A novel synthesis of 1,1'-unsymmetrical disubstituted heteroarylferrocene

Article abstract of DOI:10.1016/S0022-328X(00)00496-4

Stepwise Stille coupling reaction of 1,1'-bis(tributylstannyl)ferrocene with different heterocyclic bromides was achieved in the presence of Pd-complex catalyst via two steps to afford unsymmetrical 1,1'-disubstituted heteroarylferrocene compounds.

Full text of DOI:10.1016/S0022-328X(00)00496-4

www.elsevier.nl/locate/jorganchem
Journal of Organometallic Chemistry 612 (2000) 172–175
A novel synthesis of 1,1%-unsymmetrical disubstituted
heteroarylferrocene
Chao-Min Liu a, Yin-Long Guo b, Xiao-li Wu a, Yong-min Liang a, Yong-Xiang Ma a,*
a National Laboratory of Applied Organic Chemistry, Lanzhou Uni6ersity, Lanzhou 730000, People’s Republic of China
b Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, People’s Republic of China
Received 20 December 1999; received in revised form 1 February 2000; accepted 15 February 2000
Abstract
Stepwise Stille coupling reaction of 1,1%-bis(tributylstannyl)ferrocene with different heterocyclic bromides was achieved in the
presence of Pd-complex catalyst via two steps to afford unsymmetrical 1,1%-disubstituted heteroarylferrocene compounds. © 2000
Elsevier Science B.V. All rights reserved.
Keywords: Stille reaction; 1,1%-bis(Tributylstannyl)ferrocene; 1,1%-Unsymmetrical diheteroaryl-ferrocene
low temperature. Many heteroannularly substituted fer-
rocene derivatives, such as bromo-, phosphino-, amino-,
stannyl-compounds were prepared via this reaction.
The bromo- and stannyl-compounds were usually used
as intermediates to proceed further syntheses, while
phosphino- and amino-compounds were used as ligands
in some catalytic process.
1. Introduction
Considerable attention was recently focused on the
synthesis of 1,1%-heterodisubstituted ferrocene com-
pounds [1–8] because of their potential applications in
various fields such as electrochemistry [9–12], catalysis
[13], organic synthesis [14,15] and materials sciences
[16–19]. In a series of precursors synthesizing unsym-
metrical 1,1%-disubstituted ferrocenes, the 1-lithio-1%-
bromo, 1-lithio-1%-tributylstannyl and 1-lithio-1%-phos-
phinoferrocene are considered to be the most important
ones, which can be generated through selective
transmetalation of 1,1%-dibromoferrocene [2,4–6,20],
1,1%-bis(tributylstannyl)ferrocene [21,22], and 1,1%-fer-
rocenediylphenylphosphine [23] with n-butyllithium at
Two popular methods are available for the synthesis
of heteroarylferrocene compounds. The simpler one is
direct introduction of heteroaryl groups into Cp-rings
of ferrocene via the coupling reaction of the lithiated
ferrocene moiety with heterocycles or lithiated hetero-
cycles with bromoferrocene [8,23–29]. However, it was
only suited to the synthesis of some special structural
heterocyclic ferrocenes, such as a-ferrocenyl pyridine,
polypyridine and fused pyridine derivatives. Another
method was indirect formation of heteroarylferrocenes
[30] through classical multistep cyclization approaches.
Clearly, the lithiated ferrocene intermediates are only
suitable for some special substrates, and classical meth-
ods are too tedious to synthesize complicated het-
eroarylferrocenes, especially unsymmetrical disub-
stituted heteroarylferrocene derivatives. The 1,1%-un-
symmetrical disubstituted heteroarylferrocenes were
scarcely reported so far, maybe due to the difficulties of
their synthesis.
Scheme 1.
In our previous communications [28,29,31], we re-
ported a simple way for the preparation of various
* Corresponding author. Fax: +86-931-8912514.
E-mail address: mayx@lzu.edu.cn (Y.-X. Ma).
0022-328X/00/$ - see front matter © 2000 Elsevier Science B.V. All rights reserved.
PII: S0022-328X(00)00496-4

C.-M. Liu et al. / Journal of Organometallic Chemistry 612 (2000) 172–175
173
monoheteroarylferrocene compounds via Stille coupling
of tributylstannylferrocene with various heterocyclic
bromides. Following our initial studies, we found that
the 1,1%-bis(tributylstannyl)ferrocene (Fc(SnBu3)2) could
proceed not only in selective transmetalation reaction
but also do selective monosubstituted Stille across-cou-
pling smoothly. In the present work we wish to report
a new method of synthesizing unsymmetrical 1,1%-
diheteroarylferrocenes.
To further simplify the operation procedure, we at-
tempted to synthesize the title compounds in one pot
under different ratio of substrates. The results, how-
ever, were all unsatisfactory because of the difficulties
of tedious separation of the products. Therefore further
investigation was not continued.
In conclusion, the selective substitution of 1,1%-
bis(tributylstannyl)ferrocene by the Stille cross-coupling
opens a convenient new area of synthesizing various
unsymmetrical 1,1%-disubstituted heteroarylferrocene
derivatives.
2. Results and discussion
3. Experimental
The different heteroaryls can be introduced stepwise
into the Cp-rings of ferrocene as shown in Scheme 1.
To find the optimum conditions suitable for this
reaction, two primary factors were examined: ratio of
two substrates and reaction temperature. In the first
step (entries 1–3), we used PdCl2(PPh3)2 as the catalyst
in dry DMF and illustrated that (i) if stoichiometrical
1,1%-bis(tributylstannyl)ferrocene(Fc(SnBu3)2) was used,
large monosubstituted heteroferrocene [32], unreacted
bromide and some tributylstannyl-losing products (i.e.
ferrocene and tributylstannylferrocene) were found,
which lead to the difficult isolation of desired product;
(ii) excess Fc(SnBu3)2 can promote the consumption of
bromide, otherwise, the first coupling rate was corre-
spondingly increased, which results in the decreased
loss of the tributylstannyl group; (iii) 150% excess of
Fc(SnBu3)2 is essential in the first step. In contrast,
120% of heterocyclic bromides(Het2ꢀBr) must be used
in the second step (entries 4–9) to insure the desired
coupling could proceed as quick as possible. Concern-
ing the reaction temperature, we found that 100–125°C
is a suitable range in the first step. Higher temperatures
will lead to more loss of tributylstannyl group. In
contrast, lower temperatures would prolong the reac-
tion time in order to make the reaction complete, which
equally results in more loss of tributylstannyl group.
The results are summarized in Table 1.
Melting points were determined on a Thomas
Hoover capillary melting point apparatus and were
uncorrected. 1H-NMR spectra were measured on a
FC-80A spectrometer in CDCl3 with tetramethylsilane
as an internal standard. IR spectra were performed as
KBr pellets on a Nicolet 179SX FTIR spectrometer.
Mass spectra (MS) were taken on Finnigan TQ70 or
HP-5988 AG. CMS mass spectrometer.
3.1. 1-Tributylstannyl-1%-heteroarylferrocene (2)
3.1.1. General procedure
To the mixture of 1,1%-bis(tributylstannyl)ferrocene
(1, 6.15 g, 8.05 mmol) and PdCl2(PPh3)2 (0.18 g, 0.26
mmol) in dry DMF(15 ml), a corresponding bromide
(5.36 mmol) was added with stirring. The mixture was
heated on an oil bath at 100–125°C for the time given
in the table. After cooling the reaction mixture to r.t.,
saturated ammonium chloride solution was added into
the mixture. Then the mixture was extracted with
petroleum ether (30–60°C) or diethyl ether, washed
with saturated KF solution and water. The organic
layer was dried (MgSO4), filtered and concentrated in
vacuo. The crude product was subjected to column
chromatography on neutral or alkaline Al2O3 and af-
forded corresponding products 2.
Table 1
The results of stepwise Stille cross-coupling
Entry
Catalysts
Time (h)
Products
Yields (%)
M.p.(°C) a
First step
1
2
3
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
1.0
1.5
1.5
2a
2b
2c
70
85
83
Second step
4
5
6
7
8
9
PdCl2(dppf)
PdCl2(dppf)
PdCl2(dppf)
PdCl2(dppf)
PdCl2(dppf)
PdCl2(dppf)
3.0
3.0
2.5
2.0
2.0
1.5
3a
3b
3c
3d
3e
3f
75
81
65
78
60
80
226–228
184–186
194–196
95–98
171–173
160–162
a Uncorrected.

174
C.-M. Liu et al. / Journal of Organometallic Chemistry 612 (2000) 172–175
3.2.
(2a)
1-Tributylstannyl-1%-(2-nitropyrid-5-yl)ferrocene
3.6. 1-(2-Nitro-pyrid-5-yl)-1%-(5-acetalthien-
2-yl)ferrocene (3a)
1
1
Deep red oil (70%): H-NMR(CDCl3) 8.66(d, J=2.2
Hz, 1H), 8.20(d, J=8.2Hz, 1H), 7.99(dd, J=2.2, 8.2
Hz, 1H), 4.75(m, 2H), 4.49(m, 2H), 4.21(m, 2H),
3.96(m, 2H), 1.78–0.90(m, 27H); IR (cm−1): 3080,
2958, 2927, 2867, 1577, 1533, 1462, 1089, 1024; Anal.
Found: C, 54.64; H, 6.67; N, 4.38. Calc. for
C27H38FeN2O2Sn: C, 54.36; H, 6.37; N, 4.69%.
Deep red solid (mp 226–228°C): H-NMR(CDCl3, l,
ppm) 2.48(s, 3H), 4.40(m, 2H), 4.54(m, 2H), 4.61(m,
2H), 4.78(m, 2H), 6.62(d, J=3.7Hz, 1H), 7.25(d, J=
3.7 Hz, 1H), 7.70(dd, J=1.9, 8.4 Hz, 1H), 7.97(d,
J=8.4, 1H), 8.39(d, J=1.9 Hz, 1H); IR(cm−1, KBr)
1738, 1645, 1540, 1465, 1101, 1015, 486; MS (m/z)
432(M, 58.43%), 56(21.61%), 43(68.95%).
3.7. 1-(2-Nitro-pyrid-5-yl)-1%-(5-benzoylthien-
2-yl)ferrocene (3b)
3.3. 1-Tributylstannyl-1%-(8-methyl-6-nitro-
quino-5-yl)ferrocene (2b)
1
Deep red solid (mp 184–186°C): H-NMR(400 Hz,
1
Deep red oil (85%): H-NMR(CDCl3) 9.28(d, J=2.2
CDCl3) 4.41(s, 2H), 4.54(s, 2H), 4.64(s, 2H), 4.79(s,
2H), 6.68(d, 1H, J=3.8), 7.22(d, 1H, J=3.8), 7.50–
7.62(m, 5H), 7.69(d, 1H, J=8.3), 7.98(d, 1H, J=8.3);
8.40(s, 1H); IR(cm−1, KBr) 1725, 1618, 1530, 1460,
1101, 1024; MS (m/z) 432(M, 58.43%), 56(21.61%),
43(68.95%).
Hz, 1H), 8.58(d, J=2.3 Hz, 1H), 8.29(d, J=2.2 Hz,
1H), 8.19(d, J=2.3 Hz, 1H), 4.79(m, 2H), 4.45(m, 2H),
4.24(m, 2H), 3.96(m, 2H), 2.99(s, 3H), 1.86–0.82(m,
27H); IR(cm−1): 3084, 2958, 2927, 2865, 1612, 1528,
1093, 1026, 435; Anal. Found: C, 60.89; H, 6.23; N,
3.96. Calc. for C32H42FeN2O2Sn: C, 60.57; H, 6.00; N,
4.00%.
3.8. 1-(8-Methyl-6-nitro-quino-3-yl)-1%-(5-acetalthien-
2-yl)ferrocene (3c)
3.4. 1-Tributylstannyl-1%-(6-methyl-8-nitro-
quino-5-yl)ferrocene (2c)
1
Deep red solid (mp 194–196°C): H-NMR(400 Hz,
CDCl3) 2.20(s, 3H), 2.87(s, 3H), 4.42(m, 2H), 4.50(m,
2H), 4.58(m, 2H), 4.81(m, 2H), 6.53(d, 1H, J=3.8),
6.92(d, 1H, J=3.8), 7.83(d, 1H), 8.28(s, 1H), 8.40(s,
1H); 8.98(s, 1H); IR(cm−1, KBr) 1740, 1650, 1529,
1463, 1086, 1032; MS (m/z) 496(M, 100%), 56(7.80%),
43(12.04%).
1
Deep red oil (83%): H-NMR(CDCl3) 9.18(d, J=2.1
Hz, 1H), 8.86(d, J=1.9 Hz, 1H), 8.03(d, J=2.1 Hz,
1H), 7.89(d, J=1.9 Hz, 1H), 4.73(m, 2H), 4.42(m, 2H),
4.21(m, 2H), 3.95(m, 2H), 2.60(s, 3H), 1.82–0.80(m,
27H); IR(cm−1): 3043, 2958, 2927, 2865, 1532, 1461,
1085, 1027; Anal. Found: C, 60.83; H, 6.18; N, 3.98.
Calc. for C32H42FeN2O2Sn: C, 60.57; H, 6.00; N,
4.00%.
3.9. 1-(8-Methyl-6-nitro-quino-3-yl)-1%-
(5-benzoylthien-2-yl)ferrocene (3d)
Deep red solid (mp 94–98°C): 1H-NMR(CDCl3)
2.79(s, 3H), 4.45(m, 2H), 4.51(m, 2H), 4.64(m, 2H),
4.86(m, 2H), 6.63(d, 1H, J=4.0), 6.98(d, 1H, J=4.0),
7.40–7.78(m, 5H), 7.89(d, 1H), 8.16(s, 1H), 8.43(s, 1H);
9.03(s, 1H); IR(cm−1, KBr) 1727, 1610, 1519, 1466
1071, 1026, 969, 504; MS (m/z) 558(M, 100%),
105(29.49%), 77(19.97%), 57(18.41%), 56(6.45%),
43(12.04%).
3.5. Unsymmetrical 1,1%-disubstituted heteroarylferrocene
(3)
3.5.1. General procedure
The mixture of 2 (0.2 mmol) and the corresponding
bromides (0.24 mmol) in dry DMF (5 ml) was heated
on oil bath to 120°C, catalyst, PdCl2(dppf) (0.88 mg,
0.0012 mmol) was added in one portion, then the
mixture was stirred at 120–130°C for the time given in
the table. After cooling to r.t., saturated aminium chlo-
ride solution was added and then extracted with ether
or dichloromethane, washed with saturated KF solu-
tion, water, dried over MgSO4, and the solvent was
removed under reduced pressure. Finally, The residue
was separated by column chromatography on silica gel
eluting with petroleum–acetone to afford correspond-
ing product 3.
3.10. 1-(6-Methyl-8-nitro-quino-3-yl)-1%-(5-acetylthien-
2-yl)ferrocene (3e)
1
Deep red solid (mp 171–173°C): H-NMR(CDCl3)
2.16(s, 3H), 2.61(s, 3H), 4.45(m, 2H), 4.52(m, 2H),
4.84(m, 2H), 4.86(m, 2H), 6.45(d, 1H, J3.9), 6.82(d, 1H,
J=3.9), 7.75(d, 1H), 7.83(d, 1H), 8.07(d, 1H), 9.19(s,
1H); IR(cm−1, KBr) 1721, 1651, 1596, 1531, 1117,
1032, 497; MS (m/z) 496(M, 8.56%), 57(13.17%),
43(22.54%).

C.-M. Liu et al. / Journal of Organometallic Chemistry 612 (2000) 172–175
175
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