Convenient synthesis of ferrocene amines via Cu-catalyzed coupling reaction

Article abstract of DOI:10.1139/V08-096

An efficient copper-catalyzed Ullmann-type cross-coupling reaction without ligand of' iodo-ferrocene with amines has been reported. In this process, a range of ferrocenyl amine compounds have been prepared in moderate to good yields.

Full text of DOI:10.1139/V08-096

871
Convenient synthesis of ferrocene amines via
Cu-catalyzed coupling reaction
Jinsheng Wu, Xiaolong Li, Mingyu Yang, Yujie Gao, Qianru Lv, and Baohua Chen
Abstract: An efficient copper-catalyzed Ullmann-type cross-coupling reaction without ligand of iodo-ferrocene with
amines has been reported. In this process, a range of ferrocenyl amine compounds have been prepared in moderate to
good yields.
Key words: amines, iodo-ferrocene, cross-coupling, copper, Ullmann coupling.
Résumé : On a mis au point une méthode efficace de l’iodoferrocène avec des amines qui est catalysée par le cuivre,
mais ne donne pas lieu à une réaction de couplage croisé de type Ullmann avec le ligand. Dans ce procédé, on a pré-
paré une grande variété de ferrocénylamines avec des rendements allant de modérés à bons.
Mots-clés : amines, iodoferrocène, couplage croisé, cuivre, couplage d’Ullmann.
[Traduit par la Rédaction] Wu et al. 874
Introduction
dioxane catalyst system (8) and that of iodobenzene using a
CuI/K3PO4 /PPAPM/DMF catalyst system (9). Özçubukçu et
al. reported that ferrocenyl amides could be obtained from
iodo-ferrocene and amides, pyrazole, imidazole, and triazole
in the presence of copper (I) iodide and t–BuOK (10).
In the present work, we wish to report a rapid and conve-
nient method for the synthesis of ferrocenyl amines via a
Cu-catalyzed Ullmann-type coupling reaction of amines and
iodo-ferrocene.
During the past few decades, a wide range of substituted
ferrocene derivatives have been synthesized and studied. The
ferrocenyl moiety has played a useful role, either as back-
bone or substituent in ancillary ligands (1). In addtion, it is a
metal–organic nonlinear optical material used as a donor
moiety (2) and in functional polymers with unusual proper-
ties (3).
Although ferrocenes are classical aromatic compounds,
they can have rather unique properties due to their particular
electronic and geometric features. As an example, the syn-
thetic availability of heteroatom-substituted (oxygen, nitro-
gen) ferrocene is rather limited, since many methods for the
functionalization of aromatics are unsuitable for modifying
ferrocene derivatives. Typically, a few reports have been
published concerning the synthesis of amino and diamino-
ferrocene derivatives (4).
Although it is well-known that the Ullmann reaction (cop-
per-catalyzed N-arylation of amines) (5) predates the
palladium-catalyzed amination methodology by many de-
cades and that its applications in academic and industrial
laboratories are well-documented (6), the methods have
some deficiencies. For example, it is necessary to use tem-
peratures as high as 210 °C, highly polar solvents, and often
large amounts of copper reagents, to produce only modest
yields (7). Without doubt, these factors have limited its us-
ability in this field. Important alternatives have been re-
ported recently, using the Ullmann-type methodology for the
N-arylation of iodobenzene with a CuI/glycine/K3PO4/
Result and discussion
In the first stage of the study, we focused on the coupling
reaction between 2-nitrobenzenamine and iodo-ferrocene.
We examined the effects of various copper salts, bases, sol-
vents, and reaction time on the yields of the coupling reac-
tion. The results are shown in Scheme 1 and Table 1.
It can be seen from Table 1 that the effect of the base on
the coupling reaction was significant. In general, K2CO3
gives superior yields to those obtained by t–BuOK, K3PO4,
and Et3N (Table 1, entries 2–4). Further optimization of the
reaction conditions reveals that the use of xylene is more ef-
fective than other solvents, such as toluene, DMSO, DMF,
and benzene (Table 1, entries 4–7). In addition to Cu, we
also used CuI, Cu(acac)2, Cu2O, CuCl, CuCl2, CuBr, and
CuBr2 as the catalysts. However, the yields given by these
other seven copper catalysts are much lower than those pro-
duced with Cu. Thus, it is obvious that the inexpensive Cu is
the most desirable catalyst of this reaction.
On the basis of the above results, we consider that Cu
powder (10 mol%) /K2CO3/xylene is a very suitable catalyst
system for N-arylation (Scheme 2 and Table 2).
As expected, we have prepared a series of amino-
ferrocenes via this process. We have not found any side
product formation, such as biferrocene, bisarylamines, etc. It
seems that the electron-poor amines (e.g., Table 2, entries 1,
4–8, 10) react fairly well in the coupling. The substituted
amines having an electron-rich (Table 2, entry 14) group at
Received 29 February 2008. Accepted 15 May 2008.
Published on the NRC Research Press Web site at
canjchem.nrc.ca on 28 June 2008.
J. Wu,1 X. Li, M. Yang, Y. Gao, Q. Lv, and B. Chen.
State Key Laboratory of Applied Organic Chemistry Lanzhou
University, Lanzhou 730000 P. R. China.
1Corresponding author (e-mail: chbh@lzu.edu.cn).
Can. J. Chem. 86: 871–874 (2008)
doi:10.1139/V08-096
© 2008 NRC Canada

872
Can. J. Chem. Vol. 86, 2008
Scheme 1.
Table 2. Ullmann-type coupling of iodo-ferrocene with amines.
Table 1. Cu-catalyzed cross-coupling of iodo-ferrocene with
amines under different conditions.
Entry Catalyst
Solvent
Time (h)
Base
Yield (%)
1
2
3
Cu
Cu
Cu
Toluene
Toluene
Toluene
6
6
6
K3PO4
K2CO3
(Et)3N
t–BuOK
K2CO3
35
52
Trace
4
5
Cu
Cu
Toluene
Xylene
6
6
Trace
85
6
7
Cu
DMSO
DMF
6
6
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
0
Cu
45
0
8
CuI
Xylene
Xylene
Xylene
Xylene
Xylene
Xylene
Xylene
Xylene
6
9
CuCl
CuCl2
CuBr
CuBr2
CuO
Cu2O
Cu
6
50
36
70
28
61
72
86
10
11
12
13
14
15
6
6
6
6
6
10
Note: Reactions were carried out on a 0.25 mmol scale in
1.0 mL of solvent under argon for the specified period of time,
with 1.0 equiv. of 1a, 1.2 equiv. of 2a, 2.0 equiv. of base, and
0.10 equiv. of [Cu].
Scheme 2.
the ortho position are often more difficult, compared with
those having an electron-poor group, and those having
electron-poor groups at the para positions (Table 2, entry 15)
give no reaction. We also found that the substituent at the
para and ortho positions cannot be tolerated either (Table 2,
entries 12 and 13). The mechanism could not be completely
elucidated from these results.
In summary, we have described a simple and efficient
method for the preparation of a range of N-substituted valu-
able ferrocene derivatives via Ullmann-type coupling reac-
tion mediated by Cu powder. Attractive features of this
protocol are that the reactions are carried out easily in the
given conditions, the operation is simple, the reagents used
are inexpensive (metal salt and base), and the yields are sat-
isfactory.
Note: Reaction conditions: iodo-ferrocene (0.25 mmol), amine
(0.3 mmol), Cu (10 mol%), K2CO3 (0.5 mmol), and xylene (1 mL) at
140 °C under a ballon pressure of Ar. Reactions were carried out in 6 h.
aIsolated yield based on iodo-ferrocene.
bNo reaction.
© 2008 NRC Canada

Wu et al.
873
4.14 (s, 2H), 4.26 (s, 5H), 4.36 (s, 2H), 7.08–7.17 (m, 1H),
7.15–7.18 (m, 1H), 7.27 (s, 1H), 7.46–7.47 (m, 3H), 7.59–
7.67 (m, 2H), 9.62 (s, 1H). 13C NMR (75 MHz, CDCl3) δ:
65.4, 65.7, 69.4, 115.7, 128.1, 128.3, 129.1, 130.9, 131.4,
1333.6, 134.4, 134.5, 135.6, 199.3. Anal. calcd. for
C23H18ClFeNO: C 66.45, H 4.36, N 3.37; found: C 66.32, H
4.58, N 3.41. FAB-MS m/z: 415 [M+].
Experimental
NMR spectra were recorded in CDCl3 using TMS as in-
ternal standard on a Varian Mercury 300 spectrometer (at
300 and 75 MHz for H and 13CNMR spectra, respectively).
1
IR spectra were carried out on a Nicolet Nexus 670 FT/ IR
spectrometer. FAB-MS were obtained on a ZAB-HS mass
spectrometer. Elemental analysis was performed by an
Elementar Vario EL analyzer.
The substituted amines (Table 2, entries 5, 6, and7), as
well as iodo-ferrocene (11), were prepared according to the
literature. All other starting materials were obtained from
commercial suppliers and used without further purification.
(5-Methyl-2-(ferrocenylamino)phenyl) (phenyl)methanone
(3e)
Orange solid, mp 87–89 °C. IR (neat, cm–1) ν: 745, 1250,
1
1625, 3449. H NMR (300 MHz, CDCl3) δ: 2.20 (s, 3H),
4.18 (s, 2H), 4.24 (s, 5H), 4.40 (s, 2H), 7.06–7.09 (m, 1H),
7.16–7.19 (m, 1H) 7.29 (s, 1H), 7.45–7.60 (m, 3H), 7.64–
7.67 (m, 2H), 9.50 (s, 1H). 13C NMR (75 MHz, CDCl3) δ:
64.5, 65.3, 69.4, 114.4, 117.6, 124.2, 128.1, 129.1, 130.9,
134.5, 135.6, 140.4, 148.8, 199.3. Anal. calcd. for
C24H21FeNO: C 72.93, H 5.35, N 3.54; found: C 73.14, H
5.12, N 3.62. FAB-MS m/z: 395 [M+].
Typical procedure for the preparation of of N-
ferrocenyl-2-nitrobenzenamine (3a)
In a Erlenmeyer flask, xylene (1 mL), iodo-ferrocene
(0.25 mmol), amines (0.3 mmol), Cu powder (10 mol%),
and K2CO3 (0.5 mmol) were added successively under argon
atmosphere with stirring. The mixture was reacted at 140 °C
until complete consumption of iodo-ferrocene, as monitored
by TLC. After cooling, the mixture was extracted with ethyl
acetate (3 × 10 mL), the combined organic layer was washed
with water and brine, then dried (MgSO4), filtered, and con-
centrated in vacuo. The residue was purified by column
chromatography, petroleum/ethyl acetate. Red solid (3a) was
obtained; mp 104–105 °C. IR (neat, cm–1) ν: 489, 1265,
5-Chloro-2-(ferrocenylamino)phenyl) (m-tolyl)methanone
(3f)
Red solid, mp 110–112 °C. IR (neat, cm–1) ν: 734, 1255,
1
1504, 1625, 3093, 3304. H NMR (300 MHz, CDCl3) δ:
2.42 (s, 3H), 4.12 (s, 2H), 4.25 (s, 5H), 4.33 (s, 2H), 7.05–
7.08 (m, 1H), 7.22–7.23 (m, 1H), 7.25–7.26 (m, 1H), 7.35
(s, 1H), 7.37 (s, 1H), 7.40–7.42 (m, 1H) 7.46–7.47 (m, 1H),
9.68 (s,1H). 13C NMR (75 MHz, CDCl3) δ: 21.4, 65.0, 65.6,
69.4, 95.5, 118.4, 119.5, 126.2, 128.1, 129.4, 132.1, 133.6,
134.3, 138.2, 139.5, 149.6, 198.6. Anal. calcd. for
C24H20ClFeNO: C 67.08, H 4.69, N 3.26; found: C 66.85, H
4.88, N 3.41. FAB-MS m/z: 429 [M+].
1
1614, 3039, 3379. H NMR (300 MHz, CDCl3) δ: 4.26 (s,
5H), 4.37 (s, 2H), 4.17 (s, 2H) 6.65–6.70 (t, J = 6.9 Hz, 1H),
7.09–7.12 (d, J = 7.5 Hz, 1H), 7.32–7.36 (t, J = 7.2 Hz, 1H),
8.14–8.17 (d, J = 7.8 Hz, 1H), 9.12 (s, 1H). 13C NMR (75
MHz, CDCl3) δ: 65.8, 66.1, 69.6 94.2, 115.9, 116.4, 126.3,
132.2, 135.6, 145.2. Anal. calcd. for C16H14FeN2O2: C
59.65, H 4.38, N 8.70; found: C 59.86, H 4.58, N 8.60.
FAB-MS m/z: 322 [M+].
2-(Ferrocenylamino)benzaldehyde (3g)
Yellow solid, mp 107–109 °C. IR (neat, cm–1) ν: 750,
1
1654, 3306, 3452. H NMR (300 MHz, CDCl3) δ: 4.11 (s,
2H), 4.24 (s, 5H), 4.35 (s, 2H), 6.72–6.77 (t, J = 7.2 Hz,
1H), 7.07–7.10 (d, J = 8.4 Hz, 1H), 7.32–7.36 (t, J = 7.8 Hz,
1H), 7.47–7.49 (d, J = 7.5 Hz, 1H), 9.49 (s, 1H), 9.9 (s,1H).
13C NMR (75MHz, CDCl3) δ: 64.6, 65.5, 69.3, 113.2, 116.0,
118.7, 135.4, 136.2, 149.8, 194.1. Anal. calcd. for
C17H15FeNO: C 66.91, H 4.95, N 4.59; found: C 67.12, H
4.98, N 4.29. FAB-MS m/z: 305[M+].
Characterization data for products
N-Ferrocenyl-2-bromobenzenamine (3b)
Yellow solid, mp 110–112 °C. IR (neat, cm–1) ν: 742,
1
1521, 1592, 3405. H NMR (300 MHz, CDCl3) δ: 4.14 (s, 2
H), 4.24 (s, 5H), 4.35 (s, 2H), 5.43 (s, 1H), 6.60–6.62 (d,
1H), 7.03 (m, 1H), 7.1 (m, 1H), 7.42–7.45 (m, 1H). 13C
NMR (75 MHz, CDCl3) δ: 65.3, 69.4, 114.4, 119.1, 128.0,
132.2. Anal. calcd. for C16H14BrFeN: C 53.97, H 3.96, N
3.93; found: C 53.87, H 4.01, N 3.98. FAB-MS m/z: 355[M+].
Methyl-2-(ferrocenylamino) benzoate (3h)
Yellow solid, mp 56–58 °C. IR (neat, cm–1) ν: 748, 1246,
1
1682, 3330. H NMR (300 MHz, CDCl3) δ: 3.89 (s, 3H),
1–Ferrocenylamino-2-phenyl ethanone (3c)
4.09 (s, 2H), 4.23 (s, 5H), 4.32 (s, 2H), 6.60–6.65 (t, J = 7.2
Hz, 1H), 7.01–7.04 (d, J = 8.7 Hz, 1H), 7.26–7.30 (t, J = 6.9
Hz, 1H), 7.89–7.91 (t, J = 7.5 Hz, 1H), 8.92 (s, 1H). 13C
NMR (75 MHz, CDCl3) δ: 51.6, 64.8, 64.8, 69.2, 110.4,
113.7, 115.7, 134.1, 150.3, 169.1. Anal. calcd. for
C18H17FeNO2: C 64.50, H 5.11, N 4.18; found: C 64.27, H
5.33, N 4.32. FAB-MS m/z: 335 [M+].
Yellow solid, mp 57–59 °C. IR (neat, cm–1) ν: 745, 1244,
1
1636, 3092, 3271. H NMR (300 MHz, CDCl3) δ: 2.61 (s,
3H), 4.17 (s, 5H), 4.31 (s, 2H), 4.08 (s, 2H), 6.61–6.66 (t,
J = 7.8 Hz, 1H), 7.05–7.08 (d, J = 7.8 Hz, 1H), 7.26–7.31 (t,
J = 7.5 Hz, 1H), 7.72–7.75 (d, J = 8.1 Hz, 1H), 10.06 (s,
1H). 13C NMR (75 MHz, CDCl3) δ: 28.3, 65.4, 65.7, 69.6,
96.1, 114.4, 115.5, 118.1, 132.6, 134.9, 150.6, 201.4. Anal.
calcd. for C18H17FeNO: C 67.73, H 5.37, N 4.39; found: C
67.95, H 5.19, N 4.51. FAB-MS m/z: 319 [M+].
N-Ferrocenyl-5methyl-2-nitro-benzenamine (3i)
Orange solid, mp 89–91 °C. IR (neat, cm–1): 744, 914,
1
1519, 3381. H NMR (300 MHz, CDCl3) δ: 2.26 (s, 3H),
(5-Chloro-2-(ferrocenylamino)phenyl) (phenyl)methanone (3d)
4.15 (s, 2H), 4.19 (s, 5H), 4.24 (s, 2H), 7.04–7.07 (d, J = 8.7
Hz, 1H), 7.16–7.19 (d, J = 8.7 Hz, 1H), 7.95 (s, 1H), 9.01 (s,
1H). 13C NMR (75 MHz, CDCl3) δ: 20.0, 65.5, 66.0, 69.5,
94.8, 116.0, 125.5, 126.1, 132.0, 137.1. Anal. calcd. for
Yellow solid, mp 114–116 °C. IR (neat, cm–1) ν: 744,
1
1242, 1510, 1625, 3447. H NMR (300 MHz, CDCl3) δ:
© 2008 NRC Canada

874
Can. J. Chem. Vol. 86, 2008
Friedrichsen, and H. Wong. Coord. Chem. Re. 190, 1217
(1999).
C17H16FeN2O2: C 60.74, H 4.80, N 8.33; found: C 60.87, H
4.98, N 8.02. FAB-MS m/z: 336 [M+].
3. (a) I. Manners. Adv. Organomet. Chem. 37,131 (1995); (b) P.
Gómez-Elipe, R. Resendes, P.M. Macdonald, and I.J. Manners.
J. Am. Chem. Soc. 120, 8348 (1998); (c) J. Tsuji and T.
Mandai. Synthesis, 1 (1996).
N-Feerocenyl-2-chlorobenzenamine (3j)
Yellow solid, mp 94–96 °C. IR (neat, cm–1) ν: 744, 1524,
1
1595, 3415. H NMR (300 MHz, CDCl3) δ: 4.12 (s, 2H),
4. For aminoferrocene and derivatives thereof, please see:
(a) E.M. Acton and R.B.J. Silverstein. Org. Chem. 24,1487
(1959); (b) A.N. Nesmeyanov, V.A. Sazonova, and V.I.
Romanenko. Doklady Akademii Nauk SSSR. 157(4), 922
(1964); (c) M. Herberhold, M. Ellinger, and W. Kremnitz. J.
Organomet. Chem. 24, 1227 (1983); (d) M. Herberhold, M.
Ellinger, and L. Haumaier. In Organometallic syntheses.
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dam, 1996; (e) M. Sato and S. Ebine. Synthesis, 472 (1981);
(f) M. Herberhold, M. Ellinger, and W. Kremnitz. J. Organomet.
Chem. 241, 227 (1983); (g) C.A. Fleckenstein and H. Plenio.
Organometallics, 26, 2758 (2007); (h) V.H. Purecha, N.S.
Nandurkar, B.M. Bhanage, and J.M. Nagarkar. Tetrahedron
Lett. 49, 1384 (2008).
5. For N-arylation of anilines, please see: (a) F. Ullmann. Ber.
Dtsch. Chem. Ges. 36, 2382 (1903); (b) S. Gauthier and J.M.J.
Fréchet. Synthesis, 383 (1987); (c) R. Gujadhur, D.
Venkataraman, and J.T. Kintigh. Tetrahedron Lett. 42,
4791(2001). For N-arylation of alkylamines, please see: (d) D.
Ma, Y. Zhang, J. Yao, S. Wu, and F. Tao. J. Am. Chem. Soc.
120, 12459 (1998); (e) J.B. Arterburn, M. Pannala, and A.M.
Gonzalez. Tetrahedron Lett. 42, 1475 (2001); (f) F.Y. Kwong,
A. Klapars, and S.L. Buchwald. Org. Lett. 4, 58 (2002).
6. For a review, see: J. Lindley. Tetrahedron, 40, 1433 (1984).
7. T. Yamamoto and Y. Kurata. Can. J. Chem. 61, 86 (1983).
8. For amino acid-mediated Goldberg reactions, plase see: W.
Deng, Y.-F. Wang, Y. Zou, L. Liu, and Q.-X. Guo. Tetrahedron
Lett. 45, 2311 (2004).
4.23 (s, 5H), 4.33 (s, 2H), 5.45 (s, 1H), 6.67–6.70 (m, 1H),
7.09–7.14 (m, 2H), 7.24–7.29(s, 1H). 13C NMR (75 MHz,
CDCl3) δ: 65.2, 69.2, 114.2, 118.5, 127.4, 129.6. Anal.
calcd. for C16H14ClFeN: C 61.67, H 4.53, N 4.50; found: C
61.56, H 4.69, N 4.72. FAB-MS m/z: 311 [M+].
N-Ferrocenyl-2,5-dibromobenzenamine (3k)
Yellow solid, mp 83–85 °C. IR (neat, cm–1) ν: 744, 1514,
1
1584, 3403. H NMR (300 MHz, CDCl3) δ: 4.14 (s, 2H),
4.25 (s, 5H), 4.31 (s, 2H), 5.52 (s, 1H), 6.72–6.75 (d, J = 7.8
Hz, 1H), 7.25 (s, 1H), 7.28–7.30 (d, J = 7.2 Hz, 1H). 13C
NMR (75 MHz, CDCl3) δ: 65.5, 69.3, 116.7, 120.5, 121.5,
130.4, 133.1, 134.0. Anal. calcd. for C16H13Br2FeN: C
44.18, H 3.01, N 3.22; found: C 44.32, H 2.86, N 3.34.
FAB-MS m/z: 435 [M+].
Acknowledgements
We are grateful to the project-sponsored by SRF for
ROCS, SEM.
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© 2008 NRC Canada