Bronner and Garg
JOCNote
followed by ortho-lithiation to provide intermediate 16,
which in turn was quenched with TMSCl to install the
necessary trimethylsilyl substituent. After workup, the de-
sired silylcarbamate 17 was obtained without the need for
chromatographic purification. Notably, this robust protocol
could be carried out reliably on multigram scale.
To access the desired silyltriflate, a number of methods for
carbamate cleavage/triflation were explored. Although step-
wise routes provided initial success, we ultimately uncovered a
one-pot procedure that allowed for the conversion of carb-
amate 17 to silyltriflate 2 (Scheme 3). Exposure of carbamate
Experimental Section
Carbamate 15. To a stirred solution of phenol (5.00 g, 53.1
mmol) in CH Cl (177 mL) was added i-PrNCO (7.80 mL, 79.65
mmol, 1.5 equiv), followed by NEt (1.50 mL, 10.6 mmol, 0.2
2
2
3
equiv). The solution was stirred at 23 °C for 2 h, then concen-
trated to dryness in vacuo to provide carbamate 15 as a white
powder, which was used in the subsequent step without pur-
1
ification. R 0.23 (2:1 hexanes:Et O); H NMR (500 MHz,
CDCl ) δ 7.36 (t, J = 8 Hz, 2H), 7.20 (t, J = 7.5 Hz, 1H),
f
2
3
7
J = 8.5 Hz, 6H); C NMR (125 MHz, CDCl
.13 (d, J = 8 Hz, 2H), 4.86 (s, 1H), 3.94-3.87 (m, 1H), 1.23 (d,
13
3
) δ 153.9, 151.2,
1
29.5, 125.4, 121.8, 43.6, 23.1; IR (film) 3290, 2972, 1696, 1535
-
1
þ
cm ; HRMS-ESI (m/z) [M þ H] calcd for C H NO
10 14
SCHEME 3. Synthesis of Silyltriflate 2
2
1
80.1024, found 180.1026.
Silylcarbamate 17. The crude carbamate 15 was dissolved in
ether (530 mL) at 0 °C and TMEDA (9.40 mL, 58.41 mmol, 1.1
equiv) was added followed by a solution of TBSOTf in
n-pentane (1.30 M, 44.9 mL, 58.41 mmol, 1.1 equiv). The
mixture was allowed to stir at 0 °C for 5 min, and then was
warmed to 23 °C over 30 min. Additional TMEDA (17 mL, 106.2
mmol, 2 equiv) was added, and the reaction was cooled to -78 °C.
A solution of n-BuLi in hexanes (2.12 M, 50.09 mL, 106.2 mmol,
2.0 equiv) was added dropwise over 70 min. The mixture was
stirred at -78 °C for 1 h, then neat TMSCl (23.59 mL, 185.9 mmol,
3.5 equiv) was added dropwise over 35 min. The resulting mixture
was stirred at -78 °C for 85 min, quenched with saturated aqueous
1
7 to DBU and Et NH in CH CN at 40 °C furnished inter-
2
3
8
mediate o-silylphenol 18. After the reaction mixture was
cooled to room temperature, a solution of PhNTf in CH CN
2
3
was introduced to facilitate triflation. Following purification
by flash chromatography, silyltriflate 2 was obtained as a
colorless oil in 66% yield, over the three steps. With use of this
sequence, 5 g of phenol can be smoothly converted to >10 g of 2.
It is expected that our method for the conversion of phenol
to silyltriflate 2 will be amenable to the synthesis of other
aryne precursors. For instance, our laboratory has utilized
the methodology to elaborate hydroxyindole 19 to indolyl-
NaHSO
vigorous stirring. The organic layer was separated, washed succes-
sively with saturated aqueous NaHSO
(1 ꢀ 300 mL) and brine
SO . Evaporation under reduced
4
(200 mL), and allowed to warm to 23 °Cover45minwith
4
(
1ꢀ 300 mL), then dried over Na
2
4
pressure afforded crude silylcarbamate 17. R 0.75 (2:1 hexanes:
f
Et O); H NMR (500 MHz, CDCl ) δ7.45 (dd, J = 7.5, 6 Hz, 1H),
1
2
3
9
silyltriflate 20 (Scheme 4) in 67% yield over three steps.
7
8
.38 (td, J = 7.5, 1.5 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 7.11 (d, J =
Hz, 1H), 4.86 (d, J = 7 Hz, 1H), 4.00-3.90 (m, 1H), 1.25 (d,
SCHEME 4. Synthesis of Indolyne Precursor 20
13
J = 6.5 Hz, 6H), 0.30 (s, 9H); C NMR (125 MHz, CDCl ) δ
3
1
55.8, 154.0, 135.0, 131.8, 130.5, 125.2, 122.4, 43.6, 23.1, -0.7; IR
-1
þ
(film) 3320, 2968, 1705 cm ; HRMS-ESI (m/z) [M þ H] calcd
for C13 Si 252.1420, found 252.1418.
H22NO
2
Silyltriflate 2. To a solution of crude silylcarbamate 17 in
MeCN (530 mL) was added DBU (11.9 mL, 79.7 mmol, 1.5
equiv) and Et
ing mixture was placed in a heating bath maintained at 40 °C for
5 min, then allowed to cool to 23 °C. Next, a solution of
PhNTf (28.5 g, 79.7 mmol, 1.5 equiv) in MeCN (155 mL) was
2
NH (6.59 mL, 63.7 mmol, 1.2 equiv). The result-
4
2
added via cannula over 20 min. After being stirred for 2 h, the
reaction mixture was washed successively with saturated aqu-
eous NaHSO (2 ꢀ 300 mL) and 10% aqueous NaOH (2 ꢀ
4
Silyltriflate 20 provides a means to generate indolyne 21,
which in turn serves as a valuable precursor to a variety of
novel indole derivatives (e.g., 22-24).
3
2 4
00 mL), then dried over Na SO . Evaporation under reduced
9
pressure afforded the crude product, which was further purified
by flash chromatography (199:1 hexanes:EtOAc) to provide
In summary, we have developed an efficient procedure for
the gram-scale preparation of 2-(trimethylsilyl)phenyl tri-
fluoromethanesulfonate, a versatile precursor to o-benzyne.
The three-step sequence utilizes phenol as the starting ma-
terial, requires only one chromatographic purification, and
ultimately delivers silyltriflate 2 in 66% overall yield. We
expect the method will also prove amenable to the synthesis
of other aryne precursors.
2
6
-(trimethylsilyl)phenyl trifluoromethanesulfonate 2 (10.4 g,
6% yield over 3 steps) as a colorless oil. R 0.80 (2:1 hexanes:
) δ 7.56 (dd, J = 7.5,
f
1
EtOAc); H NMR (500 MHz, CDCl
2.0 Hz, 1H), 7.46 (m, 1H), 7.36 (m, 2H), 0.40 (s, 9H); C NMR
(125 MHz, CDCl ) δ 155.3, 136.5, 132.8, 131.5, 127.7, 119.7,
118.7 (q, J = 318 Hz, CF
3
1
3
3
3
), -0.6; IR (film) 2960, 1419, 1206
-
1
þ
cm ; HRMS-ESI (m/z) [M þ NH ] calcd for C H F NO S-
4
10 17
3
3
Si 316.0651, found 316.0650.
Acknowledgment. The authors are grateful to the Uni-
versity of California, Los Angeles and Boehringer Ingelheim
for financial support. We thank Dr. Kevin Bahnck (Pfizer)
for experimental assistance and the Garcia-Garibay labora-
tory (UCLA) for the generous access to instrumentation.
(5) 2-(Trimethylsilyl)phenyl trifluoromethanesulfonate may be pur-
chased at a cost of over $110 per five grams from Aldrich or TCI America.
(
6) Snieckus, V. Chem. Rev. 1990, 90, 879–933.
(7) (a) Kauch, M.; Snieckus, V.; Hoppe, D. J. Org. Chem. 2005, 70, 7149–
7
158. (b) Kauch, M.; Hoppe, D. Synthesis 2006, 1578–1589.
8) Et NH serves as a scavenger for isopropyl isocyanate, which is
(
2
liberated in the reaction; 1,1-diethyl-3-isopropylurea is formed as a bypro-
duct.
1
13
Supporting Information Available: HNMR and CNMR
spectra for compounds 15, 17, and 2. This material is available
free of charge via the Internet at http://pubs.acs.org.
(9) Bronner, S. M.; Bahnck, K. B.; Garg, N. K. Org. Lett. 2009, 11, 1007–
010.
1
J. Org. Chem. Vol. 74, No. 22, 2009 8843
Bronner, Sarah M.
