Recyclable Dirhodium(II) Catalyst Rh2(esp)2 for the Allylic Oxidation of Δ5-Steroids

Article abstract of DOI:10.1021/acs.joc.7b00414

The chelating dirhodium(II) catalyst Rh₂(esp)₂ was shown to efficiently catalyze the allylic oxidation of Δ⁵-steroids using T-HYDRO (70% tert-butyl hydroperoxide in water) as oxidant. Reaction yields were affected by the coordination ability of the solvent. The noncoordinating solvent n-heptane was determined to be an optimal solvent. At gram scale, the product, Δ⁵-en-7-one steroid, precipitated from the reaction mixture. The Rh₂(esp)₂ complex did not undergo catalytic degradation and was recycled using Merrifield-pyridine resin for further allylic oxidation cycles. The results of ultraviolet/visible spectral analysis suggested that the Rh₂(II,II) species, rather than the Rh₂(II,III) species, was in the catalyst resting state during the reaction, which helps to explain the high durability of the catalyst.

Full text of DOI:10.1021/acs.joc.7b00414

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Article
Recyclable Dirhodium(II) Catalyst Rh2(esp)2
for the Allylic Oxidation of #5-Steroids
Yi Wang, Yi Kuang, Hongyang Zhang, Ruocheng Ma, and Yuanhua Wang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00414 • Publication Date (Web): 12 Apr 2017
Downloaded from http://pubs.acs.org on April 13, 2017
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Recyclable Dirhodium(II) Catalyst Rh2(esp)2 for the Allylic
Oxidation of ꢀ5ꢁSteroids
Yi Wang,† Yi Kuang,† Hongyang Zhang † Ruocheng Ma,‡ and Yuanhua Wang*,†
,
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†College of Chemistry, Sichuan University, Chengdu, 610064, P. R. China
‡Jiaxiang Foreign Languages School Attached To Chengdu No.7 Middle School, Chengdu, 610023,
P.R.China
Eꢀmail: yhwang@scu.edu.cn
The chelating dirhodium(II) catalyst Rh2(esp)2 was shown to efficiently catalyze the
allylic oxidation of ꢁ5ꢀsteroids using TꢀHYDRO (70% tertꢀbutyl hydroperoxide in water)
as oxidant. Reaction yields were affected by the coordination ability of the solvent.
The nonꢀcoordinating solvent nꢀheptane was determined to be an optimal solvent. At
gram scale, the product, ∆5ꢀenꢀ7ꢀone steroid, precipitated from the reaction mixture.
The Rh2(esp)2 complex did not undergo catalytic degradation and was recycled using
Merrifieldꢀpyridine resin for further allylic oxidation cycles. The results of ultraviolet
/visible spectral analysis suggested that the Rh2(II,II) species, rather than the Rh2(II,III)
species, was catalyst resting state during the reaction, which helps to explain the high
durability of the catalyst.
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Introduction
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Allylic oxidation is a fundamental organic reaction that involves direct
transformation of an allylic CH2 group to a carbonyl group.1,2 This transformation is of
great importance given the versatility of the resulting unsaturated enones or 1,
4ꢀenediones, which can act as synthetic starting materials or drug precursors.3 In
particular, the allylic oxidation of ∆5ꢀsteroids to ∆5ꢀenꢀ7ꢀone steroids has shown
promising results for the prevention and treatment of cancer and has also been shown to
inhibit the biosynthesis of sterol.4a Further functionalization of the double bond or the
carbonyl group attracted the synthetic interest.4bꢀd Although classical oxidation
reactions using stoichiometric chromium(VI) have been extensively studied, the harsh
reaction conditions and toxic chromium regents make these methods unfavorable.5
Recently, highly efficient metalꢀcatalyzed allylic oxidation methods mediated by
tertꢀbutyl hydroperoxide (TBHP, tꢀBuOOH) have been reported (Eq 1).6 These
procedures provided a feasible approach for the oxidation of ∆5ꢀsteroids with moderate to
good reactivity. tertꢀButyl hydroperoxide acts as a source of the tertꢀbutylperoxy
radical (tꢀBuOO•), a selective oneꢀelectron oxidant. The generation of tꢀBuOO• relies
on metal complexes, such as sodium chlorite,7 copper iodide,8 bismuth salts,9 cobalt
acetate,10 dirhodium caprolactamate (Rh2(cap)4),11 ruthenium trichloride,12 and
manganese(III) acetate.6a As oneꢀelectron reductants, the metal complexes (Mn) are
thought to homolytically cleave the oxygen–oxygen bond of TBHP (Eq 1), generating
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tꢀBuOO• by hydrogen atom abstraction from TBHP by tertꢀbutoxy radical (tꢀBuO•) and
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one electron oxidative metal species (Mn+1OH).
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However, due to the radical mechanism of these oxidation reactions in the presence
of stoichiometric TBHP, irreversible decomposition of the high oxidative state
catalytically active species can occur over the course of the reaction and lead to a loss in
catalytic activity or selectivity.11b,13 Portionꢀwise addition of catalysts and/or oxidants
to the reaction system was done to minimize catalyst deactivation, however this can
complicate the method.8,11b,13 In addition, for practical applications, costly metals
necessitate a stable and recyclable catalyst. Therefore, the use of environmentally
friendly, stable, efficient, and recoverable metal catalysts would be highly beneficial for
the oxidation of ∆5ꢀsteroids.
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Recently, we reported Du Bois’ dirhodium (II) complex Rh2(esp)2 (Figure 1) as a
robust, efficient, and recyclable catalyst for solventꢀfree allylic and benzylic oxidation.15
This method requires a low catalyst loading and uses environmentally safe aqueous
TBHP (70% tertꢀbutyl hydroperoxide in water, TꢀHYDRO) as an oxidant. This method
is also operationally simple, scalable, can occur at ambient temperatures, and does not
require additives. Since Rh2(II,II) species exists in the catalyst resting state in these
reactions, the catalyst Rh2(esp)2 did not degrade under the oxidation reaction conditions
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and was recyclable (Figure 1). Based on previous studies, the oxidation of ∆5ꢀsteroids
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using the Rh2(esp)2/TꢀHYDRO protocol was investigated in the current study.
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Rh2(II,II)
Rh2(esp)2
catalyst resting state
t-BuO
+
t-BuOO
H2O
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t-BuOOH
t-BuOO
O
O
Rh2(esp)2OH
Rh2(II,III)
O
t-BuOOH
Rh
O
t-BuOOH
t-BuOH
Rh2(esp)2
Figure 1. Oneꢀelectron oxidative reaction between dirhodium(II) catalyst Rh2(esp)2.
Results and Discussion
Dehydroepiandrosterone acetate 1a was chosen as a substrate for initial studies.
Based on a previously reported solventꢀfree reaction protocol,15 the oxidation of 1a to 2a
was carried out with 1 mol% Rh2(esp)2 catalyst and 5 equiv TꢀHYDRO at 40°C. In the
absence of solvent, 1a did not fully dissolve in the aqueous TBHP and conversion to 2a
was very low. Solvent screenings were performed to determine the ideal solvent to
solubilize the steroidal substrate. However, due to the unique structure of the
dirhodium(II) complexes, some solvent molecules likely acted as labile ligands and bind
to the dirhodium(II) core axially.16a The interaction between the axial solvent molecule
ligands and the dirhodium(II) core affects the electronic properties of the dirhodium(II)
complex. The energy of the Rh2 π* to Rh2 σ* HOMO to LUMO transition band in the
dirhodium(II) complex has been shown to be strongly affected by axial ligand
coordination.16 Recently, Berry et al. and our group have reported that axial ligand
coordination to Rh2(esp)2 can change the redox potential of the complex.17 Therefore,
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selecting the appropriate solvent for this oxidation is important.
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Table 1. Optimization of Reaction Conditionsa
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entry
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deviation from the standard conditions
none
2a yield (%)b
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trace
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8711
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nꢀhexane instead of nꢀheptane
nꢀpentane instead of nꢀheptane
EtOAc instead of nꢀheptane
acetone instead of nꢀheptane
DCE instead of nꢀheptane
CH3CN instead of nꢀheptane
DME instead of nꢀheptane
TBHPc instead of TꢀHYDRO
80% CHP instead of TꢀHYDRO
30% H2O2 instead of TꢀHYDRO
600C instead of 400C
Rh2(cap)4 instead of Rh2(esp)2
Rh2(OAc)4 instead of Rh2(esp)2
Rh2(TFA)4 instead of Rh2(esp)2
Rh2(Oct)4 instead of Rh2(esp)2
Rh2(OAc)4(IMes) instead of Rh2(esp)2
Rh2(MPDP)2 instead of Rh2(esp)2
0.1 mol % Rh2(esp)2 instead
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aUnless otherwise noted, all reactions were performed with 1a (0.4 mmol), TꢀHYDRO (2.0
mmol), nꢀheptane (0.5 mL), dirhodium catalyst (1.0 mol%). bYield after column
chromatography. cTBHP (5ꢀ6 M solution in decane).
Several commonly used solvents such as ethyl acetate (EtOAc), acetone,
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1,2ꢀdichloroethane (DCE), acetonitrile (CH3CN), dimethyl ether (DME), and alkanes
(nꢀpetane, nꢀhexane, nꢀheptane) were evaulated. The reaction yields were found to be
sensitive to the type of solvent used in the reaction. High yields of 2a were obtained
rapidly with nonꢀcoordinating alkanes (Table 1, entries 1ꢀ3). These results were similar
to those given by Doyle’s dirhodium(II) caprolactamate (Rh2(cap)4), which has been
reported to catalyze the reaction with 87% yield in DCE.11 nꢀHeptane was used in
further screening, because it is suitable for practical applications compared to nꢀpentane
(flammable) and nꢀhexane (neurological toxicity).18 Conversely, reactions performed in
coordinating solvents, such as acetone, EtOAc, DCE, CH3CN, and DME, resulted in
lower yields (Table 1, entries 4ꢀ8). It is possible that coordinating solvents bind to
Rh2(esp)2, influence the reaction rates, and even deactivate the catalyst. To understand
the effect of the solvent on Rh2(esp)2 in this oxidation reaction, UV/vis spectroscopy was
used to monitor the behavior of Rh2(esp)2 in different solvents (Figure 2).
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Figure 2. UV/vis spectroscopy of Rh2(esp)2 in different solvents. I (1) Rh2(esp)2 in
acetone (λmax = 613 nm). (2) Rh2(esp)2 and TꢀHYDRO in acetone (λmax = 608 nm). (3)
Rh2(esp)2 in EtOAc (λmax = 636 nm). (4) Rh2(esp)2 and TꢀHYDRO in EtOAc (λmax
=
631 nm). II (1) Rh2(esp)2 in DME (λmax = 608 nm). (2) Rh2(esp)2 and TꢀHYDRO in
DME (λmax = 610 nm). (3) Rh2(esp)2 in CH3CN (λmax = 557 nm). (4) Rh2(esp)2 and
TꢀHYDRO in CH3CN (λmax = 559 nm).
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The transition band of Rh2 π*ꢀRh2 σ* was observed to shift to higher energy in
coordinating solvents (acetone, EtOAc, CH3CN, and DME). For example, the Rh2
π*ꢀRh2 σ* band shifts to 557 nm when Rh2(esp)2 is dissolved in CH3CN, which indicates
that CH3CN binds strongly to rhodium. Previous reports have shown that the
characteristic band of Rh2(esp)2 dissolved in DCM appears at 661 nm.17b After adding
TꢀHYDRO in one portion to the different Rh2(esp)2 solutions, all UV/vis spectra
remained relatively unchanged. These results indicate that the solvated Rh2(esp)2
remained stable under oxidative conditions and that oxidative cleavage of the RhꢀRh
bond did not occur. Furthermore, the characteristic band at ca. 800 nm of a oneꢀelectron
oxidized Rh2(II,III) species was not detected, which suggests that Rh2(II,II) exists in the
catalyst resting state.14dꢀf,15 Lower yields of 2a were obtained when coordinating
solvents were used (Table 1). The solvents coordinated to Rh2(esp)2 did not destroy the
catalyst, but inhibited catalysis and decreased the reaction rate. When more strongly
coordinating solvents were used, even lower yields were observed: 42% for CH3CN
(Table 1, entry 7) vs. 70% in EtOAc (Table 1, entry 4). These results are consistent with
the high yield of 2a that was obtained when the oxidation was carried out in
nonꢀcoordinating nꢀheptane. Rh2(esp)2 was also shown to be very stable in nꢀheptane
during oxidation (Figure 3).
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Figure 3. UV/vis spectroscopy of Rh2(esp)2 catalyst in nꢀheptane during the oxidation
reaction. (1) Rh2(esp)2 and 1a in heptane (λmax = 642 nm). (2) Rh2(esp)2, 1a and
TꢀHYDRO in heptane (1 h, λmax = 637nm). (3) Rh2(esp)2, 1a and TꢀHYDRO in heptane
(3 h, λmax = 638 nm). (4) Rh2(esp)2, 1a and TꢀHYDRO in heptane (6 h, λmax = 638 nm).
However, DCE was found to be an oxidizing solvent (likely through CꢀH abstraction)
and not a suitable solvent in the current system. The UV/vis spectra for oxidation in
DCE exhibited a typical band at 847 nm for the oneꢀelectron oxidized Rh2(II,III) species
(Figure 4),14dꢀf,15 indicating that the Rh2(II,III) species existed in the catalyst resting state
during oxidation. This active Rh2(II,III) intermediate was unstable and readily to
decrease in the concentration under oxidative reaction conditions. The gradually
degraded Rh2(II,III) species in the reaction resulted in a low yield of 2a (Table 1, entry 6).
Rh(II,III) has been previously shown to exist in a resting state in DCE, with the one
+
electron oxidized Rh2(esp)2 species reacting with DCE to give Rh2(esp)2Cl. The Clꢀ is
then axially coordinated to the oxidized species, which results in catalyst arrest.14dꢀf,16b
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Figure 4. UV/vis Spectroscopy of Rh2(esp)2 catalyst in DCE during the oxidation. (1)
Rh2(esp)2 in DCE (λmax = 654 nm). (2) Rh2(esp)2 and 1a in DCE (λmax = 648 nm). (3)
Rh2(esp)2, 1a and TꢀHYDRO in DCE (5 min, λmax = 483 nm). (4) Rh2(esp)2, 1a and
TꢀHYDRO in DCE (6 h, λmax = 475 nm).
After screening for the optimal solvent, other commercially available oxidants were
tested (Table 1, entries 9ꢀ11). The yield dropped when TBHP (5ꢀ6 M solution in decane)
was used (Table 1, entry 9). An aqueous solution of 80% cumene hydroperoxide (80%
CHP) resulted in a low yield, while 30% hydrogen peroxide resulted in only a trace
amount of product 2a. The effect of reaction temperature was also investigated. The
yield was observed to decrease to 72% when the temperature was increased from 40°C to
60°C (Table 1, entry 12). Different dirhodium(II) catalysts were also screened, with
only Rh2(OAc)4, Rh2(TFA)4 and Rh2(Oct)4 producing the desired product 2a at yields
ranging from 25 to 39% (Table 1, entries 14ꢀ16). Additionally, Rh2(OAc)4(IMes)20 and
21
the structurallyꢀsimilar chelating dirhodium(II) catalyst Rh2(MPDP)2 were found to be
less efficient compared with Rh2(esp)2 (Table 1, entries 17ꢀ18). Further evaluation
revealed that reducing the catalyst loading to 0.1 mol% Rh2(esp)2 catalysed the reaction,
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but only resulted in a 50% yield after 6 h (Table 1, entry 19). The oxidation catalysed
by Rh2(esp)2 was an overall clean reaction. NMR analysis of the crude products (Table
1, entry 1) showed that the only detectable impurities were small amounts of
overꢀoxidized products. In addition, peroxides or epoxides were not detected.
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Once the optimal reaction conditions were determined, a variety of ꢁ5ꢀsteroidal
substrates 1aꢁg were oxidized using 1 mol% of catalyst with 5 equiv of oxidant
TꢀHYDRO and heating at 40°C for 6 h. The different functional groups of
3ꢀacetateꢀꢁ5ꢀsteroids substrates 1aꢁd were each oxidized into the desired ketone products
2aꢁd with good yields (Table 2, entries 1ꢀ4). Oxidation of 3ꢀhydroxyꢀꢁ5ꢀsteroids 1eꢁf
was also successful but these substrates gave relatively lower isolated yields of
7ꢀketocholesterol 2eꢁf (Table 2, entries 5ꢀ6). If the alcohol group was protected, as with
tertꢀbutyl dimethylsilyl ethers (1g), the yield of the desired product was observed to
increase (Table 2, entry 7).
Table 2. Oxidation of Steroids Using Optimized Conditiona
entry
substrate
2 yield (%)b
1
2
3
4
5
6
7
R1 = OAc, R2 = O, R3 = O (1a)
R1 = OAc, R2 = C8H17, R3 = H (1b)
R1 = OAc, R2 = Ac, R3 = H (1c)
R1 = Cl, R2 = C8H17, R3 = H (1d)
R1 = OH, R2 = C8H17, R3 = H (1e)
R1 = OH, R2 = Ac, R3 = H (1f)
R1 = OTBS, R2 = C8H17, R3 = H (1g)
85 (2a)
72 (2b)
87 (2c)
77 (2d)
38 (2e)
43 (2f)
70 (2g)
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aAll reactions were performed using 1aꢀg (0.4 mmol), TꢀHYDRO (2 mmol), nꢀheptane (0.5
mL), Rh2(esp)2 (1.0 mol%). bYield after column chromatography.
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Since many transition metal catalysts easily degrade under oxidative conditions in
∆5ꢀsteroids oxidations, the stable Rh2(II,II) species in a catalyst resting state may aid in
catalyst stability, recovery, and recyclability. To test the recyclability of the catalyst, the
oxidation reactions were scaled up to gram levels and tested in catalyst recycling
experiments. At this scale, highly pure product 2a was observed to precipitate from the
reaction mixture when 1a (1.1 g, 3.3 mmol) was treated with 25 mg Rh2(esp)2 in 2 mL
heptane under standard conditions. Pure product 2a was readily obtained by gravity
filtration at a yield of 76%. This precipitation reaction demonstrated that this oxidation
method was operationally simple. Initial attempts to recover the Rh2(esp)2 catalyst used
column chromatography. Though the Rh2(esp)2 was successfully recovered, the
recovery rate was low (< 50%) and the method was inefficient. Using a previously
described method for immobilization of dirhodium catalysts,22 a convenient and efficient
way was developed to recovery the Rh2(esp)2 catalyst. A Merrifield resin was
synthesized as a polymer backbone and functionalized with a pyridine group. The resin
was then applied to coordinate to rhodium atoms and scavenge the Rh2(esp)2 catalyst
from the homogenous solution (Eq 2). After filtration of product 2a, 80 mg of
Merrifieldꢀpyridine resin was added to the above residue solution. After stirring for 10
min, the red MerrifieldꢀpyridineꢀRh2(esp)2 complex was recovered by filtration. The
obtained MerrifieldꢀpyridineꢀRh2(esp)2 complex was then directly added to a 2 mL
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EtOAc with 3M HCl (aq) mixed solution to release the Rh2(esp)2. A green organic
solvent containing Rh2(esp)2 released from the polymer was separated. Finally, 24 mg
of Rh2(esp)2 (96% recovery rate) was obtained after the EtOAc was removed (Figure 5).
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HCl aq
O
N
+
Rh2(esp)2
(2)
Rh2(esp)2
O
O
Rh
O
EtOAc
O
Rh
Merrifield-pyridine
O
N
Merrifield-pyridine-Rh2(esp)2 complex
(a)
(b)
(c)
(d)
(e)
Figure 5. Recovery of Rh2(esp)2. (a) Merrifieldꢀpyridine resin. (b) Residue solution
after the filtration of product. (c) Merrifieldꢀpyridine resin was added to Rh2(esp)2
complex in heptane. (d) MerrifieldꢀpyridineꢀRh2(esp)2 complex. (e) The release of
Rh2(esp)2 in HCl (aq)/EtOAc.
As it serves as an important intermediate product in vitamin D3 manufacturing,
7ꢀketoꢀcholesteryl acetate 2b was selected for further scaledꢀup reactions.11ꢀ12 After
preliminary optimization of the reaction conditions, a lower Rh2(esp)2 loading (0.1 mol%)
was observed to efficiently catalyse the allylic oxidation of 10 g of 1b using 8 equiv
TꢀHYDRO, resulting in a total yield of 52% after 16 h and 44% yield of product 2b
precipitate (Eq. 3). These results indicate that the Rh2(esp)2 catalyst tolerates scaleꢀup
for a long time
under mild reaction conditions.
This robust and
environmentallyꢀfriendly oxidation procedure may be applied in the synthesis of fine
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chemicals and pharmaceuticals.
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The less reactive 17ꢀacetyltestosterone 3a (due to a conjugated system of double
bonds and the presence of a carbonyl group) was successfully oxidized using modified
conditions (8 equiv TꢀHYDRO and 16 h reaction time instead of the standard 5 equiv
TꢀHYDRO and 6h). Although extension of the reaction time (16h), a catalyst loading of
0.1 mol% still resulted in the desired diketone product 5a at a 53% yield and a 10% yield
of the peroxide product 4a (Table 3, entry 1). These results may be attributed to the
high stability of the Rh2(esp)2 catalyst during the reaction. The formation of tertꢀbutyl
peroxide product 4a indicates that the reaction mechanism involved a free radical.
Similar results were obtained with the oxidation of 4ꢀcholestenꢀ3ꢀone 3b and
4ꢀandrosteneꢀ3, 17ꢀdione 3c (Table 3, entries 2ꢀ3).
Table 3. Oxidation of Steroids Using Lower Catalyst Loadinga
yield(%)b
entry
substrate
4
5
1
2
3
R1 = OAc, R2 = H (3a)
R1 = C8H17, R2 = H (3b)
R1 = Ac, R2 = H (3c)
10(4a)
13(4b)
6(4c)
53(5a)
38(5b)
48(5c)
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aReaction conditions: 3aꢁc (4.0 mmol), TꢀHYDRO (20.0 mmol), nꢀheptane (2.0 mL),
Rh2(esp)2 (0.1 mol%). bYields after column chromatography.
Doyle et al. previously described the mechanism of allylic oxidation.6c,11 In the
case of Rh2(cap)4, the metal catalyst generates tꢀBuOO•, which then facilitates hydrogen
abstraction from the allylic CꢀH bond (Scheme 1). The exceptional catalytic activity of
Rh2(cap)4 is provided its low oxidation potential and rapid reduction of oxidized
Rh2(II,III) species to the catalytically active Rh2(II,II) species to complete the catalytic
cycle. Interestingly, the UV/visible spectroscopy results indicate a different catalyst
resting state for Rh2(esp)2ꢀcatalyzed tꢀBuOO• generation than the previously reported
Rh2(cap)4ꢀcatalyzed reaction (Scheme 1). In the Rh2(cap)4 (E1/2 = 11 mV vs SCE)6c
catalysed oxidation reactions, the mixedꢀvalent Rh2(II,III) species exists in a resting state.
This active Rh2(II,III) intermediate is unstable and is rapidly consumed under oxidative
conditions.11b In contrast, Rh2(esp)2 has a high oxidation potential (E1/2 = 1130 mV vs
SCE)14d and can facilitate oxidation reactions and be easily recovered at the end of the
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+
reaction. Oneꢀelectron oxidation to Rh2(esp)2 can be considered the rate limiting step.
Therefore, the catalyst resting state is the stable Rh2(II,II) state. Since the reaction
(Table 1, entry 14) catalysed by Rh2(OAc)4, which has a similarly high oxidation
+
potential (E1/2 = 1170 mV vs SCE)23 as Rh2(esp)2 produces low yields of the target
product, the chelating ligand of Rh2(esp)2 likely aids in stabilizing the Rh2(II,II) oxidation
state.
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Scheme 1. Proposed Reaction Mechanism.
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Conclusion
The optimized Rh2(esp)2/TꢀHYDRO system exhibited efficient catalytic performance
under allylic oxidations for conversion of a variety of ꢁ5ꢀsteroids to corresponding
ketoꢀproducts. Reaction yields were affected by the type of coordinated solvents.
Reactions with this catalyst generally exhibited high stability in heptane, due to the
Rh2(II,II) catalyst resting state which is less prone to decomposition and allows for
recycling of the catalyst. A Merrifield resin functionalized with a pyridine group was
used to recover the Rh2(esp)2 catalyst from a homogenous solution. Future experiments
will focus on elucidating the stabilization mechanism of the chelating ligand of Rh2(esp)2
and broadening the scope of this oxidation protocol.
Experimental Section
General. Unless otherwise noted, all reagents were obtained from commercial
suppliers and used without further purification. 1H NMR spectra were recorded at 400
MHz, and 13C NMR spectra were recorded at 100 MHz. Chemical shifts (δ) were
1
referenced to either TMS or the residual solvent peak. The H NMR spectra data are
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presented as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet). Highꢀresolution mass spectra were obtained by ESIꢀTOF and
LCMSꢀITꢀTOF. Elemental analyses were performed with a Vario MICRO select
instrument.
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Typical Allylic Oxidation of ꢀ5ꢁSteroids Procedure. A steroid substrate (0.4 mmol)
and Rh2(esp)2 (3 mg, 0.004 mmol) were added to a 10 mL tube equipped with a stir bar.
The tube was sealed with a rubber septa and a purge needle. TꢀHYDRO (0.28 mL, 2
mmol) was added dropwise via syringe. After stirring for 6 h, a saturated sodium
thiosulfate solution was added to the mixture to quench the reaction. The mixture was
extracted with ethyl acetate (3 × 5 mL) and washed with water (2 × 10 mL). The
organic layers were combined and dried over Na2SO4. After evaporation of the solvent,
the residue was purified by flash column chromatography (ethyl acetate/hexane) to obtain
the desired products.
Procedure for Preparation of Merrifieldꢁpyridine Resin.22 In a 100 mL flask,
Merrifield resin (2 g, 2 mmol, 1 mmol/g) was added to a solution of tꢀbutyl ammonium
iodide (0.37 g, 1 mmol) in N,NꢀDimethylformamide (DMF, 25 mL). In a separate 50
mL round bottom flask, 4ꢀpyridinepropanol (1.1 g, 8 mmol) was added to a mixture of
sodium hydride (0.12 g, 5 mmol) in THF (5 mL). An additional 10 mL of DMF was
added to the round bottom flask and the mixture was allowed to sit for 1 h. The mixture
was then added to the Merrifield resin and stirred overnight. The resin was then drained
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and sequentially washed with THF, THF/DMF (v/v = 1/1), DMF, DMF/H2O (v/v =
1/11/1), DMF, THF/DMF (v/v = 1/1), THF, THF/DCM (v/v = 1/1), DCM. The resin
was dried under vacuum to give the Merrifieldꢀpyridine resin. Loading of pyridine was
determined by elemental analysis for nitrogen 1.24 % N, 0.88 mmol/g.
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Typical Procedure for Precipitating the product 2a and Catalyst Recycling
Experiment. A steroid substrate 1a (1.1 g, 3.3 mmol) and Rh2(esp)2 (25 mg, 0.033
mmol) were added to a 10 mL round bottom flask equipped with a stir bar. After 2 mL
of nꢀheptane was added, the flask was sealed with a rubber septa and a purge needle.
TꢀHYDRO (2.37 mL, 16.5 mmol) was added dropwise via syringe. After completion of
the reaction, product 2a was directly precipitated from the mixture and separated by
filtration. The obtained products were washed with cold nꢀheptane, then dried under
vacuum to give a yield of 76%. After filtration and washing of the product 2a, 80 mg
Merrifieldꢀpyridine resin was added to the combined residue solution. After stirring for
10 min, the red MerrifieldꢀpyridineꢀRh2(esp)2 complex was recovered by filtration. The
obtained MerrifieldꢀpyridineꢀRh2(esp)2 complex was directly added to a 2 mL EtOAc
with 3M HCl (aq) mixed solution to release the Rh2(esp)2. After stiring for some hours,
the green organic solvent containing Rh2(esp)2 released from the polymer was separated.
After the EtOAc was removed 24 mg of Rh2(esp)2 (96% recovery rate) was obtained.
Catalyst recovered from the first reaction was directly added to a 2 mL of 1a (1.1 g, 3.3
mmol) in 2 mL heptane and 5 equiv TꢀHYDRO in order to initiate the second oxidation.
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After this second reaction, the solution was cooled to 0oC, 2a precipitated (78% yield)
and 22 mg of Rh2(esp)2 complex (93% recovery rate) was recovered. This catalyst was
cycled twice more according to the procedure of cycle 2. The stable Rh2(esp)2 catalytst
system was found to maintain high activity and produce high yields after 5 cycles (see
Supporting Information (SI)).
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Rh2(esp)2:14a 1H NMR (400 MHz, CDCl3): δ 7.09 (t, J = 7.5 Hz, 2H), 6.92 (s, 2H), 6.87
(dd, J = 7.5, 1.5 Hz, 4H), 2.66 (s, 8H), 1.03 (s, 24H). HRMS (ESI+) m/z calculated for
C32H40O8Rh2 759.0906 ([M+H]+), found 759.0913.
Rh2(MPDP)2: 21a 1H NMR (400 MHz, 1% v/v d4ꢀMeOH in CDCl3): δ 7.09 (t, J = 7.5
Hz, 2H), 6.86 (dd, J = 7.6, 1.5 Hz, 4H), 6.80 (s, 2H), 2.77ꢀ2.67 (m, 8H), 2.36ꢀ2.28 (m,
8H). HRMS (ESI+) m/z calculated for C24H24O8Rh2 646.9653 ([M+H]+), found
646.9633.
Rh2(OAc)4(IMes):20c 1H NMR (400 MHz, CDCl3): δ 7.23 (s, 2H), 6.80 (s, 4H), 2.23 (s,
12H), 2.22 (s, 6H), 1.55 (s, 12H). HRMS (ESI+) m/z calculated for C29H36N2O8Rh2
746.0582 ([M]+), found 746.0584.
3βꢁAcetoxyandrostꢁ5ꢁenꢁ7.17ꢁdione (2a):8 Typical procedure was followed and flash
chromatography (nꢀhexane/EtOAc = 2/1) afforded 116 mg (85%); white solid, mp
185ꢀ187 ℃, Rf = 0.21 (nꢀhexane/EtOAc = 3/1). 1H NMR (400 MHz, CDCl3): δ 5.76 (d,
J = 1.8 Hz, 1H), 4.68ꢀ4.76 (m, 1H), 2.85ꢀ1.26 (comp, 20H), 2.05 (s, 3H), 1.24 (s, 3H),
0.89 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 200.8, 170.3, 164.8, 126.5, 72.0,
50.0, 47.9, 45.7, 44.4, 38.5, 37.8, 36.0, 35.7, 30.7, 27.3, 24.2, 21.3, 20.6, 17.4, 13.8.
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HRMS (ESI+) m/z calculated for C21H28O4 285.1849 ([M+HꢀCH3COOH]+), found
285.1862.
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3βꢁAcetoxycholestꢁ5ꢁeneꢁ7ꢁone (2b):24 Typical procedure was followed and flash
chromatography (nꢀhexane/EtOAc = 5/1) afforded 126 mg (72%); repeated column
chromatography gave analytically pure product (105 mg, 60%), white solid, mp
157ꢀ159 ℃, Rf = 0.49 (nꢀhexane/EtOAc = 5/1). 1H NMR (400 MHz, CDCl3) δ 5.70 (d,
J = 1.6 Hz, 1H), 4.67ꢀ4.75 (m, 1H), 2.57ꢀ0.99 (comp, 32H), 2.05 (s, 3H), 1.21 (s, 3H),
0.92 (d, J = 6.5 Hz, 3H), 0.87 (d, J = 1.9 Hz, 3H), 0.85 (d, J = 1.9 Hz, 3H,), 0.68 (s, 3H).
13C{1H} NMR (100MHz, CDCl3): δ 201.9, 170.3, 163.9, 126.7, 72.2, 54.8, 49.9, 45.4,
43.1, 39.5, 38.7, 38.3, 37.7, 36.1, 35.7, 28.6, 28.0, 27.4, 26.3, 23.8, 22.8, 22.6, 21.2, 18.87,
17.3, 12.0. HRMS (ESI+) m/z calculated for C29H46O3 383.3309 ([M+HꢀCH3COOH]+),
found 383.3295.
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3βꢁAcetoxypregnꢁ5ꢁeneꢁ7, 20ꢁdione (2c):24 Typical procedure was followed and flash
chromatography (nꢀhexane/EtOAc = 2/1) afforded 128 mg (87%); white solid, mp
140ꢀ142 ℃, Rf = 0.24 (nꢀhexane/EtOAc = 3/1). 1H NMR (400 MHz, CDCl3) δ 5.72 (d,
J = 1.6 Hz, 1H), 4.67ꢀ4.75 (m, 1H), 2.58ꢀ1.24 (comp, 24H), 2.13 (s, 3H), 2.05 (s, 3H),
1.21 (s, 3H), 0.65 (s, 3H). 13C{1H} NMR (100MHz, CDCl3) δ 209.8, 201.2, 170.4,
164.2, 126.5, 72.1, 62.3, 50.0, 49.6, 45.2, 44.4, 38.4, 37.7, 36.0, 31.7, 27.3, 26.5, 23.6,
21.3, 21.1, 17.3, 13.3.
HRMS (ESI+) m/z calculated for C23H32O4 313.2162
([M+HꢀCH3COOH]+), found 313.2146.
3βꢁChlorocholestꢁ5ꢁeneꢁ7ꢁone (2d):11 Typical procedure was followed and flash
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chromatography (nꢀhexane/EtOAc = 10/1) afforded 127 mg (77%); white solid, mp
143ꢀ144 ℃, Rf = 0.79 (nꢀhexane/EtOAc = 5/1). 1H NMR (400 MHz, CDCl3) δ 5.68 (s,
1H), 3.80ꢀ3.88 (m, 1H), 2.70 (d, J = 8.3 Hz, 2H), 2.35ꢀ2.43 (m, 1H), 2.14ꢀ2.26 (m, 2H),
1.88ꢀ2.05 (m, 4H), 2.71ꢀ0.99 (comp, 20H), 1.22 (s, 3H), 0.92 (d, J = 6.5 Hz, 3H), 0.87 (d,
J = 1.9 Hz, 3H), 0.86 (d, J = 1.9 Hz, 3H), 0.68 (s, 3H). 13C{1H} NMR (100MHz,
CDCl3) δ 202.0, 163.9, 126.2, 57.8, 54.8, 49.9, 45.5, 43.1, 42.7, 39.5, 38.6, 38.1, 36.2,
35.7, 32.8, 28.5, 28.0, 26.3, 23.8, 22.8, 22.6, 21.1, 18.9, 17.2, 12.0. HRMS (ESI+) m/z
calculated for C27H43ClO 419.3075 ([M+H]+), found 419.3062.
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3βꢁHydroxycholestꢁ5ꢁeneꢁ7ꢁone (2e):11 Typical procedure was followed and flash
chromatography (nꢀhexane/EtOAc = 2/1) afforded 60 mg (38%); white solid, mp
168ꢀ170 ℃, Rf = 0.16 (nꢀhexane/EtOAc = 3/1). 1H NMR (400 MHz, CDCl3) δ 5.69 (d,
J = 1.7 Hz, 1H), 3.64ꢀ3.71 (m, 1H), 2.52ꢀ0.99 (comp, 30H), 1.19 (s, 3H), 0.92 (d, J = 6.5
Hz, 3H), 0.87 (d, J = 1.9 Hz, 3H), 0.85 (d, J = 1.9 Hz, 3H), 0.68 (s, 3H). 13C{1H} NMR
(100MHz, CDCl3) δ 202.5, 165.4, 126.0, 70.5, 54.8, 50.0, 49.9, 45.4, 43.1, 41.8, 39.5,
38.7, 38.3, 36.3, 35.7, 31.1, 28.6, 28.0, 26.3, 23.8, 22.8, 22.6, 21.2, 18.9, 17.3, 12.0.
HRMS (ESI+) m/z calculated for C27H44O2 401.3414 ([M+H]+), found 401.3404.
3βꢁHydroxypregnꢁ5ꢁeneꢁ7, 20ꢁdione (2f):11 Typical procedure was followed and flash
chromatography (nꢀhexane/EtOAc = 1/1) afforded 56 mg (43%); white solid, mp
208ꢀ210 ℃, Rf = 0.30 (nꢀhexane/EtOAc = 1/1). 1H NMR (400 MHz, CDCl3) δ 5.71 (d,
J = 1.6 Hz, 1H), 3.64ꢀ3.72 (m, 1H), 2.55ꢀ1.22 (comp, 22H), 2.13 (s, 3H), 1.20 (s, 3H),
0.66 (s, 3H). 13C{1H} NMR (100MHz, CDCl3) δ 209.9, 201.6, 165.7, 125.9, 70.4, 62.3,
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50.0, 49.8, 45.2, 44.4, 41.8, 38.4, 37.7, 36.4, 31.6, 31.1, 26.5, 23.6, 21.1, 17.3, 13.3.
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HRMS (ESI+) m/z calculated for C21H30O3 331.2268 ([M+H]+), found 331.2287.
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3βꢁ[(1,1ꢁdimethylethyl)dimethylsilyl]oxycholestꢁ5ꢁeneꢁ7ꢁone
(2g):11
Typical
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procedure was followed and flash chromatography (nꢀhexane/EtOAc = 20/1) afforded
136 mg (70%); white solid, mp 215ꢀ216 ℃, Rf = 0.37 (nꢀhexane/EtOAc = 20/1). 1H
NMR (400 MHz, CDCl3) δ 5.66 (d, J = 1.2 Hz, 1H), 3.56ꢀ3.64 (m, 1H), 2.42ꢀ1.07 (comp,
29H), 1.18 (s, 3H), 0.92 (d, J = 6.5 Hz, 3H), 0.89 (s, 9H), 0.87 (d, J = 1.8 Hz, 3H), 0.85
(d, J = 1.8 Hz, 3H), 0.67 (s, 3H), 0.06 (s, 6H). 13C{1H} NMR (100MHz, CDCl3) δ
202.5, 165.9, 125.8, 71.3, 54.8, 50.0, 45.4, 43.1, 42.6, 39.5, 38.7, 38.4, 36.4, 36.2, 35.7,
31.8, 28.6, 28.0, 26.3, 25.9, 23.8, 22.8, 22.6, 21.2, 18.9, 18.2, 17.3, 12.0, ꢀ4.7.
17βꢁAcetoxyandrostꢁ4ꢁenꢁ3,6ꢁdione (4a): Typical procedure was followed and flash
chromatography (nꢀhexane/EtOAc = 3/1) afforded 165 mg (10%); repeated column
chromatography gave analytically pure product (121 mg, 7%), colourless oil, Rf = 0.55
(nꢀhexane/EtOAc = 3/1). 1H NMR (400 MHz, CDCl3) δ 5.86 (s, 1H), 4.60 (dd, J = 8.9,
8.0 Hz, 1H), 4.39 (t, J = 2.8 Hz, 1H), 2.58ꢀ0.90 (comp, 32H), 2.05 (s, 3H), 1.20 (s, 9H),
1.18 (s, 3H), 0.85 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 200.3, 171.2, 163.9,
128.5, 83.8, 82.5, 80.1, 53.5, 50.4, 42.5, 38.0, 36.9, 36.6, 34.6, 34.2, 30.2, 28.2, 27.4, 26.5,
26.4, 23.4, 21.2, 20.4, 18.1, 12.1. HRMS (ESI+) m/z calculated for C25H38O5 837.5511
([2M+H]+), found 837.5487.
Cholestꢁ4ꢁeneꢁ3,6ꢁdione (4b): Typical procedure was followed and flash
chromatography (nꢀhexane/EtOAc = 10/1) afforded 243 mg (13%); colourless oil, Rf =
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0.65 (nꢀhexane/EtOAc = 5/1). 1H NMR (400 MHz, CDCl3) δ 5.85 (s, 1H), 4.37 (t, J =
2.7 Hz, 1H), 2.58ꢀ0.96 (comp, 38H), 1.26 (s, 3H), 1.20 (s, 9H), 0.90 (d, J = 6.5 Hz, 3H),
0.86 (d, J = 1.8 Hz, 3H), 0.85 (d, J = 1.7 Hz, 3H), 0.71 (s, 3H). 13C{1H} NMR (100
MHz, CDCl3) δ 200.5, 164.5, 128.3, 84.0, 80.0, 56.1, 53.7, 42.5, 39.6, 37.9, 36.9, 36.1,
35.8, 35.1, 34.3, 30.4, 28.1, 26.6, 24.1, 23.8, 22.8, 22.6, 20.9, 18.7, 18.0, 12.0. This
compound is unstable to obtain a good HRMS or elemental analysis.
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Pregnꢁ4ꢁeneꢁ3,6,20ꢁtrione (4c): Typical procedure was followed and flash
chromatography (nꢀhexane/EtOAc = 5/1) afforded 95 mg (6%); colourless oil, Rf = 0.65
(nꢀhexane/EtOAc = 5/1). 1H NMR (400 MHz, CDCl3) δ 5.85 (s, 1H), 4.38 (t, J = 2.6
Hz, 1H), 2.55ꢀ1.10 (comp, 33H), 2.13 (s, 3H), 1.27 (s, 3H), 1.20 (s, 9H), 0.68 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 209.4, 200.3, 163.9, 128.5, 83.8, 80.1, 63.5, 56.2,
53.5, 44.0, 38.7, 37.9, 37.0, 35.0, 34.3, 31.5, 30.4, 28.2, 26.5, 24.3, 22.8, 20.9, 18.1, 13.4.
HRMS (ESI+) m/z calculated for C25H38O4 403.2843 ([M+H]+), found 403.2829.
17βꢁAcetoxyꢁ6ꢁtertꢁbutylperoxyꢁandrostꢁ4ꢁenꢁ3ꢁone (5a):25 Typical procedure was
followed and flash chromatography (nꢀhexane/EtOAc = 2/1) afforded 722 mg (53%);
white solid, mp 193ꢀ195 ℃, Rf = 0.21 (nꢀhexane/EtOAc = 3/1). 1H NMR (400 MHz,
CDCl3) δ 6.18 (d, J = 0.7 Hz, 1H), 4.64 (dd, J = 9.0, 8.0 Hz, 1H), 2.71ꢀ1.21 (comp, 20H),
2.05 (s, 3H), 1.17 (s, 3H), 0.84 (s, 3H). 13C{1H} NMR (100MHz, CDCl3) δ 201.7,
199.3, 171.1, 160.6, 125.7, 82.0, 50.9, 46.2, 42.6, 39.8, 36.2, 35.5, 34.0, 27.3, 23.3, 21.1,
20.4, 17.6, 12.0. HRMS (ESI+)
345.2059.
calculated for C21H28O4 345.2060 ([M+H]+), found
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Cholestꢁ6ꢁtertꢁbutylperoxyꢁ4ꢁeneꢁ3ꢁone (5b):26 Typical procedure was followed and
flash chromatography (nꢀhexane/EtOAc = 5/1) afforded 598 mg (38%); white solid, mp
123ꢀ125 ℃, Rf = 0.45 (nꢀhexane/EtOAc = 5/1). 1H NMR (400 MHz, CDCl3) δ 6.17 (d,
J = 0.8 Hz, 1H), 2.70ꢀ0.99 (comp, 29H), 1.16 (s, 3H), 0.92 (d, J = 6.5 Hz, 3H), 0.87 (d, J
= 1.8 Hz, 3H), 0.86 (d, J = 1.8 Hz, 3H), 0.72 (s, 3H). 13C{1H} NMR (100MHz, CDCl3)
δ 202.4, 199.6, 161.1, 125.4, 56.5, 55.9, 51.0, 46.8, 42.5, 39.8, 39.5, 39.1, 36.1, 35.6,
34.2, 34.0, 28.0, 23.9, 22.8, 22.6, 20.9, 18.6, 17.5, 11.9. HRMS (ESI+) m/z calculated
for C27H42O2 399.3258 ([M+H]+), found 399.3240.
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Pregnꢁ6ꢁtertꢁbutylperoxyꢁ4ꢁeneꢁ3,20ꢁdione (5c):26 Typical procedure was followed
and flash chromatography (nꢀhexane/EtOAc = 3/1) afforded 623 mg (48%); white solid,
mp 197ꢀ199 ℃, Rf = 0.63 (nꢀhexane/EtOAc = 3/1). 1H NMR (400 MHz, CDCl3) δ
6.19 (s, 1H), 2.72ꢀ1.22 (comp, 21H), 2.14 (s, 3H), 1.17 (s, 3H), 0.68 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3) δ 208.9, 201.7, 199.4, 160.5, 125.7, 63.1, 56.5, 50.7, 46.5, 43.9,
39.7, 38.1, 35.5, 34.0, 33.9, 31.5, 24.1, 22.8, 20.8, 17.5, 13.3. HRMS (ESI+) m/z
calculated for C21H28O3 329.2111 ([M+H]+), found 329.2105.
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website
at DOI:
Pictures of the oxidation reaction, complete catalysts recycling experiments, and copies
of 1H and 13C NMR spectra for all compounds.
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Notes
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The authors declare no competing financial interest.
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Acknowledgements.
We are grateful for financial support from National Science Foundation of China (grant
no. 21272162).
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