Communications
doi.org/10.1002/ejoc.202001602
with a phenol in the presence of K2CO3 gave phenol ether 4r,
and benzyl ether 4s could be obtained by Ag2O-promoted
reaction with benzyl alcohol, which is not acidic.
Table 3. Deoxy-functionalization of alcohols to form CÀ S and CÀ O
1
2
3
bonds.[a]
A plausible mechanism for this two-step transformation is
shown in Scheme 2. The proposed mechanism is consistent
with Jung and Ornstein’s[16a] results regarding activation of
alcohols with TMSI. First, a molecule of TMSI activates alcohol 1,
and then the nucleophilic iodide ion attacks the resulting silyl
ether (5) to generate alkyl iodide 2. Alternatively, a second TMSI
molecule may activate 5 to form intermediate 6, which then
reacts with iodide ion to afford 2. Finally, reaction of 2 with a
nucleophile generates deoxy-functionalization product 7.
Unlike Mitsunobu reaction, our protocol involves two SN2
reactions, in which the alcohol was transformed into alkyl
iodide with TMSI and then the latter was nucleophilic attacked
by nucleophiles, so the product obtained from a chiral alcohol
should theoretically retain the configuration of the alcohol. To
confirm the stereoselectivity of this protocol, we carried out
reactions of chiral alcohol S-1a (Table 4). Azide product S-3a
showed the same configuration as S-1a (the absolute config-
uration was determined with chiral HPLC and optical rotation,
see supplementary information for details), with an enantio-
meric ratio (er) of 7:93. Deoxy-azidation of a benzyl alcohol
afforded racemic product R-3t, indicating that for this alcohol,
the first step proceeded predominantly by an SN1 pathway.
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Reaction of S-1a with morpholine,
a secondary amine,
generated S-3f with partial racemization; whereas reaction with
aniline afforded almost fully racemized S-3k. Reactions with
substituted thiophenols afforded aryl sulfides S-4c, S-4e, S-4g,
S-4h, S-4i, and S-4n with excellent er values. Heteroaryl sulfide
S-4n, which was generated with an er of 90:10 by reaction of S-
1a with 2-mercaptobenzoxazole, could be hydrolyzed to the
corresponding chiral thiol.[22] Reaction between sodium ben-
zoate and the alkyl iodide intermediate generated from S-1a
afforded partially racemic ester S-4q, which indicates that both
nucleophilicity and steric hindrance affected the stereoselectiv-
ity of this deoxy-functionalization reaction.
To demonstrate the applications of our protocol, we carried
out a gram-scale reaction of 4-phenyl-2-butanol (1a, 5 mmol),
TMSI, and aniline, which afforded N-(4-phenylbutan-2-yl)aniline
(3k) in 90% yield (1.01 g, 4.5 mmol) over two steps (Scheme 3).
Next, we synthesized the enantiomer of the calcimimetic drug
cinacalcet (9) from 8 in 95% yield over two steps. Because many
drugs contain an aryl sulfide moiety, we demonstrated that the
[a] Reaction conditions, unless otherwise noted: (i) 1 (0.2 mmol) and TMSI
(0.4 mmol) in DCM (1 mL) were allowed to react at room temperature
under Ar for 16 h, and then the solvent was removed in vacuo to afford 2.
(ii) A S nucleophile (2 equiv), K2CO3 (2 equiv), and CH3CN (1 mL) were
added to 2, and the mixture was stirred at room temperature for 6 h; or an
O nucleophile (2 equiv) in DMF (1 mL) was added, and the mixture was
stirred at room temperature for 12–14 h. Isolated yields are provided. [b]
Sodium thiophenolate was used instead of NuH and K2CO3. [c] Potassium
acetate was used instead of NuH and K2CO3, and DMF was used as the
solvent. [d] Sodium benzoate was used instead of NuH and K2CO3, and
DMF was used as the solvent. [e] The reaction was carried out with 2 equiv.
of phenylmethanol and 4 equiv. of Ag2O.
reactions of substituted thiophenols and heteroaryl thiols with
primary, secondary, and benzyl alcohols generated excellent
yields of the corresponding aryl sulfides and heteroaryl sulfides
(4b–4n). O-Sulfinylation of alcohols by means of a Mitsunobu
reaction with sulfinic acid inverts the configuration of the
alcohol-bearing carbon.[20] In this study, we used sodium
benzenesulfinate as a nucleophile in a reaction with 1a, which
proceeded by attack of the S atom on the intermediate alkyl
iodide to afford S-sulfinylated compound 4o but not by O atom
that generates benzenesulfinate.[21]
We also tested our two-step protocol with O nucleophiles
(Table 3, bottom panel). Carboxylic acids are more acidic than
thiols and thiophenols, and we found that acetate and
benzoate salts were effective nucleophiles for construction of
CÀ O bonds, furnishing esters 4p and 4q in high yields. Reaction
Scheme 2. Plausible reaction mechanism.
Eur. J. Org. Chem. 2021, 1179–1183
1181
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