with the aluminum reagent.9 The temperature
In summary, Et3Al, which fails to alkylate aromatic Schiff
bases, is activated by several lanthanide catalysts. The imines
undergo selective C-alkylation, which is assumed to take
place via an alkyllanthanide intermediate. The application
of a chiral europium catalyst induces asymmetry during the
alkylation process.
(9) Eisch, J. J. In ComprehensiVe Organometallic Chemistry; Wilkinson,
G., Stone, F. G. A., Abel, E. N., Eds.; Pergamon Press: Oxford, UK, 1982;
Vol. 1, Chapter 6 and references therein.
(10) Ethylation of the nitrile was performed in the same manner as the
alkylation of the Schiff bases (see Supporting Information) except that the
quenching of the reaction mixture was carried out with 60 mL of 10%
hydrochloric acid instead of with NaOH.
(11) For typical examples, see: Molander, G. A. Chem. ReV. 1992, 92,
(4) Known products C6H5CH(CH3)NHC6H5,14 C6H5CH(C2H5)NHC6H5,15
29.
C6H5CH(C2H5)NHC6Hr-4-CH3,7,16 4-CH3-C6H4CH(C2H5)NHC6H5,7 and
(12) Hou, X. L.; Zheng, X. L.; Dai, L. X. Tetrahedron Lett. 1998, 39,
6949.
7,17
4-Cl C6H4CH(C2H5)NHC6H5
were compared with authentic samples
prepared according to the procedures reported in the literature. Physical
data (bp/mp; 1H and 13C NMR; EI-mass spectra) and elemental analyses of
all new compounds, as well as the relevant data for known compounds
that are not documented in the literature, are presented in Supporting
Information.
(13) (a) Sigalov, A. B.; Rybakova, L. F.; Beletskaya, I. P. IzV. Akad.
Nauk SSSR, Ser. Khim. 1983, 1692. (b) Yokoo, K.; Fukagawa, T.;
Yamanaka, Y.; Taniguchi, H.; Fujiwara, Y. J. Org. Chem. 1984, 49, 3237.
(c) Collin, J.; Namy, J. L.; Bied, C.; Kagan, H. B. Inorg. Chim. Acta 1987,
140, 29. (d) Rybakova, L. F.; Syutkina, O. P.; Garber, A. V.; Petrov, E. S.
Zh. Obshch. Khim. 1988, 58, 1053. (e) Syutkina, O. P.; Rybakova, L. F.;
Petrov, E. S. Metallorg. Khim. 1989, 2, 1145. (f) Inamoto, T.; Hatajiama,
T.; Nishimura, S.; Togo, H.; Yokoyama, M. Kidorui 1990, 16, 3081; Chem.
Abstr. 1991, 114, 61235z. (g) Fujiwara, Y.; Tanikguchi, Y. Kikan. Kagaku
Sosaetsu 1998, 37, 63; Chem. Abstr. 1999, 129, 330287d. (h) Zheleznova,
T. A.; Bochkarev, L. N.; Safronova, A. V.; Zhil’tsov, S. F. Russ. J. Gen.
Chem. 1999, 69, 784.
(14) Busch, M. Ber. Deutsch. Chem. Ges. 1904, 37, 2691.
(15) Busch, M.; Rinck, A. Ber. Deutsch. Chem. Ges. 1905, 38, 1761.
(16) Heutling, A.; Doye, S. J. Org. Chem. 2002, 67, 1961.
(17) Bertrand, M. P.; Feray, L.; Nouguier, R.; Perfetti, P. J. Org. Chem.
1999, 64, 9189.
(5) See, Gelman, D.; Ho¨hne, G.; Schumann, H.; Blum, J. Synthesis 2001,
591 and references therein.
(6) Calculation of the optical purity is based on the value of [R]25
)
D
26.1° reported by: Ogata, Y.; Takeuch, K. J. Org. Chem. 1970, 35, 1642.
For examples of the enantioselective addition of organoaluminums to
aldehydes, see: (a) Chan, A. S. C.; Zhang, F.-Y.; Yip, C.-W. J. Am. Chem.
Soc. 1997, 119, 4080. (b) Pagenkopf, B. L.; Carreira, E. M. Tetrahedron
Lett. 1998, 39, 9593. (c) Lu, J.-F.; You, J.-S.; Gau, H.-M. 2000, 11, 2531.
(7) Thomas, J.; Henry-Basch, E.; Fre´on, P. Bull. Soc. Chim. Fr. 1969,
109.
(8) Cf.: Gelman, D.; Schumann, H.; Blum, J. Tetrahedron Lett. 2000,
41, 7555.
1996
Org. Lett., Vol. 6, No. 12, 2004

1
Acknowledgment. We gratefully acknowledge the United
States-Israel Binational Science Foundation (BSF) for
financial support of this study through Grant 2000013.
and characterization data (mp/bp, H and 13C NMR, mass
spectra, and elemental analyses) are presented for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Supporting Information Available: Experimental pro-
cedures for the alkylation of the Schiff bases and the nitriles
OL049420+
Org. Lett., Vol. 6, No. 12, 2004
1997