Job/Unit: O20647
/KAP1
Date: 19-06-12 15:01:57
Pages: 5
Straightforward Reductive Esterification of Carbonyl Compounds
Like in the preceding method, the reaction of carboxylic benzoic acid 8 with tosylhydrazide in PhF, followed by ad-
acids with hydrazones derived from aromatic aldehydes pro- dition of K2CO3 and MW irradiation led to the obtention
ceeded well, giving rise to the corresponding benzyl esters, of phthalide 9 in quantitative yield (Scheme 4). We are cur-
and therefore, this methodology could be employed as an rently evaluating the scope of this methodology.
alternative procedure for the benzylation of carboxylic ac-
ids. However, the microwave-promoted reaction failed for
the introduction of the benzhydryl group from benzo-
phenone hydrazone. Nevertheless, this type of ester can be
formed by employing the stepwise method described above.
Interestingly, the microwave-promoted reaction is com-
patible with a variety of sulfonylhydrazones, including those
derived from enolizable dialkyl ketones, a type of hydrazone
Scheme 4. A one-pot reductive lactonization of an oxoacid.
that is particularly challenging, because it undergoes very
easy decomposition through the diazo compound to give
the corresponding alkene. Examples of the employment of
cyclic and acyclic dialkyl tosylhydrazones are presented in
Table 1 (Entries 13–15, 17–19, 20–22).
Conclusions
We have reported a new esterification methodology by
reaction of carboxylic acids with tosylhydrazones that oc-
curs through the insertion of O–H into diazo compounds
generated in situ from tosylhydrazones. The methodology
exhibits wide scope with regard to the structure of the
hydrazone, including those derived from enolizable ketones.
Moreover, the reactions proceed without the need of a cata-
lyst and are operationally very simple, safe, and fast. From
a synthetic point of view, the process can be envisioned as
a reductive esterification of carbonyl compounds promoted
by tosylhydrazide.
The diastereoselectivity of the reaction was studied by
employing hydrazones derived from 4-substituted cyclo-
hexanones (Table 1, Entries 17–19). Unfortunately, no dia-
stereoselectivity was observed, and the esters were obtained
as a 1:1 mixture of diastereoisomers.
Noteworthy, the reaction with hydrazone 6, which fea-
tures a benzyloxy group in the ortho position relative to the
hydrazone, gives rise to a mixture of expected benzyl ester
5x and dihydrobenzofuran 7. Indeed, in the absence of the
carboxylic acid, dihydrobenzofuran 7 was obtained in 56%
yield under the same reaction conditions. Formation of
compound 7 could be explained by intramolecular insertion
of the benzylic C–H bond on the incipient carbene gener-
ated from the diazo compound (Scheme 3). This transfor-
mation of o-benzyloxytosylhydrazones has been previously
reported in the presence of a Rh catalyst[10] but not under
transition-metal-free-conditions. However, the analogous
metal-free version employing o-aminobenzaldehyde deriva-
tives leading to indolines has been recently documented.[11]
We are currently evaluating the scope of this transition-
metal-free heterocyclization as a new entry to the benzo-
furan scaffold, and the results will be reported in due
course.
Experimental Section
Stepwise Esterification: A solution of the appropriate tosylhydraz-
one (0.5 mmol) in toluene (10 mL) was added to a stirred mixture
of tetrabutylammonium iodide (0.018 g, 0.05 mmol) in 0.4 m KOH
(1.25 mL, 0.5 mmol). The reaction mixture was heated at 75 °C for
1–2 h. The reaction mixture was cooled to room temperature and
the characteristic colored organic layer was separated. The aqueous
phase was extracted with dichloromethane (3ϫ10 mL). The or-
ganic phases were combined, and the corresponding carboxylic
acid (0.5 mmol) was added. Nitrogen evolution occurred, and the
resulting mixture was stirred for 10 min at room temperature. The
mixture was dried with Na2SO4 and filtered. The solvent was re-
moved under reduced pressure, and the final product was purified
by column chromatography (SiO2; hexane/AcOEt, 95:5).
Reactions Performed Under Microwave Irradiation: A 2–5-mL mi-
crowave vial was charged with potassium carbonate (241.5 mg,
3.5 equiv.), tosylhydrazone 1 (0.5 mmol), PhF (2.5 mL), the carbox-
ylic acid (0.3 mmol, 0.6 equiv.), and a magnetic stirring bar. The
vessel was sealed with a septum, placed into the microwave cavity,
and irradiated to heat the reaction mixture at the desired tempera-
ture in a Biotage Initiator microwave apparatus. The total heating
time was 10 min at 155 °C. When the reaction was complete, the
vial was cooled down to room temperature by using a propelled air
flow. It was then opened and poured into a separatory funnel. The
layers were separated, and the aqueous phase was extracted
(3ϫ10 mL) with dichloromethane. The combined organic layers
were washed with brine, dried with Na2SO4, and filtered. The sol-
vent was removed under reduced pressure, and the final product
was purified by column chromatography (SiO2; hexane/AcOEt,
Scheme 3. A C–H insertion reaction of o-benzyloxytosylhydraz-
ones.
Finally, preliminary experiments of lactonization have
been conducted. In this case, the reaction was carried out
in a one-pot fashion from the carbonyl without isolation of
the intermediate hydrazide. Thus, treatment of 2-formyl- 95:5).
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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Garcia-Munoz, Angel-Humberto
