Synthesis of 1',2',3',4',5'-pentamethyl-3,4-diphenylazaferrocene and its enantioselective C-2 functionalization via (-)-sparteine-mediated lithiation

Article abstract of DOI:10.3987/COM-08-S(N)86

Lithiation of 1',2',3',4',5'-pentamethyl-3,4-diphenylazaferrocene (9) with sec-BuLi/(-)-sparteine (2) in Et₂O at -78 °C followed by quenching with electrophiles gave the C-2 functionalized azaferrocenes (17) in good enantioselectivities (up to

Full text of DOI:10.3987/COM-08-S(N)86

HETEROCYCLES, Vol. 76, No. 2, 2008
1237
HETEROCYCLES, Vol. 76, No. 2, 2008, pp. 1237 - 1248. © The Japan Institute of Heterocyclic Chemistry
Received, 31st March, 2008, Accepted, 19th May, 2008, Published online, 22nd May, 2008. COM-08-S(N)86
SYNTHESIS OF 1’,2’,3’,4’,5’-PENTAMETHYL-3,4-DIPHENYL-
AZAFERROCENE AND ITS ENANTIOSELECTIVE C-2
FUNCTIONALIZATION VIA (–)-SPARTEINE-MEDIATED LITHIATION
a
a
b
Tsutomu Fukuda, Yasuyuki Koga, and Masatomo Iwao *
a
b
Graduate School of Science and Technology, and Department of Applied
Chemistry, Faculty of Engineering, Nagasaki University, 1-14 Bunkyo-machi,
Nagasaki 852-8521, Japan, e-mail: iwao@nagasaki-u.ac.jp
Abstract – Lithiation of 1’,2’,3’,4’,5’-pentamethyl-3,4-diphenylazaferrocene (9)
with sec-BuLi/(–)-sparteine (2) in Et O at –78 °C followed by quenching with
2
electrophiles gave the C-2 functionalized azaferrocenes (17) in good
enantioselectivities (up to 79% ee).
In contrast, treatment of 9 with
tert-BuLi/(–)-sparteine (2) leaded to lateral lithiation at the methyl group of
cyclopentadienyl ring.
INTRODUCTION
Planar chiral 2-substituted azaferrocene have attracted considerable attention as chiral catalysts or ligands
1
in asymmetric synthesis. The synthesis of chiral azaferrocenes has been effected by conventional
2
1a,1d
resolution technique or by direct HPLC separation on a chiral stationary phase.
Recently, however,
more attractive asymmetric syntheses via organolithium intermediates have been developed by two
groups. Johansen et al. generated chiral 2-azaferrocenyllithium by ligand exchange of optically pure
3
2
-azaferrocenyl p-tolyl sulfoxides.
On the other hand, we successfully employed chiral
4
ligand-mediated enantioselective lithiation technique to generate 3 and 7 (Scheme 1). Anderson et al.
extended our method to the synthesis of a broad range of chiral 2-substituted 1’,2’,3’,4’,5’-pentamethyl-
5
azaferrocene derivatives.
The application of chiral azaferrocenes to catalytic asymmetric reactions has been relatively unexplored
6
compared to that of the parental chiral ferrocene derivatives. The reason may be explained, in part, by
difficulty of handling the azaferrocene derivatives due to their thermal and chemical instability. In fact,
azaferrocenes 4 and 8 prepared by ourselves are found to be too unstable to use for the further reactions.
Efraty et al. have reported that azaferrocene changes to ferrocene under reflux in benzene and undergoes

1238
HETEROCYCLES, Vol. 76, No. 2, 2008
H
N
N
H
Li
N
Fe
E
N
Fe
N
Fe
2
electrophile
sec-BuLi, Et O, -78 °C, 1 h
-78 °C, 1 h ! 0 °C, 30 min
2
1
3
4
up to 81% ee
Et Et
O
O
N
N
N
Fe
Li
N
Fe
E
N
Fe
6
electrophile
i-Pr
i-Pr
sec-BuLi, Et O, -55 °C, 1 h
-78 °C, 1 h ! 0 °C, 30 min
2
5
7
8
up to 99% ee
Scheme 1
7
facile reactions with π-acidic and σ-donor ligands. These results suggested us that the stability of
azaferrocenes could be improved if the reactive iron center was protected from the attack of π-acidic or
σ-donor ligands by introducing bulky substituents on the pyrrolyl ring. Based upon this working
hypothesis, we designed 1’,2’,3’,4’,5’-pentamethyl-3,4-diphenylazaferrocene (9) as a stable azaferrocene.
In this paper, we report a synthesis of 1’,2’,3’,4’,5’-pentamethyl-3,4-diphenylazaferrocene (9) and its
enantioselective C-2 functionalization via chiral ligand-mediated lithiation.
RESULTS AND DISCUSSION
The synthesis of 3,4-diphenylpyrrole (14) which is required for the preparation of azaferrocene (9) was
carried out at first (Scheme 2). Commercially available iminodiacetic acid (10) was treated with thionyl
chloride in methanol to give dimethyl iminodiacetate hydrochloride (11). Acetylation of 11 with acetic
anhydride in the presence of triethylamine afforded acetamide (12). Conversion of 12 to 3,4-diphenyl-
8
pyrrole (14) was carried out by using the modified procedure of Friedman. Treatment of 12 with benzil
and sodium methoxide in refluxing methanol followed by hydrolysis gave 13 in 69% yield.
Decarboxylation of 13 in refluxing ethanolamine produced 3,4-diphenylpyrrole (14).
Ph
HO C
Ph
CO H
Ph
Ph
(
a)
(b)
(c)
(d)
MeO C
N
CO Me
2
HO C
N
H
CO H
MeO C
N
CO Me
HCl
2
2
2
2
2
H
·
Ac
2
2
N
H
N
H
10
11
12
13
14
Scheme 2 Reagents and conditions: (a) SOCl , MeOH, –10 °C then rt, 3 d (94%); (b) Ac O, Et N, 0 °C,
2
2
3
0
.5 h then rt, 4 h (91%); (c) (1) benzil (0.5 equiv.), NaOMe (10 equiv.), MeOH, reflux, 0.5 h,
(
2) H O, reflux, 0.5 h (69%); (d) ethanolamine, reflux, 1 h (92%).
2
The synthesis of 1’,2’,3’,4’,5’-pentamethyl-3,4-diphenylazaferrocene (9) is shown in Scheme 3. Pyrrole
14) was deprotonated by n-BuLi to give lithium pyrrolide (15) which was used for the next reaction as it
(

HETEROCYCLES, Vol. 76, No. 2, 2008
1239
9
stands. Deprotonation of 1,2,3,4,5-pentamethylcyclopentadiene (Cp*-H) (16) with n-BuLi followed by
successive treatment with FeCl and lithium pyrrolide (15) afforded the desired azaferrocene (9) in 63%
2
yield. Although we have not carried out precise comparison, the azaferrocene (9) was found to be
somewhat more stable than parental 1.
Ph
Ph
Ph
Ph
n-BuLi (1.0 eq), THF, 0 °C ! rt, 15 min
N
H
N
Li
14
15
Ph
1
. n-BuLi (1.0 eq), THF, 0 °C ! rt, 15 min
Ph
N
Fe
2. FeCl (1.0 eq), 0 °C ! rt, 0.5 h
2
3. 15, 0 °C ! rt, 4 h ! reflux, 0.5 h
1
6
9
6
3%
Scheme 3
Next, we examined the enantioselective C-2 lithiation of azaferrocene (9). The results were summarized
in Table 1. Since C-2 lithiation of azaferrocene (9) has not been reported, we initially tested the
feasibility of this reaction under achiral conditions. Treatment of azaferrocene (9) with sec-BuLi (1.5
equiv.) in the presence of TMEDA in Et O at –78 °C for 1 h followed by quenching with
2
paraformaldehyde produced racemic 17 in 61% yield (entry 1). The lithiations of 9 with sec-BuLi in the
presence of chiral bidentate ligands (2, 6, and 18-21) were examined next (entries 2-7). Similar to the
4
case of the parental azaferrocene (1), enantioselective lithiation of 9 was effected most satisfactory by
10
using (–)-sparteine (2) as a chiral ligand (entry 2). Other chiral ligands such as S-valine-derived
1
1
12
bis(oxazoline) (6), S-proline-derived ligand (18) and (19), N,N,N’,N’-tetramethyl-(1R,2R)-1,2-
1
3
14
diphenylethylenediamine (20), and N,N,N’,N’-tetramethyl-(1R,2R)-1,2-diaminocyclohexane (21) were
found to be less effective than (–)-sparteine (2) (entries 3-7). In order to improve the chemical yield and
enantioselectivity, we further surveyed other bases in the presence of 2 (entries 8 and 9). The lithiation
proceeded smoothly by using n-BuLi as a base, however, enantiomeric excess of 17 was decreased
considerably (entry 8). In contrast to the previous results, when tert-BuLi was used as a base, the
lithiation occurred at the methyl group of 1,2,3,4,5-pentamethylcyclopentadienyl (Cp*) ring selectively
1
5
(
entry 9).
Therefore, we examined the effect of chiral ligands on regioselectivity of the lithiation using
tert-BuLi as a base (entries 10-12). When chiral ligands (6) and (21) were used, only azaferrocene (17)
was obtained in good yields and low enantiomeric excesses (entries 10 and 12). The lithiation in the
presence of 18 resulted in non-regioselective reaction at C-2 and Cp* methyl group (entry 11). These
results suggested that the lithiation at the Cp* methyl group might occur in the presence of bulky ligand
such as 2 and 18.

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HETEROCYCLES, Vol. 76, No. 2, 2008
Table 1. Enantioselective lithiation of azaferrocene (9)
Ph
Ph
Ph
Ph
Ph
Ph
1
2
. sec-BuLi (1.5 equiv.), additive (1.7 equiv.), Et O, -78 °C, 1 h
OH
N
2
N
Fe
N
Fe
Fe
. (CH O) (10 equiv.), -78 °C, 0.5 h ! 0 °C, 0.5 h
2
n
OH
9
17
22
Et Et
H
N
N
O
O
Ph
Ph
NMe
N
OLi
N
N
N
N
H
Me
2
N
2
Me
2
N
NMe
2
i-Pr
i-Pr
2
6
18
19
20
21
1
7
a
entry
BuLi
ligand
22 (%)
a
b
yield (%)
% ee
1
2
3
4
5
6
7
8
9
sec-
sec-
sec-
sec-
sec-
sec-
sec-
n-
TMEDA
61
74
63
69
30
20
70
69
-
-
-
2
78
10
8
-
6
-
18
19
20
21
2
-
2
-
33
34
47
-
-
-
-
tert-
tert-
tert-
tert-
2
80
-
1
1
0
1
2
6
72
31
72
18
11
53
18
21
41
-
1
a
Isolated yield.
b
Enantiomeric excess was determined by HPLC analysis (Daicel Chiralpak AD).
In order to enrich the enantiomeric purity of 17, recrystallization of 17 from diethyl ether was conducted.
Unfortunately, the crystals thus obtained were found to be racemate. On the other hand, the
enantiomeric purity of the filtrate was increased. However, we could not obtain enantiomerically pure
crystalline 17 from the filtrate. The X-ray crystal structure of the racemic azaferrocene (17) is shown in
Figure 1. The iron atom has a sandwich-like coordination with the planar Cp* and pyrrolyl rings. Both
rings are equi-distant from Fe atom (the mean Fe-ring plane distance is 1.66 Å) but are slightly deviate
from parallel (interplanar angle: ca. 4.3 °) due to steric repulsion between phenyl groups of pyrrolyl ring
3
a,16
and methyl groups of Cp*.
Since we have established the best conditions for the enantioselective C-2 lithiation of 9, we next carried
out enantioselective C-2 functionalization of 9 with other electrophiles. The results were summarized in
Table 2. The lithiation of 9 using sec-BuLi/(–)-sparteine (2) followed by quenching with electrophiles

HETEROCYCLES, Vol. 76, No. 2, 2008
1241
Figure 1 X-Ray crystal structure of racemic azaferrocene (17). The thermal ellipsoids are at a 50%
probability level. Selected bond distances (Å): Fe1-N1 2.0311(18), Fe1-C1 2.010(2),
Fe1-C2 2.092(2), Fe1-C3 2.094(2), Fe1-C4 2.036(2), Fe1-C5 2.062(2), Fe1-C6 2.061(2),
Fe1-C7 2.071(2), Fe1-C8 2.053(2), Fe1-C9 2.064(2).
such as iodine, chlorotrimethylsilane, chlorodiphenylphosphine, and diphenyl disulfide produced the
corresponding products (23) in modest to good yields. The enantiomeric excesses of the products were
comparable to that obtained in the reaction with paraformaldehyde.
Finally, we would like to propose a plausible mechanistic explanation for the enantio- and
regioselectivities of the lithiation of azaferrocene (9) in the presence of (–)-sparteine (2) (Scheme 4).
When the lithiation is carried out using sec- or n-BuLi as a base, the nitrogen atom on pyrrolyl ring may
coordinate to the BuLi/(–)-sparteine complex and then butyl anion deprotonates the adjacent C-2 proton
1
7
via complex-induced proximity effect (CIPE) to give the lithio species (25) (route 1). Compared to the
n-BuLi/(–)-sparteine/9 complex (24), the rotation around
a
nitrogen-lithium bond in
Table 2. Enantioselective C-2 functionalization of azaferrocene (9)
Ph
Ph
Ph
E
Ph
1
. sec-BuLi (1.5 equiv.), 2 (1.7 equiv.), Et O, -78 °C, 1 h
N
2
N
Fe
Fe
2. electrophile, -78 °C, 0.5 h ! 0 °C, 0.5 h
9
23
a
b
entry
electrophile
I2
E
product
23a
yield (%)
% ee
1
2
3
4
I
84
61
39
88
79
TMSCl
TMS
PPh2
SPh
23b
75
Ph PCl
23c
77
2
PhSSPh
23d
76
a
Isolated yield.
b
Enantiomeric excess was estimated by HPLC analysis (Daicel Chiralpak AD).

1242
HETEROCYCLES, Vol. 76, No. 2, 2008
sec-BuLi/(–)-sparteine/9 complex (24) is more restricted due to bulkiness of sec-butyl group. Thus,
enantioselectivity of C-2 deprotonation using sec-BuLi would be superior to that using n-BuLi. In the
1
8
reaction with tert-BuLi, a tert-BuLi/(–)-sparteine complex may be too bulky to interact with the pyrrolyl
nitrogen of 9. Therefore, the complex could not lithiate at C-2 by an assistance of CIPE but deprotonate
more easily accessible methyl protons of Cp* to produce 27 (route 2).
Ph
Ph
Ph
H
Ph
Li
N
N
Fe
RLi, L*
H
Fe Li
R
route 1
L*
Ph
R: sec-Bu
n-Bu
Ph
24
25
N
Fe
Ph
Ph
9
Ph
H
Ph
N
Fe
N
Fe
H
route 2
tert-BuLi, L*
H
Li
26
27
tert-Bu Li L*
L*: (–)-sparteine
Scheme 4
In conclusion, we have succeeded in the synthesis of new chiral azaferrocenes 17 and 23 via
–)-sparteine-mediated enantioselective lithiation of 9. During the course of this study, we found out
(
that 9 could be deprotonate selectively at the methyl group of Cp* with tert-BuLi/(–)-sparteine. Proper
combination of these enantio- and regioselective lithiations may be useful in the synthesis of new types of
planar chiral azaferrocene.
EXPERIMENTAL
Melting points were determined with a Yanagimoto micro melting points apparatus and are uncorrected.
IR spectra were obtained with a Perkin-Elmer System 2000 instrument. NMR spectra were recorded on
1
13
a JEOL JNM-AL400 instrument (400 MHz for H and 100 MHz for C) using tetramethylsilane as an
internal standard. High resolution mass spectra were recorded on a JEOL JMS-700N spectrometer.
HPLC analyses were performed on a Shimadzu LC-6A apparatus. Optical rotations were measured on a
JASCO P-1020 digital polarimeter at ambient temperature. X-Ray crystal structure analysis was carried
out with a Rigaku FR-E SuperBright at Institute for Materials Chemistry and Engineering (IMCE),
Kyushu University. Flash chromatography was conducted on Silica Gel 60N, 40-50 µm (Kanto
Chemical Co., Inc.). Column chromatography was conducted on Silica Gel 60N, 63-210 µm (Kanto
Chemical Co., Inc.) or Chromatorex NH-DM1020 silica gel (Fuji Silysia Chemical Ltd.). sec- and
tert-Butyllithiums were purchased from Kanto Chemical Co., Inc. n-Butyllithium was purchased from
Aldrich Chemical Co., Inc. The alkyllithiums were used after titration with 2,5-dimethoxybenzyl

HETEROCYCLES, Vol. 76, No. 2, 2008
1243
alcohol. Dry diethyl ether and THF were distilled from Na-benzophenone ketyl under argon
immediately before use.
Dimethyl iminodiacetate hydrochloride (11)
Thionyl chloride (82.3 mL, 1.13 mol) was added dropwise to MeOH (500 mL) at –10 °C. After being
stirred for 10 min, iminodiacetic acid (50.0 g, 376 mmol) was added portionwise to the solution at –10 °C
and the suspension was allowed to warm to rt. After being stirred for 3 d, the reaction mixture was
evaporated under reduced pressure. The residue was purified by recrystallization from MeOH to give 11
as colorless needles (69.8 g, 94%). Mp 180-183 °C (decomp); IR (KBr): 1761, 1436, 1345, 1237, 1071,
–1
1
13
9
83 cm ; H NMR (400 MHz, DMSO-d ): δ 3.75 (s, 6H), 4.01 (s, 4H), 10.11 (br s, 2H); C NMR (100
6
MHz, DMSO-d ): δ 46.18, 52.52, 166.75. Anal. Calcd for C H ClNO : C, 36.47; H, 6.12; N, 7.09.
6
6
12
4
Found: C, 36.45; H, 6.08; N, 6.95.
Dimethyl N-acetyliminodiacetate (12)
Under an argon atmosphere, acetic anhydride (26.3 mL, 278 mmol) was added dropwise to a mixture of
dimethyl iminodiacetate hydrochloride (11) (50.0 g, 253 mmol) and triethylamine (74.1 mL, 531 mmol)
in CH Cl (800 mL) at 0 °C. After being stirred for 20 min, the mixture was allowed to warm to rt and
2
2
stirred for additional 4 h. The mixture was quenched with water and the product was extracted with
CH Cl . The extract was washed successively with water and brine, dried over Na SO , and evaporated
2
2
2
4
under reduced pressure. The residue was purified by recrystallization from CH Cl -hexane to give 12 as
2
2
–1
1
colorless granules (46.7 g, 91%). Mp 82-83 °C; IR (KBr): 1743, 1663, 1467, 1431, 1225, 998 cm ; H
1
3
NMR (400 MHz, CDCl ): δ 2.12 (s, 3H), 3.73 (s, 3H), 3.78 (s, 3H), 4.16 (s, 2H), 4.20 (s, 2H); C NMR
3
(
100 MHz, CDCl ): δ 21.04, 47.64, 50.76, 52.18, 52.54, 169.33, 169.77, 171.13. Anal. Calcd for
3
C H NO : C, 47.29; H, 6.45; N, 6.89. Found: C, 47.51; H, 6.37; N, 6.82.
8
13
5
3
,4-Diphenylpyrrole-2,5-dicarboxylate (13)
Under an argon atmosphere, sodium (23.0g, 1.00 mol) was added portionwise to MeOH (250 mL) at rt.
After successive addition of a solution of dimethyl N-acetyliminodiacetate (12) (20.3 g, 100 mmol) in
MeOH (125 mL) and benzil (10.5 g, 50 mmol), the reaction mixture was refluxed for 0.5 h. After being
cooled to rt, water (500 mL) was added and the mixture was refluxed for 0.5 h again. After being cooled
to rt, the mixture was evaporated under reduced pressure to remove MeOH. The residual solution was
washed with Et O and acidified with 6 M aqueous HCl. The precipitate thus formed was collected by
2
filtration, washed with water, and dried under reduced pressure. Recrystallization from EtOH gave 13
as pale brown powder (10.6 g, 69%). Mp 273-293 °C (decomp); IR (KBr): 3030, 1691, 1493, 1408,

1244
HETEROCYCLES, Vol. 76, No. 2, 2008
–
1
1
1
1
257 cm ; H NMR (400 MHz, DMSO-d ): δ 7.01-7.08 (m, 4H), 7.10-7.18 (m, 6H), 11.82 (s, 1H), 12.63
6
3
(
br s, 2H); C NMR (100 MHz, DMSO-d ): δ 122.16, 126.23, 126.96, 129.85, 130.58, 133.76, 161.28.
6
Anal. Calcd for C H NO : C, 70.35; H, 4.26; N, 4.56. Found: C, 70.20; H, 4.25; N, 4.49.
1
8
13
4
3
,4-Diphenylpyrrole (14)
Under an argon atmosphere, ethanolamine (40 mL) was heated to reflux. To this was added portionwise
,4-diphenylpyrrole-2,5-dicarboxylate (13) (5.00 g, 16.3 mmol) under reflux. After being refluxed for 1
3
h, the reaction mixture was cooled to rt, and poured into ice-cold water. The product was extracted with
CH Cl , and the extract was washed with water, dried over Na SO , and evaporated under reduced
2
2
2
4
pressure. The residue was purified by bulb-to-bulb distillation (180-185 °C/0.5 mmHg) to give 14 as
pale yellow liquid (3.27 g, 92%), which on standing solidified. Mp 96.5-97.5 °C; IR (KBr): 3446, 1602,
–
1
1
1
7
1
6
536, 1487, 1435, 1083, 1059, 768, 706 cm ; H NMR (400 MHz, CDCl ): δ 6.88 (d, J= 2.6 Hz, 2H),
3
1
3
.15-7.30 (m, 10H), 8.21 (br s, 1H); C NMR (100 MHz, CDCl ): δ 117.42, 123.61, 125.72, 128.17,
3
28.56, 135.78. Anal. Calcd for C H N: C, 87.64; H, 5.98; N, 6.39. Found: C, 87.49; H, 6.10; N,
1
6
13
.29.
Lithium 3,4-Diphenylpyrrolide (15)
Under an argon atmosphere, 3,4-diphenylpyrrole (14) (2.00 g, 9.12 mmol) was dissolved in THF (28 mL)
and the mixture was cooled to 0 °C. To the solution was added dropwise a hexane solution of n-BuLi
(
1.49 M, 6.12 mL, 9.12 mmol) at 0 °C and the mixture was allowed to warm to rt. After being stirred
for 15 min, the mixture was cooled to 0 °C. The mixture thus obtained was used for the next reaction as
it stands.
1
’,2’,3’,4’,5’-Pentamethyl-3,4-diphenylazaferrocene (9)
Under an argon atmosphere, a hexane solution of n-BuLi (1.49 M, 6.73 mL, 10.0 mmol) was added
dropwise to a solution of Cp*-H (16) (1.37 g, 10.0 mmol) in THF (28 mL) at 0 °C and the suspension was
allowed to warm to rt. After being stirred for 15 min, the suspension was cooled to 0 °C and added by
cannula to a vigorously stirring suspension of FeCl , which was prepared by treatment of FeCl ·4H O
2
2
2
(
1.99 g, 10.0 mmol) under reduced pressure at 100 °C overnight, in THF (41 mL) at 0 °C. The resulting
forest green solution was allowed to warm to rt, stirred for 0.5 h, and cooled to 0 °C. A mixture of
potassium pyrrolide (15) in THF was added by cannula at 0 °C and the reaction mixture was allowed to
warm to rt. After being stirred for 4 h, the mixture was refluxed for 0.5 h, cooled to rt, and passed
through a pad of Silica Gel 60. The filtrate was evaporated under reduced pressure. The residue was
purified by flash chromatography over Silica Gel 60N (hexane-EtOAc=3:1~EtOAc) to give 9 as orange

HETEROCYCLES, Vol. 76, No. 2, 2008
1245
solid (2.35 g, 63%). Recrystallization from Et O gave orange plates. Mp 180-185 °C (decomp) (sealed
2
–
1
1
capillary); IR (KBr): 1600, 1505, 1377, 763, 699 cm ; H NMR (400 MHz, C D ): δ 1.65 (s, 15H), 5.36
6
6
13
(
s, 2H), 7.01-7.12 (m, 6H), 7.40-7.43 (m, 4H); C NMR (100 MHz, C D ): δ 10.26, 81.22, 89.43, 94.56,
6 6
+
1
4
26.67, 128.34, 129.39, 134.98. HREIMS m/z. Calcd for C H FeN (M ): 409.1493. Found:
26 27
09.1490.
Enantioselective C-2 lithiation of azaferrocene (9). General procedure
Under an argon atmosphere, azaferrocene (9) (143 mg, 0.350 mmol) and an appropriate chiral ligand
(
0.595 mmol) were dissolved in Et O (10 mL) and the mixture was cooled to –78 °C. A solution of
2
BuLi (0.525 mmol) was added dropwise to the mixture at –78 °C. After being stirred for 1 h, a
suspension of paraformaldehyde (105 mg, 3.50 mmol) in Et O (2.0 mL) was added dropwise to the
2
mixture at –78 °C. After being stirred for 0.5 h, the mixture was allowed to warm to 0 °C and stirred for
an additional 0.5 h. The reaction mixture was quenched with water and the products were extracted with
Et O. The extract was washed with brine, dried over Na SO , and evaporated under reduced pressure.
2
2
4
The residue was purified by flash chromatography over Silica Gel 60N (hexane-EtOAc=1:1~EtOAc).
The results were shown in Table 1.
(
+)-2-Hydroxymethyl-1’,2’,3’,4’,5’-pentamethyl-3,4-diphenylazaferrocene (17)
According to the general procedure, azaferrocene (9) and paraformaldehyde were reacted under the
conditions shown in Table 1, entry 2, to give 17 as orange semisolid (114 mg, 74%). HPLC (Daicel
–1
1
Chiralpak AD, hexane–i-PrOH=1:1): 78% ee. IR (KBr): 3208, 1602, 1507, 1019, 763, 700 cm ; H
NMR (400 MHz, C D ): δ 1.63 (s, 15H), 4.48 (br s, 1H), 4.84 (dd, J= 7.3 and 12.6 Hz, 1H), 4.97 (dd, J=
6
6
2
D
4
4
.3 and 12.6 Hz, 1H), 5.18 (s, 1H), 6.95-7.23 (m, 8H), 7.62-7.66 (m, 2H). ["] +252 (c 0.167,
+
benzene). HREIMS m/z. Calcd for C H FeNO (M ): 439.1599. Found: 439.1594.
27
29
1
’-(2-Hydroxyethyl)-2’,3’,4’,5’-tetramethyl-3,4-diphenylazaferrocene (22)
According to the general procedure, azaferrocene (9) and paraformaldehyde were under the conditions
shown in Table 1, entry 9, to give 22 as orange semisolid (123 mg, 80%). IR (KBr): 3245, 1601, 1452,
–
1
1
1
3
049, 764, 699 cm ; H NMR (400 MHz, C D ): δ 1.27 (s, 6H), 1.80 (s, 6H), 2.15 (t, J= 4.9 Hz, 2H),
6 6
.88-3.97 (m, 2H), 5.22 (s, 2H), 5.76 (br s, 1H), 7.02-7.26 (m, 8H), 7.36 (d, J= 6.7 Hz, 2H). HREIMS
+
m/z. Calcd for C H FeNO (M ): 439.1599. Found: 439.1589.
2
7
29
Enantioselective C-2 functionalization of azaferrocene (9). General procedure

1246
HETEROCYCLES, Vol. 76, No. 2, 2008
Under an argon atmosphere, azaferrocene (9) (143 mg, 0.350 mmol) and (–)-sparteine (2) (140 mg, 0.595
mmol) were dissolved in Et O (10 mL) and the mixture was cooled to –78 °C. A hexane-cyclohexane
2
solution of sec-BuLi (0.525 mmol) was added dropwise to the mixture at –78 °C. After being stirred for
1
h, a mixture of an appropriate electrophile (0.700 mmol) in Et O (2.0 mL) was added dropwise to the
2
mixture at –78 °C. After being stirred for 0.5 h, the mixture was allowed to warm to 0 °C and stirred for
an additional 0.5 h. The reaction mixture was quenched with water and the products were extracted with
Et O. The extract was washed with brine, dried over Na SO , and evaporated under reduced pressure.
2
2
4
The residue was purified by flash chromatography over Silica Gel 60N using the following eluents:
hexane-EtOAc=3:1 for 23a, 23b, and 23c; hexane-EtOAc=5:1 for 23d. The results were shown in Table
2
.
(
+)-2-Iodo-1’,2’,3’,4’,5’-pentamethyl-3,4-diphenylazaferrocene (23a)
According to the general procedure, iodine (178 mg, 0.700 mmol) was reacted to give 23a as orange solid
(
158 mg, 84%). HPLC (Daicel Chiralpak AD, hexane–i-PrOH=9:1): 79% ee. IR (KBr): 1601, 1505,
–
1 1
1
3
378, 1202, 888, 766, 700 cm ; H NMR (400 MHz, C D ): δ 1.62 (s, 15H), 5.31 (s, 1H), 6.92-6.96 (m,
6 6
2
5
H), 7.05-7.20 (m, 5H), 7.50 (d, J= 7.0 Hz, 2H). ["] +82.7 (c 0.167, benzene). HREIMS m/z. Calcd
D
+
for C H FeIN (M ): 535.0459. Found: 535.0439.
26
26
(
+)-1’,2’,3’,4’,5’-Pentamethyl-3,4-diphenyl-2-(trimethylsilyl)azaferrocene (23b)
According to the general procedure, chlorotrimethylsilane (88.8 µL, 0.700 mmol) was reacted to give 23b
as orange oil (103 mg, 61%). HPLC (Daicel Chiralpak AD, hexane–i-PrOH=100:1): 75% ee. IR
–
1 1
(
KBr): 1603, 1245, 840, 766, 699 cm ; H NMR (400 MHz, C D ): δ 0.31 (s, 9H), 1.69 (s, 15H), 5.64 (s,
6 6
2
D
4
1
H), 6.92-6.99 (m, 3H), 7.04-7.20 (m, 5H), 7.55 (d, J= 7.0 Hz, 2H). ["] +364 (c 0.167, benzene).
+
HREIMS m/z. Calcd for C H FeNSi (M ): 481.1888. Found: 481.1888.
29
35
(
+)-2-Diphenylphosphino-1’,2’,3’,4’,5’-pentamethyl-3,4-diphenylazaferrocene (23c)
According to the general procedure, chlorodiphenylphosphine (126 µL, 0.700 mmol) was reacted to give
3c as orange oil (81.8 mg, 39%). HPLC (Daicel Chiralpak AD, hexane–i-PrOH=100:1): 77% ee. IR
2
–
1 1
(
KBr): 1602, 1479, 1434, 1028, 765, 741, 696 cm ; H NMR (400 MHz, C D ): δ 1.54 (s, 15H), 5.67 (s,
6 6
1
2
5
H), 6.70-6.82 (m, 3H), 6.93-7.01 (m, 4H), 7.06-7.26 (m, 9H), 7.77 (d, J= 7.5 Hz, 2H), 8.39 (t, J= 8.1 Hz,
2
D
5
+
H). ["] +154 (c 0.167, benzene). HREIMS m/z. Calcd for C H FeNP (M ): 593.1935. Found:
38 36
93.1922.
(
+)-1’,2’,3’,4’,5’-Pentamethyl-3,4-diphenyl-2-(phenylthio)azaferrocene (23d)

HETEROCYCLES, Vol. 76, No. 2, 2008
1247
According to the general procedure, diphenyl disulfide (153 mg, 0.700 mmol) was reacted to give 23d as
orange oil (160 mg, 88%). HPLC (Daicel Chiralpak AD, hexane–i-PrOH=100:1): 76% ee. IR (KBr):
–
1 1
1
3
478, 1027, 766, 738, 697 cm ; H NMR (400 MHz, C D ): δ 1.72 (s, 15H), 5.50 (s, 1H), 6.64-6.80 (m,
6 6
2
5
H), 6.90-7.20 (m, 10H), 7.64 (d, J= 6.8 Hz, 2H). ["] +172 (c 0.167, benzene). HREIMS m/z.
D
+
Calcd for C H FeNS (M ): 517.1527. Found: 517.1537.
32
31
ACKNOWLEDGEMENTS
One of the authors (T.F.) acknowledges the Ministry of Education, Culture, Sports, Science and
Technology of Japan for financial support; Grant-in-Aid for Young Scientists (B) (No. 16750084).
The authors also thank Dr. Hiroshi Furuno for X-ray structural analysis of racemic azaferrocene (17).
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