Directed Remote Lateral Metalation: Highly Substituted 2-Naphthols and BINOLs by In Situ Generation of a Directing Group

Article abstract of DOI:10.1002/anie.201805203

A general synthesis of highly substituted 2-naphthols based on a new carbanionic reaction sequence is demonstrated. The reaction exploits the dual nature of lithium bases consisting of consecutive ring opening of readily available coumarins with either LiNEt₂ or LiNiPr₂ into Z-cinnamamides, thus generating a directing group in situ and allowing, by conformational freedom, a lateral directed remote metalation for ring closure to give the aryl 2-naphthols in good to excellent yields. These transformations can be combined to provide a more efficient one-pot process. Mechanistic insight into the remote lateral metalation step, demonstrating the requirement of Z-cinnamamide, is described. Application of this methodology to the synthesis of highly substituted 3,3′-diaryl BINOL ligands is also reported.

Full text of DOI:10.1002/anie.201805203

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Accepted Article
Title: Directed Remote Lateral Metalation: Highly Substituted 2-
Naphthols and BINOLs by in situ Directing Group Generation
Authors: Victor Snieckus, Matthew Kitching, Marju Laars, Johnathan
Board, Jignesh Patel, and Wei Gan
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201805203
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10.1002/anie.201805203
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Directed Remote Lateral Metalation: Highly Substituted 2-
Naphthols and BINOLs by in situ Directing Group Generation
Jignesh J. Patel,[a] Marju Laars,[a] Wei Gan,[a] Johnathan Board,[a] Matthew O. Kitching[b] and Victor
Snieckus*[a]
In Memoriam Gilbert Stork
Abstract: A general synthesis of highly substituted 2-naphthols
based on a new carbanionic reaction sequence is demonstrated.
The reaction exploits the dual nature of lithium bases consisting of
consecutive ring opening of readily available coumarins with LiNEt2
or LDA to Z-cinnamamides generating a directing group in situ and
allowing, by conformational freedom, a lateral directed remote
metalation - ring closure reaction to give the aryl 2-naphthols in good
to excellent yields. These transformations can be combined to
provide a more efficient one pot process. Mechanistic insight into the
remote lateral metalation step demonstrating the requirement of Z-
cinnamamide is described. Application of this methodology to the
synthesis of highly substituted 3,3’-diaryl BINOL ligands is also
reported.
In the course of our efforts to uncover new directed remote
metalation (DreM) strategies1,2 we required
a
robust
methodology for the synthesis of highly substituted 2-naphthols.
Naphthol structures (Figure 1A) are core components of natural
products,3 dyes and pigments4 and essential building blocks for
dimeric anisotropic BINOLs5 which are widely used as ligands
and catalysts in enantioselective synthesis6 and molecular
recognition.7 Despite this, routes to 2-naphthols are mostly
based on classical annulation and SEAr reactions requiring
multiple isolations and purifications, limiting practical access to
elaborate substitution patterns.8, 9
We proposed to exploit the dual nucleophilic and basic nature of
lithium dialkylamide bases to achieve the synthesis of 2-
naphthols10 3 from coumarins 1 in a single reaction vessel
through a ring transposition process (Figure 1B). In this
transformation, the easily accessible coumarins 1 undergo
nucleophilic attack generating the Z-cinnamamides 2, forming a
new directing group in situ with obligatory retention of
stereochemistry. Compound 2, conformationally liberated,
undergoes bond rotation allowing spatial alignment of the amide
directing group (DMG) with the remote methyl group (2*).
Subsequent chelation of the amide by the lithium dialkylamide,
operative via the Complex Induced Proximity Effect (CIPE),11
serves as a base, promoting a DreM process and generating Li-
2*. The DMG now acts as an electrophile to deliver the 2-
naphthol 3, effecting an O- to C- ring transposition in a single
reaction step.
Figure 1. A) 2-Napthols in natural and bioactive molecules, drugs, and
materials. B) Synthesis of 2-naphthols 3 from coumarins 1 employing a one-
pot ring transposition.
To investigate the proposed transformation, we first sought to
examine each individual step within the sequence separately.
With gram quantities of coumarins 1 available from a modified
Perkin reaction protocol (See SI),12 optimum conditions for ring
opening to the Z-cinnamamides 2 were established (Table 1).13
Treatment of 1 with freshly prepared lithium diethylamide
followed by sequential reaction with NaH and MeI, without
isolation of the intermediate phenols, afforded single
stereoisomeric Z-cinnamamides 2 in good yields (Table 1). The
stereochemistry of Z-cinnamamide 2c was confirmed by NOE
experiments proving the double bond geometry had been
retained (See SI). Careful choice of the lithium dialkylamide was
essential. Whilst LDA proved equally effective as LiNEt2 in a
number of cases (e.g. Table 1 entry 2, 2b vs 2b’), in some cases,
[a]
Dr. J. Patel, Dr. M. Laars, Dr. W. Gan, Dr. J. Board, Prof. V.
Snieckus
Department of Chemistry, Queen’s University, 90 Bader Lane,
Kingston, ON, Canada, K7L 3N6
E-mail: snieckus@chem.queensu.ca
[b]
Dr. M. O. Kitching, Department of Chemistry, Durham University,
South Rd, Durham, United Kingdom, DH1 3LE.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201805203
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Table 1. Synthesis of 2-naphthols 3 from coumarins 1 via Z-cinnamamides 2.
the more basic and sterically encumbered LDA failed to give
useful yields of the cinnamamides (Table 1, entry 3, compare 2c
vs 2c’) leading to LiNEt2 being employed as our standard amide
base throughout. A range of substituted coumarins 1 afforded
the desired Z-cinnamamides 2 in good to excellent yields (52–
96% yield).
The key lateral DreM reaction was then studied on 2 and
optimized conditions using either LDA or LiTMP (1.5–2.0 equiv)
were found to be equally efficient for the conversion into the 2-
naphthols 3. (In some cases, excess LDA or Li-TMP was used,
see SI). Surprisingly, the only system which failed to afford 2-
naphthol
3 was the unsubstituted coumarin 2d’ which
decomposed under the reaction conditions. In all other
examined cases, the lateral DreM reaction proved consistently
robust across a broad substrate scope, tolerating halogen, alkyl,
and aryl substituents on the anisole ring as well as aryl and
heteroaryl cinnamamide double bond substituted systems (2e
and 2n).
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10.1002/anie.201805203
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environments (NMR analysis) and in both experiments, the
burgundy red color which was strikingly evident in the metalation
reaction of isomer Z-2c, was not observed (Scheme 2C). These
results are consistent with the obligatory requirement of the
directing group to facilitate metalation, rather than functioning as
purely a kinetic trap. On the basis of the consistency, within error
tolerance of the isolation procedure,14 of the ratios of starting Z-
and E-cinnamamide mixture Z-2c and E-2c and those of 2-
naphthol 3c and un-cyclized E-cinnamamide E-2c products, it is
evident that the Z- cinnamamide 2c stereochemistry is
necessary to effect the cyclization. Parenthetically, the
conversion of E-2c to the expected thermodynamically more
stable Z-2c is not observed under the excess LDA conditions,
indicating the absence of a potential Michael addition-elimination
reaction as may have been expected based on consideration of
the mechanism of the Baylis-Hillman reaction.15 Thus, initial
LDA-amide coordination to promote the remote lateral
metalation reaction of 2 to 3 following the CIPE concept11
constitutes a significant component of the mechanism of the
reaction.
The 2-naphthol 3 structure immediately evokes its relationship to
the venerable BINOL motif5,6 by way of dimerization. To verify
and to stimulate further investigation, 2-naphthols 3 (Scheme 3)
were subjected to one of the standard oxidative coupling
conditions16 and provided a new series of highly sterically
congested BINOLs 4 in 82–95% yields. Significantly, these
elaborate and densely functionalized molecules are accessible
in only two reaction vessels from the coumarin precursors 3,
demonstrating the power and utility of the methodology. Further
studies in this and other uses of 2-naphthols which are readily
available by this route are in progress.
Scheme 1. One-pot synthesis of 3-aryl-2-naphthols 3 from coumarins 1.
With each step investigated independently and optimized,
attention turned to the unification of these steps into a single
vessel. Thus, sequential treatment of 1 with LiNEt2 and MeI,
followed by a more basic lithium amide (LDA) without isolation of
2, afforded 3 in good to excellent yields. Importantly, in all cases
examined, the yields of this one-pot process were either
comparable (Scheme 1. 3c) or better (Scheme 1. 3d, 3p) than
those of the twostep protocol. As in the two-step process,
metalation proceeded with appearance of a vivid burgundy at
78 °C (Scheme 1, Photo Li-2*) and was complete in short
reaction times (typically 60–90 min) to furnish high yields of
products without isolation of any intermediates.
To gain insight into the mechanism of the reaction, the expected
requirement (based on CIPE considerations)11 of the Z-
stereochemistry of cinnamamide 2 for successful remote lateral
metalation-cyclization to the 2-naphthols 3 was tested (Scheme
2). First, the isolated Z-cinnamamide Z-2c had been shown to
afford product 3c. Examination of the crude reaction mixture
showed only the generation of product, with no E-cinnamamide
1
detected by H NMR (Scheme 2A). To conclusively establish if
Z/E-isomerization of the cinnamamide was possible, additional
metalation studies were conducted. Thus, the 3:1 inseparable
mixture of Z- and E-cinnamamides Z-2c and E-2c, was
subjected to LDA treatment under the standard conditions and
afforded the 2-naphthol 5c and recovered E-2c in 60–65% and
12–15% respectively (Scheme 2B). Furthermore, treatment of
pure E-cinnamamide E-2c under excess LDA conditions
followed by acidic quench resulted in quantitative recovery of the
starting material. Significantly, quenching the solution with
MeOD or d4-MeOH gave starting material without d-
incorporation at any of the potential acidic hydrogen
Scheme 2. Mechanism of the remote lateral metalation reaction of
cinnamamide 2c.
In conclusion, we have developed a general protocol for the
synthesis of highly substituted 2-naphthols
3 which are
unavailable by currently established routes for this class of
aromatics. The disclosed reaction, a directed lateral remote
metalation process assisted by CIPE,11 may be viewed as a
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Scheme 3. Highly substituted BINOL Derivatives 4 from 2-Naphthols 3.
[9]
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heterocyclic to aromatic ring transposition, 13 (Scheme 1) and
thereby may have broader synthetic consequences. Importantly,
by generating the directing group in situ, the one-pot process
becomes more efficient than the multi-step multi-pot
transformation. The availability of the 2-naphthols and BINOLs
as their O-carbamates and triflates invites both DoM and cross
coupling17 chemistry which has already been achieved on 1- and
2-naphthols and related derivatives in our laboratories.18 Overall,
we therefore anticipate application and extension of the remote
lateral metalation concept for the synthesis of new aromatic and
heteroaromatic molecules.
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Acknowledgements
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We are grateful to NSERC for support under the Discovery
Grant program, to Tallinn Technical University for a fellowship to
Marju Laars, the Royal Society for a University Research
Fellowship (M.O.K.) and to Dr. Françoise Sauriol for NMR
expertise.
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Keywords: directed remote metalation • lithiation • coumarin • 2-
naphthol • BINOL • C-H activation
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Thesis, 2009, Queens University, Kingston, ON, Canada.
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Entry for the Table of Contents (Please choose one layout)
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Jignesh J. Patel, Marju Laars, Wei Gan,
Johnathan Board, Matthew O. Kitching
and Victor Snieckus*
Page No. – Page No.
Directed Remote Lateral Metalation:
Highly Substituted 2-Naphthols and
BINOLs by in situ Directing Group
Generation
Text for Table of Contents
The Many Faces of Lithium Bases
A new ring transposition process converting coumarins to 2-napthols in a single flask is reported. A lithium amide first acts as a
nucleophile to open coumarin rings generating a directing group in situ. This conformationally liberated system then undergoes a
directed remote metalation/ring closure reaction to give 2-naphthols in excellent yields. Mechanistic insight demonstrating the
requirement of Z-cinnamamide for the reaction and the synthesis of highly substituted BINOL ligands is also reported.
446/450 characters
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