Asymmetric Oxidative Coupling of Phenols and Hydroxycarbazoles

Article abstract of DOI:10.1021/acs.orglett.7b02552

The first examples of asymmetric oxidative coupling of simple phenols and 2-hydroxycarbazoles are outlined. Generation of a more vanadium catalyst by ligand design and by addition of an exogenous Br?nsted or Lewis acid was found to be key to coupling the more oxidatively resistant phenols. The resultant vanadium complex is both more Lewis acidic and more strongly oxidizing. Good to excellent levels of enantioselectivity could be obtained, and simple trituration readily provided the products with ≥95% ee.

Full text of DOI:10.1021/acs.orglett.7b02552

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
Asymmetric Oxidative Coupling of Phenols and Hydroxycarbazoles
Houng Kang, Young Eun Lee, Peddiahgari Vasu Govardhana Reddy, Sangeeta Dey, Scott E. Allen,
Kyle A. Niederer, Paul Sung, Kirsten Hewitt, Carilyn Torruellas, Madison R. Herling,
and Marisa C. Kozlowski*
Department of Chemistry, Roy and Diana Vagelos Laboratories, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United
States
S
* Supporting Information
ABSTRACT: The first examples of asymmetric oxidative coupling of simple phenols and 2-hydroxycarbazoles are outlined.
Generation of a more vanadium catalyst by ligand design and by addition of an exogenous Brønsted or Lewis acid was found to
be key to coupling the more oxidatively resistant phenols. The resultant vanadium complex is both more Lewis acidic and more
strongly oxidizing. Good to excellent levels of enantioselectivity could be obtained, and simple trituration readily provided the
products with ≥95% ee.
he axial chiral biaryl motif is found in many natural products
(Scheme 1)1 as well as in structures important in catalysis
Scheme 2. Phenol vs Naphthol Coupling
T
Scheme 1. Examples of Chiral Biphenols and Binaphthols
such as 1,1′-binaphthol.2 Approaches involving redox-neutral
cross-couplings, in particular Suzuki couplings, have been
successful for a range of binaphthyl and biphenyl structures
with some limitations on structure.3−5 Over the past 25 years,
oxidative asymmetric catalysis has been successful in generating
enantioenriched binaphthol structures by means of Cu,6 Ru,7 V,8
and Fe9 catalysts. The absence of any prefunctionalization at the
centers undergoing C−C bond formation confers several
advantages to this latter approach with respect to overall
efficiency.
However, oxidative asymmetric coupling has been noticeably
absent with phenols vs 2-naphthols. The phenol substrate type is
both more difficult to oxidize and subject to oxidative coupling at
a larger number of reactive sites (Scheme 2). The latter feature
can be controlled by appropriate substitution and has been
addressed with a number of catalytic systems particularly with
reference to hetero cross-coupling,10 but the former issue has
proved to be a significant impediment with only one coupling
having been reported (12% yield, 13% ee).11 There are no
reports of highly enantioselective phenol couplings, although
organocatalytic approaches using a preoxidized reaction partner
(quinone or iminoquinone) have been successful.12
Based on the report of vanadyl(IV) acetoacetonate in phenol
coupling,13 we were inspired to use vanadium complexes as they
appear to have the requisite baseline reactivity to catalytically
couple phenols. In addition, the success of chiral vanadium
catalysts in the asymmetric coupling of naphthols (Scheme 3A)8
provides support for use of these architectures in the control of
Received: August 17, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02552
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
performed. Protic acids (see Supporting Information (SI))
resulted in the greatest improvement in terms of reactivity and
selectivity consistent with protonation of the catalyst being
involved. Notably, bases (e.g., Et3N) resulted in a complete loss
of reactivity. Examining concentration, equivalents of acid, and
solvent revealed that 0.5 M in CH2Cl2 or 1,2-dichloroethane
(DCE) with 6.25 equiv of HOAc was optimal with V1 producing
75% of 2a in 60% ee (Figure 1).
Scheme 3. Vanadium Catalysts in Oxidative Coupling
To further improve selectivity, modifications of the catalyst
framework were investigated. Changing the amino acid
substituent did not offer any advantage. Examination of various
dimeric vanadium catalysts with different biaryls and different
linkers resulted in no improvement. Reasoning that a large group
may be all that is needed in the position formerly occupied by the
chiral axis to confer selectivity, a monomeric catalyst with a tert-
butyl substituent at the R2 position was employed (V2) and an
improvement in selectivity was seen (66% ee). A study of various
R1 and R2 groups of the monomer found that a more Lewis
acidic, and hence more strongly oxidizing catalyst (V3), led to
both higher reactivity and higher selectivity (86:0 ortho−ortho/
para−para, 75% ee). When combined with the HOAc additive,
full conversion to only the ortho−ortho adduct was observed and
the enantioselectivity improved to 83% ee.
atroposelective couplings. In this report, we describe how
vanadium catalysts were engineered to create a more reactive
system that also enables control of enantioselectivity in oxidative
phenol coupling (Scheme 3B).14
Beginning with one of the most promising vanadium catalysts
reported in naphthol coupling, V0 (Scheme 3A),8c,d 1a was
examined (eq 1). Mixtures of two products were observed
consisting of ortho−ortho coupled 2a and para−para coupled 3a
(eq 1). Notably, none of the other possibilities (Scheme 2) were
observed.
Examination of a range of phenols (Scheme 4) showed that a
methyl group ortho to the phenol was required with groups that
Scheme 4. Scope of Phenol Couplinga
However, the reaction was irreproducible, which was
attributed to the exact preparation of the catalyst and its
resultant hydration state.8a−i Dried samples were less reactive,
presumably due to formation of oxo-bridged species. Ultimately,
a much more reproducible protocol was developed using
VO(OEt)3 to produce V1.15 With this procedure, 37% ee was
observed for 2a indicating that the catalyst V1 was capable of
controlling the enantioselectivity (Figure 1). However, the
overall reactivity was still poor with 51% of starting material 1a
remaining after 3 days. In addition, both the ortho−ortho and
para−para coupling products were formed at about the same rate
(2a:3a 28%:21%, Figure 1)
Reasoning that deprotonation of the substrate or additional
activation of the catalyst was necessary, a screen of additives was
were smaller (H) or larger (t-Bu) leading to very low or no
selectivity. However, other substrates with an ortho-methyl (1b),
ortho-allyl (1c), or ortho-propyl group (1d) gave similar
selectivities. Notably, one trituration was found to increase the
enantiomeric excess of the filtrate to ≥95% ee. More electron-
rich dioxygenated substrates 1e−1h reacted quickly even at 0 °C.
Screening of additional additives (see SI) revealed that the Lewis
acid LiCl afforded higher selectivies for 1e, 1f, and 1h.
It has been theorized that natural products such as
bismurrayafoline E (Scheme 1) are synthesized biosynthetically
by oxidative coupling.16 With vanadium catalyst V3, the parent
system (4a, R1 = Me, R2 = H, NR3 = NH) underwent unselective
oxidation, likely due to reaction of the amine. Addition of an N-
benzyl substituent gave rise to a rapid, chemoselective oxidative
coupling with V3 (70% ee). Optimization of the vanadium
substituent (see SI) revealed that V4, the isopropoxy analog of
Figure 1. Catalyst evolution in the asymmetric phenol coupling (eq 1).
B
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a
V3, was optimal (Scheme 5, 91% yield, 87% ee). For the N-
substituent, smaller (Me, 71% ee) or larger (i-Pr, 42% ee; 2,4,6-
trimethylbenzyl, 37% ee) groups were deleterious.
Table 1. Control Experiments in Asymmetric Coupling
entry
condition
conversion (%)
1
2
3
4
control
10
0.2 equiv of TEMPO
N2 atmosphere
3
a
Scheme 5. Scope of 2-Hydroxycarbazole Coupling (eq 2)
9 (3 days)
26 (3 days)
50 mol % V3, N2 atmosphere
a
Reaction of 1a with 20 mol % V3, 6.25 equiv HOAc, O2, PhMe, rt, 2
d.
Figure 2. Proposed mechanism.
exchange, and hence reaction, with the phenols. However, the
greatly improved results with acetic acid were puzzling since
naphthol or phenol deprotonation to effect ligation is often
suggested as a first step. In the presence of an excess of acid (6.25
equiv) relative to substrate, such a step seems unlikely under
these conditions. Thus, we propose an additional accelerating
effect of the acetic acid additive (or the LiCl additive) involving
activation of the vanadium complex. Namely protonation of the
vanadium oxy group (or coordination of Li+ in the case of LiCl)
generates a more Lewis acidic species A (Figure 2). The
protonated version of A was observed by mass spectrometry, and
calculations indicate a favorable association of V3 with acetic acid
(see SI). Subsequent associative exchange with phenol would
form adduct B, which was also observed by mass spectrometry.
Protonation also enhances the oxidizing ability of the vanadium-
(V) species. Redox transfer to generate a vanadium(IV) keto
radical C would account for the radical inhibitor results seen.
Coupling via an intermolecular process or, if vanadium
aggregates are formed, via an intramolecular process gives rise
to D, consistent with the nonlinear effects (see SI). Release and
tautomerization lead to product 2a.
a
Reaction conditions: 20 mol % V4, 6.5 equiv of AcOH, O2, 0.5 M
b
chlorobenzene 0 °C, 48 h. Based on recovered starting material.
c
d
Reaction was conducted at −15 °C. HFIP/PhCl as a solvent.
Scheme 5 outlines the scope of the asymmetric oxidative
couplings of N-benzylated-2-hydroxycarbazoles. With an allyl
group adjacent to the phenol, good enantioselectivity was
observed (5c). Electron-withdrawing groups on the distal ring
result in improvements in selectivity (5d−5k, 82−96% ee) with
good levels of conversion (67−87% yield). Electron-donating
groups such as methyl or methoxy result in good reactivity with
moderate selectivity (5l, 5m).
X-ray crystallographic analysis of 2a indicated the (S) absolute
axial configuration was present (eq 3). Circular dichroism
Control experiments with radical inhibitor TEMPO resulted
in a dramatic reduction in conversion (Table 1, entry 1 vs 2). In
the absence of O2, 9% and 26% conversions were observed with
20 and 50 mol % catalyst, respectively. This result indicates that
each vanadium abstracts one electron as would be the case with a
vanadium(V) to vanadium(IV) redox event.
A possible mechanism consistent with these results is outlined
in Figure 2. Water and other protic additives, which were found
to be advantageous, are proposed to prevent aggregation of the
vanadium complexes to forms that were less susceptible to ligand
C
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(2) For a review on asymmetric biaryl formation: Bringmann, G.; Price
Mortimer, A. J.; Keller, P. A.; Gresser, M. J.; Garner, J.; Breuning, M.
Angew. Chem., Int. Ed. 2005, 44, 5384.
measurements (see SI) support the same (S) axial for the
bishydroxycarbazoles. On this basis, a preliminary stereo-
chemical model can be proposed as illustrated in intermediate
C of Figure 2. The phenol coordinates to minimize steric
interactions; namely, the less hindered lone pair of the phenol
coordinates to the vanadium and the less substituted ortho-
position orients closest to the catalyst, placing the larger ortho-
substituent into unoccupied space. Approach of the second
phenol from the face opposite the tert-butyl group then gives rise
to the observed stereochemistry.
In summary, we report the first enantioselective oxidative
coupling of phenols and 2-hydroxycarbazoles to give rise to
adducts not available with alternate approaches.3−5,12 A much
more active vanadium oxidative catalyst was developed capable
of acting on these less reactive substrates to form the axial chiral
dimers efficiently. Less electron-rich ligands were employed
which stabilize the low valent vanadium(IV) and destabilize the
high valent vanadium(V) giving rise to a more potent oxidizing
species. Counterintuitively, the addition of a Brønsted or Lewis
acid was found to accelerate the process, indicating that ligand
exchange of the substrate is not driven by deprotonation of the
phenol. Rather, the Brønsted acid likely activates the vanadium
catalyst enhancing both its oxidizing properties and its ability to
coordinate a neutral phenol. Together, these features should
prove useful in the design of other asymmetric oxidants.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b02552.
(9) (a) Egami, H.; Katsuki, T. J. Am. Chem. Soc. 2009, 131, 6082.
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Experimental procedures for all experiments and charac-
terization data (PDF)
Crystallographic data for 2a (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: marisa@sas.upenn.edu.
ORCID
Marisa C. Kozlowski: 0000-0002-4225-7125
Notes
(11) Takizawa, S.; Katayama, T.; Somei, H.; Asano, Y.; Yoshida, T.;
Kameyama, C.; Rajesh, D.; Onitsuka, K.; Suzuki, T.; Mikami, M.;
Yamataka, H.; Jayaprakash, D.; Sasai, H. Tetrahedron 2008, 64, 3361.
(12) (a) Chen, Y.-H.; Cheng, D.-J.; Zhang, J.; Wang, Y.; Liu, X.-Y.; Tan,
B. J. Am. Chem. Soc. 2015, 137, 15062. (b) Wang, J.-Z.; Zhou, J.; Xu, C.;
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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Sun, H.; Kurti, L.; Xu, Q.-L. J. Am. Chem. Soc. 2016, 138, 5202.
We are grateful to the NIH (GM-112684) and the NSF
(CHE1464778) for financial support of this research. Partial
instrumentation support was provided by the NIH and NSF
(1S10RR023444, 1S10RR022442, CHE 0840438, CHE-
0848460, 1S10OD011980). P.V.G.R. acknowledges the Raman
Fellowship for financial support [F.No.5.102/2016(1c)]. Drs.
Rakesh Kohli and Charles W. Ross III (UPenn) are acknowl-
edged for obtaining HRMS data. We thank Virgil Percec and
Benjamin Partridge (UPenn) for assistance with CD measure-
ments.
̈
(13) Hwang, D. R.; Chen, C. P.; Uang, B. J. Chem. Commun. 1999,
1207.
(14) Parts of this work are described in: (a) Allen, S. E., Studies Toward
the Asymmetric Oxidative Coupling of Phenols. PhD, Univ.
Pennsylvania, 2013. (b) Lee, Y. E. Selective Oxidative Homo and
Cross Coupling of Phenols. PhD, Univ. Pennsylvania, 2016.
(15) Hartung, J.; Drees, S.; Greb, M.; Schmidt, P.; Svoboda, I.; Fuess,
H.; Murso, A.; Stalke, D. Eur. J. Org. Chem. 2003, 2003, 2388.
(16) Racemic coupling of 4a has been reported with para-chloroanil in
modest yield (38%): Knolker, H.-J.; Goesmann, H.; Hofmann, C. Synlett
̈
1996, 1996, 737.
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DOI: 10.1021/acs.orglett.7b02552
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