Cleavage of tert-Butyl Benzoates with NaH in DMF: Comments on the ­Mechanism and a Simple and Safe Alternative Procedure

Abstract

The hazardous and inconvenient Schmidt procedure for tert-butyl benzoate ester cleavage by NaH in DMF has been reinvestigated. The reaction is suggested to involve B _AC 2 ester cleavage, facilitated by adventitious, NaH-derived NaOH, rather than the proposed E2 elimination of isobutylene by DMF-derived NaNMe₂. Powdered KOH in THF is a significantly safer and simpler alternative that effects cleavage of tert-butyl benozoates, at ambient temperature, in excellent yield (94-99%).

tert-butyl esters - cleavage - hydrides - DMF - hazard

References and Notes

See, for example:

<A NAME="RG26808ST-1A">1a</A> Kocienski PJ. Protecting Groups   3rd ed.:  Thieme; Stuttgart: 2003. 

<A NAME="RG26808ST-1B">1b</A> Wuts PGM. Greene TW. Greene’s Protective Groups in Organic Synthesis   4th ed.:  John Wiley and Sons; New Jersey: 2007. 

<A NAME="RG26808ST-2">2</A> Paul S. Schmidt RR. Synlett  2002,  1107 

The reaction of DMF with NaH has been reported to generate NaNMe₂ and either an equimolar mixture of H₂ and CO, or formaldehyde:

<A NAME="RG26808ST-3A">3a</A> Nasipuri D. Bhattacharya A. Hazra BG. J. Chem. Soc. D  1971,  660 

<A NAME="RG26808ST-3B">3b</A> Powers JC. Seidner R. Parsons TG. Tetrahedron Lett.  1965,  6:  1713 

<A NAME="RG26808ST-4">4</A> 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.  p.1181 ; and references therein

<A NAME="RG26808ST-5">5</A> For the synthesis of unlabelled parent compound 2a, see: Hoots JE. Rauchfuss TB. Wrobleski DA. Inorg. Synth.  1982,  21:  175 

<A NAME="RG26808ST-6">6</A> Serrano-Wu MH. Regueiro-Ren A. St. Laurent DR. Carroll TM. Balabsubramanian BN. Tetrahedron Lett.  2001,  42:  8593 

<A NAME="RG26808ST-7">7</A>

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 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.

<A NAME="RG26808ST-8">8</A> Lowry TH. Richardson KS. Mechanism and Theory in Organic Chemistry   3rd ed.:  Harper and Row; New York: 1987.  p.718-719  

<A NAME="RG26808ST-9">9</A> Gassman PG. Schenk WN. J. Org. Chem.  1977,  42:  918 

<A NAME="RG26808ST-10">10</A> Roberts W. Whiting MC. J. Chem. Soc.  1965,  1290 

<A NAME="RG26808ST-11">11</A> Pedersen CJ. J. Am. Chem. Soc.  1967,  89:  7017 

<A NAME="RG26808ST-12">12</A>

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.

<A NAME="RG26808ST-13">13</A>

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), R _f (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]: δ = 7.24 [ddd, ^³ J(^¹H,^¹H) = 7.9 Hz, ^³ J(^¹H,^¹H) = 7.4 Hz, ⁴ J(^¹H,^¹H) = 1.7 Hz, 1 H, H(4)], 7.48 [ddd, ^³ J(^¹H,^¹H) = 7.7 Hz, ^³ J(^¹H,^¹H) = 7.4 Hz, ⁴ J(^¹H,^¹H) = 1.2 Hz, 1 H, H(5)], 7.71 [ddd, ^³ J(^¹H,^¹H) = 7.7 Hz, ⁴ J(^¹H,^¹H) = 1.7 Hz, ⁵ J(^¹H,^¹H) = 0.5 Hz, 1 H, H(6)], 7.99 [ddd, ^³ J(^¹H,^¹H) = 7.9 Hz, ⁴ J(^¹H,^¹H) = 1.2 Hz, ⁵ J(^¹H,^¹H) = 0.5 Hz, 1 H, H(3)], 13.29 (br s, 1 H, CO₂H). [¹8]

<A NAME="RG26808ST-14">14</A>

Typical Experimental Procedure for Ester Cleavage with Loss of Iodide
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): δ = 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]

For the reduction of ArI to ArH by NaH in THF, see:

<A NAME="RG26808ST-15A">15a</A> Nelson RB. Gribble GW. J. Org. Chem.  1974,  39:  1425 

<A NAME="RG26808ST-15B">15b</A> For the reduction of methyl o-iodobenzoate by NaOMe, MeOH, with radiation (λ = 350 nm), to methyl benzoate, see: Kashimura T. Kudo K. Mori S. Sugita N. Chem. Lett.  1986,  851 

<A NAME="RG26808ST-16">16</A>

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] ) and anecdotal evidence of such occurrences. These strongly support the conclusion that the procedure in Scheme  [²] is potentially very hazardous.

<A NAME="RG26808ST-17A">17a</A> Furniss BS. Handford AJ. Smith PWG. Tatchell AR. Vogel’s Textbook of Practical Organic Chemistry   5th ed.:  Longman; London: 1989. 

<A NAME="RG26808ST-17B">17b</A> Krasnokutskaya EA. Semenischeva NI. Filimonov VD. Knochel P. Synthesis  2007,  81 

<A NAME="RG26808ST-18">18</A> Spectroscopic data were identical to those obtained from commercially available samples (Aldrich) of 4a and 4c

<A NAME="RG26808ST-19">19</A> Concise Chemical and Technical Dictionary   1st ed.:  Bennett H. Chemical Publishing Co.; New York: 1947.  p.107