Reactions of lithium silylcuprates with pyrazolium and indazolium salts

Article abstract of DOI:10.1002/ejoc.200700742

Although pyrazolium salts have been shown to be unreactive toward lithium carbocuprates, these substrates were opened by lithium silylcuprate reagents to give versatile N-silylated β-enaminoimines stabilized by coordination of the silyl group with both ni

Full text of DOI:10.1002/ejoc.200700742

FULL PAPER
DOI: 10.1002/ejoc.200700742
Reactions of Lithium Silylcuprates with Pyrazolium and Indazolium Salts
Ana M. González-Nogal,*[a] Mariola Calle,[a] and Purificación Cuadrado[a]
Keywords: Silicon / Heterocycles / Enaminoimines / Silylindazolines
Although pyrazolium salts have been shown to be unreactive
toward lithium carbocuprates, these substrates were opened
by lithium silylcuprate reagents to give versatile N-silylated
β-enaminoimines stabilized by coordination of the silyl group
with both nitrogen atoms. In contrast, the behaviour of indaz-
olium salts on treatment with the same reagents is more com-
plex. Depending on the substitution patterns of the indaz-
olium salts, the nature of the silylcuprate and even on the
temperature, we obtained 3-silylindazolines and other inter-
esting products resulting either from the opening of the het-
erocyclic ring or from modification by its opening/closing.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
more advantageous because they substantially cheapen the
synthesis and simplify the isolation process.
Introduction
Pyrazolium salts are not reactive toward organolithium
and Grignard reagents,[1,2] except when they bear a nitro
group at C-4. Nevertheless, in previous papers[3] we have
reported the regioselective synthesis of silylated pyrazolines
and indazolines by treatment of pyrazolium and indazolium
salts with silyllithium reagents. On the other hand, we have
not found any descriptions of the behaviour of these sub-
strates toward lithium carbocuprates, but have verified their
lack of reactivity. 2,3,5-Trimethyl-1-phenylpyrazolium io-
dide was recovered unchanged after treatment with lithium
dimethylcuprate.
3,5-Alkyl- or -aryl-substituted 2-methyl-1-phenylpyraz-
olium iodides 1a–c react with the mixed higher-order lith-
ium butyl(dimethylphenylsilyl)cuprate 2, but not with the
bulky lithium butyl(tert-butyldiphenylsilyl)cuprate 3, to give
N-silylated β-enaminoimines 4a–c (Scheme 1).
In contrast, however, this pyrazolium salt was shown to
be reactive toward lithium dimethylphenylsilylcuprate. In
this paper we describe in full the results obtained relating to
the reactions of lithium silylcuprates with pyrazolium and
benzopyrazolium salts.
Scheme 1.
The high affinity of Cu towards N and the presence of a
good leaving iminium group could explain the easy forma-
tion of a copper(III) amidocuprate intermediate, which se-
lectively transfers the silyl ligand to the nitrogen atom, af-
fording the N-silyl derivatives A upon reductive elimination
(Scheme 2). Because of the easy metalotropy of the silyl
groups, the β-enaminoimines A should exist in tautomeric
equilibrium with the β-enaminoimines B. Nevertheless, in
Results and Discussion
Reactions of Pyrazolium Salts with Lithium Silylcuprates
With the aim of identifying the scope and limitations of
this reaction, without counterpart in carbon chemistry, as
substrates we used differently substituted and function-
alized pyrazolium salts and as reagents two mixed higher-
order lithium alkylsilylcuprates[4] of different size and reac-
tivity: Bu(Me2PhSi)Cu(CN)Li2 (2) and Bu(tBuPh2Si)Cu-
(CN)Li2 (3), which selectively transfer a silyl group and
consequently behave like lithium bis(silyl)cuprates, but are
1
all the cases tested the H NMR spectra of the reaction
mixture showed single signals for the NMe and =CH pro-
tons. Moreover, although the silicon–nitrogen bond is very
weak and easily hydrolysed with water or methanol, 4a–c
surprisingly retain their silyl groups after hydrolysis of their
reaction mixtures with saturated aqueous ammonium chlo-
ride. These facts could justify admitting a stabilized che-
lated structure C, in which the silyl group is coordinated
with both nitrogen atoms.
[a] Departamento de Química Orgánica, Universidad de Valladolid,
47011 Valladolid, Spain
Fax: +34-983-423013
E-mail: agn@qo.uva.es
Eur. J. Org. Chem. 2007, 6089–6096
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6089

A. M. González-Nogal, M. Calle, P. Cuadrado
FULL PAPER
Moreover, the N-silyl-β-enaminoimines 4a–c are interest-
ing synthons, as they exhibit reactivity analogous to that
already known from the β-enaminoketones.[6] Thus, 4b was
regioselectively[7] converted into 3-methyl-5-phenylisoxazole
(7) by treatment with hydroxylamine hydrochloride
(Scheme 5).
Scheme 5.
Scheme 2.
We have extended this reaction to differently function-
alized pyrazolium salts. With the object of preparing syn-
thetic equivalents of silylated β-enaminones, the applica-
tions of which to the synthesis of silyl heterocycles (pyr-
roles, pyrazoles, pyrimidines and pyridinones) have been es-
tablished by us,[8] we studied the behaviour of differently
silylated N-phenylpyrazolium salts with lithium butyl(di-
methylphenylsilyl)cuprate. Unfortunately the presence of an
electron-donating silyl group in the heterocyclic ring pre-
vents the addition of the silylcuprate. The 4- or 5-silylpyraz-
olium salts 1f or 1g/1h were shown to be unreactive towards
lithium butyl(dimethylphenylsilyl)cuprate 2 (Scheme 6).
In contrast, when 1,2-dimethylpyrazolium salts 1d and
1e were treated with the dimethylphenylsilylcuprate 2, de-
quaternization of the pyrazolium ring took place, leading
to pyrazoles 5a and 5b. This behaviour, which is different
from that observed with silyllithium reagents,[3] may be ex-
plained in terms of coordination of the Cu at the N-methyl-
pyrazolium ion, elimination of the corresponding pyrazoles
5a and 5b and subsequent transfer of the silyl ligand at
[5]
the Me group and reductive elimination to give PhSiMe3
(Scheme 3).
Scheme 6.
Although the presence of electron-withdrawing groups
increases the electron deficiency of the pyrazolium ring and
therefore the reactivity of this system toward silylcuprates,
the 4-nitro- and 4-bromo-2-ethyl-3,5-dimethyl-1-phenylpyr-
azolium salts 1i and 1j were shown to be unreactive toward
the silylcuprate reagent 2. The same lack of reactivity was
observed by us on treatment of 1i and 1j with silyllithium
reagents.[3b] Nevertheless, the 4-ethoxycarbonylpyrazolium
tetrafluoroborate 1k reacted with the silylcuprate 2 to give
a mixture of the two tautomeric desilylated β-enamino-
imines 4d (Scheme 7).
Scheme 3.
These N-silyl-β-enaminoimines 4a–c may be regarded as
synthetic equivalents of the corresponding β-enamino-
ketones 6a–c, obtained by heating at reflux with a mixture
of EtOH/H2O 1.5:1 (Scheme 4).
The hydrolytic lability of the initially formed N-silylated
α-ethoxycarbonyl-β-enaminoimine may be attributed to the
conjugative stabilization of the enol form of the ester group
by the C=N functionalities (Scheme 8).
The behaviour of ethoxycarbonylpyrazolium salts toward
lithium dimethylphenylsilylcuprate depends on the position
of the ester group in the ring. Treatment of 5-ethoxycarbon-
ylpyrazolium salt 1l with the silylcuprate 2 gave the 5-
ethoxycarbonyl-3-pyrazoline
8 (Scheme 9). This result
could be satisfactorily explained in terms of a single-elec-
Scheme 4.
tron-transfer (SET) mechanism. Nevertheless, we think that
6090
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 6089–6096

Reactions of Lithium Silylcuprates with Pyrazolium and Indazolium Salts
Scheme 9.
Scheme 7.
Reactions of Indazolium Salts with Lithium Silylcuprates
We were also interested in the behaviour of benzopyraz-
olium salts with silylcuprate reagents. We started from 3-
unsubstituted (9a and 9b), 3-substituted (9c) and 3-func-
tionalized (9d) indazolium salts, as the natures of the prod-
ucts obtained depend on the substitution patterns of the
substrates. Furthermore, we have been able to establish dif-
ferent behaviour relating to the structures of the silylcuprate
reagents. In this case we used the mixed lithium silylcup-
rates 2 or 3 and the corresponding lithium bis(silyl)-
cuprates (Me2PhSi)2Cu(CN)Li2 (10) and (tBuPh2Si)2Cu-
(CN)Li2 (11).
Scheme 8.
The reactivity of benzopyrazolium salts toward silylcup-
rates is complex and difficult to explain. In general, the or-
the compound 8 could also arise through desilylation of the ganocuprates, besides being interesting nucleophilic rea-
initially formed 5-silylated 5-ethoxycarbonyl-3-pyrazoline, gents, are capable of electron transfer processes, and on oc-
because we obtained the same result when we carried out casions they can also behave as basic reagents. This can
the reaction with the silyllithium reagent.[3b] The with- explain the different results obtained in the reactions be-
drawing ester group at C-5 increases the electronic de- tween indazolium salts and silylcuprates depending on the
ficiency in this position, facilitating the conjugated addition structure of the benzopyrazolium salt, the nature of the
of the silylcuprate 2 to the α,β-unsaturated iminium system silylcuprate and the reaction conditions.
and giving a coordinated copper(III) intermediate, which
Thus, 3-unsubstituted indazolium and isoindazolium
transfers the silicon at C-5 with concomitant reductive eli- salts 9a and 9b underwent nucleophilic addition of mixed
mination of copper(I) to afford the corresponding 5-silyl-3- silylcuprates 2 and 3 to give the corresponding 3-silyl-
pyrazoline. Sensitivity to desilylation in this compound may indazolines 12a–c and reductive ring opening, possibly
be attributed to conjugative stabilization of the enol form through a single-electron-transfer mechanism, leading to
by the gem-ester functionality.
the β-enaminoimines 13a and 13b (Scheme 10).
When the ethoxycarbonyl group is attached at C-3 in-
The use of lithium bis(silyl)cuprates increases regioselec-
stead of at C-4 or C-5, the activity of the pyrazolium salt tivity. Both indazolium salts 9a and 9b, on treatment with
toward the nucleophilic attack is less, as was also previously higher-order bis(silyl)cuprates 10 and 11, yielded 3-silyl-
observed by us[3b] in the reactions of these substrates with indazolines 12a–c exclusively (Scheme 11).
silyllithium reagents. When we treated the 2-ethyl-3-ethoxy-
The lack of regioselectively when 9a and 9b were treated
carbonyl-5-methyl-1-phenylpyrazolium salt 1m with the si- with the mixed silylcuprates 2 and 3 at 0 °C could be due
lylcuprate 2, no reaction took place at –78 °C, whereas at to the presence of lithium dibutylcuprate in dynamic equi-
0 °C a complex mixture (of no synthetic interest) resulting librium with the lithium silylcuprates. As we did not find
from the attack of the reagent at the ring and the ester any references concerning the reactivity of these substrates
group was obtained.
with lithium organocuprates, we initially studied the reac-
Eur. J. Org. Chem. 2007, 6089–6096
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6091

A. M. González-Nogal, M. Calle, P. Cuadrado
FULL PAPER
mixed lithium butyl(dimethylphenylsilyl)cuprate (2) to af-
ford a mixture of 3-silylindazoline 12d and 2-methyl-1,4-
diphenyldihydroquinazoline 14. Meanwhile, the bulky tert-
butyldiphenylsilylcuprate 3 (less nucleophilic and more ba-
sic than 2) did not add to this indazolium salt, and the
hydroquinazoline 14 was the only isolable product
(Scheme 13). This behaviour by the tert-butyldiphenylsilyl
cuprate as a base was observed by us in its reactions with
phenylallenes. In contrast with dimethylphenylsilylcuprate,
which is added to phenylallenes to afford vinylsilanes,[9] the
basic tert-butyldiphenylsilylcuprate (tert-butyl alcohol inac-
tivates it) induces the isomerization of the phenylallenes
into acetylenes.[10]
Scheme 10.
Scheme 13.
The ring expansion from 9c to 14 could take place by a
heterocyclic opening/closing mechanism, probably initiated
by the action of the silylcuprate reagent as a base to give a
diazatriene, which undergoes an electrocyclic closure
(Scheme 14).
Scheme 11.
tion of the indazolium tetrafluoroborates 9a–c toward lith-
ium dimethylcuprate. These indazolium salts underwent re-
ductive ring opening, probably through an electron-transfer
process, giving the benzo-β-enaminoimines 13a–c
(Scheme 12).
Scheme 14.
When treatment of 9c with either silylcuprate 2 or 3 was
carried out at 0 °C, only the reductive heterocycle opening
took place, providing the same β-enaminoimine 13c that
had resulted from the treatment of 9c with lithium dimeth-
ylcuprate (Scheme 15).
The same result was obtained with the bis(silyl)cuprates
10 and 11.
Finally, we studied the reactivity of the 3-(ethoxycar-
bonyl)indazolium tetrafluoroborate 9d toward the higher-
order silylcuprates 2 and 10 (Scheme 16). Surprisingly, when
Scheme 12.
Nevertheless, the behaviour of the 3-phenylpyrazolium 9d was treated with the mixed carbosilylcuprate 2, this
salt 9c with lithium silylcuprates was more complex and transferred the butyl group instead of the dimethylphenyl-
temperature dependent. Thus, 9c reacted at –78 °C with the silyl group. We obtained the 3-butylindazoline 12e together
6092
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 6089–6096

Reactions of Lithium Silylcuprates with Pyrazolium and Indazolium Salts
Scheme 15.
with minor amounts of the β-enaminoamide 15 resulting
from the initial reaction of the silylcuprate with the ester
group.[11] Undoubtedly, the use of bis(dimethylphenylsilyl)
cuprate 10 prevents the alkylation of the ring but it did not
Scheme 18.
enhance the reactivity. Only minor amounts (5%) of the
enaminoamide 15 were obtained.
Conclusions
We have studied a reaction without precedent in carbon
chemistry. We have for the first time synthesized versatile
N-silyl-β-enaminoimines through the opening of pyraz-
olium salts with lithium silylcuprates. The isolation of these
compounds takes advantage of the stabilizing effect of the
N-silyl framework. In addition to their applications as
powerful silylating agents, silylamines are used in organic
synthesis in several ways. In the first of these, silicon is es-
sentially a protecting group, where its presence in place of
hydrogen enables us to carry out reactions, at the nitrogen
atom or elsewhere in the molecule, which would otherwise
be thwarted. Moreover, a silylated amine is a reactive nitro-
gen nucleophile toward a wide variety of electrophiles (hal-
ogens, alkyl or acyl halides, ketenes, isocyanates, anhydrides
etc.), due to the fact that a relatively weak Si–N bond is
replaced by the much stronger Si–O or Si–X bond.
Furthermore, the application of this methodology to ind-
azolium salts has allowed us to synthesize 3-silylindazol-
ines and other interesting new products such as the N-
silylated oxindole 16, precursor for the synthesis of dif-
ferently substituted and functionalized 3-aminooxindoles
with potential biological activity.[12] Oxindoles, appropri-
ately substituted at both nitrogen and C-3, are precursors
in the synthesis of biologically active alkaloids,[13] and some
of the compounds derived from the oxindole moiety are
among the most active dopamine receptor agonists.[14]
Functionalized indolin-2-ones have also turned out to be
key synthons in the synthesis of antiinflammatory agents.[15]
Scheme 16.
In contrast, the bis(tert-butyldiphenylsilyl)cuprate 11 was
shown to be especially reactive towards this salt 9d, leading
to the N-silylated ethylamino-N-phenyloxindole 16 with a
good yield (Scheme 17).
Scheme 17.
This result could be tentatively explained in terms of the
simultaneous addition of the silylcuprate at C-3 and the es-
ter group, to give a silylindazoline containing an acylsilane
moiety, which is opened with concomitant silyl rearrange-
ment from carbon to nitrogen. The acylsilane unit of this
intermediate is attacked by the fluoride ion present in the
reaction medium, affording a ketene, which experiences a
5-endo-dig intramolecular nucleophilic addition, yielding 16
in the final hydrolysis (Scheme 18).
Experimental Section
General: THF was distilled from sodium benzophenone ketyl in a
recycling still. Dichloromethane was distilled from P2O5. Copper(I)
cyanide was dried in vacuo over P2O5. All chromatographic and
workup solvents were distilled prior to use. The 2-methylpyraz-
olium or -indazolium iodides were prepared by heating of the cor-
responding pyrazoles or indazoles with methyl iodide in a pressure
tube, whereas 2-ethylpyrazolium tetrafluoroborates were prepared
by treatment of the corresponding pyrazoles and indazoles with
Eur. J. Org. Chem. 2007, 6089–6096
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6093

A. M. González-Nogal, M. Calle, P. Cuadrado
FULL PAPER
triethyloxonium fluoroborate in dry dichloromethane at room tem-
perature for several hours (12–20 h). All pyrazolium and indazol-
ium salts were recrystallized from acetone/ether. Lithium bis(di-
methylphenylsilyl)cuprate[9,16] (10) and bis(tert-butyldiphenylsilyl)-
cuprate[10,17] (11) were prepared as described previously, and the
mixed silylcuprate reagents 2 and 3 in the same way, through mix-
ing of one equivalent of the corresponding silyllithium, one equiva-
lent of butyllithium and one equivalent of copper(I) cyanide.[4] All
reactions involving organometallic reagents were carried out under
an atmosphere of nitrogen. 1H and 13C NMR spectra were re-
corded at 300 and 75 MHz, respectively, in CDCl3 as an internal
standard. Carbon multiplicities were assigned by DEPT experi-
ments. Reactions were monitored by TLC on precoated silica gel 60
plates (nano-SIL-20, Macherey–Nagel). Flash chromatography was
performed on silica gel 60 (230–400 mesh, M–N).
H), 7.23 (dd, J = 7.8, 7.3 Hz, 2 H), 8.91 (br. s, 1 H) ppm. Tautomer
B (57%): H NMR (300 MHz, CDCl3): δ = 1.24 (t, J = 7.0 Hz, 3
1
H), 1.35 (t, J = 7.1 Hz, 3 H), 1.70 (s, 3 H), 2.55 (s, 3 H), 3.51 (q,
J = 7.0 Hz, 2 H), 4.22 (q, J = 7.1 Hz, 2 H), 6.82 (d, J = 7.7 Hz, 2
H), 7.07 (t, J = 7.6 Hz, 1 H), 7.27 (dd, J = 7.7, 7.6 Hz, 2 H),
9.42 (br. s, 1 H) ppm. IR (film): ν = 1723, 1585, 730, 690 cm–1.
˜
C16H22N2O2 (274.17): calcd. C 70.04, H 8.08, N 10.21; found C
69.83, H 8.32, N 9.91.
2-Ethyl-5-ethoxycarbonyl-3-methyl-1-phenyl-3-pyrazoline (8): Yield:
1
553 mg (71%); oil. H NMR (300 MHz, CDCl3): δ = 1.11 (t, J =
7.0 Hz, 3 H), 1.36 (t, J = 7.1 Hz, 3 H), 1.89 (s, 3 H), 3.16 (q, J =
7.0 Hz, 2 H), 4.31 (q, J = 7.1 Hz, 2 H), 4.74 (d, J = 2.4 Hz, 1 H),
4.84 (d, J = 2.4 Hz, 1 H), 6.97 (t, J = 7.4 Hz, 1 H), 7.10 (d, J =
7.9 Hz, 2 H), 7.28 (dd, J = 7.4, 7.9 Hz, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 10.08, 12.70, 14.28, 46.59, 61.15, 73.28,
98.88, 114.73, 120.33, 127.83, 145.14, 152.46, 172.22 ppm. IR
General Procedure for the Reactions of Pyrazolium and Indazolium
Salts with Lithium Silylcuprate Reagents: A THF solution of the
lithium silylcuprate reagent 2, 3, 10 or 11 (3 mmol) was added at
0 °C or –78 °C under an atmosphere of N2 to a stirred solution of
the pyrazolium or indazolium salt (3 mmol) in dry THF (2 mL).
The reaction mixture was stirred at this temperature until TLC
indicated that the reaction was complete. When the reaction was
carried out at 0 °C, the mixture was quenched with aqueous
NH4Cl, and with methanol in the reactions at –78 °C. The organic
layer was extracted with Et2O and dried with MgSO4, and the sol-
vent was removed under reduced pressure. The residue was purified
by flash chromatography to give the following products.
(film): ν = 1735, 1595, 1500, 825 cm–1. MS (EI, 70 eV): m/z (%) =
˜
260 (3) [M]+, 245 (42), 231 (4), 215 (30), 187 (51), 77 (100).
C15H20N2O2 (260.15): calcd. C 69.20, H 7.74, N 10.76; found C
69.45, H 7.91, N 10.52.
3-tert-Butyldiphenylsilyl-1,2-dimethylindazoline
(12a):
Yield:
625 mg (54%) from 3 and 868 mg (75%) from 11; oil. Rf = 0.43
1
(hexane/CH2Cl2, 1:1). H NMR (300 MHz, CDCl3): δ = 1.22 (s, 9
H), 2.40 (s, 3 H), 2.56 (s, 3 H), 4.38 (s, 1 H), 6.38 (d, J = 7.9 Hz,
1 H), 6.57 (m, 2 H), 6.95 (m, 1 H), 7.19–7.60 (m, 10 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 19.22, 28.62, 41.30, 48.08, 62.21,
110.19, 120.16, 122.72, 126.71, 127.22, 127.27, 127.62, 129.11,
Enamine 4a: Yield: 463 mg (48%); oil. 1H NMR (300 MHz,
130.69 132.75, 134.95, 136.75, 136.87, 150.24 ppm. IR (film): ν =
˜
CDCl3): δ = 0.40 (s, 6 H), 1.89 (s, 3 H), 2.03 (s, 3 H), 2.97 (s, 3 H), 1598, 1490, 1106 cm–1. MS (EI, 70 eV): m/z (%) = 329 (100) [M –
4.74 (s, 1 H), 6.87 (dd, J = 1.2, 8.3 Hz, 2 H), 7.05 (tt, J = 1.2, tBu]+, 309 (15), 224 (22), 146 (31), 77 (40), 57 (53). C25H30N2Si
7.1 Hz, 1 H), 7.33 (dd, J = 7.1, 8.3 Hz, 2 H), 7.35–7.50 (m, 3 H), (386.22): calcd. C 77.67, H 7.82, N 7.25; found C 77.37, H 7.95, N
7.60 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = –4.04, 19.11, 7.04.
20.90, 29.43, 93.63, 121.92, 127.59, 128.30, 128.49, 132.87, 133.72,
3-Dimethylphenylsilyl-1-ethyl-2-phenylindazoline
(12b):
Yield:
139.65, 151.75, 156.81, 166.36 ppm. IR (film): ν = 3100, 1580, 1250,
˜
343 mg (32%) from 2 and 590 mg (55%) from 10; oil. Rf = 0.49
1100 cm–1. MS (EI, 70 eV): m/z (%) = 322 (2) [M]+, 187 (21), 135
(100), 93 (40), 77 (78). C20H26N2Si (322.19): calcd. C 74.48, H 8.13,
N 8.69; found C 74.77, H 7.95, N 8.36.
1
(hexane/CH2Cl2, 1:1). H NMR (300 MHz, CDCl3): δ = 0.42 (s, 3
H), 0.46 (s, 3 H), 1.24 (t, J = 7.2 Hz, 3 H), 2.85 (dq, J = 14.2,
7.2 Hz, 1 H), 3.12 (dq, J = 14.2, 7.2 Hz, 1 H), 4.61 (s, 1 H), 6.74
(d, J = 7.5 Hz, 1 H), 6.86 (m, 2 H), 7.10–7.64 (m, 11 H) ppm. 13C
Enamine 4b: Yield: 840 mg (73%); oil. 1H NMR (300 MHz,
CDCl3): δ = 0.35 (s, 6 H), 2.07 (s, 3 H), 3.06 (s, 3 H), 4.91 (s, 1 H), NMR (75 MHz, CDCl3): δ = –3.97, 14.22, 45.03, 53.27, 112.37,
6.68 (dd, J = 1.2, 8.3 Hz, 2 H), 6.83 (tt, J = 1.2, 7.1 Hz, 1 H), 7.08
(dd, J = 7.1, 8.3 Hz, 2 H), 7.36–7.42 (m, 3 H), 7.56 (m, 2 H) ppm.
112.75, 116.25, 120.98, 123.87, 127.65, 128.37, 129.21, 132.94,
132.45, 133.80, 139.74, 149.64, 155.25 ppm. IR (film): ν = 3015,
˜
13C NMR (75 MHz, CDCl3): δ = –4.08, 19.46, 30.44, 95.44, 121.46, 1590, 1486, 1250, 1100 cm–1. MS (EI, 70 eV): m/z (%) = 343 (16)
127.59, 127.69, 127.87, 128.17, 128.42, 129.22, 129.62, 132.97,
[M – Me]+, 281 (5), 223 (100), 194 (19), 135 (31), 77 (14).
139.71, 139.97, 150.42, 159.49, 166.55 ppm. IR (film): ν = 3120, C23H26N2Si (358.19): calcd. C 77.05, H 7.31, N 7.81; found C
˜
1585, 1250, 1100 cm–1. MS (EI, 70 eV): m/z (%) = 384 (3) [M]+, 77.32, H 7.49, N 7.67.
249 (19), 193 (100), 135 (11), 77 (45). C25H28N2Si (384.20): calcd.
C 78.07, H 7.34, N 7.28; found C 77.87, H 7.51, N 7.06.
Enamine 4c: Yield: 1.01 g (76%); oil. 1H NMR (300 MHz, CDCl3):
3-tert-Butyldiphenylsilyl-1-ethyl-2-phenylindazoline (12c): Yield:
582 mg (42%) from 3 and 887 mg (64%) from 11; oil. Rf = 0.50
1
(hexane/CH2Cl2, 1:2). H NMR (300 MHz, CDCl3): δ = 1.02 (t, J
δ = 0.33 (s, 6 H), 2.96 (s, 3 H), 5.03 (s, 1 H), 6.75 (dd, J = 1.2, = 7.2 Hz, 3 H), 1.33 (s, 9 H), 2.25 (dq, J = 14.1, 7.2 Hz, 1 H), 2.51
8.3 Hz, 2 H), 6.86 (tt, J = 1.2, 7.1 Hz, 1 H), 7.13 (dd, J = 7.1,
(dq, J = 14.1, 7.2 Hz, 1 H), 5.28 (s, 1 H), 6.61 (m, 2 H), 6.94 (m,
8.3 Hz, 2 H), 7.18–7.48 (m, 15 H), 7.56 (m, 2 H) ppm. 13C NMR 2 H), 7.14–7.54 (m, 15 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
(75 MHz, CDCl3): δ = –4.00, 32.12, 97.54, 118.83, 121.71, 122.57, 14.03, 19.01, 28.45, 50.93, 63.27, 111.95, 117.23, 121.02, 121.15,
125.12, 125.68, 127.61, 127.90, 128.14, 128.32, 128.75, 129.16,
133.71, 136.76 138.77, 139.47, 150.16, 167.88, 166.55 ppm. IR
122.22, 126.46, 127.17, 127.79, 128.69, 129.36, 132.45, 133.89,
134.77, 135.66, 137.01, 137.08, 150.02, 157.18 ppm. IR (film): ν =
˜
(film): ν = 3115, 1580, 1250, 1100 cm–1. MS (EI, 70 eV): m/z (%)
3018, 1596, 1486, 1105 cm–1. MS (EI, 70 eV): m/z (%) = 405 (100)
[M – tBu]+, 300 (18), 222 (11), 105 (15), 77 (20), 57 (54).
C31H34N2Si (462.25): calcd. C 80.47, H 7.41, N 6.05; found C
80.25, H 7.56, N 5.91.
˜
= 446 (1) [M]+, 431 (11), 369 (23), 311 (98), 296 (26), 220 (100),
180 (12), 135 (7), 118 (14), 77 (73). C30H30N2Si (446.22): calcd. C
80.67, H 6.77, N 6.27; found C 80.88, H 6.54, N 6. 46.
Enamine 4d: Yield: 616 mg (75%); oil. Tautomer A (43%): 1H
NMR (300 MHz, CDCl3): δ = 1.09 (t, J = 7.2 Hz, 3 H), 1.41 (t, J
= 7.1 Hz, 3 H), 2.01 (s, 3 H), 2.37 (s, 3 H), 3.06 (m, 2 H), 4.36 (q,
J = 7.1 Hz, 2 H), 6.78 (d, J = 7.8 Hz, 2 H), 7.00 (t, J = 7.3 Hz, 1
3-Dimethylphenylsilyl-2-ethyl-1,3-diphenylindazoline (12d): Yield:
585 mg (45%) from 2; oil. Rf = 0.43 (hexane/CH2Cl2, 1:1). 1H
NMR (300 MHz, CDCl3): δ = 0.23 (s, 3 H), 0.25 (s, 3 H), 1.11 (t,
J = 7.1 Hz, 3 H), 3.05 (m, 2 H), 6.90 (t, J = 7.4 Hz, 1 H), 7.05 (m,
6094
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 6089–6096

Reactions of Lithium Silylcuprates with Pyrazolium and Indazolium Salts
3 H), 7.18 (dd, J = 7.6, 8.0 Hz, 1 H), 7.21–7.68 (m, 14 H) ppm. 13
CDCl3): δ = 14.78, 34.69, 115.40, 117.91, 118.69, 120.47, 122.20,
C
NMR (75 MHz, CDCl3): δ = –4.87, 12.13, 52.19, 71.25, 112.05,
121.60, 122.72, 124.11, 127.21, 127.48, 127.90, 128.38, 128.90,
127.42, 129.21, 131.95, 141.54, 145.15, 169.44 ppm. IR (CHCl ): ν
˜
3
= 3300 (br.), 3015, 1630, 1590, 1500, 740, 690 cm–1. C15H16N2O
129.41, 132.31, 133.68, 139.22, 143.17, 145.38, 147.55 ppm. IR (240.13): calcd. C 74.97, H 6.71, N 11.66; found C 74.72, H 6.63,
(film): ν = 3015, 1590, 1486, 1250, 1100 cm–1. MS (EI, 70 eV): m/z N 11.85.
˜
(%) = 419 (11) [M – Me]+, 300 (17), 299 (35), 222 (41), 135 (22), 77
(100). C29H30N2Si (434.22): calcd. C 80.14, H 6.96, N 6.45; found C
80.36, H 7.14, N 6.63.
3-[N-(tert-Butyldiphenylsilyl)-N-ethylamino]-1-phenylindolin-2-one
(16): Yield: 1.14 g (78%); oil. Rf = 0.34 (hexane/CH2Cl2, 1:1). H
NMR (300 MHz, CDCl3): δ = 0.91 (t, J = 7.0 Hz, 3 H), 1.33 (s, 9
1
H),3.10 (m, 2 H), 5.00 (s, 1 H), 6.82 (d, J = 7.7 Hz, 1 H), 7.13 (t,
J = 7.2 Hz, 1 H), 7.23 (t, J = 7.7 Hz, 1 H), 7.39–7.57 (m, 13 H),
7.97 (m, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 16.44, 20.08,
29.18, 41.90, 60.83, 109.52, 122.74, 124.97, 126.41, 127.71, 127.90,
128.33, 129.30, 129.38, 129.60, 134.65, 134.80, 135.04, 135.58,
Ethyl 3-Butyl-2-ethyl-1-phenylindazoline-3-carboxylate (12e): Yield:
443 mg (42%) from 2; oil. Rf = 0.48 (hexane/CH2Cl2, 1:1). 1H
NMR (300 MHz, CDCl3): δ = 0.82 (t, J = 7.1 Hz, 3 H), 1.16 (t, J
= 7.0 Hz, 3 H), 1.19 (t, J = 7.0 Hz, 3 H), 1.20–1.34 (m, 4 H), 1.79
(dt, J = 13.6, 4.7 Hz, 1 H), 2.04 (dt, J = 13.6, 4.7 Hz, 1 H), 2.81
(m, 2 H), 4.15 (q, J = 7.1 Hz, 2 H), 6.96 (t, J = 7.3 Hz, 1 H), 7.04
(t, J = 7.4 Hz, 1 H), 7.15 (d, J = 7.7 Hz, 1 H), 7.27 (dd, J = 7.3,
7.7 Hz, 2 H), 7.30 (dd, J = 7.4, 7.7 Hz, 1 H), 7.37 (d, J = 7.4 Hz,
1 H), 7.47 (d, J = 7.7 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 13.49, 13.83, 13.91, 22.76, 26.25, 36.54, 47.20, 61.16, 78.16,
116.16, 116.63, 12151, 122.35, 125.33, 127.87, 128.57, 133.87,
136.38, 136.57, 143.22, 177.75 ppm. IR (film): ν = 1723, 1611, 1595,
˜
1501, 1105 cm–1. C32H34N2OSi (490.24): calcd. C 78.32, H 6.98, N
5.71; found C 78.54, H 7.15, N 5.52.
Hydrolysis of N-Silyl-β-enaminoimines. General Procedure: A solu-
tion of the N-silyl-β-enaminoimine 4a–c (1 mmol) in an ethanol/
water mixture (1.5:1, 8 mL) was stirred at reflux for 1 h 30 min.
The ethanol was then evaporated under reduced pressure, and the
reaction mixture was extracted with diethyl ether. The organic layer
was dried (MgSO4) and concentrated. The residue was purified by
flash chromatography on silica gel with CH2Cl2 as eluent to give
the following β-aminoenones.
145.12, 148.77, 171.09 ppm. IR (film): ν = 3015, 1735, 1590, 1486,
˜
750, 685 cm–1. MS (EI, 70 eV): m/z (%) = 352 (5) [M]+, 307 (36),
279 (55), 218 (11), 250 (22), 77 (100). C22H28N2O2 (352.22): calcd.
C 74.97, H 8.01, N 7.95; found C 75.22, H 7.94, N 8.11.
N-[2-(Methylamino)benzylidene]methylamine (13a): Yield: 159 mg
(36%); oil. Rf = 0.79 (hexane/CH2Cl2, 1:1). 1H NMR (300 MHz,
CDCl3): δ = 3.05 (d, J = 5.1 Hz, 3 H), 3.27 (s, 3 H), 6.40–7.40 (m,
(Z)-4-(Phenylamino)pent-3-en-2-one (6a): Yield: 166 mg (95%); oil.
Rf = 0.57 (CH2Cl2). 1H NMR (300 MHz, CDCl3): δ = 1.98 (s, 3
H), 2.09 (s, 3 H), 5.18 (s, 1 H), 7.09 (d, J = 8.7 Hz, 2 H), 7.17 (t,
J = 7.4 Hz, 1 H), 7.32 (dd, J = 8.7, 7.4 Hz, 2 H), 9.49 (br. s, 1
4 H), 8.11 (s, 1 H), 9.00 (br. s, 1 H) ppm. IR (film): ν = 3015, 1590,
˜
1495, 830 cm––1. C9H12N2 (148.10): calcd. C 72.94, H 8.16, N
18.90; found C 73.20, H 8.29, N 19.16.
H) ppm. IR (film): ν = 3240, 1620, 1595, 1501, 752, 680 cm–1.
˜
C11H13NO (175.10): calcd. C 75.40, H 7.48, N 7.99; found C 75.64,
H 7.31, N 7.85.
N-[2-(Ethylamino)benzylidene]phenylamine (13b): Yield: 235 mg
(35%) from 2 and 282 mg (42%) from 3; oil. Rf = 0.68 (hexane/
CH2Cl2, 1:1). 1H NMR (300 MHz, CDCl3): δ = 1.28 (t, J = 7.1 Hz,
3 H), 3.35 (dq, J = 5.1, 7.1 Hz, 2 H), 6.57–7.72 (m, 9 H), 8.57 (s,
(Z)-4-Phenyl-4-(phenylamino)but-3-en-2-one (6b): Yield: 225 mg
1
(95%); oil. Rf = 0.55 (CH2Cl2). H NMR (300 MHz, CDCl3): δ =
1 H), 9.19 (br. s, 1 H) ppm. IR (film): ν = 3015, 1590, 1495, 830,
˜
2.21 (s, 3 H), 5.40 (s, 1 H), 6.74 (d, J = 7.8 Hz, 2 H), 6.96 (t, J =
7.4 Hz, 1 H), 7.11 (dd, J = 7.8, 7.4 Hz, 2 H), 7.33 (m, 5 H), 9.69
(br. s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 29.81, 100.47,
123.09, 123.89, 127.73, 128.32, 128.67, 129.28, 135.47, 139.80,
750, 680 cm–1. C15H16N2 (224.13): calcd. C 80.32, H 7.19, N 12.49;
found C 80.51, H 6.92, N 12.66.
N-[2-(Phenylamino)phenylbenzyliden]ethylamine
(13c):
Yield:
159.62, 197.42 ppm. IR (film): ν = 3280, 1610, 1590, 1500, 740,
˜
405 mg (45%) from 2 and 558 mg (62%) from 3; oil. Rf = 0.46
685 cm–1. C16H15NO (237.12): calcd. C 80.98, H 6.37, N 5.90;
found C 81.18, H 6.45, N 6.15.
1
(hexane/AcOEt, 10:1). H NMR (300 MHz, CDCl3): δ = 1.28 (t, J
= 7.2 Hz, 3 H), 3.30 (q, J = 7.2 Hz, 2 H), 6.57 (t, J = 7.2 Hz, 1 H),
6.86 (dd, J = 7.3, 7.8 Hz, 1 H), 7.01–7.54 (m, 12 H), 12.34 (br. s, 1
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 16.66, 47.60, 113.77,
116.38, 120.96, 122.06, 127.43, 128.09, 128.47, 129.26, 130.24,
(Z)-1,3-Diphenyl-3-(phenylamino)prop-2-en-1-one
(6c):
Yield:
290 mg (97%); oil. Rf = 0.32 (CH2Cl2). 1H NMR (300 MHz,
CDCl3): δ = 5.70 (s, 1 H), 6.65 (d, J = 7.8 Hz, 2 H), 7.06 (t, J =
7.4 Hz, 1 H), 7.15 (dd, J = 7.8, 7.4 Hz, 2 H), 7.43 (m, 8 H), 7.90
132.00, 133.46, 137.01, 141.94, 146.05, 171.27 ppm. IR (film): ν =
˜
3010, 1600, 1490, 830, 745, 690 cm–1. C21H20N2 (300.16): calcd. C
83.96, H 6.71, N 9.33; found C 84.28, H 6.51, N 9.69.
˜
(m, 2 H), 11.33 (br. s, 1 H) ppm. IR (film): ν = 3300, 1615, 1580,
1500, 745, 695 cm–1. C21H17NO (299.13): calcd. C 84.25, H 5.72,
N 4.68; found C 84.41, H 5.65, N 4.82.
2-Methyl-1,4-diphenyl-1,2-dihydroquinazoline (14): Yield: 277 mg
(31%) from 2 and 196 mg (22%) from 3; oil. Rf = 0.40 (hexane/
AcOEt, 2:1). 1H NMR (300 MHz, CDCl3): δ = 1.47 (d, J = 6.2 Hz,
3 H), 5.79 (q, J = 6.2 Hz, 1 H), 6.80 (t, J = 7.3 Hz, 1 H), 7.06 (d,
J = 8.1 Hz, 2 H), 7.14 (dd, J = 7.3, 8.1 Hz, 2 H), 7.27–7.64 (m, 9
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 18.31, 71.91, 117.64,
118.77, 119.86, 122.65, 123.71, 128.08, 128.39, 128.58, 129.15,
Reaction between N-Silyl-β-enaminoimine 4b and Hydroxylamine
Hydrochloride. Regioselective Synthesis of 3-Methyl-5-phenylisox-
azole (7): Hydroxylamine hydrochloride (1.12 mmol) and Na2CO3
(0.46 mmol) were added to a solution of 4b (1 mmol) in an ethanol/
water mixture (1:1, 10 mL). The mixture was heated at reflux for
3 h and then extracted with diethyl ether. The ethereal layer was
dried (MgSO4), the solvent was removed and the residue was
recrystallized from ethanol to give 7. Yield: 133 mg (84%). M.p.
67–68 °C (ref.[18] 65 °C).
129.35, 132.05, 138.02, 143.21, 144.70, 163.30 ppm. IR (film): ν =
˜
3018, 1664, 1607, 1494, 762, 690 cm–1. C21H18N2 (298.15): calcd. C
84.53, H 6.08, N 9.39; found C 84.77, H 6.21, N 9.47.
N-Ethyl-2-(phenylamino)benzamide (15): Yield: 36 mg (5%) from 2
and 10; m.p. 74–75 °C (cyclohexane). 1H NMR (300 MHz, CDCl3):
δ = 1.25 (t, J = 7.3 Hz, 3 H), 3.48 (dq, J = 5.4, 7.3 Hz, 2 H), 6.21
(br. s, 1 H), 6.76 (t, J = 8.0 Hz, 1 H), 7.01 (dd, J = 7.1, 7.6 Hz, 1
Acknowledgments
We thank the Ministerio de Ciencia y Tecnología of Spain for sup-
H), 7.18–7.43 (m, 7 H), 9.32 (s, 1 H) ppm. 13C NMR (75 MHz, porting this work.
Eur. J. Org. Chem. 2007, 6089–6096
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6095

A. M. González-Nogal, M. Calle, P. Cuadrado
FULL PAPER
[9] I. Fleming, M. Rowley, P. Cuadrado, A. M. González-Nogal,
F. J. Pulido, Tetrahedron 1989, 45, 413–424.
[10] A. Barbero, P. Cuadrado, A. M. González-Nogal, F. J. Pulido,
I. Fleming, J. Chem. Soc. Perkin Trans. 1 1991, 2811–2816.
[11] The β-enaminoamide 15 was obtained by us, as the only prod-
uct, from the reactions of the same indazolium salt 9e with
silyllithium reagents (ref.[3b]).
[12] For leading references to the biological activity of indolin-2-
ones, see: a) A. Canas-Rodriguez, P. R. Leeming, J. Med.
Chem. 1972, 15, 762–770; b) M. J. Kornet, A. P. Thio, J. Med.
Chem. 1976, 19, 892–898; c) W. Fischer, E. Schilling, R.
Schmiedel, M. Muller, Pharmazie 1982, 37, 12–18.
[13] a) Q.-S. Yu, A. Brossi, Heterocycles 1988, 27, 7–12; b) K. Shish-
ido, E. Shitara, H. Komatsu, K. Hiroya, K. Fukumoto, T. Ka-
metani, J. Org. Chem. 1986, 51, 3007–3011; c) P. G. Cozzi, C.
Palazzi, D. Potenza, C. Scolostico, W. Y. Sun, Tetrahedron Lett.
1990, 31, 5661–5664.
[14] a) J. P. Hieble, Annu. Rep. Med. Chem. 1987, 22, 107–113; b) J.
Weinstock, D. E. Gaitanopoulus, O. D. Stringer, R. G. Franz,
J. P. Hieble, L. B. Kintor, W. A. Mann, K. E. Flaim, G.
Gessner, J. Med. Chem. 1987, 30, 1166–1176.
[1] J. Elguero, R. Jacquier, D. Tizané, Bull. Soc. Chim. Fr. 1970,
1121–1129.
[2] P. Cuadrado, A. M. González-Nogal, S. Martínez, Tetrahedron
1997, 53, 8585–8598.
[3] a) P. Cuadrado, A. M. González-Nogal, Tetrahedron Lett.
1998, 39, 1449–1452; b) A. M. González-Nogal, M. Calle,
L. A. Calvo, P. Cuadrado, A. González-Ortega, Eur. J. Org.
Chem. 2005, 4663–4669.
[4] The reagents 2 and 3 used by us in this paper are mixed lithium
alkylsilylcyanocuprates, prepared as described by Oehlschlager
from silyllithium/alkyllithium/copper(I) cyanide in 1:1:1 ratio,
see: S. Sharma, A. C. Oehlschlager, J. Org. Chem. 1991, 56,
770–776. The NMR studies described in this paper suggest that
when the ratio of silyl anion to alkyl anion to cuprous ion
is 1:1:1, the mixed silylcuprates, irrespective of the mode of
preparation, revert to the same R3Si(R)Cu(CN)Li2 species with
the nitrile ligand bound to copper (13C NMR and IR spectra).
These species, which are higher-order mixed alkylsilylcuprates,
transfer the R3Si group in preference to alkyl ligand.
[5] The identification of PhSiMe3 was impossible because in the
chromatographic separation it was isolated in the first fraction,
together with the remaining dimethylphenylsilanes formed in
the workup of the reaction mixture.
[15] A. J. Lewis, N. S. Doherty, N. R. Ackerman, Therapeutic Ap-
proaches to Inflammatory Diseases, Elsevier, New York, 1989,
pp. 229–239.
[16] I. Fleming, T. W. Newton, F. Roessler, J. Chem. Soc. Perkin
Trans. 1 1981, 2527–2532.
[17] A. Barbero, P. Cuadrado, I. Fleming, A. M. González-Nogal,
F. J. Pulido, A. Sánchez, J. Chem. Soc. Perkin Trans. 1 1995,
1525–1532.
[6] U. Kuckländer “The Chemistry of Functional Groups” in En-
aminones as Synthones Part 1 (Ed.: Z. Rappoport), Wiley-Inter-
science, New York, 1994, ch. 10.
[7] When starting from the corresponding β-diketones a mixture
of two regioisomeric isoxazoles is obtained.
[8] a) L. A. Calvo, A. M. González-Nogal, A. González-Ortega,
M. C. Sañudo, Tetrahedron Lett. 2001, 42, 8981–8984; b) M.
Calle, L. A. Calvo, A. González-Ortega, A. M. González-No-
gal, Tetrahedron 2006, 62, 611–618.
[18] G. Bianchi, P. Grünanger, Tetrahedron 1965, 21, 817–822.
Received: August 10, 2007
Published Online: November 15, 2007
6096
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 6089–6096