Mild and rapid method for the generation of ortho -(naphtho)quinone methide intermediates

Article abstract of DOI:10.1021/ol203196n

A new mild method has been devised for generating o-(naphtho)quinone methides via fluoride-induced desilylation of silyl derivatives of o-hydroxybenzyl(or 1-naphthylmethyl) nitrate. The reactive o-(naphtho)quinone methide intermediates were trapped by C,

Full text of DOI:10.1021/ol203196n

ORGANIC
LETTERS
2012
Vol. 14, No. 2
584–587
Mild and Rapid Method for the Generation
of ortho-(Naphtho)quinone Methide
Intermediates
Abdul kadar Shaikh,† Alexander J. A. Cobb,‡ and George Varvounis*,†
Department of Chemistry, University of Ioannina, Section of Organic Chemistry and
Biochemistry, 451 10 Ioannina, Greece, and School of Pharmacy, University of Reading,
Whiteknights, Reading RG6 6AD, U.K.
gvarvoun@cc.uoi.gr
Received November 30, 2011
ABSTRACT
A new mild method has been devised for generating o-(naphtho)quinone methides via fluoride-induced desilylation of silyl derivatives of
o-hydroxybenzyl(or 1-naphthylmethyl) nitrate. The reactive o-(naphtho)quinone methide intermediates were trapped by C, O, N, and S
nucleophiles and underwent “inverse electron-demand” hetero-DielsÀAlder reaction with dienophiles to give stable adducts. The method has
useful potential application in natural product synthesis and drug research.
Short-lived, highly reactive, ortho-quinone methide
(o-QM) species are generated in situ by a large variety of
syntheticmethods. Whenthese intermediatesare produced
in the absence of other reagents they form dimers and
trimers; otherwise, they undergo 1,4-conjugate addition
with nucleophiles as well as DielsÀAlder cycloadditions
with various dienophiles.1a,b o-QMs have been used for the
synthesis of several natural products1c,d and are the cyto-
toxins responsible for the effect of some antitumor drugs,
antibiotics,1e and DNA alkylators.1a,f A recent example of
o-QM application in drug chemistry is the hybrid drug
NO-ASA1g (Figure 1). The main synthetic methods of
generating o-QMs are by tautomerization; oxidative, ther-
mal, or photochemical initiation; using acid or base cata-
lysis; and olefination of o-quinones, as described in a
review by Van de Water and Pettus.1h Since that time photo-
chemical excitation has been the most frequently used
method to generate o-QMs.1iÀk Suitable precursors for
generating o-QMs thermally are 2-hydroxy benzyl acet-
ates,2aÀd N,N-dialkyl-9-aminomethyl-10-phenanthrols,
and their naphthalene analogues1q and methyl-4H-1,2-
benzoxazine-3-carboxylates.2e,f o-QMs can also be gener-
ated from either chemical or enzymatic oxidation of 3-(4-
hydroxyphenyl)- 4-methyl-2H-chromen-7-ol derivatives,2g
from Lewis acid catalyzed dehydration of o-hydroxyl
benzyl alcohols,2d or from the Lewis acid cleavage of
the MOM group of 2-(methoxymethoxy)benzyl aceta-
tes.2h Strong bases and weak nucleophiles generate
o-QMs equally well from appropriate precursors.
† Department of Chemistry, University of Ioannina.
‡ School of Pharmacy, University of Reading.
Figure 1. Structure of hybrid drug NO-ASA.
r
10.1021/ol203196n
Published on Web 01/10/2012
2012 American Chemical Society

Recent examples include the treatment of o-hydroxy-
benzyl acetate with isopropylmagesium chloride,3a the
reaction of [trialkyl(or triaryl)silylmethyl]-1,4-benzoqui-
nones with oxygen nucleophiles,3b fluoride induced
desilylation of silyl derivatives of o-hydroxybenzyl
acetates1r and -benzyl iodides,3c and the base catalyzed
or sodium dithionite reduction of (2-hydroxy-1-phenyl)-
methyltrimethylammonium iodides.3d Less popular
methods for o-QM generation involve the use of metal
complexes such as the selective alkyl deprotonation of
oxo-dienyl rhodium complexes {Cp*Rh[η5-(MeC5H4O
or i-PrC5H4O)][BF4]} by base to give rhodiumÀo-QM
complexes {Cp*Rh[η4-(C7H6O or Me2C7H4O)]}.3e
Considering the importance of o-QMs as active inter-
mediates in many biological processes and in drugs, we
became interested in developing a mild and efficient meth-
od for o-QM production that would be useful in drug
research. We therefore present a novel fluoride-induced
desilylation of nitrate esters 4a,b and 8 (Schemes 1, 3)
leading to o-QMs or o-naphthoquinone methides that are
thentrappedby a rangeof nucleophiles or dienophiles. The
starting materials used to synthesize nitrate esters 4a,b are
the commercially available 2-hydroxybenzaldehyde (1a)
and 2-hydroxy-1-napthaldehyde (1b) (Scheme 1). In the
first step of this synthesis, the hydroxy group of 1a,b
undergoes protection using tert-butyldimethylsilyl chlo-
ride (TBSCl), DMAP, and NEt3 in dichloromethane, to
yield the silyl ethers 2a,b. The silyl ethers were then reduced
using NaBH4 in methanol to give the alcohols 3a,b. The
alcohol derivatives were then reacted with AgNO3 and
SOCl2 to afford the desired nitrate esters 4a,b in 55 and
63% yields, respectively. In order to test the viability of
the aforementioned method of in situ o-QM generation,
Michael addition was the first reaction chosen to trap these
intermediates. Thus the nitrate ester 4a (Table 1) was
dissolved in dry THF under an argon atmosphere, the
temperature was lowered to À78 °C, and then the appro-
priate nucleophile (RH) was added followed by dropwise
addition of TBAF. The reaction is postulated to proceed
by attack of the fluoride anion onto the silyl ether, break-
age of the SiÀO bond, and elimination of a nitrate anion
to generate the corresponding o-QM in situ. The latter is
then trapped by different C, O, S, and N nucleophiles to
generate Michael addition products 5aÀm. The type of
nucleophiles used, the products, and the yields obtained
are shown in Table 1.
Scheme 1. Synthesis of 2-(tert-Butyldimethylsilyloxy)benzyl
Nitrate 4a and (2-{[tert-Butyl(dimethyl)silyl]oxy}-1-naphthyl)-
methyl Nitrate 4b
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The ability of a dienophile to react with the in situ
generated o-QM was explored next. The nitrate ester 4a
(Scheme 2) was dissolved in dry THF under an argon
atmosphere, the temperature was lowered to À78 °C, and
then a 100-fold excess of the appropriate dienophile, ethyl
vinyl ether (EVE), or ethyl vinyl sulfide was added fol-
lowed by dropwise addition of TBAF. The o-QM gener-
ated in this reaction acts as a heterodiene which reacts with
the respective dienophile and undergoes “inverse electron-
demand” hetero-DielsÀAlder reaction to yield the corre-
sponding chromanes 6a,b in 20 and 17% yields, respec-
tively. The low yield of these reactions may be accounted
for by the competing facile trimerization of the very
reactive o-QM. The insoluble material from the reaction
mixtures of 6a,b was recrystallized from acetone, and the
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Org. Lett., Vol. 14, No. 2, 2012
585

Since an electron-donating substituent on the o-QM would
increase the net nucleophilicity of the heterodiene and hence
encourage an “inverse electron-demand” hetero-DielsÀAlder
reaction, nitro ester 8(Scheme 3) was chosen as a substrate for
this purpose and synthesized from known alcohol 7.3c
Table 1. Michael Addition of C, O, S, and N Nucleophiles to the
in Situ Generated o-QM
Scheme 3. Synthesis of 5-(Benzyloxy)-2-(tert-butyldimethyl-
silyloxy)benzyl Nitrate 8 and Its Hetero-DielsÀAlder Reaction
with EVE and Ethyl Vinyl Sulfide
Compound 8 was reacted with a 100-fold excess of ethyl
vinyl ether or ethyl vinyl sulfide, in the same way as
described for compound 4a, to give chromanes 9a and 9b
in 84 and 74% yields, respectively. The high yields of
compounds 9a and 9b compared to the low yields of the
corresponding compounds 6a and 6b reflect the more
efficient cycloaddition reaction between the electron-poor
heterodiene and electron-rich dienophiles.
The applicability of this reaction was next tested with
naphthylmethyl nitrate 4b as a substrate (Scheme 4).
Again, using the reaction conditions applied to the ester
4a, ester 4b was reacted with thiophenol or 4-methoxyaniline
in dry THF under argon at À78 °C and TBAF to afford
Michael addition products 10a and 10b in 75 and 47% yields,
respectively. Once again, this is assumed to occur, via the in
situ generation of the o-naphthoquinonemethide.
a Isolated yields. b 18-crown-6 was added as a catalyst. c Instead of
using THF as a solvent, methanol and isopropanol were used. d Sodium
hydride was used to generate the carbanion from diethyl malonate.
melting point was found tobe the same asthat of the trimer
reported by Cavitt et al.4a and confirmed later by Mao and
Boekelheide.4b
Scheme 4. Michael Addition of Thiophenol and 4-Methoxy
Aniline to the in Situ Generated o-Naphthoquinone Methide
Scheme 2. Hetero DielsÀAlder Reaction of the in Situ Gener-
ated o-QM with EVE and Ethyl Vinyl Sulfide
586
Org. Lett., Vol. 14, No. 2, 2012

Indeed when the reaction of compound 4b was repeated
in the absence of a dienophile in THF, with dropwise
addition of TBAF, the transient o-naphthoquinone
methide underwent diene-dienophile cycloaddition to give
the spiro dimer 11 (Scheme 5) in 40% yield. The absence of
the trimerization product in this reaction is presumably
because the benzene ring of the naphthalen-2(1H)-one 11
blocks the γ- and δ-carbons of the cyclohexa-2,4-dien-1-
one ring and stops further diene-dienophile cycloaddition,
as in the case of the dimer derived from o-QM. Further-
more, applying the reaction conditions of compound 4b
used for the Michael additions but substituting the nucleo-
philes for EVE lead to a hetero-DielsÀAlder reaction
occurring with the transient o-naphthoquinone methide
to give 3-ethoxy-2,3-dihydro-1H-benzo[f]chromene 12, in
23% yield (Scheme 5).
intermediacyofo-(naphtho)quinone methides in the afore-
mentioned reactions.
Scheme 6. Substitution Reaction of a Nitrate Anion in 4a by
Pyrrolidine
In conclusion, we have presented a new method of
producing o-(naphtho)quinone methides from benzo
and naphtho precursors bearing methylnitrate and tert-
butyldimethylsilyloxy substituents at adjacent positions
of the aromatic ring. The method of o-(naphtho)quinone
methide generation involves fluoride anion nucleophilic
cleavage of the silyloxy σ-bond by n-tetrabutylammonium
fluoride followed by concomitant elimination of a nitrate
anion. The intermediate o-(naphtho)quinone methides
were trapped by nucleophiles and dienophiles showing
the wide applicability of this method.
Scheme 5. Hetero-DielsÀAlder Reaction of in Situ Generated
o-Naphthoquinone Methide by Dimerization and with EVE
Acknowledgment. We thank the State Scholarship
Foundation (I.K.Y.) of Greece (for a studentship to A.
K.S., Grant No. 1210) for support. We appreciate the use
of NMR and mass spectrometry facilities funded by the
Network of Research Supporting Laboratories of the
University of Ioannina and thank Dr. V. Exarchou and
Dr. P. Stathopoulos of the University of Ioannina for 2D
NMR spectra and mass spectra, respectively.
Finally, reaction of nitrate ester 4a with pyrrolidine
(Scheme 6) at À78 °C in THF for 6 h did not produce
any product that could be detected by TLC. However,
heating the reaction mixture for 24 h afforded compound
13 where nucleophilic substitution of nitrate by pyrrolidine
had occurred. This reaction confirms beyond doubt the
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Org. Lett., Vol. 14, No. 2, 2012
587