Miller
JOCNote
TABLE 2. Stability of p-Toluenesulfonate Esters (Tosylates)
20% piperidine/DMFa
NaOHd
BBr3
f
R
TFE 13
Ph 14
Neo 15
TFMB 16
TCE 17
HFIP 18
stable (95% 13)b
stable (97% 14)b
stable (93% 15)b
stable (92% 16)b
cleaved (25% 17, 75% TsPip)c
cleaved (mixture)
c
cleaved (82% NaOTs)e
cleaved (72% NaOTs)e
stable (95% 15)b
stable (100% 13)b
stable (95% 14)b
cleaved (0% 15)b
cleaved (0% 16)b
stable (100% 17)b
stable (100% 18)b
cleaved (65% NaOTs)e
cleaved (80% NaOTs)e
cleaved (82% NaOTs)e
d
a16 h, rt. bIsolated recovery of starting material. Estimated from NMR of the crude material. 2 equiv of NaOH in 9:1 DCM/MeOH, 16 h, rt.
eIsolated product. f3 equiv of BBr3, CH2Cl2, 0 °C, 2.5 h.
filtration and/or extraction. In the case of 16, simple filtration
afforded pure sodium p-toluenesulfonate (NaOTs). For 13,
the filtered product was contaminated with sodium trifluor-
oethoxide but could be purified by subsequent acidification
and removal of the trifluoroethanol. Alternatively, extraction
rather than filtration affords pure NaOTs.
(0.5 mmol) were dissolved in 2 mL of CH2Cl2. DABCO18
(67.5 mg, 0.6 mmol) in 1 mL of CH2Cl2 was added, resulting
in rapid warming and precipitate formation. After completion,
the reaction was directly purified by silica gel flash chromatog-
raphy (0-25% ethyl acetate in hexanes).
5-Dimethylamino-naphthalene-1-sulfonic Acid 2,2,2-Trifluoro-
1
ethyl Ester (TFE Dansylate, 9). Yellow oil (147 mg, 88%). H
Conversely, treatment with 3 equiv of BBr3 at 0 °C cleaves
both Neo and TFMB tosylates but leaves TFE, Ph, HFIP,
and TCE tosylates unaffected. Complete cleavage of 15 and
16 could also be achieved with 1 equiv of BBr3 at -78 °C. No
neopentyl bromide or alcohol was recovered, suggesting that
methyl migration occurred during the deprotection.15
Replacement of BBr3 with the milder Lewis acid BCl3 was
equally effective, allowing the isolation of NaOTs in 92% yield
after treatment of 15 with 1 equiv of BCl3 for 30 min at 0 °C.
Overall, Neo, TFE, and Ph groups are the most broadly
stable sulfonate protecting groups. Ph exhibits the highest
stability to nucleophiles, even hot NaN3. TFE and Ph are
cleaved under basic conditions, whereas Neo is complemen-
tary in its stability as it is cleaved by hot aqueous acid or
strong Lewis acid treatment (Table 1). TFMB sulfonates can
be cleaved under acidic or basic conditions yet exhibit high
stability to most nucleophiles. TCE and HFIP sulfonates are
poorly stable and reactive under basic conditions but are
highly stable to iodide and acidic conditions. TCE esters are
also uniquely labile to reducing conditions (Table 1).3
These screening results have established the intrinsic labi-
lity of sulfonate esters based on commercially available
alcohols and can serve as a guide for the judicious selection
of a sulfonate protecting group. Moreover, two mild clea-
vage conditions have been described that together cleave
virtually all sulfonate protecting groups, at or below room
temperature. Most sulfonates, including TFE and Ph, can be
cleaved at room temperature with NaOH under nonaqueous
conditions. Sulfonates that are prone to solvolysis in hot
protic acid, such as Neo and TFMB, can be cleaved with a
stoichiometric amount of BBr3 or BCl3 at well below room
temperature. Finally, the general stability of fluorinated
sulfonate protecting groups suggests that, like the neopentyl
group, they are suitable platforms for the construction of
protecting groups with engineered lability.
NMR (CDCl3): δ 8.66 (dt, 1H, J = 8.4, 1.2 Hz), 8.28 (dd, 1H, J =
7.6, 1.2 Hz), 8.22 (dt, 1H, J = 8.4, 1.2 Hz), 7.63 (dd, 1H, J = 7.6, 8
Hz), 7.56 (dd, 1H, J = 7.6, 8.4), 7.24 (m, 1H), 4.31 (q, 2H, JHF = 8
Hz), 2.89(s, 6H). 19FNMR(CDCl3):δ-74.06 (t, JHF =8Hz).13
C
NMR (CDCl3): δ 152.2, 132.8, 131.1, 130.3, 130.1, 130.0, 129.4,
123.1, 122.1 (q, 1JCF = 275 Hz), 119.2, 116.1, 65.0 (q, 2JCF = 38.1
Hz), 45.6. HR-EIMS m/z calculated for C14H15F3NO3S 334.0725,
found 334.0706.
General Procedure for the Synthesis of p-Toluenesulfonate
Esters 13-18. p-Toluenesulfonyl chloride (1.9 g, 10 mmol)
and an alcohol (10 mmol) were dissolved in 15 mL of CH2Cl2.
DABCO (1.35 g, 12 mmol) in 5 mL of CH2Cl2 was added,
resulting in rapid warming and precipitate formation. After
completion, 3 mL of 1 M NaOH was added, and the reaction
was diluted into 100 mL of ethyl acetate. The organic layer was
extracted with 5% NaHCO3 (3 ꢀ 50 mL), 0.1 M HCl (3 ꢀ 50 mL),
water (25 mL), and brine (25 mL). The solvent was dried with
sodium sulfate and removed in vacuo.
Toluene-4-sulfonic Acid 2,2,2-Trifluoro-1-phenyl-ethyl Ester
(TFMB Tosylate, 16). White powder (2.94 g, 89%). H NMR
1
(CDCl3): δ 7.65 (m, 2H), 7.4-7.27 (m, 5H), 7.21 (m, 2H), 5.66 (q,
1H, J = 6.4 Hz), 2.39 (s, 3H). 19F NMR (CDCl3): δ -76.48 (d,
3JHF = 5.6 Hz). 13C NMR (CDCl3): δ 145.6, 133.2, 130.5,
1
129.94, 129.85, 128.8, 128.3, 128.1, 122.5 (q, JCF =279 Hz),
78.3 (q, JCF = 34.4 Hz), 21.8. HR-EIMS m/z calculated for
C15H13F3O3SNa 353.0435, found 353.0431.
2
Cleavage of Trifluoroethyl p-Toluenesulfonate. To a solution
of 13 (254 mg, 1 mmol) in CH2Cl2 (10 mL) was added 2 M NaOH
in MeOH (1.1 mL, 2.2 equiv). After stirring for 3 h at room
temperature, significant precipitation was observed. Water (5 mL)
was added, and the aqueous layer was extracted. The aqueous
layer was then neutralized with 10% H2SO4 and dried by rotary
evaporation. The resulting solid was taken up in MeOH (5 mL).
After removal of the insoluble Na2SO4 by filtration, rotary
evaporation afforded sodium p-toluenesulfonate (153 mg, 79%)
as a white powder. 1H NMR (CD3OD): δ 7.72 (d, 2H, J = 8.4
Hz), 7.23 (d, 2H, J = 8 Hz), 2.36 (s, 3H). 1H NMR (D2O): δ 7.53
(d, 2H, J = 8 Hz), 7.20 (d, 2H, J = 8 Hz), 2.22 (s, 3H). 13C NMR
(CD3OD): δ 142.3, 140.6, 128.6, 125.8, 20.2. 13C NMR (D2O): δ
142.7, 139.5, 129.6, 125.5, 20.6. Spectral data were identical to
those of the commercially available material.
Experimental Section
General Procedure for the Synthesis of Dansyl Sulfonate Esters
1-12. Dansyl chloride (135 mg, 0.5 mmol) and an alcohol
Cleavage of Neopentyl p-Toluenesulfonate. A solution of 15
(242 mg, 1 mmol) in CH2Cl2 (5 mL) was cooled to 0 °C in an ice
bath. Boron trichloride (1 mL, 1 M inCH2Cl2, 1 equiv) was added
dropwise, and the solution was stirred on ice for 30 min. The
volatiles were removed under vacuum. Water (5 mL) was added,
€
(18) Hartung, J; Hunig, S.; Kneuer, R.; Schwarz, M.; Wenner, H.
Synthesis 1997, 1433.
4634 J. Org. Chem. Vol. 75, No. 13, 2010