Lithiation of 2,5-dimethylazaferrocene

Article abstract of DOI:10.1016/j.jorganchem.2003.11.038

Reaction of 2,5-dimethylazaferrocene with sec -BuLi/TMEDA in THF at -78 °C, followed by quenching with D₂O brought about incorporation of deuterium into the Cp ring (54%), methyl groups (38%) and the pyrrolyl β-position (8%). When benzyl chloride or p-methoxybenzaldehyde was used as quenchers products originated from the lateral lithiation were only formed, accompanied by recovered starting material. For this reaction a radical pathway is suggested.

Full text of DOI:10.1016/j.jorganchem.2003.11.038

Journal of Organometallic Chemistry 689 (2004) 1046–1049
www.elsevier.com/locate/jorganchem
Lithiation of 2,5-dimethylazaferrocene
*
Konrad Kowalski, Janusz Zakrzewski
Department of Organic Chemistry, Institute of Chemistry, University of Łꢀodꢀz, Narutowicza 68, Łꢀodꢀz 90136, Poland
Received 16 September 2003; accepted 17 November 2003
Abstract
Reaction of 2,5-dimethylazaferrocene with sec-BuLi/TMEDA in THF at )78 °C, followed by quenching with D2O brought
about incorporation of deuterium into the Cp ring (54%), methyl groups (38%) and the pyrrolyl b-position (8%). When benzyl
chloride or p-methoxybenzaldehyde was used as quenchers products originated from the lateral lithiation were only formed, ac-
companied by recovered starting material. For this reaction a radical pathway is suggested.
Ó 2004 Elsevier B.V. All rights reserved.
Keywords: Azaferrocene; Lithiation
1. Introduction
preferential reaction site(s) of 2 and study of reactivities
of resulting lithio compounds would be of interest for
syntheses of specifically substituted azaferrocenes with
possible applications in asymmetric syntheses [5,7] or in
the study of photoinduced electron transfer reactions
involving metalloporphyrins and metallophthalocya-
nines [8]. Herein, we report preliminary results of such a
research.
Lithiation of methyl-substituted ferrocenes takes
place at the Cp rings not at the methyl groups [1].
Ferrocenyl group does not seem to stabilize the negative
charge in the a-position to an extent making CH3 pro-
tons more acidic than those of the Cp rings [2,3].
However, it has been reported that bis-lithiation of
1,2,3,4,5-pentamethylferrocene proceeds at the Cp ring
and at one of the methyl groups [4]. In contrast, it has
recently been found that 10,2,20,30,40,5,50,-heptamethy-
lazaferrocene 1 undergoes lithiation at the methyl group
of the pyrrolyl ligand [5]. The activating effect of the
nitrogen atom can be compared to that observed in 2-
methylpyridine, undergoing lateral lithiation more easily
than toluene [6].
2. Results and discussion
In our first attempts, we treated 2 with sec-BuLi/
TMEDA in THF at )78 °C for 1.5 h and then quenched
with D2O. To determine the extent of deuteration the
recovered metallocene was treated with neat methyl io-
dide, which transformed it quantitatively into the cor-
responding N-methyl iodide, [2-Me]þ Iꢀ [9]. The FAB
mass spectrum of this complex in the positive peaks
mode displays an intense peak corresponding to the
mass of the cationic part of the complex. Comparison
of this spectrum with that of the N-methyl iodide of
the starting 2 led to conclusion that complete deutera-
tion took place with some concomitant bis-deuteration
(10–15%).
N
N
Fe
Fe
1
2
In contrast to 1, 2,5-dimethylazaferrocene 2 contains
three potential reaction sites: methyl groups, Cp- and
pyrrolyl rings. We thought that determination of the
2
The deuteration sites were determined from the H
NMR spectrum of the reaction mixture (Fig. 1).
The most intense signal (4.25 ppm) corresponds to
deuterium incorporated to the Cp ring, but the signal at
* Corresponding author. Tel.: +4842-678-4731; fax: +4842-678-6583.
E-mail address: janzak@uni.lodz.pl (J. Zakrzewski).
0022-328X/$ - see front matter Ó 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2003.11.038

K. Kowalski, J. Zakrzewski / Journal of Organometallic Chemistry 689 (2004) 1046–1049
1047
bond can be estimated: Cp:Me:b-pyrrolyl ¼ 2.7:1.6:1). It
is interesting to compare these results with those ob-
tained by Pyshnograeva et al. [10] for lithiation of par-
ent, unsubstituted azaferrocene with n-BuLi. Using
quenching with D2O or methyl iodide, they found that
lithiation occurs in the Cp ring and at the a-position of
the pyrrolyl ligand at comparable rates.
In the following experiment, 2 was treated with sec-
Buli-TMEDA in THF at )78 °C for 1.5 h and then
quenched at the same temperature with benzyl chloride.
Unexpectedly, the only azaferrocene product isolated
was 3 (35%), along with a significant amount (55%) of
recovered 2 (Eq. (2)). No other benzylated derivatives of
2 were detected in this reaction. Similarly, when p-
methoxybenzaldehyde was used as a quencher, 4 (30%)
was obtained along with 2 (50% recovery). According to
1H NMR, only one diastereomer was formed.
N
Fe
2
1. sec-BuLi/TMEDA/-78˚C
2. PhCH2Cl
1. sec-BuLi/TMEDA/-78˚C
2. p-MeOPhCHO
Fig. 1. 2H NMR spectrum of deuterated 2.
ð2Þ
2.34 ppm must be assigned to the CH2D group (the
same chemical shifts are displayed by the corresponding
protons in the H NMR spectrum of nondeuterated 2).
There is also a weaker signal at 4.44 ppm, which we
assigned to deuterium incorporated in the b-positions of
the pyrrolyl ligand. Integration of these signals allowed
determination of the yields of deuterated products 2a–c
(Eq. (1)).
OH
1
Ph-OMe(p)
N
N
Ph
Fe
Fe
4
3
The separation of compounds 3 and 4 from recovered
2 was easily achieved by column chromatography.
Apart from these compounds a nonpolar, colorless,
purely organic fraction was also collected. GC–MS
analysis revealed that it contains mainly (>90%) dib-
enzyl (PhCH2CH2Ph). In reaction quenched with benzyl
chloride a small amount (3%) of bis-azaferrocene 5, with
the bond between Cp rings, was also isolated.
N
Fe
2
1. sec-BuLi/TMEDA/-780C
2. D2O
N
Fe
N
Fe
ð1Þ
D
.
D
N
Fe
N
Fe
N
Fe
6
Fe
N
5
D
2c (8%)
2b (38%)
2a (54%)
.
N
Fe
The above experiment confirms the presence in 2 of
three competitive lithiation sites. Interestingly, lateral
lithiation takes place to a significant extent even in the
presence of reactive cyclopentadienyl C–H bonds.
Moreover, lithiation of the pyrrolyl b-position is also
observed (taking into account different numbers of C–H
bonds in each site, relative reactivities of a single C–H
7
The formation of 3 and 4 indicates that 2 lithiated at
the methyl group reacts efficiently with the alkylating
reagent (note that the yields of 3 and 4 are close to that
of 2b) with formation of the C–C bond. On the other

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K. Kowalski, J. Zakrzewski / Journal of Organometallic Chemistry 689 (2004) 1046–1049
hand, such a reaction does not appear to take place in
the case of lithio derivatives of 2 metallated at the Cp or
pyrrolyl rings. Formation of dibenzyl and 5, as well as a
significant recovery of 2, suggest a radical pathway,
3.1. Lithiation of 2,5-dimethylazaferrocene followed by
quenching with D2O
Sec-BuLi (1.4 M in cyclohexane, 1 ml, 1.4 mmol) was
added to an argon-saturated THF (6 ml) solution of 2,5-
dimethylazaferrocene (226 mg, 1.05 mmol) and TME-
DA (30 ll, 0.20 mmol) at )78 °C. The orange coloration
of the solution rapidly turned brown. The mixture was
stirred for 1.5 h at )78 °C and quenched with D2O in
THF. Evaporation to dryness and flash chromatogra-
phy afforded red oil which was dissolved in methyl io-
dide (5 ml). After 1 h, the precipitate of deuteriated [2-
Me]þIꢀ was filtered off, washed with ether and dried
under vacuum.
Å
leading to the benzyl radical, PhCH2 and 6 or 7, un-
dergoing subsequent abstraction of the HÅ from the
solvent or dimerization.
The mass spectrum (EI, 70 eV) of 3 presents a feature,
which seems worthy to emphasize. The base peak is
observed at m=e 214, which corresponds to azaferroce-
nyl carbenium ion (HR spectrum gave m=e ¼ 214:0319;
value calculated for C11H12NFe is 214.0319) ion formed
from the parent ion by the loss of benzyl radical as
shown in Eq. (3).
In a separate experiment non-deuteriated [2-Me]þIꢀ
was prepared analogously from 1 and methyl iodide.
1
+
.
Spectral and analytical data: H NMR d (D2O): 5.24
N
Fe
Ph
(s, 2H, b-pyrrolyl), 4.90 (s, 5H, C5H5), 3.50 (s, 3H, Nþ–
CH3), 2.61 (s, 6H, CH3-pyrrolyl). Anal. Calcd. for
C12H16NIFe: C, 40.37; H, 4.52; N, 3.92. Found: C,
40.21; H, 4.56; N, 3.85. FAB (+ve) MS (nba) for the
starting [1-Me]þIꢀ m=e 230.1 [M]þ, 231.1 [M]þ. FAB
MS (+ve, nba) (nba) of [1-Me]þIꢀ after lithiation and
quenching with D2O m=e 231.1 [M]þ, 232.1 [M]þ.
.
PhCH
2
ð3Þ
+
CH
CH
2
N
Fe
N
Fe
2
+
3.2. Lithiation of 2,5-dimethylazaferrocene followed by
reaction with benzyl chloride
So far attempts to generate azaferrocenyl carbenium
ions in solution were unsuccessful [10b], suggesting low
stability of such species. We now have evidence that an
azaferrocenylmethyl cation can display (at least under
conditions used in MS) a significant stability.
In conclusion, we have demonstrated that 2,5-dime-
thylazaferrocene possess three lithiation sites: Cp ring,
methyl groups and pyrrolyl b-position. Despite com-
petitive character of these sites, lithiation of 2,5-dime-
thylazaferrocene followed by reaction with an organic
electrophile can be used in syntheses of 2,5-substituted
azaferrocenes. Further studies on the scope and limita-
tion of this reaction as well its mechanism are currently
under investigation.
Sec-BuLi (1.4 M in cyclohexane, 1 ml, 1.4 mmol) was
added to an argon-saturated THF (6 ml) solution of 2,5-
dimethylazaferrocene (226 mg, 1.05 mmol) and TME-
DA (30 ll, 0.20 mmol) at )78 °C. The orange coloration
of the solution rapidly turned brown. After the mixture
was stirred for 1.5 h at )78 °C, benzyl chloride (167 ll,
1.46 mmol) was added and the stirring was continued
for 1.5 h. The reaction mixture was warmed to room
temperature and poured onto water. Extraction with
dichloromethane, drying over MgSO4 and solvent re-
moval gave brown oil which was subjected to column
chromatography.
The following fractions were collected:
(a) Colorless, containing according to GC–MS >90% of
dibenzyl m=e ¼ 182 [M]þ, 91 [M–CH2Ph]þ, 1H
NMR d (CDCl3): 7.24 (m, 10H, C6H5), 2.96 (s,
4H, CH2).
3. Experimental
All reactions were carried out under argon. Chro-
matographic separations were carried out using silica gel
60 (Merck, 230–400 mesh ASTM) using CHCl3–MeOH
(50:1) as eluent. NMR spectra were recorded on a
Varian Gemini 200BB and Bruker AC 300 spectrome-
ters. Mass spectra were run on a Finnigan MAT 95
spectrometer. 2,5-Dimethylazaferrocene was prepared
according to the literature procedure [9]. Tetrahydro-
furan was distilled over sodium benzophenone ketyl.
Other solvents and reagents were of reagent grade and
were used without prior purification.
(b) Orange, containing 3. Yield: 107 mg (35%). 1H
NMR d (CDCl3): 7.25 (m, 5H, C6H5), 4.37 (d, 1H,
J ¼ 1:8 Hz, b-pyrrolyl), 4.30 (d, 1H, J ¼ 1:8 Hz,
b-pyrrolyl), 4.16 (s, 5H, C5H5), 2.91 (m, 4H, CH2),
2.31 (s, 3H, CH3). EIMS (70 eV) m=e ¼ 305 [M]þ,
240 [M–C5H5]þ, 214 [M–CH2Ph]þ. HRMS of [M–
CH2Ph]þ: m=e ¼ 214:0319 (Calcd. for C11H12NFe,
214.0319). Anal. Calcd. for C18H19NFe: C, 70.84;
H, 6.27; N, 4.59. Found: C, 70.62; H, 6.31; N, 4.73.
(c) Orange containing recovered 2. Yield: 124 mg (55%).

K. Kowalski, J. Zakrzewski / Journal of Organometallic Chemistry 689 (2004) 1046–1049
1049
(d) Orange-red containing 5. Yield: 7 mg (3%). 1H
References
NMR d (CDCl3): 4.30 (bs, 4H, C5H5), 4.25 (bs,
4H, C5H5), 4.14 (s, 4H, b-pyrrolyl), 1.99 (s, 12H,
CH3). EIMS (70 eV) m=e ¼ 428 [M]þ, 334 [M–
C6H8N]þ. HRMS m=e ¼ 428:0632 (calcd. for
C22H24N2Fe2: 428.0638).
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1
with recovered 2 (Yield: 50%). 4: H NMR d (CDCl3):
7.33 (AB d, 2H, J ¼ 8:6 Hz, C6H4), 6.86 (AB d, 2H,
J ¼ 8:6 Hz, C6H4), 4.65 (dd, 1H, J ¼ 9:2 Hz, J ¼ 4:0
Hz, CH), 4.41 (d,1H, J ¼ 2:1 Hz, b-pyrrolyl), 4.33 (d,
1H, J ¼ 2:1 Hz, b-pyrrolyl), 4.17 (s, 5H, C5H5), 3.81 (s,
3H, OCH3), 3.11 (dd, 1H, J ¼ 14:6 Hz, J ¼ 9:2 Hz,
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3334 (OH). HRMS m=e ¼ 351:0915 (calcd. for
C19H21O2NFe: 351.0921).