(-)-Sparteine-mediated stereoselective directed ortho metalation of ferrocene diamides

Article abstract of DOI:10.1139/V06-008

The utility of (-)-sparteine-mediated directed ortho metalation (DoM) has been investigated in stereoselective preparation of planar chiral ferrocenes derived from 1,1′-N,N,N′,N′- tetraisopropylferrocenedicarboxamide (5). In the synthesis of C ₂-symmetric analogs of 5, the protocol (base, solvent, and two-step DoM) was found to be crucial for obtaining high enantio- and diastereo-selectivities of the products. A variety of highly enantioenriched mono and doubly functionalized derivatives of 5 have been synthesized. The synthetic applications of these compounds as chiral ligands in asymmetric alkylation of aldehydes and asymmetric palladium-catalyzed allylic substitutions have been demonstrated.

Full text of DOI:10.1139/V06-008

356
(–)-Sparteine-mediated stereoselective directed
ortho metalation of ferrocene diamides1
Radoslaw Laufer, Ulrich Veith, Nicholas J. Taylor, and Victor Snieckus
Abstract: The utility of (–)-sparteine-mediated directed ortho metalation (DoM) has been investigated in stereoselective
preparation of planar chiral ferrocenes derived from 1,1′-N,N,N′,N′-tetraisopropylferrocenedicarboxamide (5). In the
synthesis of C2-symmetric analogs of 5, the protocol (base, solvent, and two-step DoM) was found to be crucial for
obtaining high enantio- and diastereo-selectivities of the products. A variety of highly enantioenriched mono and dou-
bly functionalized derivatives of 5 have been synthesized. The synthetic applications of these compounds as chiral lig-
ands in asymmetric alkylation of aldehydes and asymmetric palladium-catalyzed allylic substitutions have been
demonstrated.
Key words: directed ortho metalation, stereoselective deprotonation, ferrocene ligands, asymmetric catalysis.
Résumé : On a étudié l’utilité de l’ortho métallation dirigée (oMD) orientée par la (–)-spartéine, dans la préparation
stéréosélective de ferrocènes chiraux planaires dérivés du 1,1′-N,N,N′,N′-tétraisopropylferrocènedicarboxamide (5).
Dans la synthèse d’analogues de symétrie C2 du composé 5, on a trouvé que le protocole expérimental (base, solvant et
oMD en deux étapes) est crucial si on veut obtenir des valeurs élevées d’énantio- et de diastéréo-sélectivités des pro-
duits. On a pu synthétiser avec un degré d’énantioenrichissement élevé une grande variété de dérivés du composé 5
mono- et di-fonctionnalisés avec un degré d’énantioenrichissement élevé. On a démontré l’utilité synthétique de ces
composés, en particulier comme ligands chiraux dans l’alkylation asymétrique d’aldéhydes et dans les substitutions al-
lyliques asymétriques catalysées par le palladiium.
Mots clés : ortho métallation dirigée, déprotonation stéréosélective, ligands ferrocènes, catalyse asymétrique.
[Traduit par la Rédaction] Laufer et al. 369
The disclosure, with an interesting socio-chemical history,
tion (DoM) and subsequent reaction with electrophiles and
which relies on a chiral auxiliary directed metalation group
(DMG) for the central to planar chirality transfer. Following
these pioneering studies, Kagan and co-workers (10) demon-
strated a high diastereoselective DoM reaction using chiral
sulfoxide DMGs, which was followed by rapid accumulation
of reports using other DMGs, providing convincing evidence
for the generality of the diastereoinduction process (11, 12)
(Scheme 1).
In 1996, stimulated by the results of Hoppe and Hense
(13) and Beak et al. (14), we reported on the highly enantio-
selective synthesis of planar chiral ferrocenecarboxamides
1a → 2a by (–)-sparteine-mediated DoM chemistry (Scheme 2)
(15). This constituted the first general and direct synthetic
method to enantiomerically pure ferrocenyls that avoids sub-
strate-specific resolution (9a, 16) and chiral auxiliary intro-
duction and removal (10, 17). In subsequent work, we
addressed a limitation of the diethyl amide DMG of “seldom
allow(ing) functional group modification” (10b) by introduc-
ing the N-cumyl-N-ethylferrocenecarboxamide (1b), which
behaved equally well in sparteine-mediated DoM chemistry
to afford planar chiral ferrocenes in high yields and % ee,
and served, after mild decumylation, as convenient syntheses
of optically active Ugi amines, little-known esters, and new
phosphines (18). Another limitation, “the disadvantage of the
(availability of a) single enantiomeric form of (–)-sparteine”
(19) was addressed by showing that 2-TMS-N-ethylferro-
cenecarboxamide (3, E = TMS) undergoes C-5 rather than
C-1′ deprotonation and thereby allows a latent silicon protec-
of the correct structure of ferrocene over half a century ago
constituted a landmark achievement that heralded an entirely
new theme of organometallic chemistry (1). The continuing
significance of the field of ferrocene chemistry (2) is attested
by research in areas of asymmetric catalysis (3, 4), enantio-
selective synthesis (2, 5), diverse material science (2), and
biological (6) areas and, most spectacularly, industrial appli-
cations (7). Shortly after the excellent summary of the field
by SchlÅgl (8), Ugi and co-workers (9) reported the effective
preparation of optically active planar chiral ferrocenes,
which proceeds by diastereoselective directed ortho metala-
Received 10 August 2005. Published on the NRC Research
Press Web site at http://canjchem.nrc.ca on 30 March 2006.
Dedicated to friend and former colleague, Arthur Carty, in
recognition of his forefront and continuing contributions to
organometallic chemistry and chemistry in Canada, and for
early fruitful collaboration in diazepine irontricarbonyl
chemistry.
R. Laufer, U. Veith, N.J. Taylor, and V. Snieckus.2,3
Department of Chemistry, University of Waterloo, Waterloo,
ON N2L 3G1, Canada.
1This article is part of a Special Issue dedicated to Professor
Arthur Carty.
2Present address: Department of Chemistry, Queen’s
University, Kingston, ON KL7 3N6, Canada.
3Corresponding author (e-mail: snieckus@chem.queensu.ca).
Can. J. Chem. 84: 356–369 (2006)
doi:10.1139/V06-008
© 2006 NRC Canada

Laufer et al.
357
Scheme 1.
E
DMG
DMG
DMG
1. RLi
2. E+
E
Fe
Fe
Fe
A
B
O
O
(98%)10b
OMe
(92%)9a
(96%)10a
S
DMG (dr %) =
NMe2
O
t-Bu
O
R
(R = Ph: 98%;17a R = t-Bu:94%;17b R = i-Pr 95%17c);
N
Ph
Ph
(98%)11b
(90-96%)11a
N
N
Me
N
OMe
OMe
E
Scheme 2.
1. n-BuLi / (–)-sparteine
Et2O or Et2O-PhMe / -78 oC
2. E+
CONR1R2
CONR1R2
Fe
Fe
1a R1,R2 = i-Pr
2a (45%-96% yld, 81%-99% ee)
2b (69%-89% yld, 88% -96% ee)
1b R1= Et, R2 = C(Me)2Ph
(E = TMS)
E
CONHEt
CONHEt
1. n-BuLi / TMEDA
CF3CH2OH
I
Fe
Fe
THF / -78 oC
2. I2
on 2b
(61%-99% yld)
3
4
3. TBAF
(29% yld)
b
F-
TMS
CONHEt
Fe
BuLi / E+
a
"Silicon trick"
tion route (4, 20, 21) to the valuable enantiomeric ferrocene
(S) series (Scheme 2).
ferrocenyldiamide 5 in Et2O using chlorotrimethylsilane
(TMSCl) as the electrophilic partner. Only later, we discov-
ered that application of TMSCl led to exceptional results. As
gleaned from the results in Table 1, use of more than
2 equiv. of both n-BuLi and (–)-sparteine led to effective
electrophilic trapping of doubly deprotonated 5 (Table 1, en-
tries 2 and 3) in very good yields, however, with unsatisfac-
tory levels of both diastereoselectivity (dr meso:dl, 2:1, 7a:
E = TMS) and optical activity (54% optical purity).4 Appli-
cation of s-BuLi and (–)-sparteine allowed for quantitative
conversions of 5 into 7a (Table 1, entry 5), but the reaction
As part of efforts to expand the scope of the (–)-sparteine-
mediated enantioinduction of planar chirality, we recently
reported (22) on the synthesis of highly enantioenriched
mono- and double-functionalized derivatives of ferrocenyl
1,1′-bisamides, 6 and 7 (Scheme 3) by combined DoM–Pd-
catalyzed Suzuki–Miyaura and Stille cross-coupling reac-
tions (23). Herein we present the full details of our studies.
At the outset of our initial investigation, we attempted to
establish the optimal reaction conditions for DoM of
4 Neither ( )-6a nor ( )-7a could be resolved on chiral HPLC. The requisite homochiral crystals of (+)-7a were obtained by recrystallizations
of the enantioenriched 7a from hexanes.
© 2006 NRC Canada

358
Can. J. Chem. Vol. 84, 2006
Table 1. Metalation of 1,1′-ferrocenyldiamide 5 in Et2O (E+ = TMSCl).
Yield (%)
No.
Base
Equiv.
6a
7a
7a dra dl:meso
Opb (dl-7a)
1
2
3
4
5
6
n-BuLi–(–)-sparteine
n-BuLi–(–)-sparteine
n-BuLi–(–)-sparteine
n-BuLi–TMEDA
s-BuLi–(–)-sparteine
s-BuLi–TMEDA
2.1
3.1
4.2
4.2
4.2
4.2
10
3
Trace
38
—
Trace
88
87
46
99
46:54
30:70
37:63
49:51
4:96
—
54
—
—
15
—
—
99
25:75
Note: Conditions: RLi–(–)-sparteine or TMEDA; Et2O at –78 °C for 2 h then excess TMSCl; –78 °C → rt.
aDetermined by GC analysis of crude reaction mixtures.
bOp (optical purity); homochiral 7a: [α]23 +49.2° (c 0.24, CHCl3).
578
Scheme 3.
Table 2. Monometalation of 5 in Et2O (base is n-BuLi).
E
1. RLi / (–)-sparteine
PhMe / -78 oC
2. E+
No.
E+
Product (E)
Yield (%)
ee (%)
CON(i-Pr)2
CON(i-Pr)2
CON(i-Pr)2
1
2
MeI
I2
6b (Me)
6c (I)
56
53
68
59
Fe
Fe
CON(i-Pr)2
(45%-92%, 71%-97% ee)
3
Ph2C=O
6d (Ph2C-OH)
77
64
6
5
Note: Conditions: 4.2 equiv. n-BuLi–(–)-sparteine; Et2O; –78 °C for 2 h
then 6 equiv. E+, –78 °C → rt for 4 h.
E
1. RLi / (–)-sparteine
PhMe / -78 oC
2. E+
CON(i-Pr)2
CON(i-Pr)2
Fe
low enantioinductions was observed with a number of
different electrophiles (Table 3). Under these reaction condi-
tions, monocarbinol 6d was isolated as the only product in
low yield and low enantiomeric excess (Table 3, entry 6).
Interestingly, unlike 2,2′-bis(diphenylphosphine) (7c), which
was obtained in respectable yield either directly from 5 uti-
lizing s-BuLi (Table 3, entry 5) or stepwise, with n-BuLi via
6g (vide infra, Table 4), all attempts to prepare the 2,2′-
bis(diphenylhydroxymethyl) derivative by DoM of 5 or
monocarbinol 6d were unsuccessful.
E
(45%-75%, 91%-97% ee)
dl-7
exhibited prohibitively strong preference for the meso
diastereomer and very low optical induction for dl-7a (15%
optical purity). Interestingly, in all cases DoM-
trimethylsilylation of 5 utilizing n-BuLi or s-BuLi together
with TMEDA led to modestly (Table 1, entries 3 vs. 4 and 5
vs. 6) improved contents of racemic dl-7a.
Gratifyingly, use of solvents of lower coordinating abili-
ties (Table 5, entries 1–3) allowed the preparation of 1,1′,2-
trisubstituted derivatives (6b–6i) in augmented optical and
chemical yields. Toluene was found to give the optimal bal-
ance between the level of enantioinduction and chemical
yield, e.g., the diphenylphosphine derivative 6g was obtained
in 53% yield and 97% ee without a recrystallization (Ta-
ble 5, entry 9). Interestingly, the opposite solvent effect on
the entantioselectivty of (–)-sparteine-assisted DoM was
observed in applications of N,N-diisopropylferrocenylcar-
boxamide (15). Reduction of the amount of n-BuLi–(–)-
sparteine to 2.2 equiv. caused a slight decline in the chemi-
cal yield of the product 6d (Table 5, entry 5 vs. 6), but did
not lead to the erosion of ee. Again, utilization of TMSCl as
the electrophile afforded 2,2′-disilylated product 7a as the
major product (71% yield, dr dl:meso, 3:1, 97% optical pu-
rity) when 4.2 equiv. of base was used (Table 5, entry 12).
Lesser amount of the base (2.2 equiv.) resulted in formation
of the monosilylated 6a as the major product with 7a iso-
lated as a minor component (16% yield, dr dl:meso, 68:32,
99% optical purity) (Table 5, entry 13).
For electrophilies other than TMSCl, the reactions of 1,1′-
ferrocenyldiamide (5) with 4.2 equiv. of n-BuLi–(–)-
sparteine in Et2O at –78 °C are markedly different. As illus-
trated in Table 2, the protocol furnished, almost exclusively,
products from electrophilic trapping of monolithium anion
in good yields but with moderate enantioselectivities. At
present, the high yields for the double DoM of 5 in the reac-
tions involving TMSCl are difficult to rationalize. Related
reactions, involving deprotonation of hindered lithium
dialkylamides and in situ TMSCl as the electrophilic trap,
have been shown to give superior yields and stereo-
selectivities. Effects of the in situ generated LiCl has been
suggested as the causative agent (24). Despite the apparent
incompatibility of n-BuLi with TMSCl, we have observed a
modest LiCl effect on DoM of 5. Under unchanged reaction
conditions, DoM of 5 with 4.2 equiv. of n-BuLi–(–)-
sparteine in the presence of 2.0 equiv. of LiCl followed by a
quench with an excess of MeI led to improved yields and
greatly enhanced stereoselectivities for both the mono-6b
(61% yield, 79% ee vs. Table 2, entry 1) and dimethylated
7b. Compound 7b was obtained in 16% yield (3:1 dr
dl:meso, 80% ee), compared with only trace amounts ob-
served under LiCl-free conditions.
The enantiomeric excess for stannane 6f (Table 5, entry 8)
was determined by its transformation into carbinol 6d in a
sequence involving a lithiodestannylation–benzophenone
quench. Under these unoptimized conditions, the relatively
lower ee of 6d (82% ee) derived from 6f may be the result
of partial racemization, occurring via an intermolecular Li-H
Although double DoM–electrophile quench was effected
much more efficiently with s-BuLi–(–)-sparteine, the same
general trend for the unfavorable diastereoselectivities and
© 2006 NRC Canada

Laufer et al.
Table 3. Double DoM of 5 in Et2O using s-BuLi and TMEDA or (–)-sparteine.
359
No.
E+
Diamine
Product (E)
Yield (%)a
dl-7:meso-7
ee (%)
1
2
3
4
5
MeI
MeI
TMSCl
TMSCl
PPh2Cl
(–)-Sparteine
TMEDA
(–)-Sparteine
TMEDA
7b (Me)
7b
7a (TMS)
7a
70
19
99
99
49
24:76b
21:79b
4:96c
53b
—
15d
—
25:75c
<5:>95e
(–)-Sparteine
7c (PPh2)
—
32b
6
7
Ph2C=O
(–)-Sparteine
6d (Ph2C-OH)
7d (PhS)
36 f
NA
31:69b
Ph2S2
TMEDA
51
—
Note: Conditions: 4.2 equiv. s-BuLi–(–)-sparteine or TMEDA; Et2O at –78 °C for 2 h then 6 equiv. E+ at –78 °C → rt for 4 h.
aCombined yields.
bDetermined by chiral HPLC.
cDetermined by GC analysis of crude reaction mixtures.
dAs optical purity.
eDetermined by 31P NMR.
fOnly the mono derivative 6d was isolated.
Table 4. n-BuLi–(–)-sparteine-induced monometalation of 2-substituted derivatives, 6a, 6g, and 6h.
(SM) ee (%)
E+
Product
Yield (%)
dl:meso
ee (%)
TMSCla
TMSCld
Ph2PCle
7a
7a
7c
86
75
45
72b
91b
98b
51:49
84:16
(6a) 0
(6a) —c
(6g) 97
>95:<5 f
99:1g
97g
a
(6h) 89
(PhS)2
7d
60
a2.1 equiv. of n-BuLi–(–)-sparteine were used.
bDetermined as optical purity.
c[α]23 +67.5° (c 0.54, CHCl3).
578
d4.2 equiv. of n-BuLi–(–)-sparteine were used.
e1.5 equiv. of n-BuLi–(–)-sparteine were used.
fDetermined by 31P NMR.
gDetermined by chiral HPLC.
exchange. The heteroatom-tethered phenyl derivatives
(thioether, diphenylphosphine, and phenylselenide) 6g–6i
(Table 5, entries 9–11) were found to surrender their optical
integrity on standing in solution. For example, 2-
(phenylthio)-1,1′-ferrocenediamide derivative 6h undergoes
racemization in a mixture of hexanes and i-PrOH at a faster
rate (t1/2 ≈ 9 h) (25) compared with the corresponding deriv-
ative of N,N-diisopropylferrocenylcarboxamide (t1/2 ≈ 24 h)
(15). Noteworthy is the fact that the solution of C2-symmetric
analog, chiral 2,2′-bis(diphenylthio)-1,1′-ferrocenediamide
(7d), exhibited a very low tendency towards isomerization
losing ~30% ee and de on standing at room temperature (rt)
for 19 days (25).
Highly diastereo- and enantio-enriched, tetrasubstituted
ferrocenyldiamides dl-7 were prepared by subjecting 1,2,1′-
trisubstituted ferrocenes 6 to a further asymmetric DoM (Ta-
ble 4). This constituted the first reported preparation of C2-
symmetric ferrocenes outfitted exclusively with the element
of planar chirality (26). Quench with electrophiles furnished
products 7a, 7c, and 7d with diastereoselective amplification
of enantioselectivity as demonstrated by converting 6h (89%
ee) into optically active, 2,2′-bis(diphenylthio)-1,1′-ferro-
cenediamide (7d, 97% ee, 99:1 dl:meso) (27).
To demonstrate the combined potential of DoM-cross cou-
pling strategy (28) as a route to aryl-substituted ferrocenes,
the iodo (6c) and stannane (6f) ferrocenediamides were sub-
jected to Suzuki–Miyaura and Gronowitz-modified Stille
(29) cross-coupling conditions (Scheme 4). Thus, the reac-
tion of 6c (89% ee) with (2,4-dimethoxyphenyl)boronic acid
afforded the aryl derivatives 6k in a modest yield (20%
yield, 89% ee) together with recovered 6c (70% yield). Pal-
ladium coupling of 6f and bromobenzene led to a formation
of 6l (35% yield) along with destannylated product 5 (51%
yield).
X-ray crystallographic analysis of
compounds 7a and 6d
The (S) absolute configuration (8), established by single
crystal X-ray crystallography analysis of carbinol 6d
(Fig. 1),5 was provisionally assigned to all of the 2-
substituted ferrocenediamides 6a–6l. This is the same sense
of enantioinduction as previously seen in (–)-sparteine-
assisted DoM of N-cumyl-N-ethyl and N,N-diisolpropyl
ferrocenyl monoamides (15, 18). The (R,R) absolute config-
uration of the C2-symmetric derivatives of 5 (7a, 7c, and 7d,
5 Supplementary data for this article are available on the journal Web site (http://canjchem.nrc.ca) or may be purchased from the Depository
of Unpublished Data, Document Delivery, CISTI, National Research Council Canada, Ottawa, ON K1A 0R6, Canada. DUD 5008. For more
information on obtaining material refer to http://cisti-icist.nrc-cnrc.gc.ca/irm/unpub_e.shtml. CCDC 295149 and 602324 contain the crystal-
lographic data for this manuscript. These data can be obtained, free of charge, via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the
Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax +44 1223 336033; or deposit@ccdc.cam.ac.uk).
© 2006 NRC Canada

360
Can. J. Chem. Vol. 84, 2006
Table 5. n-BuLi–(–)-sparteine-induced monolithiation of 5.
No.
E+
Product (E)
Solvent
Yield (%)
ee (%)
1
2
3
4
5
59
70
89
92
94
I2
I2
I2
MeI
6c (I)
6c
6c
6b (Me)
6d (Ph2C-OH)
Et2O
53
77
70
71
92
72a
45
58
53
71
82
t-BuOMe
PhMe
PhMe
PhMe
Ph2C=O
6
7
Ph2C=O
Et2C=O
Bu3SnCl
Ph2PCl
(PhS)2
6d
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
96
6e (Et2C-OH)
6f (Bu3Sn)
6g (Ph2P)
6h (PhS)
6i (PhSe)
91
8
≥82b
97c
89c
71c
9
10
11
(PhSe)2
d
12
13
TMSCl
TMSCl
6a (TMS)
6a
PhMe
PhMe
16
68a
—
—
e
Note: Conditions: 4.2 equiv. s-BuLi–(–)-sparteine, solvent at –78 °C for 2 h then 6 equiv. E+ at –78 °C → rt for 4 h.
a2.1 equiv. of both n-BuLi and (–)-sparteine were used.
bee was determined after conversion into 6d (1, n-BuLi; 2, Ph2C=O).
cee determination was carried out immediately after purification.
d[α]23 +64.3° (c 0.11, CHCl3); 7a was also isolated in 71% yield (dr dl:meso, 72:28); 97% optical purity.
578
e[α]23 +67.5° (c 0.54, CHCl3); also 7a was isolated in 16% yield (dr dl:meso, 68:32); 99% optical purity.
578
Scheme 4.
X
Ar
CON(i-Pr)2
CON(i-Pr)2
CON(i-Pr)2
CON(i-Pr)2
Pd / ArY
Fe
Fe
Method A or B
6c X = I (89% ee)
6k Ar =2,4-(MeO)2C6H3 (89% ee)
6l Ar = Ph
6f X = n-Bu3Sn (≥82% ee)
Methods: A. on 6c: 2,4-(MeO)2C6H3B(OH)2 / Pd(PPh3)4 / 2 mol/L aq. Na2CO3 /
DME / 85 °C / 5 d (20% yld)
B. on 6f: PhBr / PdCl2(dppf) / CuO / DMF /150 °C / 18 h (35% yld)
Table 4) must be derived from (R) stereochemistry of the
corresponding chiral precursors (6a, 6g, and 6h). The forma-
tion of meso-7 products necessitates that the second
deprotonation occurs with the opposite stereoselectivity,
which may be the result of a cooperative effect of the two
DMGs.
In the crystal structure of 6d, the Cp rings are almost
eclipsed with respect to each other, deviating by 14.0° from
a fully eclipsed conformation. A hydrogen bond between the
carbonyl group of carboxamide and the proximal hydroxyl
group (O16—H16, 1.94 Å) is evident. Presumably, owing to
packing effects, the two carboxylamides remain in a relative
proximity.
phino)-2,2′-ferrocenyldiamide (7c, 98% ee) was tested as an
auxiliary ligand for enantioselective Pd-catalyzed allylic
substitution of ( )-phenylcinnamyl acetate (Scheme 5) (30).
The reactions were conducted using palladium allyl chlo-
ride dimer (2.5 mol%) as the Pd source utilizing the Trost
alkylation conditions (31) or sodiodimethylmalonate. In both
cases, alkylated product 8 was obtained in essentially quanti-
tative yield and with good enantiocontrol (96% yield, 84%
ee (R)). The enantiomeric excess was determined by chiral
HPLC and the absolute configuration of the product was as-
signed by comparison of the optical rotation with literature
values (32).
In an additional classic test for enantioinduction, the
1,1′,2-ferrocenyldiamides (6d, 6e, and 6k) were shown to
exhibit moderate to good catalytic activities in the reaction
of diethylzinc with benzaldehyde (Scheme 6, Table 6) (33).
Thus, in a typical reaction, a stirred solution of
benzaldehyde (1 mmol) and chiral additive (6d, 6e, 6k)
(5 mol%) in either hexane or PhMe under argon, was treated
with diethylzinc (1.6 equiv.) and the resultant mixture was
stirred at rt for 48–72 h. The crude product was analyzed by
chiral HPLC, purified by flash chromatography, and the ab-
solute configuration was determined by a comparison of its
Compound meso-7a proved amenable to X-ray analysis
and its crystal structure is shown in Fig. 1.5 The center of in-
version structure entails the staggered conformation for both
Cp rings with minimum interactions among the four sub-
stituents.
Applications of the ferrocenediamides
In an initial study of utility the new planar chiral
ferrocenes in asymmetric synthesis, 1,1′-bis(diphenylphos-
© 2006 NRC Canada

Laufer et al.
361
Fig. 1. X-ray crystallographic structures of 6d and meso-7a.
Scheme 5.
MeO2C
Ph
CO2Me
Ph
OAc
Ph
2.5 mol% [Pd(η3-C3H5)Cl]2
10 mol% 7c (98% ee)
Conditions A or B
+ -CH(CO2Me)2
Ph
8 84% ee
Conditions:
A. N,O-bis(trimethylsilyl)acetamide / AcOK / CH2(CO2Me)2 / CH2Cl2 / rt / 10 h
B. NaCH(CO2Me)2 / THF / rt / 36 h
Scheme 6.
Z
CON(i-Pr)2
OH
*
O
Fe
CON(i-Pr)2
6d,6e,6k
1.5 mol%
Et
H
+
Et2Zn
solvent / rt / 2 to 3 days
2. HCl / H2O
9 (S) or (R)
up to 90% ee
optical rotation with the literature values (34). The results
are summarized in Table 6. Ethylations of benzaldehyde in
hexanes catalyzed by carbinols 6d and 6e proceed with the
same degree of enantioinduction; however, for 6e, the chem-
ical yield is greatly diminished, presumably as a conse-
quence of the lower solubility of the catalyst (Table 6,
entries 1 and 4). Quite unusual and, to our knowledge, previ-
ously unobserved, is the variation in the enantiotopicity of
the reaction as a function of the solvent (Table 6, entry 1 vs.
entry 2) and use of lithium salt of carbinol 6d (Table 6, en-
try 2 vs. entry 3). The lithium salt of the 6d-catalyzed reac-
tion proceeded in PhMe with greater optical efficiency (47%
ee) than the free carbinol 6d (12% ee) and with a reversal of
enantioselection (Table 6, entries 2 and 3). The best optical
yield (90% ee) was observed for a nonprotic ligand 6k (Ta-
ble 6, entry 5). Attempts to lower the temperature of the pro-
cess led to prohibitively long reaction times. These
variations in the entantiotopiciy of the reaction are currently
not understood.
In summary, direct and highly efficient enantioselective
syntheses of mono- (6a–6i) and C2-symmetric, homoleptic
(7a, 7c, and 7d) ferrocene diamides from achiral ferrocenyl-
dicarboxamide 5 using (–)-sparteine-mediated DoM and
combined DoM-cross coupling (6k, and 6l) have been dem-
onstrated. The preliminary encouraging results in asymmet-
ric synthesis and the current intense activity in ferrocene-
© 2006 NRC Canada

362
Can. J. Chem. Vol. 84, 2006
Table 6. 2-Substituted derivatives (6d, 6e, 6k) (catalyzed Et2Zn addition to PhCHO).
No.
Z
Ligand (ee, %)
Solvent
Yield (%)
ee (%)a
1
2
3
4
5
Ph2C(OH)
6d (96)
6d (96)
6d·Li (95)
6e (90)
Hexanes
PhMe
98
98
70
37
43
61 (S)
12 (R)
47 (S)b
60 (S)
90 (S)
Ph2C(OH)
Ph2C(OLi)
Et2C(OH)
PhMe
Hexanes
2,4-(MeO)2C6H3
6k (89)
PhMe
aDetermined on a Chiracel OD column and compared to racemic material.
b[α]23 –21.7° (c 3.43, CHCl3).
D
based catalysis (4, 35) may stimulate continuing efforts in
the design, synthesis, and application of similar planar chiral
ferrocenyl ligands.
with Et2O, washing the organic extracts (brine), drying
(MgSO4), filtration, and concentration under reduced pres-
sure. Flash column chromatography was carried out using
Merck silica gel 60 (0.040–0.063 mm).
Experimental section
Standard methods
General procedures
(A) Lithiation of 1,1′-N,N,N′,N′-tetraisopropylferrocenedi-
carboxamide (5)
Melting points were determined on a Buchi SMP-20 or a
Fisher hot stage melting point apparatus and were uncor-
rected. IR spectra were recorded on a BOMEM MB-100 and
PerkinElmer 1600 FT-IR spectrophotometer as either neat
A solution of (–)-sparteine (0.91 mL, 4.20 mmol) or
TMEDA (0.64 mL, 4.20 mmol) in PhMe or Et2O (20 mL)
under Ar was stirred at rt (5 min), cooled to –78 °C, and
treated with either n-BuLi or s-BuLi (4.20 mmol). After stir-
ring (10 min) at –78 °C, a solution of 5 (0.44 g, 1.0 mmol)
in either PhMe (4.5 mL) or Et2O (10 mL) was added
dropwise (ca. 1 drop / 10 s). After stirring for 2 h at –78 °C,
the reaction mixture was quenched by an addition of
electrophile (6 mmol) and then allowed to warm to rt over
4 h. Standard workup afforded the crude product.
film, a CH2Cl2 solution, or a KBr pellet. H NMR and 13C
1
NMR spectra were recorded on either a Bruker AM-250 or
an AC-200 instrument with tetramethylsilane or CDCl3 as an
internal standard. 31P NMR spectra were recorded on an AC-
200 instrument with H3PO4 as an external standard.
Mass spectra (MS) were determined on a high-resolution
Varian MAT-CH7 instrument at 70 eV (Monsanto Co., St.
Louis, Missouri and Guelph Centre for Mass Spectrometry
Service, University of Waterloo Mass Spectrometry Service).
Elemental analyses were performed by Chemisar Labora-
tories, Guelph, Ontario. Stereoselectivities of the reactions
were determined using and a Waters HPLC system consist-
ing of a 600E multisolvent delivery system, a Waters 486
UV detector (λ = 254 nm), and a Waters 746 integrator/re-
corder. The columns used were: Chiralpak, Chiracel OD,
and Whelk-O1. Optical rotations were determined using a
PerkinElmer 241 polarimeter at λ = 578 or 589 nm at rt. All
dry solvents used were purified according to Perrin and
Armarego (36): THF and Et2O were freshly distilled from
sodium benzophenone ketyl under nitrogen prior to use. Hex-
ane and PhMe were distilled from CaH2 and Na, respec-
tively.
(B) Lithiation of 2-substituted derivatives of 1,1′-
N,N,N′,N′-tetraisopropylferrocenedicarboxamide (6a, 6g, 6h)
A solution of (–)-sparteine (0.45–0.91 mL, 2.1–4.2 mmol)
in PhMe (20 mL) under Ar was stirred at rt (5 min), cooled
to –78 °C, and treated with n-BuLi (4.2 mmol). After stir-
ring (10 min) at –78 °C, a solution of a 6 (1.0 mmol) in
PhMe (2.5 mL) was added slowly. After stirring for 2 h at
–78 °C, the reaction mixture was quenched by addition of
the electrophile (3.0–6.0 mmol), allowed to warm to rt over
4 h, and then subjected to standard workup to afford the
crude product.
Experimental procedures
n-BuLi and s-BuLi were purchased from Sigma-Aldrich
Chemical Co., as solutions in hexanes and cyclohexane, re-
spectively. They were stored in resealable containers and ti-
trated periodically against 2,5-dimethoxybenzyl alcohol (37)
or s-butanol-1,10-phenanthroline (38). N,N,N′,N′-Tetra-
methylenethylenediamine (TMEDA) and (–)-sparteine were
dried and distilled over CaH2 and stored under argon. All
commercial materials were purchased from Sigma-Aldrich
Chemical Co. or Lancaster Synthesis Ltd. Pd(PPh3)4 was
prepared following a literature procedure (39).
All the reactions were performed in oven-dried glassware
under argon, using syringe-septum cap techniques. The
–78 °C temperature designation is approximate and achieved
by a dry ice – acetone bath. The phrase “standard workup”
refers to addition of water or satd. aq. NH4Cl, extraction
1,1′-Ferrocenedicarboxylic acid
A solution of n-BuLi (72.2 mL, 1.66 mol/L solution in
hexane, 120 mmol) was added to a solution of ferrocene
(10.1 g, 53.7 mmol) and TMEDA (20.0 mL, 132 mmol) in
hexane (150 mL) under Ar at 0 °C. The reaction mixture
was stirred for 12 h at rt. The hexane supernatant solution
was removed via cannula and THF (150 mL) was added to
dissolve the precipitate. The resultant solution was cooled to
–78 °C and purged with carbon dioxide for 1 h. Later the re-
action mixture was allowed to warm to rt and treated with
H2O (50 mL). THF was removed under reduced pressure.
The aqueous residue was extracted with Et2O (2 × 100 mL)
and acidified with 2 N aq. HCl. The precipitate (bright yel-
low) was collected by filtration, dried in vacuo, and used
without further purification (10.6 g, 72%); mp > 300 °C
© 2006 NRC Canada

Laufer et al.
363
(dec). IR (KBr) νmax: 915, 1029, 1167, 1292, 1372, 1403,
as an orange solid (0.32 g, 71%); mp 123 to 124 °C. CSP
HPLC analysis (Chiralcel OD; eluent: n-hexane–i-PrOH–
Et2NH (99:1:0.01, flow 0.75 mL/min) determined 92% ee
1
1487, 1675, 2825 (br). H NMR (DMSO-d6) δ: 4.30 (s, 4H,
Cp-H), 4.78 (s, 4H, Cp-H), 10.75–11.60 (br, 2H, COOH).
13C NMR (DMSO-d6) δ: 71.2, 72.5, 73.4, 171.0. MS m/z (rel
intensity) (FAB): 274.2 (M+, 8), 257.1 (11), 231.2 (8).
HRMS calcd. for C12H1056FeO4: 273.9929; found: 273.9969.
(tR(major dl) = 26.95 min, tR(minor) = 29.35 min). [α]23
578
+63.2° (c 0.66, CHCl3). IR (KBr) νmax: 1025, 1044, 1111,
1137, 1157, 1204, 1316, 1372, 1453, 1615, 2954, 3001,
1
3086. H NMR (CDCl3) δ: 0.65–1.82 (br, 24H, CH(CH3)2)),
2.02 (s, 3H, CpCH3), 3.25–3.55 and 3.70–4.05 (br, 4H,
CH(CH3)2), 4.18 (m, 2H, Cp-H), 4.39 (m, 2H, Cp-H), 4.57
(m, 2H, Cp-H), 4.67 (br, 1H, Cp-H). 13C NMR (CDCl3) δ:
12.7, 20.1, 20.7, 20.9, 21.0, 45.3, 50.2, 67.8, 68.2, 70.8,
71.3, 71.4, 71.6, 72.0, 82.1, 85.1, 88.2, 169.2. MS m/z (rel
intensity) (EI): 454 (27), 426 (4), 169 (6). HRMS calcd. for
C25H3856FeN2O2: 454.2283; found: 454.2242.
1,1′-N,N,N′,N′-Tetraisopropylferrocenedicarboxamide (5)
To a stirred solution of 1,1′-ferrocenedicarboxylic acid
(10.0 g, 36.2 mmol) in PhMe (100 mL) at rt, DMF
(1.10 mL, 14.1 mmol) and oxalyl chloride (12.8 mL,
149 mmol) were added sequentially. The reaction mixture
was stirred for 1 h at rt before PhMe and the excess of
oxalyl chloride were removed under reduced pressure. The
residue was dissolved in Et2O (250 mL), cooled to 0 °C, and
treated with an excess of HN(i-Pr)2 (28.4 mL, 217 mmol).
The reaction mixture was stirred for 8–12 h at rt. Standard
workup followed by column chromatography (EtOAc–hex-
ane, 1:2) and crystallization gave 5 as an orange solid
(11.1 g, 80%); mp 133 to 134 °C (Et2O–hexane) (lit. value
(40) mp 127 to 128 °C). IR (KBr) νmax: 1000, 1050, 1105,
1162, 1198, 1225, 1289, 1377, 1458, 1561, 1684, 2803,
2957, 3091. 1H NMR (CDCl3) δ: 1.05–1.70 (br, 24H,
CH(CH3)2), 3.30–3.58, 4.35–4.55 (br, 2H, CH(CH3)2), 4.37
2-Iodo-1,1′-N,N,N′,N′-tetraisopropylferrocenedicar-
boxamide (6c)
According to Standard method A, a solution of (–)-
sparteine (0.97 mL, 4.20 mmol) and n-BuLi (2.47 mL,
1.70 mol/L solution in hexane, 4.20 mmol) was sequentially
treated with solutions of 5 (0.44 g, 1.0 mmol) and iodine
(1.52 g, 6.00 mmol) in PhMe (4.5 mL and 14 mL, respec-
tively). Standard workup followed by column chromatogra-
phy (EtOAc–hexane, 1:10) afforded 6c as a slowly
solidifying orange oil (0.37 g, 70%); mp 113–115 °C. CSP
HPLC analysis ((S,S)-Whelk-O1; eluent: n-hexane–i-PrOH
(96:4, flow 0.5 mL/min) determined 89% ee (tR(major) =
25.84 min, tR(minor) = 21.68 min). [α]23 +33.2 (c 0.47,
CHCl3). IR (neat) νmax: 807, 1037, 1206, 1D316, 1369, 1460,
(t, J = 2.0 Hz, 4H, C5H4), 4.58 (t, J = 2.0 Hz, 4H, C5H4). 13
C
NMR (CDCl3) δ: 21.0, 70.9, 71.3, 83.2, 167.1. MS m/z (rel
intensity) (EI): 440 (M+, 100), 340 (16), 312 (9), 270 (6),
248 (20), 213 (10), 186 (11), 177 (5), 156 (12), 146 (9), 121
(19), 92 (10), 65 (7). HRMS calcd. for C24H3654FeN2O2:
438.2169; found: 438.2173.
1
1635, 2931, 2966. H NMR (CDCl3) δ: 0.92–1.72 (m, 24H,
CH(CH3)2), 3.38–3.70 (m 4H, CH(CH3)2), 4.26–6.60 and
4.82–4.88 (m, 7H, CpH). 13C NMR (CDCl3) δ: 20.41, 20.54,
40.64, 45.6, 50.4, 68.9, 70.3, 72.8, 74.1, 74.7, 75.1, 83.7,
92.8, 165.6, 168.0. MS m/z (rel intensity) (EI): 566 (M+,
0.5), 502 (8), 414 (6), 219 (25), 131 (40), 69 (100). HRMS
calcd. for C24H3556FeIN2O2: 566.1092; found: 566.1103.
2-(Trimethylsilyl)-1,1′-N,N,N′,N′-tetraisopropylferrocenedi-
carboxamide (6a)
According to Standard method A, a solution of (–)-
sparteine (0.49 mL, 2.2 mmol) and n-BuLi (1.4 mL,
1.65 mol/L solution in hexane, 2.2 mmol) was sequentially
treated with a solution of 5 (0.47 g, 1.1 mmol) in PhMe and
TMSCl (0.34 mL, 2.7 mmol). Standard workup followed by
column chromatography (EtOAc–hexane, 1:30) afforded
compound 6a as an orange solid (0.42 g, 68%); mp 107.0–
2-(Diphenylhydroxymethyl)-1,1′-N,N,N′,N′-tetraisopropyl-
ferrocenedicarboxamide (6d)
107.5 °C (hexanes). [α]23
+67.5° (c 0.54, CHCl3). IR
(KBr) νmax: 2962, 2883, 1624, 1449, 1325, 1204, 1149,
Method 1
578
According to Standard method A, a solution of (–)-
sparteine (0.91 mL, 4.1 mmol) and n-BuLi (2.36 mL,
1.75 mol/L solution in hexane, 4.1 mmol) was sequentially
treated with solutions of 5 (0.433 g, 0.98 mmol) and benzo-
phenone (1.07 g, 5.90 mmol) in PhMe (4.5 mL and 10.0 mL,
respectively). Standard workup followed by column chroma-
tography (EtOAc–hexane, 1:15) afforded the title compound
(6d) as an orange solid (0.56 g, 92%); mp 179–182 °C
(Et2O). CSP HPLC analysis ((S,S)-Whelk-O1; eluent: n-hex-
ane–i-PrOH 92:8, flow 0.75 mL/min) determined 94% ee
1
1040, 829, 754. H NMR (CDCl3) δ: 0.23 (s, 9H, Si(CH3)3),
0.80–1.60 (br, 24H, CH(CH3)2)), 3.2–4.1 (br, 4H,
CH(CH3)2), 4.20, 4.38, 4.43, 4.49, 4.57, 4.67 (m, 7H, Cp-H).
13C NMR (CDCl3) δ: 0.5, 20.7, 21.2, 71.0, 72.03, 72.23,
75.7, 82.4, 93.5, 168.6. MS m/z (rel intensity) (EI): 512 (M+,
51), 510 (4), 497 (100), 439 (7), 220 (9), 149 (14), 73 (14).
HRMS calcd. for C27H4454FeN2O2Si: 510.2568; found:
510.2551. Two other isolated fractions contained dl-4a
(0.032g, 5%), [α]23578 +49.2° (c 0.49, CHCl3), 99% op (opti-
cal purity) and meso-4a (0.015 g, 2%).
(tR(major) = 12.06 min, tR(minor) = 15.15 min). [α]23
D
+161.1° (c 0.54, CHCl3). IR (KBr) νmax: 704, 752, 765, 818,
2-Methyl-1,1′-N,N,N′,N′-tetraisopropylferrocenedicar-
boxamide (6b)
832, 1031, 1047, 1134, 1161, 1202, 1320, 1368, 1456, 1594,
1
2875, 2932, 2966, 3066, 3204. H NMR (CDCl3) δ: 0.65–
According to Standard method A, a solution of (–)-
sparteine (0.91 mL, 4.1 mmol) and n-BuLi (2.35 mL,
1.75 mol/L solution in hexane, 4.12 mmol) was sequentially
treated with a solution of 5 (0.437 g, 0.98 mmol) in PhMe
and MeI (0.37 mL, 5.9 mmol). Standard workup followed by
column chromatography (EtOAc–hexane, 1:4) afforded 6b
1.48 (br, 24H, CH(CH3)2), 2.87, 3.15, 3.44, 4.20 (m, 4H,
CH(CH3)2), 3.67, 4.29, 4.56, 4.63, 4.92 (m, 7H, Cp-H), 5.81
(s, 1H, OH), 7.06–7.40, 7.55 (m, 10H, PhH), 7.94 (s, 1H,
CH(OH)Ph2). 13C NMR (CDCl3) δ: 20.4, 20.5, 40.6, 45.6,
50.4, 68.9, 70.3, 72.8, 74.07, 74.7, 75.1, 83.7, 92.8, 165.6,
168.0. MS m/z (rel intensity) (EI): 622 (M+, 2), 614 (8), 502
© 2006 NRC Canada

364
Can. J. Chem. Vol. 84, 2006
(50), 414 (42), 354 (3), 218 (78), 131 (100), 70 (98). HRMS
calcd. for C37H4656FeN2O3: 622.2858; found: 622.2836.
(CDCl3) δ: 0.79–1.83 (br, 51H, CH(CH3)2, Bu-H), 3.19–3.68
(br, 4H, CH(CH3)2)), 4.22–4.33 (m, 3H, Cp- H), 4.30–4.52
(m, 2H, Cp-H), 4.52–4.68 (m, 2H, Cp-H). 13C NMR
(CDCl3) δ: 11.22, 13.7, 14.6, 14.8, 21.0, 26.8, 27.4, 28.0,
29.2, 46.1, 50.0, 69.9, 70.4, 71.1, 71.5, 72.0, 74.2, 76.1,
82.3, 88.4, 168.9, 169.4. MS m/z (rel intensity) (FAB): 730
(M+, 7), 673 (100), 630 (9), 558 (28), 495 (28), 426 (16),
368 (20). Anal. calcd. for C36H62FeN2O2Sn: C 59.28, H
8.57, N 3.84; found: C 58.99, H 8.49, N 3.80.
Method 2
By Sn-Li exchange from 2-(tributylstannyl)-1,1′-
N,N,N′,N′-tetraisopropylferrocenedicarboxamide (6f).
n-BuLi (0.09 mL, 1.67 mol/L solution in hexane,
0.15 mmol) was added to a cold (–78 °C), stirred solution of
2-(tributylstannyl)-1,1′-N,N,N′,N′-tetraisopropylferrocenedi-
carboxamide (6f) (0.10 g, 0.14 mmol) in PhMe (5 mL). The
resulting solution was stirred for 15 min, benzophenone
(0.052 g, 0.28 mmol) in PhMe (0.5 mL) was added, and stir-
ring was continued for 40 min at –78 °C before the reaction
mixture was allowed to warm to rt. Standard workup and
flash chromatography (EtOAc–hexane, 8:1) afforded pure 6d
(0.022 g, 25%) and also 5 (3 mg, 5%) and unreacted 2-
(tributylstannyl)-1,1′-N,N,N′,N′-tetraisopropylferrocenedicar-
boxamide (6f) (51 mg, 49%). The crude product was
analysed by CSP HPLC ((S,S)-Whelk-O1; eluent: n-hexane–
i-PrOH 97:3, flow 0.5 mL/min) and found to be 82% ee
(tR(major) = 22.88 min, tR(minor) = 35.98 min).
2-(Diphenylphosphino)-1,1′-N,N,N′,N′-tetraisopropylferro-
cenedicarboxamide (6g)
According to Standard method A, a solution of (–)-
sparteine (1.04 mL, 4.20 mmol) and n-BuLi (2.40 mL,
1.75 mol/L solution in hexane, 4.20 mmol) was sequentially
treated with a PhMe (4.5 mL) solution of 5 (0.440 g,
1.00 mmol) and neat chlorodiphenylphosphine (1.1 mL,
6.0 mmol). After stirring for 1 h at –78 °C, the reaction mix-
ture was allowed to warm to 0 °C and quenched with satd.
aq. NH4Cl. Standard workup followed by column chroma-
tography (SiO2 deactivated by additon of 2% Et3N, EtOAc–
hexane 1:10) afforded 6g as an orange solid (0.335 g, 54%);
mp 142–144 °C (dec). CSP HPLC analysis (Chiracel OD;
eluent: n-hexane–i-PrOH 98:2, flow 0.25 mL/min) deter-
mined 97% ee (tR(major) = 31.31 min, tR(minor) =
2-(Diethylhydroxymethyl)-1,1′-N,N,N′,N′-tetraisopropyl-
ferrocenedicarboxamide (6e)
According to Standard method A, a solution of (–)-
sparteine (0.97 mL, 4.4 mmol) and n-BuLi (2.31 mL,
1.90 mol/L solution in hexane, 4.40 mmol) was sequentially
treated with solutions of 5 (0.459 g, 1.04 mmol) and 3-
pentanone (0.63 mL, 6.2 mmol) in PhMe (4.5 and 5.0 mL,
respectively). Standard workup followed by column chroma-
tography (EtOAc–hexane, 1:6) afforded 6e as an orange
solid (0.25 g, 45%); mp 121 to 122 °C. CSP HPLC analysis
(Chiralcel OD; eluent: n-hexane–i-PrOH 98:2, flow
0.15 mL/min) determined 90% ee (tR(major) = 37.02 min,
34.24 min). [α]23 +225.5° (c 0.31, CH2Cl2). IR (KBr) νmax
:
D
1
2963, 1624, 1449, 1336, 1206, 820, 751, 701. H NMR
(CDCl3) δ: 0.32–1.75 (br, 24 CH(CH3)2), 3.03–3.48 (br, 4H,
CH(CH3)2), 3.90, 4.26, 4.34, 4.37, 4.45, 4.51, 4.58, 4.65,
4.80 (m, 7H, CpH), 7.18–7.62 (br, 10H, C6H5). 13C NMR
(CDCl3) δ: 20.3, 21.4, 31.6, 71.7, 72.2, 73.4, 74.7, 76.9,
80.3, 82.7, 86.0, 98.3, 128.1, 128.2, 128.7, 133.0, 133.4,
134.1, 134.6, 137.9, 139.2, 166.7. MS m/z (rel. intensity)
(EI): 625 (M+, 62), 539 (71), 423 (100), 346 (84), 245 (69).
HRMS calcd. for C36H4656FeN2O2P: 625.2674; found:
625.2646.
tR(minor) = 39.18 min). [α]23 –31.2° (c 0.34, CHCl3). IR
578
(KBr) νmax: 814, 970, 1038, 1038, 1113, 1135, 1157, 1200,
1
1340, 1453, 1604, 2939, 3343. H NMR (CDCl3) δ: 0.47 (t,
J = 7.5 Hz, 3H, CH2CH3), 0.72–1.98 (m, 31H, CH(CH3)2,
CH2CH3, CH2CH3, 3.29–3.55 (br, 4H, CH(CH3)2), 4.10–
4.32 (m, 3H, CpH), 4.47 (s, 1H, CpH), 4.60 (s, 2H, CpH),
4.73 (s, 1H, CpH), 6.10 (s, 1H, OH). 13C NMR (CDCl3) δ:
7.6, 9.2, 20.3, 20.7, 20.9, 29.6, 33.9, 46.2, 50.8, 67.7, 69.5,
71.7, 72.2, 72.6, 82.0, 83.1, 101.4, 168.9, 171.4. MS m/z (rel
intensity) (EI): 526 (M+, 18), 508 (100), 446 (3), 338 (4),
316 (12), 306 (5), 265 (5), 231 (5), 161 (7), 105 (9), 91 (8),
86 (7). HRMS calcd. for C29H4656FeN2O3: 526.2858; found:
526.2893. Anal. calcd. for C29H46FeN2O3: C 66.15, H 8.80,
N 5.22; found: C 66.17, H 8.65, N 4.93.
2-(Phenylthio)-1,1′-N,N,N′,N′-tetraisopropylferrocene-
dicarboxamide (6h)
According to Standard method A, a solution of (–)-
sparteine (0.93 mL, 4.2 mmol) and n-BuLi (2.76 mL,
1.52 mol/L solution in hexane, 4.2 mmol) was sequentially
treated with solutions of 5 (0.440 g, 1.00 mmol) and Ph2S2
(1.30 g, 5.95 mmol) in PhMe (4.5 mL and 10.0 mL, respec-
tively). Standard workup followed by column chromatogra-
phy (EtOAc–hexane, 1:6) afforded 6h (0.39 g, 71%); mp
135–137 °C. CSP HPLC analysis (Chiralcell OD; eluent: n-
hexane–i-PrOH (0.1% solution of Et2NH of 99.1:0.9,
flow mL/min) determined 89% ee (tR(major) = 17.54 min,
2-(Tributylstannyl)-1,1′-N,N,N′,N′-tetraisopropylferrocene-
dicarboxamide (6f)
tR(minor) = 21.21 min). [α]23 +97.7° (c 1.41, CHCl3). IR
578
According to Standard method A, a solution of (–)-
sparteine (0.92 mL, 4.2 mmol) and n-BuLi (5.17 mL,
1.68 mol/L solution in hexane, 8.69 mmol) was sequentially
treated with a PhMe (4.5 mL) solution of 5 (0.903 g,
1.00 mmol) and neat tributyltin chloride (3.51 mL,
12.41 mmol). Standard workup followed by column chroma-
tography (EtOAc–hexane, 1:10) afforded 6f as a red oil,
which was purified by Kugelrohr distillation (0.86 g, 58%).
[α]23 +90.4° (c 0.44, CHCl3). IR (neat) νmax: 1039, 1158,
12045,781280, 1323, 1372, 1457, 1614, 2930. 1H NMR
(KBr) νmax: 738, 814, 814, 840, 1041, 1143, 1205, 1337,
1
1453, 1611, 2935. H NMR (CDCl3) δ: 0.33–1.61 (br, 24H,
CH(CH3)2), 3.12–3.78 (br, 4H, CH(CH3)2), 4.35–4.98 (m,
7H, Cp-H), 7.01–7.37 (m, 5H, C6H5). 13C NMR (CDCl3) δ:
19.99, 20.4, 20.7, 20.9, 45.8, 50.5, 70.6, 71.7, 72.6, 72.9,
73.7, 73.9, 77.7, 79.0, 83.7, 92.8, 125.4, 127.3, 128.7, 139.7,
165.5, 168.6. MS m/z (rel intensity) (FAB): 548 (M+, 45),
460 (62), 372 (72), 328 (31), 185 (100), 132 (88). Anal.
calcd. for C30H40FeN2O2S: C 65.67, H 7.35, N 5.11; found:
C 65.80, H 7.28, N 5.05.
© 2006 NRC Canada

Laufer et al.
365
(3 mL) was heated to 150 °C for 30 min and treated with a
2-(Phenylselenyl)-1,1′-N,N,N′,N′-tetraisopropylferrocene-
dicarboxamide (6i)
solution of 2-(tributylstannyl)-1,1′-N,N,N′,N′-tetraisopropyl-
ferrocenedicarboxamide (6f) (0.107 g, 0.15 mmol, [α]23
According to Standard method A, a solution of (–)-
sparteine (0.92 mL, 4.2 mmol) and n-BuLi (2.49 mL,
1.68 mol/L solution in hexane, 4.19 mmol) was sequentially
treated with solutions of 5 (0.439 g, 1.00 mmol) and Ph2Se2
(1.87 g, 5.98 mmol) in PhMe (4.5 and 2.5 mL, respectively).
Standard workup followed by column chromatography
(EtOAc–hexane, 1:4) afforded 6i (0.36 g, 82%); mp 126 to
127 °C. CSP HPLC analysis (Chiralcel OD; eluent: n-hex-
ane–i-PrOH 99:1, flow 0.3 mL/min) determined 71% ee
578
+90.4° (c 0.44, CHCl3), i.e., ≥82% ee) in DMF (0.3 mL).
The resulting reaction mixture was stirred for 18 h at
100 °C, cooled to rt, passed through Celite, concentrated and
subjected to standard workup followed by column chroma-
tography (hexane–EtOAc, 6:1) to afford 6l as a brown oil
(27 mg, 35%) and separately 1,1′-N,N,N′,N′-tetraisopropyl-
ferrocenedicarboxamide (5) (24 mg, 51%). Compound 6l:
[α]23 –266.1° (c 0.17, CHCl3). IR (neat) νmax: 764, 815,
10385,781111, 1135, 1159, 1207, 1261, 1318, 1372, 1457,
(tR(major) = 32.92 min, tR(minor) = 35.90 min). [α]23
578
1
1508, 1623, 2926, 2964. H NMR (CDCl3) δ: 0.24–1.72 (br,
+216° (c 0.23, CHCl3). IR (CH2Cl2) νmax: 1037, 1135, 1160,
24H, CH(CH3)2), 3.13–3.60 (br, 4H, CH(CH3)2), 4.25–4.92
(br, 7H, CpH), 7.25 (m, 3H, C6H5), 7.56 (m, 2H, C6H5). 13C
NMR (CDCl3) δ: 19.5, 19.8, 20.8, 20.9, 21.0, 22.7, 29.7,
45.7, 50.6, 68.6, 70.0, 70.9, 72.0, 72.9, 73.4, 74.3, 82.4,
85.6, 90.1, 126.6, 128.1, 137.5, 167.5, 168.9. MS m/z (rel in-
tensity) (FAB): 517 (MH+, 22), 416 (5), 330 (3), 277 (8),
185 (100), 116 (5). HRMS calcd. for C30H4156FeN2O2
(MH+): 517.2518; found: 517.2495.
1205, 1266, 1322, 1372, 1463, 1475, 1621, 2971, 2934,
1
3053. H NMR (CDCl3) δ: 0.37–1.60 (br, 24H, CH(CH3)2)),
3.11–3.76 (br, 4H, CH(CH3)2)), 4.40 (dd, J = 2.8, 1.3 Hz,
1H, Cp-H), 4.48–4.70 (m, 3H, Cp-H), 4.68 (dt, J = 1.3,
2.6 Hz, 1H, Cp-H), 4.90 (dt, J = 1.3, 2.6 Hz, 1H, CpH),
7.08–7.19 (m, 3H, C6H5), 7.27–7.35 (m, 2H, C6H5). 13C
NMR (CDCl3) δ: 14.1, 21.0, 22.6, 31.5, 45.8, 49.8, 50.4,
71.1, 71.2, 72.2, 72.6, 73.4, 73.2, 74.2, 77.3, 83.4, 92.4,
126.1, 128.8, 130.3, 133.7, 166.0, 168.5. MS m/z (rel inten-
sity) (FAB): 597 (M+, 9), 553 (8), 517 (6), 461 (11), 369
(32), 356 (5), 277 (100), 241 (8). HRMS calcd. for
C30H4156FeN2O2Se: 597.1683; found: 597.1678.
2,2′-Bis(trimethylsilyl)-1,1′-N,N,N′,N′-tetraisopropyl-
ferrocenedicarboxamide (7a)
Method 1
From 1,1′-N,N,N′,N′-tetraisopropylferrocenedicarboxamide
(5). According to Standard method A, a solution of (–)-
sparteine (0.51 mL, 2.30 mmol) and n-BuLi (1.36 mL,
1.69 mol/L solution in hexane, 2.30 mmol) in PhMe (20 mL)
was sequentially treated with a solution of 1,1′-N,N,N′,N′-
tetraisopropylferrocenedicarboxamide (5) (0.24 g, 0.55 mmol)
PhMe (4.5 mL) and then TMSCl (0.42 mL, 3.3 mmol). Stan-
dard workup followed by column chromatography (EtOAc–
hexane, 1:30) gave separately dl-7a (0.153 g, 50%), meso-7a
(0.065 g, 21%), and 2-(trimethylsilyl)-1,1′-N,N,N′,N′-tetra-
isopropylferrocenedicarboxamide (6a) (0.043 g, 16%,
2-(2,4-Dimethoxyphenyl)-1,1′-N,N,N′,N′-tetraisopropyl-
ferrocenedicarboxamide (6k)
A mixture of Pd(PPh3)4 (0.070 g, 0.06 mmol), 2-iodo-1,1′-
N,N,N′,N′-tetraisopropylferrocenedicarboxamide (6c) (0.34 g,
0.61 mmol, 89% ee), degassed aq. Na2CO3 solution
(1.80 mL, 2 mol/L, 3.66 mmol), and 2,4-dimethoxyphenyl-
boronic acid (0.18 g, 0.97 mmol) in freshly distilled DME
(15 mL) was refluxed for 5 days. The crude material was
passed through Celite, and the filtrate was subjected to stan-
dard workup. Purification by column chromatography
(EtOAc–hexane, 1:8) afforded 6k as a brown-red solid
(0.069 g, 20%); mp 161–163 °C. CSP HPLC analysis
(Chiralcel OD; eluent: n-hexane–i-PrOH 98.5:1.5, flow
0.20 mL/min) determined 89% ee (tR(major) = 67.93 min,
tR(minor) = 75.04 min). [α]23578 +8.9° (c 0.18, CHCl3). IR
(KBr) νmax: 817, 1036, 1151, 1205, 1317, 1370, 1454, 1533,
1619, 2936. 1H NMR (CDCl3) δ: 0.25–1.75 (br, 24H,
CH(CH3)2), 3.05–3.65 (b, 2H, CH(CH3)2), 3.72 (s, 3H,
OCH3), 3.78 (s, 3H, OCH3), 4.32–4.44 (m, 3H, CpH), 4.54
(m, 2H, CpH), 4.67–4.70 (m, 1H, CpH), 4.76–4.79 (m, 1H,
CpH), 6.38 (d, J = 2.6 Hz, 1H, H(3)-C6H3), 6.45 (dd, J =
2.6, 8.4 Hz, 1H, H(5)-C6H3), 7.70 (d, J = 8.4 Hz, 1H, H(6)-
C6H3). 13C NMR (CDCl3) δ: 19.5, 19.9, 20.9, 21.0, 45.5,
50.4, 55.4, 69.3, 69.8, 71.5, 71.7, 73.0, 73.4, 74.7, 81.4,
82.4, 90.0, 98.2, 104.2, 117.7, 127.9, 128.1, 130.4, 132.6,
134.7, 134.9, 157.9, 159.8, 167.7, 169.3. MS m/z (rel inten-
sity) (CI): 577 (MH+, 46), 576 (42), 476 (9), 441 (17), 349
(6), 330 (13), 309 (6), 253 (16), 233 (13), 194 (16), 145
(22), 131 (15), 117 (100), 100 (14), 86 (19), 71 (10). HRMS
calcd. for C32H4456FeN2O4: 576.2650; found: 576.2675.
[α]23 +64.3° (c 0.11, CHCl3)) as orange solids.
578
dl-2,2′-Bis(trimethylsilyl)-1,1′-N,N,N′,N′-tetraisopropylferro-
cenedicarboxamide (7a): [α]23
+48.0° (c 0.51, CHCl3).
Optical purity: 97%; mp 192–517984 °C (hexanes). IR (KBr)
ν
max: 833, 1041, 1069, 1120, 1155, 1207, 1246, 1279, 1330,
1
1371, 1455, 1627, 2934. H NMR (CDCl3) δ: 0.25 (s, 18H,
Si(CH3)3), 0.77–1.12 (br, 24H, CH(CH3)2), 3.15–3.50, 3.80–
4.06 (br, 4H, CH(CH3)2), 4.15 (s, 2H, Cp-H), 4.60 (s, 4H,
Cp-H). 13C NMR (CDCl3) δ: 0.6, 20.7, 45.9, 50.1, 73.0,
73.5, 74.0, 74.4, 92.6, 168.9. MS m/z (rel intensity) (EI):
585 (M+, 76), 442 (26), 312 (16), 220 (22), 128 (17), 73
(95). Anal. calcd. for C30H5256FeN2O2Si2: C 61.62, H 8.96,
N 4.79; found: C 61.50, H 8.73, N 4.79.
meso-2,2′-Bis(trimethylsilyl)-1,1′-N,N,N′,N′-tetraisopropyl-
ferrocenedicarboxamide (7a): mp 192–194 °C (Et2O–
hexane). IR (KBr) νmax: 904, 1040, 1067, 1127, 1156, 1207,
1
1279, 1349, 1454, 1623, 2963, 3088. H NMR (CDCl3) δ:
1.32 (s, 18H, Si(CH3)3), 0.75–1.70 (br, 24H, CH(CH3)2),
3.15–3.44, 3.73–4.05 (br, 4H, CH(CH3)2), 4.34 (s, 2H, Cp-
H), 4.43 (s, 2H, Cp-H), 4.52 (s, 2H, Cp-H). 13C NMR
(CDCl3) δ: 0.0, 20.7, 45.7, 50.1, 70.5, 72.6, 74.8, 92.2,
168.7. MS (EI) m/z (rel intensity): 585 (M+, 5), 370 (2), 204
(3), 100 (5), 73 (100). Anal. calcd. for C30H5256FeN2O2Si2:
C 61.62, H 8.96, N 4.79; found: C 61.80, H 8.85, N 4.79.
2-Phenyl-1,1′-N,N,N′,N′-tetraisopropylferrocenedicar-
boxamide (6l)
A mixture of PdCl2(dppf) (37 mg, 0.051 mmol), CuO
(95 mg, 1.2 mmol), and PhBr (0.02 mL, 0.19 mmol) in DMF
© 2006 NRC Canada

366
Can. J. Chem. Vol. 84, 2006
Method 2
as the starting material 1,1′-N,N,N′,N′-tetraisopropylferro-
cenedicarboxamide (5) (0.018 g, 8%).
From 2-(trimethylsilyl)-1,1′-N,N,N′,N′-tetraisopropylferro-
cenedicarboxamide (6a). According to Standard method B, a
solution of (–)-sparteine (0.71 mL, 3.23 mmol), and n-BuLi
(1.96 mL, 1.65 mol/L solution in hexane, 3.23 mmol) in
PhMe (20 mL) was sequentially treated with a solution of 2-
(trimethylsilyl)-1,1′-N,N,N′,N′-tetraisopropylferrocenedicar-
2,2′-Bis(diphenylphosphino)-1,1′-N,N,N′,N′-tetraiso-
propylferrocenedicarboxamide (7c)
Preparation of dl-7c from 2-(diphenylphosphino)-1,1′-
N,N,N′,N′-tetraisopropylferrocenedicarboxamide (6g). Ac-
cording to Standard method B, a solution of (–)-sparteine
(0.30 mL, 1.4 mmol) and n-BuLi (0.67 mL, 2.00 mol/L solu-
tion in hexane, 1.3 mmol) in PhMe (20 mL) was sequen-
tially treated with a solution of 2-(diphenylphosphino)-1,1′-
N,N,N′,N′-tetraisopropylferrocenedicarboxamide (6g) (0.400 g,
0.91 mmol, 97% ee) in PhMe (2.5 mL) and Ph2PCl
(0.36 mL, 1.9 mmol). The reaction mixture was quenched
with satd. aq. NH4Cl and extracted with CH2Cl2. The or-
ganic extract was washed with brine and concentrated under
reduced pressure. The residue was purified by column chro-
matography (SiO2 pretreated with 2% Et3N, EtOAc–hexane
1:6) to give compound 7c as a bright yellow solid (0.29 g,
45%); dr(dl:meso) >95:<5 by 31P NMR; mp 233–236 °C
(dec) (lit. value (41) mp 228–230 °C). [α]20 +277° (c 0.76,
CH2Cl2), 98% optical purity. IR (KBr) νmDax: 3088, 2938,
1625, 1531, 1454, 1371, 1333, 1279, 1244, 1204, 1154,
boxamide (6a, 0.39 g, 0.76 mmol, [α]23 +67.5° (c 0.54,
578
CHCl3)) in PhMe (2.5 mL) and then TMSCl (0.60 mL,
4.6 mmol). Standard workup followed by column chroma-
tography (EtOAc–hexane, 1:30) gave the title compounds
(7a) as orange solids; dl-7a (0.336 g, 75%) and meso-7a
(0.056 g, 12%), dl-7a ([α]23578 +44.8° (c 0.42, CHCl3)); 91%
optical purity.
2,2′-Dimethyl-1,1′-N,N,N′,N′-tetraisopropylferrocenedicar-
boxamide (7b)
Method 1
From 1,1′-N,N,N′,N′-tetraisopropylferrocenedicarboxamide
(5) using s-BuLi. According to Standard method A, a solu-
tion of (–)-sparteine (0.90 mL, 4.1 mmol) and s-BuLi
(3.44 mL, 1.18 mol/L solution in cyclohexane, 4.06 mmol)
in Et2O (20 mL) was sequentially treated with a solution of
1
1039. H NMR (CDCl3) δ: 0.34–1.53 (br, 24H, CH(CH3)2),
3.04–3.26 and 3.92–4.13 (br, 4H, CH(CH3)2), 3.53 (s, 2H,
Cp-H), 4.78–4.82 (m, 4H, Cp-H), 7.12–7.43 (br, 20H,
C6H5). 13C NMR (CDCl3) δ: 13.7, 19.0, 20.3, 50.0, 72.7,
74.8, 76.7, 81.1, 90.5, 127.9, 128.0, 128.1, 128.2, 129.1,
130.0, 130.4, 132.7, 133.1, 133.5, 133.6, 133.9, 137.9,
138.1, 139.0, 167.0. 31P NMR(CDCl3) δ: –22.27. Anal.
calcd. for C48H5456FeN2O2P2: C 71.28, H 6.73, N 3.46:
found: C 71.36, H 6.75, N 3.51.
1,1′-N,N,N′,N′-tetraisopropylferrocenedicarboxamide
(5)
(0.447 g, 1.02 mmol) in Et2O (10 mL) followed by MeI
(0.38 mL, 6.1 mmol). Standard workup followed by column
chromatography (EtOAc–hexane, 1:15) afforded a mixture
of meso-7b and dl-7b diastereomers (0.33 g, 70%) as an or-
ange solid. CSP HPLC analysis (Chiralcel OD; eluent: n-
hexane–i-PrOH 99.4:0.6, flow 1.0 mL/min) determined dr
(meso:dl, 76:24) and 52% ee (tR(major dl) = 5.74 min,
tR(minor dl) = 6.96 min, tR(meso diastereomer) = 9.30 min).
IR (KBr) νmax: 815, 1022, 1037, 1076, 1134, 1156, 1210,
1314, 1346, 1371, 1455, 1629, 2937, 3088. 1H NMR
(CDCl3) δ: 0.62–1.78 (br, 24H, CH(CH3)2), 2.02 (s, 6H,
CpCH3), 3.18–4.00 (br, 4H, CH(CH3)2), 4.15 (m, 2H, Cp-
H), 4.36 (m, 2H, Cp-H), 4.52 (m, 1H, Cp-H), 4.66 (m, 1H,
Cp-H). 13C NMR (CDCl3) δ: [12.06], 12.44, 20.75, [20.48],
45.35, 49.85, [68.50], 69.41, [69.98], 72.11, 84.76, [86.76],
87.10, 167.90. MS m/z (rel intensity) (FAB): 468 (M+, 100),
396 (2), 368 (35), 262 (26), 213 (5), 134 (13), 55 (11).
HRMS calcd. for C26H4056FeN2O2: 468.2439; found:
468.2390. Values in square parentheses indicate resonances
assigned to the dl-diastereomer.
Preparation of meso-7c from 1,1′-N,N,N′,N′-tetraisopropyl-
ferrocenedicarboxamide (5) using s-BuLi
According to Standard method A, a solution of (–)-
sparteine (1.9 mL, 8.4 mmol) and s-BuLi (7.1 mL,
1.18 mol/L solution in cyclohexane, 8.4 mmol) in Et2O
(40 mL) was sequentially treated with a solution of 1,1′-
N,N,N′,N′-tetraisopropylferrocenedicarboxamide (5) (0.883 g,
2.01 mmol) in Et2O (20 mL) and Ph2PCl (2.16 mL,
12.0 mmol). The reaction mixture was quenched with satd.
aq. NH4Cl and extracted with excess CH2Cl2. The organic
extract was washed with brine and concentrated under re-
duced pressure. The residue was purified by column chroma-
tography (SiO2 pretreated with 2% Et3N, EtOAc–hexane
1:6) to give meso-7c as a bright yellow solid (0.79 g, 49%).
The diastereomeric composition was determined by 31P
NMR dr(meso:dl) >95:<5; mp 235–237 °C (dec). IR (KBr)
Method 2
From 1,1′-N,N,N′,N′-tetraisopropylferrocenedicarboxamide
(5) using n-BuLi in the presence of LiCl. According to Stan-
dard method A, a solution of (–)-sparteine (0.49 mL,
2.2 mmol), vacuum-dried LiCl (0.048 g, 2.1 mmol), and n-
BuLi (1.32 mL, 1.69 mol/L solution in hexane, 4.2 mmol) in
Et2O (10 mL) was sequentially treated with a solution of 1,1′-
N,N,N′,N′-tetraisopropylferrocenedicarboxamide (5) (0.23 g,
0.53 mmol) in Et2O (5 mL) and MeI (0.37 mL, 6.0 mmol).
Standard workup followed by column chromatography
(EtOAc–hexane, 1:15) afforded a mixture of dl-7b and meso-
7b diastereomers (0.040 g, 16%). CSP HPLC analysis deter-
mined 80% ee and dr = 72:28 (dl:meso); 2) and separately
2-methyl-1,1′-N,N,N′,N′-tetraisopropylferrocenedicarboxamide
(6b) (0.15 g, 61%), 79% ee by CSP HPLC analysis, as well
ν
max: 3063, 2924, 1629, 1451, 1373, 1330, 1205, 1159,
1093, 822. 1H NMR (CDCl3) δ: 0.34–1.68 (br, 24H,
CH(CH3)2), 2.92–3.25 and 3.43–3.96 (br, 4H, CH(CH3)2),
4.20 and 4.76 (m, 6H, Cp-H), 7.12–7.67 (br, 20H, C6H5).
13C NMR (CDCl3) δ: 20.3, 72.8, 81.1, 90.8, 91.2, 128.0,
128.0, 128.2, 128.9, 132.8, 133.1, 134.5, 134.9, 139.6,
139.9, 166.3. 31P NMR (CDCl3) δ: –22.68. MS m/z (rel in-
tensity) (FAB): 808 (M+, 3), 766 (8), 639 (16), 625 (47).
Anal. calcd. for C48H5456FeN2O2P2: C 71.28, H 6.73, N
3.46; found: C 71.39, H 6.79, N 3.52.
Diphenylphosphine derivatives 6g and 7c were found to
be air-sensitive, but could be stored for months as solids un-
© 2006 NRC Canada

Laufer et al.
367
der argon at low temperatures (–20 °C). Purification by col-
umn chromatography required deactivation of silica gel with
Et3N.
jected to the standard workup. Purification by column chro-
matography (EtOAc–hexane, 1:5) gave compound 8 as a
pale yellow solid (0.313 g, 96%). CSP HPLC analysis
(eluent: n-hexane–i-PrOH 99:1, flow 0.2 mL/min) deter-
mined 84% ee (tR(major) = 58.78 min, tR(minor) =
2,2′-Bis(phenylthio)-1,1′-N,N,N′,N′-tetraisopropylferro-
cenedicarboxamide (7d)
63.50 min). [α]23 +15.9° (c 0.71, EtOH). IR (neat) νmax
:
According to Standard method B, a solution of (–)-
sparteine (0.07 mL, 0.31 mmol and n-BuLi (0.19 mL,
1.67 mol/L solution in hexane, 0.15 mmol) in PhMe (5 mL)
was sequentially treated with a solution of 2-(phenylthio)-
1,1′-N,N,N′,N′-tetraisopropylferrocenedicarboxamide (6h)
(0.084 g, 0.15 mmol, 89% ee) in PhMe (0.5 mL) and Ph2S2
(0.131 g, 0.6 mmol) in PhMe (0.5 mL). Standard workup
followed by column chromatography (EtOAc–hexane, 1:10)
gave 7d as an orange solid (0.06 g, 60%). CSP HPLC analy-
sis (Chiralcel OD; eluent: n-hexane–i-PrOH 99:1, flow
0.4 mL/min) determined dr(dl:meso) = 98.5:1.5 and 97% ee
(tR(major dl) = 15.97 min, tR(minor dl) = 19.14 min, tR(meso
diastereomer) = 22.00 min).
2995, 1758, 160D5, 1493, 1454, 1316, 1259. 1H NMR
(CDCl ) : 3.52 (s, 3H, CO CH ), 3.70 (s, 3H, CO CH ),
δ
3
2
2
3
3.95 (d, J = 10.9 Hz, 1H, CH(CO23CH3)2), 4.27 (dd, J = 10.9,
8.0 Hz, 1H, Ph-CH), 6.32 (dd, J = 8.0, 15.7 Hz, 1H,
-CH=CH-Ph), 6.51 (d, J = 15.7 Hz, 1H, Ph-CH=), 7.19–7.33
(m, 10H, C6H5). 13C NMR (CDCl ) : 48.9, 52.0, 52.2, 57.3,
δ
3
126.1, 126.9, 127.3, 127.6, 127.9, 128.2, 128.4, 128.9,
131.5, 136.5, 140.0, 167.4, 167.9. MS m/z (rel intensity)
(EI): 324 (M+, 56), 292 (29), 264 (37), 232 (41), 204 (84),
193 (98), 178 (53), 165 (39), 152 (18), 139 (12), 128 (42),
115 (100), 102 (43), 91 (74), 78 (42), 69 (43). HRMS calcd.
for C20H20O4: 324.1361; found: 324.1353.
Method 2 (utilizing NaH)
dl-2,2′-Bis(phenylthio)-1,1′-N,N,N′,N′-tetraisopropylferro-
cenedicarboxamide (dl-7d)
A solution of 1,3-diphenyl-1-acetoxy-2-propene (0.095 g,
0.38 mmol), 2,2′-bis(diphenylphosphino)-1,1′-N,N,N′,N′-
tetraisopropylferrocenedicarboxamide (7c, 0.027 g, 0.038 mmol,
96% ee), allylpalladium chloride dimer (0.004 g, 0.011 mmol),
and THF (2 mL) was stirred for 15 min at rt and then treated
with a THF (3 mL) solution of NaCH(CO2Me)2 (prepared by
the addition of NaH (60% in oil, 0.05 g, 1.13 mmol) to
dimethylmalonate (0.15 g, 1.13 mmol) in THF (3 mL) at
0 °C) at rt. The reaction reaction mixture was stirred for
36 h at rt, quenched with water, and subjected to the stan-
dard workup. Purification by column chromatography af-
forded compound 8 (0.117 g, 96%), which, as determined by
CSP HPLC, was 84% ee (R-enantiomer).
mp 200–202 °C (dec). IR (KBr) νma1x: 2954, 1628, 1458,
1372, 1325, 1207, 1159, 1127, 1033. H NMR (CDCl3) δ:
0.42–1.71 (br, 24H, CH(CH3)2), 3.24 (sept, J = 11 Hz, 2H,
CH(CH3)2), 3.72 (sept, J = 11 Hz, 2H, CH(CH3)2), 4.71 (s,
4H, Cp-H), 4.59 (m, 2H, Cp-H), 7.02–7.28 (br, 10H, C6H5).
13C NMR (CDCl3) δ: 20.9, 50.6, 74.0, 77.4, 80.6, 92.5,
125.5, 127.6, 128.6, 139.2, 165.3. MS m/z (rel intensity)
(FAB): 657 (MH+, 98), 656 (M+, 100), 557 (17), 548 (14),
455 (34), 356 (16), 318 (28), 302 (89), 201 (69), 185 (59),
154 (69), 137 (59). HRMS calcd. for C36H4556FeN2O2S2
(MH+): 657.2272; found: 657.2294. Anal. calcd. for
C36H4456FeO2N2S2: C 65.84, H 6.75, N 4.26; found: C
66.02, H 6.68, N 4.32.
1-Phenylpropan-1-ol (9) (Et2Zn addition to benzaldehyde)
To a stirred solution of benzaldehyde (0.10 mL,
1.6 mmol) and chiral ferrocenyl ligand (6d, 6e, 6k, 6l)
(0.05 mmol) in either hexane (15 mL) or PhMe (5 mL) was
added a solution of Et2Zn (1.60 mL, 1.0 mol/L in hexane,
1.60 mmol) at rt and the reaction mixture was further stirred
for 1–3 days. The reaction mixture was quenched with ex-
cess 0.2 mol/L aq. HCl solution at 0 °C. After standard
workup, the crude material was analyzed by CSP HPLC
(Chiralcel OD column, eluent: n-hexane–isopropyl alcohol
99:1, flow 0.5 mL/min, tR 29.66 min, tR 27.20 min) and pu-
rified by column chromatography (hexane–EtOAc, 10:1) to
yield compound 9 as a colorless oil. IR (CH2Cl2) νmax: 700,
meso-2,2′-Bis(phenylthio)-1,1′-N,N,N′,N′-tetraisopropyl-
ferrocenedicarboxamide (meso-7d)
mp 201–203 °C (dec). IR (KBr) νmax: 2949, 1631, 1459,
1
1372, 1316, 1207, 1034. H NMR (CDCl3) δ: 0.26–1.79 (br,
24H, CH(CH3)2), 3.24 (m, 2H, CH(CH3)2), 3.67 (m, 2H,
CH(CH3)2), 4.53, 4.70, 4.90 (m, 6H, Cp-H), 6.92–7.38 (br,
10H, C6H5). 13C NMR (CDCl3) δ: 20.0, 20.7, 45.8, 50.5,
71.4, 74.2, 79.1, 82.1, 125.5, 127.7, 128.7, 137.0, 165.1. MS
m/z (rel intensity) (FAB): 657 (MH+, 8), 656 (M+, 7), 556
(2), 547 (2), 455 (5), 338 (5), 302 (14), 246 (16), 201 (9),
185 (100), 154 (59), 137 (65). HRMS calcd. for
C36H4556FeN2O2S2 (MH+): 657.2272; found: 657.2292.
1
756, 1097, 1454, 1493, 2875, 2930, 2966, 3030, 3369. H
NMR (CDCl3) δ: 0.92 (t, J = 7.3 Hz, 3H, CH2CH3), 1.81 (m,
2H, CH2CH3), 1.90–2.00 (br, 1H, OH), 4.59 (t, J = 6.6 Hz,
1H, CH(OH)CH2), 7.20–7.40 (m, C6H5). 13C NMR (CDCl3)
δ: 10.1, 31.8, 76.0, 126.0, 127.4, 128.3. MS m/z (rel inten-
sity) (EI): 136 (M+, 32), 117 (2), 107 (100), 97 (0.5). HRMS
calcd. for C9H12O: 136.0888; found: 136.0897.
Dimethyl 1,3-diphenylprop-2-enylmalonate (8) —
Asymetric Pd-catalyzed allylic substitution
Method 1 (utilizing BSA and AcOK)
A solution of 1,3-diphenyl-1-acetoxy-2-propene (0.25 g,
1.0 mmol) (42), 2,2′-bis(diphenylphosphino)-1,1′-N,N,N′,N′-
tetraisopropylferrocenedicarboxamide (7c, 0.071 g, 0.1 mmol,
96% ee), and allylpalladium chloride dimer (0.009 g,
0.025 mmol) in CH2Cl2 (3.5 mL) was stirred for 15 min at rt
before a solution (CH2Cl2, 3.5 mL) of BSA (0.74 mL,
3.0 mmol), dimethyl malonate (0.40 g, 3.0 mmol), and
AcOK (0.004 g, 0.04 mmol) was added. The reaction mix-
ture was stirred for 10 h at rt, quenched with water, and sub-
Et2Zn addition to benzaldehyde catalyzed by the lithium
salt of 2-(diphenylhydroxymethyl)-1,1′-N,N,N′,N′-tetra-
isopropylferrocenedicarboxamide (6d)
A solution of n-BuLi (0.05 mL, 1.67 mol/L in hexane,
0.85 mmol) was added to a cold (–78 °C) solution of 6d
(53.4 mg, 0.086 mmol) in PhMe (20 mL). PhCHO (0.19 mL,
© 2006 NRC Canada

368
Can. J. Chem. Vol. 84, 2006
Hegedus. Organometallics, 23, 1010 (2004); (e) O.G.
Mancheño, R.G. Arrayás, and J.C. Carretero. Organometallics,
24, 557 (2005); ( f ) R.G. Arrayás, I. Alonso, O. Familiar, and
J.C. Carretero. Organometallics, 23, 1991 (2004).
0.86 mmol) and Et2Zn (1.37 mL, 1.0 mol/L in hexane,
1.37 mmol) were added and stirring was continued at rt for
3 days. The reaction mixture was quenched with excess
0.2 mol/L HCl at 0 °C. Standard workup followed by flash
chromatography afforded compound 9 (0.082 g, 70%, 47% ee).
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Acknowledgements
We warmly thank Dr. Heiner Jendralla, Novartis (formerly
Hoechst) for exchange of correspondence and insightful
comments. We are grateful to the Natural Sciences and Engi-
neering Research Council of Canada (NSERC) for support
under the Industrial Research Chair (Monsanto Company)
and Research Grant programs. RL was an Ontario Graduate
Scholar, 1996 to 1997.
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