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C. M. Grombein et al. / Tetrahedron Letters 54 (2013) 6615–6618
Scheme 1. Reagents and conditions: (a) n-BuLi, B(OMe3), THF, À78 °C; (b) 3-
Bromopyridine, Pd(PPh3)4, toluene/ethanol, aq Na2CO3, 90 °C; (c) aq HBr (48%),
reflux; (d) Tf2O, pyridine, DCM, 0 °C; (e) PhSH, i-Pr2NEt, Pd2(dba)3, Xantphos,
dioxane, reflux; (f) PhSH, K2CO3, DMF, 100 °C; (g) m-CPBA, DCM, rt.
substitution, that is, omission of catalyst, change of solvent from
1,4-dioxane to DMF and replacement of DIPEA by K2CO3, resulted
in a new product 5a. ESI-MS showed a mass (m/z) of 329.94
[M+H]+ which was not consistent with the calculated mass of sub-
stitution product 4 (314.42 [M+H]+). Oxidation with one equivalent
of m-CPBA yielded product 6 exhibiting a mass of 346.01 [M+H]+.
The structures of these two compounds were determined by X-
ray diffraction8 with crystals obtained from dichloromethane. It
turned out that the trifluoromethanesulfonyl group was cleaved
to expose the phenol group, while the aromatic proton ortho
to the trifluoromethanesulfonyl group was displaced by the
phenylthio moiety. Other than the desired phenylthio-analogue,
compound 5a (Fig. 1) turns out to be 1-(phenyl-thio)-3-(pyridin-
3-yl)-2-naphthol and compound 6 (Fig. 2) is actually 1-(phen-
ylsulfinyl)-3-(pyridin-3-yl)-2-naphthol. Although the compounds
are different from the originally designed inhibitors, compound 6
showed potent inhibition of human CYP11B2 with an IC50 value
of 33 nM, which is in the range of the lead compounds’ activity.
This interesting unexpected SNAr-reaction provides a novel syn-
thetic approach to 1-arylthio-2-naphthols. Since the reported
methods to synthesize this class of compounds either employed
Figure 2. X-ray structure of compound 6.
explore the influence on the conversion of 3a–5a (Table 1). It
turned out that the use of Et3N, THF, and 1,4-dioxane did not
achieve the reaction, whereas K3PO4 in DMF or NaH in DMSO led
to low yields (22%). In contrast, K2CO3 or NaH in DMF gave similar
high yields (73–79%).
Furthermore, triflate 3a was treated with various thiophenols in
the presence of K2CO3 in DMF (Table 2). Both thiophenols with
electron donating (OMe, entries 2–4) and electron withdrawing
groups (CF3, entries 5–7) resulted in the desired products. Never-
theless, CF3 analogues generally presented higher yields (around
85%) compared to the OMe ones (yields ranging from 34% to
62%). Thiophene-2-thiol, in contrast, only gave a modest yield of
34%. Employment of aliphatic thiols (cyclohexanethiol, entries 9
and 10) or other nucleophiles, such as phenol (entry 11) and ani-
line (entry12) did not yield the desired products. Replacement of
the substituent at the 3-position of the naphthalene core (3-pyri-
dyl) by a bulkier 4-isoquinolinyl (3b, entry 13) or removal of it to
H (3c, entry 15) gave similar yields of around 60% when reacted
with thiophenol. 4-Isoquinolinyl triflate 3b even showed a higher
yield of 71% (entry 14) compared to 3-pyridyl triflate 3a (42%, en-
try 3) when treated with 3-methoxybenzenethiol. However, after
the triflate core was altered to benzene, no reaction occurred
(entry 16). Moreover, using mesylates instead of the corresponding
triflates was also attempted, however, this procedure did not yield
the desired products.
9a
expensive catalyst VO(acac)2 or involved complicated photo-
chemistry,9b our approach is apparently cheaper and easier to han-
dle. More importantly, this approach and the route shown in
Scheme 1 are suitable for the synthesis of 3-aryl substituted
1-phenylthio-2-naphthols, which are rarely reported. The only
example in the literature, to the best of our knowledge, is 3,4-
bis(4-methoxyphenyl)-1-(p-tolylsulfinyl)-2-naphthol10 prepared
via a palladium-catalyzed annulation, which is obviously not
feasible for structural diversification.
A hypothetical mechanism for this atypical nucleophilic substi-
tution reaction is proposed in Scheme 2. Thiophenol was first
Encouraged by these advantages, we further optimized the
reaction conditions and investigated the reaction scope11 before
initiating an extensive synthetic program and subsequent screen-
ing of this new compound class for biological activity. Various
bases (including K2CO3, NaH, K3PO4, and Et3N) and different sol-
vents (e.g., DMF, DMSO, THF, and 1,4-dioxane) were employed to
Table 1
Optimization of reaction conditionsa
N
solvent, base
N
thiophenol,reflux
OH
OTf
S
Ph
3a
5a
Entry
Base
Solvent
Yieldb (%)
1
2
3
4
5
6
7
K2CO3
NaH
K3PO4
NEt3
NaH
DMF
DMF
DMF
DMF
DMSO
THF
73
79
22
0c
22
NaH
NaH
0c
1,4-Dioxane
0c
a
Conditions: 0.5 mmol base, 0.3 mmol thiophenol, 0.25 mmol 3a, 2 ml solvent,
100 °C, 1 h.
b
Yields after purification by flash-chromatography on silica gel (0.5% methanol
in DCM), purity >95%.
c
No product was detected by TLC and LC–MS (ESI).
Figure 1. X-ray structure of compound 5a.
Grombein, Cornelia M.
