Lithiation of N-Boc-protected ferrocenylalkylamines: Preparation of unsymmetrical 1,1′-disubstituted ferrocenes

Article abstract of DOI:10.1021/om030468l

Treatment of N-Boc-1-ferrocenylethylamine or N-Boc-ferrocenylmethylamine with 2 equiv of n-BuLi results in selective N,1′-dimetalation. Trapping of the dianions with various electrophiles is a convenient route to unsymmetrical 1,1′-disubstituted ferrocenes. Under similar conditions, the pivalamide of 1-ferrocenylethylamine undergoes predominantly N,2-dilithiation while urea derivatives give mixtures of regioisomers.

Full text of DOI:10.1021/om030468l

1010
Organometallics 2004, 23, 1010-1014
Lith ia tion of N-Boc-P r otected F er r ocen yla lk yla m in es:
P r ep a r a tion of Un sym m etr ica l 1,1′-Disu bstitu ted
F er r ocen es
J . Michael Chong*,† and Louis S. Hegedus‡
Guelph-Waterloo Centre for Graduate Work in Chemistry and Biochemistry (GWC2),
Department of Chemistry, University of Waterloo, Waterloo, Ontario, Canada N2L 3G1, and
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523
Received J une 17, 2003
Treatment of N-Boc-1-ferrocenylethylamine or N-Boc-ferrocenylmethylamine with 2 equiv
of n-BuLi results in selective N,1′-dimetalation. Trapping of the dianions with various
electrophiles is a convenient route to unsymmetrical 1,1′-disubstituted ferrocenes. Under
similar conditions, the pivalamide of 1-ferrocenylethylamine undergoes predominantly N,2-
dilithiation while urea derivatives give mixtures of regioisomers.
Sch em e 1
Ugi showed some three decades ago that ferrocenyl
derivatives such as the dimethylamine species 1 can be
lithiated with high diastereoselectivity, and the result-
ing organolithium may be trapped with various elec-
trophiles to provide 1,2-disubstituted ferrocenes 2
(Scheme 1).1 Subsequently, other researchers have used
this reaction to prepare various 1,2-disubstituted fer-
rocenes, including phosphines,2 carboxylic acids,3 car-
boxaldehydes,4 and boronic acids.5 Many groups other
than Me2N- (e.g. acetals,6 oxazolines,7 sulfoxides,8
SAMP hydrazones,9 and pyrrolidines10) have also been
used to access 1,2-disubstituted ferrocenes. In fact, the
diastereoselective metalation/electrophilic quenching of
chiral ferrocene derivatives (i.e. 3 f 4) has become a
standard method for the synthesis of 1,2-disubstituted
planar chiral ferrocenes, compounds of current interest
for applications in asymmetric synthesis.11
from 1-ferrocenylethylamine,12 was treated with n-BuLi
and the resulting dianion was treated with CO2 followed
by CH2N2. A single product was isolated in good yield;
however, its 1H NMR spectrum did not exhibit a 5H
singlet around 4.2 ppm that would be expected for the
unsubstituted Cp ring of the 1,2-disubstituted ferrocene
6.13 Rather, it was obvious from the spectral data that
the new product formed was the unexpected 1,1′-
disubstituted ferrocene 7a (Scheme 2).
In connection with a project to prepare a 1,2-disub-
stituted ferrocene, the Boc derivative 5, easily prepared
* To whom correspondence should be addressed. E-mail: jmchong@
uwaterloo.ca.
† University of Waterloo.
‡ Colorado State University.
(1) Marquarding, D.; Klusacek, H.; Gokel, G.; Hoffmann, P.; Ugi, I.
J . Am. Chem. Soc. 1980, 92, 5389-5393.
While the 1,1′-disubstituted product 7a was not
expected, on the basis of many examples of directed
ortho lithiations,1-11 there is one previous report of a
similar reaction: it was noted that ferrocenecarbalde-
hyde upon treatment with lithium 4-methylpipirazide
followed by t-BuLi undergoes selective 1′-lithiation.14
Electrophilic quenching gave modest (17-69%) yields
of mixtures of products (1,1′:1,2 ) (90:10)-(96:4)). This
chemistry has also been extended for the preparation
of highly substituted ferrocenes with planar chirality.15
(2) (a) Apsimon, J . W.; Collier, T. L. Tetrahedron 1986, 42, 5157-
5254 and references therein. (b) Togni, A.; Bieler, N.; Burckhardt, U.;
Ko¨llner, C.; Pioda, G.; Schneider, R.; Schnyder, A. Pure Appl. Chem.
1999, 71, 1531-1537.
(3) Cullen, W. R.; Wickenheiser, E. B. Can. J . Chem. 1990, 68, 705-
707.
(4) (a) Lu, X.; Chen, G. Tetrahedron 1998, 54, 12539-12546. (b)
Fukuzawa, S.; Tsuchiya, D.; Sasamoto, K.; Hirano, K.; Ohtaguchi, M.
Eur. J . Org. Chem. 2000, 2877-2883.
(5) Søtofte, I.; Norrild, J . C. J . Chem. Soc., Perkin Trans. 2 2001,
727-732.
(6) (a) Riant, O.; Samuel, O.; Kagan, H. B. J . Am. Chem. Soc. 1993,
115, 5835-5836. (b) Riant, O.; Samuel, O.; Flessner, T.; Taudien, S.;
Kagan, H. B. J . Org. Chem. 1997, 62, 6733-6745.
(7) Sammakia, T.; Latham, H. A.; Schaad, D. R. J . Org. Chem. 1995,
60, 10-11.
(12) (a) Gokel, G. W.; Marquarding, D.; Ugi, I. K. J . Org. Chem.
1972, 37, 7, 3052-3058. (b) Woltersdorf, M.; Kranich, R.; Schmalz,
H.-G. Tetrahedron 1997, 53, 7219-7230. (c) Enders, D.; Lochtman, R.;
Raabe, G. Synlett 1996, 126-128. (d) Fukuda, T.; Takehara, A.; Haniu,
N.; Iwao, M. Tetrahedron: Asymmetry 2000, 11, 4083-4091.
(13) Pickett, T. E.; Richards, C. J . Tetrahedron Lett. 1999, 40, 5251-
5254.
(8) Riant, O.; Argouarch, G.; Guillaneux, D.; Samuel, O.; Kagan, H.
B. J . Org. Chem. 1998, 63, 3511-3514.
(9) Enders, D.; Peters, R.; Lochtman, R.; Runsink, J . Eur. J . Org.
Chem. 2000, 2839-2850.
(10) Farrell, A.; Goddard, R.; Guiry, P. J . J . Org. Chem. 2002, 67,
4209-4217.
(11) For a recent review, see: Richards, C. J .; Locke, A. J . Tetra-
hedron: Asymmetry 1998, 9, 2377-2407.
(14) Iftime, G.; Moreau-Bossuet, C.; Manoury, E.; Balavoine, G. G.
A. J . Chem. Soc., Chem. Commun. 1996, 527-528.
10.1021/om030468l CCC: $27.50 © 2004 American Chemical Society
Publication on Web 01/29/2004

Lithiation of N-Boc-Protected Ferrocenylalkylamines
Organometallics, Vol. 23, No. 5, 2004 1011
Sch em e 2
Sch em e 3
Ta ble 1. P r ep a r a tion of 1,1′-Disu bstitu ted
F er r ocen es 7 fr om 5
coupling reactions.20 Essentially identical results were
obtained using t-BuLi or n-BuLi/TMEDA for metalation,
but no electrophile incorporation was observed with
n-BuLi using ether as solvent. Also, only starting
material was recovered when LDA was used as the base.
Thus, it seems that metalation of 5 requires an alkyl-
lithium base in THF.
To further probe the metalation of N-Boc-ferrocenyl-
alkylamines, Boc derivatives of ferrocenylmethylamine21
(8) and 1-ferrocenyl-2-methylpropylamine22 (10) were
prepared (Scheme 3). Methylamine derivative 8 behaved
like its homologue 5: metalation with n-BuLi (2 equiv,
THF, -40 °C) followed by treatment with Me3SiCl gave
the 1,1′-disubstituted ferrocene 9 as the sole product in
excellent yield. In contrast, the isopropyl-substituted
amine 10 resisted metalation even with excess n-BuLi
at 0 °C. Perhaps the isopropyl group in 10 sterically
encumbers coordination of the Boc group to n-BuLi, and
thus lithiation is not facilitated as it is in compounds 5
and 8.
Other amine derivatives that have been shown to be
useful for lithiations of benzylamines were also exam-
ined (Scheme 4).23 Ureas 11a -c were readily prepared
from 1-ferrocenylethylamine and the corresponding
dialkylcarbamyl chloride while pivalamide 14 was made
using pivaloyl chloride. Dimethylurea 11a could be
completely metalated under the “usual” conditions (2
equiv of n-BuLi, THF, -40 °C) to give, after Me3SiCl
trapping, a mixture of 1,2-disubstituted 12a and 1,1′-
disubstituted 13a in a ratio of 1:3, respectively. Dieth-
ylurea 11b behaved similarly and gave a similar (12b:
13b ) 1:4) mixture of products. Diisopropylurea 11c,
like isopropyl-substituted derivative 10, proved to be
more resistant to metalation: an excess (5 equiv) of
n-BuLi was needed to obtain significant metalation.
Here a 1:2 (12c:13c) mixture was obtained. For each of
these ureas, the 1,2-disubstituted product 12 was
isolated as a single diastereomer.24 Finally, pivalamide
14 afforded a mixture of products, of which 1,2-disub-
entry
E+
E
product
yield (%)a
1
2
3
4
5
6
7
CO2, CH2N2
Me3SiCl
Me3SnCl
I2
Me2NCHO
Ph2CdO
PhCHO
CO2Me
Me3Si
Me3Sn
I
C(O)H
Ph2COH
CH(OH)Ph
7a
7b
7c
7d
7e
7f
96
95
86
71
84
97
80
7gb
a
b
Isolated yield of chromatographed product. Isolated as a 3:1
mixture of diastereomers.
Ferrocenylethylamine12 and other related primary amines
are readily available in enantioenriched form16 and so
could be used to prepare novel derivatives of use as
chiral ligands and auxiliaries. In addition, such chiral
derivatives might be useful as materials with nonlinear
optical and liquid crystalline properties.17 Previous
routes to 1,1′-disubstituted ferrocenes typically begin
with symmetrical compounds (e.g. 1,1′-dibromofer-
rocene,17 1,1′-bis(tributylstannyl)ferrocene,18 1,1′-fer-
rocenedicarbaldehyde19) and thus often experience prob-
lems with statistics. Therefore, we decided to examine
the lithiation of 5 and related compounds more closely.
Treatment of 5 with n-BuLi (2 equiv, THF, -40 °C)
followed by a variety of electrophiles afforded 1,1′-
disubstituted products cleanly with no evidence of other
isomers or multiple substitution (Table 1). The trimeth-
ylstannyl (7c) and iodo (7d ) products are particularly
interesting, as they are potential substrates for cross-
(15) (a) Iftime, G.; Daran, J . C.; Manoury, E.; Balavoine, G. G. A.
Organometallics 1996, 15, 4808-4815. (b) Iftime, G.; Daran, J . C.;
Manoury, E.; Balavoine, G. G. A. Angew. Chem., Int. Ed. 1998, 37,
1698-1701. (c) Chiffre, J .; Coppel, Y.; Balavoine, G. G. A.; Daran, J .
C.; Manoury, E. Organometallics 2002, 21, 4552-4555.
(16) In our hands, CBS reduction of acetylferrocene gave (R)-1-
ferrocenylethanol with >98% ee, essentially as described in ref
(20) Stille and Suzuki couplings of ferrocene derivatives have been
described: (a) Kasak, P.; Miklas, R.; Putala, M. J . Organomet. Chem.
2001, 637-639, 318-326. (b) Liu, C.-M.; Liang, Y.; Wu. X.; Liu, W.;
Ma, Y. J . Organomet. Chem. 2001, 637-639, 723-726. (c) Liu, C.-M.;
Guo, Y.-L.; Wu, X.; Liang, Y.; Ma, Y. J . Organomet. Chem. 2000, 612,
172-175. (d) J ensen, J . F.; Søtofte, I.; Sørensen, H. O.; J ohannsen, M.
J . Org. Chem. 2003, 68, 1258-1265.
(21) Widhalm, M.; Nettekoven, U.; Mereiter, K. Tetrahedron: Asym-
metry 1999, 10, 4369-4391.
(22) Cushman, M.; Chen, J . K. J . Org. Chem. 1987, 52, 1517-1521.
(23) Katsoulos, G.; Schlosser, M. Tetrahedron Lett. 1993, 34, 6263-
6264.
12b. [R]22 ) -12.9° (c ) 1.1, EtOAc), -31.6° (c ) 1.05, C6H6); lit.12a
D
[R]22 ) -30.5° (c ) 1.1, C6H6). Conversion of this alcohol to 1-ferro-
D
cenylethylamine and derivatization with (S)-MTPA-Cl gave a single
amide (19F NMR -68.5 ppm vs -68.6 ppm for the other diastereomer).
(17) Lai, L.-L.; Dong, T.-Y. J . Chem. Soc., Chem. Commun. 1994,
2347-2348
(18) Liu, C.-M.; Guo, Y.-L.; Wu, X.-I.; Liang, Y.-M.; Ma, Y.-X. J .
Organomet. Chem. 2000, 612, 172-175.
(19) Argyropoulos, N.; Coutouli-Argyropoulou, E. J . Organomet.
Chem. 2002, 654, 117-122.

1012 Organometallics, Vol. 23, No. 5, 2004
Chong and Hegedus
1H NMR: δ 4.68 (br s, 1H), 4.57 (br s, 1H), 4.17 (s, 5H), 4.2-
4.1 (m, 4H), 1.47 (s, 9H), 1.42 (d, J ) 7 Hz, 3H). 13C NMR: δ
154.9, 92.0, 79.0, 68.4 (5C), 67.8, 67.4, 66.8, 65.7, 44.9, 28.4
(3C), 21.5. MS (FAB): m/z 329 (M+, 100), 273 (28), 213 (35).
Anal. Calcd for C17H23FeNO2: C, 62.02; H, 7.04; N, 4.25.
Sch em e 4
Found: C, 62.22; H, 6.81; N, 4.34. (R)-5: [R]22 ) -16.1 (c )
D
1.8, EtOAc).
Gen er a l P r oced u r e for th e Lith ia tion of N-Boc-1-
fer r ocen yleth yla m in e (5) a n d Rea ction w ith Electr o-
p h iles. To a cold (-50 °C), stirred solution of 5 (0.3 mmol) in
THF was added n-BuLi (1.6 M in hexanes, 0.75 mmol), and
the resulting orange solution was stirred at -50 °C for 2 h. It
was then cooled to -78 °C, the appropriate electrophile (0.9
mmol) was added, and the resulting mixture was stirred at
-78 °C for 20 min and then warmed to room temperature.
Standard aqueous workup using ether/aqueous NH4Cl pro-
vided crude materials which were purified by flash chroma-
tography on silica gel using hexanes-ether mixtures.
Meth yl 1′-(N-ter t-bu toxyca r bon yl-1-a m in oeth yl)-1-fer -
r ocen eca r boxyla te (7a ). This compound was prepared ac-
cording to the general procedure using solid CO2 as the
electrophile. The crude resulting crude carboxylic acid was
treated with excess CH2N2 (prepared from N-methyl-N-ni-
trosourea26). From 119 mg of 5, there was obtained, after flash
chromatography (hexanes/ether, 2:1), 135 mg (96%) of 7a as
a red oil. IR (neat): 3363 (br), 1714, 1280, 1172 cm-1 1H
.
NMR: δ 4.98 (br s, 1H), 4.81 (br s, 2H), 4.53 (m, 1H), 4.41 (br
s, 2H), 4.22 (br s, 1H), 4.17 (br s, 2H), 4.09 (br s, 1H), 3.82 (s,
3H), 1.48 (s, 9H), 1.42 (d, J ) 7 Hz, 3H). 13C NMR: δ 171.7,
154.9, 93.8, 79.0, 71.6, 71.1, 70.6, 70.2, 69.3, 69.1, 67.9, 67.8,
51.6, 44.2, 28.4, 21.2. MS (ESI): m/z 387 (M+, 28), 332 (16),
271 (100). Anal. Calcd for C19H25FeNO4: C, 58.93; H, 6.51; N,
3.62. Found: C, 59.16; H, 6.27; N, 3.60.
stituted derivative 15 was the major (∼90%) product
and could be isolated as a single diastereomer in 78%
yield.
1-(N-ter t-bu toxyca r bon yl-1-a m in oeth yl)-1′-tr im eth yl-
silylfer r ocen e (7b). This compound was prepared according
to the general procedure using chlorotrimethylsilane as the
electrophile. From 139 mg of 5 there was obtained, after flash
chromatography (hexanes/ether, 6:1), 161 mg (95%) of 7b as
a yellow solid. Mp: 63-65 °C. IR (cast): 3352 (br), 1714, 1247,
Overall, there seems to be no obvious correlation
between the structure of the N-protecting group and the
regioselectivity of lithiation for the ferrocenylalkyl-
amines examined. Nonetheless, it is noteworthy that
Boc derivatives such as 5 and 8 are quite special in their
ability to undergo 1′-lithiation with very high regiose-
lectivities. Electrophilic trapping allows for the prepara-
tion of unsymmetrical 1,1′-disubstituted ferrocenes in
excellent yields.
1165 cm-1 1H NMR: δ 4.72 (br s, 1H), 4.58 (br s, 1H), 4.34
.
(br s, 2H), 4.16 (br s, 1H), 4.13-4.09 (m, 5H), 1.50 (s, 9H),
1.44 (d, J ) 7 Hz, 3H), 0.25 (s, 9H). 13C NMR: δ 154.9, 92.0,
79.1, 73.3, 73.1, 72.5, 71.4, 68.7, 68.1, 67.8, 66.9, 65.8, 44.9,
28.4, 21.6, -0.2. MS (FAB) m/z 401 (M+, 100), 345 (30), 285
(34). Anal. Calcd for C20H31FeNO2Si: C, 59.85; H, 7.78; N, 3.49.
Found: C, 59.91; H, 7.71; N, 3.26.
Exp er im en ta l Section
1-(N-ter t-bu toxyca r bon yl-1-a m in oeth yl)-1′-tr im eth yl-
sta n n ylfer r ocen e (7c). This compound was prepared accord-
ing to the general procedure using chlorotrimethylstannane
as the electrophile. From 145 mg of 5, there was obtained, after
flash chromatography (hexanes/ether, 6:1), 187 mg (86%) of
7c as a red solid. Mp: 45-47 °C. IR (cast): 3353 (br), 1713,
All reactions were carried out under argon using flame-dried
glassware. NMR data were recorded on 300 MHz (300 MHz
1
for H, 75 MHz for 13C) instruments in CDCl3 unless otherwise
noted. Elemental analyses were performed by MHW Labora-
tories, Phoenix, AZ. Ether and THF were distilled from Na/
benzophenone. Alkyllithiums were purchased from Aldrich
Chemical Co. and were titrated using N-benzylbenzamide.25
1-Ferrocenylethylamine12b and ferrocenylmethylamine19 were
prepared from the corresponding acetates using aqueous NH3
with sonication.
1172 cm-1 1H NMR: δ 4.72 (br s, 1H), 4.58 (br s, 1H), 4.36
.
(br s, 2H), 4.2-4.0 (m, 6H), 1.49 (s, 9H), 1.44 (d, J ) 7 Hz,
3H), 0.29 (s, 9H, J Sn-H ) 55 Hz). 13C NMR: δ 155.0, 91.9, 79.1,
74.5 (J Sn-C ) 49 Hz), 74.4 (J Sn-C ) 49 Hz), 71.2 (J Sn-C ) 38
Hz), 69.3, 67.9, 67.5, 67.0, 65.6, 44.9, 28.4, 21.6, -8.7 (J Sn-C
)
340/355 Hz). MS (ESI): m/z 493 (M + H+, 12), 422 (3), 376
(3), 213 (100). Anal. Calcd for C20H31FeNO2Sn: C, 48.82; H,
6.35; N, 2.85. Found: C, 48.94; H, 6.55; N, 2.85. (R)-7c:
N-Boc-1-fer r ocen yleth yla m in e (5). A solution of 1-fer-
rocenylethylamine (1.162 g, 5.07 mmol), Et3N (1 mL), and
(BOC)2O (1.33 g, 6 mmol) in THF (25 mL) was stirred at
ambient temperature for 2 h. The mixture was diluted with
ether, washed twice with water, dried (Na2SO4), and concen-
trated. Purification of the resulting residue by flash chroma-
tography (CH2Cl2) provided a yellow solid that was recrystal-
lized from hexanes to afford 5 (1.64 g, 98% yield) as orange
[R]22 ) -15.5 (c ) 1.6, EtOAc).
D
1-(N-ter t-bu toxyca r bon yl-1-a m in oeth yl)-1′-iod ofer r o-
cen e (7d ). This compound was prepared according to the
general procedure using iodine as the electrophile. From 157
mg of 5, there was obtained, after flash chromatography
(hexanes/ether, 5:1), 153 mg (71%) of 7d as a red oil which
solidified on standing. Mp: 62-64 °C. IR (neat): 3349 (br),
crystals. Mp: 87-88 °C. IR (cast): 3349 (br), 1699, 1172 cm-1
.
(24) When t-BuLi was used in place of n-BuLi, mixtures of 12 and
13 were formed and 12 was isolated as an inseparable mixture of
diastereomers with modest (∼3:1) stereoselectivity.
(25) Burchat, A. F.; Chong, J . M.; Nielsen, N. J . Organomet. Chem.
1997, 542, 281-283.
1693, 1245, 1168 cm-1 1H NMR: δ 4.72 (br s, 1H), 4.62 (m,
.
(26) Arndt, F. Organic Syntheses; Wiley: New York, 1943; Collect.
Vol. II, pp 165-167.

Lithiation of N-Boc-Protected Ferrocenylalkylamines
Organometallics, Vol. 23, No. 5, 2004 1013
1H), 4.39 (br s, 2H), 4.20-4.04 (m, 6H), 1.47 (s, 9H), 1.43 (d,
J ) 7 Hz, 3H). 13C NMR: δ 154.8, 93.6, 79.2, 75.0, 74.9, 71.2,
70.9, 69.7, 69.4, 69.2, 44.7, 39.8, 28.5, 21.9. MS (FAB): m/z
(28). Anal. Calcd for C19H29FeNO2Si: C, 58.76; H, 7.79; N, 3.61.
Found: C, 58.95; H, 7.50; N, 3.64.
N-Boc-1-fer r ocen yl-2-m eth ylp r op yla m in e (10). A solu-
tion of 1-ferrocenyl-2-methylpropylamine22 (1.00 g, 3.9 mmol)
and (BOC)2O (0.98 g, 4.5 mmol) in THF (25 mL) was stirred
at ambient temperature for 2 h. The mixture was diluted with
ether, washed twice with water, dried (Na2SO4), and concen-
trated. The resulting yellow solid was recrystallized from
hexanes to afford 10 (1.25 g, 90% yield) as yellow needles.
455 (M+, 100), 399 (30), 385 (10), 329 (50). (R)-7d : [R]22
-7.5 (c ) 2.7, EtOAc).
)
D
1′-(N-ter t-b u t oxyca r b on yl-1-a m in oet h yl)fer r ocen e-
ca r ba ld eh yd e (7e). This compound was prepared according
to the general procedure using N,N-dimethylformamide as the
electrophile. From 151 mg of 5, there was obtained, after flash
chromatography (hexanes/ether, 1:1), 138 mg (84%) of 7e as a
1
Mp: 125-126 °C. IR (KBr): 3326, 1670, 1541, 1171 cm-1. H
1
red oil. IR (neat): 3345 (br), 1682, 1246, 1171 cm-1. H NMR:
NMR: δ 4.82 (br d, 1H, J ) 5 Hz), 4.34 (dd, J ) 5, 7 Hz, 1H),
4.18 (s, 5H), 4.14 (br s, 1H), 4.10 (br s, 2H), 3.98 (br s, 1H),
1.79 (octet, J ) 7 Hz, 1H), 1.51 (s, 9H), 0.82 (d, J ) 7 Hz, 3H),
0.78 (d, J ) 7 Hz, 3H). 13C NMR: δ 155.4, 90.1, 78.9, 68.7
(5C), 68.4, 67.2, 67.0, 65.0, 55.0, 34.6, 28.4 (3C), 18.8, 17.8.
MS (ESI): m/z 357 (M+, 100). Anal. Calcd for C19H27FeNO2:
C, 63.87; H, 7.62; N, 3.92. Found: C, 64.05; H, 7.42; N, 4.00.
Gen er a l P r oced u r e for th e P r ep a r a tion of Ur ea s 11.
To a cold (-78 °C), stirred solution of 1-ferrocenylethylamine
(4 mmol) in CH2Cl2 (10 mL) was added Et3N (6 mmol) followed
by the appropriate dialkylcarbamyl chloride (4.8 mmol). The
reaction mixture was warmed to ambient temperature and
stirred for 12 h. Water was added, and the mixture was stirred
vigorously for 30 min. The usual aqueous workup involving
dilution with ether and sequential washing with water, 1 M
HCl, saturated NaHCO3, and brine, followed by drying (Mg-
SO4) and concentration, afforded the crude ureas 11, which
were further purified by chromatography or crystallization.
N-1-F er r ocen yleth yl-N′,N′-d im eth ylu r ea (11a ). Treat-
ment of 1-ferrocenylethylamine with dimethylcarbamyl chlo-
ride as described above gave 11a as orange crystals, which
were recrystallized from hexanes (86% yield): Mp: 107-110
°C. IR (KBr): 3379, 1625, 1527 cm-1; 1H NMR: δ 4.71 (quintet,
J ) 7 Hz, 1H), 4.61 (br d, J ) 7 Hz, 1H), 4.21-4.09 (m, 4H),
4.15 (s, 5H), 2.91 (s, 6H), 1.44 (d, J ) 7 Hz, 3H); 13C NMR: δ
157.3, 92.4, 68.2 (5C), 67.8, 67.42, 67.35, 65.6, 44.5, 36.0 (2C),
21.4. MS (ESI): m/z 300 (M+, 3), 213 (100). Anal. Calcd for
δ 9.97 (s, 1H), 4.80-4.50 (m, 5H), 4.22 (br s, 4H), 1.48 (s, 9H),
1.39 (d, J ) 7 Hz, 3H). 13C NMR: δ 193.4, 155.0, 94.3, 79.4,
79.2, 73.7, 70.2, 70.0, 69.96, 69.8, 69.2, 69.0, 68.0, 67.4, 44.4,
28.3, 21.6. MS (FAB): m/z 357 (M+, 65), 307 (33), 154 (100).
Anal. Calcd for C20H23FeNO3: C, 60.52; H, 6.49; N, 3.92.
Found: C, 60.40; H, 6.60; N, 3.90.
[1′-(N-ter t-bu toxyca r bon yl-1-a m in oeth yl)fer r ocen yl]-
d ip h en ylm eth a n ol (7f). This compound was prepared ac-
cording to the general procedure using benzophenone as the
electrophile. From 154 mg of 5, there was obtained, after flash
chromatography (hexanes/ether, 4:1), 232 mg (97%) of 7f as a
red oil. IR (neat): 3434 (br), 3334 (br), 1693, 1170, 701 cm-1
.
1H NMR: δ 7.35-7.22 (m, 10H), 5.22 (br s, 1H), 4.43 (br s,
1H), 4.29-3.99 (m, 8H), 3.27 (s, 1H), 1.45 (s, 9H), 1.30 (d, J )
7 Hz, 3H). 13C NMR: δ 155.1, 147.2, 146.8, 127.5, 127.4, 126.9,
98.6, 93.4, 79.1, 77.8, 69.3, 69.1, 68.4, 68.1, 67.5, 44.6, 28.6,
21.6. MS (FAB): m/z 511 (M+, 100), 494 (27), 225 (25). Anal.
Calcd for C30H33FeNO3: C, 70.45; H, 6.50; N, 2.74. Found: C,
70.60; H, 6.48; N, 2.61.
[1′-(N-ter t-bu toxyca r bon yl-1-a m in oeth yl)fer r ocen yl]-
p h en ylm eth a n ol (7g). This compound was prepared accord-
ing to the general procedure using benzaldehyde as the
electrophile. From 148 mg of 5, there was obtained, after flash
chromatography (hexanes:ether, 3:2), 157 mg (80%) of 7g as
a red oil. 1H NMR data show the presence of two diastereomers
in a 72:28 ratio. IR (neat): 3394 (br), 1691, 1170 cm-1 1H
.
C
15H20FeN2O: C, 60.02; H, 6.72; N, 9.33. Found: C, 59.96; H,
NMR: δ 7.41-7.25 (m, 5H), 5.50 (br s, 0.72H), 5.28 (br s,
0.28H), 4.6-4.1 (m, 10H), 1.50 (s, 9H), 1.43 (d, J ) 7 Hz, 0.8H),
1.41 (d, J ) 7 Hz, 2.2H). 13C NMR: δ 155.1, 143.5, 131.7, 128.4,
128.3, 128.2, 127.6, 127.5, 126.2, 126.1, 94.0, 93.1, 79.2, 72.5,
72.2, 72.1, 71.7, 69.8, 68.6, 68.3, 68.0, 67.9, 67.7, 67.3, 66.8,
66.1, 44.9, 28.5, 21.8, 21.7. MS (ESI): m/z 435 (M+, 81), 418
(47), 214 (52), 158 (100) Anal. Calcd for C24H29FeNO3: C, 66.22;
H, 6.71; N, 3.22. Found: C, 65.93; H, 6.96; N, 3.01.
6.92; N, 9.49.
N-1-F er r ocen ylet h yl-N′,N′-d iet h ylu r ea (11b ). Treat-
ment of 1-ferrocenylethylamine with diethylcarbamyl chloride
as described above gave 11b, which was purified by flash
chromatography on silica gel (hexanes/ether, 1:1) to provide a
tan solid (88% yield): Mp: 76-77 °C. IR (KBr): 3455, 1639,
1504 cm-1. H NMR: δ 4.74 (quintet, J ) 7 Hz, 1H), 4.57 (br
1
d, J ) 7 Hz, 1H), 4.17 (br s, 1H), 4.15 (s, 5H), 4.15-4.09 (m,
3H), 3.27 (q, J ) 7 Hz, 4H), 1.43 (d, J ) 7 Hz, 3H), 1.16 (t,
J ) 7 Hz, 6H). 13C NMR: δ 155.8, 92.4, 67.8 (5C), 67.4, 67.1,
66.8, 65.3, 43.8, 40.7 (2C), 21.2, 13.6 (2C). MS (FAB): m/z 328
(100, M+), 263 (10), 213 (37). Anal. Calcd for C17H24FeN2O:
C, 62.21; H, 7.37; N, 8.53. Found: C, 62.08; H, 7.20; N, 8.42.
N-1-Fer r ocen yleth yl-N′,N′-diisopr opylu r ea (11c). Treat-
ment of 1-ferrocenylethylamine with diisopropylcarbamyl
chloride as described above gave 11c, which was purified by
flash chromatography on silica gel (hexanes/ether, 3:2) to
N-Boc-1-fer r ocen ylm eth yla m in e (8). A solution of 1-fer-
rocenylmethylamine19 (0.70 g, 3.3 mmol), Et3N (0.7 mL) and
(BOC)2O (1.07 g, 4.9 mmol) in THF (10 mL) was stirred at
ambient temperature for 2 h. The mixture was diluted with
ether, washed twice with water, dried (Na2SO4), and concen-
trated. Purification of the resulting residue by flash chroma-
tography (hexanes:ether:CH2Cl2, 8:2:1) provided a yellow solid
which was recrystallized from hexanes to afford 8 (0.70 g, 68%
yield) as orange crystals. Mp 91-92 °C. IR (cast): 3387 (br),
1693, 1504, 1163 cm-1; 1H NMR: δ 4.68 (br s, 1H), 4.18 (br s,
5 + 2H), 4.14 (s, 2H), 3.99 (d, J ) 5 Hz, 2H), 1.46 (s, 9H). 13C
NMR: δ 154.4, 85.6, 79.0, 68.3 (5C), 67.8, 39.6, 28.3 (3C). MS
(FAB): m/z 315 (M+, 100), 259 (35), 199 (31). Anal. Calcd for
provide a thick red oil (83% yield): IR (neat): 3375, 1637 cm-1
.
1H NMR: δ 4.82 (br s, 1H), 4.48 (br s, 1H), 4.4.2-4.1 (m, 4H),
4.19 (s, 5H), 3.92 (br s, 2H), 1.47 (br s, 3H), 1.28 (br 2, 12H).
13C NMR: δ 155.9, 92.5, 67.9 (5C), 67.4, 67.0, 66.6, 65.4, 44.6
(2C), 43.7, 21.5, 21.11 (2C), 21.05 (2C). MS (FAB): m/z 356
(100), 213 (35). Anal. Calcd for C19H28FeN2O: C, 64.05; H, 7.92;
N, 7.86. Found: C, 64.22; H, 8.15; N, 7.79.
C
16H21FeNO2: C, 60.97; H, 6.72; N, 4.44. Found: C, 60.76; H,
6.78; N, 4.45.
1-(N-ter t-bu toxyca r bon yla m in om eth yl)-1′-tr im eth ylsi-
lylfer r ocen e (9). This compound was prepared according to
the general procedure using chlorotrimethylsilane as the
electrophile. From 98 mg of 8, there was obtained, after flash
chromatography (hexanes/ether, 6:1), 107 mg (89%) of 9 as an
orange oil which, upon standing, became a yellow solid. Mp:
N-1-(2-Tr im eth ylsilylfer r ocen yl)eth yl-N′,N′-d im eth yl-
u r ea (12a ) a n d N-1-(1′-Tr im eth ylsilyl-fer r ocen yl)eth yl-
N′,N′-d im eth ylu r ea (13a ). Lithiation of urea 11a and trap-
ping with Me3SiCl as described for 5 provided the 1,2-
disubstituted isomer 12a and the 1,1′-disubstituted isomer 13b
in a ratio of 23:77, respectively, as determined by integration
1
71-72 °C. IR (cast): 3394 (br), 1692, 1162 cm-1. H NMR: δ
4.74 (br s, 1H), 4.33 (s, 2H), 4.16 (s, 2H), 4.10 (d, J ) 5 Hz),
4.09 (s, 4H), 1.47 (s, 9H), 0.24 (s, 9H). 13C NMR: δ 155.5, 85.6,
79.2, 73.3 (2C), 72.6, 71.4 (2C), 68.2 (2C), 68.1 (2C), 39.7, 28.4
(3C), -0.3 (3C). MS (FAB): m/z 387 (M+, 100), 331 (36), 271
1
of the H NMR spectrum of crude material. These compounds
were separated by flash chromatography on silica gel (CH2-
Cl2/ether, 3:1) to give 12a (Rf ) 0.53, double elution with CH2-

1014 Organometallics, Vol. 23, No. 5, 2004
Chong and Hegedus
Cl2/ether, 2:1) followed by 13a (Rf ) 0.41, double elution with
CH2Cl2/ether, 2:1). 12a : orange solid (16% yield). Mp: 105-
108 °C. IR (cast): 3332 (br), 1630, 1522 cm-1. 1H NMR: δ 4.81
(m, 1H), 4.38 (br s, 1H), 4.28 (br s, 1H), 4.19 (br s, 1H), 4.11
(s, 5H), 4.06 (br s, 1H), 2.80 (br s, 6H), 1.51 (d, J ) 6 Hz, 3H),
0.24 (s, 9H). 13C NMR: δ 156.9, 95.2, 74.8, 71.7, 69.6, 69.2
(5C), 46.1, 36.1 (2C), 20.9, 0.1 (3C). MS (FAB): m/z 372 (100,
M+), 307 (8), 285 (40). Anal. Calcd for C18H28FeN2OSi: C,
58.06; H, 7.58; N, 7.52. Found: C, 58.09; H, 7.76; N, 7.22.
13a : orange solid (55% yield). Mp: 95-96 °C. IR (cast): 3258,
4.30 (br s, 1H), 4.12 (s, 5H), 4.06 (br s, 1H), 3.97 (br d, J ) 6
Hz, 1H), 3.66 (br septet, J ) 7 Hz, 2H), 1.51 (br d, J ) 6 Hz,
3H), 1.18 (d, J ) 7 Hz, 3H), 1.16 (d, J ) 7 Hz, 6H), 0.27 (s,
9H). 13C NMR: δ 155.4, 95.6, 74.6, 71.5, 69.5, 69.0 (5C), 68.8,
45.4, 45.2 (2C), 21.6, 21.23 (2C), 21.06 (2C), 0.18 (3C). MS
(FAB): m/z 428 (100), 363 (5), 285 (35). Anal. Calcd for C22H36
-
FeN2OSi: C, 61.68; H, 8.47; N, 6.54. Found: C, 61.31; H, 8.48;
N, 6.39. 13c: red oil (38% yield). IR (neat): 3376, 1637, 1499
1
cm-1. H NMR: δ 4.80 (br s, 1H), 4.38 (br s, 1H), 4.33 (br s,
2H), 4.22-4.05 (m, 7H), 3.88 (m, 2H), 1.45 (br s, 3H), 1.26 (br
d, J ) 6 Hz, 12H), 0.20 (s, 9H). 13C NMR; δ 156.3, 92.9, 73.4,
73.2, 72.6, 71.6, 71.5, 68.4, 68.0, 67.4, 65.9, 45.0 (2C), 44.4,
21.8, 21.55 (2C), 21.49 (2C), -0.24 (3C). MS (FAB): m/z 428
(100, M+), 327 (9), 285 (51). Anal. Calcd for C22H36FeN2OSi:
C, 61.68; H, 8.47; N, 6.54. Found: C, 61.90; H, 8.62; N, 6.43.
N-P iva loyl-1-fer r ocen yleth yla m in e (14). To a solution
of 1-ferrocenylethylamine (1.556 g, 6.79 mmol) in CH2Cl2 at
-20 °C was added Et3N (13.6 mmol) followed by pivaloyl
chloride (10 mmol). The mixture was warmed to room tem-
perature and was stirred for a further 1 h. The reaction was
quenched with aqueous NH4Cl and the mixture was diluted
with ether. The organic layer was washed sequentially with
water, 1 M HCl, and NaHCO3, dried (Na2SO4), and concen-
trated. Purification of the resulting residue by flash chroma-
tography (CH2Cl2:ether, 20:1) provided pivamide 14 as a yellow
solid (1.91 g, 90% yield). Mp: 134-135.5 °C. IR (KBr): 3328,
1625, 1530, 830 cm-1 1H NMR: δ 4.74 (quintet, J ) 7 Hz,
.
1H), 4.54 (br d, J ) 7 Hz, 1H), 4.29 (br s, 2H), 4.19 (br s, 1H),
4.13-4.05 (m, 5H), 2.90 (s, 6H), 1.44 (d, J ) 7 Hz, 3H), 0.20
(s, 9H). 13C NMR: δ 157.4, 92.3, 73.3, 72.9, 72.6, 71.4, 71.3,
68.3, 67.9, 67.6, 65.6, 44.7, 36.1 (2C), 21.5, -0.2 (3C). MS
(FAB): m/z 372 (100, M+), 285 (33), 235 (11). Anal. Calcd for
C
18H28FeN2OSi: C, 58.06; H, 7.58; N, 7.52. Found: C, 57.86;
H, 7.34; N, 7.38.
N-1-(2-Tr im et h ylsilylfer r ocen yl)et h yl-N′,N′-d iet h yl-
u r ea (12b) a n d N-1-(1′-Tr im eth ylsilylfer r ocen yl)eth yl-
N′,N′-d ieth ylu r ea (13b). Lithiation of urea 11b and trapping
with Me3SiCl as described for 5 provided the 1,2-disubstituted
isomer 12b and the 1,1′-disubstituted isomer 13b in a ratio of
18:82, respectively, as determined by integration of the 1H
NMR spectrum of crude material. These compounds were
separated by flash chromatography on silica gel (hexanes/
ether, 4:5) to give 12b (Rf ) 0.23) followed by 13b (Rf ) 0.17).
12b: red oil (18% yield). IR (neat): 3353, 1634, 1504 cm-1. 1H
NMR: δ 4.89 (m, 1H), 4.40 (br s, 2H), 4.30 (br s, 1H), 4.12 (s,
5H), 4.09 (br s, 2H), 3.3-3.0 (m, 4H), 1.52 (d, J ) 6 Hz, 3H),
1.07 (t, J ) 7 Hz, 6H), 0.27 (s, 9H). 13C NMR: δ 155.6, 95.7,
74.9, 71.8, 69.7, 69.3 (5C), 69.2, 45.8, 40.8 (2C), 21.1, 13.8 (2C),
0.1 (3C). MS (FAB): m/z 400 (100, M+), 335 (7), 285 (41). Anal.
Calcd for C20H32FeN2OSi: C, 59.99; H, 8.05; N, 7.00. Found:
C, 60.23; H, 8.12; N, 6.85. 13b: red oil (69% yield). IR (neat):
3351, 1622, 1526 cm-1. 1H NMR: δ 4.76 (m, 1H), 4.53 (m, 1H),
4.31 (br s, 2H), 4.18 (br s, 1H), 4.15-4.05 (m, 5H), 3.27 (q,
J ) 7 Hz, 4H), 1.44 (d, J ) 6 Hz, 3H), 1.15 (t, J ) 7 Hz, 3H),
0.21 (s, 9H). 13C NMR: δ 156.3, 92.7, 73.4, 73.0, 72.6, 71.4,
71.3, 68.3, 68.0, 67.5, 65.7, 44.4, 41.1 (2C), 21.5, 13.9 (2C), 0.29
(3C). MS (FAB): m/z 400 (100, M+), 327 (5), 285 (42), 263 (12).
Anal. Calcd for C20H32FeN2OSi: C, 59.99; H, 8.05; N, 7.00.
Found: C, 60.12; H, 7.96; N, 7.11.
1632, 1528 cm-1 1H NMR: δ 5.89 (d, J ) 6.3 Hz, 1H), 4.80
.
(dq, J ) 6.3, 6.8 Hz, 1H), 4.16 (s, 5H), 4.14 (br s, 2H), 4.12 (m,
1H), 4.07 (m, 1H), 1.40 (d, J ) 6.8 Hz, 3H), 1.22 (s, 9H). 13C
NMR: δ 176.8, 91.6, 68.2 (5C), 67.8, 67.6, 67.0, 65.5, 42.9, 38.4,
27.5 (3C), 20.6. MS (FAB): m/z 313 (M+, 100), 248 (11), 213
(36). Anal. Calcd for C17H23FeNO: C, 65.19; H, 7.40; N, 4.47.
Found: C, 64.90; H, 7.26; N, 4.47.
1-(N-P ivaloylam in oeth yl)-2-tr im eth ylsilylfer r ocen e (15).
This compound was prepared according to the general proce-
dure for the lithiation of 5 using chlorotrimethylsilane as the
electrophile. From 101 mg of 14, there was obtained, after flash
chromatography (CH2Cl2/ether, 30:1), 97 mg (78%) of 15 as a
yellow solid. A minor (∼10%) lower Rf product (likely the 1,1′-
disubstituted product) was not isolated. Since 15 exhibited a
single set of 13C NMR resonances, it is likely to be a single
diastereomer. Mp: 114-116 °C. IR (KBr): 3320, 1630, 1519,
1
838 cm-1. H NMR: δ 5.38 (m, 1H), 4.89 (m, 1H), 4.41 (br s,
N-1-(2-Tr im et h ylsilylfer r ocen yl)et h yl-N′,N′-d iisop r o-
p ylu r ea (12c) a n d N-1-(1′-Tr im et h ylsilyl-fer r ocen yl)-
eth yl-N′,N′-d iisop r op ylu r ea (13c). Lithiation of urea 11c
and trapping with Me3SiCl as described for 5 (with the
exception that 5 equiv of n-BuLi was used) provided the 1,2-
disubstituted isomer 12c and the 1,1′-disubstituted isomer 13c
in a ratio of 35:65, respectively, as determined by integration
1H), 4.32 (br s, 1H), 4.13 (s, 5H), 4.09 (br s, 2H), 1.49 (d, J )
6 Hz, 3H), 1.11 (s, 9H), 0.26 (s, 9H). 13C NMR: δ 176.3, 94.2,
74.7, 71.7, 69.9, 69.8, 69.1 (5C), 44.9/44.8, 38.3, 27.53/27.47,
20.1, 0.29/0.24. MS (ESI): m/z 408 (M + Na+, 100), 385 (M+,
29). Anal. Calcd for C20H31FeNOSi: C, 62.34; H, 8.11; N, 3.64.
Found: C, 62.50; H, 8.34; N, 3.62.
1
of the H NMR spectrum of crude material. These compounds
Ack n ow led gm en t. We thank the National Science
Foundation for financial support (Grant No. CHE
9908661) and the University of Waterloo for granting a
period of sabbatical leave to J .M.C.
were separated by flash chromatography on silica gel (hexanes/
ether, 1:1) to give 12c (Rf ) 0.42) followed by 13c (Rf ) 0.26)
as well as recovered starting material 11c (29%). 12c: orange
crystals (26% yield). Mp: 97-99 °C. IR (cast): 1644, 1494 cm-1
.
1H NMR: δ 4.88 (br quintet, J ) 6 Hz, 1H), 4.39 (br s, 1H),
OM030468L