Organic Letters
Letter
respective substituted α-naphthols 3af−aj in good yields.
Interestingly, our protocol was also successful in synthesizing
a binaphthol class of compounds. In view of the importance of
such motifs, naphthylacetylene (2m) was treated with β-
ketoesters 1a and 1b using optimized reaction conditions to
obtain 3am and 3bm in good yields (59 and 65%). Alkyl-
substituted α-naphthol motifs exhibit potent biological
activities, and direct synthesis of these compounds is a highly
challenging task for synthetic chemists. We therefore planned
to explore our method to synthesize such naphthols by
replacing the aromatic terminal alkynes with aliphatic terminal
alkynes (2n−s). When aliphatic acetylenes 2n−s were treated
with β-ketoesters 1a and 1b, the corresponding aliphatic α-
naphthols 3an and 3bo−br and cyclohexyl-containing naphthol
3bs were obtained in good to excellent yields in a single step
(Scheme 3). Mono- (1b and 1e), di- (1h), and trisubstituted β-
ketoesters (1i) gave α-naphthols (3bd, 3bg, 3bi, 3bm, 3bt, 3ed,
3ha, 3id, 3ij, and 3ii) in good yields (51%−73%) upon reaction
with various substituted alkynes (2a, 2d, 2g, 2i, 2m, and 2t).
Further, we studied the scope of 1,2-diarylalkynes, which
could give 3,4-diaryl-α-naphthol derivatives. When we
attempted a reaction with diphenylacetylene, unfortunately,
the starting material was isolated as such, and no traces of
product were detected. Considering the inertness of the
diarylacetylene, we picked up an activated internal alkyne, i.e.,
ethyl phenylpropiolate. Delightedly, the reaction of 1a with 2u
not only proceeded smoothly but also furnished the 1,2,3,4-
tetrasubstituted highly functionalized naphthalene 3au in 64%
yield with high regioselectivity. The interesting regioselectivity
prompted us to pave a pathway toward the construction of the
arylnaphthalene lignan natural products 4−6. Before attempt-
ing the synthesis of lignan natural products (4−6), we
evaluated the generality of this new protocol with different β-
ketoesters (1a,b,d−j) and a few aryl propiolates (2u−w), which
led to the generation of a 4-aryl-1-naphthol skeleton (3au, 3av,
3bu, 3bv, 3du, 3eu, 3ev, 3gw, 3hw, and 3iu) and a 4-aryl-1-
anthracenol skeleton (3jv) having two consecutive ester
functionalities with excellent regioselectivity (Scheme 4).
Moderate yields of the products in a few cases were due to
the competitive homo-dimerization of β-ketoesters (5−10%).
The structure of compound 3av was unambiguously confirmed
by single-crystal X-ray analysis.
Our literature search indicated that Ag(I) and the persulfate
system follows the reaction through the radical pathway.10 To
verify whether the present method is also yielding the product
via a radical mechanism, we conducted a few control
experiments (see the Supporting Information) in the presence
of radical scavengers such as TEMPO (2,2,6,6-tetramethylpi-
peridin-1-yloxy) and BHT (butylated hydroxytoluene). Pro-
gress of the reaction was almost halted from the product
formation indicating involvement of radical intermediates,
which is in line with the literature precedents.
On the basis of control experiments and previous reports,10
we proposed a possible reaction pathway as shown in Scheme
5. Initially, in the presence of silver(I) salts, persulfate anion
Scheme 5. Possible Reaction Pathway for the Construction
of Polysubstituted Arylnaphthols
disproportionates into the sulfate dianion and sulfate radical
anion to produce active Ag(II) species. This Ag(II) oxidizes
substrate 1a to generate the highly stabilized radical A,10b which
on subsequent addition to the alkyne (2a) furnishes the vinyl
radical B. Selective formation of B may probably be due to the
stabilization of radical by tethered aryl/alkyl groups.11 Intra-
molecular cyclization of B produces the cyclic radial
intermediate C, which might be immediately converted to D
followed by aromatization (enol formation) to furnish the
desired product.
Scheme 4. Substrate Scope of Propiolates for the Synthesis
of Poly Substituted Arylnaphthol Derivatives
To show the potential application of the current method, we
embarked on the synthesis of biologically significant arylnaph-
thalene containing lignan natural products12 such as diphyllin
(4), taiwanin E (5), and justicidin A (6). Diphyllin (4) was
isolated from many traditional medicinal plants.13 Taiwanin E
(5) and justicidin A (6) were isolated from the heartwood of
the Japanese trees Taiwania cryptomerioides (Taxodiaceae)14
and Justicia ciliata,15 respectively. Very limited approaches
appeared in the literature for synthesis of these natural products
(4−6)16 using multiple steps and several linear functional
group transformations. Our retrosynthetic analysis indicated
that lignan natural products 4 and 5 can be synthesized in two
steps and 6 in three steps by applying our protocol (see the
Supporting Information).
To test our hypothesis, diphyllin synthesis was initiated by
carrying out a reaction with ethyl 3-(3,4-dimethoxyphenyl)-3-
C
Org. Lett. XXXX, XXX, XXX−XXX