Simultaneous Construction of Planar and Central Chiralities as Well as Unprecedented Axial Chirality on and around a Ferrocene Backbone

Article abstract of DOI:10.1021/acs.joc.8b03221

Simultaneous generation of planar, central and axial chiralities on and around a ferrocene backbone via a d-phenylglycinol-induced intramolecular iminium cyclization was disclosed, which is rare and differs from known methods. A series of chiral spiro[cyclopentadienyl-1,2,3,3a-tetrahydropentalenyliron(II)-1,2′-pyrrolidine] derivatives were prepared acording to the new method, and their structures were characterized unambiguously. The axial chirality caused by the ferrocene backbone and the rigid spiral structure was verified by NOESY and variable-temperature NMR experiments and single-crystal XRD analyses. Mechanism for the stereoselective iminium cyclization reaction was suggested, which was influenced by steric hindrance and hydrogen bonding.

Full text of DOI:10.1021/acs.joc.8b03221

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Article
Simultaneous Construction of Planar and Central Chiralities as well as
Unprecedented Axial Chirality on and around A Ferrocene Backbone
Hongjie Li, Peijing Jia, Naixin Qian, Shasha Li, and Peng Jiao
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03221 • Publication Date (Web): 31 Jan 2019
Downloaded from http://pubs.acs.org on January 31, 2019
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Simultaneous Construction of Planar and Central Chiralities as well as
Unprecedented Axial Chirality on and around A Ferrocene Backbone
Hongjie Li, Peijing Jia, Naixin Qian, Shasha Li and Peng Jiao*
Key Laboratory of Radiopharmaceuticals, College of Chemistry, Beijing Normal University,
Beijing 100875, P. R. China.
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E-mail: pjiao@bnu.edu.cn
O
H
O
N
Fe
O
H
(
R)
Ph
CF3CO2
N (S)
Ph
O
O
O
CF3CO2H
CF3CO2H
N
N
Fe
or
Fe
Fe
(R)
CH2Cl2, 0 °C
Ph
Ph
O
H
N
H
CF3CO2
CF3CO2
O
Fe
Ph
2
3a
1 : 1
3b
CF3CO2
O
HO
N
LiAlH4
N
Ph
HO
Ph
H
Fe
Fe
H
hydrolysis
(
Ra)-4a, 42% yield
(Ra)-5a, 80% yield
axial chirality
generation
O
LiAlH4
N
N
OH
OH
Fe
Fe
H
H
Ph
(Ra)-4b, 43% yield
Ph
(Ra)-5b, 80% yield
ABSTRACT: Simultaneous generation of planar, central and axial chiralities on and around a
ferrocene backbone via a D-phenylglycinol-induced intramolecular iminium cyclization was
disclosed, which is rare and differs from known methods. A series of chiral spiro[cyclopentadienyl
1
,2,3,3a-tetrahydropentalenyl iron (II)-1,2ʹ-pyrrolidine] derivatives were prepared in the new
method, and their structures characterized unambiguously. The axial chirality caused by the
ferrocene backbone and the rigid spiral structure was verified by NOESY and variable temperature
NMR experiments, and single-crystal XRD analyses. Mechanism for the stereoselective iminium
cyclization reaction was suggested, which was influenced by steric hindrance and hydrogen bonding.
INTRODUCITON
The synthesis of ferrocene was a milestone in the development of organometallic chemistry. It was
1
the first organometallic sandwich compound reported. Since the discovery of ferrocene, various
ferrocene compounds have been reported, and they have been used for a broad range of chemical
2
3–7
applications. Ferrocene-derived diphosphines
are used as chiral ligands for asymmetric
3
reactions, taking advantage of the planar chiral structure brought by ferrocene. Xyliphos is used for
the iridium-catalysed asymmetric hydrogenation of an imine to produce (S)-metolachlor in a large-
scale asymmetric process. Dimethylamino pyridine (DMAP) derivatives bearing a planar chiral
ferrocene backbone were developed by Fu and used in asymmetric reactions.8
Great efforts have been devoted to the synthesis of chiral compounds from ferrocene to fully exploit
the planar chirality that could be built on the ferrocene backbone. Ugi’s amine (Figure 1a), has been
used to prepare planar chiral ferrocene derivatives via dimethylamino-directed ortho-lithiation
9
(
Figure 1b) followed by electrophilic substitution. Hayashi and Kumada pioneered the preparation
1
0
of ferrocenylphosphines with planar chirality. Catalytic asymmetric C–H bond functionalizations
1
1
12
reported by You and Gu (Figure 1c) emerged as efficient methods to introduce planar chirality
to ferrocene. Here, we report an unprecedented simultaneous installation of both planar chirality
and a carbon stereocenter controlled by a remote stereogenic center in D-phenylglycinol (Figure
1
d).
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NMe2
NMe2
NMe2
Br
N
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Li
H
H
Fe
Fe
Fe
Fe
Fe
OH
Ph
(
a) Ugi's amine
(b) Directed ortho-lithiation
(c) Catalytic asymmetric C-H
functionalization
(d) Our method: asymmetric one-pot
cyclization
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Figure 1. Known methods and our method for introducing planar chirality to ferrocene.
We aimed to prepare spiro[cyclopentadienyl 1,2,3,3a-tetrahydropentalenyl iron (II)-1,2ʹ-
pyrrolidin]-5ʹ-one (1) and explore the use of its derivatives as chiral ligands in the future (Scheme
1
). We expected to prepare 1 via an intramolecular cyclization initiated by an acyl iminium
intermediate, which was generated from a tetrahydropyrrolo[2,1-b]oxazol-5-one precursor.
1
3
14
Meyers’ and Vernon’s methods could be used to construct the bicyclic unit. D-Phenylglycinol
was used as a chiral inductor as well as to form diastereomers that could be separated in a facile
manner.
O
O
O
O
N
intramolecular
cyclization
N
H
N
N
O
Ph
Fe
Fe
Fe
Fe
OH
OH
Ph
Ph
1
acyl iminium intermediate tetrahydropyrrolo[2,1-b]oxazol-5-
one
O
OH
H N
2
OH
O
Fe
+
Ph
D-phenylglycinol
Scheme 1. Retrosynthesis of spiro[cyclopentadienyl 1,2,3,3a-tetrahydropentalenyl iron (II)-1,2ʹ-
pyrrolidin]-5ʹ-one (1).
RESULTS AND DISCUSSION
We commenced our synthesis with ferrocenecarboxaldehyde and ethyl levulinate (Scheme 2). A
piperidine and acetic acid-mediated aldol condensation followed by hydrogenation and hydrolysis
produced 6-ferrocenyl-4-oxo-hexanoic acid in 87% yield, which was verified by single-crystal XRD
analysis (Figure 2). Condensation of 6-ferrocenyl-4-oxo-hexanoic acid with D-phenylglycinol gave
compound 2 in 85% yield. The crystal structure clearly showed the newly generated carbon
stereocenter was in the (R)-configuration and the nitrogen stereocenter was in the (S)-configuration
(
Figure 2). The relative syn-configuration of the two substituents at the 3- and 7a- positions of the
bicyclic ring was previously reported for several compounds.13
O
O
OH
N
CHO
O
i), ii)
O
iii)
O
Ph
O
Fe
+
Fe
Fe
O
2
Scheme 2. Preparation of (3R,4S,7aR)-7a-(2-ferrocenylethyl)-3-phenyltetrahydropyrrolo[2,1-
b]oxazol-5-one (2): i) piperidine, acetic acid, benzene, reflux, 88% yield; ii) Pd/C, 1 atm H , rt; aq.
2
NaOH. 99% yield; iii) D-phenylglycinol, toluene, reflux, 85% yield.
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O
O
N
OH
O
Ph
Fe
O
Fe
2
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0
O
O
N
N
Fe
Fe
Ph
Ph
CF CO2
CF CO2
3
3
3
a
3b
O
O
N
H
O
N
Fe
OH
Ph
H
Fe
H
Ph
4a
4b
H
H
N
N
Ph
O
Fe
Fe
O
H
H
Ph
5a
5b
H
H
O
O
N
N
Fe
Fe
Ph
Ph
6a
6b
Figure 2. Crystal structures of 6-ferrocenyl-4-oxo-hexanoic acid, (3R,4S,7aR)-2, (R )-4a, (R )-4b,
a
a
(
R )-5a, (R )-5b, (R ,1R,3′R,4′R,7′aS)-6a and (S ,1S,3′R,4′R,7′aS)-6b.
a a p p
With 2 in hand, we attempted the intramolecular cyclization reaction. We first tested AlCl as a
3
Lewis acid. Despite laborious attempts, disappointing results were obtained. A complicated mixture
that could not be separated by chromatography was obtained with approximately 10% of the starting
material recovered. Trifluoroacetic acid was used as a Brønsted acid to promote the intramolecular
cyclization reaction (Scheme 3). After optimizations of the reaction conditions, we identified three
compounds 3, 4a, and 4b (Figure 2) in the reaction mixture by thin layer chromatography (TLC).
Compound 3 was the major species in the crude product. After aqueous workup and column
chromatography on silica gel, we isolated and characterized 3, 4a and 4b by 1H and 13C NMR.
Repeated silica gel chromatographies of the crude product showed that 3 was unstable under
chromatographic conditions and tended to convert into 4a and 4b though NMR indicated 3 thus
obtained was a pure compound. The conversion of 3 to 4b was faster than 4a.
Then, a crude mixture containing predominantly 3 and small amounts of 4a and 4b was treated with
wet tetrahydrofuran (THF) at rt (Scheme 3). A 1:1 mixture of 4a and 4b was observed with the
complete disappearance of 3. Single crystals of 4a and 4b were obtained. Crystal structures showed
4
a had an (R ,1R,R) configuration and 4b had an (S ,1S,R) configuration (Figure 2). Careful
p p
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examination of the crystal structures of 4a and 4b prompted us to hypothesize the possibility of
axial chirality, which could be caused by restricted rotation about the C–N bond highlighted in pink
(Figure 2, 3). As far as we know, the axial chirality due to restricted rotation about a N–Csp3 bond
as in 4a or 4b, has not been reported. Tentatively, we assigned the new chirality as (Ra).15 Thus,
three consecutive stereogenic elements that give the molecule planar, central and axial chirality were
generated due to induction by D-phenylglycinol.
0
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1
5 equiv CF CO H
hydrolysis
3
2
2
3, 4a, 4b
4a (42%), 4b (43%)
2
anhydrous CH Cl2
0
°C, 2 d
Scheme 3. Intramolecular cyclization of 2 promoted by CF CO H and subsequent hydrolysis of 3,
3
2
4
a, 4b.
O
O
N
N
Ph
OH
atropisomer of 4b
OH Fe
Ph
Fe
H
H
atropisomer of 4a
Figure 3. Supposed atropisomers of 4a and 4b.
To clarify the structure of 3, we treated 2 with CF CO H under strictly anhydrous conditions. Upon
3
2
complete consumption of 2, the reaction mixture was concentrated under vacuum with no aqueous
workup. The resulting crude product was promptly chromatographed on silica gel to give 3 in high
purity. Both the H and 13C NMR spectra of 316 indicated it was a mixture of two diastereomers,
which were inseparable by TLC. HRMS indicated the [M+H] for 3 was 512.1130. According to
these data, we suggested that two oxazolinium salts of CF CO H (3a, 3b), formed from CF CO H
1
3
2
3
2
−
17
and 4a or 4b by dehydrative cyclization, were present in 3 (Figure 2). Oxazolinium salts of BF ,
4
−
18
− 19
− 20
− 21
− 22
− 17c
I , Br , TfO , TsO , ClO , and CF CO
2
have been reported previously. These reported
4
3
oxazolinium salts were only moderately stable and could decompose upon chromatography, which
was consistent with the observed properties of 3. The initially isolated 3 (Scheme 3) was actually
3
a, which was a result due to the hydrolysis of 3b to 4b during workup.
When a mixture of 3, 4a and 4b was subjected to LiAlH reduction in THF (Scheme 4), two
4
products, 5a and 5b, were obtained in 90% yield and were easily separated by chromatography. The
structures of 5a and 5b, having (Ra)15 axial chirality, were verified by XRD analyses (Figure 2).
When 3, prepared with no aqueous workup, was reduced with LiAlH in THF for 12 h, 6 was
4
1
13
produced in 60% yield in addition to 5a (16% yield) and 5b (16% yield) (Scheme 5). H and C
NMR indicated 6 was a mixture of two diastereomers,16 though the two components were
inseparable by TLC. Single crystals of 6a were obtained from the mixture of reaction products. Pure
6
b was prepared in a different method, the structure of which was verified by XRD analysis (Figure
), H and 13C NMR. The crystal structures of 6a and 6b (Figure 2) clearly showed that five
1
2
stereogenic elements were present in the molecules, and four of them, including one nitrogen chiral
center, were formed by induction. When a mixture of 5a, 5b and 6 (Scheme 5) was further reduced
with LiAlH in THF, 5a and 5b were obtained and 6 disappeared. In another experiment, when 3
4
was reduced with LiAlH in THF for 24 h (Scheme 5), 5a and 5b were obtained in 88% yield without
4
6.
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1
5 equiv CF CO H
6 equiv LiAlH4
3
2
2
3, 4a, 4b
5a (45%), 5b (45%)
anhydrous CH Cl2
0
anhydrous THF
40 °C, 24 h
2
°C, 2 d
Scheme 4. Intramolecular cyclization of 2 promoted by CF CO H and subsequent reduction of 3,
3
2
4
a, 4b.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
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4
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0
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0
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0
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6
7
8
9
0
6 equiv LiAlH4
6 equiv LiAlH4
5
a (16%), 5b (16%), 6 (60%)
5a (45%), 5b (45%)
anhydrous THF
40 °C, 12 h
anhydrous THF
40 °C, 12 h
3
6
equiv LiAlH4
5a (44%), 5b (44%)
anhydrous THF
0 °C, 24 h
4
Scheme 5. Reductions of 3 by LiAlH4.
To confirm 4a, 4b, 5a or 5b was an atropisomer instead of a conformer, we did NOESY experiments
at rt in CDCl on 4b, 5b and the p-bromobenzoates 7 and 8, which were prepared from 4a and 5a,
3
respectively. 7 or 8 was used in order to exclude possible influences to the C–Nsp3 bond rotation
caused by intramolecular hydrogen bond. The crystal structures of 7 and 8 were shown in Figure 4.
The observed NOE16 in 4b, 5b, 7 or 8 indicated the hydrogen in the chiral center of D-
phenylglycinol and the hydrogen in the unsubstituted Cp ring were in proximity, which quite
possibly meant the C–Nsp3 bond rotation was restricted and a single atropisomer resembling the
structure in the crystal (Figure 2, Figure 4) was present in each compound.
O
N
Ph
Fe
H
O
O
Br
N
Ph
H
Fe
O
O
7
8
Br
Figure 4. Crystal structures of (R )-7 and (R )-8.
a
a
Possible formation pathways of 3a, 3b, 4a, and 4b from 2 are shown in Scheme 6. The acyl iminium
salt, formed from 2 and CF CO H, adopted two reactive conformations denoted 9 and 9′, and rapidly
3
2
underwent intramolecular cyclization giving (R ,1R)-4a or (S ,1S)-4b having exclusively (R ) axial
p
p
a
chirality. Due to its distance from the reacting Cp ring, the stereocenter in the D-phenylglycinol did
not influence the conformations 9 and 9′, which were equally possible, leading to a 1:1 ratio of the
two components in 3. The inaccessible conformations to produce the unobserved (S ,1R) or (R ,1S)
p
p
diastereomers are shown in Figure 5a, which might cause severe repulsion between the substituted
Cp ring and the phenylglycinol substructure (pink colored). Concerning the formation of the (Ra)
chirality, hydrogen bonding contributed to the exclusive selectivity. In both cases (shown in Scheme
6
), hydrogen bonding between the carbonyl and the hydroxy groups should stabilize the
conformations 9 and 9′, which resulted in the (R ) axial chirality in the corresponding product. The
a
reaction conformations, which might lead to the atropisomers as shown in Figure 3, were
unfavourable due to the absence of the hydrogen bonding (Figure 5b). Once 4a or 4b was formed,
excess CF CO H would immediately convert it to the corresponding oxazolinium salt, respectively,
3
2
which accounted for 3 being the major species in the reaction mixture.
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Si face
O
O
H
CF CO H
3
2
O
O
N
N
H
O
N

H
Ph
H
2
Fe
Fe
Fe
H
H
Ph
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Ph
CF CO H
3
2
CF CO
3
2
9
4a
HO
0
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0
1
2
3
4
5
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7
8
9
0
O
O
CF CO H
N
3
2
N
Fe
Fe
Ph
Ph
CF CO
3
2
3a
Re face
O
O
O
H
O
CF CO H
3
2
O
N
N
H
H
2
H
N

H
Fe
Fe
Fe
Ph
Ph
H
O
Ph
CF CO H
3
2
CF CO
3
2
9'
4b
OH
O
O
CF CO H
N
3
2
N
Fe
Fe
Ph
Ph
CF CO
3
2
3b
Scheme 6. Possible pathways for the formation of 3a, 3b, 4a and 4b from 2.
a Inaccessible conformations
b Unfavourable conformations
H
O H
Ph
O
O
O
Ph
H
O
H
O
H
N
N
N
N
Fe
Fe
Ph
HO
CF CO2
Ph
H
Fe
Fe
OH
CF CO
3
CF CO
3 2
2
3
CF CO2
3
Figure 5. Inaccessible and unfavourable conformations of the acyl iminium salt from 2.
We attributed the generation of the axial chirality in 4a or 4b to the rigidity of both the ferrocene
backbone and the neighbouring spiral structure. The phenyl ring and the hydroxymethyl group
originating from the D-phenylglycinol moiety were too bulky to allow the C–N bond to rotate freely
in the crowded space adjacent to the ferrocene backbone. Once the hydroxymethyl group was
converted to a smaller one, the C–N bond would rotate freely. We tried to simultaneously eliminate
the axial chirality as well as the central chirality from the D-phenylglycinol by derivatization. An
equimolar mixture of 4a and 4b was treated with LiOH·H O in dimethyl sulfoxide (DMSO) at 160
2
°
C (Scheme 7a). Racemic dehydration product 10 bearing a styrene substructure was obtained in
2% yield. In addition, the racemate of 11 was isolated in 8% yield as a side product, and its structure
7
was clearly identified by XRD analysis (Figure 6). The formation of 10 and 11 as racemates clearly
indicated the disappearance of the axial and central chirality in 4a and 4b. Hydrolysis of (±)-10 gave
(
±)-1 in 60% yield (Scheme 7b), the structure of which was determined by XRD analysis (Figure
6
).
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a
O
O
O
O
2
0 equiv LiOH·H O
2
N
N
0.1 equiv hydroquinone
N
N
Ph
H
H
Fe
Fe
Fe
+
Fe
HO
OH
Ph
Ph
Ph
DMSO, 160 °C
4a
4b
(±)-10
(±)-11
1
:1
72%
8%
1
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
b
O
O
N
6 N HCl
THF, 40 °C
N
H
Fe
Fe
Ph
(
±)-10
(±)-1, 60%
Scheme 7. a Simultaneous elimination of the axial and central chiralities from 4a and 4b. b
Hydrolysis of (±)-10.
O
O
N
N
H
Fe
Fe
Ph
(±)-11
(±)-1
Figure 6. Crystal structures of (±)-11 and (±)-1.
O
O
O
2
0 equiv LiOH·H O
2
N
0.1 equiv hydroquinone
N
6 N HCl
Ph
N , THF, 60 °C
N
H
H
Fe
Fe
Fe
OH
Ph
DMSO, 160 °C
2
4b
(-)-10
2%
(-)-1
60%
7
LiAlH4
THF, 60 °C
N
H
Fe
(
8
-)-12
8%
Scheme 8. Preparations of (−)-1, (−)-10, and (−)-12.
The absence of axial chirality in enantiomerically pure 10 at rt and the presence of axial chirality in
1
(S ,1S,R ,R)-4b at rt were verified by the following variable temperature H NMR experiments. We
p
a
prepared (R ,1R)-10 and (S ,1S)-10 from 4a and 4b (Scheme 8), respectively, and further converted
p
p
them to 12 via 1. The crystal structures of (R ,1R)-10 and (S ,1S)-10 are shown in Figure 7a.
p
p
1
Enantiomerically pure (R ,1R)-10 was subjected to H NMR analyses in the temperature range from
p
25 °C to −60 °C (Figure 7d). The “singlet” peaks (δ = 6.29 and 5.48 at 25 °C), corresponding to the
two ethylenic protons of CH =C, each began to separate into two peaks at −20 °C and became two
2
completely isolated peaks at temperatures of −40 °C and lower. The integration of each set of newly
formed peaks indicated a ratio of 3:2. A peak (δ = 7.60 at 25 °C) corresponding to two phenyl ring
protons showed similar changes as the temperature decreased. At temperatures below −10 °C, two
isolated singlets corresponding to two distinct unsubstituted Cp rings (δ = 4.09 and 3.78 at −40 °C)
appeared. We believed the 3:2 ratio was for an atropisomeric mixture of (R ,1R,S )-10 (Figure 7b)
p
a
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and (R ,1R,R )-10 (Figure 7c), among which (R ,1R,S )-10, existing in the crystal, was the major
p
a
p
a
species. These results showed the C–N single bond rotated freely at rt, and the rotation was restricted
to produce axial chirality at −40 °C and below. For comparison, enantiomerically pure 4b was also
1
subjected to variable temperature H NMR experiments (Figure 7e). None of the “singlet” peaks
became two peaks as the temperature decreased from 25 °C to −60 °C. The peak corresponding to
0
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9
0
the CH O proton shifted from δ = 4.71 to δ = 5.50, and the peak corresponding to the proton of NCH
2
shifted from δ = 6.12 to δ = 6.29. The above NMR results clearly supported that the axial chirality
in 4a, 4b, 5a, 5b, 7 or 8 was indeed present and stable at rt, while (R ,1R)-10 did not show axial
p
1
chirality at rt. Further, the H NMR spectra of 4b, which had been heated at 150 °C for 24 h, was
compared with that of 4b in DMSO-d6.16 No obvious changes were observed for all the peaks.
1
Variable temperature (20–140 °C) H NMR spectra of 4b in DMSO-d also indicated no obvious
6
changes of the peaks.16 These results clearly support the axial chirality in 4b is stable in a
temperature range up to 150 °C.
a
O
O
N
N
Fe
Fe
Ph
Ph
(
R ,1R)-10
(S ,1S)-10
p
p
b
d
c
O
O
N
N
Fe
Fe
(
R ,1R,S )-10
(R ,1R,R )-10
p a
p
a
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0
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5
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7
8
9
0
e
Figure 7. a Crystal structures of (R ,1R)-10 and (S ,1S)-10. b Putative structure of (R ,1R,S )-10. c
p
p
p
a
1
Putative structure of (R ,1R,R )-10. d Variable temperature H NMR spectra of (R ,1R)-10 in CDCl .
p
a
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e Variable temperature H NMR spectra of (S ,1S,R ,R)-4b in CDCl .
p
a
3
CONCLUSION
In summary, we reported the synthesis of a new class of chiral compounds bearing a ferrocene
backbone and a chiral center α to the Cp ring. The unique chiral structure was built in a single step
with simultaneous generation of planar, central and axial chiralities. To the best of our knowledge,
such a simultaneous generation of multiple chiralities on and surrounding a ferrocene backbone has
not been reported previously. The axial chirality caused by restricted N–Csp3 bond rotation, which
differs from chiralities caused by restricted C–C bond rotation and those present in 2-substituted or
2,6-disubstituted aniline derivatives, is unprecedented, and was verified by NOESY and variable
0
1
2
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9
0
1
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0
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1
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0
1
temperature H NMR experiments. Studies on the preparation and use of chiral compounds bearing
a spiro[cyclopentadienyl 1,2,3,3a-tetrahydropentalenyl iron (II)-1,2ʹ-pyrrolidine] structure are
ongoing in our laboratory.
EXPERIMENTAL SECTION
All glassware for reactions using anhydrous solvents were dried under high vacuum (< 0.1 torr)
using a heat gun. General Schlenk techniques were applied for addition and transfer operations.
Commercial reagents and solvents were purchased from Acros, Alfa Aesar, J&K Scientific Ltd.,
Sinopharm Chemical Reagent Co. or Beijing Chemical Works, and used as received unless
otherwise noted. THF was distilled over sodium benzophenone ketyl under N . CH Cl was distilled
2
2
2
over CaH under N . Silica gel products were purchased from Qingdao Haiyang Chemical Co..
2
2
Thin-layer chromatography was performed on precoated silica gel (0.2–0.25 mm thick) plates with
fluorescent indicator 254 nm. The plate was visualized with 254 nm UV lamp, PMA or KMnO4
stain. Column chromatography was performed on 200–300 mesh silica gel.
1
13
H NMR and C NMR spectra were recorded on a JEOL ECZ 600R spectrometer at 600 MHz and
1
13
150 MHz respectively. Chemical shifts of H NMR and C NMR were referred to TMS (δ = 0) or
chloroform (δ = 7.26 for H NMR, 77.0 for 13C NMR) respectively. The following abbreviations
1
were used to denote the multiplicity of each peak: s (singlet), d (doublet), t (triplet), q (quartet), dd
(
doublet of doublets), m (multiplet). IR spectra were recorded on a Nicolet AVATAR 360 FT-IR
spectrometer. The sample was prepared as a thin-film on a NaCl disc. MS spectra were obtained on
a Waters Quattro Micro triple quadrupole mass spectrometer. Specific rotation was measured on a
Perkin-Elmer 343 Polarimeter using the 589 nm D-line of sodium lamp and a quartz cell with 10
cm path length. X-ray diffraction experiment was conducted on a Rigaku Oxford Diffraction
SuperNova Dual Atlas S2 diffractometer using Mo or Cu Kα radiation.
Ferrocenecarboxaldehyde
To a dry flask, N-methylformanilide (10.6 mL, 80.0 mmol) and POCl (4.7 mL, 50.0 mmol) were
3
added. After stirring for 5 min, ferrocene (5.58 g, 30.0 mmol) was added in portions over 20 min.
The mixture was stirred at room temperature for 1 h and then at 40 °C for 5 h. The mixture was
cooled to 0 °C, and NaOAc solution (25 g in 200 mL H O) was added. After stirring at 0 °C
2
overnight, the reaction mixture was extracted with CH Cl . The organic layers were combined,
2
2
washed with 1 N HCl, saturated NaHCO and H O (all saturated with NaCl). The CH Cl solution
3
2
2
2
was concentrated to about 20 mL. Saturated NaHSO (100 mL) was added while stirring. The
3
mixture was cooled to 0 °C. The precipitate was collected by filtration, washed with ice-cold
saturated NaHSO and CH Cl to get a yellow solid. To a round-bottom flask, the yellow solid and
3
2
2
1
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N NaOH (100 mL) were added. The mixture was stirred at room temperature for 1 h. Then, it was
extracted with CH Cl . The organic layers were washed with brine, dried over Na SO and
2
2
2
4
concentrated. The remaining solvent was removed under high vacuum to afford
ferrocenecarboxaldehyde as a dark-red solid (4.87 g, 76% yield).
(
E)-Ethyl 6-ferrocenyl-4-oxo-5-hexenoate
To a three-necked flask with a Dean-Stark apparatus, ethyl levulinate (4.7 mL, 33 mmol), piperidine
0.65 mL, 6.5 mmol), acetic acid (1.96 mL, 34.0 mmol) and benzene (22 mL) were added. The
1
1
1
1
1
1
1
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2
2
2
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2
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3
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3
4
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4
4
5
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5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
mixture was heated to gentle reflux. Ferrocenecarboxaldehyde (3.52 g, 16.5 mmol) in benzene (22
mL) was added dropwise. Then the mixture was stirred at 90 °C (oil bath) for 16 h. Water was
removed via Dean-Stark apparatus. The solvent was removed by rotary evaporation. The residue
was dissolved in CH Cl , washed with 2 N HCl, saturated NaHCO and brine, and dried over
2
2
3
anhydrous Na SO . CH Cl was evaporated, and excess ethyl levulinate was distilled out under high
2
4
2
2
vacuum and recovered. The crude product was purified by column chromatography (4:1
hexanes/AcOEt) to afford (E)-ethyl 6-ferrocenyl-4-oxo-5-hexenoate as a purple solid (4.93 g, 88%
1
yield). TLC (hexanes/ethyl acetate, 4:1 v/v): R = 0.32; H NMR (400 MHz, CDCl ): δ 7.51 (d, J =
f
3
16.0 Hz, 1H), 6.37 (d, J = 16.0 Hz, 1H), 4.51 (t, J = 2.0 Hz, 2H), 4.44 (t, J = 1.6 Hz, 2H), 4.20–4.13
13
1
(
(
(
m, 7H), 2.92 (t, J = 6.8 Hz, 2H), 2.67 (t, J = 6.8 Hz, 2H), 1.27 (t, J = 6.8 Hz, 3H); C{ H} NMR
150 MHz, CDCl ): δ 197.3, 173.0, 144.5, 123.3, 78.6, 71.2, 69.7, 68.8, 60.5, 34.8, 28.3, 14.2; IR
3
−
1
film) vmax 3096, 2980, 2907, 1732, 1657, 1616, 1601, 1364, 1157, 1105, 1028, 822, 496, 482 cm ;
+
HRMS (ESI-TOF) m/z: [M + Na] Calcd for C H FeNaO 363.0660; Found 363.0654.
1
8
20
3
Ethyl 6-ferrocenyl-4-oxo-hexanoate
To a round-bottom flask, (E)-ethyl 6-ferrocenyl-4-oxo-5-hexenoate (4.93 g, 14.5 mmol), 10% Pd/C
(0.2 g), and EtOH (40 mL) were added. The mixture was well stirred under hydrogen atmosphere
overnight. Pd/C was filtered and washed with EtOH. The filtrate was concentrated and the residue
dried in vacuo to give ethyl 6-ferrocenyl-4-oxo-hexanoate as a yellow liquid, which was directly
1
used without further purification. TLC (hexanes/ethyl acetate, 2:1 v/v): R = 0.78; H NMR (400
f
13
1
MHz, CDCl ): δ 4.16–4.05 (m, 11H), 2.73–2.57 (m, 8H), 1.26 (t, J = 7.4 Hz, 3H); C{ H} NMR
3
(100 MHz, CDCl ): δ 208.3, 172.8, 87.7, 68.5, 68.0, 67.3, 60.6, 44.2, 37.2, 28.0, 23.6, 14.2; IR
3
(film) vmax 3092, 2980, 2926, 2851, 1732, 1717, 1410, 1371, 1350, 1308, 1182, 1105, 1024, 1001,
−
1
+
924, 820, 598, 484, 436 cm ; HRMS (ESI-TOF) m/z: [M + Na] Calcd for C H FeNaO 365.0816;
1
8
22
3
Found 365.0810.
-Ferrocenyl-4-oxo-hexanoic acid
6
To a round-bottom flask, ethyl 6-ferrocenyl-4-oxo-hexanoate and EtOH/H O (25 mL/25 mL) were
2
added. To this solution, NaOH (1.16 g, 29.0 mmol) in 25 mL H O was added dropwise. After stirring
2
for 1 h at room temperature, 1 N HCl was added dropwise till pH was approximately 7. EtOH was
evaporated. 1 N HCl was added dropwise with stirring till pH was about 1. The precipitate was
filtered and washed with hexanes. The product was dried in vacuo to obtain a yellow solid (4.52 g,
1
9
9% yield). TLC (hexanes/ethyl acetate, 2:1 v/v): R = 0.39; H NMR (400 MHz, CDCl ): δ 4.10
f
3
1
3
1
(s, 5H), 4.04 (s, 4H), 2.70–2.62 (m, 8H); C{ H} NMR (100 MHz, CDCl ): δ 208.1, 178.7, 87.6,
3
68.5, 67.9, 67.3, 44.1, 36.9, 27.7, 23.6; IR (film) vmax 3092, 2924, 2861, 1709, 1410, 1369, 1287,
−
1
+
1
254, 1227, 1175, 1105, 1001, 924, 820, 484 cm ; HRMS (ESI-TOF) m/z: [M + Na] Calcd for
C H FeNaO 337.0503; Found 337.0497; m.p. 117.7–118.9 °C.
1
6
18
3
(3R,4S,7aR)-7a-(2-Ferrocenylethyl)-3-phenyltetrahydropyrrolo[2,1-b]oxazol-5-one (2)
To a three-necked flask, 6-ferrocenyl-4-oxo-hexanoic acid (11.57 g, 36.8 mmol), D-phenylglycinol
1
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6
(
5.05 g, 36.8 mmol) and 80 mL toluene were added. The reaction mixture was heated at 130 °C (oil
bath) to reflux. Water was removed by a Dean-Stark apparatus. After stirring for 36 h, the solvent
was removed by rotary evaporation. The residue was purified by column chromatography (4:1
hexanes/AcOEt) to afford 2 as a yellow solid (13.01 g, 85% yield). TLC (hexanes/ethyl acetate, 2:1
2
0
1
v/v): R = 0.44; [α] −77.0 (c 1.03, CHCl ); H NMR (400 MHz, CDCl ): δ 7.37–7.25 (m, 5H),
f
D
3
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
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4
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1
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0
5.23 (t, J = 7.4 Hz, 1H), 4.65 (t, J = 8.4 Hz, 1H), 4.14 (dd, J = 8.8, 6.8 Hz, 1H), 4.01–3.93 (m, 9H),
2
1
1
.90–2.80 (m, 1H), 2.61 (ddd, J = 17.6, 10.2, 2.8 Hz, 1H), 2.40–2.33 (m, 3H), 2.24–2.15 (m, 1H),
1
3
1
.98–1.90 (m, 1H), 1.84–1.76 (m, 1H); C{ H} NMR (100 MHz, CDCl ): δ 179.3, 140.0, 128.7,
3
27.5, 125.4, 102.2, 87.7, 72.3, 68.3, 67.7, 67.4, 67.1, 57.4, 37.5, 33.1, 30.8, 23.7; IR (film) vmax
−
1
3090, 2951, 2928, 2880, 1713, 1497, 1450, 1364, 1292, 1236, 1028, 820, 716, 484 cm ; HRMS
+
(ESI-TOF) m/z: [M + H] Calcd for C H FeNO 416.1313; Found 416.1307; m.p. 101.6–103.5 °C.
2
4
26
2
Intramolecular cyclization of 2 promoted by CF CO H and subsequent hydrolysis
3
2
A Schlenk tube was charged with anhydrous CH Cl (13 mL) and anhydrous CF CO H (5.02 mL,
2
2
3
2
7
5.0 mmol) under N atmosphere. The solution was cooled to 0 °C. Compound 2 (2.08 g, 5.0 mmol)
2
was added in one portion. The mixture was stirred at 0 °C for 48 h. Saturated NaHCO was added
3
to quench the reaction. The mixture was extracted with CH Cl for several times. The organic layers
2
2
were combined and washed with brine. The solvent was removed by rotary evaporation to give a
mixture of 3, 4a, and 4b. Silica gel chromatography would give pure 3a, 4a and 4b. The mixture
could be used directly for hydrolysis without further purification.
A mixture of 3, 4a, and 4b was dissolved in a solution of THF/H O (10 mL/25 mL), and then stirred
2
overnight. When 3 was completely converted, the volatiles were removed by rotary evaporation.
The residue was extracted with CH Cl for several times. The CH Cl solution was dried over
2
2
2
2
Na SO and concentrated. The crude product was purified by column chromatography (2:1
2
4
hexanes/AcOEt) to afford 4a as a yellow solid (0.87 g, 42% yield) and 4b as a yellow solid (0.89 g,
3% yield).
4
(R ,1R,3ʹR)-3ʹ-Phenyl-spiro[cyclopentadienyl tetrahydropentalenyl iron (II)-1,5ʹ-tetrahydro
p
pyrrolo[2,1-b]oxazolium trifluoroacetate] (3a)
1
TLC (hexanes/ethyl acetate, 1:1 v/v): R = 0.65; H NMR (600 MHz, CDCl ): δ 7.46–7.33 (m, 5H),
f
3
6
.22 (dd, J = 9.6, 7.2 Hz, 1H), 5.58 (dd, J = 10.8, 9.0 Hz, 1H), 5.00 (dd, J = 10.8, 6.6 Hz, 1H), 4.27
(t, J = 2.1 Hz, 1H), 4.16 (m, 1H), 4.12 (s, 5H), 3.85 (d, J = 2.4 Hz, 1H), 2.52–2.45 (m, 2H), 2.42–
2
.32 (m, 2H), 2.22–2.17 (m, 1H), 2.10–2.07 (m, 1H), 1.95 (dd, J = 12.0, 6.6 Hz, 1H), 1.80–1.75 (m,
1
3
1
1
H); C{ H} NMR (150 MHz, CDCl ): δ 178.1, 156.9 (q, J = 43 Hz, CF CO ), 137.2, 128.9, 128.0,
3
3
2
127.0, 114.9 (q, J = 287 Hz, CF ), 97.3, 91.0, 71.0, 69.7, 69.5, 68.4, 61.9, 57.4, 54.9, 39.5, 34.0,
3
2
9.6, 22.9; IR (film) vmax 3086, 2939, 1786, 1690, 1439, 1408, 1354, 1223, 1153, 1107, 825, 698
−
1
+
cm ; HRMS (ESI-TOF) m/z: [M + H] Calcd for C H F FeNO 512.1136; Found 512.1130.
2
6
25
3
3
N-((R)-2-Hydroxy-1-phenethyl)-(R ,1R,R )-spiro[cyclopentadienyl tetrahydropentalenyl iron
p
a
(II)-1,2ʹ-pyrrolidin]-5ʹ-one (4a)
2
0
1
TLC (hexanes/ethyl acetate, 1:1 v/v): R = 0.25; [α] +211 (c 1.02, CHCl ); H NMR (600 MHz,
f
D
3
CDCl ): δ 7.42–7.35 (m, 4H), 7.30 (t, J = 7.2 Hz, 1H), 6.07 (d, J = 4.8 Hz, 1H), 4.88 (dd, J = 10.2,
3
1.8 Hz, 1H), 4.52–4.47 (m, 1H), 4.27–4.24 (m, 2H), 4.16 (s, 6H), 3.80 (d, J = 3.0 Hz, 1H), 2.58–
2
.43 (m, 3H), 2.35 (dd, J = 14.7, 8.1 Hz, 1H), 2.24–2.18 (m, 1H), 2.16–2.12 (m, 1H), 1.94 (dd, J =
1.1, 6.3 Hz, 1H), 1.83–1.78 (m, 1H); 13C{ H} NMR (150 MHz, CDCl ): δ 177.9, 138.0, 128.7,
1
1
3
127.1, 126.7, 97.9, 90.9, 70.7, 70.1, 69.5, 66.1, 61.9, 58.6, 57.3, 39.4, 34.3, 29.5, 23.0; IR (film) vmax
366, 3329, 2937, 2855, 1665, 1495, 1449, 1420, 1356, 1294, 1179, 1107, 1080, 1055, 1032, 1001,
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24, 808, 729, 698, 679, 511, 459 cm ; HRMS (ESI-TOF) m/z: [M + H] Calcd for C H FeNO
24 26 2
16.1313; Found 416.1307; m.p. 117.6–118.4 °C.
N-((R)-2-Hydroxy-1-phenethyl)-(S ,1S,R )-spiro[cyclopentadienyl tetrahydropentalenyl iron
p
a
(II)-1,2ʹ-pyrrolidin]-5ʹ-one (4b)
2
0
1
TLC (hexanes/ethyl acetate, 1:1 v/v): R = 0.11; [α] −77.9 (c 1.01, CHCl ); H NMR (600 MHz,
f
D
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CDCl ): δ 7.45–7.40 (m, 4H), 7.32 (t, J = 7.2 Hz, 1H), 6.13 (d, J = 4.8 Hz, 1H), 4.72–4.70 (m, 1H),
3
4
3
2
.67–4.62 (m, 1H), 4.26 (m, 1H), 4.13 (d, J = 1.2 Hz, 1H), 4.07 (t, J = 2.4 Hz, 1H), 3.97 (s, 5H),
.29 (d, J = 1.8 Hz, 1H), 2.66 (dd, J = 18.3, 9.9 Hz, 1H), 2.58–2.44 (m, 3H), 2.30–2.22 (m, 2H),
1
3
1
.14–2.10 (m, 1H), 1.92–1.86 (m, 1H); C{ H} NMR (100 MHz, CDCl ): δ 177.8, 136.7, 128.5,
3
126.9, 126.4, 97.6, 91.3, 70.5, 69.8, 69.7, 65.7, 61.6, 58.4, 57.7, 38.3, 33.6, 29.6, 23.0; IR (film) vmax
−
1
3
366, 3090, 2932, 2853, 1670, 1449, 1420, 1356, 1296, 1177, 1051, 910, 822, 806 cm ; HRMS
+
(
ESI-TOF) m/z: [M + H] Calcd for C H FeNO 416.1313; Found 416.1307; m.p. 216.8–217.2 °C.
2
4
26
2
Preparation of 3 with no aqueous workup
A Schlenk tube was charged with anhydrous CH Cl (4 mL) and anhydrous CF CO H (1.0 mL, 15.0
2
2
3
2
mmol) under N atmosphere. The solution was cooled to 0 °C. Compound 2 (416 mg, 1.0 mmol)
2
was added in one portion. The mixture was stirred at 0 °C for 48 h. The volatiles were removed
under vacuum and the crude product promptly chromatographed on silica gel to give 3 as a brown
1
oil (362 mg, 71%). H NMR indicated a molar ratio of 3a:3b = 0.87:1. The NMR data of 3b was
identified from that for a mixture of 3a and 3b.
Mixture of 3a and 3b
IR (film) vmax 2936, 2855, 1792, 1786, 1695, 1686, 1560, 1541, 1364, 1356, 1223, 1153, 826, 808,
−
1
7
31, 698 cm .
(S ,1S,3ʹR)-3ʹ-Phenyl-spiro[cyclopentadienyl tetrahydropentalenyl iron (II)-1,5ʹ-tetrahydro
p
pyrrolo[2,1-b]oxazolium trifluoroacetate] (3b)
1
TLC (hexanes/ethyl acetate, 1:1 v/v): R = 0.65; H NMR (600 MHz, CDCl ): δ 7.46–7.33 (m, 5H),
f
3
6.15 (dd, J = 10.2, 5.2 Hz, 1H), 5.58 (dd, J = 10.8, 9.0 Hz, 1H), 5.04 (dd, J = 10.8, 6.0 Hz, 1H), 4.13
(
m, 1H), 4.07 (m, 1H), 3.97 (s, 5H), 3.22 (m, 1H), 2.65 (dd, J = 18.6, 10.8 Hz, 1H), 2.56 (m, 1H),
1
3
1
2
.48 (m, 2H), 2.26 (m, 1H), 2.19 (m, 1H), 2.11 (m, 1H), 1.83 (m, 1H); C{ H} NMR (150 MHz,
CDCl ): δ 177.9, 157.2 (q, J = 43 Hz, CF CO ), 135.2, 128.7, 128.0, 126.4, 114.5 (q, J = 287 Hz,
3
3
2
CF ), 96.8, 91.0, 70.6, 70.3, 69.5, 68.0, 61.7, 58.3, 54.1, 37.8, 33.4, 29.5, 23.0.
3
Reductions of 3 and 4a, 4b by LiAlH4
A mixture of 3, 4a, and 4b was prepared from 2 (2.08 g, 5.0 mmol) according to the above procedure.
A Schlenk tube was charged with the mixture of 3, 4a, and 4b, and anhydrous THF (50 mL). The
solution was cooled to 0 °C. LiAlH (1.14 g, 30.0 mmol) was added in portions at 0 °C. After that,
4
the mixture was stirred at 40 °C for 24 h. The mixture was cooled to 0 °C. 1 N NaOH (30 mL) was
added dropwise at 0 °C to quench the reaction. AcOEt was added and the mixture well stirred for
4
0 min. The mixture was filtered through Celite, and the filter cake washed with AcOEt. The filtrate
was dried over Na SO and concentrated. The residue was purified by column chromatography
2
4
(
20:1 hexanes/AcOEt) to afford 5a as a yellow liquid (0.91 g, 45% yield) and 5b as an orange solid
(0.91 g, 45% yield).
N-((R)-2-Hydroxy-1-phenethyl)-(R ,1R,R )-spiro[cyclopentadienyl tetrahydropentalenyl iron
p
a
(II)-1,2ʹ-pyrrolidine] (5a)
2
0
1
TLC (hexanes/ethyl acetate, 6:1 v/v): R = 0.15; [α] +15.0 (c 1.03, CHCl ); H NMR (600 MHz,
f
D
3
CDCl ): δ 7.42–7.36 (m, 4H), 7.29 (t, J = 7.2 Hz, 1H), 5.28 (dd, J = 10.8, 6.0 Hz, 1H), 4.21–4.05
3
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2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
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4
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4
4
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5
5
5
5
5
5
5
5
6
(
m, 7H), 3.91 (dd, J = 10.2, 5.4 Hz, 1H), 3.83 (t, J = 10.2 Hz, 1H), 3.79 (d, J = 1.8 Hz, 1H), 3.17–
3
.14 (m, 3H), 2.67–2.62 (m, 1H), 2.36 (dd, J = 14.4, 7.2 Hz, 1H), 2.15–2.10 (m, 1H), 1.89 (dd, J =
1
3
1
10.8, 6.0 Hz, 1H), 1.78–1.71 (m, 3H), 1.55 (m, 1H); C{ H} NMR (150 MHz, CDCl ): δ 140.5,
3
1
28.3, 128.2, 127.0, 101.9, 90.6, 69.4, 69.2, 62.6, 61.1, 59.0, 57.8, 45.4, 40.2, 39.8, 23.8, 22.5; IR
−
1
(film): 3422, 3084, 2953, 2936, 2851, 1447, 1312, 1288, 1175, 1105, 1030, 1001, 818, 704 cm ;
+
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
HRMS (ESI-TOF) m/z: [M + H] Calcd for C H FeNO 402.1520; Found 402.1514; m.p. 134.6–
2
4
28
1
36.0 °C.
N-((R)-2-Hydroxy-1-phenethyl)-(S ,1S,R )-spiro[cyclopentadienyl tetrahydropentalenyl iron
p
a
(II)-1,2ʹ-pyrrolidine] (5b)
2
0
1
TLC (hexanes/ethyl acetate, 6:1 v/v): R = 0.13; [α] −214 (c 1.01, CHCl ); H NMR (600 MHz,
f
D
3
CDCl ): δ 7.48 (d, J = 7.8 Hz, 2H), 7.39 (t, J = 7.2 Hz, 2H), 7.29 (t, J = 7.2 Hz, 1H), 5.54 (dd, J =
3
9
.3, 5.7 Hz, 1H), 4.10–4.06 (m, 8H), 3.80 (t, J = 9.9 Hz, 1H), 3.63 (d, J = 1.8 Hz, 1H), 3.12–3.08
(m, 1H), 2.97 (td, J = 8.7, 4.2 Hz, 1H), 2.94 (s, 1H), 2.59 (dd, J = 14.4, 7.8 Hz, 1H), 2.40 (dd, J =
13
1
1
4.4, 7.8 Hz, 1H), 2.17–2.06 (m, 2H), 1.87–1.71 (m, 3H), 1.55 (m, 1H); C{ H} NMR (100 MHz,
CDCl ): δ 140.5, 128.3, 128.0, 126.8, 98.9, 91.9, 70.6, 69.6, 69.5, 62.7, 61.1, 59.6, 59.3, 45.3, 43.3,
3
38.8, 23.6, 22.9; IR (film) vmax 3422, 3088, 2953, 2940, 2851, 1491, 1447, 1375, 1306, 1288, 1229,
−1
+
1
207, 1180, 1142, 1105, 1030, 883, 818, 746, 702, 459 cm ; HRMS (ESI-TOF) m/z: [M + H]
Calcd for C H FeNO 402.1520; Found 402.1514; m.p. 105.0–106.1 °C.
2
4
28
Reduction of 3 by LiAlH4
A Schlenk tube was charged with 3 (1.02 g, 2 mmol) and anhydrous THF (20 mL). The mixture
was cooled to 0 °C. LiAlH (456 mg, 12.0 mmol) was added in portions at 0 °C. After that, the
4
mixture was stirred at 40 °C for 12 h. The mixture was cooled to 0 °C. 1 N NaOH (12 mL) was
added dropwise at 0 °C to quench the reaction. AcOEt was added and the mixture well stirred for
4
0 min. The mixture was filtered through Celite, and the filter cake washed with AcOEt. The filtrate
was dried over Na SO and concentrated. The residue was purified by column chromatography
2
4
(20:1 hexanes/AcOEt) to afford 6 as orange solids (480 mg, 60% yield), 5a as a yellow liquid (128
mg, 16% yield) and 5b as an orange solid (132 mg, 16% yield).
Orange single crystals of 6a were obtained from a solution of 6a and 6b, which were inseparable
by silica gel chromatography.
(R ,1R,3ʹR,4ʹR,7ʹaS)-3ʹ-Phenyl-spiro[cyclopentadienyl tetrahydropentalenyl iron (II)-1,5ʹ-
p
hexahydropyrrolo[2,1-b]oxazole] (6a)
2
0
1
TLC (hexanes/ethyl acetate, 6:1 v/v): R = 0.60; [α] +105 (c 1.03, CHCl ); H NMR (600 MHz,
f
D
3
CDCl ): δ 7.54 (d, J = 7.8 Hz, 2H), 7.36 (t, J = 8.1 Hz, 2H), 7.23 (t, J = 7.5 Hz, 1H), 6.07 (t, J = 6.3
3
Hz, 1H), 4.98 (d, J = 4.2 Hz, 1H), 4.41 (t, J = 7.8 Hz, 1H), 4.18 (t, J = 1.8 Hz, 1H), 4.06 (d, J = 1.8
Hz, 1H), 3.98 (s, 5H), 3.83 (d, J = 1.8 Hz, 1H), 3.72 (dd, J = 8.4, 6.0 Hz, 1H), 2.63–2.58 (m, 1H),
1
3
1
2.35–2.31 (m, 1H), 2.17–2.05 (m, 3H), 1.95–1.87 (m, 2H), 1.70–1.65 (m, 1H); C{ H} NMR (150
MHz, CDCl ): δ 144.9, 128.5, 126.5,125.7, 98.6, 97.1, 92.8, 74.3, 71.4, 70.3, 69.4, 62.6, 61.3, 60.1,
3
4
1
4.3, 37.5, 29.0, 23.5; IR (film) vmax 3084, 3023, 2937, 2853, 1719, 1601, 1493, 1449, 1373, 1308,
−
1
287, 1163, 1132, 1105, 1074, 1043, 1024, 1001, 820, 806, 735, 702, 662, 505, 478, 461 cm ;
+
HRMS (ESI-TOF) m/z: [M + H] Calcd for C H FeNO 400.1364; Found 400.1358; m.p. 117.8–
2
4
26
1
19.5 °C.
Sp,1S,3ʹR,4ʹR,7ʹaS)-3ʹ-Phenyl-spiro[cyclopentadienyl tetrahydropentalenyl iron (II)-1,5ʹ-
hexahydropyrrolo[2,1-b]oxazole] (6b)
TLC (hexanes/ethyl acetate, 6:1 v/v): R = 0.60; [α] −180 (c 1.00, CHCl ); H NMR (400 MHz,
(
20
1
f
D
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CDCl ) δ: 7.55 (m, 2H), 7.37 (m, 2H), 7.23 (m, 1H), 5.11 (d, J = 5.1 Hz, 1H), 4.85 (t, J = 6.9 Hz,
3
1
H), 4.35 (t, J = 7.9 Hz, 1H), 4.02 (m, 1H), 3.94 (m, 1H), 3.81 (m, 1H), 3.78 (s, 5H), 3.67 (dd, J =
8.0, 6.7 Hz, 1H), 2.69 (m, 1H), 2.39 (m, 1H), 2.18–2.04 (m, 3H), 1.95–1.86 (m, 2H), 1.71–1.57 (m,
13
1
1
6
H); C{ H} NMR (100 MHz, CDCl ) δ: 143.6, 128.4, 126.9, 126.5, 103.0, 98.9, 90.3, 74.3, 70.6,
3
8.8, 68.7, 62.2, 60.5, 58.2, 37.1, 36.8, 29.1, 24.4; IR (film) vmax 3084, 2958, 2935, 2855, 1448,
−
1
+
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
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2
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4
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7
8
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0
1
2
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4
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6
7
8
9
0
1
2
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5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1369, 1298, 1107, 1074, 999, 815, 700 cm ; HRMS (ESI-TOF) m/z: [M + H] Calcd for
C H FeNO 400.1364; Found 400.1358; m.p. 147.5–148.2 °C.
2
4
26
N-((R)-2-(4-Bromobenzoyloxy)-1-phenethyl)-(R ,1R,R )-spiro[cyclopentadienyl
p
a
tetrahydropentalenyl iron (II)-1,2ʹ-pyrrolidine]-5′-one (7)
To a Schlenk tube were added 4a (415 mg, 1.0 mmol), DMAP (122 mg, 1.0 mmol), Et N (0.3 mL,
3
2
.0 mmol) and CH Cl (10 mL). The mixture was cooled in an ice bath. p-Bromobenzoyl chloride
2 2
(
439 mg, 2.0 mmol) in CH Cl (10 mL) was added dropwise. Then the mixture was stirred at rt for
2 2
3 h before it washed with 1 N HCl, saturated aq. NaHCO and brine. The organic layer was dried
3
over anhydrous Na SO and concentrated. The crude product was purified by column
2
4
chromatography (4:1 hexanes/AcOEt) to give (R )-7 as a yellow solid (572 mg, 96% yield). R =
a
f
0.38 (hexanes/AcOEt, 1:1 v/v); [α]D20 +261 (c 1.00, CHCl ); H NMR (400 MHz, CDCl ) δ: 7.97
1
3
3
(
(
(
d, J = 8.5 Hz, 2H), 7.61 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 7.6 Hz, 2H), 7.41(t, J = 7.4 Hz, 2H), 7.32
t, J = 7.3 Hz, 1H), 6.11 (t, J = 7.3 Hz, 1H), 5.32 (d, J = 7.4 Hz, 2H), 4.12 (s, 7H), 3.60 (s, 1H), 2.51
1
3
1
m, 2H), 2.42 (m, 1H), 2.35 (m, 1H), 2.20 (m, 1H), 2.08 (m, 1H), 2.01 (m, 1H), 1.75 (m, 1H); C{ H}
NMR (100 MHz, CDCl ) δ: 176.2, 165.1, 138.0, 131.6, 130.8, 128.8, 128.3, 127.9, 127.2, 126.9,
3
9
2
7.1, 90.4, 70.4, 69.3, 69.2, 65.5, 61.5, 57.1, 55.4, 38.9, 33.8, 29.4, 22.6.; IR (film) vmax: 3090, 3030,
−
1
938, 2855, 2245, 1714, 1589, 1410, 1269, 1105, 1069, 756, 731, 698 cm ; HRMS (ESI-TOF) m/z:
+
[M + H] Calcd for C H BrFeNO 598.0680; Found 598.0675; m.p. 151.8–152.3 °C.
3
1
29
3
N-((R)-2-(4-Bromobenzoyloxy)-1-phenethyl)-(R ,1R,R )-spiro[cyclopentadienyl
p
a
tetrahydropentalenyl iron (II)-1,2ʹ-pyrrolidine] (8)
A dry Schlenk tube was charged with 5a (147 mg, 0.35 mmol), DMAP (43 mg, 0.5 equiv), Et N
3
(0.7 mL, 2.0 equiv) and CH Cl (5 mL). The mixture was cooled to 0 °C. 4-Bromobenzoyl chloride
2 2
(
154 mg, 2.0 equiv) in CH Cl (5 mL) was added dropwise. The mixture was stirred at 0 °C for 24
2
2
h. After that, the mixture was washed with 1 N HCl, saturated NaHCO , and brine. The mixture was
3
dried over anhydrous Na SO and concentrated. The residue was purified by column
2
4
chromatography (10:1 hexanes/AcOEt) to afford (R )-8 as a pale brown crystalline solid (103 mg,
a
5
0% yield).
2
0
1
TLC (hexanes/ethyl acetate, 6:1 v/v): R = 0.75; [α] +67.5 (c 1.01, CHCl ); H NMR (600 MHz,
f
D
3
CDCl ): δ 7.85 (d, J = 8.4 Hz, 2H), 7.53 (t, J = 7.8 Hz, 4H), 7.38 (t, J = 7.2 Hz, 2H), 7.28–7.27 (m,
3
1
H), 5.80 (t, J = 7.2 Hz, 1H), 4.99 (dd, J = 12.0, 7.8 Hz, 1H), 4.72 (dd, J = 11.4, 7.2 Hz, 1H), 4.12–
4.05 (m, 7H), 3.70 (d, J = 1.8 Hz, 1H), 3.19–3.08 (m, 2H), 2.55–2.50 (m, 1H), 2.33 (dd, J = 14.4,
13
1
7
.2 Hz, 1H), 2.13–2.08 (m, 1H), 1.90–1.83 (m, 2H), 1.78–1.72 (m, 2H), 1.52–1.47 (m, 1H); C{ H}
NMR (150 MHz, CDCl ): δ 165.9, 141.9, 131.8, 131.1, 128.3, 127.6, 126.7, 100.2, 91.4, 69.6, 69.4,
3
6
9.2, 66.9, 61.1, 58.5, 55.6, 46.8, 41.3, 39.7, 23.4, 22.9; IR (film) vmax 2959, 2934, 1719, 1589, 1267,
−
1
+
1173, 1115, 1103, 1070, 1013, 818, 806, 756 cm ; HRMS (ESI-TOF) m/z: [M + H] Calcd for
C H BrFeNO 584.0888; Found 584.0880; m.p. 175.1–176.0 °C.
3
1
31
2
Dehydration of 4a and 4b
A dry Schlenk tube was charged with a mixture of 4a and 4b (415 mg, 1.0 mmol), DMSO (20 mL),
hydroquinone (11 mg, 0.1 mmol) and LiOH·H O (0.84 g, 20.0 mmol). The mixture was stirred at
2
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5
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6
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60 °C for 18 h. DMSO was removed by vacuum distillation. To the residue was added CH Cl ,
2
2
and the solution was stirred for 12 h. The mixture was filtered through Celite, and the filter cake
washed with CH Cl . The filtrate was dried over anhydrous Na SO and then concentrated. The
2
2
2
4
residue was purified by column chromatography (3:1 hexanes/AcOEt) to afford (±)-10 as a yellow
solid (285 mg, 72% yield) and (±)-11 as an orange solid (31 mg, 8% yield).
0
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2
3
4
5
6
7
8
9
0
1
2
3
4
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7
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0
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(±)-N-(1-Phenylethenyl)-spiro[cyclopentadienyl
tetrahydropentalenyl
iron
(II)-1,2ʹ-
pyrrolidin]-5ʹ-one (10)
1
TLC (hexanes/ethyl acetate, 1:2 v/v): R = 0.37; H NMR (600 MHz, CDCl ): δ 7.58 (d, J = 7.2 Hz,
f
3
2
H), 7.41–7.34 (m, 3H), 6.27 (s, 1H), 5.45 (s, 1H), 4.13–3.59 (m, 8H), 2.62–2.52 (m, 3H), 2.25–
1
3
1
2.21 (m, 3H), 2.09–1.95 (m, 2H); C{ H} NMR (100 MHz, CDCl ): δ 175.7, 141.4, 135.8, 128.7,
3
1
3
28.4, 125.3, 117.2, 98.2, 90.0, 70.8, 70.1, 69.6, 61.1, 58.7, 39.6, 34.7, 29.7, 23.2; IR (film) vmax
−
1
084, 2965, 2936, 2853, 1701, 1626, 1493, 1447, 1360, 1296, 1175, 912, 810, 777, 714 cm ; HRMS
+
(ESI-TOF) m/z: [M + H] Calcd for C H FeNO 398.1207; Found 398.1201.
2
4
24
(R ,R)-N-(1-Phenylethenyl)-spiro[cyclopentadienyl tetrahydropentalenyl iron (II)-1,2ʹ-
p
pyrrolidin]-5ʹ-one (10)
[α]D20 +225 (c 1.01, CHCl ); m.p. 173.8–175.8 °C.
3
(±)-N-Benzyl-spiro[cyclopentadienyl tetrahydropentalenyl iron (II)-1,2ʹ-pyrrolidin]-5ʹ-one
(11)
1
TLC (hexanes/ethyl acetate, 1:1 v/v): R = 0.39; H NMR (600 MHz, CDCl ): δ 7.36 (t, J = 8.4 Hz,
f
3
2H), 7.29–7.25 (m, 3H), 5.10 (d, J = 15.6 Hz, 1H), 5.01 (d, J = 15.6 Hz, 1H), 4.19–4.11 (m, 7H),
3
.72 (s, 1H), 2.62 (d, J = 8.4 Hz, 1H), 2.51–2.42 (m, 2H), 2.34 (s, 1H), 2.27–2.22 (m, 1H), 2.15–
1
3
1
2
.10 (m, 1H), 1.98–1.96 (m, 1H), 1.85–1.80 (m, 1H); C{ H} NMR (150 MHz, CDCl ): δ 176.1,
3
138.3, 128.5, 126.7, 126.0, 98.0, 91.2, 70.5, 69.8, 68.5, 61.8, 57.8, 42.8, 39.7, 34.3, 29.2, 23.2; IR
film) vmax 2940, 1690, 1676, 1398, 1387, 1358, 1180, 1107, 1001, 820, 806, 731, 706, 459 cm−1;
(
+
HRMS (ESI-TOF) m/z: [M + H] Calcd for C H FeNO 386.1207; Found 386.1201.
2
3
24
(R ,R)-N-Benzyl-spiro[cyclopentadienyl tetrahydropentalenyl iron (II)-1,2ʹ-pyrrolidin]-5ʹ-
p
one (11)
[
α]D20 +242 (c 0.990, CHCl3).
(±)-Spiro[cyclopentadienyl tetrahydropentalenyl iron (II)-1,2ʹ-pyrrolidin]-5ʹ-one (1)
A dry Schlenk tube was charged with (±)-10 (153 mg, 0.38 mmol), THF (3 mL) and H O (3 mL).
2
The solution was degassed in three freeze-vacuum-thaw cycles. Concentrated HCl (3.0 mL) was
added dropwise under N atmosphere. Then the mixture was stirred at 40 °C under N for 24 h.
2
2
After that, saturated NaHCO was added dropwise at 0 °C to quench the reaction. The mixture was
3
extracted with CH Cl . The combined organic layers were washed with brine, dried over anhydrous
2
2
Na SO and concentrated. The residue was purified by column chromatography (3:1
2
4
hexanes/AcOEt) to afford (±)-1 as a yellow solid (68 mg, 60% yield). TLC (hexanes/ethyl acetate,
1
1
:2 v/v): R = 0.26; H NMR (400 MHz, CDCl ): δ 5.71 (s, 1H), 4.13-4.11 (m, 7H), 3.95 (d, J = 2.4
f 3
Hz, 1H), 2.66–2.28 (m, 6H), 2.17–2.11 (m, 1H), 2.02–1.94 (m, 1H); 13C{ H} NMR (150 MHz,
1
CDCl ): δ 176.9, 98.1, 93.1, 70.3, 69.0, 64.2, 61.9, 57.8, 43.7, 34.4, 31.0, 23.5; IR (film) v 3196,
3
max
3094, 3075, 2980, 2965, 2934, 2847, 1688, 1474, 1449, 1429, 1406, 1381, 1358, 1296, 1215, 1175,
−
1
1
103, 1015, 995, 980, 824, 810, 754, 696, 665, 538, 521, 480 cm ; HRMS (ESI-TOF) m/z: [M +
+
H] Calcd for C H FeNO 296.0738; Found 296.0732; m.p. 200 °C decompose.
1
6
18
(R ,R)-Spiro[cyclopentadienyl tetrahydropentalenyl iron (II)-1,2ʹ-pyrrolidin]-5ʹ-one (1)
p
[
α]D20 +336 (c 1.02, CHCl ); m.p. 200 °C decompose.
3
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(
Sp,S)-Spiro[cyclopentadienyl tetrahydropentalenyl iron (II)-1,2ʹ-pyrrolidine (12)
A dry Schlenk tube was charged with (S ,S)-1 (48 mg, 0.16 mmol) and anhydrous THF (5 mL). The
p
solution was cooled to 0 °C. LiAlH (37 mg, 0.96 mmol) was added at 0 °C. After that, the mixture
4
was stirred at 60 °C overnight. The mixture was cooled to 0 °C. 1 N NaOH (1 mL) was added
dropwise at 0 °C to quench the reaction. AcOEt was added and the mixture well stirred for 40 min.
The mixture was filtered through Celite, and the filter cake washed with AcOEt. The filtrate was
dried over Na SO and concentrated. (S ,S)-12 was obtained as a brown oil (40 mg, 88% yield).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
4
p
2
0
1
TLC (ethyl acetate): R = 0.05; [α] −84.9 (c 0.990, CHCl ); H NMR (400 MHz, CDCl ): δ 4.67
f
D
3
3
(br s, 1H), 4.22 (s, 5H), 4.08 (s, 1H), 4.04 (s, 1H), 4.03 (s, 1H), 3.28 (br s, 2H), 2.85–2.77 (m, 1H),
1
3
1
2.49–2.44 (m, 1H), 2.33–2.22 (m, 2H), 2.06–1.85 (m, 3H), 1.72–1.66 (m, 1H); C{ H} NMR (100
MHz, CDCl ): δ 99.1, 93.1, 69.9, 69.2, 68.4, 61.3, 58.3, 45.7, 43.5, 37.5, 24.8, 24.1; IR (film) v
3
max
−
1
3
383, 3086, 2928, 2855, 1562, 1543, 1400, 1377, 1308, 1103, 1042, 810 cm ; HRMS (ESI-TOF)
+
m/z: [M + H] Calcd for C H FeN 282.0945; Found 282.0937.
1
6
20
ACKNOWLEDGEMENT
Financial supports from Beijing Normal University and National Natural Science Foundation of
China (NSFC) are acknowledged. This work was supported in part by a grant (No. 2015BAK45B01)
from Ministry of Science and Technology (MOST) of the People’s Republic of China. Prof. Jia-Xin
Zhang, Jin-Ping Qiao at College of Chemistry, Beijing Normal University are acknowledged for
his/her assistance with NMR/HRMS experiments, respectively. We thank Prof. Xiang Hao and
Junfeng Xiang at Institute of Chemistry, Chinese Academy of Science (ICCAS) for their help with
XRD analyses and NOESY experiments.
Author Contributions
H. Li, P. Jia and N. Qian contributed equally to this work.
Author Information
Corresponding Author
E-mail: pjiao@bnu.edu.cn
ORCID
Peng Jiao: 0000-0003-4039-8300
Supporting Information
NOESY and ROESY spectra, variable temperature H NMR spectra of 4b in DMSO-d , H and C
1
1
13
6
NMR spectra, and crystal data.
Accession Codes
The X-ray crystallographic data for all the reported crystals have been deposited at the Cambridge
Crystallographic Data Centre (CCDC). 6-Ferrocenyl-4-oxo-hexanoic acid: CCDC 1855403; (±)-1:
CCDC 1855412; 2: CCDC 1855404; 4a: CCDC 1855405; 4b: CCDC 1855406; 5a: CCDC 1857202;
5b: CCDC 1855409; 6a: CCDC 1855407; 6b: CCDC 1867995; 7: CCDC 1886077; 8: CCDC
1
855408; (R ,1R)-10: CCDC 1855410; (S ,1S)-10: CCDC 1857203; (±)-11: CCDC 1855411.
p p
Notes
The authors declare no competing financial interests.
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(15)We suggest the following rule to define the sense of the new type of axial chirality. Since the
hydrogen atom of phenylglycinol should be uniformly positioned close to the iron (II) nucleus
no matter what the chiral sense of phenylglycinol is (see the text), the phenyl group, the
hydroxymethyl group and the carbon stereocenter of phenylglycinol are imagined to resemble
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2
-hydroxynaphthyl as shown below. Comparison of the chiral sense of (R)-BINOL with that of
an imagined model compound from 4b is shown below. Accordingly, 4b is suggested to have
(
Ra) chirality.
O
O
OH
OH
N
N
OH
Fe
H
Fe
CH OH
2
4b
model compound similar to (R )-4b
(R)-BINOL
a
(16)See Supporting Information for details.
(
17)(a) Sahasrabudhe, K.; Gracias, V.; Furness, K.; Smith, B. T.; Katz, C. E.; Reddy, D. S.; Aubé,
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2
003, 125, 7914–7922. (b) Allin, S. M.; Gaskell, S. N.; Elsegood, M. R. J.; Martin, W. P.
Asymmetric Synthesis of Tetracyclic Benzo[a]quinolizidine Targets. J. Org. Chem. 2008, 73,
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6
Gelmi, M. L. 1H-Azepine-2-oxo-5-amino-5-carboxylic Acid: A 310 Helix Inducer and An
Effective Tool for Functionalized Gold Nanoparticles. J. Org. Chem. 2015, 80, 5507–5516. (d)
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C.; Bosch, J.; Amat, M. Stereocontrolled Generation of Benzo[a]- and indolo[2,3-
a]quinolizidines from (S)-Tryptophanol and (S)-(3,4-Dimethoxyphenyl)alaninol-Derived
Lactams. Eur. J. Org. Chem., 3858–3863.
(
18)(a) Roa, L. F.; Gnecco, D.; Galindo, A.; Terán, J. L.; Bernès, S. Syntheses of Pyridin-4-ylium
chirons: Applications in A Synthesis of (+)-Coniine. Tetrahedron: Asymmetry 2004, 15, 847–
850. (b) Yan, L.-H.; Dagorn, F.; Gravel, E.; Séon-Méniel, B.; Poupon, E. Synthesis and
Reactivity of Pelletierine-Derived Building Blocks and Pelletierine Analogs. Tetrahedron
2
012, 68, 6276–6283.
(19)(a) Castro, A.; Ramírez, J.; Juárez, J.; Terán, J. L.; Orea, L.; Galindo, A.; Gnecco, D. Preparation
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