Catalytic Aerobic Cross-Dehydrogenative Coupling of Phenols and Catechols

Article abstract of DOI:10.1021/acscatal.8b04443

We describe a selective, catalytic aerobic cross-dehydrogenative coupling (CDC) reaction of phenols and catechols that creates aryl ethers. To avoid challenges of selectivity, we employ copper (Cu) coordination to confine substrate redox to the inner coor

Full text of DOI:10.1021/acscatal.8b04443

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Article
A Catalytic Aerobic Cross-Dehydrogenative
Coupling of Phenols and Catechols
Wenbo Xu, Zheng Huang, Xiang Ji, and Jean-Philip Lumb
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b04443 • Publication Date (Web): 18 Mar 2019
Downloaded from http://pubs.acs.org on March 18, 2019
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A Catalytic Aerobic Cross-Dehydrogenative
Coupling of Phenols and Catechols
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Wenbo Xu,1‡ Zheng Huang,1‡ Xiang Ji,1 and Jean-Philip Lumb1,2,
*
Department of Chemistry, McGill University, Montreal, QC H3A 0B8, Canada.
KEYWORDS: Aerobic Copper Catalysis, Cross-Dehydrogenative Coupling, Aryl Ethers,
Catechols, Phenols, Alkaloids
ABSTRACT: We describe a selective, catalytic aerobic cross-dehydrogenative coupling
(CDC) reaction of phenols and catechols that creates aryl ethers. To avoid well-known
challenges of selectivity, we employ copper (Cu) coordination to confine substrate redox to the
inner coordination sphere of the metal. This minimizes non-selective radical chain processes
to provide high levels of selectivity for cross over homo coupling, by C-O instead of C-C bond
formation. The method remains efficient on synthetically useful substrates and scales, and
enables a convergent synthesis of the tetrahydroisoquinoline alkaloid (S, S)-thalicarpine
featuring diaryl ether formation in the late stages of the synthesis. Related molecules are
difficult to prepare by traditional Ullman-type coupling, and provide a benchmark for
evaluating the potential utility of our methodology.
Introduction
Catechols are important functional groups of many essential and naturally occurring small
molecules and materials (Fig. 1A).1-2 They are also building blocks for agrochemicals,
pharmaceuticals, perfumes and resins, making their functionalization an important step in the
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chemical value chain.3-5 Electrophilic aromatic substitution (EArS) and nucleophilic
displacement reactions are among the most common ways to functionalize the C-H and O-H
bonds, respectively (Fig. 1B, left).1-2, 4 Both employ catechols as nucleophiles, and are thus
limited to electrophilic coupling partners, and both can suffer poor regioselectivity.6 They also
frequently employ stoichiometric amounts of activators or require an equivalent of base,
creating an undesirable waste stream. A complementary, but underutilized approach to
functionalize catechols is by aerobic oxidation (Fig. 1B, right).4, 7-15 This inverts their polarity,
extends the potential scope of coupling partners to nucleophiles, and couples the energetic
requirements of bond formation to the favorable reduction of molecular oxygen (O2) (Fig. 1B
inset). Because of their atom efficiency, reactions of this more general family, namely catalytic
aerobic cross-dehydrogenative coupling reactions (CDCs), have been extensively
investigated.16-18
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OH
A.
Common Catechols
6
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9
OH
OH
OH
OH
Privileged Structure
OH
OH
OH
OH
OH
HO
natural products
adhesives / materials
pharmaceuticals
agrochemicals
O
HN
CO2H
H
N
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Me
HO
HO2C
NH2
HO
OH
pigments
4-methyl-catechol
cross linker
L-DOPA
neurotransmitter
DHICA
precursor to melanin
adrenaline
hormone
catechin
constituent of tea
B. Catechol Functionalization
OH
OH
OH
O
OH
OH
electrophile
nucleophile
OH
O
OH
O
Aerobic
Oxidation
R
R
R
R
R
Nucleophilic
Addition
E
ArS
common functionalization
challenges
uncommon functionalization
potential advantages
nucleophile
electrophile
regioselectivity
complementary coupling partners
H2O is the only byproduct
atom economy
1/2 O2
H2O
C.
Polymerization of Catechols
Redox Equilibrium
OH
OH
aerobic
polymerization
OH
OH
i. C-C coupling
ii. tautomerization
O
R
2
OH
R
SQ
R
OH
1 e | 1 H+
OH
conproportionation
K2
disproportionation
K3
OH
2
OH
K1
R
Polycatechols
OH
OH
OH
O
OH
R
CAT
K1 increases
at
OH
R
O
poorly soluble
increasing pH
OH
R
OH
mixture of regioisomers
redox active
R
OH
R
R
CAT
OQ
metal chelating
Figure 1. (A) Commonly encountered catechols. (B) Commonly employed functionalization reactions of catechols
take advantage of their nucleophilicity functionalize C-H and O-H bonds (to left). A less common and
complementary approach is by aerobic oxidation (to left). (C) The aerobic polymerization of catechols to
polycatechols.
Catechols are challenging substrates for aerobic CDC reactions because they undergo
polymerization in the presence of O2 (Fig. 1C).19-20 This can occur spontaneously at or above
neutral pH, and it is catalyzed by a range of transition metals.7, 9, 21 Catechols (CAT) undergo
facile 1 e | 1 H+ oxidation to afford an equilibrating mixture of ortho-semiquinone (SQ),
ortho-quinone (OQ) and CAT. By analogy to “free” radicals, “free” SQs are fleetingly stable,22
and undergo irreversible C-C bond formation. This leads eventually to poly-catechols: an often-
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complex mixture of materials with poor solubility.23-25 They are redox active and have a high
affinity for transition metals,26 giving them multiple avenues to deteriorate a reaction’s mass
balance.
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To avoid appreciable concentrations of SQs, most synthetically practiced catechol oxidations
employ at least one oxidizing equivalent (2 e | 2 H+) of a strong oxidant (Fig. 2A). Examples
include sodium periodate27 or silver (I) oxide,28 which either increase the rate of oxidation (K1)
relative to conproportionation (K2), or oxidize SQ to OQ more rapidly than it can polymerize.
This results in a net 2 e | 2 H+ oxidation of CAT to OQ that can be conducted on scales and
substrates suitable for synthesis.29 It also represents the oxidative component of a CDC
reaction, which would proceed by nucleophilic addition to OQ (Fig. 2A).10-14, 30-34 Following
re-aromatization, this would afford substituted catechol (sCAT), which is the formal product
of CDC coupling. In cases where sCAT is more electron rich than CAT, redox exchange
between sCAT and OQ proceeds quickly (e.g. second order rate constants in excess of 106
M1s1).35-37 Since this is often faster than nucleophilic attack onto OQ, many addition reactions
consume excess OQ to provide the more highly substituted quinone product (sOQ) along with
reduced starting material (i.e. CAT). In our own experience, OQ functionalization under these
conditions are low yielding. For example, the base promoted cyclization of acetamide 1 affords
a mixture of products with a ~25% loss of mass balance that results from competitive redox
exchange between 1 and 2 (Fig. 2B).36 Likewise, the addition of magnesium phenolate 5 to
ortho-quinone (6) under the conditions of Barrow consumes excess 6 to provide only a 43%
yield of 7, following redox exchange between 8 and 6.38 Finally, a bio-catalytic aerobic CDC
reaction of 1,3-di-carbonyl 9 and catechol (10) mediated by a laccase was reported by Beifuss
(Fig. 2D).32 Catechol 11 is produced in a high yield of 76% by a proposed sequence of
successive C-C and C-O bond formations. It appears that the enzyme plays an important role
in limiting the formation of any semi-quinone radicals, but mechanistic details have not been
reported.
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Figure 2. (A) Synthetically practiced catechol oxidations employ strong oxidants. The resulting CDC reactions with
nucleophiles are complicated by competitive redox exchange between sCAT and OQ. (B) Base mediated
cyclization of acetanilide 1 is complicated by competitive redox exchange of 1 and 2. (C) The nucleophilic addition
of magnesium phenolate 5 to 6 consumes excess 6. (D) The bio-catalyzed catalytic aerobic CDC reaction of
catechols and 1,3-dicarbonyls.
As part of a general program in aerobic Cu-catalysis,39-44 we became interested in CDC
reactions of catechols, and the potential role that metals could play in controlling their
selectivity. In previous work, we reported an aerobic oxygenation of phenols, in which we had
observed high selectivity for coupled ortho-quinone 17 (Fig. 3A).45 It is interesting that two
new C-O bonds form in this process. The first is a well-known oxygenation of 13 via 14 to
afford 16, following a mechanism of atom transfer that mimics aspects of the enzyme
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tyrosinase.46 The second C-O bond formation, which installs the aryl ether, is less common.47-
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Under oxidizing conditions, phenols favor C-C instead of C-O bond formation.7, 50 This
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reflects their ease of oxidation to the phenoxyl radical, and the significant spin density that
localizes on the less electronegative and more abundant carbon atoms.51 C-O bond formation
has been attributed to metal coordination, most notably by Hay, to explain the selectivity of the
Cu-catalyzed aerobic polymerization of phenols to (poly)phenylene ethers.52-54 This lead us to
consider an oxidative coupling between semi-quinone radical 15 and phenolate 16, as a means
of explaining the formation of 17 under the oxidizing conditions.
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Figure 3. (A) Previous work on the oxygenative coupling of phenols. (B) Previous work on the catalytic aerobic
CDC reaction of phenols and ortho-quinones. (C) This Work: a proposal for the catalytic aerobic CDC reaction of
phenols and catechols.
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Interested in the potential value of this aryl ether synthesis, but unable to extend our initial
conditions to a cross coupling, we investigated an alternative CDC reaction between phenols
and ortho-quinones (Fig. 3B).29 These conditions take advantage of a well-known redox
process between Cu-(I) and ortho-quinones to produce semi-quinone radical 19. A similar
mechanism of C-O bond formation with phenolate 16 could then provide quinone 20 as the
product of cross coupling. While pleased about the improved versatility of this process, we
were cognizant of certain drawbacks presented by the use of ortho-quinones. Because of their
instability, ortho-quinones have limited commercial availability,55 they are incompatible with
many common functional groups, and, as discussed above, they are most commonly
synthesized by oxidation of the corresponding catechol using a synthetic oxidant. Consequently,
a more efficient coupling reaction would unite the corresponding catechol with a phenol (Fig.
3C). This would replace a stoichiometric oxidation with a catalytic aerobic alternative, while
also improving the commercial availability of the coupling partner.
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A catechol-phenol cross coupling presents several challenges that are not present in the polarity
matched coupling of phenols and ortho-quinones. First, catechols and ortho-quinones are
related by a 2 e | 2 H+ redox couple that requires a distinct oxidative mechanism in order to
form the key semi-quinone radical 23 (Fig. 3C). While we anticipated 1 e oxidation of Cu-
(II)-catecholate 22 to be most straightforward, we also recognized the challenges of forming
an electrophilic semi-quinone radical (e.g. 23) under standard catalytic conditions. This would
create an inevitable competition between homo versus cross coupling, which ultimately
requires preferential bond formation with phenolate 16 in the presence of catecholate 22. A
second difference relates to the equilibrium between free and metal-bound quinone 18. This
was not a complication in the quinone-phenol cross coupling, where the dissociation of 19
simply regenerated starting material (Fig. 3B). However, in a phenol-catechol cross coupling,
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dissociation of quinone 18 from semi-quinone radical 23 would create the possibility for
conproportionation with the starting catechol 21, as discussed in Fig. 1C.
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Herein, we describe our efforts to address these challenges, and report conditions for a selective
catalytic aerobic CDC of phenols and catechols that is selective for C-O bond formation. The
reaction employs simple, commercially available components, proceeds within minutes at
room temperature, and exhibits a relatively broad substrate scope. This includes the late-stage
installation of (S, S)-thalicarpine’s diaryl ether, which benchmarks the efficiency of our new
conditions relative to more traditional alternatives. The aerobic oxidation of phenols and
catechols is a versatile, but underutilized transformation.44 We hope that our work provides a
useful approach to address certain challenges of selectivity, which have historically limited its
utility.
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Results and Discussion
At the outset of our work, we investigated the oxidative coupling of guaiacol (25) and 4-methyl-
catechol (26) to coupled ortho-quinone 27 (Scheme 1). To bias the equilibrium towards Cu-(II)
complexes 28 and 29, we employed excess CuCl2 (4 equiv) and 4-methoxy-pyridine (4-MeO-
Py) (8 equiv). The reaction mixture, including CH2Cl2 and 4 Å molecular sieves (4 Å MS) was
assembled under an inert atmosphere of N2, before purging the headspace with O2 and applying
a pressure of 1.2 atm. This triggered an immediate and pronounced darkening of the reaction
mixture, which persisted for the duration of oxygenation (30 min). Aqueous acidic work-up
delivered 27 in 73% NMR yield without observation of other products (entry 1). Consumption
of catechol 26 was complete, whereas trace quantities of guaiacol (25) remained (~5 % by 1H-
NMR). This encouraging result appeared to support our mechanistic hypothesis. Because of
their considerably lower oxidation potentials (Eox ~ 1V),56-57 a catecholate Cu-(II) complex
should oxidize in preference to a phenolate Cu-II complex. In our case, this would selectively
invert the polarity of 29 to electrophilic 30, while retaining the nucleophilicity of 28. C-O
coupling should then proceed, by analogy to our previous work (Fig. 3A-B).
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OH
Me
O
CuCl2
OH
O
(4 equiv)
O
2 (1.2 atm)
OH
MeO
4 Å M.S.
CH2Cl2, rt
O
OMe
N
OMe
Me
25
26
)
guaiacol (
(1 equiv)
)
4-Me-catechol (
(1 equiv)
27
(73% yield)
4-MeO-Py
(8 equiv)
9
Oxidation # 2
1 H+ | 3 e
3 HX
3 HX
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Oxidation # 1
1 e
O
Cu Ln
O
O
Cu Ln
O
O
O
O
Cu
Ln
X
O
Cu
Ln
X
Me
Me
Me
Me
28
29
28
30
polarity reversal
nucleophile
electrophile
Consumption (%)
Yield (%)
Stoichiometric Conditions
CuCl2 (4 equiv.) | 4-MeO-Py (8 equiv.)
Entry
1
25
26
27
Pre-mix reagents, then add O2 (1 atm) fo 30 min
95
100
73
Change to reaction conditions:
2
3
No O2
30
61
100
100
6
No O2, use Cu(OAc)2
19
Me
Py
Cl
O
O
Cl
4
No O2, use
with 4-MeO-Py
58
100
42
Cu
Cu
Py
Me
31
sparge with
N2
O2
then add
CuCl
4-MeO-Py
5
6
100
100
100
100
56
93
solution of
25
26
and
30 min
N2
O2
then add
CuCl
solution of
4-MeO-Py
25
26
and
30 min
30 min
Scheme 1. Mechanistic proposal for the oxidative coupling of 26 and 27 in the presence of stoichiometric amounts
of CuCl2.
To improve selectivity, we evaluated the effect of changing the oxidant (Scheme 1, entries 2-
6). Under otherwise identical conditions, maintaining the N2 atmosphere and omitting O2
affords quinone 27 in only 6% NMR yield at complete consumption of catechol 26 and 30%
consumption of guaiacol (25) (entry 2). No other discernable products were isolated, and we
attribute poor mass balance to the polymerization of catechol 26, and to a lesser extent, guaiacol
(25). It is important to note that with 4 equivalents of Cu(II), there is sufficient oxidizing
capacity to produce 27 in the absence of O2. Recognizing that radical polymerization could
initiate from outer sphere oxidation, we evaluated Cu salts with more basic counter anions,
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with the goal of driving ligand exchange towards Cu-II complexes 28 and 29. Consistent with
this hypothesis, the yield of 27 improved to 19% when we employed Cu(OAc)2 (entry 3) and
42% when we employed bridged methoxy-chloride complex 31 (entry 4). Demmin and Rojic
first described complex 31 in the 1970s,58-59 along with its preparation by aerobic oxidation of
CuCl and pyridine (Py) in methanol. The same authors also demonstrated that a similar
oxidation of CuCl, but in aprotic solvents, afforded a Brønsted basic Cu-(II) species, of
undetermined structure.60-63 This led us to generate a similar Cu-(II) reagent in situ, by applying
1.2 atm of O2 to a solution of CuCl (4 equiv) and 4-MeO-Py (8 equiv) in CH2Cl2 possessing
molecular sieves (entry 5). After 30 min, we discontinued oxygenation, and removed O2 by
sparging with N2. To the resulting anaerobic mixture, we added a solution of catechol (26) (1
equiv) and guaiacol (25) (1 equiv), which was then allowed to react for an additional 30 min
under an inert atmosphere of N2. This returned 27 in 56% yield at complete consumption of
both substrates, demonstrating comparable reactivity between complex 31 and the Cu-(II)
oxidant generated in situ from CuCl. While O2 is not required for C-O coupling it is beneficial,
and if instead of sparging with N2, we simply add a 1:1 mixture of the substrates to the Cu-(II)
reagent under an atmosphere of O2 (entry 6), the yield of quinone 27 improves to 93%. To
account for this improvement to selectivity, we believe that aerobic oxidation of CuCl in an
organic solvent produces a Brønsted basic, but not overly oxidizing, Cu-(II)-oxo. We believe
that this species participates in a cleaner ligand exchange with catechol and phenol that
minimizes electron transfer outside of the metal coordination sphere. We also believe that O2
accelerates the oxidation of 29, so that homocoupling between 30 and unoxidized 29 is limited.
This then leaves 30 to react selectively with 28, and provide C-O coupled quinone 27.
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The clean formation of quinone 27 takes an important first step towards a CDC of catechols
and phenols, but extending these conditions to a catalytic alternative presented several
challenges. Under catalytic conditions, Cu-(II) is not present in excess (Scheme 2). This creates
a competition between phenol 25 and catechol 26 for binding to Cu-(II) that should favor the
more thermodynamically favored catecholate complex 29. This creates a problem upon 1 e
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oxidation of 29 to semi-quinone radical 30, since phenolate 28 would not be available for C-O
coupling. Since we would anticipate poor selectivity under these conditions, we were not
surprised to obtain only a 20% yield of 27 after a mixture consisting of CuCl (10 mol%), 4-
MeO-Py (20 mol%), catechol 26 (1 equiv.) and guaiacol (25) (1 equiv.) was oxidized with O2
(1.2 atm) for 1h. We do not recover starting material, and instead observe complex mixtures of
varying solubility.
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LnCuX2
O
Cu Ln
O
OH
OH
(10 mol %)
oxidation in the absence
28
OMe
OH
of
leads to polymerization
Me
Me
4-Me-catechol (26)
25
(1 equiv)
guaiacol (
)
29
(1 equiv)
formed preferentially
O2 (1.2 atm)
O
CuCl (10 mol%)
4-MeO-Py (20 mol%)
O
25
26
)
guaiacol (
(1 equiv)
)
4-Me-catechol (
(1 equiv)
O
CH2Cl2, rt, 1h
OMe
Me
27
25
26
complete consumption of
and
20% yield
Scheme 2. Preliminary attempts to catalyze the CDC of 26 and 27.
This result contrasts the very high levels of selectivity when we used four equivalents of Cu
(Scheme 1), and led us to conclude that a high concentration of Cu-(II) relative to substrate
was an important criterion for selectivity. To maintain this ratio while using only catalytic
amounts of Cu, we considered a slow addition64 of substrate to match the introduction of
catechol and phenol to the rate of a single turnover (Scheme 3). This would ensure a sufficiently
high concentration of free Cu-(II) to coordinate both phenol and catechol, and thus avoid the
coexistence of the electrophilic semi-quinone radical 30 with catechol 26 or catecholate 29.
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Scheme 3. Proposed mechanism for the catalytic aerobic CDC of 26 and 27 using a slow addition to control the
relative concentrations of substrate and the Cu-(II) catalyst.
In practice, slow addition works remarkably well (Scheme 3). At an optimized rate of 0.6 mol
/ sec, the addition of a 1:1 mixture of catechol 26 and guaiacol (25) to a mixture of CuCl (10
mol%), 4-MeO-Py (20 mol%) and molecular sieves held under 1.2 atm of O2, provides a > 95%
yield of quinone 27 (optimal conditions). There is a ~10% decrease in yield when molecular
sieves are omitted (entry 1), and consistent with our hypothesis, the rate of substrate addition
effects selectivity (entries 2 and 3). It is important to maintain a 1:1 ratio of catechol to phenol,
as even slight deviation towards excess catechol leads to decreases in yield (entries 4 and 5).
We observe a less pronounced sensitivity towards the stoichiometry of phenol (entries 6 and
7), suggesting that any pre-equilibrium between the phenol and Cu-(II) is reversible, and easily
displaced towards catecholate 29. Finally, we highlight an important feature of the reaction set-
up that requires oxygenation of the pre-catalyst mixture for 2-3 minutes prior to the addition of
substrate. We believe that this time allows a clean oxidation of CuCl to the unspecified Cu-
(II)-oxo. The lifetime of this in situ generated catalyst is not indefinite, and we observe
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decreased yield if we oxygenate the pre-catalyst mixture for more than 30 min prior to the
addition of substrate (entry 8).
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Because of our interest in forming the diaryl ether of (S, S)-thalicarpine (Scheme 5), we
optimized conditions for a reductive work-up using NaBH4 in MeOH before exploring
substrate scope (Scheme 4). This provides catechol 32 directly, with the new diaryl ether
installed selectively at C4 (product numbering). We have conducted the procedure on scales of
up to 8 mmols, which delivers 1.65 g of diaryl ether 32 in 89% isolated yield.
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Scheme 4. Optimized conditions for the synthesis of diaryl ethers by oxidative coupling / reductive work-up.
This procedure remains selective for phenol itself (Figure 4, Entry 1), as well as a broad range
of ortho-, meta- or para-substituted derivatives. Functional groups sensitive towards oxidation
are tolerated. This includes 1o or 2o alcohols (Entries 8, 21 and 24), a 1o acetamide (Entry 7)
and activated benzylic hydrogen atoms (Entries 9 and 13).65-66 A benzaldehyde is not oxidized
to the corresponding carboxylic acid,65 and is preserved in the reductive work-up by using a
modified protocol consisting of tert-butyl thiol and camphor sulfonic acid. The inclusion of an
aryl bromide demonstrates complementarity with more traditional Ullman-type coupling
reactions (Entry 5), and a boronic ester is tolerated, albeit in a reduced yield (Entry 6). Sterically
encumbered diaryl ethers can be synthesized from the corresponding 3, 5-disubstituted catechol
(Entry 26), and a preference is observed for the less sterically encumbered C5-position of a
non-symmetric 3, 6-di-substituted derivative (Entry 25). Less highly substituted catechols are
also tolerated (Entries 27-31), however, catechol itself is not a viable substrate. Substituents
can include aliphatic groups bearing an ethyl ester, a Boc-protected 1o or 2o amine, or a free
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alcohol (Entries 22-24 and 31). Finally, successful coupling of 3-benzyl catechol demonstrates
compatibility with easily oxidized and enolizable hydrogen atoms (Entry 30) that were not
tolerated under our previous conditions employing ortho-quinones as coupling partners.29
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Figure 4. [a]Reaction performed in CH2Cl2; [b]Reaction performed in CH3CN; [c]Reaction performed in a mixture of
CH2Cl2/CH3CN; [d]Reaction performed on 4.0 mmol scale; [e]Reductive work-up with tBuSH (3 equiv.)/TsOH (3
equiv); [f]Slow addition of 4-Me-catechol to a mixture of estradiol and catalyst.
Having evaluated scope, we turned our efforts to the diaryl ether adjoining the two halves of
(S, S)-thalicarpine (32) (Scheme 5). Interest in this alkaloid peaked in the 1970’s, when it
progressed to phase II clinical trials for the treatment of cancer (Scheme 5A).67 To support
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biological studies, and to confirm the natural product’s structure, Kupchan and co-workers
attempted to synthesize 33 by an Ullman coupling of phenol 34 and bromide 35 (Scheme 5a).
These efforts were not successful, and ultimately required the group to synthesize the biaryl
ether in the early stages of the synthesis from 36 and 37 by nucleophilic aromatic substitution.67
While Kupchan did not have access to more modern variants of the Ullman coupling, recent
work of Opatz and co-workers, in the related total synthesis of (+)-tetramethylmagnolamine
(39), highlight persistent challenges of late-stage diaryl ether synthesis (Scheme 5B).68-70 In
this instance, cross coupling of phenol 38 with aryl bromide 35 using Ma’s di-methyl-glycine
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mediated conditions71 at 160 C in the microwave led to only 50% yield of 39 on relatively
small scale.
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Scheme 5. (A) Previous work towards the synthesis of (S, S)-thalicarpine (33) by Kupchan. (B) Late-stage Ullman
coupling in the Opatz synthesis of (+)-tetramethylmagnolamine (39). (C) This work: total synthesis of 33 by phenol-
catechol cross coupling. (D) Synthesis of thalicarpine analogues via late-stage derivatization of quinone 43.
Conditions: a) MeI, Cs2CO3, DMSO; b) LAH, THF, reflux, 12 h | 74% over two-steps for 33; c) 3-pyroline (44) (1.2
equiv), 4 Å M.S. DCM | 63% for 45; d) 46 (2 equiv), DCM, 40 oC for 40 min, then, 100 oC for 4 h | 60% for 47.
The application of our methodology to a synthesis of thalicarpine requires cross coupling of
aporphine 40 with catechol 41 (Scheme 5C). These are challenging substrates for a number of
reasons. Both contain multiple sites for Cu coordination, aporphine 40 possesses a relatively
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planar biaryl bond that could delocalize spin density to weaken the putative Cu-(II)-
phenolate.42, 72 And there is potential for intramolecular oxidative cyclization of catechol 41 to
form an aporphine.73-76 These challenges notwithstanding, the disconnection simplifies the
natural product into two halves of comparable complexity, which we can prepare on multi-
gram scale in high enantiopurity by capitalizing on Noyori’s asymmetric transfer
hydrogenation77 and Fagnou’s aporphine synthesis78-79 (See Scheme S1 in the Supporting
Information). Catalytic aerobic CDC under our standard conditions provides catechol 42 in 76%
isolated yield, allowing us to complete an 11-step, longest linear sequence that delivers 33 in
20% overall yield. By contrast to Kupchan’s previous work,67 the point of convergence is only
two steps from the end, which allows structural variation of the natural product’s two halves
by fragment coupling (c.f. Entry 32 in Figure 4). The remaining central aromatic ring can be
further diversified from the corresponding ortho-quinone 43 (Scheme 5D), which we can
isolate in 68% yield on gram scale as the immediate product of dehydrogenative coupling. The
two carbonyls of 43 are electronically differentiated as an enone and a vinylogous ester,
allowing selective addition to the more electrophilic C4 carbonyl. Using 3-pyroline (44), redox-
condensation triggers C-sp2 | N-sp2 bond formation,55 and returns N-aryl-pyrrole 45 as a single
regioisomer. Alternatively, coumarin 47 can be prepared as a single regioisomer by C-C bond
formation with stabilized ylide 46,80 providing a synthesis of analogues that capitalizes on the
restoration of aromaticity to drive aromatic C-N and C-C bond formation.81-82
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Conclusion
Catalytic aerobic CDC reactions provide a means of creating molecular complexity with high
atom and step economy.16-18 Despite their efficiency, fundamental challenges of controlling
their selectivity remain.83 In this work, we have described a new approach for promoting cross
coupling between phenols and catechols, which remain particularly difficult substrates for this
class of transformation. Our work takes advantage of Cu-catalysis to both stabilize reactive
intermediates and promote a constructive cross coupling, and also exploits a slow substrate
addition to approximate stoichiometric conditions while only using catalytic quantities of
catalyst. This gives rise to a synthesis of diaryl ethers at room temperature, using inexpensive
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starting materials, and simple, commercially available catalyst components.84-86 We hope that
our work provides a platform from which to increase the use of catechols and phenols in fine
chemical synthesis, since both are available from traditional petroleum and next-generation
renewable feedstocks.87 As such, the current work provides a methodology that can bridge
current and future sources of carbon. This is increasingly important as the field of chemical
synthesis moves to a more sustainable future.
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ASSOCIATED CONTENT
Supporting Information.
The Supporting Information is available free of charge on the ACS Publications website at
Additional information including reagent information; analytical information; experimental
protocols; 1 H and 13C NMR spectra.
AUTHOR INFORMATION
Corresponding Author
* jean-philip.lumb@mcgill.ca
Author Contributions
‡ These Authors Contribute Equally
ACKNOWLEDGMENT
Financial support was provided by the Natural Sciences and Engineering Council (NSERC) of
Canada (Discovery Grant to J.-P. L.); the Fonds de Recherche Quebecois Nature et
Technologies (FRQNT) (Team Grant to J.-P. L.); McGill University Faculty of Science (Milton
Leong Fellowship in Science to Z. H.) the FRQNT Center for Green Chemistry and Catalysis
(Fellowship to X. J.).
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Table of Contents Graphic |
Me
5
6
7
8
N
H
OMe
OMe
O2
OH
MeO
9
OH
OMe
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CuCl (10 mol%)
4-MeO-Py (20 mol%)
O
Me
N
OH
H
OMe
OMe
selective for cross C-O coupling
simple catalyst components
room temperature | 1h
(S,S) thalicarpine
late-stage diaryl ether formation
MeO
OMe
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