Directed Iron-Catalyzed ortho-Alkylation and Arylation: Toward the Stereoselective Catalytic Synthesis of 1,2-Disubstituted Planar-Chiral Ferrocene Derivatives

Article abstract of DOI:10.1021/acs.organomet.7b00799

The iron-catalyzed directed ortho-functionalization of arenes developed to an important method in the field of C-H activation. On the other hand, the iron-catalyzed ortho-functionalization of ferrocenes bearing ortho-directing groups (ODGs) has scarcely been investigated. Herein we present the iron-catalyzed ortho-alkylation and -arylation of ODG-substituted ferrocenes bearing a bidentate ODG with the formation of racemic 1,2-disubstituted ferrocenes in up to 94% yield. The approach toward an enantioselective iron-catalyzed C-H activation resulted in an ortho-phenylation with a promising enantiomeric excess of 46%. The first iron-catalyzed diastereoselective ortho-methylation gave an excellent diastereomeric excess of ≥99%.

Full text of DOI:10.1021/acs.organomet.7b00799

Article
Cite This: Organometallics XXXX, XXX, XXX−XXX
Directed Iron-Catalyzed ortho-Alkylation and Arylation: Toward the
Stereoselective Catalytic Synthesis of 1,2-Disubstituted Planar-Chiral
Ferrocene Derivatives
David Schmiel and Holger Butenschon*
̈
Institut fur Organische Chemie, Leibniz Universitat Hannover, Schneiderberg 1B, D-30167 Hannover, Germany
̈
̈
S
* Supporting Information
ABSTRACT: The iron-catalyzed directed ortho-functionaliza-
tion of arenes developed to an important method in the field of
C−H activation. On the other hand, the iron-catalyzed ortho-
functionalization of ferrocenes bearing ortho-directing groups
(ODGs) has scarcely been investigated. Herein we present the
iron-catalyzed ortho-alkylation and -arylation of ODG-sub-
stituted ferrocenes bearing a bidentate ODG with the
formation of racemic 1,2-disubstituted ferrocenes in up to 94% yield. The approach toward an enantioselective iron-catalyzed
C−H activation resulted in an ortho-phenylation with a promising enantiomeric excess of 46%. The first iron-catalyzed
diastereoselective ortho-methylation gave an excellent diastereomeric excess of ≥99%.
salts,27 the use of iron as metal catalyst is even more
1. INTRODUCTION
preferable.28−32
While the electrophilic aromatic substitution has dominated the
functionalization of arenes for many years, ortho-lithiation in the
The progress on iron-catalyzed C−H activation reactions of
arenes resulting in newly formed C−C bonds was greatly
presence of an ortho directing group (ODG) has recently
significantly enlarged the toolbox of synthetic methods.1−3
influenced by the work of Nakamura et al. as well as of
Ackermann et al. Mainly, the use of Grignard or organozinc
Application to ferrocene using a chiral ODG afforded planar
chiral 1,2-disubstituted ferrocenes with high enantiomeric
reagents enabled the success of these reactions, as they form the
excess,4−8 which found widespread use as powerful ligands in
catalytically active species by the reaction with the appropriate
iron(II)- or iron(III)-salt.33−42 In addition, Nakamura et al.
reported the use of organoborates for the arylation and
alkenylation of C(sp2)-H or C(sp3)-H bonds.43,44 The first
example of an iron-catalyzed C−H activation of an ODG-
substituted ferrocene was recently presented by Ackermann et al.
with the reaction of ferrocenoylamide 5 with allyl chloride to give
the allylated 1,2-disubstituted product in 47% yield.45,46
Herein, we present an approach toward the unexplored
enantioselective iron-catalyzed C−H activation of ODG-
substituted ferrocenes bearing a bidentate ODG.47 Among the
investigated substrates was ferrocenoylamide 1 bearing the 8-
aminoquinolinyl group, which had been investigated by Daugulis
et al. for the first time.48
asymmetric catalysis.9 However, this method suffers from the
drawback that only a limited range of electrophiles can
successfully be used in the functionalization step after the
lithiation. Lately, directed catalytic C−H activation at ferrocene
derivatives came into play as an alternative for the synthesis of
1,2-disubstituted ferrocene derivatives. The major interest in this
context is the development of enantioselective metal-catalyzed
C−H activation reactions, and the progress in this field has
recently been reviewed.10−13 For a greater part of the reported
catalytic enantioselective C−H functionalizations of ODG-
substituted ferrocenes, Pd(OAc)2-catalyzed C(sp2)-C(sp2)
bond-forming reactions were presented, for instance, the highly
enantioselective intramolecular ortho-alkenylation reported by
You et al.14 A different interesting approach was the
enantioselective intramolecular ortho-silylation and -germylation
without the need of any particular ODG.15−18
In addition to palladium, other noble metals were used as
metal catalysts (Ir,19 Rh,20,21 Au,22 Pt,23 Cu24). Therefore, the
development of enantioselective C−H functionalization reac-
tions of ferrocenes using economically as well as environmentally
more benign metal catalysts is desirable. Recently, we reported
on the cobalt-catalyzed ortho-methylation of ODG-substituted
ferrocenes, yielding the 1,2-disubstituted products in racemic
form.25 We note that Yoshikai et al. just provided another
example using a cobalt(II) N-heterocyclic carbene complex as
the catalyst.26 However, because of the high toxicity of Co(II)
2. RESULTS AND DISCUSSION
In first experiments, the iron-catalyzed ortho-benzylation of 1 was
investigated by using a catalytic system developed by Nakamura
et al.37 with the difference that the commercially available 2,3-
dichlorobutane (DCB, meso/rac mixture) was used instead of
1,2-dichloro-2-methylpropane (dichloroisobutane, DCIB). With
this dichloroalkane acting as a mild oxidant, the transfer of the
Grignard substituent to the product is achieved. 1,2-Bis-
Received: November 2, 2017
© XXXX American Chemical Society
A
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(diphenylphosphino)ethene (dppen) was used as the ligand, and
the THF-soluble complex ZnBr2·TMEDA (N,N,N′,N′-tetrame-
thylethylenediamine) was used for the in situ formation of the
organozinc species together with benzylmagnesium chloride.
Unfortunately, only traces of the desired product rac-2 could be
observed (Scheme 1).
equilibrium to the zincate complex and shows a beneficial effect
on the yield in this case. However, this positive outcome was not
observed to this extent in the other investigated reactions.
Two further representatives with bidentate ODGs could also
successfully be used as the substrate for ortho-phenylation
(Scheme 2). The triazole-containing TAM-group in 5,
introduced by Ackermann et al.,45 showed a similar potency as
the 8-aminoquinoinyl-group, yielding rac-6 in 84% yield and the
byproduct 7 in 14% yield, whereas the PIP-group in 8, developed
by Shi et al.,52 selectively gave a slightly lower yield of the desired
product rac-9 without the observation of the respective
diphenylation byproduct. In contrast to this type of iron-
catalyzed ortho-arylation of arenes, the use of a bidentate ODG
substituted ferrocene derivative seemed to be mandatory, as 2-
ferrocenylpyridine did not show reactivity under the optimized
reaction conditions.
Scheme 1
Additional arylmagnesium bromides (ArMgBr) were tested
for the ortho-arylation of 1 and 5 (Scheme 3). The oil bath
temperature was increased to 85 °C in order to ensure a full
conversion of the respective starting material, as the product
yields were lower at an oil bath temperature of 55 °C. Again, the
desired 1,2-disubstituted racemic products were isolated as the
main products in yields between 58 and 90%.
After some slight changes [1,2-bis(diphosphino)ethane
(dppe) as the ligand, 6.0 equiv instead of 4.0 equiv of the
Grignard reagent], rac-2 was isolated but still in a low yield of
11% together with unreacted starting material. Nevertheless, the
capability of the adjusted catalytic system was proven even at a
slightly lower oil bath temperature of 55 °C (Table 1). The ortho-
phenylation of 1 delivered the desired 1,2-disubstituted product
rac-3 in a very high yield of 85% together with the product of a 2-
fold ortho-phenylation 4 in 10% yield (Table 1, entry 1).
In contrast to similar known examples of palladium-catalyzed
C−H activation reactions at the amide 1,49−51 which needed
much higher reaction temperatures, the single ortho-phenylation
product rac-3 prevailed under these conditions as the main
product and showed only a low tendency to undergo a second
ortho-phenylation. This result surpasses the only similar example
for a mono ortho-arylation of 1, which gave yields of 4−12%.49
The use of dppe and ZnX2·TMEDA (X = Br, Cl) was crucial as
the reaction failed in the absence of either one of them (entries
2−3). ZnBr2·TMEDA gave slightly higher yields for the ortho-
arylation. Next, the influence of changing the amount of
Grignard reagent and ZnBr2·TMEDA was investigated (entries
4−5). Reduction of the amount of ZnBr2·TMEDA to 2.0 equiv
gratifyingly increased the yield of the desired product rac-3 to
94%, whereas the formation of the byproduct 4 was limited to 2%
yield. A simultaneous decrease of the amount of phenyl-
magnesium bromide led to a still very high yield of 86% of rac-
3. A ratio of 1:3 between ZnBr2·TMEDA and the Grignard
reagent presumably leads to a shift of the respective Schlenk
After these successful C(sp2)-C(sp2)-bond formation reac-
tions, C(sp2)-C(sp3)-ortho-alkylations in addition to the initial
ortho-benzylation were envisaged. For this purpose, the reactions
of 1 with methyl- and with ethylmagnesium bromide were
examined (Table 2).
The yield of rac-16 could be improved to 45% by increasing
the oil bath temperature from 55 to 85 °C (entries 1−3) At 85 °C
reaction temperature, the starting material was completely
consumed, and 17 was isolated as the byproduct in low yields.
Interestingly, ZnCl2·TMEDA gave a slightly better yield than
ZnBr2·TMEDA (entry 4). A further increase of the reaction
temperature by using the higher boiling methoxycyclopentane
(cyclopentylmethyl ether, CPME)53 as co-solvent did not
improve the yield (entry 5). The use of DCIB instead of DCB
lowered the yield by 10% (entry 6). In contrast to the ortho-
arylation, in spite of a complete consumption of the starting
material, the yield of the desired product remained moderate,
presumably because of the formation of side products. The ortho-
methylation of 1 resulted in a moderate yield of rac-18 at 55 °C
(entries 7−8) alongside of 19 as the result of a 2-fold ortho-
methylation. At 70 °C, there was a complete consumption of 1,
a
Table 1. Investigations of the ortho-Phenylation of 1
entry
ligand (15 mol %)
ZnBr2·TMEDA (equiv)
PhMgBr (equiv)
isolated yield of rac-3 (%)
isolated yield of 4 (%)
1
2
3
4
5
dppe
dppe
3.0
6.0
6.0
6.0
6.0
4.0
85
10
3.0
2.0
2.0
dppe
dppe
94
86
2
6
a
Ferrocenoylamide 1 (0.25 mmol), PhMgBr (3.0 M in Et2O, 1.5 mmol), ZnBr2·TMEDA (0.75 mmol), Fe(acac)3 (10 mol %), dppe (15 mol %),
DCB (0.38 mmol), and THF (2 mL) under inert gas at 55 °C for 16 h.
B
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Scheme 2
conditions of entry 9, two unexpected side products 20 and rac-
21 were isolated and fully characterized (Scheme 4).
Scheme 3
These compounds had formed by an unanticipated dehydro-
genative dimerization of ferrocene derivative 1, and in the case of
rac-21, by a subsequent ortho-methylation of 20. The formation
of these compounds accounts for the moderate yield of the
desired 1,2-disubstituted product rac-18. Regarding the ortho-
ethylation under the conditions of entry 3, 20 could also be
isolated in 9% yield. It was possible to obtain crystals of 20
suitable for an X-ray crystal structure analysis (Figure 1).
Interestingly, 20 exists only in its racemic form. DFT-calculations
showed that the rac-form is slightly more stable in the ground
state than the meso-form.54 The steric hindrance between the 8-
aminoquinolinyl and ferrocenyl groups is probably more
accentuated in the meso-form.
The dehydrogenative dimerization of ODG-substituted
arenes, e.g., under cobalt promotion55 or cobalt,56 palladium57,58
or ruthenium catalysis,59 is well-known but unprecedented in
and 19 was obtained as the main product (entry 9), indicating
that the catalytic ortho-methylation showed a higher reactivity in
comparison to the previously tested ortho-ethylation. Under the
ferrocene chemistry. Jackle et al. succeeded in the stereoselective
̈
Negishi coupling and dimerization of a chiral ferrocenyl
sulfoxide.60 The formation of 20 represents the first example of
a
Table 2. Optimization of the ortho-Ethylation and -Methylation of 1
entry
RMgBr
ZnX2·TMEDA
oil bath temperature (°C)
product (yield)
product (yield)
1
2
3
4
EtMgBr
EtMgBr
EtMgBr
EtMgBr
EtMgBr
EtMgBr
MeMgBr
MeMgBr
MeMgBr
X = Br
X = Br
X = Br
X = Cl
X = Br
X = Cl
X = Br
X = Cl
X = Br
55
70
rac-16 (23%)
rac-16 (36%)
rac-16 (45%)
rac-16 (48%)
rac-16 (39%)
rac-16 (38%)
rac-18 (38%)
rac-18 (42%)
rac-18 (22%)
17 (0%)
17 (0%)
85
17 (4%)
85
17 (traces)
17 (traces)
17 (traces)
19 (17%)
19 (7%)
b
5
110
85
c
6
7
8
9
55
55
70
19 (31%)
a
Ferrocenoylamide 1 (0.25 mmol), MeMgBr (3.0 M in Et2O, 1.5 mmol) or EtMgBr (1.0 M in THF, 1.5 mmol), ZnX2·TMEDA (0.75 mmol),
b
Fe(acac)3 (10 mol %), dppe (15 mol %), DCB (0.38 mmol), and THF (2 mL) under inert gas at 55−85 °C for 16 h. Isolated yields: CPME/THF
1:1 (2 mL) as solvent at 110 °C. Isolated yields: DCIB (0.38 mmol) instead of DCB.
c
C
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Scheme 4
system did not lead to significantly better results for the
alkylation.
As the most promising results were obtained with the ortho-
phenylation of 1 and 5, respectively, the following attempts
toward an enantioselective iron-catalyzed C−H activation were
conducted with this reaction (Table 3).
A range of commercially available chiral P,P-ligands was tested
as sources of chirality in the enantioselective C−H activation. It
was striking that an alkylchain-backbone was mandatory, as no
reaction took place in the presence of (S)-BINAP as chiral ligand
(entry 1). (R,R)-Chiraphos has an obvious similarity with dppe
and consequently gave the highest yield and enantiomeric excess
with either one, 1 and 5, as starting material. (+)-3 was obtained
in 95% yield and 43% ee, and (+)-6 was obtained in 89% yield
and 46% ee (entries 2−3). Other chiral ligands with an ethylene
bridge gave high (entries 6, 10) or low (entry 5) yields, but the
measured enantiomeric excesses were not as good as for (R,R)-
Chiraphos. Longer alkyl backbones between the two phosphorus
atoms resulted in both poorer yields and enantiomeric excesses.
Unfortunately, we had to cope with issues in reproducing the
promising results obtained with (R,R)-Chiraphos as the chiral
ligand (entries 2−3). The yields were consistently excellent, but
the measured ee fluctuated in a range of 20 to 46%. At 23 °C
reaction temperature, the yield was still very good, but the ee did
not improve and was 36% ee as the best result of two conducted
reactions (entry 4). Besides, different alkyldihalides (DCIB, 1,2-
dichloroethane, trans-1,2-dichlorocyclohexane) were tested
under the conditions of entry 4, all resulting in lower ee than
with using DCB. Yet, in an NMR experiment with a slight excess
of DCB, we could exclude by integration of the 1H NMR signals
of the meso and the rac diastereoisomers of DCB before and after
the reaction that one of them had preferentially been consumed.
A deeper understanding of the transfer of chirality into this type
of C−H activation is therefore mandatory in order to achieve
higher enantioselectivities in a reliable manner. Nevertheless, we
could provide an encouraging first example for an enantiose-
lective iron-catalyzed C−H activation of ODG-substituted
ferrocenes, and with (R,R)-Chiraphos as the lead structure, it
will presumably be possible to improve the enantioselectivity of
this ortho-arylation and related ortho-functionalization reactions
at ferrocenes.
Figure 1. Structure of 20 in the crystal. Hydrogen atoms omitted for
clarity; blue (C), orange (Fe), violet (N), red (O) (see Accession Code
information).
a dehydrogenative dimerization of an ODG-substituted
ferrocene derivative by C−H activation. Further investigations
to improve the yield of 20 and to study the mechanistic details are
currently underway. With 5 as the starting material, the yields of
the desired ortho methylation and ethylation products rac-22 and
rac-24 were low to moderate, with the difference that products of
a dehydrogenative dimerization of 5 could not be identified
(Scheme 4).
To improve the yields of the alkylation, a benzylation using the
method recently introduced by Cook et al.61,62 was tested.
Treatment of 1 with 10 mol % of Fe(acac)3 in the presence of 15
mol % of dppe, 3.75 equiv of phenylmagnesium bromide, and 3.0
equiv of benzyl chloride afforded 49% of rac-2. Using the double
amount of Fe(acac)3 and of dppe afforded 57% yield, however,
the high amount of catalyst makes this less attractive. An attempt
toward a methylation resulted in only 22% yield. Thus, the Cook
In a second stereoselective approach, we envisaged that a chiral
bidentate ODG might lead to a diastereoselective iron-catalyzed
D
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a
Table 3. Enantioselective ortho-Phenylation of 1
entry
ligand
(S)-BINAP
reaction temp (°C)
product (isolated yield)
highest ee (%)
1
55
55
55
23
55
23
55
23
55
23
55
no reaction
3 (95%)
6 (89%)
6 (89%)
6 (13%)
6 (83%)
no reaction
6 (46%)
6 (traces)
6 (81%)
6 (traces)
2
(R,R)-Chiraphos
(R,R)-Chiraphos
(R,R)-Chiraphos
(R,R)-i-Pr-BPE
(R,R)-DIPAMP
(R,R)-DIOP
43
46
36
4
3
4
5
6
24
7
8
(R)-Josiphos derivative
(R,R)-BCPM
0
9
10
11
(R)-Prophos
5%
(S,S)-BDPP
a
Ferrocenoylamide 1 (0.2 mmol), PhMgBr (3.0 M in Et2O, 1.2 mmol), ZnBr2·TMEDA (0.6 mmol), Fe(acac)3 (10 mol %), chiral ligand (15 mol %),
DCB (0.3 mmol), and THF (2 mL) under inert gas at 23−55 °C for 16 h. ee determined by chiral HPLC.
Scheme 5
ortho-functionalization. The work of Chen et al. inspired us to
synthesize the chiral ferrocene derivative (S)-26 in a five-step
procedure starting from ferrocenecarboxylic acid and 2-amino-2-
methylpropanoic acid63 and to test this compound as the starting
material in the iron-catalyzed C−H activation (Scheme 5). The
ortho-methylation of (S)-26 at 85 °C with dppe as the ligand
E
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yielded the desired product 27 reproducibly in 17% yield
together with dimethylation product (S)-28 in 31% yield and
EXPERIMENTAL SECTION
■
General Information. All reactions were carried out in an argon
atmosphere using the Schlenk technique. Reaction vessels were heated
at reduced pressure with a heat gun and flushed with argon prior to use.
This procedure was repeated three times. THF was distilled from
sodium wire/benzophenone under argon. N,N,N′,N′-Tetramethyl-
ethane-1,2-diamine (TMEDA) was distilled from CaH2 and collected
in a Schlenk flask over molecular sieves (4 Å) under argon. 1,68 5,45
ZnX2·TMEDA (X = Cl, Br),69 ferrocenecarboxylic acid,70 2-(2-pyridyl)-
2-propanamine,52 and 1,2-dichloro-2-methylpropane (dichloroisobu-
tane, DCIB)71 were synthesized according to literature procedures.
Commercially unavailable Grignard reagents were prepared according
to a literature protocol72 and titrated prior to use.73 All other chemicals
were obtained from commercial sources and were used without further
purification. 1H and 13C NMR spectra were recorded with Bruker
Ultrashield 400 MHz or Ascend 400 MHz (1H, 400 MHz; 13C, 100.6
MHz) instruments. Chemical shifts (δ) are reported in parts per million
(ppm) referenced to residual solvent signals as internal standards. 19F
NMR spectra were referenced to benzotrifluoride as external standard.
IR spectra were measured with a Perkin-Elmer FT 1710 spectrometer;
intensities are indicated as br (broad), s (strong), m (medium), and w
(weak). High-resolution mass spectra (HRMS) were recorded with a
Micromass LCT spectrometer with a lock-spray unit (ESI). Analytical
TLC was performed with Merck 60F-254 silica gel thin-layer plates.
Column chromatography was performed with J. T. Baker silica gel (60
μm) as the stationary phase. Petroleum ether (bp 40−60 °C) and ethyl
acetate as eluents were obtained in analytical reagent grade and used
without further purification. Melting points were measured with an
Electrothermal IA9000 instrument. Specific rotations were measured
with a Perkin-Elmer 341 polarimeter. Chiral HPLC was performed with
a Beckmann System Gold (125 Solvent Module, 166 Detector)
instrument using a Chiralcel OJ or Chiralcel OD-H column with
hexane/2-propanol 9:1 as the eluent and with a flow rate of 0.5 mL/min.
N-[2-(2-Pyridyl)propan-2-yl]ferrocenoylamide (8). Ferrocenecar-
boxylic acid (0.96 g, 4.2 mmol) was placed in a Schlenk tube and
dissolved in CH2Cl2 (40 mL). At 23 °C, oxalyl chloride (0.72 mL, 8.3
mmol) was added dropwise. After the evolution of gas had finished, the
reaction mixture was stirred for an additional 30 min. The solvent was
removed under reduced pressure. The obtained ferrocenoyl chloride
was dissolved in CH2Cl2 (15 mL) and subsequently added dropwise at
23 °C to a solution of 2-(2-pyridyl)-2-propaneamine (1.10 g, 8.3 mmol)
and pyridine (2.1 mL, 25.8 mmol) in CH2Cl2 (15 mL). The reaction
mixture was stirred for 16 h and afterward quenched with satd aq
NaHCO3 (15 mL). The aqueous layer was extracted with portions of
CH2Cl2 (10 mL) until the organic layer was colorless. The combined
organic layers were washed with brine (30 mL), dried with MgSO4,
filtered, and concentrated at reduced pressure. Column chromatography
(30 cm × 5 cm, petroleum ether/ethyl acetate 6:1 to 2:1) afforded 8
(0.87 g, 2.5 mmol, 60%) as a yellow solid (mp 153−155 °C).
Spectroscopic data are missing in the literature.50 1H NMR (400 MHz,
CDCl3): δ = 1.86 (s, 6H, CH3), 4.22 (s, 5H, CpH), 4.33 + 4.75 (AA′BB′,
2 × 2H, CpH), 7.23 (dd, J = 7.3, 4.9 Hz, 1H, C5H4N), 7.47 (d, J = 8.1 Hz,
1H, C5H4N), 7.75 (dt, J = 7.8, 1.7 Hz, 1H, C5H4N), 8.24 (br s, 1H, NH),
8.59−8.60 (m, 1H, C5H4N) ppm. 13C NMR (CDCl3, 100.6 MHz): δ =
27.9 (CH3), 56.6 [C(CH3)2], 68.4 (CCpH), 69.9 (C5H5), 70.2 (CCpH),
78.2 (CCpC), 119.7 (CPyH), 122.0 (CPyH), 137.3 (CPyH), 147.8
unreacted starting material (45%). Fortunately, the 1H and 13
C
NMR spectra of 27 showed only one set of signals, respectively.
To compare this highly diastereoselective ortho-methylation of
(S)-26, a diastereoselective ortho-lithiation protocol followed by
quenching with methyl iodide was tested. In this case, 27 was
obtained in 34% yield in a diastereomeric ratio of 1.7:1 in favor of
the diastereomer, which had been formed in the diastereose-
lective ortho-methylation (see Supporting Information). To
determine the absolute configuration, 27 was transformed into
the literature-known carboxylic acid 29.64 The measurement of
the specific rotation of the product and the comparison with the
reported specific rotation proved that we had (Sp)-29 in hand.
Therefore, (S,Sp)-27 had been obtained. Unfortunately, the
ortho-phenylation of (S)-26 under the same conditions as the
ortho-methylation gave no conversion. This matches our
observation in related cobalt catalyzed reactions, which gave
only poor yields in attempted phenylations.25 Yet, (S)-26 is a
promising chiral substrate for other diastereoselective metal-
catalyzed C−H activation reactions.
The removal of an ODG represents a useful method for
subsequent functionalization steps after the desired C−H
activation.65 In this context, we intended to transform the
secondary amide rac-13 into an aldehyde by following a protocol
developed by Charette et al.66 (Scheme 6). Remarkably, instead
Scheme 6
of an aldehyde, the nitrile rac-30 was obtained in 68% yield. The
observation of the characteristic IR band for nitriles at 2220 cm−1
1
as well as the H and 13C NMR-spectra of rac-30 are fully
consistent. Beller et al. reported a similar hydrosilane-mediated
dehydration of amides to nitriles.67
CONCLUSION
■
In summary, we were able to achieve the iron-catalyzed ortho-
functionalization of ODG-substituted ferrocene compounds by
directed C−H activation with C(sp2)-C(sp2) or C(sp2)-C(sp3)
coupling. The ortho-arylation delivered good to excellent and in
general better yields than the conducted ortho-alkylation
reactions. The moderate yields of the investigated ortho-
methylation and -ethylation of 1 are explained by the occurrence
of an unprecedented dehydrogenative dimerization of the
ferrocene derivative and a subsequent ortho-alkylation, which
lowered the yields of the desired C−H activation. The first
enantioselective ortho-phenylation of 1 and 5 with (R,R)-
Chiraphos as the chiral ligand gave excellent yields and an
enantiomeric excess of up to 46%. Furthermore, the highly
diastereoselective ortho-methylation of (S)-26 yielded the
desired product in ≥99% de, albeit in a low yield. These are
the first promising examples for stereoselective iron-catalyzed
C−H activation reactions at ferrocenes, and as such the starting
point for further studies directed toward enantioselective iron-
catalyzed C−H activation, which will include not only
phosphane but also N-heterocyclic carbene ligands.26,46
(C H), 165.0 (C C), 169.4 (CO) ppm. IR (ATR): v = 3335 (w),
̃
Py
Py
2970 (w), 1632 (s), 1589 (w), 1570 (w), 1520 (s), 1466 (m), 1431 (m),
1298 (s), 1221 (m), 1105 (m), 1049 (m), 1015 (m), 851 (s), 785 (s),
748 (s), 625 (s) cm−1. HRMS (ESI) m/z calcd for C19H21FeN2O [(M +
H)+] 349.1003, found 349.1003.
General Procedure (GP) for the Iron-Catalyzed ortho-
Arylation and -Alkylation. At 23 °C, ferrocenoylamide (0.25
mmol, 1.0 equiv) and ZnBr2·TMEDA (256 mg, 0.75 mmol) or
ZnCl2·TMEDA (189 mg, 0.75 mmol) were placed in a Schlenk tube and
dissolved in THF (1 mL). The Grignard reagent (1.5 mmol) was added
dropwise, and the reaction mixture was stirred for 10 min. A solution of
Fe(acac)3 (11 mmol, 0.03 mmol) and dppe (16 mg, 0.04 mmol) in THF
(1 mL) was added dropwise with a syringe followed by the addition of
F
DOI: 10.1021/acs.organomet.7b00799
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
DCB (40 μL, 0.4 mmol). The reaction mixture was heated for 16 h at
55−85 °C oil bath temperature, then it was cooled to 23 °C. CH2Cl2 (5
mL) and satd aq NH4Cl (5 mL) were added, and the aqueous layer was
extracted with portions of CH2Cl2 (5 mL) until the organic layer was
colorless. The combined organic layers were washed with brine (10
mL), dried with MgSO4, filtered, and concentrated at reduced pressure.
The crude product was purified by column chromatography with
petroleum ether/ethyl acetate or toluene/ethyl acetate as eluent.
N-(8-Quinolinyl)-2-benzylferrocenoylamide (rac-2). GP; 1 (90 mg,
0.25 mmol), ZnCl2·TMEDA, and BnMgCl (1.4 M in THF, 1.1 mL, 1.5
mmol) at 70 °C oil bath temperature; column chromatography (25 cm
× 2.5 cm; petroleum ether/ethyl acetate 10:1) afforded rac-2 (12 mg,
0.03 mmol, 11%) as an orange oil. 1H NMR (400 MHz, [D6]acetone): δ
= 3.97 (d, J = −14.8 Hz, 1H, CH2), 4.32 (s, 5H, CpH), 4.41 (ABC, 1H,
CpH), 4.44 (ABC, 1H, CpH), 4.48 (d, J = −14.8 Hz, 1H, CH2), 4.87
(ABC, 1H, CpH), 7.12−7.16 (m, 1H, C6H5), 7.22−7.26 (m, 2H, C6H5),
7.38 (d, J = 7.4 Hz, 2H, C6H5), 7.62−7.66 (m, 3H, C9H6N), 8.40 (dd, J =
8.3, 1.6 Hz, 1H, C9H6N), 8.81 (dd, J = 7.0 Hz, 1.9 Hz, 1H, C9H6N), 8.99
(dd, J = 4.2 Hz, 1.6 Hz, 1H, C9H6N), 10.43 (s, 1H, NH) ppm. 13C NMR
(100.6 MHz, [D6]acetone): δ = 35.2 (CH2), 69.2 (CCpH), 69.6 (CCpH),
71.4 (C5H5), 73.3 (CCpH), 76.2 (CCpC), 90.9 (CCpC), 116.5 (CQuinH),
121.9 (CQuinH), 123.0 (CQuinH), 126.6 (CArH), 128.1 (CQuinH), 128.9
(CArH), 129.2 (CQuinC), 129.6 (CArH), 136.0 (CQuinC), 137.5 (CQuinH),
139.3 (CQuinC), 143.1 (CArC), 149.6 (CQuinH), 169.8 (CO) ppm. IR
(m), 1499 (s), 1449 (m), 1362 (m), 1277 (m), 1107 (m), 1049 (m),
1001 (m), 908 (m), 820 (m), 764 (s), 723 (s), 694 (s) cm−1. HRMS
(ESI) m/z calcd for C35H33FeN4O [(M + H)+] 581.2004, found
581.2000.
rac-6: 1H NMR (400 MHz, CDCl3): δ = 1.58 (s, 3H, CH3), 1.64 (s,
3H, CH3), 4.18 (s, 5H, CpH), 4.37 (ABC, 1H, CpH), 4.44 (ABC, 1H,
CpH), 4.84 (ABC, 1H, CpH), 5.49 (s, 2H, CH2), 6.12 (br s, 1H, NH),
7.28−7.37 (m, 8H, C6H5), 7.41 (s, 1H, CH), 7.58 (d, J = 7.2 Hz, 2H, Cp-
C6H5) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 27.8 (CH3), 28.2
(CH3), 51.3 [C(CH3)2], 54.2 (CH2), 68.8 (CCpH), 70.6 (CCpH), 71.1
(C5H5), 72.9 (CCpH), 76.7 (CCpC), 88.7 (CCpC), 120.8 (CH), 127.5
(CPhH), 128.2 (CPhH), 128.3 (CPhH), 128.7 (CPhH), 129.2 (CPhH),
130.8 (CPhH), 135.0 (CPhC), 136.7 (CPhC), 153.5 (BnNCHC), 169.2
(CO) ppm. IR (ATR): v = 3374 (w), 3117 (w), 2972 (w), 1638 (s),
̃
1600 (w), 1514 (s), 1503 (s), 1454 (m), 1287 (s), 1217 (m), 1049 (s),
818 (s), 760 (s), 737 (w), 718 (s), 696 (s) cm−1. HRMS (ESI) m/z calcd
for C29H29FeN4O [(M + H)+] 505.1691, found 505.1685.
N-[2-(2-Pyridyl)propan-2-yl]-2-phenylferrocenoylamide (rac-9).
GP; 8 (90 mg, 0.25 mmol), ZnBr2·TMEDA, and PhMgBr (3 M in
Et2O, 0.5 mL, 1.5 mmol) at 70 °C oil bath temperature; column
chromatography (25 cm × 2.5 cm; petroleum ether/ethyl acetate 4:1)
afforded rac-9 (75 mg, 0.18 mmol, 68%) as an orange oil. 1H NMR (400
MHz, CDCl3): δ = 1.72 (s, 3H, CH3), 1.76 (s, 3H, CH3), 4.27 (s, 5H,
CpH), 4.38 (ABC, 1H, CpH), 4.48 (ABC, 1H, CpH), 4.88 (ABC, 1H,
CpH), 7.09−7.11 (m, 1H, C5H4N), 7.20−7.30 (m, 3H, C6H5), 7.36 (d, J
= 8.2 Hz, 1H, C5H4N), 7.62−7.68 (m, 3H, C5H4N + C6H5), 7.84 (br s,
1H, NH), 8.27−8.28 (m, 1H, C5H4N) ppm. 13C NMR (100.6 MHz,
CDCl3): δ = 27.5 (CH3), 27.8 (CH3), 56.9 [C(CH3)2], 68.5 (CCpH),
70.5 (CCpH), 71.1 (C5H5), 72.6 (CCpH), 78.3 (CCpC), 88.8 (CCpC),
119.4 (CPyH), 121.6 (CPyH), 127.1 (CPhH), 128.0 (CPhH), 130.6
(CPhH), 136.9 (CPyH), 137.0 (CPhC), 147.6 (CPyH), 164.6 (CPyC),
(ATR): v = 3350 (w), 3026 (w), 2918 (w), 1701 (w), 1665 (s), 1518 (s),
̃
1483 (s), 1423 (s), 1381 (s), 1325 (s), 1244 (m), 1105 (m), 999 (m),
880 (m), 824 (s), 791 (s), 702 (s), 486 (s) cm−1. HRMS (ESI) m/z calcd
for C27H23FeN2O [(M + H)+] 447.1160, found 447.1161.
N-(8-Quinolinyl)-2-phenylferrocenoylamide (rac-3) and N-(8-
Quinolinyl)-2,5-diphenylferrocenoylamide (4).54 GP; 1 (90 mg, 0.25
mmol), ZnBr2·TMEDA, and PhMgBr (3 M in Et2O, 0.5 mL, 1.5 mmol)
at 55 °C oil bath temperature; column chromatography (25 × 2.5 cm;
toluene/ethyl acetate 20:1).
168.9 (CO) ppm. IR (ATR): v = 2930 (w), 2833 (w), 1603 (m), 1557
̃
(w), 1510 (s), 1462 (m), 1439 (m), 1418 (m), 1302 (m), 1246 (s), 1173
(s), 1107 (m), 1032 (s), 957 (m), 816 (s), 779 (m), 750 (m), 441 (s)
cm−1. HRMS (ESI) m/z calcd for C25H25FeN2O [(M + H)+] 425.1316,
found 425.1316.
I: 4 (13 mg, 0.03 mmol, 10%) was isolated as an orange oil, and
identified spectroscopically (1H NMR54).
II: rac-3 (92 mg, 0.2 mmol, 85%) was isolated as an orange oil.
1
rac-3: H NMR (400 MHz, CDCl3): δ = 4.34 (s, 5H, CpH), 4.51
N-(8-Quinolinyl)-2-(4-methylphenyl)ferrocenoylamide (rac-10).
GP; 1 (100 mg, 0.28 mmol, 1.0 equiv), ZnBr2·TMEDA, and 4-
methylphenylmagnesium bromide (1 M in THF, 1.7 mL, 1.7 mmol) at
85 °C oil bath temperature; column chromatography (25 × 2.5 cm;
toluene/ethyl acetate 20:1) afforded rac-10 (86 mg, 0.19 mmol, 69%) as
an orange oil. 1H NMR (400 MHz, CDCl3): δ = 2.33 (s, 3H, CH3), 4.34
(s, 5H, CpH), 4.49 (ABC, 1H, CpH), 4.61 (ABC, 1H, CpH), 5.03
(ABC, 1H, CpH), 7.10−7.12 + 7.56−7.58 (AA′BB′, 2 × 2H, C6H4),
7.37 (dd, J = 8.2, 4.2 Hz, 1H, C9H6N), 7.45−7.48 (m, 1H, C9H6N), 7.53
(d, J = 7.9 Hz, 1H, C9H6N), 8.11 (dd, J = 8.2, 1.6 Hz, 1H, C9H6N), 8.52
(dd, J = 4.2, 1.6 Hz, 1H, C9H6N), 8.81 (dd, J = 7.6, 1.3 Hz, 1H, C9H6N),
10.30 (br s, 1H, NH) ppm. 13C NMR (CDCl3, 100.6 MHz): δ = 21.3
(CH3), 69.1 (CCpH), 70.5 (CCpH), 71.4 (C5H5), 73.1 (CCpH), 76.9
(CCpC), 89.6 (CCpC), 116.1 (CQuinH), 121.0 (CQuinH), 121.5 (CQuinH),
127.6 (CQuinH), 128.0 (CQuinC), 128.9 (CArH), 130.3 (CArH), 133.4
(CArC), 135.1 (CQuinC), 136.1 (CQuinH), 136.9 (CArC), 138.6 (CQuinC),
(ABC, 1H, CpH), 4.64 (ABC, 1H, CpH), 5.05 (ABC, 1H, CpH), 7.27−
7.32 (m, 3H, C6H5), 7.36 (dd, J = 8.3, 4.2 Hz, 1H, C9H6N), 7.45−7.48
(m, 1H, C9H6N), 7.52−7.56 (m, 1H, C9H6N), 7.68−7.70 (m, 2H,
C6H5), 8.10 (dd, J = 8.3, 1.7 Hz, 1H, C9H6N), 8.51 (dd, J = 4.2, 1.7 Hz,
1H, C9H6N), 8.80−8.82 (m, 1H, C9H6N), 10.28 (br s, 1H, NH) ppm.
13C NMR (100.6 MHz, CDCl3): δ = 69.2 (CCpH), 70.7 (CCpH), 71.5
(C5H5), 73.4 (CCpH), 77.0 (CCpC), 89.5 (CCpC), 116.1 (CQuinH), 121.1
(CQuinH), 121.5 (CQuinH), 127.2 (CPhH), 127.6 (CQuinH), 128.0
(CQuinC), 128.2 (CPhH), 130.5 (CPhH), 135.0 (CQuinC), 136.1
(CQuinH), 136.6 (CPhC), 138.6 (CQuinC), 147.9 (CQuinH), 169.0 (C
O) ppm. IR (ATR): v = 3310 (w), 3051 (w), 1663 (s), 1518 (s), 1481
̃
(s), 1448 (m), 1423 (s), 1383 (m), 1325 (s), 1242 (m), 1123 (m), 1107
(m), 1001 (m), 874 (m), 824 (s), 791 (s), 762 (s), 694 (s) cm−1. HRMS
(ESI) m/z calcd for C26H21FeN2O [(M + H)+] 433.1003, found
433.1005.
147.8 (CQuinH), 169.2 (CO) ppm. IR (ATR): v = 3306 (w), 2918
̃
N-[2-(1-Benzyl-1H-1,2,3-triazol-4-yl)propan-2-yl]-2-phenylferro-
cenoylamide (rac-6) and N-[2-(1-Benzyl-1H-1,2,3-triazol-4-yl)-
propan-2-yl]-2,5-diphenylferrocenoyl-amide (7). GP; 5 (120 mg,
0.28 mmol, 1.0 equiv), ZnBr2·TMEDA, and PhMgBr (3 M in Et2O, 0.57
mL, 1.7 mmol) at 55 °C oil bath temperature; column chromatography
(25 cm × 2.5 cm; petroleum ether/ethyl acetate 4:1 to 2:1).
I: 7 (22 mg, 0.04 mmol, 14%) was isolated as an orange oil.
II: rac-6 (118 mg, 0.23 mmol, 84%) was isolated as an orange solid
(mp 114.5−115.5 °C).
(w), 1661 (s), 1595 (w), 1578 (w), 1516 (s), 1481 (s), 1423 (s), 1381
(s), 1325 (s), 1107 (m), 1101 (m), 874 (m), 816 (s), 789 (s), 486 (s)
cm−1. HRMS (ESI) m/z calcd for C27H23FeN2O [(M + H)+] 447.1160,
found 447.1161.
N-(8-Quinolinyl)-2-(4-trifluoromethylphenyl)ferrocenoylamide
(rac-11). GP; 1 (100 mg, 0.28 mmol, 1.0 equiv), ZnBr2·TMEDA, and
(4-trifluoromethyl-phenyl)magnesium bromide (1 M in THF, 1.7 mL,
1.7 mmol) at 85 °C oil bath temperature; column chromatography (25
cm × 2.5 cm; toluene/ethyl acetate 20:1) afforded rac-11 (81 mg, 0.16
mmol, 58%) as a red oil. 1H NMR (400 MHz, CDCl3): δ = 4.35 (s, 5H,
CpH), 4.57 (ABC, 1H, CpH), 4.69 (ABC, 1H, CpH), 5.08 (ABC, 1H,
CpH), 7.40 (dd, J = 8.2, 4.2 Hz, 1H, C9H6N), 7.48−7.57 (m, 4H, C6H4 +
C9H6N), 7.78−7.80 (AA′BB′, 2H, C6H4), 8.14 (dd, J = 8.3, 1.6 Hz, 1H,
C9H6N), 8.54 (dd, J = 4.2, 1.7 Hz, 1H, C9H6N), 8.80 (dd, J = 7.5, 1.4 Hz,
1H, C9H6N), 10.30 (br s, 1H, NH) ppm. 13C NMR (CDCl3, 100.6
MHz): δ = 69.8 (CCpH), 71.2 (CCpH), 71.7 (C5H5), 73.3 (CCpH), 77.3
(CCpC), 87.4 (CCpC), 116.1 (CQuinH), 121.4 (CQuinH), 121.7 (CQuinH),
7: 1H NMR (400 MHz, CDCl3): δ = 1.66 (s, 6H, CH3), 4.18 (s, 5H,
CpH), 4.61 (s, 2H, CpH), 5.47 (s, 2H, CH2), 6.71 (br s, 1H, NH), 7.21−
7.25 (m, 8H, C6H5), 7.32 (s, 1H, CH), 7.34−7.37 (m, 3H, C6H5), 7.51−
7.53 (m, 4H, C6H5) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 27.6
(CH3), 52.0 [C(CH3)2], 54.2 (CH2), 68.3 (CCpH), 72.6 (C5H5), 83.9
(CCpC), 88.1 (CCpC), 120.9 (CH), 126.9 (CpCPhH), 128.05 (CpCPhH),
128.07 (CH2CPhH), 128.8 (CH2CPhH), 129.0 (CpCPhH), 129.2
(CH2CPhH), 135.0 (CH2CPhC), 137.1 (CpCPhC), 153.5 (BnNCHC),
167.9 (CO) ppm. IR (ATR): v = 3397 (w), 2974 (w), 1655 (s), 1601
̃
G
DOI: 10.1021/acs.organomet.7b00799
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
124.5 (q, JC,F = 272 Hz, CF3), 125.0 (q, JC,F = 3.8 Hz, CArH), 127.6
(CQuinH), 128.1 (CQuinC), 129.1 (q, JC,F = 32 Hz, CArCF3), 130.5
(CArH), 134.8 (CQuinC), 136.3 (CQuinH), 138.5 (CQuinC), 141.2 (d, JC,F
= 1.5 Hz, CArC), 148.0 (CQuinH), 168.6 (CO) ppm. 19F NMR (376.5
1153 (m), 1121 (s), 1105 (s), 1070 (s), 1049 (s), 841 (s), 824 (s), 775
(m), 719 (s) cm−1. HRMS (ESI) m/z calcd for C30H28FeN4OF3 [(M +
H)+] 573.1565, found 573.1561.
N-[2-(1-Benzyl-1H-1,2,3-triazol-4-yl)propan-2-yl]-2-(4-
methoxyphenyl)ferrocenoylamide (rac-15). GP; 5 (107 mg, 0.25
mmol), ZnBr2·TMEDA, and 4-methoxyphenylmagnesium bromide
(0.5 M in THF, 3.0 mL, 1.5 mmol) at 85 °C oil bath temperature;
column chromatography (25 cm × 2.5 cm; petroleum ether/ethyl
acetate 4:1 to 2:1) affored rac-15 (109 mg, 0.20 mmol, 82%) as a yellow
oil. 1H NMR (400 MHz, CDCl3): δ = 1.59 [s, 3H, C(CH3)2], 1.64 [s,
3H, C(CH3)2], 3.83 (s, 3H, OCH3), 4.17 (s, 5H, CpH), 4.34 (ABC, 1H,
CpH), 4.38 (ABC, 1H, CpH), 4.81 (ABC, 1H, CpH), 5.49 (s, 2H, CH2),
6.16 (br s, 1H, NH), 6.87−6.89 + 7.50−7.52 (AA′BB′, 2 × 2H, C6H4),
7.27−7.28 (m, 2H, C6H5), 7.33−7.39 (m, 3H, C6H5), 7.43 (s, 1H, CH)
ppm. 13C NMR (CDCl3, 100.6 MHz): δ = 27.8 [C(CH3)2], 28.3
[C(CH3)2], 51.2 [C(CH3)2], 54.2 (CH2), 55.5 (OCH3), 68.6 (CCpH),
70.4 (CCpH), 71.0 (C5H5), 72.8 (CCpH), 76.3 (CCpC), 88.5 (CCpC),
113.8 (CArH), 120.9 (CH), 128.2 (CPhH), 128.4 (CArC), 128.8 (CPhH),
129.2 (CPhH), 131.9 (CArH), 135.0 (CPhC), 153.5 (BnNCHC), 159.2
MHz, CDCl ): δ = −63.39 (s, CF ) ppm. IR (ATR): v = 3325 (w), 1736
̃
3
3
(w), 1665 (s), 1616 (m), 1518 (s), 1483 (s), 1425 (m), 1321 (s), 1242
(m), 1161 (s), 1119 (s), 1103 (s), 1069 (s), 1001 (m), 843 (s), 791 (s)
cm−1. HRMS (ESI) m/z calcd for C27H19FeN2OF3Na [(M + Na)+]
523.0697, found 523.0697.
N-(8-Quinolinyl)-2-(4-methoxyphenyl)ferrocenoylamide (rac-12).
GP; 1 (90 mg, 0.25 mmol), ZnBr2·TMEDA, and 4-methoxyphenyl-
magnesium bromide (0.5 M in THF, 3.0 mL, 1.5 mmol) at 85 °C oil
bath temperature; column chromatography (25 cm × 2.5 cm; petroleum
ether/ethyl acetate 8:1 to 5:1) affored rac-12 (104 mg, 0.23 mmol, 90%)
as an orange oil.
1H NMR (400 MHz, CDCl3): δ = 3.78 (s, 3H, OCH3), 4.33 (s, 5H,
CpH), 4.48 (ABC, 1H, CpH), 4.58 (ABC, 1H, CpH), 5.03 (ABC, 1H,
CpH), 6.84−6.86 + 7.60−7.62 (AA′BB′, 2 × 2H, C6H4), 7.37 (dd, J =
8.2, 4.2 Hz, 1H, C9H6N), 7.45−7.48 (m, 1H, C9H6N), 7.52−7.56 (m,
1H, C9H6N), 8.11 (dd, J = 8.2, 1.6 Hz, 1H, C9H6N), 8.53 (dd, J = 4.2, 1.6
Hz, 1H, C9H6N), 8.81 (dd, J = 7.6, 1.2 Hz, 1H, C9H6N), 10.29 (br s, 1H,
NH) ppm. 13C NMR (CDCl3, 100.6 MHz): δ = 55.4 (OCH3), 69.0
(CCpH), 70.4 (CCpH), 71.3 (C5H5), 73.1 (CCpH), 76.7 (CCpC), 89.5
(CCpC), 113.7 (CArH) 116.1 (CQuinH), 121.0 (CQuinH), 121.5 (CQuinH),
127.6 (CQuinH), 128.0 (CQuinC), 128.5 (CArC), 131.6 (CArH), 135.1
(CQuinC), 136.1 (CQuinH), 138.6 (CQuinC), 147.8 (CQuinH), 159.1
(C C), 169.3 (CO) ppm. IR (ATR): v = 3410 (w), 1649 (s), 1609
̃
Ar
(w), 1518 (s), 1456 (m), 1244 (s), 1175 (m), 1105 (m), 1047 (m), 1030
(m), 980 (s), 820 (s), 721 (s) cm−1. HRMS (ESI) m/z calcd for
C30H31FeN4O2 [(M + H)+] 535.1796, found 535.1788.
N-(8-Quinolinyl)-2-ethylferrocenoylamide (rac-16)54 and N-(8-
Quinolinyl)-2,5-diethylferrocenoylamide (17).51 GP; 1 (135 mg, 0.4
mmol, 1.0 equiv), ZnBr2·TMEDA, and EtMgBr (1 M in THF, 2.4 mL,
2.4 mmol) at 85 °C oil bath temperature; column chromatography (25
cm × 2.5 cm; petroleum ether/ethyl acetate 10:1). Compound 17 (6
mg, 0.01 mmol, 4%) was isolated as an orange oil and identified
spectroscopically (1H NMR55). Compound rac-16 (65 mg, 0.17 mmol,
45%) was isolated as an orange oil and identified spectroscopically (1H
NMR49).
(C C), 169.2 (CO) ppm. IR (ATR): v = 3306 (w), 1734 (w), 1659
̃
Ar
(s), 1609 (m), 1516 (s), 1481 (s), 1423 (m), 1381 (m), 1325 (m), 1242
(s), 1175 (m), 1105 (m), 1032 (m), 824 (s), 791 (s), 727 (s) cm−1.
HRMS (ESI) m/z calcd for C27H23FeN2O2 [(M + H)+] 463.1109, found
463.1110.
N-[2-(1-Benzyl-1H-1,2,3-triazol-4-yl)propan-2-yl]-2-(4-
methylphenyl)ferrocenoyl-amide (rac-13). GP; 5 (120 mg, 0.28
mmol, 1.0 equiv), ZnBr2·TMEDA, and (4-methylphenyl)magnesium
bromide (1 M in THF, 1.7 mL, 1.7 mmol) at 85 °C oil bath temperature;
column chromatography (25 cm × 2.5 cm; petroleum ether/ethyl
acetate 4:1 to 2:1) afforded rac-13 (109 mg, 0.21 mmol, 75%) as a yellow
solid (mp 134−136.5 °C). 1H NMR (400 MHz, CDCl3): δ = 1.58 [s,
3H, C(CH3)2], 1.63 [s, 3H, C(CH3)2], 2.36 (s, 3H, ArCH3), 4.18 (s, 5H,
CpH), 4.36 (ABC, 1H, CpH), 4.42 (ABC, 1H, CpH), 4.83 (ABC, 1H,
CpH), 5.49 (s, 2H, CH2), 6.15 (br s, 1H, NH), 7.13−7.15 + 7.26−7.28
(AA′BB′, 2 × 2H, C6H4), 7.33−7.37 (m, 3H, C6H5), 7.45−7.47 (m, 3H,
C6H5 + CH) ppm. 13C NMR (CDCl3, 100.6 MHz): δ = 21.3 (ArCH3),
27.8 [C(CH3)2], 28.3 [C(CH3)2], 51.2 [C(CH3)2], 54.2 (CH2), 68.6
(CCpH), 70.5 (CCpH), 71.0 (C5H5), 72.8 (CCpH), 76.5 (CCpC), 88.6
(CCpC), 120.9 (CH), 128.1 (CPhH), 128.7 (CPhH), 129.0 (CArH), 129.2
(CPhH), 130.6 (CArH), 133.5 (CArC), 135.0 (CPhC), 137.3 (CArC),
N-(8-Quinolinyl)-2-methylferrocenoylcarbamide (rac-18) and N-
(8-Quinolinyl)-2,5-dimethylferrocenoylcarbamide (19).51 GP; 1 (90
mg, 0.25 mmol), ZnCl2·TMEDA, and MeMgBr (3 M in Et2O, 0.5 mL,
1.5 mmol) at 55 °C oil bath temperature; column chromatography (25
cm × 2.5 cm; petroleum ether/ethyl acetate 10:1).
I: 19 (7 mg, 0.02 mmol, 7%) was isolated as an orange oil and
identified spectroscopically (1H NMR51).
II: rac-18 (39 mg, 0.11 mmol, 42%) was isolated as an orange oil.
rac-18: 1H NMR (400 MHz, CDCl3): δ = 2.42 (s, 3H, CH3), 4.25 (s,
5H, C5H5), 4.29 (ABC, 1H, CpH), 4.36 (ABC, 1H, CpH), 4.82 (ABC,
1H, CpH), 7.46−7.60 (m, 3H, ArH), 8.19 (dd, J = 8.3 Hz, 1.7 Hz, 1H,
ArH), 8.81 (dd, J = 7.2 Hz, 1.9 Hz, 1H, ArH), 8.88 (dd, J = 4.4 Hz, 1.7
Hz, 1H, ArH), 10.43 (bs, 1H, NH) ppm. 13C NMR (100.6 MHz,
CDCl3): δ = 14.9 (CH3), 68.2 (CCpH), 68.8 (CCpH), 70.7 (CCpH), 73.3
(CCpH), 75.9 (CCpC), 85.7 (CCpC), 116.2 (CQuinH), 121.1 (CQuinH),
121.7 (CQuinH), 127.7 (CQuinH), 128.2 (CQuinC), 135.1 (CQuinC), 136.5
(CQuinH), 138.8 (CQuinC), 148.4 (CQuinH), 170.3 (CO) ppm. IR
153.5 (BnNCHC), 169.2 (CO) ppm. IR (ATR): v = 3404 (w), 2941
̃
(w), 1638 (s), 1506 (s), 1452 (w), 1348 (m), 1267 (m), 1109 (m), 1051
(m), 1001 (m), 814 (s), 766 (m), 718 (s), 498 (s) cm−1. HRMS (ESI)
m/z calcd for C30H31FeN4O [(M + H)+] 519.1847, found 519.1846.
N-[2-(1-Benzyl-1H-1,2,3-triazol-4-yl)propan-2-yl]-2-(4-
trifluoromethylphenyl)ferrocenoylamide (rac-14). GP; 5 (120 mg,
0.28 mmol, 1.0 equiv), ZnBr2·TMEDA, and (4-trifluoromethylphenyl)
magnesium bromide (1 M in THF, 1.7 mL, 1.7 mmol) at 85 °C oil bath
temperature; column chromatography (25 cm × 2.5 cm; petroleum
ether/ethyl acetate 4:1 to 2:1) afforded rac-14 (112 mg, 0.20 mmol,
70%) as a yellow solid (mp 156−158 °C). 1H NMR (400 MHz, CDCl3):
δ = 1.68 (s, 3H, CH3), 1.72 (s, 3H, CH3), 4.21 (s, 5H, CpH), 4.41 (ABC,
1H, CpH), 4.51 (ABC, 1H, CpH), 4.79 (ABC, 1H, CpH), 5.50 (s, 2H,
CH2), 6.46 (br s, 1H, NH), 7.27−7.29 (m, 2H, C6H5), 7.33−7.39 (m,
3H, C6H5), 7.41 (s, 1H, CH), 7.52−7.54 + 7.66−7.68 (AA′BB′, 2 × 2H,
C6H4) ppm. 13C NMR (CDCl3, 100.6 MHz): δ = 28.1 (CH3), 51.6
[C(CH3)2], 54.3 (CH2), 69.1 (CCpH), 70.8 (CCpH), 71.4 (C5H5), 72.4
(CCpH), 77.9 (CCpC), 86.7 (CCpC), 120.4 (CH), 124.4 (q, JC,F = 272
Hz, CF3), 124.9 (q, JC,F = 3.8 Hz, CArH), 128.2 (CPhH), 128.9 (CPhH),
129.0 (q, JC,F = 32 Hz, CArCF3), 129.3 (CPhH), 130.4 (CArH), 134.8
(CPhC), 141.5 (d, JC,F = 1.5 Hz, CArC), 153.7 (BnNCHC), 168.8 (C
O) ppm. 19F-NMR (376.5 MHz, CDCl3): δ = −63.43 (s, CF3) ppm. IR
(ATR): v = 3352 (w), 2922 (w), 1665 (s), 1593 (w), 1518 (s), 1483 (s),
̃
1424 (m), 1379 (m), 1325 (m), 1072 (m), 999 (m), 881 (m), 824 (s),
789 (s) cm−1. HRMS (ESI) m/z calcd for C21H19FeN2O [(M + H)+]
371.0847, found 371.0848.
meso-N,N′-Bis(8-quinolinyl)-1,1′-diferrocenoylamide (20) and
N,N′-Bis(8-quinolinyl)-2-methyl-1,1′-diferrocenoylamide (rac-21).
GP; 1 (90 mg, 0.25 mmol), ZnBr2·TMEDA, and MeMgBr (3 M in
Et2O, 0.5 mL, 1.5 mmol) at 70 °C oil bath temperature; column
chromatography (25 cm × 2.5 cm; petroleum ether/ethyl acetate 10:1).
I: 19 (29 mg, 0.08 mmol, 31%) was isolated as an orange oil (vide
supra).
II: rac-18 (20 mg, 0.06 mmol, 22%) was isolated as an orange oil (vide
supra).
III: rac-21 (9 mg, 0.01 mmol, 5%) was isolated as an orange oil.
IV: 20 (20 mg, 0.03 mmol, 11%) was isolated as an orange solid (mp
210 °C, dec.).
20: 1H NMR (400 MHz, CDCl3): δ = 4.40 (br s, 10H, 2 × C5H5),
4.56 (m, 2H, CpH), 5.03 (m, 4H, C9H6N), 7.29−7.37 (m, 6H, C9H6N),
8.01−8.04 (m, 2H, C9H6N), 8.59−8.63 (m, 4H, C9H6N), 9.91 (br s, 2H,
NH) ppm. 13C NMR (CDCl3, 100.6 MHz): δ = 69.1 (CCpH), 70.4
(CCpH), 71.2 (C5H5), 76.7 (CCpH), 79.7 (CCpC), 83.4 (CCpC), 116.4
(ATR): v = 3408 (w), 1643 (s), 1616 (m), 1506 (s), 1325 (s), 1267 (m),
̃
H
DOI: 10.1021/acs.organomet.7b00799
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
(CQuinH), 120.7 (CQuinH), 121.4 (CQuinH), 127.4 (CQuinH), 127.9
(CQuinC), 134.9 (CQuinC), 136.0 (CQuinH), 138.6 (CQuinC), 147.7
C6H5), 7.47 (s, 1H, CH) ppm. 13C NMR (CDCl3, 100.6 MHz): δ = 14.7
(CpCH3), 28.5 [C(CH3)2], 51.9 [C(CH3)2], 54.3 (CH2), 69.3 (CCpH),
70.9 (C5H5), 79.9 (CCpC), 83.8 (CCpC), 120.3 (CH), 128.2 (CArH),
128.9 (CArH), 129.3 (CArH), 134.8 (CArC), 154.3 (BnNCHC), 170.2
(CQuinH), 168.4 (CO) ppm. IR (ATR): v = 3306 (w), 2918 (w), 1719
̃
(w), 1655 (s), 1518 (s), 1481 (s), 1423 (m), 1383 (m), 1323 (m), 1258
(m), 1143 (m), 1099 (m), 1003 (m), 826 (s), 791 (s), 762 (s), 478 (s)
cm−1. HRMS (ESI) m/z calcd for C40H31Fe2N4O2 [(M + H)+]
711.1146, found 711.1141.
(CO) ppm. IR (ATR): v = 1649 (s), 1544 (w), 1499 (s), 1377 (m),
̃
1223 (m), 1192 (m), 1165 (m), 1105 (s), 1049 (s), 1001 (s), 814 (s),
723 (s) cm−1. HRMS (ESI) m/z calcd for C25H28FeN4ONa [(M +
Na)+] 479.1510, found 479.1506.
rac-21: 1H NMR (400 MHz, CDCl3): δ = 2.23 (s, 3H, CH3), 4.34 (br
s, 10H, 2 × C5H5), 4.43 (ABC, 1H, Cp′H), 4.49 (d, J = 2.4 Hz, 1H,
CpH), 4.85 (ABC, 1H, Cp′H), 4.90 (d, J = 2.4 Hz, 1H, CpH), 4.99
(ABC, 1H, Cp′H), 7.24−7.25 (m, 2H, C9H6N), 7.31−7.39 (m, 4H,
C9H6N), 8.00 (dd, J = 8.3, 1.7 Hz, 1H, C9H6N), 8.06 (dd, J = 8.2, 1.6 Hz,
1H, C9H6N), 8.53−8.59 (m, 3H, C9H6N), 8.62−8.65 (m, 1H, C9H6N),
9.93 (br s, 2H, NH) ppm. 13C NMR (CDCl3, 100.6 MHz): δ = 15.1
(CH3), 68.9 (CCpH), 69.8 (CCpH), 71.0 (CCpH), 71.2 (C5H5), 71.9
(C5H5), 73.3 (CCpH), 76.5 (CCpH), 79.2 (CCpC), 80.5 (CCpC), 83.2
(CCpC), 84.2 (CCpC), 86.0 (CCpC), 116.0 (CQuinH), 116.3 (CQuinH),
120.6 (CQuinH), 120.7 (CQuinH), 121.29 (CQuinH), 121.31 (CQuinH),
127.3 (CQuinH), 127.5 (CQuinH), 127.8 (CQuinC), 127.9 (CQuinC), 134.8
(CQuinC), 135.0 (CQuinC), 135.9 (CQuinH), 136.0 (CQuinH), 138.5
(CQuinC), 138.6 (CQuinC), 147.56 (CQuinH), 147.63 (CQuinH), 168.4
Enantioselective Phenylation of 1. Table 3, entry 2: GP; 1 (90 mg,
0.25 mmol), ZnBr2·TMEDA (256 mg, 0.75 mmol), (R,R)-Chiraphos
(16 mg, 0.04 mmol), and PhMgBr (3 M in Et2O, 0.5 mL, 1.5 mmol);
column chromatography (25 cm × 2.5 cm, petroleum ether/ethyl
acetate 6:1) afforded (+)-3 (103 mg, 0.24 mmol, 95%) as an orange oil,
[α]D20: + 31.6 (c = 1.0, CHCl3 for 43% ee). The enantiomeric excess was
determined by HPLC: Daicel Chiralcel OJ, hexane/2-propanol as eluent
with a flow rate of 0.5 mL/min, λ = 254 nm, t(minor) = 30.72 min,
t(major) = 36.63 min. For details, see Supporting Information. Entry 3:
GP; 5 (86 mg, 0.2 mmol), ZnBr2·TMEDA (205 mg, 0.6 mmol), (R,R)-
Chiraphos (13 mg, 0.03 mmol), and PhMgBr (3 M in Et2O, 0.4 mL, 1.2
mmol); column chromatography (25 cm × 2.5 cm, petroleum ether/
ethyl acetate 6:1) afforded (+)-6 (90 mg, 0.18 mmol, 89%) as an orange
solid, [α]D20: + 2.7 (c = 1.0, CHCl3 for 46% ee). Analytical data: see rac-
6. The enantiomeric excess was determined by Daicel Chiralcel OD-H,
hexane/2-propanol as eluent with a flow rate of 0.5 mL/min, λ = 254
nm, t(minor) = 48.22 min, t(major) = 54.48 min. For details, see
Supporting Information.
(CO), 168.5 (CO) ppm. IR (ATR): v = 3314 (w), 2922 (w), 1721
̃
(w), 1655 (s), 1518 (s), 1481 (s), 1423 (m), 1381 (m), 1325 (m), 1260
(m), 1107 (m), 1003 (m), 822 (s), 791 (s), 482 (s) cm−1. HRMS (ESI)
m/z calcd for C41H33Fe2N4O2 [(M + H)+] 725.1302, found 725.1304.
Crystal Structure Analysis of 20. Single crystals of 20 were obtained
by crystallization from dichloromethane/hexane (1:5). C40H30Fe2N4O2,
orange plates, Mr = 710.38 g mol−1, crystal system monoclinic, space
group P21/c, a = 15.3908(9), b = 9.0106(5), c = 22.4692(15) Å, β =
96.489(2)°, V = 3096.1(3) Å3, Z = 4, ρcalcd = 1.524 g cm−3, μ = 0.982
mm−1, crystal size 0.16 × 0.28 × 0.58 mm3; F(000) = 1464, Bruker
Smart X2S diffractometer, T = 199(2) K, Mo Kα radiation (λ = 0.71073
Å), 2.44° ≤ θ ≤ 27.50°, index ranges −19 ≤ h ≤ 19, −11 ≤ k ≤ 11, −26
≤ l ≤ 29, reflections collected/unique 41150/7102, parameter/
restraints 433/0, structure solution, and refinement with SHELXL-
2014/7,74 refinement method full-matrix least-squares, multiscan
absorption correction (SADABS), goodness-of-fit on F2 = 1.037, R1 =
0.0426 [I > 2σ(I)], wR2 = 0.0996 (all data), and final difference electron
density 0.478 and −0.295 e Å−3.
(S)-N-[2-(4-Benzyloxazolin-2-yl)propan-2-yl]ferrocenoylamide
[(S)-26]. In a Schlenk flask, (S)-2-(4-benzyloxazolin-2-yl)-2-propanyli-
soindoline-1,3-dione (1.22 g, 3.5 mmol) was dissolved in ethanol (25
mL), and NH2NH2·H2O (85%, 0.7 mL, 10.5 mmol) was added. The
mixture was heated at 70 °C for 3 h. After cooling to 23 °C, the solvent
was evaporated under reduced pressure. The residue was taken up in
diethyl ether (20 mL) and filtered. The solvent was evaporated under
reduced pressure. The amine was dissolved in CH2Cl2 (25 mL), and the
solution was cooled to 0 °C. Then, NEt3 (0.7 mL, 5.3 mmol) was added.
In a second Schlenk flask, ferrocenecarboxylic acid (0.81 g, 3.5 mmol)
was dissolved in CH2Cl2 (25 mL). At 23 °C, oxalyl chloride (0.6 mL, 7.0
mml) was added dropwise. After the evolution of gas had ended, the
reaction mixture was stirred for additional 30 min. The solvent was
evaporated under reduced pressure. The obtained ferrocenoyl chloride
was dissolved in CH2Cl2 (20 mL) and subsequently added at 0 °C to the
other Schlenk flask. 4-(Dimethylamino)pyridine (DMAP, 20 mg, 0.2
mmol) was added, and the mixture was warmed to 23 °C and stirred for
16 h. The reaction was quenched by addition of water (20 mL). After
phase separation, the organic layer was washed with satd aq NaHCO3
(20 mL) and with water (20 mL). The combined aqueous layers were
extracted with CH2Cl2 (20 mL). The combined organic layers were
washed with brine (25 mL), dried with MgSO4, filtered, and
concentrated at reduced pressure. Column chromatography (35 cm ×
5 cm; petroleum ether/ethyl acetate 4:1 to 1:1) afforded (S)-26 (0.76 g,
1.8 mmol, 51%) as a yellow solid (mp 110−112.5 °C). 1H NMR (400
MHz, CDCl3): δ = 1.65 (s, 3H, CH3), 1.67 (s, 3H, CH3), 2.78 (dd, J =
−13.7, 7.6 Hz, 1H, CH2), 3.07 (dd, J = −13.7, 5.4 Hz, 1H, CH2), 4.10−
4.14 (m, 1H, OCH2), 4.22 (s, 5H, CpH), 4.31−4.35 (m, 3H, OCH2 and
CpH), 4.43−4.50 (m, 1H, NCH), 4.67 (AA′BB′, 2H, CpH), 6.98 (s, 1H,
NH), 7.22−7.25 (m, 3H, C6H5), 7.30−7.33 (m, 2H, C6H5) ppm. 13C
NMR (CDCl3, 100.6 MHz): δ = 24.9 (CH3), 25.1 (CH3), 41.6 (CH2),
53.2 [C(CH3)2], 66.7 (NCH), 68.30 (CCpH), 68.33 (CCpH), 69.9
(C5H5), 70.4 (CCpH), 73.1 (OCH2), 77.0 (CCpC), 126.7 (CPhH), 128.6
(CPhH), 129.6 (CPhH), 137.7 (CPhC), 169.3 (CO), 171.5 (CN)
N-[2-(1-Benzyl-1H-1,2,3-triazol-4-yl)propan-2-yl]-2-ethylferroce-
noylamide (rac-22). GP; 5 (120 mg, 0.28 mmol, 1.0 equiv), ZnCl2·
TMEDA, and EtMgBr (1 M in THF, 1.7 mL, 1.7 mmol) at 85 °C oil bath
temperature; column chromatography (25 cm × 2.5 cm; petroleum
ether/ethyl acetate 4:1 to 2:1) affored rac-22 (18 mg, 0.04 mmol, 14%)
as a yellow oil. 1H NMR (400 MHz, CDCl3): δ = 1.17 (t, J = 7.5 Hz, 3H,
CH2CH3), 1.82 (s, 3H, CH3), 1.83 (s, 3H, CH3), 2.58−2.77 (m, 2H,
CH2CH3), 4.11 (s, 5H, CpH), 4.14 (ABC, 1H, CpH), 4.23 (ABC, 1H,
CpH), 4.46 (ABC, 1H, CpH), 5.52 (br. s, 2H, CH2), 6.64 (br s, 1H,
NH), 7.28−7.40 (m, 5H, C6H5), 7.47 (s, 1H, CH) ppm. 13C NMR
(CDCl3, 100.6 MHz): δ = 15.1 (CH2CH3), 22.0 (CH2CH3), 28.43
(CH3), 28.46 (CH3), 51.7 [C(CH3)2], 54.4 (CH2), 67.6 (CCpH), 68.2
(CCpH), 70.3 (C5H5), 70.6 (CCpH), 75.6 (CCpC), 92.2 (CCpC), 120.4
(CH), 128.2 (CArH), 128.9 (CArH), 129.3 (CArH), 134.9 (CArC), 154.4
(BnNCHC), 170.6 (CO) ppm. IR (ATR): v = 3383 (w), 1636 (s),
̃
1516 (s), 1458 (m), 1045 (m), 1001 (m), 820 (m), 795 (m), 719 (s),
696 (m) cm−1. HRMS (ESI) m/z calcd for C25H29FeN4O [(M + H)+]
457.1691, found 457.1688.
N-[2-(1-Benzyl-1H-1,2,3-triazol-4-yl)propan-2-yl]-2-methylferro-
cenoylamide (rac-24)32 and N-[2-(1-Benzyl-1H-1,2,3-triazol-4-yl)-
propan-2-yl]-2,5-dimethylferrocenoylamide (25). GP; 5 (120 mg,
0.28 mmol, 1.0 equiv), ZnCl2·TMEDA, and MeMgBr (3 M in Et2O, 0.6
mL, 1.7 mmol) at 70 °C oil bath temperature; column chromatography
(25 cm × 2.5 cm; petroleum ether/ethyl acetate 4:1 to 2:1).
I: 25 (22 mg, 0.05 mmol, 17%) was isolated as an orange solid (mp
159−161 °C).
ppm. IR (ATR): v = 1638 (s), 1521 (s), 1454 (m), 1439 (m), 1383 (m),
̃
1354 (m), 1298 (m), 1217 (m), 1138 (s), 1105 (m), 1024 (m), 1001
(m), 978 (m), 910 (m), 819 (m), 727 (s), 700 (s), 482 (s) cm−1. HRMS
(ESI) m/z calcd for C24H27FeN2O2 [(M + H)+] 431.1422 found
431.1419; [α]D20: −12.3 (c = 1.0, CHCl3).
II: rac-24 (46 mg, 0.10 mmol, 37%) was isolated as an orange solid,
and identified spectroscopically (1H NMR25).
(S,Sp)-N-[2-(4-Benzyl-2-oxazolinyl)propan-2-yl]-2-methylferroce-
noylamide [(S,Sp)-27] and (S)-N-[2-(4-benzyl-2-oxazolinyl)propan-2-
yl]-2,5-dimethylferrocenoylamide [(S)-28]. GP; (S)-26 (86 mg, 0.20
mmol, 1.0 equiv), ZnBr2·TMEDA, and MeMgBr (3 M in Et2O, 0.4 mL,
25: 1H NMR (400 MHz, CDCl3): δ = 1.84 [s, 6H, C(CH3)2], 2.12 (s,
6H, CpCH3), 4.02 (s, 2H, CpH), 4.05 (s, 5H, CpH), 5.52 (s, 2H, CH2),
6.96 (br s, 1H, NH), 7.28−7.30 (m, 2H, C6H5), 7.35−7.40 (m, 3H,
I
DOI: 10.1021/acs.organomet.7b00799
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
1.2 mmol) at 85 °C oil bath temperature; column chromatography (25
cm × 2.5 cm; petroleum ether/ethyl acetate 3:1 to 1:1).
I: (S)-28 (28 mg, 0.06 mmol, 31%) was isolated as an orange oil.
II: (S,Sp)-27 (15 mg, 0.03 mmol, 17%, ≥ 99% de) was isolated as an
orange oil.
(m), 1001 (m), 957 (w), 816 (s), 718 (m), 542 (s) cm−1. HRMS (ESI)
m/z calcd for C18H16FeN [(M + H)+] 302.0632, found 302.0620.
ASSOCIATED CONTENT
* Supporting Information
■
S
1
(S)-28: H NMR (400 MHz, CDCl3): δ = 1.69 [s, 3H, C(CH3)2],
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.7b00799.
1.72 [s, 3H, C(CH3)2], 2.13 (s, 3H, CpCH3), 2.14 (s, 3H, CpCH3), 2.79
(dd, J = −13.8, 7.3 Hz, 1H, CH2), 3.02 (dd, J = −13.8, 6.0 Hz, 1H, CH2),
4.03 (s, 2H, CpH), 4.07 (s, 5H, CpH), 4.10−4.14 (m, 1H, OCH2),
4.33−4.38 (m, 1H, OCH2), 4.45−4.52 (m, 1H, NCH), 7.22−7.24 (m,
1
Diastereoselective ortho-lithiation of (S)-26, H and 13C
3H, C6H5), 7.28−7.32 (m, 2H, C6H5), 7.50 (br s, 1H, NH) ppm. 13
C
NMR spectra of new compounds, enantioselective
phenylation of 1 and 5 (PDF)
NMR (CDCl3, 100.6 MHz): δ = 14.63 (CpCH3), 14.67 (CpCH3), 24.7
[C(CH3)2], 25.0 [C(CH3)2], 41.7 (CH2), 53.6 [C(CH3)2], 66.8
(NCH), 69.19 (CCpH), 69.21 (CCpH), 70.9 (C5H5), 73.2 (OCH2),
80.0 (CCpC), 83.8 (CCpC), 83.9 (CCpC), 126.7 (CPhH), 128.6 (CPhH),
129.5 (CPhH), 137.8 (CPhC), 169.7 (CO), 171.6 (CN) ppm. IR
Accession Codes
CCDC 1566265 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
(ATR): v = 3385 (w), 2922 (w), 1645 (s), 1506 (s), 1450 (s), 1379 (m),
̃
1356 (m), 1146 (s), 1105 (m), 999 (m), 968 (m), 932 (m), 862 (m),
816 (m), 731 (s), 700 (s) cm−1. HRMS (ESI) m/z calcd for
C26H31FeN2O2 [(M + H)+] 459.1735, found 459.1735; [α]D20: − 3.2
(c = 1.0, CHCl3).
(S,Sp)-27: 1H NMR (400 MHz, CDCl3): δ = 1.67 [s, 3H, C(CH3)2],
1.68 [s, 3H, C(CH3)2], 2.26 (s, 3H, CpCH3), 2.80 (dd, J = −13.8, 7.4
Hz, 1H, CH2), 3.04 (dd, J = −13.8, 5.6 Hz, 1H, CH2), 4.11−4.14 (m,
2H, OCH2 and CpH), 4.15 (s, 5H, CpH), 4.22 (ABC, 1H, CpH), 4.32−
4.37 (m, 1H, OCH2), 4.44−4.50 (m, 2H, NCH and CpH), 7.14 (br s,
1H, NH), 7.23−7.25 (m, 3H, C6H5), 7.29−7.33 (m, 2H, C6H5) ppm.
13C NMR (CDCl3, 100.6 MHz): δ = 14.9 (CpCH3), 24.9 [C(CH3)2],
25.0 [C(CH3)2], 41.6 (CH2), 53.3 [C(CH3)2], 66.7 (NCH), 67.6
(CCpH), 68.4 (CCpH), 70.4 (C5H5), 72.8 (CCpH), 73.1 (OCH2), 75.9
(CCpC), 85.2 (CCpC), 126.7 (CPhH), 128.6 (CPhH), 129.6 (CPhH),
AUTHOR INFORMATION
Corresponding Author
*Phone: +49 511 762 4661. E-mail: holger.butenschoen@mbox.
oci.uni-hannover.de.
ORCID
■
Holger Butenschon: 0000-0002-7689-1992
̈
Notes
The authors declare no competing financial interest.
137.7 (C C), 170.2 (CO), 171.6 (CN) ppm. IR (ATR): v = 2962
̃
Ph
(w), 1645 (s), 1510 (s), 1451 (m), 1381 (w), 1356 (m), 1260 (s), 1142
(s), 1103 (s), 1028 (s), 968 (m), 932 (m), 868 (m), 802 (s), 750 (s), 700
(s) cm−1. HRMS (ESI) m/z calcd for C25H29FeN2O2 [(M + H)+]
445.1578, found 445.1580. [α]D20: −66.1 (c = 1.0, CHCl3).
ACKNOWLEDGMENTS
We thank Marius Saxarra for technical help with the experiments
■
and Dr. Gerald Drager for support with the crystal structure
̈
analysis. We are indebted to Innospec Deutschland GmbH for a
generous donation of ferrocene.
(Sp)-2-Methyl-1-ferrocenecarboxylic Acid [(Sp)-29]. (S,Sp)-27 (40
mg, 0.09 mmol) was dissolved in 1,4-dioxane (1 mL) and 6N H2SO4 (1
mL), and FeCl3 (6 mg, 0.36 mmol) was added. The mixture was heated
at 100 °C for 16 h. After cooling to 23 °C, ethyl acetate (10 mL) was
added. The organic layer was extracted with 2N NaOH (3 × 5 mL). The
combined aqueous layers were acidified with conc HCl until pH < 5 and
extracted with CH2Cl2 (2 × 5 mL). The combined organic layers were
washed with brine (5 mL), dried with MgSO4, filtered, and concentrated
at reduced pressure. Compound (Sp)-29 (11 mg, 0.05 mmol, 50%) was
obtained as an orange solid and identified spectroscopically (1H
NMR64); [α]D20: −7.2 (c = 0.1, CHCl3).
2-(4-Methylphenyl)ferrocene-1-carbonitrile (rac-30). Procedure
according to ref 66. rac-13 (190 mg, 0.4 mmol) was dissolved in
CH2Cl2 (1.5 mL), and 2-fluoropyridine (35 μL, 0.4 mmol) was added.
The solution was cooled to −78 °C, then trifluoromethylsulfonic acid
anhydride (Tf2O, 66 μL, 0.4 mmol) was added dropwise and the mixture
was stirred for 10 min. The solution was heated to 0 °C and stirred for
additional 10 min. Et3SiH (65 μL, 0.4 mmol) was added dropwise. The
solution was stirred at 0 °C for 10 min and after warming to 23 °C for
additional 16 h. Then, an aqueous solution of citric acid (0.08 M, 1.5
mL) and THF (1.5 mL) were added. The mixture was heated at 45 °C
for 3 h. After cooling to 23 °C, the aqueous layer was extracted with
CH2Cl2 (3 mL). The combined organic layers were washed with brine
(5 mL), dried with MgSO4, filtered, and concentrated at reduced
pressure. Column chromatography (25 cm × 2.5 cm; petroleum ether/
ethyl acetate 10:1) afforded rac-30 (77 mg, 0.25 mmol, 68%) as a red oil.
1H NMR (400 MHz, CDCl3): δ = 2.37 (s, 3H, CH3), 4.25 (s, 5H, CpH),
4.49 (ABC, 1H, CpH), 4.75 (ABC, 1H, CpH), 4.77 (ABC, 1H, CpH),
7.18−7.20 (m, 2H, C6H4), 7.59−7.61 (m, 2H, C6H4) ppm. 13C NMR
(CDCl3, 100.6 MHz): δ = 21.3 (CH3), 50.8 (CCpC), 70.1 (CCpH), 70.5
(CCpH), 72.2 (C5H5), 72.7 (CCpH), 89.8 (CCpC), 120.7 (CN), 127.4
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