LETTER
Base-Mediated tert-Butyl Ester Cleavage
207
cleavage of 1a (0.2 M) employing NHEt2 and NaH in anhyd-
rous THF proceeded to 45% conversion (to 4b) over a period
of 4 d.
O
OH
NaH, DMF
46%
O
4a
(8) Lowry, T. H.; Richardson, K. S. Mechanism and Theory in
Organic Chemistry, 3rd ed.; Harper and Row: New York,
1987, 718–719.
O
O
KOH, THF
94%
OH
(9) Gassman, P. G.; Schenk, W. N. J. Org. Chem. 1977, 42, 918.
(10) Roberts, W.; Whiting, M. C. J. Chem. Soc. 1965, 1290.
(11) Pedersen, C. J. J. Am. Chem. Soc. 1967, 89, 7017.
(12) NaOH in DMF was less effective, see ref. 7. For reactions in
THF, replacement of KOH by NaOH or LiOH led to a
significant reduction in yield of 2a from 1a. Reduction in the
formal number of equivalents of KOH results in a reduction
of reaction rate. Increasing to 16 equiv of KOH resulted in
quantitative conversion of 3a to 4a in <2 h.These effects may
relate to the surface area of the KOH exposed to the THF
medium.
I
3c
4c
I
Scheme 3 Contrasting outcomes from cleavage of tert-butyl ester
3c with NaH in DMF2 and KOH in THF.13 Acids 4a and 4c are obtai-
ned after acidic workup.
situ (Figure 1) together with co-generation of tert-butanol
through BAC2-type cleavage (Scheme 1, pathway B),
weigh against the proposed2 NaNMe2-mediated E2 pro-
cess (pathway A). Since NaH can undergo uncontrollable
exothermic reaction with DMF, particularly at scale, and
with onset temperatures as low as 26 °C when the DMF is
not dry,4 the NaH in DMF method2 is potentially very haz-
ardous.16 KOH in THF was found to be an operationally
simpler and much safer alternative procedure for the
cleavage of tert-butyl benzoates under basic conditions,
affording the corresponding benzoic acids in high yields
(Table 1).
(13) Typical Experimental Procedure for Ester Cleavage
tert-Butyl o-iodobenzoate (3c, 304 mg, 1.00 mmol, 1 equiv)
was dissolved in THF (10 mL), and then ground KOH (449
mg, 8.00 mmol, 8 equiv) added. The resulting suspension
was stirred at r.t. for 3 h, after which TLC analysis [hexane–
EtOAc (20:1), Rf(3c) = 0.54] indicated complete reaction.
After addition of H2O (10 mL) and washing the resulting
aqueous solution with EtOAc (10 mL), the solution was
acidified to pH 1, resulting in precipitation. The aqueous
suspension was extracted with EtOAc (3 × 10 mL) and the
extracts combined, dried (MgSO4), filtered, and the volatiles
removed in vacuo to yield 4c as a white amorphous solid,
232 mg (94%); Mp 160–161 °C (lit.17 162 °C). 1H NMR
[300 MHz, (CD3)2SO, TMS]: d = 7.24 [ddd, 3J(1H,1H) = 7.9
Hz, 3J(1H,1H) = 7.4 Hz, 4J(1H,1H) = 1.7 Hz, 1 H, H(4)], 7.48
[ddd, 3J(1H,1H) = 7.7 Hz, 3J(1H,1H) = 7.4 Hz,
Acknowledgment
We thank the University of Bristol and the ESPRC for funding.
G.C.L.-J. holds a Royal Society Wolfson Research Merit.
4J(1H,1H) = 1.2 Hz, 1 H, H(5)], 7.71 [ddd, 3J(1H,1H) = 7.7
Hz, 4J(1H,1H) = 1.7 Hz, 5J(1H,1H) = 0.5 Hz, 1 H, H(6)], 7.99
[ddd, 3J(1H,1H) = 7.9 Hz, 4J(1H,1H) = 1.2 Hz,
References and Notes
5J(1H,1H) = 0.5 Hz, 1 H, H(3)], 13.29 (br s, 1 H, CO2H).18
(14) Typical Experimental Procedure for Ester Cleavage with
Loss of Iodide
(1) See, for example: (a) Kocienski, P. J. Protecting Groups,
3rd ed.; Thieme: Stuttgart, 2003. (b) Wuts, P. G. M.;
Greene, T. W. Greene’s Protective Groups in Organic
Synthesis, 4th ed.; John Wiley and Sons: New Jersey, 2007.
(2) Paul, S.; Schmidt, R. R. Synlett 2002, 1107.
Compound 3c (152 mg, 0.50 mmol, 1 equiv) was dissolved
in DMF (5 mL), followed by the addition of NaH (60% w/w
in mineral oil, 96 mg, 4.00 mmol, 8 equiv) resulting in gas
evolution. The resulting suspension was stirred at r.t. for 48
h. After cooling to 0 °C, the remaining NaH was quenched
by the careful addition of H2O (10 mL), and the resulting
aqueous solution was washed with EtOAc (10 mL). The
solution was acidified to pH 1, resulting in product
precipitation, and the aqueous suspension was extracted into
EtOAc (3 × 10 mL). The organic extracts were combined,
dried (MgSO4), filtered, and the volatiles removed in vacuo
to yield crude 4a as a yellow oil. This was applied to a
presolvated silica gel column (1.5 × 11 cm) and eluted with
7:1 PE (40:60 fraction)–EtOAc, collecting 5 mL fractions.
Fractions 7–15 were combined and the volatiles removed in
vacuo to give 4a as a white amorphous solid, 28 mg (46%);
mp 114–118 °C (lit.19 122 °C). 1H NMR (300 MHz, CDCl3,
TMS): d = 7.48 [m, 2 H, H(3,5)], 7.62 [m, 1 H, H(4)], 8.13
[m, 2 H, H(2,6)], 11.42 (br s, 1 H, CO2H).18
(3) The reaction of DMF with NaH has been reported to
generate NaNMe2 and either an equimolar mixture of H2 and
CO, or formaldehyde: (a) Nasipuri, D.; Bhattacharya, A.;
Hazra, B. G. J. Chem. Soc. D 1971, 660. (b) Powers, J. C.;
Seidner, R.; Parsons, T. G. Tetrahedron Lett. 1965, 6, 1713.
(4) Mixtures of NaH and DMF can undergo uncontrollable
exothermic decomposition at temperatures as low as 26 °C,
with higher onset temperatures in very dry solvent. In some
cases these exothermic reactions have resulted in violent
eruptions of the mixture from the reaction vessel, in
particular when conducted at scale. See: Bretherick, L.
Handbook of Reactive Chemical Hazards, 4th ed.;
Butterworth-Heinemann: Oxford, 1990, 1181; and
references therein.
(5) For the synthesis of unlabelled parent compound 2a, see:
Hoots, J. E.; Rauchfuss, T. B.; Wrobleski, D. A. Inorg.
Synth. 1982, 21, 175.
(15) For the reduction of ArI to ArH by NaH in THF, see:
(a) Nelson, R. B.; Gribble, G. W. J. Org. Chem. 1974, 39,
1425. (b) For the reduction of methyl o-iodobenzoate by
NaOMe, MeOH, with radiation (l = 350 nm), to methyl
benzoate, see: Kashimura, T.; Kudo, K.; Mori, S.; Sugita, N.
Chem. Lett. 1986, 851.
(16) Whilst we did not experience any uncontrollable reactions of
NaH with the DMF (up to scales of ca. 10 mL DMF, 0.19 g
NaH, at 21 °C), there are ample literature reports (see ref. 4)
(6) Serrano-Wu, M. H.; Regueiro-Ren, A.; St. Laurent, D. R.;
Carroll, T. M.; Balabsubramanian, B. N. Tetrahedron Lett.
2001, 42, 8593.
(7) Reaction of 3b and powdered NaOH in DMF proceeded to
74% conversion (to 4b) over a period of 6 d. The generation
of NaOH in situ (by NaH and H2O) may lead to a much more
reactive (nonaggregated) form of NaOH, possibly meta-
stable. Alternatively, NaH may mediate deprotonation of the
tetrahedral intermediate in pathway B. tert-Butyl ester
Synlett 2009, No. 2, 205–208 © Thieme Stuttgart · New York