Synergistic Catalysis: Pd(II) Catalyzed Oxidation of 1,4-Dihydroquinones in the Pd(II) Catalyzed 1,4-Oxidation of Cyclic 1,3-Dienes

Article abstract of DOI:10.1021/acs.joc.5b02769

Palladium(II) carboxylate salts have been shown to catalyze the oxidation of various hydroquinones to benzoquinones in the presence of t-BuOOH. This new catalytic system has been integrated into the oxidative 1,4-functionalization of cyclic 1,3-dienes where the palladium plays a remarkable dual role, catalyzing both the diene oxidation itself and the regeneration of the active quinone oxidant, which is required for diene functionalization. These new conditions offer considerable increases in reaction rate over prior art and allow a significant decrease in the equivalents of the nucleophilic carboxylate required for full conversion.

Full text of DOI:10.1021/acs.joc.5b02769

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Article
Synergistic Catalysis: Pd(II) Catalyzed Oxidation of 1,4-Dihydroquinones
in the Pd(II) Catalyzed 1,4-Oxidation of Cyclic-1,3-Dienes
Bin Zheng, Michael A. Schmidt, and Martin D. Eastgate
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02769 • Publication Date (Web): 29 Feb 2016
Downloaded from http://pubs.acs.org on March 1, 2016
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Synergistic Catalysis: Pd(II) Catalyzed Oxidation of 1,4-Dihydroquinones in the Pd(II) Catalyzed 1,4-
Oxidation of Cyclic-1,3-Dienes
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Bin Zheng, Michael A. Schmidt and Martin D. Eastgate*
Chemical Development, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, NJ, 08903, USA
Martin.Eastgate@bms.com
RECEIVED DATE (will be automatically inserted after manuscript is accepted).
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Abstract:
Palladium (II) carboxylate salts have been shown to catalyze the oxidation of various
hydroquinones to benzoquinones in the presence of t-BuOOH. This new catalytic system has been
integrated into the oxidative 1,4-functionalization of cyclic 1,3-dienes where the palladium plays a
remarkable dual role, catalyzing both the diene oxidation itself and the regeneration of the active
quinone oxidant, which is required for diene functionalization. These new conditions offer considerable
increases in reaction rate over prior art and allow a significant decrease in the equivalents of the
nucleophilic carboxylate required for full conversion.
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Introduction:
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The stoichiometric, palladium-mediated, 1,4-functionalization of a cyclic diene was first demonstrated
by Brown and Davidson in 1971,1 a discovery which was later thoroughly studied, optimized and
transformed into a catalytic process by Bäckvall (Scheme 1).2 This reaction has been developed into a
highly versatile methodology capable of transforming simple dienes with a range of nucleophilic
partners such as carboxylic acids, alcohols and halogens, into useful 1,4-allylic systems. Importantly,
the transformation often proceeds with high π-facial stereocontrol, and in the case of carboxylic acid
nucleophiles, can be modified to selectively yield either the cis-2 or trans-3 stereoisomers3 (Scheme 1).
However, two main limitations to the current procedures are: 1) the requirement for use of toxic
benzoquinone (BQ) and 2) the use of a vast excess of the nucleophile (>8 equivalents of the carboxylic
acid are generally employed). BQ appears to be a uniquely effective oxidant for this reaction, but
unfortunately presents several limitations aside from toxicity and a tendency to sublime. Reaction
mixtures tend to be very dark, with a gel-like consistency which complicates work-up and isolation of
the product. As such, a catalytic system that does not require the handling of stoichiometric quantities
of BQ or the necessity of vast excesses of the nucleophilic component would be desirable in further
broadening the scope of this powerful transformation.
We previously showed that during the 1,4-functionalization of cyclohexadiene (CHD) with carboxylic
acids, the Diels-Alder adduct (DA) 1 (Scheme 1) is formed from CHD and BQ, which is not just an
innocent side-product of this reaction, but also is a competent ligand for palladium.4 In fact, when
palladium is ligated with DA adduct 1, the oxidation proceeds with a significantly increased rate, which
is believed to be caused by the reaction entering a cationic pathway (Figure 1). Subsequently, this
phenomenon was also suggested by Bäckvall in a related transformation.5 We considered the possibility
that this new, highly reactive pathway may allow alternate oxidants to be employed in lieu of BQ.
While previous work had focused on rendering the reaction catalytic in BQ, through the use of co-
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oxidants (for example O2 with catalytic Fe(pc)6 and superstoichiometric MnO2 ), these procedures have
inherent problems, such as a requirement for slow addition of the diene, highly dilute reaction
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conditions, and/or the use of an oxygen atmosphere with organic solvents. Additionally, BQ
stoichiometry was only reduced to ca 25 mol%.
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Herein we report our initial efforts in this area, which have resulted in the identification of a new
terminal oxidant for this process which markedly reduces the amount of BQ required. Palladium plays a
fascinating dual role in this new system, catalyzing both the diene functionalization and the
regeneration of the BQ oxidant required for the functionalization. Through the discovery of a second
catalytic cycle, the toxic, volatile benzoquinone can be replaced with the more easily handled
hydroquinone (HQ). As a further benefit, this highly reactive system allows for a dramatic reduction in
carboxylic acid equivalents (to only a slight excess), which now opens the door for the practical use of
more structurally complex acids to be used as nucleophiles.
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Scheme 1: Previously reported reaction pathways for cyclohexadiene (CHD).2,4
Figure 1. Proposed palladium-ligated catalytic cycle.4
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Results and Discussion:
Before we probed new oxidants for this process, we first focused on optimizing the metal pre-
catalyst. We found the in situ complexation of the ligand 1 to Pd(0), using Pd2dba3 as a pre-catalyst,
was the optimal method for entering the catalytic cycle (Figure 1); the displaced dba had no observable
impact on the transformation. The use of Pd2dba3 was more beneficial than the more traditionally
employed Pd(OAc)2, as it does not provide a source of AcOH, which is a competing nucleophile when
other acids are employed in the oxidation. This proved especially important as we reduced the
concentration of the carboxylate nucleophile to stoichiometric levels (vide infra) where the presence of
10-20 mol% AcOH corresponded to a significant loss of yield. Consistent with previous reports, the
reaction was rendered highly trans-selective by the simple addition of small amounts (0.4 equiv.) of
either the corresponding Li-carboxylate or LiOH.3 With a basic mechanistic understanding in place, a
variety of peroxide-based oxidants were screened for reactivity in the trans-selective 1,4-
dicarboxylation of CHD with benzoic acid under these standard conditions [3.6 equiv. PhCO2H, 0.4
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equiv. PhCO2Li, Pd2dba3 (2.5 mol%), DA ligand 1 (15 mol%) in acetone], in an attempt to eliminate
benzoquinone from the process (Table 1).
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Initially, benzoyl peroxide (BPO, 2.0 equiv.) was examined, as it has been reported to function as a
terminal oxidant in a palladium-catalyzed allylic oxidation reactions.8 However, BPO failed to give
appreciable amounts of the product in its anhydrous form, while the 25% wet suspension showed a
small amount of conversion (Table 1, Entries 1 and 2). A screen of solvents revealed mixtures of
alcohols in acetone improved efficiency. Addition of small amounts of EtOH provided a dramatic
increase in yield with BPO (from ~5% to 40%, Table 1, Entry 3), with a solvent composition of 75:25
v/v% EtOH/acetone being optimal. While conversion remained modest, it was interesting to note that
the trans-selectivity remained high.
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tert-Butyl hydroperoxide (t-BuOOH) provided a modest 51% yield after 24 h, along with maintaining
excellent trans-selectivity (93:7 trans:cis, Entry 4). Importantly, in the absence of DA ligand 1 no
oxidation was observed (Entry 5). Other peroxide sources, H2O2 or Na2S2O8 (previously employed by
Dong as an oxidant in C-H activation)9 gave inferior results (Table 1, Entries 6 and 7). Thus, t-BuOOH
seemed to provide a suitable balance between reactivity and selectivity and thus was chosen for further
optimization. While the combination of palladium salts and t-BuOOH have been shown to oxidize
olefins to epoxides, allylic peroxides and/or enones,10 in the present study, the peroxide seems to act
predominantly as a terminal oxidant for palladium rather than incorporating oxygen into the substrate.
This new t-BuOOH system was slower than the stoichometric quinone-based system,4 and required
approximately 24 h for complete conversion of CHD. Additionally, we observed significant reaction
variability, which prompted a comprehensive, systematic evaluation of all the reaction parameters. We
succeeded in identifying benzoquinone contamination in the DA ligand 1 as the source of the variability.
The deliberate addition of a small amount of benzoquinone (<5 mol%) was found to have a dramatic
effect on both reaction rate and overall yield with a 73% yield being obtained in only 5 h at room
temperature and with high trans-selectivity (93%) (Entry 8). A screen of other alcoholic solvents
revealed that IPA produced a slight increase in yield, presumably through a reduced potential for
product degradation through transesterification. MeOH was not effective for this transformation, while
t-BuOH resulted in a significantly slower reaction. There was some conversion in IPA/acetone in the
absence of the Diels-Alder ligand 1 and BQ, though only ~10% of 3a was formed in 24 h (Entry 10).
Interestingly, addition of hydroquinone (HQ) instead of BQ, produced almost identical results (Entry 11),
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suggesting that HQ may be oxidized to BQ under the reaction conditions. Indeed, HQ conversion to BQ
was confirmed by 1H NMR analysis of the crude reaction mixture. Since only 5 mol% HQ is used, we felt
that it was possible that a second catalytic cycle was being accessed where HQ is oxidized to BQ by
palladium and t-BuOOH. We next set out to understand this oxidation.
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Table 1: Oxidant and solvent optimization.
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While the oxidation of HQ occurred under the reaction conditions, t-BuOOH was inactive in oxidizing
HQ alone, only in the presence of Pd(II)-carboxylate [Pd(OBz)2 or Pd(OAc)2] did the oxidation take place;
the DA ligand 1 was not necessary. A control experiment, where t-BuOOH was omitted and the
reaction was left open to air, led to a very slow conversion of HQ to BQ (<3% conversion after 20 h),
excluding the possibility of oxygen mediating the transformation. Surprisingly, Pd(II) is not commonly
known to catalyze hydroquinone oxidation with peroxides11 yet in our hands, Pd(OBz)2 and t-BuOOH
smoothly oxidizes a range of hydroquinones in near quantitative yield, with low catalyst loading (Table
2).
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Mechanistically, we propose a catalytic cycle outlined in Scheme 2. Initially, a heteroleptic palladium
peroxo-carboxylate is formed through the t-BuOOH displacement of one of the carboxylate ligands
from (RCO2)Pd. Complexes such as these were isolated by Mimoun & Weiss and, relevant to this work,
shown to be competent oxidizing π-systems.12 After hydroquinone binding to palladium, followed by
proton-transfer and elimination of water, BQ and t-BuOH are released, all without redox of the metal
center. Similar mechanisms have been suggested for Wacker oxidations mediated by t-BuOOH.13 This
catalyst system is extremely mild, and can be performed in a preparative sense. Thus a range of
hydroquinones are smoothly oxidized to their corresponding benzoquinones with t-BuOOH and just 1
mol% Pd(OBz)2 in IPA/acetone (Table 2).
Scheme 2: Proposed mechanism for the oxidation of HQ to BQ.
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Table 2: Oxidation of Hydroquinones with t-BuOOH/Pd(OBz)2.
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After studying the HQ to BQ catalytic cycle, we focused our attention back to the oxidative
functionalization of dienes. Initial order dependencies of this new system indicated an apparent zero-
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order dependence on carboxylic acid concentration (see supporting information) – this is in contrast to
the initial conditions4 which demonstrated first-order dependence on the acid nucleophile. Thus,
reduction in the concentration of the nucleophilic component could easily be achieved without
impacting rate, 2.2 equiv (only a 0.2 equiv. excess) could be used with minimal impact on yield or
selectivity. Concurrently, a reduction in the amount of LiOH was required to prevent partial hydrolysis
of the product. The final optimized conditions were 2.5 mol% Pd2dba3, 10 mol% 1, 5 mol % HQ, 2.2
equiv. BzOH, 2.0 equiv. t-BuOOH in 75:25 v/v% IPA/Acetone at 25 °C.
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With these new conditions in hand, a survey of cyclic dienes was investigated (Table 3).
Cyclopentadiene (6) failed to react under these conditions; and interestingly no HQ-to-BQ oxidation
occurred in the presence of 6. Deliberate addition of 10 mol% 6 to a standard CHD reaction did not
affect the reaction in anyway, suggesting the inactivity of 6 is not related to catalyst inhibition.
However, dicyclopentadiene was observed indicating that 6 undergoes Diels-Alder homodimerization
faster than the 1,4-difunctionalization. Conversely, 1,3-cycloheptadiene (7) smoothly underwent
oxidation, to give the cis-isomer 8 with an 80:20 (cis:trans) ratio in good overall yield (65%, Entry 4),
though elevated temperatures (40-45 ˚C) were needed to achieve reasonable reaction rates. The
preference for cis-stereochemistry in the oxidation of 7 has been described previously.14 1,3-
Cyclooctadiene (9) was unreactive even at elevated temperatures. Interestingly, attempts to carry out
a cis-selective oxidation of CHD by conducting the reaction in the absence of LiOH, failed to yield
product under these conditions, in sharp contrast to the stoichiometric benzoquinone conditions (Entry
3). However, addition of 0.3 equivalents of LiCl to reaction mixture did predominately afford the cis-
product (87:13), consistent with prior work,3 though with poor conversion (2%). The trans-selectivity
and lack of order dependence in acid suggest a different mechanism predominates under these new
conditions.
A proposed catalytic cycle is shown (Scheme 3), our data suggests that the Pd plays a very unusual
dual role, catalyzing both product formation as well as production of its own re-oxidant. Based on the
evidence so far obtained, we propose that the role of the BQ is to act as an oxidation state transporter –
from peroxide to palladium. Again, a control experiment performed in air without t-BuOOH, afforded
very low levels of product (2%, 85:15 trans:cis) after 20 h. The trans-product 3, observed in this study,
is generally thought to form from an intramolecular SN2’-like reductive elimination of a resident η1-
bound Pd-allyl species (Scheme 3).15
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Scheme 3: Proposed catalytic cycle for the oxidation of cyclic dienes by t-BuOOH/Pd with BQ-based
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oxidation transport.
The reduced acid concentrations achieved with these conditions (a nearly stoichiometric 2.2 equiv.)
enable the economical use of a wider range of carboxylic acids, and opens the possibility of using chiral
acids to effect doubly diastereoselective additions. Thus a range of complex, chiral acids were utilized,
each providing good yields of the addition adduct (Table 4). In this preliminary exploration, little to no
diastereoselectivity was observed with respect to the forming stereogenic centers. Despite this lack of
selectivity, further exploration of chiral palladium systems is warranted as the product 1,4-
dicarboxylates are extremely valuable synthons.
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Table 3: A survey of dienes.
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Table 4: Use of more complex acids.
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Summary:
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In summary we have expanded the conditions for the oxidation of cyclic dienes to 1,4-dicarboxylated-
alk-2-enes utilizing ligand 1. These new reaction conditions proceed rapidly and afford products in good
yields. By studying the kinetics of this new system, the concentration of the carboxylic acid was
dramatically reduced, allowing wider range of complex carboxylic acids to be used in this chemistry.
Additionally, through the discovery of a second palladium-catalyzed cycle where hydroquinones can be
oxidized to benzoquinones with t-BuOOH, the BQ oxidant can be significantly reduced, and even
replaced with HQ – resulting in a fascinating transformation where Pd bridges two symbiotic catalytic
processes.
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Experimental:
1
General: Solvents and reagents were used without further purification unless otherwise indicated. H
NMR spectra were recorded at 500 MHz using respective solvent as internal standard. 13C NMR spectra
were proton-decoupled and recorded at 126 MHz using the respective solvent as internal standard.
Mass spectrometery was obtained with a hybrid quadrupole-Orbitrap mass spectrometer. The trans/cis
ratios were determined by reverse phase HPLC analysis running the following methods: Method A:
Using a Phenomenex Kinetex C18 (2.6 μm, 4.6 x 150 mm) column at a flow rate of 1.0 mL/min and a 220
nm detector wavelength. The mobile phases consisted of A) 0.01 M NH4OAc in 5:95 v/v% CH3CN/Water
and B) 0.01 M NH4OAc in 95:5 v/v% CH3CN/Water. A gradient of t = 0 min, 20% B, t = 5 min, 50% B, t =
20 min, 70% B, t = 25 min 100% B, t = 30 min, 100% B was used. Method B: Using a Zorbax Eclipse Plus
C18 (1.8 μm, 4.6 x 50 mm) column at a flow rate of 1.2 mL/min and a 220 nm detector wavelength. The
mobile phases consisted of A) 0.05% TFA in 5:95 v/v% CH3CN/Water and B) 0.05% TFA in 95:5 v/v%
CH3CN/Water. A gradient of t = 0 min, 15% B, t = 13 min, 100% B, t = 15 min, 100% B was used. The
diastereomeric ratios for Table 4 were determined by normal phase HPLC analysis using a Chiralpak IA
(5 μm, 4.6 x 250 mm) column at a 1.0 mL/min flow rate and a 220 nm detector wavelength. The mobile
phases consisted of A) heptanes and B) 50:50 v/v% methanol/ethanol. A gradient of t = 0 min, 30% B, t
= 15 min, 60% B, t = 20 min, 60% B was used. Column chromatography was performed with 230-400
mesh silica gel. All reported yields are isolated yields unless specified otherwise.
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Quinone Oxidations:
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p-Benzoquinone (BQ): Hydroquinone (HQ, 1.0 g, 9.1 mmol) and Pd(OBz)2 (32 mg, 0.09 mmol, 1.0 mol%)
were dissolved in a 75:25 v/v% IPA/Acetone (15 mL, 15 mL/g HQ) solution. A 70 wt% aqueous solution
of t-BuOOH (2.3 g, 18 mmol, 2.0 equiv.) was added and the mixture was stirred at room temperature.
After 5h the reaction was judged complete by NMR. The mixture was concentrated in vacuo; the
resulting yellow crystals were pure by proton NMR analysis. The material was recrystallized from hot
water (8 mL/g) to give large needles, which were chilled and dried under vacuum to afford the quinone
BQ (0.62 g, 5.7 mmol, 62%). Its spectra data were identical to that reported in literature.16
2-Methyl-1,4-benzoquinone (5a): 2-Methylbenzene-1,4-diol (4a, 1.0 g, 8.1 mmol) was used, and the
procedure for BQ was followed (reaction time 48 h) to provide the benzoquinone 4a (0.60 g, 4.9 mmol,
61%).
Its
spectra
data
were
identical
to
that
reported
in
literature.17
2,6-Dimethyl-1,4-benzoquinone (5b): 2,6-dimethylbenzene-1,4-diol (4b, 1.11 g, 8.03 mmol) was used,
and the procedure for BQ was followed (reaction time 48 h) to provide the benzoquinone 5b (0.86 g,
6.3 mmol, 78%). Its spectra data were identical to that reported in literature.18
Naphthalene-1,4-dione (5c): Naphthalene-1,4-diol (4c, 1.29 g, 8.05 mmol) was used, and the procedure
for BQ was followed (reaction time 48 h) to provide the benzoquinone 5c (1.21 g, 7.65 mmol, 95%). Its
spectra
data
were
identical
to
that
reported
in
literature.19
Diene Oxidation; General Conditions:
To a vial was added Pd2dba3 (2.5 mol%), DA ligand 1 (10 mol%), hydroquinone (5 mol%), PhCO2H (2.2
equiv.) and LiOH•H2O (0.20 equiv.). A 75:25 v/v% IPA/Acetone (30 mL/g based on diene) solution was
added and the mixture was stirred 30 min at room temperature. A 70 wt% aqueous solution of t-
BuOOH (2 equiv.) and freshly distilled diene (1 equiv.) were added. Once the reaction was complete the
solvent was removed under vacuum and the residue dissolved in MTBE (20 mL/g) and washed with 1N
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NaOH (3 x 20 mL/g), dried over MgSO4 and concentrated in vacuo. The product was then purified by
column chromatography.
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Experimental Table 3:
trans-Cyclohex-2-ene-1,4-diyl dibenzoate (3a): To a vial was added Pd2dba3 (57 mg, 0.062 mmol, 2.5
mol%), DA ligand 1 (47 mg, 0.25 mmol, 10 mol%), hydroquinone (14 mg, 0.125 mmol, 5 mol%), benzoic
acid (670 mg, 5.5 mmol, 2.2 equiv.) and LiOH hydrate (21 mg, 0.50 mmol, 0.20 equiv.). A 75:25 v/v%
IPA/Acetone (6.0 mL) solution was added and the mixture was stirred 30 min at room temperature.
After stirring for 30 min at room temperature, t-BuOOH (70 wt% aqueous solution, 643 mg, 5.0 mmol,
2.0 equiv.) and freshly distilled cyclohexa-1,3-diene (200 mg, 2.5 mmol, 1.0 equiv.) were added. After 16
h, the solvent was concentrated in vacuo and the residue dissolved in MTBE (20 mL) and washed with a
1N NaOH (3 x 4 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by flash
column chromatography (ethyl acetate/ hexanes eluent) to afford 582 mg (73% yield) of a mixture of
the trans/cis products (HPLC ratio 97:3) whose spectra data were identical to that reported in
literature.20
cis-Cyclohept-2-ene-1,4-diyl dibenzoate (8): Following the procedure for 3a using cyclohepta-1,3-diene
(7, 235 mg, 2.5 mmol, 1.0 equiv.) at 45 °C provided 545 mg (65% yield) of a mixture of the trans/cis
products (ratio 20:80; Waters Eclipse Plus C18 column, 0.05% TFA/MeCN/water). The cis-isomer can be
isolated by flash column chromatography (eluent 5% ethyl acetate/heptane), and its spectra data were
identical
to
that
reported
in
literature.20
Experimental Table 4:
(2S,2'S)-Cyclohex-2-ene-1,4-diyl bis(2-phenylpropanoate) (11a): To a vial was added Pd2dba3 (28 mg,
0.031 mmol, 2.5 mol%), DA ligand 1 (23 mg, 0.125 mmol, 10 mol%), hydroquinone (6.7 mg, 0.062 mmol,
5 mol%), (S)-2-Phenylpropionic acid (10a, 412 mg, 2.75 mmol, 2.2 equiv.) and anhydrous LiOH (6.0 mg,
0.25 mmol, 0.20 equiv.). A 75:25 v/v% IPA/Acetone (3.0 mL) solution was added and the mixture was
stirred 30 min at room temperature. After stirring for 30 min at room temperature, t-BuOOH (70 wt%
aqueous solution, 321 mg, 2.5 mmol, 2.0 equiv.) and freshly distilled cyclohexa-1,3-diene (100 mg, 1.25
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mmol, 1.0 equiv.) were added. After 24 h, the solvent was concentrated in vacuo and the residue
dissolved in MTBE (20 mL) and washed with a 10 wt% aqueous K3PO4 solution (3 x 10 mL), dried over
MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (acetone/
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hexanes eluent) to afford 371 mg (79% yield) of the diastereomeric products (1H NMR ratio 57:43). H
NMR (CDCl3): δ 7.43 - 7.22 (m, 10H), 5.90 (s, 1H), 5.72 (s, 1H), 5.28 (br. s., 2H), 3.77 - 3.64 (m, 2H), 2.09
(d, J=7.9 Hz, 1H), 1.89 (d, J=9.0 Hz, 1H), 1.68 (d, J=8.4 Hz, 1H), 1.56 - 1.44 (m, 7H). 13C NMR (CDCl3): δ
174.0, 174.0, 140.4, 140.4, 130.2, 130.0, 128.6, 127.4, 127.4, 127.1, 67.9, 67.5, 45.6, 45.5, 25.7, 25.1,
18.5, 18.4. HR MS (ESI) calcd. for C24H30NO4 [M+NH4]+, 396.2169; found, 396.2168. The trans/cis ratio
was determined to be 91:9 (Waters Eclipse Plus C18 column, 0.05% TFA/MeCN/water).
(2S,2'S)-Cyclohex-2-ene-1,4-diyl bis(2-(6-methoxynaphthalen-2-yl)propanoate) (11b): Following the
procedure for 11a using (S)-2-(6-methoxynaphthalen-2-yl)propanoic acid (10b, 316 mg, 1.37 mmol, 2.2
equiv.) provided 275 mg (82% yield) of the diastereomeric products (1H NMR ratio 50:50). H NMR
1
(CDCl3): δ 7.73 - 7.62 (m, 6H), 7.38 (t, J=7.4 Hz, 2H), 7.18 - 7.07 (m, 4H), 5.89 (s, 1H), 5.67 (s, 1H), 5.27 (d,
J=11.0 Hz, 2H), 3.92 (s, 6H), 3.86 - 3.78 (m, 2H), 2.08 (d, J=6.6 Hz, 1H), 1.86 (d, J=8.9 Hz, 1H), 1.69 - 1.63
(m, 1H), 1.55 (d, J=6.9 Hz, 3H), 1.56 (d, J=6.9 Hz, 3H), 1.45 (m, 1H). 13C NMR (CDCl3): δ 174.2, 174.1,
157.6, 135.6, 135.5, 133.6, 133.6, 130.2, 130.0, 129.2, 129.2, 128.9, 127.1, 126.1, 126.1, 125.9, 125.8,
119.0, 118.9, 105.5, 67.9, 67.6, 55.3, 45.5, 45.5, 25.7, 25.1, 18.5, 18.4. HR MS (ESI) calcd. for C34H38NO6
[M+NH4]+, 556.2694; found, 556.2690. The trans/cis ratio was determined to be 88:12 (Waters Eclipse
Plus C18 column, 0.05% TFA/MeCN/water).
(8S,8'S,9S,9'S,10R,10'R,13S,13'S,14S,14'S,17S,17'S)-Cyclohex-2-ene-1,4-diyl bis(10,13-dimethyl-3-oxo-
2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-carboxylate)
(11c): Following the procedure for 11a using 3-oxo-4-androstene-17β-carboxylic acid (10c, 218 mg, 1.37
mmol, 2.2 equiv.) provided 113 mg (51% yield) of the diastereomeric products (1H NMR ratio 54:46). 1H
NMR (CDCl3): δ 5.92 (s, 1H), 5.90 (s, 1H), 5.74 (s, 2H), 5.38 (m, 1H), 5.32 (m, 1H), 2.47 - 2.26 (m, 10H),
2.20 - 2.08 (m, 4H), 2.08 - 1.97 (m, 4H), 1.89 - 1.76 (m, 2H), 1.75-1.64 (m, 6H), 1.60-1.51 (m, 2H), 1.49-
1.37 (m, 2H), 1.35-1.24 (m, 6H), 1.19 (s, 6H), 1.16 - 1.05 (m, 3H), 1.03-0.94 (m, 2H), 0.89 (t, J=6.9 Hz, 1H),
0.72 (d, J=3.4 Hz, 6H). 13C NMR (CDCl3): δ 199.5, 173.4, 173.4, 171.0, 171.0, 130.4, 130.2, 123.9, 67.1,
67.0, 64.9, 55.4, 55.1, 55.1, 53.7, 53.7, 44.0, 44.0, 38.6, 38.2, 38.2, 35.7, 34.8, 33.9, 32.8, 31.9, 29.6,
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29.6, 29.3, 29.2, 28.6, 27.0, 26.1, 25.9, 25.6, 24.4, 23.5, 23.4, 22.7, 20.9, 17.4, 14.1, 13.5, 13.4. HR MS
(ESI) calcd. for C46H66NO6 [M+NH4]+, 728.4890; found, 728.4882. The trans/cis ratio was determined to
be 89:11 (Waters Eclipse Plus C18 column, 0.05% TFA/MeCN/water).
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(2S,2'S)-1-Dibenzyl O'2,O2-(cyclohex-2-ene-1,4-diyl) bis(pyrrolidine-1,2-dicarboxylate) (11d): Following
the procedure for 11a using (S)-1-((benzyloxy)carbonyl)pyrrolidine-2-carboxylic acid (10d, 342 mg, 1.37
1
mmol, 2.2 equiv.) provided 309 mg (86% yield) of the diastereomeric products (HPLC ratio 51:49). H
NMR (CDCl3): δ 7.42 - 7.26 (m, 10H), 5.96 - 5.81 (m, 1H), 5.76 - 5.60 (m, 1H), 5.38 - 5.26 (m, 1H), 5.23 -
5.09 (m, 4H), 5.09 - 4.99 (m, 1H), 4.42 - 4.27 (m, 2H),3.69 - 3.57 (m, 2H), 3.58 - 3.42 (m, 2H), 2.32 - 2.17
(m, 2H), 2.08 - 1.82 (m, 8H), 1.76 - 1.32 (m, 2H). 13C NMR (CDCl3): δ 172.2, 172.0, 172.0, 154.8, 154.7,
154.1, 136.6, 136.4, 136.3, 130.1, 130.1, 130.0, 129.9, 129.8, 128.4, 128.3, 128.0, 127.9, 127.8, 127.8,
68.1, 68.0, 68.0, 68.0, 67.9, 67.8, 67.0, 66.9, 66.9, 59.3, 59.3, 59.3, 59.2, 58.9, 58.8, 46.9, 46.4, 30.9,
29.9, 29.8, 25.4, 25.3, 25.2, 25.1, 24.2, 23.4. HR MS (ESI) calcd. for C32H40N3O8 [M+NH4]+, 594.2810;
found, 594.2797. The trans/cis ratio was determined to be 91:9 (Phenomenex Kinetex C18 column,
0.01M NH4OAc/MeCN/water), and the diasteroisomeric ratio to be 51:49 (Chiralpak IA column,
heptanes/EtOH-MeOH).
(2R,2'R)-4-Di-tert-butyl O'1,O1-(cyclohex-2-ene-1,4-diyl) bis(2-(((benzyloxy)carbonyl)amino)succinate)
(11e): Following the procedure for 11a using (R)-2-(((benzyloxy)carbonyl)amino)-4-(tert-butoxy)-4-
oxobutanoic acid hydrate (10e, 469 mg, 1.37 mmol, 2.2 equiv.) provided 416 mg (92% yield) of the
diastereomeric products (HPLC ratio 50:50). 1H NMR (CDCl3): δ 7.37 - 7.30 (m, 10H), 5.91 - 5.83 (m, 2H),
5.77 (d, J=8.5 Hz, 2H), 5.36 (br. s., 2H), 5.13 (s, 4H), 4.61 - 4.51 (m, 2H), 2.99 - 2.87 (m, 2H), 2.81 - 2.68
(m, 2H), 2.15 - 2.03 (m, 2H), 1.74 - 1.63 (m, 2H), 1.42 (s, 18H). 13C NMR (CDCl3): δ 170.4, 170.3, 169.9,
169.9, 155.9, 136.1, 130.0, 129.9, 128.5, 128.1, 128.0, 81.8, 81.7, 68.8, 68.5, 67.0, 50.5, 37.6, 27.9, 25.3,
25.1. HR MS (ESI) calcd. for C38H52N3O12 [M+NH4]+, 742.3546; found, 742.3533. The trans/cis ratio was
determined to be 87:13 (Phenomenex Kinetex C18 column, 0.01M NH4OAc/MeCN/water), and the
diasteroisomeric ratio to be 50:50 (Chiralpak IA column, heptanes/EtOH-MeOH).
(2S,2'S)-cyclohex-2-ene-1,4-diyl bis(2-(((benzyloxy)carbonyl)amino)propanoate) (11f): Following the
procedure for 11a using (S)-2-(((benzyloxy)carbonyl)amino)propanoic acid (10f, 307 mg, 1.37 mmol, 2.2
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equiv.) provided 301 mg (90% yield) of the diastereomeric products (HPLC ratio 51:49). 1H NMR (CDCl3):
δ 7.45 - 7.29 (m, 10H), 5.90 (d, J=16.8 Hz, 2H), 5.37 - 5.26 (m, 4H), 5.12 (br. s., 4H), 4.44 - 4.20 (m, 2H),
2.18 - 1.93 (m, 2H), 1.70 - 1.66 (m, 2H), 1.42 (s, 3H), 1.41 (s, 3H). 13C NMR (CDCl3): δ 172.5, 155.5, 136.2,
130.1, 130.0, 128.5, 128.2, 128.1, 68.4, 66.9, 49.7, 25.3, 18.5. HR MS (ESI) calcd. for C28H36N3O8
[M+NH4]+, 542.2497; found, 542.2492. The trans/cis ratio was determined to be 85:15 (Phenomenex
Kinetex C18 column, 0.01M NH4OAc/MeCN/water), and the diasteroisomeric ratio to be 51:49
(Chiralpak IA column, heptanes/EtOH-MeOH).
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(2R,2'R)-4-dibenzyl O'1,O1-(cyclohex-2-ene-1,4-diyl) bis(2-((tert-butoxycarbonyl)amino)succinate)
(11g): Following the procedure for 11a using (R)-4-(benzyloxy)-2-((tert-butoxycarbonyl)amino)-4-
oxobutanoic acid (10g, 445 mg, 1.37 mmol, 2.2 equiv.) provided 403 mg (89% yield) of the
diastereomeric products (HPLC ratio 53:47). 1H NMR (CDCl3): δ 7.44 - 7.29 (m, 10H), 5.84 (s, 1H), 5.71 (s,
1H), 5.46 (d, J=8.2 Hz, 2H), 5.29 (br. s., 2H), 5.13 (m, 4H), 4.60 - 4.49 (m, 2H), 3.09 - 2.98 (m, 2H), 2.93 -
2.83 (m, 2H), 2.12 - 2.01 (m, 1H), 1.96 - 1.85 (m, 1H), 1.73 - 1.63 (m, 1H), 1.53 - 1.48 (m, 1H), 1.45 (s,
18H). 13C NMR (CDCl3): δ 170.8, 170.5, 155.4, 135.3, 129.9, 128.6, 128.5, 128.5, 128.4, 128.3, 80.2, 68.8,
66.8, 50.1, 36.8, 28.3, 25.4, 25.1. HR MS (ESI) calcd. for C38H52N3O12 [M+NH4]+, 742.3546; found,
742.3539. The trans/cis ratio was determined to be 89:11 (Phenomenex Kinetex C18 column, 0.01M
NH4OAc/MeCN/water), and the diasteroisomeric ratio was found to be 53:47 (Chiralpak IA column,
heptanes/EtOH-MeOH).
Associated Content
Supporting Information:
The Supporting Information is available free of charge on the ACS Publication website at DOI: XX
Rate study with variable carboxylic acid concentration.
1H, 13C NMR, and HPLC Spectra.
Author Information
Corresponding Author
*E-mail: Martin.Eastgate@bms.com
Notes
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The authors declare no competing financial interest.
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Acknowledgement:
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The authors would like to thank Dr. Rajendra Deshpande, Dr. Wendel Doubleday and Dr. David
Kronenthal for support. We would also like to thank Dr. Chris Sfouggatakis and Dr. David Conlon for
useful discussions.
1 Brown, R. G.; Davidson, J. M. J. Chem. Soc. (A) 1971, 1321.
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For reviews of this work see; Bäckvall, J.-E. in Metal-Catalyzed Cross-Coupling Reactions, Wiley-VCH, Weinheim, 2004, 2nd
Ed., v 2, 479.
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5 Persson, A. K. Å.; Bäckvall, J.-E. Angew. Chem. Int. Ed. 2010, 49, 4624.
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Ce, V, I2, Cu, have been shown to catalyze the oxidation of HQ with peroxides: a) Fischer, A.; Henderson, G. N. Synthesis,
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15 Bäckvall, J.-E.; Nordberg, R. E.; Björkman, E. E.; Moberg, C. J. Chem. Soc. Chem. Commun. 1980, 943.
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Pratt, D. V.; Ruan, F.; Hopkins, P. B. J. Org. Chem. 1987, 52, 5053.
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20 Bäckvall, J.-E.; Granberg, K. L.; Hopkins, R. B. Acta Chem. Scand. 1990, 44, 492.
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