A facile access to 4-substituted-2-naphthols via a tandem Friedel-Crafts reaction: A β-chlorovinyl ketone pathway

Article abstract of DOI:10.1021/ol502951v

A one-pot synthesis of 2-naphthol derivatives is accomplished using a tandem Friedel-Crafts reaction sequence. The developed methodology allows for a concomitant construction of up to three C-C bonds between readily available alkynes and phenylacetyl chloride derivatives by an intermolecular Friedel-Crafts acylation of alkynes followed by an intramolecular Friedel-Crafts alkylation of β-chlorovinyl ketone intermediates.

Full text of DOI:10.1021/ol502951v

Letter
pubs.acs.org/OrgLett
A Facile Access to 4‑Substituted-2-naphthols via a Tandem Friedel−
Crafts Reaction: A β‑Chlorovinyl Ketone Pathway
Hun Young Kim and Kyungsoo Oh*
College of Pharmacy, Chung-Ang University, 84 Heukseok-ro, Dongjak, Seoul 156-756, Republic of Korea
S
* Supporting Information
ABSTRACT: A one-pot synthesis of 2-naphthol derivatives is
accomplished using a tandem Friedel−Crafts reaction
sequence. The developed methodology allows for a con-
comitant construction of up to three C−C bonds between
readily available alkynes and phenylacetyl chloride derivatives
by an intermolecular Friedel−Crafts acylation of alkynes
followed by an intramolecular Friedel−Crafts alkylation of β-
chlorovinyl ketone intermediates.
β-Chlorovinyl ketones are a class of versatile building blocks,
serving as immediate synthetic precursors to various hetero-
cycles such as furans, pyrazoles, and pyridines (Scheme 1).1
derivatives;11 however, these reaction protocols concomitantly
introduce an extra substituent at the 3-position. Recently, the
group of Kozlowski reported an optimized protocol for the
synthesis of 2-naphthol derivatives that possess a hydroxyl
group at the 4-position and an ester moiety at the 3-position
during the total synthesis of perylenequinone natural
products.12 While the introduction of a methyl group at the
4-position of 2-naphthols was recently accomplished by the
group of Feng using a series of palladium-catalyzed Stille
coupling and Heck reactions, this method does not allow the
introduction of other alkyl and aryl substituents at the 4-
position.13 A recent study by the group of Okuma overcame the
synthetic limitation of Feng’s protocol by using the reactions of
benzyne with 1,3-diketones followed by an intramolecular aldol
condensation.14 However, the Okuma’s protocol exhibits
modest regioselectivities over the formation of 1-naphthols
(1-naphthol/2-naphthol = 2:1 to 1:4) and is limited to the
introduction of an aryl group at the 4-position of 2-naphthols.
Motivated by the significant limitations in the preparation of
4-substituted-2-naphthols combined with our strong interests in
the design of multifaceted chiral catalysts such as BINOLs, we
investigated the potential use of β-chlorovinyl ketones as
immediate synthetic precursors to 2-naphthol derivatives.
Previously, we observed the formation of 2-naphthol derivative
4a as a byproduct during the preparation of β-chlorovinyl
ketones 3a using the Friedel−Crafts alkylation of alkynes with
phenylacetyl chloride 2a (Scheme 2). While the reaction at 0
°C resulted in the preferential formation of a 4:1 mixture of
(E)- and (Z)-β-chlorovinyl ketones 3a, the emergence of 2-
naphthol derivative 4a as a major product was evident upon
increasing the reaction temperature to 23 °C. Thus, a simple
change of reaction temperature led to the exclusive formation of
4-substituted-2-naphthanol 4a in 73% yield. To confirm the
intermediacy of 3a in the subsequent intramolecular Friedel−
Scheme 1. Synthetic Utility of β-Chlorovinyl Ketones and
Proposed Synthetic Route to 2-Naphthols
Our recent mechanistic study revealed that β-chlorovinyl
ketones undergo a facile α-vinyl enolization, leading to
[3]cumulenol and alkynyl enol intermediates under mild base
conditions using Et3N.2 This newly discovered soft α-vinyl
enolization of β-chlorovinyl ketones has sparked a renewed
interest in their potential as latent nucleophiles3 as well as
electrophiles.4 With the aim of further exploiting the synthetic
utility of β-chlorovinyl ketones, we became interested in the
synthesis of 2-naphthol derivatives from β-chlorovinyl ketone
intermediates that are readily available from the Friedel−Crafts
acylation of alkynes.5
The preparation of 2-naphthols is of great importance in
synthetic chemistry, as they are frequently used in the synthesis
of binaphthyl-containing natural products6 and their use in
asymmetric catalysis.7 While the electrophilic aromatic
substitutions of naphthol derivatives could provide a stepwise
introduction of substituents, such methods typically suffer from
lengthy synthetic procedures and result in a mixture of
isomers.8 In particular, the synthesis of 4-substituted 2-
naphthols is not trivial, considering the multistep synthesis of
starting materials that are used in the intramolecular
carbocyclization of alkynyl ketones.9 The electrocyclization of
alkynones10 as well as the [2 + 2] cycloaddition−Dieckmann
condensation of ynolate anions provide access to 2-naphthol
Received: October 6, 2014
© XXXX American Chemical Society
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Letter
Scheme 2. One-Pot Synthesis of 4-Pentyl-2-naphthol
Scheme 3. Scope of the One-Pot Synthesis of Substituted 2-
Naphthols
Crafts alkylation, we subjected a mixture of 3a under the
identical reaction conditions where a clean formation of 2-
naphthol derivative 4a was observed (3a and 4a).15 The use of
two commercially available starting materials, alkyne and
phenylacetyl chloride, is a significant advantage from the
synthetic point of view, in addition to its operational simplicity
(i.e., one pot, short reaction time, and high yielding process).
The one-pot synthesis of 4-substituted-2-naphthols from the
reaction of alkynes and phenylacetyl chloride derivatives is
general. Thus, terminal alkynes with an aliphatic as well as aryl
substituent smoothly underwent the desired cyclization process
to provide 2-naphthol derivatives in good to excellent yields
(Scheme 3).16 In addition, various functional groups were
tolerated under the reaction conditions; however, the use of
trimethylsilyl acetylene resulted in the formation of 3-
(trimethylsilyl)-2-naphthol 4l, 2-naphthol 5, and alkynyl ketone
6 due to the low regioselectivity of the Friedel−Crafts acylation
of trimethylsilyl acetylene. Thus, it is reasonable to assume that
the trimethylsilyl acetylene does not lead to the regioselective
β-chlorovinyl ketone intermediates, the key requirement for
accessing to 4-substituted-2-naphthols, under our Friedel−
Crafts acylation conditions.17 Interestingly, the use of
disubstituted alkynes resulted in the regioselective formation
of 4g, allowing an access to 3,4-disubstituted-2-naphthol due to
the regioselective formation of β-chlorovinyl ketone inter-
mediates.18 The investigation into the electronic effect of
phenylacetyl chloride derivatives revealed low reactivity for the
electron-deficient phenylacetyl chloride derivative (2b, R3 =
Cl). Consistently, the use of an electron-rich phenylacetyl
chloride derivative (2c, R3 = OMe) displayed a fast reaction
rate but led to the formation of a spiro[4.5]decane 7 in 84%
yield.19
a
Use of 2.2 equiv of AlCl3.
Scheme 4. Application to Other Aryl Compounds
The amount of AlCl3 employed in this tandem Friedel−
Crafts reaction sequence can be increased to promote another
C−C bond formation. Thus, the use of 2.5 equiv of AlCl3 on
substrate 1h led to the formation of 2,3-dihydro-1H-phenalene
8 in 80% yield, presumably via the intermediacy of a secondary
carbocation (Scheme 4). Additionally, the synthetic access to
1,1′-bi-2-naphthols from the tandem Friedel−Crafts reaction
sequence can be demonstrated. Thus, quenching the reaction
mixture after complete consumption of phenylacetyl chloride
derivative 2a using water followed by the treatment of the
organic layer with FeCl3 resulted in the formation of BINOL
derivative 9 in 57% yield over a two-step sequence. This
B
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1 h for both stereoisomers. The use of a catalytic amount of AlCl3 (i.e.,
10−40 mol%) is sufficient in inducing the intramolecular Friedel−
Crafts alkylation of (E)/(Z)-β-chlorovinyl ketones at 0−23 °C.
(16) In most cases the intermediacy of β-chlorovinyl ketones has
been confirmed by either NMR monitoring of the reaction mixtures or
isolation of intermediates.
(17) Our effort to isolate β-chlorovinyl ketone intermediates from
the reaction of trimethylsilyl acetylene was not successful. Previously,
Juteau and coworkers at Merck Frost Canada reported the synthesis of
3-(triisopropylsilyl)-2-naphthols under similar reaction conditions
using triisopropylsilyl acetylene; see: Juteau, H.; Gareau, Y.;
Lachance, H. Tetrahedron Lett. 2005, 46, 4547.
(18) The greater stability of the vinylic cation by a phenyl rather than
an alkyl group has been invoked; see: Martens, H.; Janssens, F.;
Hoornaert, G. Tetrahedron 1975, 31, 177.
(19) (a) Haack, R. A.; Beck, K. R. Tetrahedron Lett. 1989, 30, 1605.
(b) Boyle, F. T.; Hares, O.; Matusiak, Z. S.; Li, W.; Whiting, D. A. J.
Chem. Soc., Perkin Trans. 1 1997, 2707.
synthetic route to BINOL derivatives significantly improves
regioselectivity as well as chemical efficiency compared to other
existing synthetic approaches to BINOL derivatives.7
In summary we discovered a tandem Friedel−Crafts reaction
sequence that readily allows the synthesis of substituted 2-
naphthol derivatives through the regioselective formation of β-
chlorovinyl ketone intermediates. While there are a few
commercially available phenylacetyl chloride derivatives, the
utilization of two readily available starting materials greatly
broadens the structural diversity of 2-naphthol derivatives that
might be useful in further synthetic modifications to more
valuable chemical entities. Consequently, we are currently
investigating the synthetic utility of 4-substituted-2-naphthols,
and our results will be reported in due course.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and characterization data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: kyungsoooh@cau.ac.kr.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was made possible by the generous support from
Chung-Ang University (CAU). The authors thank Mr. Jian-
Yuan Li and Mr. Edward Rooney at Indiana University Purdue
University Indianapolis (IUPUI) for their valuable experimental
feedback.
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C
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