BF3·OEt2-Promoted Synthesis of 2,3-Metallocenocyclohexanones: A 1,2-Hydride Shift and Cationic Cyclization Strategy

Article abstract of DOI:10.1021/acs.joc.5b01511

A BF₃·OEt₂-promoted cyclization of metallocenyl enones to form cyclohexanone-fused metallocenes is reported. 2,3-Metallocenocyclohexanones were formed exclusively, and no normal Nazarov-type cyclopentanone analogues were detected. The reaction possibly proceeded via an unusual cationic 1,2-hydride shift followed by Friedel-Crafts alkylative cyclization process. During the studies of the alkylation reaction of these keto esters, an unusual and rare facial selectivity was observed. The electrophiles would be attacked from the same face as the second Cp ring.

Full text of DOI:10.1021/acs.joc.5b01511

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pubs.acs.org/joc
BF3·OEt2‑Promoted Synthesis of 2,3-Metallocenocyclohexanones: A
1,2-Hydride Shift and Cationic Cyclization Strategy
Congfa He, Jie Wang, and Zhenhua Gu*
Department of Chemistry, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui 230026, P. R. China
S
* Supporting Information
ABSTRACT: A BF3·OEt2-promoted cyclization of metallocenyl enones to form cyclohexanone-fused metallocenes is reported.
2,3-Metallocenocyclohexanones were formed exclusively, and no normal Nazarov-type cyclopentanone analogues were detected.
The reaction possibly proceeded via an unusual cationic 1,2-hydride shift followed by Friedel−Crafts alkylative cyclization
process. During the studies of the alkylation reaction of these keto esters, an unusual and rare facial selectivity was observed. The
electrophiles would be attacked from the same face as the second Cp ring.
Scheme 1. Synthesis of 2,3-Ferrocenocyclohexenone and Its
Application
INTRODUCTION
■
The discovery of ferrocene and elucidation of its sandwich-like
structure is an important event in organic chemistry, which is
also regarded as the starting point of modern organometallic
chemistry.1,2 The discovery of ferrocene was serendipitous;
however, it had a great impact on several related fields,
including material science, catalysis, biochemistry, and electro-
chemical sensors, etc.3,4 Because of its good stability and its
unique sandwich-like structure, ferrocene as well as its planar
chiral analogues were also proven to be one of the most
successful scaffolds for chiral ligands or catalysts in organic
synthesis. The wide applications in various areas required the
synthesis of different functionalized ferrocenes for different
purposes. Although great efforts were made, methods that
could be applied to efficiently functionalize ferrocenes and
other related metallocenes are still limited.
2,3-Ferrocenocyclohexanone was the first optically active
planar chiral ferrocene compound,5 and some useful ligands
and catalysts, such as aminophosphine I,6a diphosphine II,6a
and aminoalcohol III,6b were prepared from chiral 2,3-
ferrocenocyclohexanone (Scheme 1A). However, there are
very limited methods that could be applied to synthesize 2,3-
ferrocenocyclohexanone derivatives, which currently were
prepared from ferrocene via a classic multistep synthesis
developed in the 1950s: Friedel−Crafts acylation, Clemmensen
reduction, and Friedel−Craft acylation (Scheme 1B).7 To our
knowledge, currently this is the only reliable and practical
method for the synthesis of this class of compounds, which still
suffered from its low functional group tolerance and structural
diversity. For example, it is hard to introduce other
functionalities in the 2,3-ferrocenocyclohexanone skeleton via
this protocol. Thus, the development of practical and
convenient methods for the synthesis of cyclohexanone-fused
metallocenes is urgent yet still challenging. Here, we report an
alternative synthesis of this class of compounds via an unusual
BF3·OEt2-promoted cationic 1,2-hydride shift followed by
Friedel−Crafts alkylative cyclization.
RESULTS AND DISCUSSION
■
Nazarov cyclization reaction is a powerful method for the
construction of cyclopentenone analogues via a 4π-electrocyclic
ring closure process, where the formation of pentadienyl cation
intermediate is crucial.8 As a result of contributions from the
groups of West, Frontier, Flynn, Tius, and others, a variety of
cyclopentenones with different functionalities have been
synthesized, including the application of complex natural
product synthesis.9 By introducing cyclopropanyl functionality
in place of the vinyl group into the molecules, cyclohexanone
analogues could be obtained.10 Originally, in order to access
Received: July 2, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b01511
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Featured Article
some ring-fused ferrocenes, we hypothesized that ferrocenocy-
clopentanones might be synthesized via Brønsted or Lewis acid
catalyzed Nazarov cyclization of metallocenylenones.
Initially, we chose enones 1a and 2a as the substrates;
however, no cyclized product could be obtained, and most of
1a was recovered, while 2a completely decomposed. In the
presence of stoichiometric AlCl3, it was interesting to find that
cyclohexanone analogue 4a formed in 27% yield when enone
3a was used, and no cyclopentanone product was detected
(Table 1, entry 1). In a classic Nazarov reaction, cyclo-
cyclohexanone product 4a when BF3·OEt2 was used (entry 5).
Further screening of different solvents indicated that DMF,
MeCN, and THF were ineffective for this reaction, while
toluene was superior over other solvents (entries 6−9).
Increasing the loading of BF3·OEt2 could significantly improve
the isolated yield of 4a to 88% even at only 40 °C, where 4% of
byproduct 4a′ could be isolated (entry 10). The requirement of
large amounts of BF3·OEt2 was possibly due to the relatively
higher Lewis basicity of the product 4a over enone ester 3a. By
use of BF3·CH3CN as Lewis acid, relative lower yields were
obtained along with isolation of an unidentified Ritter-type
product (entries 11 and 12).
a
Table 1. Reaction Condition Optimization
We tested the generality of this protocol by applying different
substituted metallocenylenones to the optimized conditions
(Table 2). The enone with a 3-pentyl side chain was also a
compatible substrate, although a relatively lower yield was
obtained (entry 1). The reaction of enone containing a 2-butyl
or 1-(1-phenylpropyl) side chain gave a mixture of planar and
center chiral diastereomers with dr of 3:1 and 1:1, respectively
(entries 2 and 3). Currently, though it is still not very clear, it is
thought that the diastereoselectivity is possibly controlled by
steric differences of the substitutents. It should be noted that
the cyclized compound from 3d contains the mixture of enol
and ketone, along with the diastereomers, whose spectroscopies
are messy. However, this could be overcome by the
decarboxylative reaction to form ketone 5d. The reactions of
enones with cyclopentyl, cyclohexyl, and cycloheptyl chains
worked uneventfully to give spiro compounds in good to
excellent yields (entries 4−6). With ethyl ester, the reaction
also proceeded smoothly to give 4h in excellent yield (entry 7),
while the bulky menthyl ester 3i was inert under our standard
conditions probably due to the steric congestion (entry 8). The
reaction of 3j, an enone with 1-(2-methylpropyl) substituent,
only resulted the decomposition of starting material (entry 9).
The substituent on the second Cp ring could be either an
electron-donating group or an electron-withdrawing group,
where the strong electron-deficient substituent significantly
decreased the reaction rate (entries 10−12). For example, when
3l, bearing a benzoyl group at the second Cp ring, was used as
the substrate, a total of 36 h was necessary for the reaction to
reach full conversion even in the presence of 6.0 equiv of BF3·
OEt2 (entry 11). Notably, bis(cyclopentadienyl)ruthenium
(ruthenocene) derivatives were suitable substrates, which
showed superior reactivity over ferrocenylenones, and relatively
higher yields could be achieved (entries 13−15).
entry
1
cat. (equiv)
AlCl3 (1.0)
solvent
T (°C)
yield (%)
DCE
80
27
−
−c
−
b
2
Sc(OTf)3 + LiClO4 (1.0)
Ti(OiPr)4 (1.0)
(+)-CSA (1.0)
DCE
rt to 80
80
3
DCE
4
DCE
100
80
5
BF3·OEt2 (1.0)
BF3·OEt2 (1.0)
BF3·OEt2 (1.0)
BF3·OEt2 (1.0)
BF3·OEt2 (1.0)
BF3·OEt2 (3.0)
BF3·MeCN (1.0)
BF3·MeCN (3.0)
DCE
50
6
DMF
80
−
−
−
7
CH3CN
THF
80
8
40
9
toluene
toluene
toluene
toluene
80
59
d
10
40
88
e
11
e
80
33
38
12
80
a
The reaction was conducted on 3a (24 mg, 0.070 mmol) in the
b
c
indicated solvent (0.10 M) at 40−80 °C. 5 mol % of Sc(OTf)3. The
d
recovered SM was contaminated with 16% of isopropyl ester. 4% of
e
4a′ was isolated. An unidentified product with HRMS [M+H]+
382.1108 was isolated.
The NMR spectra of the keto esters show a pair of mixtures
due to the keto−enol equilibrium, and the spectra of 4 vary
depending on the workup, solvent, and concentration for
NMR, which was difficult to assign. However, the keto esters
readily underwent decarboxylative reaction under aqueous basic
conditions to deliver metallocenyl ketones, which provided
clear and simplified spectroscopies in comparison with the keto
esters (Scheme 2).
The alkylation of keto ester 4a by the use of MeI and BnBr
provided alkylated products 6a and 6b in moderate to good
yields with excellent stereoselectivity, which also gave clear
NMR spectroscopies via inhibition of the formation of enols. It
is interesting to find that the alkylation took place at the same
face as the second Cp ring, which was confirmed by NOE
correlation studies and single-crystal X-ray analysis.13 This
unexpected facial selectivity was possibly caused by the block of
the coordinated solvents to sodium atom. To avoid the steric
congestion, the coordination molecules would stay at the outer
hexenones were usually prepared by introducing a cyclopropyl
group via ring-opening processes.10 Compound 4a was possibly
formed via 1,2-hydride shift followed by Friedel−Crafts type
carbocation cyclization. This type of rearrangement/cyclization
process was also observed by Frontier, Eisenberg, and co-
workers in the Nazarov cyclization of 2-furyl and 2-benzofuryl
enones.11 It should be noted that in their studies only 2-furyl
enone analogues underwent this type of rearrangement, which
was significantly different from pyrrolyl, indolyl, and thienyl
enones. This interesting observation promoted us to pursue
further investigation. With the Frontier catalyst system [5 mol
% of Sc(OTf)3 and stoichiometric LiClO4],12 no product was
found and only starting material was recovered either at
ambient conditions or elevated reaction temperature (entry 2).
Neither Ti(O-i-Pr)4 nor (+)-CSA was effective catalyst for this
transformation, and the starting material merely changed
(entries 3 and 4). To our delight, the reaction gave 50% of
B
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a
Table 2. Substrate Scope
a
b
The reactions were conducted on 0.070 mmol of 3 in toluene (0.1 M) at 80 °C for the time indicated in the table. The yield was for two steps:
c
cyclization and decarboxylation. 6.0 equiv of BF3·OEt2 was used.
and CH2Cl2, which indicated that more complicated
intermediates could account for this facial selectivity.
Scheme 2. Decarboxylation of 4
The plausible pathways of this transformation are listed in
Scheme 4A. The interaction of BF3·OEt2 with the malonate
moiety of 3 would give A, whose resonnance structure is
zwitterion B. The 1,2-hydride shift of B would afford tertiary
cation D, while no normal Nazarov product C was formed from
the cyclization of B. The reason that ferrocenocyclopetanone
product C is not formed is that the ferrocene Cp ring would
not undergo a ring-slippage reaction.14 The intramolecular
Friedel−Crafts alkylation of D followed by aqueous workup
delivered the product 4. According to the results of Frontier
and Eisenberg’s calculation,11a the furyl structure is crucial for
the rearrangement and cyclization process.15 It was found that
furyl cation D1 was 1.11 kcal/mol lower than B1 while the
corresponding pyrrolyl intermediate D2 was 1.72 kcal/mol
higher than B2, which gave normal Nazarov 4π-electro-
cyclization product. However, the formation of metallocenyl
keto esters 4 was possibly not only controlled by the relative
stability between D and B but also influenced by steric facts
since the expected stable cation G failed to furnish the
sphere of ferrocene skeleton, which led to the complete block
of the top face. Thus, the electrophiles would come from the
same face as the second Cp ring (Scheme 3). Considering that
the solvent could play an important role for this facial
selectivity, additional investigations were conducted in different
solvents. In DMF, the reaction gave the best diastereoselectivity
and yield. However, to our surprise, good facial selectivity still
could be achieved in “non-coordination” solvents such toluene
C
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Scheme 3. Alkylation of 4
mL) at −20 °C dropwise. After the addition, the mixture was stirred at
−20 °C for 30 min and then chilled to −78 °C. Acetylferrocene (0.456
g, 2.0 mmol, 1.0 equiv) in THF (2.0 mL) was added to the mixture,
and the resulting mixture was stirred for 30 min followed by the
addition of isobutyraldehyde (0.2 mL, 2.2 mmol, 1.1 equiv). After the
mixture was stirred at −78 °C for 30 min, it was quenched with
saturated aqueous Na2CO3, and the mixture was extracted with ethyl
acetate (20 mL × 3). The combined organic phase was washed with
brine, dried over anhydrous Na2SO4, and concentrated. The residue
was purified by column chromatography on silica gel (hexanes/ethyl
pentanone compound 7q (Scheme 4B). An alternative 6π-
electrocyclization pathway was also plausible: deprotonation of
B would give metallocenyldiene F, which would deliver the final
product after 6π-electrocyclic ring closure and isomerization.
However, on the basis of the formation of 4a′ as well as the
failure of the cyclization of 3j, the cationic alkylative cyclization
pathway is preferred.
CONCLUSION
■
1
acetate = 20:1) to afford 1a as a red solid (0.150 g, 26%): H NMR
In conclusion, we reported a BF3·OEt2-promoted cyclization of
metallocenylenones via a rare 1,2-hydride shift of the allylic
cation followed by a Friedel−Crafts alkylation process. This
method provided an efficient way to access cyclohexanone-
fused metallocenes, which would be good supplement for the
synthesis of ring-fused metallocenes. An unusual facial
selectivity was observed during the studies of alkylation of
compounds 4.
(400 MHz, CDCl3) δ 7.01 (dd, J = 15.6, 7.2 Hz, 1 H), 6.46 (dd, J =
15.6, 1.2 Hz, 1 H), 4.82 (t, J = 2.0 Hz, 2 H), 4.53 (t, J = 2.0 Hz, 2 H),
4.18 (s, 5 H), 2.58−2.50 (m, 1 H), 1.14 (d, J = 6.8 Hz, 6 H); 13C{1H}
NMR (100 MHz, CDCl3) δ 193.5, 151.8, 123.7, 80.3, 72.4, 70.0, 69.7,
31.2, 21.6; HRMS (APCI) calcd for C16H18O56FeNa [M + Na]+
305.0605, found 305.0617.
Preparation of Compound 2a.17 The mixture of sodium hydride
(60% in mineral oil, 0.224 g, 5.6 mmol, 2.8 equiv), dimethyl carbonate
(0.360 g, 4.0 mmol, 2.0 equiv), and toluene (2.0 mL) was heated to
reflux. Acetylferrocene (0.456 g, 2.0 mmol, 1.0 equiv) in toluene was
added dropwise to the mixture within 10 min. After additional reflux
for 2 h, the solution was cooled to room temperature and quenched
with acetic acid (1.0 mL), followed by the addition of water. The
mixture was extracted with ethyl acetate (50 mL × 3), and the
combined organic phase was washed with brine, dried over anhydrous
Na2SO4, and concentrated. The residue was purified by column
chromatography on silica gel (hexanes/ethyl acetate = 5:1) to afford
methyl 3-oxo-3-ferrocenylpropanoate as a red solid (0.484 g, 85%): 1H
NMR (400 MHz, CDCl3) δ 4.79 (t, J = 2.0 Hz, 2 H), 4.57 (t, J = 2.0
Hz, 2 H), 4.26 (s, 5 H), 3.78 (s, 3 H), 3.76 (s, 2 H); 13C{1H} NMR
(100 MHz, CDCl3) δ 195.7, 167.9, 78.2, 72.9, 70.0, 69.6, 52.2, 46.6;
HRMS (ESI) calcd for C14H14O356FeNa [M + Na]+ 309.0190, found
309.0182.
EXPERIMENTAL SECTION
■
General Information. All reactions were carried out under a
nitrogen atmosphere in flame-dried glassware unless the reaction
procedure states otherwise. Tetrahydrofuran (THF) was distilled from
sodium benzophenone in a continuous still under an atmosphere of
N2. Dioxane was distilled from sodium benzophenone under an
atmosphere of nitrogen. Dichloromethane was distilled from calcium
hydride in a still under an atmosphere of nitrogen. Room-temperature
reactions were carried out between 20 and 25 °C. Flash column
chromatography was performed using 40−63 μm silica gel as the
1
stationary phase. H and 13C NMR spectra were referenced by using
solvent residue as an internal reference (1H NMR: 7.26 ppm for
CDCl3; 13C NMR: 77.00 ppm for CDCl3). Electron spray ionization
(ESI) mass spectrometry data were acquired by using an LTQ
analyzer.
The mixture of 3-oxo-3-ferrocenylpropanoate (0.286 g, 1.0 mmol,
1.0 equiv), HCHO (37% aq, 80 μL, 1.0 mmol, 1.0 equiv), and
Cu(OAc)2 (18.2 mg, 0.1 mmol, 0.1 equiv) in AcOH (4.0 mL) was
stirred at 90 °C for 4 h. After the mixture was cooled to the room
temperature, the solvent was removed. The residue was purified by
Preparation of Compound 1a.16 n-Butyllithium (2.4 M in hexane,
0.88 mL, 2.1 mmol, 1.05 equiv) was added to a solution of
diisopropylamine (0.29 mL, 2.1 mmol, 1.05 equiv) in THF (2.0
D
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Scheme 4. Plausible Pathways
column chromatography on silica gel (hexanes/ethyl acetate = 20:1)
to afford 2a as a red solid (63.2 mg, 21%): H NMR (400 MHz,
132.9, 132.0, 79.9, 78.2, 72.6, 72.5, 70.6, 70.4, 70.2, 70.1, 52.0, 51.9,
29.1, 28.8, 22.2, 21.9; HRMS (ESI) calcd for C18H20O356FeNa [M +
Na]+ 363.0660, found 363.0660.
1
CDCl3) δ 6.58 (d, J = 0.8 Hz, 1 H), 6.10 (d, J = 0.8 Hz, 1 H), 4.77 (t, J
= 2.0 Hz, 2 H), 4.59 (t, J = 2.0 Hz, 2 H), 4.25 (s, 5 H), 3.84 (s, 3 H);
13C{1H} NMR (100 MHz, CDCl3) δ 196.2, 164.9, 141.5, 129.2, 77.7,
73.1, 70.6, 70.3, 52.4; HRMS (EI) calcd for C15H14O356Fe [M]+
298.0292, found 298.0297.
Preparation of Compound 3b. The reaction of methyl 3-oxo-3-
ferrocenylpropanoate (0.200 g, 0.70 mmol, 1.0 equiv) and 2-
ethylbutanal (84 mg, 0.84 mmol, 1.2 equiv) by following typical
procedure A afforded 3b (0.165 g, 64%, E/Z = 6.0:4.0): 1H NMR (400
MHz, CDCl3) δ 6.82 (d, J = 11.6 Hz, 0.6 H), 6.43 (d, J = 10.8 Hz, 0.4
H), 4.76 (t, J = 1.6 Hz, 0.8 H), 4.74 (t, J = 1.6 Hz, 1.2 H), 4.55 (t, J =
1.6 Hz, 0.8 H), 4.53 (t, J = 2.0 Hz, 1.2 H), 4.24 (s, 3.0 H), 4.22 (s, 2.0
H), 3.82 (s, 1.8 H), 3.79 (s, 1.2 H), 2.83−2.73 (m, 0.4 H), 2.18−2.09
(m, 0.6 H), 1.65−1.54 (m, 1.0 H), 1.50−1.25 (m, 3 H), 0.95 (t, J = 7.6
Hz, 2.40 H), 0.80 (t, J = 7.6 Hz, 3.60 H); 13C{1H} NMR (100 MHz,
CDCl3) δ 198.4, 195.5, 166.4, 165.3, 152.0, 151.8, 135.8, 134.2, 80.1,
78.2, 72.6, 72.2, 70.6, 70.3, 70.2, 52.1, 51.8, 42.6, 42.1, 27.6, 26.8, 11.9,
11.4; HRMS (ESI) calcd for C20H24O356FeNa [M + Na]+ 391.0973,
found 391.0974.
Preparation of Compound 3c. The reaction of methyl 3-oxo-3-
ferrocenylpropanoate (0.200 g, 0.70 mmol, 1.0 equiv) and 2-
methylbutanal (90 mg, 1.05 mmol, 1.5 equiv) by following typical
procedure A afforded 3c (0.174 g, 70%, E/Z = 7.0:3.0): 1H NMR (400
MHz, CDCl3) δ 6.81 (d, J = 11.2 Hz, 0.70 H), 6.46 (d, J = 10.4 Hz,
0.30 H), 4.78−4.75 (m, 1.30 H), 4.72−4.71 (m, 0.70 H), 4.56−4.53
(m, 2.00 H), 4.25 (s, 3.50 H), 4.22 (s, 1.50 H), 3.81 (s, 2.10 H), 3.80
(s, 0.90 H), 2.99−2.92 (m, 0.30 H), 2.37−2.29 (m, 0.70 H), 1.52−1.43
(m, 0.60 H), 1.40−1.33 (m, 1.40 H), 1.12 (d, J = 6.8 Hz, 0.90 H), 1.00
(d, J = 6.8 Hz, 2.10 H), 0.97 (t, J = 7.2 Hz, 0.90 H), 0.82 (t, J = 7.6 Hz,
Preparation of Compound 3a (Typical Procedure A). Titanium-
(IV) chloride (1.8 mmol in 0.2 mL CH2Cl2, 2.6 equiv) was added
dropwise to dry THF (3.0 mL) at 0 °C. A mixture of the methyl 3-
oxo-3-ferrocenylpropanoate (0.200 g, 0.70 mmol, 1.0 equiv) and
isobutyraldehyde (0.061 g, 0.84 mmol, 1.2 equiv) in dry THF (3.0
mL) was added to the above solution dropwise and stirred at 0 °C for
an additional 0.5 h. The mixture was then added by pyridine (0.4 mL)
and warmed to room temperature. After being stirred for 24 h, the
reaction was quenched by addition of water and extracted with ethyl
acetate three times. The combined organic phase was washed with a
saturated solution of sodium bicarbonate followed by brine, dried over
anhydrous Na2SO4, and concentrated. The residue was purified by
column chromatography on silica gel (hexanes/ethyl acetate = 10:1)
1
to afford 3a as a red solid (0.195 g, 82%, E/Z = 7.4:2.6): H NMR
(400 MHz, CDCl3) δ 6.81 (d, J = 11.2 Hz, 0.74 H), 6.48 (d, J = 10.4
Hz, 0.26 H), 4.75 (t, J = 2.0 Hz, 0.52 H), 4.74 (t, J = 2.0 Hz, 1.48 H),
4.55 (t, J = 2.0 Hz, 2.00 H), 4.25 (s, 3.70 H), 4.22 (s, 1.30 H), 3.81 (s,
2.22 H), 3.80 (s, 0.78 H), 3.22−3.12 (m, 0.26 H), 2.62−2.52 (m, 0.74
H), 1.14 (d, J = 6.8 Hz, 1.56 H), 1.02 (d, J = 6.4 Hz, 4.44 H); 13C{1H}
NMR (100 MHz, CDCl3) δ 198.0, 195.8, 166.0, 165.4, 153.9, 153.5,
E
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2.10 H); 13C{1H} NMR (100 MHz, CDCl3) δ 198.0, 195.6, 166.1,
165.3, 152.8, 152.7, 134.1, 133.0, 80.0, 78.3, 72.60, 72.55, 72.4, 72.3,
70.7, 70.5, 70.3, 70.1, 70.0, 52.0, 51.8, 35.7, 35.5, 29.6, 29.3, 19.8, 19.4,
11.8, 11.5; HRMS (ESI) calcd for C19H22O356FeNa [M + Na]+
377.0816, found 377.0817.
for 2 h, the solution was cooled to room temperature and quenched
with acetic acid (1.0 mL), followed by addition of water. The mixture
was extracted with ethyl acetate (30 mL × 3), and the combined
organic phase was washed with brine, dried over anhydrous Na2SO4,
and concentrated. The residue was purified by column chromatog-
raphy on silica gel (hexanes/ethyl acetate = 10:1) to afford ethyl 3-
Preparation of Compound 3d. The reaction of methyl 3-oxo-3-
ferrocenylpropanoate (0.200 g, 0.70 mmol, 1.0 equiv) and 2-
phenylbutanal (0.124 g, 0.84 mmol, 1.2 equiv) by following typical
procedure A afforded 3d (0.172 g, 59%, E/Z = 6.7:3.3): 1H NMR (400
MHz, CDCl3) δ 7.37−7.28 (m, 2.00 H), 7.27−7.19 (m, 2.00 H), 7.16
(d, J = 11.6 Hz, 0.67 H), 7.07−7.05 (m, 1.00 H), 6.73 (d, J = 10.8 Hz,
0.33 H), 4.89−4.88 (m, 0.67 H), 4.69−4.68 (m, 0.33 H), 4.68−4.66
(m, 0.33 H), 4.60−4.58 (m, 0.66 H), 4.52 (t, J = 2.0 Hz, 0.67 H),
4.47−4.44 (m, 1.34 H), 4.21 (s, 3.35 H), 4.20−4.17 (m, 0.33 H), 4.13
(s, 1.65 H), 3.82 (s, 2.00 H), 3.81 (s, 1.00 H), 3.37 (dt, J = 11.2, 7.2
Hz, 0.67 H), 1.90−1.86 (m, 0.67 H), 1.77−1.70 (m, 1.34 H), 0.96 (t, J
= 7.2 Hz, 1.00 H), 0.75 (t, J = 7.2 Hz, 2.00 H); 13C{1H} NMR (100
MHz, CDCl3) δ 197.8, 195.6, 165.9, 165.1, 150.1, 149.3, 142.2, 141.3,
133.8, 133.0, 128.8, 128.6, 127.6, 127.5, 126.8, 126.7, 79.7, 78.2, 72.7,
72.6, 72.2, 71.2, 70.51, 70.47, 70.4, 70.3, 70.2, 69.6, 52.1, 51.9, 47.2,
46.3, 29.4, 28.5, 12.0, 11.6; HRMS (ESI) calcd for C24H24O356FeNa
[M + Na]+ 439.0973, found 439.0972.
1
oxo-3-ferrocenylpropanoate as a red solid (0.368 g, 61%): H NMR
(400 MHz, CDCl3) δ 4.80 (t, J = 2.0 Hz, 2 H), 4.56 (t, J = 2.0 Hz, 2
H), 4.26 (s, 5 H), 4.24 (q, J = 7.2 Hz, 2 H), 3.74 (s, 2 H), 1.30 (t, J =
7.2 Hz, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ 195.9, 167.5, 78.2,
72.9, 70.0, 69.6, 61.2, 46.8, 14.1; HRMS (ESI) calcd for
C15H16O356FeNa [M + Na]+ 323.0347, found 323.0340.
The reaction of ethyl 3-oxo-3-ferrocenylpropanoate (0.210 g, 0.70
mmol, 1.0 equiv) and isobutyraldehyde (76 mg, 1.05 mmol, 1.5 equiv)
by following typical procedure A afforded 3h (0.100 g, 40%, E/Z =
7.4:2.6): 1H NMR (400 MHz, CDCl3) δ 6.79 (d, J = 10.8 Hz, 0.74 H),
6.46 (d, J = 10.0 Hz, 0.26 H), 4.75 (t, J = 2.0 Hz, 0.52 H), 4.73 (d, J =
2.0 Hz, 1.48 H), 4.54 (t, J = 2.0 Hz, 2.00 H), 4.27 (q, J = 7.2 Hz, 2.00
H), 4.25 (s, 3.70 H), 4.22 (s, 1.30 H), 3.20−3.10 (m, 0.26 H), 2.67−
2.54 (m, 0.74 H), 1.290 (t, J = 6.8 Hz, 0.78 H), 1.286 (t, J = 7.2 Hz,
2.22 H), 1.14 (d, J = 6.4 Hz, 1.56 H), 1.03 (d, J = 6.4 Hz, 4.44 H);
13C{1H} NMR (100 MHz, CDCl3) δ 198.1, 165.0, 153.5, 153.4, 133.4,
132.3, 80.0, 78.2, 72.6, 72.4, 70.6, 70.4, 70.10, 70.06, 61.2, 61.0, 29.1,
28.8, 22.2, 22.0, 14.2, 14.1; HRMS (ESI) calcd for C19H22O356FeNa
[M + Na]+ 377.0816, found 377.0811.
Preparation of Compound 3e. The reaction of methyl 3-oxo-3-
ferrocenylpropanoate (0.200 g, 0.70 mmol, 1.0 equiv) and cyclo-
pentanecarbaldehyde (83 mg, 0.84 mmol, 1.2 equiv) by following
1
typical procedure A afforded 3e (0.199 g, 78%, E/Z = 8.0:2.0): H
Preparation the Compound 3i. A mixture of l-menthol (0.328 g,
0.21 mmol, 3.0 equiv) and methyl 3-oxo-3-ferrocenylpropanoate
(0.200 g, 0.70 mmol, 1.0 equiv) was refluxed in toluene under N2
atmosphere until the total consumption of methyl 3-oxo-3-
ferrocenylpropanoate by TLC. The product menthyl 3-oxo-3-
ferrocenylpropanoate was obtained by chromatography (hexane/
ethyl acetate = 10:1) as a red solid (0.278 g, 97%), the excess l-
NMR (400 MHz, CDCl3) δ 6.93 (d, J = 11.2 Hz, 0.80 H), 6.61 (d, J =
10.4 Hz, 0.20 H), 4.75 (t, J = 2.0 Hz, 0.40 H), 4.73 (t, J = 2.0 Hz, 1.60
H), 4.55 (t, J = 2.0 Hz, 1.60 H), 4.54 (t, J = 2.0 Hz, 0.40 H), 4.24 (s,
4.00 H), 4.21(s, 1.00 H) 3.81 (s, 2.40 H), 3.79 (s, 0.60 H), 3.31−3.21
(m, 0.20 H), 2.69−2.58 (m, 0.80 H), 2.03−1.97 (m, 0.40 H), 1.83−
1.75 (m, 2.00 H), 1.71−1.63 (m, 2.00 H), 1.54−1.49 (m, 1.60 H),
1.43−1.33 (m, 2.00 H); 13C{1H} NMR (100 MHz, CDCl3) δ 198.0,
195.8, 166.1, 165.3, 152.9, 152.5, 133.5, 132.2, 79.9, 78.3, 72.6, 72.5,
70.6, 70.3, 70.2, 70.1, 52.0, 51.8, 40.3, 39.9, 33.5, 33.2, 25.6; HRMS
(ESI) calcd for C20H22O356FeNa [M + Na]+ 389.0816, found
389.0815.
1
menthol was removed by sublimation at 90 °C: H NMR (400 MHz,
CDCl3) δ 4.80−4.78 (m, 2 H), 4.75 (dd, J = 10.8, 4.4 Hz, 1 H), 4.55
(t, J = 1.6 Hz, 2 H), 4.27 (s, 5 H), 3.76 (d, J = 15.2 Hz, 1 H), 3.71 (d, J
= 14.8 Hz, 1 H), 2.10−2.07 (m, 1 H), 1.94−1.86 (m, 1 H), 1.69−1.64
(m, 2 H), 1.53−1.45 (m, 1 H), 1.41−1.36 (m, 1 H), 1.10−1.04 (m, 1
H), 1.00 (t, J = 11.2 Hz, 1 H), 0.91 (d, J = 6.4 Hz, 3 H), 0.87 (d, J =
6.8 Hz, 3 H), 0.86−0.83 (m, 1 H), 0.77 (d, J = 7.2 Hz, 3 H); 13C{1H}
NMR (100 MHz, CDCl3) δ 196.0, 167.2, 78.2, 75.3, 72.82, 72.80, 70.0,
69.6, 69.5, 47.1, 46.9, 40.7, 34.1, 31.3, 26.0, 23.2, 21.9, 20.7, 16.1;
HRMS (ESI) calcd for C23H30O356FeNa [M + Na]+ 433.1442, found
433.1450.
Preparation of Compound 3f. The reaction of methyl 3-oxo-3-
ferrocenylpropanoate (0.500 g, 1.75 mmol, 1.0 equiv) and cyclo-
hexanecarbaldehyde (0.236 g, 2.10 mmol, 1.2 equiv) by following
1
typical procedure A afforded 3f (0.440 g, 66%, E/Z = 7.3:2.7): H
NMR (400 MHz, CDCl3) δ 6.84 (d, J = 10.8 Hz, 0.73 H), 6.52 (d, J =
10.4 Hz, 0.27 H), 4.74−4.73 (t, J = 2.0 Hz, 2.00 H), 4.55−4.53 (t, J =
2.0 Hz, 2.00 H), 4.24 (s, 3.65 H), 4.21 (s, 1.35 H), 3.80 (s, 0.81 H),
3.79 (s, 2.19 H), 2.95−2.85 (m, 0.27 H), 2.34−2.23 (m, 0.73 H),
1.89−1.82 (m, 0.54 H), 1.80−1.75 (m, 0.54 H), 1.71−1.60 (m, 4.19
H), 1.43−1.32 (m, 0.54 H), 1.27−1.15 (m, 4.19 H); 13C{1H} NMR
(400 MHz, CDCl3) δ 198.0, 195.9, 166.0, 165.5, 152.6, 152.1, 133.1,
132.4, 80.0, 78.3, 72.6, 72.4, 70.6, 70.3, 70.07, 70.04, 52.0, 51.8, 38.7,
38.3, 32.1, 31.8, 25.7, 25.5, 25.2, 24.9; HRMS (ESI) calcd for
C21H24O356FeNa [M + Na]+ 403.0973, found 403.0970.
Typical Procedure B.11a The mixture of menthyl 3-oxo-3-
ferrocenylpropanoate (0.228 g, 0.56 mmol, 1.0 equiv), isobutyralde-
hyde (62 mg, 0.85 mmol, 1.5 equiv), piperidine (53 μL, 0.56 mmol,
1.0 equiv), AcOH (5.4 μL, 0.29 mmol, 0.5 equiv), and 4 Å MS (0.6 g)
in benzene (6 mL) was refluxed for 48 h under N2. The mixture was
allowed to reach room temperature, ethyl acetate was added, and the
mixture was filtered through Celite. The solvent was removed under
reduced pressure. The residue was purified by column chromatog-
raphy on silica gel (hexanes/ethyl acetate = 10:1) to afford 3i as a red
Preparation of Compound 3g. The reaction of methyl 3-oxo-3-
ferrocenylpropanoate (0.200 g, 0.70 mmol, 1.0 equiv) and cyclo-
heptanecarbaldehyde (0.132 g, 1.05 mmol, 1.5 equiv) by following
1
solid (0.148 g, 57%, E/Z = 7.0:3.0): H NMR (400 MHz, CDCl3) δ
6.74 (d, J = 10.8 Hz, 0.70 H), 6.43 (d, J = 10.0 Hz, 0.30 H), 4.84−4.80
(m, 0.30 H), 4.81−4.80 (m, 0.70 H), 4.79−4.78 (m, 0.30 H), 4.76−
4.75 (m, 0.30 H), 4.72 (td, J = 10.8, 4.4 Hz, 0.70 H), 4.63−4.62 (m,
0.70 H), 4.54−4.52 (m, 1.30 H), 4.50−4.49 (m, 0.70 H), 4.25 (m, 3.50
H), 4.21 (m, 1.50 H), 3.16−3.07 (m, 0.30 H), 2.73−2.64 (m, 0.70 H),
2.12−2.07 (m, 0.30 H), 2.06−2.00 (m, 0.70 H), 1.90−1.84 (m, 0.30
H), 1.82 (dd, J = 8.0, 1.2 Hz, 0.30 H), 1.71−1.60 (m, 3.50 H), 1.52−
1.44 (m, 1.00 H), 1.36−1.28 (m, 1.00 H), 1.14 (d, J = 6.4 Hz, 1.80 H),
1.08 (d, J = 2.8 Hz, 2.10 H), 1.06 (d, J = 2.8 Hz, 2.10 H), 1.03−0.93
(m, 1.90 H), 0.90 (d, J = 6.8 Hz, 0.90 H), 0.88 (d, J = 6.4 Hz, 2.10 H),
0.83 (d, J = 6.8 Hz, 0.90 H), 0.80 (d, J = 7.2 Hz, 2.10 H), 0.75 (d, J =
6.8 Hz, 0.90 H), 0.70 (d, J = 6.8 Hz, 2.10 H); 13C{1H} NMR (100
MHz, CDCl3) δ 198.1, 195.8, 165.3, 164.6, 152.7, 152.6, 134.1, 132.9,
80.2, 78.2, 75.2, 72.39, 72.36, 72.1, 71.8, 70.69, 70.67, 70.3, 70.0, 69.93,
69.89, 46.83, 46.78, 40.65, 40.63, 34.1, 31.4, 31.3, 29.1, 28.7, 25.7, 25.6,
23.1, 23.0, 22.21, 22.16, 22.1, 22.0, 21.9, 20.7, 16.1, 15.9; HRMS (ESI)
calcd for C27H36O356FeNa [M + Na]+ 487.1912, found 487.1905.
1
typical procedure A afforded 3g (0.131 g, 47%, E/Z = 7.3:2.7): H
NMR (400 MHz, CDCl3) δ 6.91 (d, J = 11.2 Hz, 0.73 H), 6.59 (d, J =
10.4 Hz, 0.27 H), 4.74 (t, J = 2.0 Hz, 0.54 H), 4.72 (t, J = 2.0 Hz, 1.46
H), 4.54−4.53 (t, J = 2.0 Hz, 2.00 H), 4.24 (s, 3.65 H), 4.21 (s, 1.35
H), 3.788 (s, 0.81 H), 3.785 (s, 2.19 H), 3.08−2.98 (m, 0.27 H),
2.52−2.39 (m, 1.00 H), 1.89−1.83 (m, 0.54 H), 1.77−1.32 (m, 11.19
H); 13C{1H} NMR (100 MHz, CDCl3) δ 198.1, 196.0, 166.0, 165.6,
153.2, 152.6, 131.8, 130.9, 80.0, 78.3, 72.6, 72.4, 70.6, 70.3, 70.10,
70.06, 52.0, 51.8, 39.7, 39.5, 34.0, 33.5, 28.41, 28.37, 26.4, 26.0; HRMS
(ESI) calcd for C22H26O356FeNa [M + Na]+ 417.1129, found
417.1134.
Preparation of Compound 3h. The mixture of sodium hydride
(60% in mineral oil, 0.224 g, 5.6 mmol, 2.8 equiv), diethyl carbonate
(0.473 g, 4.0 mmol, 2.0 equiv), and toluene (2.0 mL) was heated to
reflux. Acetylferrocene (0.456 g, 2.0 mmol, 1.0 equiv) in toluene was
added dropwise to the mixture within 10 min. After additional reflux
F
DOI: 10.1021/acs.joc.5b01511
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
Preparation the Compound 3j. The reaction of methyl 3-oxo-3-
ferrocenylpropanoate (0.100 g, 0.35 mmol, 1.0 equiv) and 3-
methylbutanal (36 mg, 0.42 mmol, 1.2 equiv) by following typical
procedure A afforded 3j (0.074 g, 60%, E/Z = 7.7:2.3): 1H NMR (400
MHz, CDCl3) δ 7.08 (t, J = 7.6 Hz, 0.23 H), 6.72 (t, J = 7.6 Hz, 0.77
H), 4.76 (t, J = 2.0 Hz, 1.54 H), 4.72 (t, J = 2.0 Hz, 0.46 H), 4.56−4.53
(m, 2.00 H), 4.24 (s, 1.15 H), 4.22 (s, 3.85 H), 3.81 (s, 0.69 H), 3.79
(s, 2.31 H), 2.45 (t, J = 7.2 Hz, 1.54 H), 2.06 (t, J = 7.2 Hz, 0.46 H),
1.91−1.82 (m, 0.77 H), 1.80−1.70 (m, 0.23 H), 1.01 (d, J = 6.8 Hz,
4.62 H), 0.89 (d, J = 6.4 Hz, 1.38 H); 13C{1H} NMR (100 MHz,
CDCl3) δ 198.0, 195.7, 166.0, 165.2, 146.9, 146.8, 135.9, 134.7, 79.8,
78.2, 72.6, 72.5, 70.5, 70.3, 70.2, 70.0, 52.0, 51.8, 38.6, 38.2, 28.5, 28.3,
22.5, 22.4; HRMS (ESI) calcd for C19H22O356FeNa [M + Na]+
377.0816, found 377.0816.
(30 mL × 3). The combined organic phase was washed with brine,
dried over anhydrous Na2SO4, and concentrated. The resulting
mixture was purified by column chromatography on silica gel
(hexanes/ethyl acetate = 10:1) to afford 1-acetyl-1′-benzoylferrocene
as red solid (0.366 g, 42%): 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J
= 7.2 Hz, 2 H), 7.58 (t, J = 7.2 Hz, 1 H), 7.49 (t, J = 7.6 Hz, 2 H), 4.92
(t, J = 1.6 Hz, 2 H), 4.75 (t, J = 1.6 Hz, 2 H), 4.58 (t, J = 1.6 Hz, 2 H),
4.50 (t, J = 1.6 Hz, 2 H), 2.29 (s, 3 H); 13C{1H} NMR (100 MHz,
CDCl3) δ 201.4, 197.9, 139.1, 132.0, 128.4, 128.1, 80.6, 79.5, 74.1,
73.9, 72.9, 71.3, 27.5; HRMS (ESI) calcd for C19H16O256FeNa [M +
Na]+ 355.0397, found 355.0390.
The mixture of sodium hydride (60% in mineral oil, 0.112 g, 2.8
mmol, 2.8 equiv), dimethyl carbonate (0.178 g, 1.98 mmol, 2.0 equiv),
and toluene (1.0 mL) was heated to reflux. 1-Acetyl-1′-benzoylferro-
cene (0.328 g, 0.99 mmol, 1.0 equiv) in toluene was added dropwise to
the mixture within 10 min. After additional reflux for 2 h, the solution
was cooled to room temperature and quenched with acetic acid (0.5
mL) followed by the addition of water. The mixture was extracted with
ethyl acetate (30 mL × 3), and the combined organic phase was
washed with brine, dried over anhydrous Na2SO4, and concentrated.
The residue was purified by column chromatography on silica gel
(hexanes/ethyl acetate = 10:1) to afford methyl 3-oxo-3-(1′-benzoyl)-
Preparation of Compound 3k. A solution of 2-methylpropan-2-ol
(92 μL, 1.0 mmol, 1.0 equiv) in dichloromethane (3 mL) was added to
the mixture of acetylferrocene (0.228 g, 1.0 mmol, 1.0 equiv) and
AlCl3 (0.267 g, 2.0 mmol, 2.0 equiv) in dichloromethane (5 mL) at 0
°C within 30 min. After being stirred for 12 h, the reaction was
quenched by addition of crushed ice and extracted with dichloro-
methane (30 mL × 3). The combined organic phase was washed with
brine, dried over anhydrous Na2SO4, and concentrated. The residue
was purified by column chromatography on silica gel (hexanes/ethyl
acetate = 40:1) to afford the 1-acetyl-1′-tert-butylferrocene as a red
1
ferrocenylpropanoate as a red solid (0.159 g, 41%): H NMR (400
MHz, CDCl3) selected peaks for keto: δ 7.84 (d, J = 7.2 Hz, 2 H), 7.58
(t, J = 7.2 Hz, 1 H), 7.48 (t, J = 7.2 Hz, 2 H), 4.96 (t, J = 1.6 Hz, 2 H),
4.75 (t, J = 2.0 Hz, 2 H), 4.64 (t, J = 1.6 Hz, 2 H), 4.55 (t, J = 1.6 Hz, 2
H), 3.74 (s, 3 H), 3.67 (s, 2 H); 13C{1H} NMR (100 MHz, CDCl3) δ
197.8, 195.3, 167.6, 138.9, 132.1, 128.4, 128.1, 79.7, 79.5, 74.6, 74.5,
74.0, 73.0, 72.9, 72.7, 71.3, 69.0, 52.3, 46.4; HRMS (ESI) calcd for
C21H18O456FeNa [M + Na]+ 413.0452, found 413.0451.
1
solid (60 mg, 21%): H NMR (400 MHz, CDCl3) δ 4.75 (t, J = 2.0
Hz, 2 H), 4.50 (t, J = 2.0 Hz, 2 H), 4.12 (t, J = 2.0 Hz, 2 H), 4.05 (t, J
= 2.0 Hz, 2 H), 2.38 (s, 3 H), 1.20 (s, 9 H); 13C{1H} NMR (100 MHz,
CDCl3) δ 202.0, 103.9, 79.1, 72.7, 69.7, 69.1, 66.6, 31.3, 30.2, 27.4;
HRMS (ESI) calcd for C16H21O56Fe [M + H]+ 285.0942, found
285.0934.
The mixture of sodium hydride (60% in mineral oil, 24.0 mg, 0.59
mmol, 2.8 equiv), dimethyl carbonate (38.0 mg, 0.42 mmol, 2.0
equiv), and toluene (0.4 mL) was heated to reflux. 1-Acetyl-1′-tert-
butylferrocene (60 mg, 0.21 mmol, 1.0 equiv) in toluene was added
dropwise to the mixture within 10 min. After additional reflux for 2 h,
the solution was cooled to room temperature and quenched with
acetic acid (0.1 mL), followed by the addition of water. The mixture
was extracted with ethyl acetate (5 mL × 3), and the combined organic
phase was washed with brine, dried over anhydrous Na2SO4, and
concentrated. The residue was purified by column chromatography on
silica gel (hexanes/ethyl acetate = 5:1) to afford methyl 3-oxo-3-(1′-
tert-butyl)ferrocenylpropanoate as a red solid (48.0 mg, 67%): 1H
NMR (400 MHz, CDCl3) δ 4.77 (t, J = 2.0 Hz, 2 H), 4.56 (t, J = 1.6
Hz, 2 H), 4.19 (t, J = 2.0 Hz, 2 H), 4.10 (t, J = 2.0 Hz, 2 H), 3.78 (s, 3
H), 3.74 (s, 2 H), 1.20 (s, 9 H); 13C{1H} NMR (100 MHz, CDCl3) δ
196.5, 195.7, 168.01, 167.97, 107.3, 104.4, 78.0, 73.4, 70.3, 70.2, 69.8,
69.3, 68.8, 66.8, 66.5, 52.3, 46.6, 46.5, 31.3, 31.2, 30.7, 30.3; HRMS
(ESI) calcd for C18H22O356FeNa [M + Na]+ 365.0816, found
365.0816.
The reaction of methyl 3-oxo-3-(1′-benzoyl)ferrocenylpropanoate
(50 mg, 0.128 mmol, 1.0 equiv), isobutyraldehyde (14 mg, 0.190
mmol, 1.5 equiv), piperidine (13.3 μL, 0.145 mmol, 1.1 equiv), AcOH
(1.2 μL, 0.067 mmol, 0.5 equiv), and 4 Å MS (0.2 g) by following
1
typical procedure B afforded 3l (42.9 mg, 76%, E/Z = 3.0:1.0): H
NMR (400 MHz, CDCl3) δ 7.87−7.84 (m, 2.00 H), 7.60−7.56 (m,
1.00 H), 7.51−7.47 (m, 2.00 H), 6.81 (d, J = 11.2 Hz, 0.75 H), 6.42
(d, J = 10.0 Hz, 0.25 H), 4.96 (t, J = 2.0 Hz, 1.50 H), 4.95 (t, J = 2.0
Hz, 0.50 H), 4.76−4.74 (m, 2.00 H), 4.68−4.67 (m, 1.50 H), 4.61 (t, J
= 2.0 Hz, 0.50 H), 4.54 (t, J = 2.0 Hz, 2.00 H), 3.79 (s, 2.25 H), 3.77
(s, 0.75 H), 3.16−3.10 (m, 0.25 H), 2.50−2.44 (m, 0.75 H), 1.11 (d, J
= 6.4 Hz, 1.50 H), 0.99 (d, J = 6.4 Hz, 4.50 H); 13C{1H} NMR (100
MHz, CDCl3) δ 198.1, 197.1, 165.7, 165.0, 154.8, 154.0, 139.1, 132.6,
132.0, 131.9, 131.6, 128.4, 128.3, 128.2, 128.1, 80.9, 79.4, 74.9, 74.8,
73.0, 72.9, 72.1, 71.5, 52.1, 51.9, 29.2, 28.8, 22.1, 21.9; HRMS (ESI)
calcd for C25H24O456FeNa [M + Na]+ 467.0922, found 467.0926.
Preparation of Compound 3m. A solution of acetyl chloride
(0.204 g, 2.60 mmol, 1.5 equiv) in CH2Cl2 (10 mL) was added to a
solution of N,N-dimethylferrocenecarboxamide (0.455 g, 1.73 mmol,
1.0 equiv) and AlCl3 (0.691 g, 5.20 mmol, 3.0 equiv) in CH2Cl2 (20
mL) at 0 °C. After additional stirring for 1 h at room temperature, the
reaction was quenched by the addition of crushed ice and extracted
with CH2Cl2 (30 mL × 3). The combined organic phase was washed
with brine, dried over anhydrous Na2SO4, and concentrated. The
resulting mixture was purified by column chromatography on silica gel
(hexanes/ethyl acetate = 1:1) to afford 1′-acetyl-N,N-dimethylferro-
cenecarboxamide (0.466 g, 90%): 1H NMR (400 MHz, CDCl3) δ 4.81
(t, J = 2.0 Hz, 2 H), 4.62 (t, J = 2.0 Hz, 2 H), 4.57 (t, J = 2.0 Hz, 2 H),
4.32 (t, J = 2.0 Hz, 2 H), 3.06 (bs, 6 H), 2.42 (s, 3 H); 13C{1H} NMR
(100 MHz, CDCl3) δ 202.1, 169.2, 80.7, 80.1, 73.9, 71.9, 71.3, 70.6,
38.9, 36.2, 27.6; HRMS (EI) calcd for C15H17NO256Fe [M]+ 299.0609,
found 299.0585.
The reaction of methyl 3-oxo-3-(1′-tert-butyl)ferrocenylpropanoate
(0.176 g, 0.52 mmol, 1.0 equiv) and isobutyraldehyde (56 mg, 0.77
mmol, 1.5 equiv) by following typical procedure A afforded 3k (0.110
1
g, 53%, E/Z = 7.0:3.0): H NMR (400 MHz, CDCl3) δ 6.81 (d, J =
10.8 Hz, 0.70 H), 6.47 (d, J = 10.4 Hz, 0.30 H), 4.72 (t, J = 2.0 Hz,
0.60 H), 4.71 (t, J = 2.0 Hz, 1.40 H), 4.55−4.53 (m, 2.00 H), 4.20 (t, J
= 2.0 Hz, 1.40 H), 4.15 (t, J = 2.0 Hz, 0.60 H), 4.08 (t, J = 2.0 Hz, 1.40
H), 4.04 (t, J = 2.0 Hz, 0.60 H), 3.81 (s, 2.10 H), 3.79 (s, 0.90 H),
3.21−3.12 (m, 0.30 H), 2.61−2.52 (m, 0.70 H), 1.194 (s, 6.30 H),
1.189 (s, 2.70 H), 1.13 (d, J = 6.4 Hz, 1.80 H), 1.01 (d, J = 6.8 Hz,
4.20 H); 13C{1H} NMR (100 MHz, CDCl3) δ 197.8, 195.6, 165.4,
153.9, 153.6, 133.0, 132.0, 104.2, 104.1, 79.7, 73.1, 73.0, 70.8, 70.2,
69.9, 69.6, 67.1, 66.9, 52.0, 51.8, 31.3, 30.3, 29.1, 28.8, 22.2, 22.0;
HRMS (ESI) calcd for C22H28O356FeNa [M + Na]+ 419.1286, found
419.1284.
Preparation of Compound 3l. A solution of benzoyl chloride
(0.553 g, 3.95 mmol, 1.5 equiv) in CH2Cl2 (5 mL) was added to a
mixture of acetylferrocene (0.600 g, 2.63 mmol, 1.0 equiv) and AlCl3
(0.701 g, 5.26 mmol, 2.0 equiv) in CH2Cl2 (20 mL) at 0 °C. After
being stirred for additional 3 h at room temperature, the reaction was
quenched by the addition of crushed ice and extracted with CH2Cl2
The mixture of sodium hydride (60% in mineral oil, 0.112 g, 2.8
mmol, 2.8 equiv), dimethyl carbonate (0.180 g, 2.0 mmol, 2.0 equiv),
and toluene (1.0 mL) was heated to reflux. 1′-Acetyl-N,N-
dimethylferrocenecarboxamide (0.300 g, 1.0 mmol, 1.0 equiv) in
toluene was added dropwise to the mixture within 10 min. After
additional reflux for 2 h, the solution was cooled to room temperature
and quenched with acetic acid (0.5 mL), followed by the addition of
water. The mixture was extracted with ethyl acetate (30 mL × 3). The
G
DOI: 10.1021/acs.joc.5b01511
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1
combined organic phase was washed with brine, dried over anhydrous
Na2SO4, and concentrated. The residue was purified by column
chromatography on silica gel (hexanes/ethyl acetate = 1:1) to afford
methyl 3-oxo-3-(1′-N,N-dimethycarboxyl)ferrocenylpropanoate as a
typical procedure A afforded 3p (0.166 g, 70%, E/Z = 5.6:4.4): H
NMR (400 MHz, CDCl3) δ 6.78 (d, J = 11.2 Hz, 0.56 H), 6.58 (d, J =
10.4 Hz, 0.44 H), 5.02 (t, J = 2.0 Hz, 2.00 H), 4.80 (t, J = 2.0 Hz, 0.88
H), 4.79 (t, J = 2.0 Hz, 1.12 H), 4.59 (s, 2.80 H), 4.58 (s, 2.20 H), 3.77
(s, 1.32 H), 3.75 (s, 1.68 H), 2.92−2.82 (m, 0.44 H), 2.36−2.26 (m,
0.56 H), 1.83−1.63 (m, 5.00 H), 1.40−1.31 (m, 1.00 H), 1.26−1.10
(m, 4.00 H); 13C{1H} NMR (100 MHz, CDCl3) δ 195.4, 194.5, 165.6,
165.4, 152.8, 151.8, 132.3, 132.0, 84.6, 82.7, 73.8, 73.5, 72.5, 72.2, 72.0,
71.3, 51.9, 51.7, 38.7, 38.1, 32.1, 31.8, 25.6, 25.5, 25.2, 25.0; HRMS
(ESI) calcd for C21H24O3102RuNa [M + Na]+ 449.0667, found
449.0677.
1
red solid (0.283 g, 80%): H NMR (400 MHz, CDCl3) δ 4.80 (t, J =
2.0 Hz, 2 H), 4.64 (t, J = 2.0 Hz, 2 H), 4.61 (t, J = 2.0 Hz, 2 H), 4.35
(t, J = 2.0 Hz, 2 H), 3.89 (s, 2 H), 3.75 (s, 3 H), 3.03 (bs, 6 H);
13C{1H} NMR (100 MHz, CDCl3) δ 196.3, 169.2, 168.2, 81.6, 79.2,
74.4, 72.1, 71.7, 70.6, 52.2, 46.6, 39.0, 36.2; HRMS (EI) calcd for
C17H19NO456Fe [M]+ 357.0664, found 357.0653.
The reaction of 3-oxo-3-(1′-N,N-dimethycarboxyl)-
ferrocenylpropanoate (0.350 g, 0.98 mmol, 1.0 equiv) and
isobutyraldehyde (0.106 g, 1.47 mmol, 1.5 equiv), piperidine (98
μL, 1.08 mmol, 1.1 equiv), AcOH (9.1 μL, 0.49 mmol, 0.5 equiv), and
4 Å MS (1.0 g) by following typical procedure B afforded 3m (0.220 g,
55%, E/Z = 7.7:2.3): 1H NMR (400 MHz, CDCl3) selected peaks for
the major isomer δ 6.82 (d, J = 11.2 Hz, 0.77 H), 6.48 (d, J = 10.4 Hz,
0.23 H), 4.79−4.78 (m, 2.00 H), 4.67−4.64 (m, 4.00 H), 4.41 (t, J =
2.0 Hz, 1.54 H), 4.35 (t, J = 2.0 Hz, 0.46 H), 3.81 (s, 3.00 H), 3.06 (m,
0.23 H), 3.06 (bs, 6.00 H), 2.55−2.46 (m, 0.77 H), 1.13 (d, J = 6.8 Hz,
1.38 H), 1.09 (d, J = 6.8 Hz, 4.62 H); 13C{1H} NMR (100 MHz,
CDCl3) δ 197.7, 195.3, 169.2, 166.0, 165.1, 154.1, 153.5, 132.8, 131.8,
81.1, 80.4, 75.2, 75.1, 72.1, 72.03, 71.93, 71.7, 71.5, 71.4, 52.0, 51.9,
38.9, 36.2, 29.1, 28.9, 22.1, 21.8; HRMS (ESI) calcd for
C21H25NO456FeNa [M + Na]+ 434.1031, found 434.1037.
Preparation of Compound 3n. The mixture of sodium hydride
(60% in mineral oil, 0.112 g, 2.8 mmol, 2.8 equiv), dimethyl carbonate
(0.180 g, 2.0 mmol, 2.0 equiv), and toluene (1.0 mL) was heated to
reflux. Acetylruthenocene (0.280 g, 1.0 mmol, 1.0 equiv) in toluene
was added dropwise to the mixture within 10 min. After additional
reflux for 2 h, the solution was cooled to room temperature and
quenched with acetic acid (0.5 mL), followed by the addition of water.
The mixture was extracted with ethyl acetate (30 mL × 3). The
combined organic phase was washed with brine, dried over anhydrous
Na2SO4, and concentrated. The residue was purified by column
chromatography on silica gel (hexanes/ethyl acetate = 5:1) to afford
methyl 3-oxo-3-ruthenocenylpropanoate (0.308 g, 93%): 1H NMR
(400 MHz, CDCl3) δ 5.10 (t, J = 2.0 Hz, 2 H), 4.82 (t, J = 2.0 Hz, 2
H), 4.63 (s, 5 H), 3.76 (s, 3 H), 3.64 (s, 2 H); 13C{1H} NMR (100
MHz, CDCl3) δ 193.5, 167.9, 83.1, 74.1, 72.3, 70.9, 52.3, 45.8; HRMS
(ESI) calcd for C14H14O3102RuNa [M + Na]+ 354.9884, found
354.9886.
Preparation of Compound 3q. The reaction of methyl 3-oxo-3-
ferrocenylpropanoate (0.200 g, 0.70 mmol, 1.0 equiv) and 4-
methoxybenzaldehyde (0.114 g, 0.84 mmol, 1.5 equiv) by following
1
typical procedure A afforded 3q (0.240 g, 85%, E/Z = 10.0:1.0): H
NMR (400 MHz, CDCl3) major isomer: δ 7.85 (s, 1 H), 7.36 (d, J =
8.8 Hz, 2 H), 6.75 (d, J = 8.8 Hz, 2 H), 4.64 (t, J = 2.0 Hz, 2 H), 4.44
(t, J = 2.0 Hz, 2 H), 4.15 (s, 5 H), 3.88 (s, 3 H), 3.75 (s, 3 H);
13C{1H} NMR (100 MHz, CDCl3) δ 199.4, 165.8, 161.2, 142.2, 140.1,
132.4, 131.5, 129.7, 125.9, 114.2, 114.0, 79.5, 72.9, 72.5, 70.8, 70.5,
70.2, 70.1, 69.7, 55.4, 55.2, 52.3, 52.2; HRMS (APCI) calcd for
C22H20O456FeNa [M + Na]+ 427.0609, found 427.0616.
BF3·OEt2-Promoted Cyclization of Metallocenyl Enones.
Preparation of Compound 4a. BF3·OEt2 (26.0 μL, 0.21 mmol, 3.0
equiv) was added to the solution of 3a (24.1 mg, 0.071 mmol, 1.0
equiv) in toluene (0.7 mL), and then the reaction was warmed to 80
°C. After being stirred for 4 h, the reaction was quenched with
aqueous sodium bicarbonate and extracted with ethyl acetate (10 mL
× 3). The combined organic layer was washed with brine, dried over
anhydrous Na2SO4, and concentrated. The residue was purified by
column chromatography on silica gel (hexanes/ethyl acetate = 10:1)
to afford 4a as a red solid (21.1 mg, 88%). Compound 4a′ (7.5 mg,
4%) could be isolated by column chromatography on silica gel when
the reaction was conducted at the scale of 0.204 g (0.60 mmol) of 3a.
4a: 1H NMR (400 MHz, CDCl3) selected peaks for keto: δ 4.89 (dd, J
= 2.8, 1.6 Hz, 1 H), 4.56 (t, J = 2.4 Hz, 1 H), 4.41 (dd, J = 2.4, 1.2 Hz,
1 H), 4.31 (s, 5 H), 3.84 (s, 3 H), 3.42 (dd, J = 13.2, 5.2 Hz, 1 H), 2.73
(t, J = 13.2 Hz, 1 H), 1.97 (dd, J = 13.2, 5.2 Hz, 1 H), 1.48 (s, 3 H),
1.14 (s, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ 198.5, 171.9,
103.3, 72.6, 71.1, 70.5, 69.9, 68.1, 65.8, 52.8, 52.3, 41.9, 30.2, 29.4,
28.8; HRMS (ESI) calcd for C18H20O356FeNa [M + Na]+ 363.0660,
1
found 363.0660. 4a′: H NMR (400 MHz, CDCl3) δ 5.09 (t, J = 2.0
Hz, 2 H), 4.34 (t, J = 2.0 Hz, 2 H), 4.16 (s, 5 H), 3.71 (s, 3 H), 2.78 (s,
2 H), 1.46 (s, 6 H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.2.,
166.0, 98.8, 84.4, 72.6, 70.5, 70.0, 69.7, 50.7, 44.4, 28.3; HRMS (ESI)
calcd for C18H20O356FeNa [M + Na]+ 363.0660, found 363.0659.
Preparation of Compound 5a. The mixture of 4a (18.1 mg, 0.053
mmol, 1.0 equiv) and KOH (12.3 mg in 0.20 mL H2O, 0.22 mmol, 4.0
equiv) in EtOH (1.0 mL) were refluxed under N2 for 4 h. After being
cooled to room temperature, the mixture was quenched by the
addition of HCl (1.0 M) and extracted with ethyl acetate (10 mL × 3).
The combined organic layer was washed with brine and dried over
Na2SO4. After filtration, the solvent was removed. The residue was
purified by chromatography on silica gel (hexane/ethyl acetate = 10:1)
The reaction of methyl 3-oxo-3-ruthenocenylpropanoate (0.232 g,
0.70 mmol, 1.0 equiv) and isobutyraldehyde (76 mg, 0.84 mmol, 1.5
equiv) by following typical procedure A afforded 3n (0.206 g, 76%, E/
Z = 7.9:2.1): 1H NMR (400 MHz, CDCl3) δ 6.76 (d, J = 10.8 Hz, 0.79
H), 6.55 (d, J = 10.4 Hz, 0.21 H), 5.03 (t, J = 2.0 Hz, 2.00 H), 4.81 (t,
J = 1.6 Hz, 0.42 H), 4.79 (t, J = 1.6 Hz, 1.58 H), 4.60 (s, 3.95 H), 4.58
(s, 1.05 H), 3.78 (s, 0.63 H), 3.76 (s, 2.37 H), 3.19−3.10 (m, 0.21 H),
2.70−2.58 (m, 0.79 H), 1.11 (d, J = 6.4 Hz, 1.26 H), 1.06 (d, J = 6.4
Hz, 4.74 H); 13C{1H} NMR (100 MHz, CDCl3) δ 195.5, 194.4, 165.7,
165.3, 154.1, 153.1, 132.2, 131.7, 84.6, 82.8, 73.9, 73.6, 72.5, 72.3, 72.1,
71.4, 52.0, 51.8, 29.4, 28.6, 22.2, 22.1; HRMS (ESI) calcd for
C18H20O3102RuNa [M + Na]+ 409.0354, found 409.0355.
1
to obtain 5a as a red solid (14.0 mg, 93%): H NMR (400 MHz,
Preparation of Compound 3o. The reaction of methyl 3-oxo-3-
ruthenocenylpropanoate (0.232 g, 0.70 mmol, 1.0 equiv) and
cyclopentanecarbaldehyde (82 mg, 0.84 mmol, 1.2 equiv) by following
CDCl3) δ 4.86 (dd, J = 2.4, 1.2 Hz, 1 H), 4.50 (t, J = 2.4 Hz, 1 H),
4.38 (dd, J = 2.4, 1.2 Hz, 1 H), 4.21 (s, 5 H), 2.60−2.50 (m, 1 H),
2.44−2.30 (m, 2 H), 1.83−1.74 (m, 1 H), 1.46 (s, 3 H), 1.12 (s, 3 H);
13C{1H} NMR (100 MHz, CDCl3) δ 204.6, 103.8, 73.6, 70.5, 70.1,
67.7, 65.3, 38.2, 36.1, 30.2, 29.1, 28.9; HRMS (ESI) calcd for
C16H19O56Fe [M + H]+ 283.0785, found 283.0776.
1
typical procedure A afforded 3o (0.176 g, 61%, E/Z = 8.2:1.8): H
NMR (400 MHz, CDCl3) δ 6.87 (d, J = 11.2 Hz, 0.82 H), 6.68 (d, J =
10.0 Hz, 0.18 H), 5.04−5.02 (m, 2.00 H), 4.81−4.79 (m, 2.00 H), 4.59
(s, 4.10 H), 4.58 (s, 0.90 H), 3.773 (s, 0.54 H), 3.769 (s, 2.46 H),
3.29−3.18 (m, 0.18 H), 2.74−2.63 (m, 0.82 H), 2.01−1.95 (m, 0.54
H), 1.87−1.80 (m, 1.84 H), 1.76−1.53 (m, 3.16 H), 1.45−1.31 (m,
2.46 H); 13C{1H} NMR (100 MHz, CDCl3) δ 195.5, 194.3, 165.8,
165.3, 153.0, 152.0, 132.8, 132.0, 84.6, 82.8, 73.9, 73.6, 72.5, 72.3, 72.1,
71.4, 52.0, 51.8, 40.5, 39.8, 33.5, 33.4, 25.6; HRMS (ESI) calcd for
C20H22O3102RuNa [M + Na]+ 435.0510, found 435.0518.
Preparation of Compound 4b. The reaction of 3b (25.8 mg, 0.07
mmol, 1.0 equiv) and BF3·OEt2 (26.0 μL, 0.21 mmol, 3.0 equiv)
1
afforded 4b (17.3 mg, 67%). H NMR (400 MHz, CDCl3) (keto) δ
4.89 (dd, J = 2.4, 1.2 Hz, 1 H), 4.58 (t, J = 2.4 Hz, 1 H), 4.44 (dd, J =
2.4, 1.2 Hz, 1 H), 4.31 (s, 5 H), 3.84 (s, 3 H), 3.41 (dd, J = 13.2, 5.2
Hz, 1 H), 2.57 (t, J = 13.2 Hz, 1 H), 2.18 (dd, J = 12.8, 5.2 Hz, 1 H),
1.84−1.74 (m, 2 H), 1.32−1.25 (m, 2 H), 0.99 (t, J = 7.6 Hz, 3 H),
0.66 (t, J = 7.2 Hz, 3 H), (enol) 12.4 (brs, 0.58 H), 4.68 (dd, J = 2.4,
1.2 Hz, 0.58 H), 4.35 (t, J = 2.4 Hz, 0.58 H), 4.19 (dd, J = 2.4, 1.2 Hz,
Preparation of Compound 3p. The reaction of methyl 3-oxo-3-
ruthenocenylpropanoate (0.186 g, 0.56 mmol, 1.0 equiv) and
cyclohexanecarbaldehyde (94 mg, 0.84 mmol, 1.5 equiv) by following
H
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1
0.58 H), 4.17 (s, 2.90 H), 3.79 (s, 1.74 H), 2.65 (d, J = 15.2 Hz, 0.58
H), 2.36 (d, J = 15.2 Hz, 0.58 H), 2.00−1.92 (m, 1.16 H), 1.64−1.55
(m, 1.16 H), 1.02 (t, J = 7.6 Hz, 1.74 H), 0.53 (t, J = 7.6 Hz, 1.74 H);
13C{1H} NMR (100 MHz, CDCl3) δ 198.4, 172.3, 102.1, 72.7, 71.4,
70.9, 70.6, 70.0, 69.9, 65.7, 52.3, 51.9, 38.8, 35.5, 28.8, 28.6, 8.1, 7.6;
HRMS (ESI) calcd for C20H24O356FeNa [M + Na]+ 391.0973, found
391.0974.
afforded 4f (33.1 mg, 87%): H NMR (400 MHz, CDCl3) selected
peaks for keto: δ 4.90 (dd, J = 2.4, 1.2 Hz, 1 H), 4.54 (t, J = 2.4 Hz, 1
H), 4.47 (dd, J = 2.0, 1.2 Hz, 1 H), 4.31 (s, 5 H), 3.84 (s, 3 H), 3.32
(dd, J = 12.0, 6.8 Hz, 1 H), 2.49 (dd, J = 13.6, 6.4 Hz, 1 H), 2.45 (t, J =
13.2 Hz, 1 H), 1.94−1.81 (m, 2 H), 1.75−1.38 (m, 5 H), 1.33−1.17
(m, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ 198.8, 172.1, 103.8,
72.8, 71.1, 70.9, 70.8, 70.5, 70.4, 69.8, 68.2, 65.8, 52.3, 51.8, 37.4, 36.9,
35.3, 32.8, 26.0, 22.5, 21.8; HRMS (ESI) calcd for C21H25O356Fe [M +
H]+ 381.1153, found 381.1150.
Preparation of Compound 4c. The reaction of 3c (24.8 mg, 0.07
mmol, 1.0 equiv) and BF3·OEt2 (26.0 μL, 0.21 mmol, 3.0 equiv)
afforded 4c (21.8 mg, 88%, dr = 3:1). The following data refer to the
Preparation of Compound 5f. A solution of 4f (26.0 mg, 0.068
mmol, 1.0 equiv) and DABCO (76.3 mg, 0.68 mmol, 10 equiv) in
toluene (1.0 mL) was refluxed under N2. Until the total consumption
of 4f, the reaction was cooled to room temperature. The mixture was
purified by chromatography on silica gel (hexane/ethyl acetate = 10:1)
1
keto-isomers: H NMR (400 MHz, CDCl3) δ (major isomer) 4.90
(dd, J = 2.4, 1.2 Hz, 1 H), 4.55 (t, J = 2.4 Hz, 1 H), 4.41−4.40 (m, 1
H), 4.30 (s, 5 H), 3.84 (s, 3 H), 3.37 (dd, J = 13.2, 5.2 Hz, 1 H), 2.52
(t, J = 13.2 Hz, 1 H), 2.11 (dd, J = 13.2, 5.6 Hz, 1 H), 2.04−1.95 (m, 1
H), 1.90−1.81 (m, 1 H), 1.08 (s, 3 H), 1.05 (t, J = 7.6 Hz, 3 H),
(minor isomer) 4.88 (dd, J = 2.8, 1.2 Hz, 0.35 H), 4.56 (t, J = 2.8 Hz,
0.35 H), 4.41−4.40 (m, 0.35 H), 4.32 (s, 1.75 H), 3.83 (s, 1.05 H),
3.39 (dd, J = 13.2, 5.2 Hz, 0.35 H), 2.69 (t, J = 13.2 Hz, 0.35 H), 2.06
(dd, J = 13.6, 5.6 Hz, 0.35 H), 1.46−1.33 (m, 0.70 H), 1.39 (s, 1.05
H), 0.80 (t, J = 7.2 Hz, 1.05 H); 13C{1H} NMR (100 MHz, CDCl3) δ
198.6, 198.4, 172.1, 172.0, 104.4, 102.6, 72.5, 71.2, 71.0, 70.5, 69.9,
69.3, 68.0, 65.72, 65.69, 52.5, 52.3, 52.2, 40.0, 38.3, 33.8, 33.6, 33.2,
32.5, 25.5, 24.6, 9.1, 8.1; HRMS (ESI) calcd for C19H22O356FeNa [M +
Na]+ 377.0816, found 377.0808.
Preparation of Compound 5d. BF3·OEt2 (26.0 μL, 0.21 mmol, 3.0
equiv) was added to the solution of 3d (29.1 mg, 0.070 mmol, 1.0
equiv) in toluene (0.7 mL), and then the reaction was warmed up to
80 °C. After being stirred for 8 h, the reaction was quenched with a
solution of sodium bicarbonate followed extraction with ethyl acetate
(10 mL × 3). The combined organic layer was washed with brine,
dried over anhydrous Na2SO4, and concentrated.
The above residue was dissolved in ethanol (1.0 mL) followed by
the addition of a mixture of aqueous KOH (15.7 mg in 0.3 mL H2O,
0.28 mmol, 4.0 equiv) and refluxed for 5 h.18 The mixture was allowed
to reach room temperature, water was added, and the resulting mixture
was extracted with ethyl acetate three times. The combined organic
layer was washed with brine, dried over anhydrous Na2SO4, and
concentrated. The residue was purified by column chromatography on
silica gel (hexanes/ethyl acetate = 10:1) to afford 5d as a red solid
(12.6 mg, 50%, dr =1:1): 1H NMR (400 MHz, CDCl3) δ 7.67 (dd, J =
8.8, 1.2 Hz, 2 H), 7.46 (t, J = 7.2 Hz, 2 H), 7.33 (tt, J = 7.2, 1.2 Hz, 1
H), 7.19 (tt, J = 7.6, 1.2 Hz, 2 H), 7.12 (tt, J = 7.2, 1.2 Hz, 1 H), 7.03−
7.01 (m, 2 H), 4.95 (dd, J = 2.8, 1.2 Hz, 1 H), 4.87 (dd, J = 2.4, 1.2 Hz,
1 H), 4.71 (dd, J = 2.4, 1.2 Hz, 1 H), 4.66 (t, J = 2.4 Hz, 1 H), 4.50 (t,
J = 2.8 Hz, 1 H), 4.37 (dd, J = 2.4, 1.2 Hz, 1 H), 4.29 (s, 5 H), 3.94 (s,
5 H), 2.96 (td, J = 12.4, 4.0 Hz, 1 H), 2.76 (dt, J = 17.6, 4.0 Hz, 1 H),
2.60 (dd, J = 9.6, 3.2 Hz, 2 H), 2.52−2.43 (m, 2 H), 2.31−2.26 (m, 1
H), 2.27−2.2.16 (m, 2 H), 2.05−1.95 (m, 2 H), 1.85−1.76 (m, 1 H),
0.87 (t, J = 7.6 Hz, 3 H), 0.61 (t, J = 7.6 Hz, 3 H); 13C{1H} NMR (100
MHz, CDCl3) δ 204.3, 204.2, 144.3, 143.1, 128.1, 127.9, 127.5, 126.9,
126.4, 126.0, 102.4, 102.3, 75.0, 73.8, 70.9, 70.6, 70.5, 70.4, 70.30,
70.28, 65.5, 65.4, 42.2, 41.4, 36.2, 35.6, 35.5, 35.3, 34.0, 31.2, 9.7, 9.4;
HRMS (ESI) calcd for C22H22O56FeNa [M + Na]+ 381.0918, found
381.0923.
1
to obtain 5f as a red solid (10.8 mg, 49%): H NMR (400 MHz,
CDCl3) δ 4.87 (dd, J = 2.4, 1.2 Hz, 1 H), 4.49 (t, J = 2.4 Hz, 1 H),
4.43 (dd, J = 2.4, 1.2 Hz, 1 H), 4.21 (s, 5 H), 2.54−2.48 (m, 1 H),
2.33−2.24 (m, 2 H), 2.10−2.00 (m, 1 H), 1.90−1.80 (m, 2 H), 1.75−
1.62 (m, 3 H), 1.54−1.45 (m, 1 H), 1.44−1.36 (m, 1 H), 1.34−1.27
(m, 2 H), 1.17 (td, J = 12.8, 4.4 Hz, 1 H); 13C{1H} NMR (100 MHz,
CDCl3) δ 204.9, 104.4, 73.9, 70.5, 70.0, 67.9, 65.4, 37.2, 36.8, 35.2,
32.9, 31.3, 26.1, 22.6, 21.9; HRMS (ESI) calcd for C19H22O56FeNa [M
+ Na]+ 345.0918, found 345.0922.
Preparation of Compound 4g. The reaction of 3g (27.6 mg, 0.07
mmol, 1.0 equiv) and BF3·OEt2 (26.0 μL, 0.21 mmol, 3.0 equiv)
1
afforded 4g (21.4 mg, 78%): H NMR (400 MHz, CDCl3) selected
peaks for keto: δ 4.88 (dd, J = 2.4, 1.2 Hz, 1 H), 4.57 (t, J = 2.4 Hz, 1
H), 4.48 (dd, J = 2.4, 1.2 Hz, 1 H), 4.31 (s, 5 H), 3.84 (s, 3 H), 3.38
(dd, J = 13.2, 5.2 Hz, 1 H), 2.59 (t, J = 12.8 Hz, 1 H), 2.24 (dd, J =
12.8, 5.2 H, 1 H), 2.16−2.10 (m, 1 H), 1.94−1.88 (m, 1 H), 1.74−1.36
(m, 10 H); 13C{1H} NMR (100 MHz, CDCl3) δ 198.7, 172.1, 104.6,
72.4, 71.2, 71.1, 70.7, 70.5, 70.0, 68.7, 65.8, 52.25, 52.20, 40.5, 40.4,
39.9, 36.1, 31.1, 30.6, 23.44, 23.36; HRMS (ESI) calcd for
C22H26O356FeNa [M + Na]+ 417.1129, found 417.1125.
Preparation of Compound 4h. The reaction of 3h (24.8 mg, 0.07
mmol, 1.0 equiv) and BF3·OEt2 (26.0 μL, 0.21 mmol, 3.0 equiv)
1
afforded 4h (23.3 mg, 94%): H NMR (400 MHz, CDCl3) selected
peaks for keto: δ 4.89 (dd, J = 2.8, 1.2 Hz, 1 H), 4.55 (t, J = 2.4 Hz, 1
H), 4.41 (dd, J = 2.4, 1.2 Hz, 1 H), 4.32 (s, 5 H), 4.31 (q, J = 7.2 Hz, 2
H), 3.39 (dd, J = 13.2, 5.2 Hz, 1 H), 2.73 (t, J = 13.2 Hz, 1 H), 1.98
(dd, J = 12.8, 5.2 Hz, 1 H), 1.48 (s, 3 H), 1.36 (t, J = 7.2 Hz, 3 H),
1.15 (s, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ 198.6, 171.4,
103.3, 72.6, 71.1, 70.6, 70.4, 69.8, 68.0, 65.7, 61.2, 53.0, 41.9, 30.2,
29.4, 28.8, 14.3; HRMS (ESI) calcd for C19H23O356Fe [M + H]+
355.0997, found 355.0991.
Preparation of Compound 4k. The reaction of 3k (27.7 mg, 0.07
mmol, 1.0 equiv) and BF3·OEt2 (26.0 μL, 0.21 mmol, 3.0 equiv)
1
afforded 4k (19.3 mg, 70%): H NMR (400 MHz, CDCl3) (keto) δ
4.86 (dd, J = 2.4, 1.2 Hz, 1 H), 4.56 (t, J = 2.4 Hz, 1 H), 4.41−4.40 (m,
1 H), 4.37−4.35 (m, 1 H), 4.34−4.32 (m, 1 H), 4.26−4.23 (m, 1 H),
4.08−4.07 (m, 1 H), 3.84 (s, 3 H), 3.43 (dd, J = 13.2, 5.2 Hz, 1 H),
2.69 (t, J = 12.8 Hz, 1 H), 1.96 (dd, J = 13.2, 5.6 Hz, 1 H), 1.48 (s, 3
H), 1.18 (s, 9 H), 1.14 (s, 3 H), (enol) δ 4.88 (dd, J = 2.4, 1.2 Hz, 0.66
H), 4.60 (t, J = 2.4 Hz, 0.66 H), 4.42−4.41 (m, 0.66 H), 4.26−4.23
(m, 0.66 H), 4.18−4.16 (m, 0.66 H), 4.11−4.10 (m, 0.66 H), 4.07−
4.06 (m, 0.66 H), 4.05 (s, 1.98 H), 2.50 (d, J = 14.8 Hz, 0.66 H), 2.44
(d, J = 14.8 Hz, 0.66 H), 1.48 (s, 1.98 H), 1.19 (s, 5.94 H), 0.95 (s,
1.98 H); 13C{1H} NMR (100 MHz, CDCl3) δ 198.3, 172.0, 104.1,
103.7, 102.8, 102.3, 72.4, 72.1, 71.9, 70.5, 70.3, 69.9, 69.8, 68.5, 68.3,
68.2, 67.8, 66.6, 66.4, 66.2, 55.3, 52.7, 52.2, 41.8, 35.4, 31.3, 30.7, 30.4,
30.34, 30.31, 29.71, 29.65, 28.8, 27.8; HRMS (ESI) calcd for
C22H28O356FeNa [M + Na]+ 419.1286, found 419.1277.
Preparation of Compound 4e. The reaction of 3e (25.6 mg, 0.07
mmol, 1.0 equiv) and BF3·OEt2 (26.0 μL, 0.21 mmol, 3.0 equiv)
1
afforded 4e (18.2 mg, 71%): H NMR (400 MHz, CDCl3) (keto) δ
4.87 (dd, J = 2.4, 1.2 Hz, 1 H), 4.54 (t, J = 2.4 Hz, 1 H), 4.40 (dd, J =
2.4, 1.2 Hz, 1 H), 4.30 (s, 5 H), 3.83 (s, 3 H), 3.37 (dd, J = 13.6, 5.2
Hz, 1 H), 2.83 (t, J = 12.8 Hz, 1 H), 2.28−2.14 (m, 1 H), 2.06 (dd, J =
13.2, 5.2 Hz, 1 H), 1.85−1.64 (m, 6 H), 1.45−1.40 (m, 1 H), (enol) δ
12.39 (brs, 0.38 H), 4.66 (dd, J = 2.4, 1.2 Hz, 0.38 H), 4.33 (t, J = 2.4
Hz, 0.38 H), 4.17 (s, 1.90 H), 4.16 (dd, J = 2.4, 1.2 Hz, 0.38 H), 3.79
(s, 1.14 H), 2.65 (d, J = 14.8 Hz, 0.38 H), 2.50 (d, J = 14.8 Hz, 0.38
H), 2.28−2.14 (m, 0.38 H), 1.85−0.80 (m, 2.66 H); 13C{1H} NMR
(100 MHz, CDCl3) δ 199.0, 171.8, 102.2, 73.0, 71.3, 70.4, 69.9, 68.7,
65.9, 53.9, 52.2, 41.7, 40.8, 39.6, 39.3, 25.5, 24.9; HRMS (ESI) calcd
for C20H22O356FeNa [M + Na]+ 389.0816, found 389.0812.
Preparation of Compound 4l. The reaction of 3l (36.6 mg, 0.082
mmol, 1.0 equiv) and BF3·OEt2 (60.0 μL, 0.49 mmol, 6.0 equiv)
1
afforded 4l (22.1 mg, 60%): H NMR (400 MHz, CDCl3) (keto) δ
7.81 (d, J = 7.6 Hz, 2 H), 7.58−7.52 (m, 1 H), 7.49−7.42 (m, 2 H),
5.06 (dd, J = 2.4, 1.2 Hz, 1 H), 4.98 (dd, J = 2.4, 1.2 Hz, 1 H), 4.91
(dd, J = 2.8, 1.2 Hz, 1 H), 4.82 (dd, J = 2.4, 1.2 Hz, 1 H), 4.75 (dd, J =
2.4, 1.2 Hz, 1 H), 4.52 (dd, J = 2.4, 1.2 Hz, 1 H), 4.37 (dd, J = 2.4, 1.2
Hz, 1 H), 3.82 (s, 3 H), 3.40 (dd, J = 13.2, 5.2 Hz, 1 H), 2.66 (t, J =
Preparation of Compound 4f. The reaction of 3f (38.0 mg, 0.10
mmol, 1.0 equiv) and BF3·OEt2 (40.0 μL, 0.30 mmol, 3.0 equiv)
I
DOI: 10.1021/acs.joc.5b01511
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The Journal of Organic Chemistry
Featured Article
13.2 Hz, 1 H), 1.97 (dd, J = 13.2, 5.2 Hz, 1 H), 1.36 (s, 3 H), 1.11 (s, 3
H), (enol) δ 12.2 (s, 0.50 H), 7.81 (d, J = 7.6 Hz, 1.0 H), 7.58−7.52
(m, 0.5 H), 7.49−7.42 (m, 1.0 H), 5.02 (dd, J = 2.8, 1.6 Hz, 0.50 H),
4.94 (dd, J = 2.4, 1.2 Hz, 0.50 H), 4.70 (dd, J = 2.4, 1.2 Hz, 0.50 H),
4.58−4.56 (m, 0.50 H), 4.52 (t, J = 2.4 Hz, 0.50 H), 4.34 (t, J = 2.4 Hz,
0.50 H), 4.14 (dd, J = 2.4, 0.8 Hz, 0.50 H), 3.79 (s, 1.50 H), 2.46 (d, J
= 15.2 Hz, 0.50 H), 2.36 (d, J = 15.2 Hz, 0.50 H), 1.35 (s, 1.50 H),
0.90 (s, 1.50 H); 13C{1H} NMR (100 MHz, CDCl3) δ 198.0, 197.9,
172.1, 171.6, 139.4, 139.1, 132.0, 131.7, 128.4, 128.18, 128.16, 128.1,
104.9, 79.2, 75.6, 74.7, 74.5, 74.3, 73.9, 73.34, 73.31, 73.1, 72.7, 72.3,
70.9, 67.6, 67.3, 65.8, 52.7, 52.4, 51.4, 41.8, 37.3, 30.5, 30.1, 29.4, 28.7,
28.4, 27.7; HRMS (ESI) calcd for C25H24O456FeNa [M + Na]+
467.0922, found 467.0922.
CDCl3) δ 196.4, 171.8, 106.4, 78.4, 72.8, 72.7, 72.2, 71.7, 70.7, 67.3,
52.2, 51.5, 37.7, 36.6, 36.1, 32.5, 25.9, 22.8, 21.8. HRMS (ESI) calcd
for C21H24O3102RuNa [M + Na]+ 449.0667, found 449.0657.
Procedures for Alkylation of Keto Ester.19 Preparation of
Compound 6a. To a 10 mL round-bottomed flask containing a
suspension of NaH (60% in mineral oil, 2.2 mg, 0.054 mmol, 1.32
equiv) in THF (0.5 mL) was added 4a (14.0 mg, 0.041 mmol, 1.0
equiv) in THF (0.5 mL) dropwise at 0 °C. The mixture was stirred at
rt for 1 h. The resulting nearly homogeneous mixture was cooled with
an ice bath, and CH3I (9.3 mg, 0.066 mmol, 1.6 equiv) was added. The
resulting mixture was stirred at room temperature overnight. Water
was added, the organic solvent was removed by evaporation under
reduced pressure, and the residue was extracted with ethyl acetate. The
organic phase was dried over Na2SO4, filtrated, and concentrated, and
the residue was purified by chromatography on silica gel (hexane/ethyl
acetate = 10:1) to give 6a as a red solid (12.3 mg, 85%, dr = 25:1): 1H
NMR (400 MHz, CDCl3) δ 4.99 (dd, J = 2.4, 1.2 Hz, 1 H), 4.55 (t, J =
2.4 Hz, 1 H), 4.37 (dd, J = 2.4, 1.2 Hz, 1 H), 4.19 (s, 5 H), 3.61 (s, 3
H), 2.44 (d, J = 14.0 Hz, 1 H), 2.34 (d, J = 13.6 Hz, 1 H), 1.57 (s, 3
H), 1.43 (s, 3 H), 1.03 (s, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ
201.9, 175.2, 102.8, 73.1, 71.2, 70.2, 67.6, 66.5, 53.0, 52.5, 51.0, 30.7,
30.2, 29.5, 24.3; HRMS (ESI) calcd for C19H22O356FeNa [M + Na]+
377.0816, found 377.0813.
Preparation of Compound 6b. The reaction of 4a (35.0 mg, 0.103
mmol, 1.0 equiv), benzyl bromide (52.8 mg, 0.309 mmol, 3.3 equiv),
and NaH (60% in mineral oil, 15.0 mg, 0.371 mmol, 3.6 equiv)
afforded 6b (23.4 mg, 53%, dr >25:1): 1H NMR (400 MHz, CDCl3) δ
7.41 (d, J = 8.8 Hz, 2 H), 7.33 (t, J = 7.6 Hz, 2 H), 7.24 (t, J = 7.2 Hz,
1 H), 4.88 (dd, J = 2.8, 1.2 Hz, 1 H), 4.45 (t, J = 2.4 Hz, 1 H), 4.27
(dd, J = 2.4, 1.2 Hz, 1 H), 3.78 (d, J = 13.2 Hz, 1 H), 3.68 (s, 5 H),
3.64 (s, 3H), 2.92 (d, J = 13.2 Hz, 1 H), 2.50 (d, J = 13.6 Hz, 1 H),
2.31 (d, J = 13.6 Hz, 1 H), 1.38 (s, 3 H), 1.03 (s, 3 H); 13C{1H} NMR
(100 MHz, CDCl3) δ 199.8, 174.6, 136.6, 132.3, 128.0, 127.2, 101.9,
74.4, 71.0, 69.7, 67.2, 66.3, 58.7, 52.6, 45.5, 40.9, 31.1, 30.5, 29.73;
HRMS (ESI) calcd for C25H26O356FeNa [M + Na]+ 453.1129, found
453.1133.
Preparation of Compound 4m. The reaction of 3m (28.8 mg, 0.07
mmol, 1.0 equiv) and BF3·OEt2 (26.0 μL, 0.21 mmol, 3.0 equiv)
1
afforded 4m (23.1 mg, 80%): H NMR (400 MHz, CDCl3) selected
peaks for keto δ 4.92 (dd, J = 2.8, 1.2 Hz, 1 H), 4.78−4.77 (m, 1 H),
4.69 (dd, J = 2.8, 1.2 Hz, 1 H), 4.66 (t, J = 2.4 Hz, 1 H), 4.54−4.50 (m,
2 H), 4.49 (dd, J = 2.8, 1.2 Hz, 1 H), 3.83 (s, 3 H), 3.42 (dd, J = 13.2,
5.6 Hz, 1 H), 3.04 (brs, 6 H), 2.71 (t, J = 13.2 Hz, 1 H), 1.99 (dd, J =
13.2, 5.6 Hz, 1 H), 1.50 (s, 3 H), 1.13 (s, 3 H); 13C{1H} NMR (100
MHz, CDCl3) δ 198.2, 171.8, 169.1, 104.0, 101.2, 93.6, 80.6, 74.5,
73.0, 72.6, 72.4, 72.2, 72.0, 71.7, 71.6, 71.53, 71.48, 71.0, 67.8, 67.4,
65.6, 52.7, 52.2, 51.3, 42.0, 38.9, 37.4, 36.4, 30.6, 30.1, 29.4, 28.7, 28.6,
27.8; HRMS (ESI) calcd for C21H25NO456FeNa [M + Na]+ 434.1031,
found 434.1027.
Preparation of Compound 5m. The mixture of 4m (40.5 mg,
0.099 mmol, 1.0 equiv) and KOH (22.1 mg in 0.4 mL H2O, 0.394
mmol, 4.0 equiv) was refluxed under N2 in EtOH (2.0 mL) for 4 h.
The mixture was quenched by the addition of HCl (1.0 M) and
extracted with EtOAc three times. The combined organic layer was
then washed with brine and dried over Na2SO4. After filtration, the
solvent was removed, and the residue was purified by chromatography
on silica gel (hexane/ethyl acetate = 10:1) to afford 5m as a red solid
(19.7 mg, 56%): 1H NMR (400 MHz, CDCl3) δ 4.89 (dd, J = 2.8, 1.2
Hz, 1 H), 4.71 (dd, J = 2.4, 1.6 Hz, 1 H), 4.69 (dd, J = 2.4, 1.2 Hz, 1
H), 4.56 (t, J = 2.4 Hz, 1 H), 4.44 (dd, J = 2.4, 1.2 Hz, 1 H), 4.34−4.31
(m, 2 H), 3.08 (bs, 3 H), 3.05 (bs, 3 H), 2.55−2.45 (m, 1 H), 2.42−
2.31 (m, 2 H), 1.82−1.73 (m, 1 H), 1.48 (s, 3 H), 1.11 (s, 3 H);
13C{1H} NMR (100 MHz, CDCl3) δ 204.1, 169.0, 104.7, 80.0, 74.2,
73.2, 72.2, 72.1, 71.51, 71.47, 70.0, 66.8, 38.9, 38.0, 36.5, 36.2, 30.2,
29.0, 28.9; HRMS (ESI) calcd for C19H23NO256FeNa [M + Na]+
376.0976, found 376.0979.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b01511.
1H and 13C{1H} NMR spectra for all new compounds
(PDF)
CIF file for compound 6b (CIF)
Preparation of Compound 4n. The reaction of 3n (27.0 mg, 0.07
mmol, 1.0 equiv) and BF3·OEt2 (26.0 μL, 0.21 mmol, 3.0 equiv)
1
afforded 4n (27.0 mg, 99%): H NMR (400 MHz, CDCl3) selected
peaks for keto: δ 5.14 (dd, J = 2.0, 1.6 Hz, 1 H), 4.76−4.75 (m, 2 H),
4.68 (s, 5 H), 3.79 (s, 3 H), 3.37 (dd, J = 13.2, 5.2 Hz, 1 H), 2.30 (t, J
= 12.8 Hz, 1 H), 1.87 (dd, J = 12.8, 5.2 Hz, 1 H), 1.27 (s, 3 H), 1.24
(s, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ 196.1, 171.7, 106.0,
78.2, 72.9, 72.7, 72.3, 71.8, 70.5, 67.3, 52.5, 52.2, 42.7, 29.9, 29.6, 28.2;
HRMS (ESI) calcd for C18H21O3102Ru [M + H]+ 387.0534, found
387.0536.
AUTHOR INFORMATION
Corresponding Author
*E-mail: zhgu@ustc.edu.cn.
Notes
■
The authors declare no competing financial interest.
Preparation of Compound 4o. The reaction of 3o (28.8 mg, 0.07
mmol, 1.0 equiv) and BF3·OEt2 (26.0 μL, 0.21 mmol, 3.0 equiv)
ACKNOWLEDGMENTS
1
■
afforded 4o (24.7 mg, 86%): H NMR (400 MHz, CDCl3) selected
This work was supported by the “973” project from the MOST
of China (2015CB856600), NSFC (21272221, 21472179), the
Recruitment Program of Global Experts, and the Fundamental
Research Funds for the Central Universities (WK 2060190028,
2060190026 and 3430000001).
peaks for keto: δ 5.13 (dd, J = 2.4, 0.8 Hz, 1 H), 4.76 (t, J = 2.4 Hz, 1
H), 4.73 (dd, J = 2.4, 0.8 Hz, 1 H), 4.67 (s, 5 H), 3.79 (s, 3 H), 3.31
(dd, J = 13.2, 4.8 Hz, 1 H), 2.42 (t, J = 12.8 Hz, 1 H), 1.96 (dd, J =
12.8, 4.8 Hz, 1 H), 1.91−1.50 (m, 8 H); 13C{1H} NMR (100 MHz,
CDCl3) δ 196.6, 171.6, 104.5, 78.6, 72.8, 72.7, 72.5, 71.8, 71.1, 67.4,
53.6, 52.2, 41.55, 41.50, 40.0, 38.3, 25.6, 24.6; HRMS (ESI) calcd for
C20H22O3102RuNa [M + Na]+ 435.0510, found 435.0505.
REFERENCES
Preparation of Compound 4p. The reaction of 3p (29.8 mg, 0.07
■
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DOI: 10.1021/acs.joc.5b01511
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
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(13) CCDC 1401059. For details, see the Supporting Information.
(14) O’Connor, J. M.; Casey, C. P. Chem. Rev. 1987, 87, 307.
(15) This type of 1,2-hydride shift and alkylation was also observed
in 3-acylindole by Bergman and Venemalm; see: Bergman, J.;
Venemalm, L. Tetrahedron Lett. 1987, 28, 3741.
(16) Chong, J. M.; Shen, L.; Taylor, N. J. J. Am. Chem. Soc. 2000, 122,
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K
DOI: 10.1021/acs.joc.5b01511
J. Org. Chem. XXXX, XXX, XXX−XXX