Aqueous Phosphoric Acid for Deprotection
conversion after 24 h. Greene and Wuts46 have described the
tert-butyl ether as “one of the more underused alcohol protecting
groups considering its stability”, which has typically been
attributed to the operational inconvenience of its introduction
(i.e., use of gaseous isobutylene) and limited choices for its
deprotection. A convenient method for the installation of tert-
butyl ether was recently introduced by Bartoli et al.43 using
(BOC)2O in the presence of Mg(ClO4)2. The phosphoric acid
deprotection method reported herein is an attractive alternative
for accomplishing tert-butyl ether cleavage. Not surprisingly,
the protocol also works well for tert-butyl carbonate deprotection
(Table 3, entry 5).
This feature is advantageous in production settings where use
of a pH probe is not readily applicable.
Conclusion
In conclusion, aqueous phosphoric acid (85 wt %) can be
used as an alternate reagent for the deprotection of tert-butyl
carbamates, esters, and ethers. While the method lacks selectivity
among tert-butyl carbamates, esters and ethers, it is compatible
with many other acid-sensitive functionalities, including the CBZ
group, azetidine, methyl and benzyl esters, TBDMS, and methyl
phenyl ethers. It is noteworthy that it effected the removal of
the tert-butyl ester in a clean manner in the synthesis of ketolide
intermediate 4 in the presence of acid labile glycosidic bond
and acetate ester while all other conditions tried failed.
Aqueous H3PO4 is more economical than many other acids54
commonly used in deprotection of tert-butyl carbamates, esters,
and ethers. It is environmentally benign and presents no safety
hazards to laboratory and pilot plant personnel. In fact, the
concomitant removal of N-BOC group and hydration of olefin
using aqueous H3PO4 was employed in production scale for the
manufacture of 36 kg of CP-481715 (1).
In a typical experimental procedure, 85 wt % aqueous
phosphoric acid is added to a solution of the reaction substrate
in an organic solvent (THF, acetonitrile, toluene or methylene
chloride). Typically, a solvent of good solubility for the substrate
is chosen. The mixture is vigorously stirred at room temperature
until the reaction was complete (monitored by HPLC, typically
3-14 h). Water is added to dilute the reaction mixture, and
sodium hydroxide solution is added to adjust the pH to 7-8
(pH adjustment is not necessary for carboxylic acid products).
After extractive workup and removal of solvent, the product
obtained is typically >98% purity by HPLC assay without
further purification. The reaction is conducted at high concentra-
tion, typically with 1 mL of solvent/g52 of substrate, using 2.5-
5.0 equiv of 85 wt % aqueous phosphoric acid. The use of a
larger amount of organic solvent is undesirable, as it generates
a biphasic reaction mixture that slows down the reaction
significantly. When no other acid-sensitive functional groups
are present, the reaction can be heated (50 °C, 2 h, entries 1
and 2, Table 2). We have noted that at higher reaction
temperature (50 °C), methyl and benzyl esters suffer from partial
deprotection. The use of a large excess53 of aqueous 85% H3-
PO4 is unnecessary, as it does not appear to increase the rate of
the reaction. If the reaction mixture is biphasic, effective mixing
is critical in driving the reaction to completion within reasonable
time frames (3-14 h). Nonetheless, use of phase transfer
catalysts is not recommended, as it complicates product isolation
in many cases.
Experimental Section
General Procedure for N-BOC Deprotection. 3-Amino-1-
benzhydrylazetidine (Entry 1, Table 9). To a solution of tert-
butyl 1-benzhydrylazetidin-3-ylcarbamate (1.0 g, 2.95 mmol) in
CH2Cl2(1 mL) at room temperature was added aqueous phosphoric
acid (85 wt %, purchased from Aldrich Chemical Co.) (0.51 mL,
7.39 mmol) dropwise. The mixture was vigorously stirred for 3 h,
and HPLC assay showed reaction completion.Then 5 mL of water
was added and the mixture was cooled to 0 °C. A 50 wt % NaOH
solution was added slowly (Caution: exothermic) to adjust to the
pH to ∼8. The mixture was then extracted with CH2Cl2 (2 × 20
mL). The combined organic phase was dried over magnesium
sulfate and concentrated in vacuo to give the desired product as a
white solid (0.64 g, 91%). The product showed 98.7% HPLC purity
(by area percent), and coeluted with an authentic sample. NMR
and MS spectra were identical to those generated from an authentic
sample.
(3R,5S)-5-((S)-1-Amino-2-(3-fluorophenyl)ethyl)-dihydro-3-(3-
hydroxy-3-methylbutyl)furan-2(3H)-one (Table 1, Entry 7). The
crude compound 213 (79.2 g, 202.2 mmol) was stirred with 78 mL
of toluene and 300 mL of 85% phosphoric acid with good agitation.
After 7 h, the reaction was complete. The mixture was cooled to 0
°C after diluting with water (300 mL), and 50% NaOH was added
until the pH was in the range of 7-8.5. Ethyl acetate was added
(900 mL), and the layers were separated. The organic solution was
dried over magnesium sulfate and concentrated to an oil under
vacuum to give 48.8 g (157.8 mmol, 78%) of the product as an
colorless oil: MS m/z (API-ES) 310 (M + H)+, 292 (M +H -
H2O)+. Anal. Calcd. for C17H24FNO3: C, 66.00; H, 7.82; F, 6.14;
N, 4.53. Found: C, 65.86; H, 7.95; F, 6.03; N, 4.41. NMR
characterization is available in the Supporting Information.
General Procedure for tert-Butyl Ester Deprotection. Benzyl
Malonate (Table 2, Entry 4). To a solution of benzyl tert-butyl
malonate (1.5 g, 6.0 mmol) in toluene (1.5 mL) at room temper-
ature) was added aqueous phosphoric acid (85 wt %, purchased
from Aldrich Chemical Co. 2.05 mL, 30 mmol) dropwise. The
mixture was stirred for 6 h, and HPLC assay showed the reaction
was complete. Water (30 mL) was added, and the mixture was
extracted with ethyl acetate (3 × 30 mL). The combined ethyl
When pH adjustment is needed for the workup, we have
found that concentrated aqueous NaOH (50% solution in water)
is most convenient. The resultant aqueous layer is almost fully
saturated with sodium phosphate (formed in the pH adjustment),
which enhances the product partition in the organic phase.
Sodium phosphates formed in the workup also act as a pH
buffer, which effectively prevents the pH of the mixture from
going too high in case of overcharge of the NaOH solution.
(46) Greene, T. W.; Wuts, P. G. M. In ProtectiVe Groups in Organic
Synthesis, 3rd ed.; Wiley: New York, 1999; pp 65-67.
(47) Liu, Y.-T.; Wong, J. K.; Tao, M.; Osterman, R.; Sannigrahi, M.;
Girijavallabhan, V. M.; Saksena, A. Tetrahedron Lett. 2004, 45, 6097-
6100.
(48) Lall, M. S.; Ramtohul, Y. K.; James, M. N. G.; Vederas, J. C. J.
Org. Chem. 2002, 67, 1536-1547.
(49) Ross, D. L.; Skinner, C. G.; Shive, W. J. Org. Chem. 1959, 24,
1440-1442.
(50) Ganguly, N. C.; De, P.; Dutta, S. Synthesis 2005, 7, 1103-1108.
(51) Gerstenberger, B. S.; Konopelski, J. P. J. Org. Chem. 2005, 70,
1467-1470.
(52) For reactions on a milligram scale, typically 0.5 mL of the solvent
and 0.5 mL of aqueous 85 wt% H3PO4 were used so that adequate stirring
of the mixture could be ensured.
(53) For the concomitant hydration of the olefin and deprotection of 2
in the synthesis CP-481715, a large excess of aqueous 85 wt% H3PO4 (15
equiv) was needed.
(54) Sulfuric acid in CH2Cl2 appears to be another economical option
when no other acid-sensitive groups are present: Strazzolini, P.; Misuri,
N.; Polese, P. Tetrahedron Lett. 2005, 46, 2075-2078.
J. Org. Chem, Vol. 71, No. 24, 2006 9049