Cerium(IV)-promoted ethylation of Schiff bases by triethylaluminum

Article abstract of DOI:10.1055/s-2006-942379

Schiff bases Ar¹CH=NAr² that are refractory towards Et₃Al are activated at room temperature by cerium(IV) compounds. The ethylation takes place selectively at the methine moiety of the imine. The process is strongly influe

Full text of DOI:10.1055/s-2006-942379

PAPER
1819
Cerium(IV)-Promoted Ethylation of Schiff Bases by Triethylaluminum
C
erium(IV)-Promo
m
ted
E
thylation of
S
i
chif
f
Ba
t
ses by
r
T
riethyl
y
a
luminum Tsvelikhovsky,a Herbert Schumann,b Jochanan Blum*a
a
Department of Organic Chemistry, The Hebrew University, Jerusalem 91904, Israel
Fax +972(2)6513832; E-mail: jblum@chem.ch.huji.ac.il
Institut für Chemie, Technische Universität, 10623 Berlin, Germany
Fax +49(30)31422168; E-mail: schumann@chem.tu-berlin.de
b
Received 12 January 2006; revised 10 February 2006
Table 1 Ethylation of PhCH=NPh by Et3Al in the Presence of Lan-
Abstract: Schiff bases Ar1CH=NAr2 that are refractory towards
Et3Al are activated at room temperature by cerium(IV) compounds.
The ethylation takes place selectively at the methine moiety of the
imine. The process is strongly influenced by steric hindrance and
depends on the electronic nature of the substrate: electron-donating
substituents promote the reaction while electron-withdrawing
groups cause it to slow down. Application of cerium(IV) ammoni-
um nitrate as promoter gives the best results. In the absence of ex-
cess Et3Al it causes, however, transformation of the Schiff base to
the corresponding aldehydes and amines.
thanide Trichlorides under Comparable Conditionsa
Entry
Rare earth
compound
Yield of products (%)b
PhCH(Et)NHPh
PhCH2NHPh
1
2
3
4
5
6
LaCl3
NdCl3
SmCl3
TmCl3
LuCl3
YCl3
9
25
19
20
8
0
10
0
Key words: cerium(IV) compounds, C-ethylation, lanthanides,
Schiff bases, triethylaluminum
15
0
0
11
Although triethylaluminum is a powerful ethylation re-
agent for many carbon–carbon and carbon–heteroatom
double bonds,1 it fails to affect Schiff bases under stan-
dard laboratory conditions.2 Recently, however, the group
a Reaction conditions: Schiff base (3.35 mmol) in benzophenone ketyl
dried benzene (30 mL). LnCl3 (3.35 mmol) and Et3Al (1M, in hexane,
3.35 mmol); r.t. , 24 h under Ar.
b Yields of the isolated products are the average of at least two exper-
of Szymoniak and our own group have succeeded in acti- iments that did not differ by more than 2%. The missing percentage
reflects the unreacted Schiff base.
vating Et3Al for the ethylation of Schiff bases by applying
either dicyclopentadienylzirconium(IV)3, or some europi-
um(III) or praseodymium(III) shift reagents as catalysts.4
Table 2 indicates that among the three Ce(IV) derivatives
We have now attempted to extend this study and use, in
studied, cerium ammonium hexanitrate (CAN), cerium
the reaction of PhCH=NPh and Et3Al, a series of chlorides
sulfate and cerium tetrafluoride, the former is by far the
of other trivalent rare earths elements. Unfortunately, only
most effective promoter. In the presence of excess Et3Al
low yields of ethylation could be achieved. Furthermore,
(three equivalents) electron-neutral and electron-rich
the neodymium and thulium salts led to contamination of
imines form almost quantitative yields of the ethylation
the expected product with the non-alkylated amine, and
product (see entries 3, 4, 12 and 14). Although CAN acts
the yttrium chloride afforded solely this ethyl-deficient
as a catalyst, we usually employed 0.75–1 equivalent rel-
amine (see Table 1). Curiously CeCl3, which has already
ative to the substrate in order to achieve good yields with-
been shown to have a stimulating effect on the cross-cou-
in a reasonable time. At lower CAN:substrate ratios (see
pling reactions of Et3Al,5 proved completely inactive in
e.g., entry 6), the alkylation could be brought to comple-
the Schiff base ethylation. However, by replacing CeCl3
tion only after considerable extension of the reaction peri-
by cerium(IV) compounds, alkylation of a variety of
od. The application of three equivalents of Et3Al is
imines could be accomplished at room or even at sub-
necessary in order to prevent substantial transformation of
room temperature. Representative results of this regiose-
the Schiff bases back to aldehydes during the ethylation
lective ethylation are shown in Scheme 1 and summarized
in Table 2.
(vide infra). Under these conditions, relatively small
amounts of the corresponding aldehydes were formed in
only three of the cases studied (entries 13, 15 and 19). Nei-
ther Ce(SO4)2 nor CeF4 causes the formation of PhCHO
during the ethylation process.
1) Ce(IV) compd, Et3Al,
C6H6, 25 °C
Ar2
Ar2
Ar1
Ar1
N
NH
2) H2O
Table 2 reveals also that the CAN-promoted ethylation
depends on the electronic nature of the substrate. While
the unsubstituted imine (entry 3), and the one substituted
by a methyl group at the benzylidene moiety (entry 10) re-
act quite fast, the Cl, Br and CN substituted imines (en-
tries 13,15 and 16) are ethylated at a slower rate. This
Scheme 1
SYNTHESIS 2006, No. 11, pp 1819–1822
Advanced online publication: 05.05.2006
DOI: 10.1055/s-2006-942379; Art ID: Z01006SS
x
x.
x
x
.
2
0
0
6
© Georg Thieme Verlag Stuttgart · New York

1820
D. Tsvelikhovsky et al.
PAPER
Table 2 Ethylation of Schiff Bases Ar1CH=NAr2 by Et3Al in the Presence of Cerium(IV) Compoundsa
Entry
Substrate
Ar1
Et3Al (equiv) Cerium compd
(equiv)b
Products, yield (%)c
Ar 2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
1
2
Ph
1.0
1.0
3.0
3.0
3.0
3.0
1.0e
1.0
2.0e
3.0
3.0
CAN (1.0)
CAN (0.5)
CAN (1.0)
CAN (0.75)
CAN (0.25)
CAN (0.1)
Ce(SO4)2 (1.0)
CeF4 (1.0)
CeF4 (1.0)
CAN (0.75)
CeF4 (0.75)
PhCH(Et)NHPh (37), PhCHO (45)d
PhCH(Et)NHPh (35), PhCHO (34)d
PhCH(Et)NHPh (93)
Ph
3
Ph
4
Ph
PhCH(Et)NHPh (93)
5
Ph
PhCH(Et)NHPh (77)
6
Ph
PhCH(Et)NHPh (49)
7
Ph
PhCH(Et)NHPh (13)
8
Ph
PhCH(Et)NHPh (32)
9
Ph
PhCH(Et)NHPh (64)
10
11
4-MeC6H4
4-MeC6H4
4-MeC6H4CH(Et)NHPh (85)
4-MeC6H4CH(Et)NHPh (26), 4-MeC6H4CH2NHPh
(22)
12
13
14
15
Ph
4-MeOC6H4
Ph
3.0
3.0f
3.0
3.0
CAN (0.75)
CAN (0.75)
CAN (0.75)
CAN (0.75)
PhCH(Et)NHC6H4-4-OMe (99)
4-ClC6H4
Ph
4-ClC6H4CH(Et)NHPh (57), 4-ClC6H4CHO (19)d
PhCH(Et)NHC6H4-4-Cl (98),
4-ClC6H4
Ph
4-BrC6H4
4-BrC6H4(Et)NHPh (28), 4-BrC6H4CHO (11)d
4-BrCH2NHPh (26)
16
17
18
19
4-NCC6H4
3-HOC6H4
2-C5H4N
Ph
Ph
3.0
3.0g
3.0
3.0
CAN (0.75)
CAN (0.75)
CAN (0.75)
CAN (0.75)
4-NCC6H4CH(Et)NHPh (50)
3-HOC6H4CH(Et)NHPh (98)
2-C5H4NCH(Et)NHPh (99)
Ph
Ph
2-C10H7
PhCH(Et)NH-2-C10H7 (58), PhCHO (8)d
a Reaction conditions: Schiff base (3.35 mmol) in benzophenone ketyl-dried benzene (30 mL). Treatment with the calculated amount of the
cerium compound and Et3Al (1 M) at 25 °C, 20 h under Ar.
b CAN = ceriumammonium hexanitrate.
c The results are the average of at least two experiments that did not differ by more than 3%. The missing percentage reflects the unreacted
Schiff base.
d Contaminated with varying amounts of aniline (or its derivatives) which could not be determined quantitatively.
e No change in yield was observed when the number of equivalents was increased to 3.0.
f When the number of equivalents was reduced to 1.0 the yield of the aldehyde increased to 41%.
g In the absence of excess (>1.0 equivalents) Et3Al, no alkylation took place.
electronic effect is opposite to that observed in the lan- unaffected. The ethylation of N-(3-hydroxyphenyl)meth-
thanide(III)-catalyzed ethylation of Schiff bases by Et3Al ylene-N-phenylamine (entry 17) is remarkable. Although
where electron-withdrawing groups increase the rate and the hydroxyl group destroys one equivalent of the alumi-
electron-donating functions slow it down. The substitu- num reagent (and therefore equimolar quantities of the
ents on the aniline moiety do not seem to have a signifi- substrate and the ethylating reagent do not yield the ex-
cant effect on the rate (cf., entries 12 and 14). The low pected product) the use of excess Et3Al permits smooth
yield of the ethylation of N-(4-bromophenyl)methylene- ethylation of the Schiff base.
N-phenylamine (entry 15) may be associated with the for-
Steric hindrance, too, has an effect on the ethylation.
Thus, while N-2-naphthyl-N-(phenylmethylen)amine is
mation of free radicals by the aromatic bromine atom.6
Curiously, when an equimolar mixture of 4-
ethylated as indicated in entry 19, the more hindered 1-
BrC6H4CH=NC6H5 and 4-NCC6H4CH=NC6H5 were re-
naphthyl isomer does not react with Et3Al in the presence
acted with Et3Al and CAN, only the bromo compound re-
of CAN. Likewise, substitution of the phenyl group of the
parent Schiff base with methylated equivalents such as N-
acted and the cyano-substituted Schiff base remained
Synthesis 2006, No. 11, 1819–1822 © Thieme Stuttgart · New York

PAPER
Cerium(IV)-Promoted Ethylation of Schiff Bases by Triethylaluminum
1821
(2,6-dimethylphenyl)methylene-N-phenylamine, prevents active, may also be rationalized by this redox process pro-
the ethylation. We have noticed previously4 that the Schiff voking the activation of the triethylaluminum.
base formed from aniline and 2-pyridinecarboxaldehyde
In conclusion, some Ce(IV) compounds, used frequently
reacts slowly with Et3Al even in the absence of a catalyst.
as oxidizing reagents, promote room temperature selec-
The reaction rate is however, increased in the presence of
tive C-ethylation of sterically unhindered Schiff bases by
CAN. We rationalized this phenomenon by the possible
Et3Al. Cerium(IV) ammonium nitrate acts as a catalyst
formation of a reactive aluminum–imine complex via the
and is more active than cerium(IV) sulfate and cerium(IV)
pyridine nitrogen atom (cf., such complexes with Me3Al
fluoride. However, in the absence of excess Et3Al, CAN
and Me3Ga, reported in reference 7). The tendency of the
also promotes the hydrolysis of unreacted Schiff base to
aluminum reagent to form complexes with heteroatoms1
the corresponding starting components, presumably by a
led us to choose hetereoatom-free solvents for our pro-
redox process that involves the nitro groups of CAN and
cess. Reactions in aromatic hydrocarbons (benzene, tolu-
the disproportionated ethylation reagent.
ene) and in aliphatic ones (n-hexane) have been found to
proceed equally well provided the substrates are soluble in
The various Schiff bases were prepared mostly from commercially
these solvents. No ethylation takes place in THF. Studies
available aldehydes and amines (Aldrich Chemical Co.) by the con-
at a wide range of reaction temperatures, from –78 to
ventional methods summarized by Vázquez et al.11 and the proper-
80 °C, revealed that the best results, where minimum side
products were formed, were obtained between 20 and
30 °C.
ties of PhCH=NPh,4 4-MeC6H4CH=NPh,4 2,6-Me2C6H3CH=NPh,12
PhCH=NC6H4-4-OMe,13 4-ClC6H4CH=NHPh,4 PhCH=NC6H4-4-
Cl,13
4-BrC6H4CH=NPh,12
4-NCC6H4CH = NPh,4
3-
HOC6H4CH=NPh,14 PhCH=N-1-C10H7,15 PhCH=N-2-C10H7,16 and
(2-C5H4N)CH=NPh4 were comparable to those reported previously.
The reference compounds for the ethylated Schiff bases
PhCH(Et)NHPh,4 4-MeC6H4CH(Et)NHPh,4 PhCH(Et)NHC6H4-4-
OCH3,3 PhCH(Et)NHC6H4-4-Cl,13 4-NCC6H4CH(Et)NHPh4 and 2-
(C5H4N)CH(Et)NHPh4 were prepared as described in the literature.
The non-ethylated amines were obtained by Pd–C-catalyzed hydro-
genation of the corresponding Schiff bases. The lanthanide com-
pounds were obtained from Aldrich Chemical Co. and from Alfa
Aesar in the purest state available.
The ethylations listed in Tables 1 and 2 require the com-
plete absence of moisture, otherwise the Schiff bases un-
dergo catalytic hydrolysis into the starting aldehydes and
amines. While the aldehydes can be isolated, the interac-
tion of the amines with the aluminum reagents usually
prevents their complete isolation from the reaction mix-
tures. For this reason,, the hygroscopic lanthanide salts
were dried over P2O5, in the dark, under reduced pressure
for at least one week prior to their application. Neverthe-
less, the formation of the aldehyde was still found to take
place (in the absence of excess Et3Al) whenever CAN was
employed, even in its purest anhydrous state. No hydroly-
sis was observed when other lanthanide derivatives, in-
cluding the Ce(IV) compounds Ce(SO4)2 and CeF4 were
used. Since both the reactions of CAN8 and some other ad-
ditions to C=N double bonds of imines were shown to oc-
casionally involve free radicals,9 we performed the
ethylation listed as entries 1–3 in Table 1 in the presence
of either benzoyl peroxide or AIBN. As neither free radi-
cal initiators caused any changes in the rate of ethylation
Infrared spectra were taken on a Bruker Vector 22-FTIR spectrom-
eter. 1H and 13C NMR spectra were recorded on a Bruker AMX-300
instrument. Mass spectral measurements were performed on a
Hewlett-Packard model 4989A mass spectrometer equipped with an
HP gas chromatograph model 5890 series II. Gas chromatographic
separations and analysis were carried out with the aid of a comput-
er-operated Hewlett-Packard model Agilent 4890D gas chromato-
graph.
Cerium(IV)-Promoted Ethylation of Schiff Bases; General Pro-
cedure
The Schiff base (3.35 mmol) was dissolved under exclusion of air
at r.t. (25 °C) in benzophenone ketyl dried benzene (30 mL). The
nor altered the ratio between PhCH(Et)NHPh and Ph- mixture was stirred for 10 min and the appropriate cerium(IV) com-
pound (2.53 mmol) was added. After 20 min, Et3Al (1 M in n-hex-
ane, 10.05 mL, 10.05 mmol) was added to the suspension. The
CHO, we conclude that the formation of the ethylated
amine and of the aldehyde (in the presence of stoichiomet-
mixture was stirred at r.t. for 20 h and then quenched either with
ric quantities of Et3Al) do not involve a free radical mech-
H2O alone (100 mL) or with MeOH (80 mL) and KOH (15 g). The
anism. Because the benzaldehydes are formed only in the
mixture was extracted with Et2O (2 × 100 mL). The organic layer
presence of CAN and neither with Ce(SO4)2 nor with
CeF4, we assume that the amount of water required for the
hydrolysis process originates from the (NH4)2Ce(NO3)6,
was then washed with H2O (2 × 100 mL), dried over MgSO4 and
concentrated. The crude products were then purified either by col-
umn chromatography or by distillation under reduced pressure. The
purity of the known products were determined by gas chromatogra-
phy and their 1H and 13C NMR, IR and MS compared with those of
authentic samples.
–
via a redox reaction between the nitrate anions, NO3 of
CAN and aluminum hydride species EtnAlH3–n, formed by
b-hydride elimination of CH2=CH2 from AlEt3.1 Support
for this assumption was found in an experiment in which
the reaction mixture described in entry 1 of Table 2 gave,
upon treatment with aqueous FeSO4, a positive indication
N-[1-(4-Bromophenyl)propyl]phenylamine
Yellow-brown viscous oil.
1H NMR (300 MHz, CDCl3): d = 0.96 (t, J = 7.5 Hz, 3 H, CH3),
1.82 (dq, Jd = Jq = 7.5 Hz, 2 H, CH2), 4.22 (t, J = 7.5 Hz, 1 H, CH),
6.48 (d, J = 8 Hz, 2 H, ArH), 6.70 (t, J = 8 Hz, 1 H, ArH), 7.10 (t,
J = 8 Hz, 2 H, ArH), 7.25 (t, J = 8 Hz, 2 H, ArH), 7.43 (d, J = 8 Hz,
2 H, CBrCH).
–
for the presence of nitrite as the reduction product of NO3 .
The ability of CAN to promote the ethylation of Schiff
bases while Ce(III) derivatives are completely inactive
and Ce(SO4)2, CeF4, and other Ln(III) compounds are less
Synthesis 2006, No. 11, 1819–1822 © Thieme Stuttgart · New York

1822
D. Tsvelikhovsky et al.
PAPER
13C NMR (75 MHz, CDCl3): d = 10.9, 31.7, 59.3, 113.4, 117.5,
120.6, 126.6, 128.4, 129.2, 143.2, 147.3.
Acknowledgement
We gratefully acknowledge the support for this study by the Ex-
change Program between the Hebrew University of Jerusalem and
the Technische Universität, Berlin, as well as by the United States–
Israel Binational Science Foundation through grant No. 2000013.
MS (EI, 70 eV): m/z (%) = 287, 289 (16) [M – 2H]+, 260, 258 (100)
[C13H9BrN]+, 179 (15) [C13H9N]+, 170, 168 (18) [C7H5Br]+, 117
(13) [C9H9]+, 115 (14) [C9H7]+, 104 (93) [C7H6N]+, 93 (19)
[C6H7N]+, 91 (17) [C6H5N]+, 77 (54) [C6H5]+.
Anal. Calcd for C15H16BrN: C, 62.08; H, 5.56; N, 4.83. Found: C,
62.49; H, 5.95; N, 4.76.
References
(1) Eisch, J. J. In Comprehensive Organometallic Chemistry,
Vol. 1; Wilkinson, G.; Stone, F. G. A.; Abel, E. N., Eds.;
Pergamon Press: Oxford UK, 1982, Chap. 6, and references
therein.
(2) (a) Alberola, A.; Cermeño, F. A.; Anton, A. An. Quim. 1977,
73, 886. (b) Schumann, H.; Kaufmann, J.; Dechert, S.;
Schmalz, H.-G. Tetrahedron Lett. 2002, 43, 3507.
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Tetrahedron Lett. 2003, 44, 8593.
N-[1-(3-Hydroxyphenyl)propyl)]phenylamine
Pale-yellow viscous oil.
1H NMR (300 MHz, CDCl3): d = 0.99 (t, J = 7.5 Hz, 3 H, CH3),
1.97 (dq, Jd = Jq = 7.5 Hz, 2 H), 3.95 (br s, NH, 1 H), 4.19 (t, J = 7.5
Hz, CH, 1 H), 4.42 (s, 1 H, OH), 6.78 (t, J = 8 Hz, 3 H, ArH), 6.88–
7.15 (m, ArH, 5 H), 7.17 (t, J = 8 Hz, 1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 10.7, 29.6, 62.9, 115.2, 116.0,
117.1, 120.1, 121.1, 126.1, 128.4, 128.5, 129.3, 129.4, 146.8, 156.5.
MS (EI, 70 eV): m/z (%) = 209 (100) [M-H2O]+, 180 (89)
[C13H10N]+, 151 (42) [C9H11NO]+, 104 (27) [C7H6N]+, 93 (46)
[C6H7N]+, 76 (45) [C6H4]+.
(6) Blum, J.; Rosenfeld, A.; Gelman, F.; Schumann, H.; Avnir,
D. J. Mol. Catal. A: Chem. 1999, 146, 117.
(7) Kim, S.-J.; Yang, N.; Kim, D.-H.; Kang, S. O.; Ko, J.
Organometallics 2000, 19, 4036.
(8) Reinheckel, H.; Haage, K.; Jahnke, D. Organomet. Chem.
Rev., Sect. A 1969, 4, 47.
Anal. Calcd for C15H17NO: C, 79.26; H, 7.54; N, 6.16. Found: C,
79.18; H, 7.51; N, 6.14.
N-(2-Naphthyl)-N-(1-phenylpropyl)amine
Yellow viscous oil.
1H NMR (300 MHz, CDCl3): d = 1.01 (t, J = 7.5 Hz, 3 H, CH3),
1.93 (dq, Jd = Jq = 7.5 Hz, 2 H, CH2), 4.00 (br s, 1 H, NH), 4.37 (t,
J = 7.5 Hz, 1 H, CH), 6.67 (s, 1 H, ArH), 6.90 (d, J = 8 Hz, 1 H,
ArH), 7.15 (t, J = 7.5 Hz, 1 H, ArH), 7.23 (t, J = 7.5 Hz, 1 H, ArH),
7.29–7.41 (m, 5 H, ArH), 7.46 (d, J = 8 Hz, 1 H, ArH), 7.57 (d,
J = 8 Hz, 1 H, ArH), 7.61 (d, J = 8 Hz, 1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 11.0, 31.6, 59.8, 105.6, 118.2,
122.0, 126.1, 126.3, 126.6, 127.1, 127.5, 127.7, 128.7, 128.9,
143.71, 145.16.
(9) Baciocchi, E.; Del Giacco, T.; Murgia, S. M.; Sebastiani, G.
V. Tetrahedron 1988, 44, 6651.
(10) Friestad, G. K. Tetrahedron 2001, 57, 5461;and references
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(16) Koslo, N. G.; Basalaeva, L. I. Russ. J. Gen. Chem. (Engl.
Transl.) 2001, 71, 250.
MS (EI, 70 eV): m/z (%) = 259 (34) [M – 2H]+, 230 (100)
[C17H12N]+, 153 (5) [C11H7N]+, 142 (11) [C10H8N]+, 126 (19)
[C10H6]+, 114 (15) [C9H6]+, 91 (27) [C7H7]+, 77 (9) [C6H5]+.
Anal. Calcd for C19H19N: C, 87.31; H, 7.33; N, 5.36. Found: C,
87.40; H, 7.38; N, 5.36.
Synthesis 2006, No. 11, 1819–1822 © Thieme Stuttgart · New York