our lab to clarify the pathways for methylations employing
DMC/DBU.
(TBAI) to the reaction mixture, methylation of phenol 4
under the same microwave conditions can be further ac-
celerated to 6 min (98% yield), which represents greater than
a 1,900-fold rate increase! The reason for this striking rate
Microwave heating has been shown to promote a variety
of chemical transformations.11-17 For example, synthesis of
aromatic ethers under microwave irradiation has been
reported by several laboratories.18 Therefore, microwave
irradiation is another potential strategy, besides employing
a suitable catalyst, to accelerate the rate of methylation. The
substrates in Table 1 along with a mixture of DMC/DBU
were subjected to microwave radiation in a continuous-flow
reactor. This reactor has an in-line thermal sensor, which
allows for the monitoring of the actual reaction temperature
during the entire course of reaction. This reactor also has an
in-line pressure control valve, which provides the capability
to process volatile DMC safely at elevated temperatures
above its boiling point (90 °C). In a typical procedure, a
solution containing a substrate, DBU (1 equiv), DMC, and
enhancement by adding a PTC to a homogeneous reaction
19,20
system
is not fully understood. For NH-containing
heteroaromatic compounds, such as benzimidazole 5 and 6,
rate acceleration of a magnitude of up to a 30-fold is observed
when microwave conditions are employed (entries 5-6).
Under the same conditions, methylations of 2-phenylindole
7 (48 min, 66%, entry 7) and carbazole 8 (36 min, 69%,
entry 8) are much slower with lower yields than imidazoles
(entries 5 and 6). To optimize the methylation for indole 7
and carbazole 8, TBAI (1 equiv) was added under microwave
conditions. This addition shortens the reaction time and
increases the methylation yield of 7 and 8 to 91% (30 min,
entry 7) and 97% (30 min, entry 8), respectively.
a solvent (either CH
through the microwave reactor which is preheated to 160
C at 20 bar by microwave irradiation. Under these condi-
tions, the methylation rate for phenols is accelerated from
hours to minutes, which represents a rate increase of up to
3
CN or DMF) is circulated by a pump
In summary, methylation of phenols, indoles, and benz-
imidazoles with DMC can be achieved under conventional
thermal conditions without using an autoclave by employing
DBU as a highly effective catalyst (chemical acceleration).
This protocol provides a practical, efficient, and environ-
mentally friendly process for an important chemical trans-
formation. Methylation rates can be further accelerated by
utilizing microwave heating (physical acceleration). Dramatic
rate enhancement greater than 1,900-fold is observed for an
unactivated and congested phenol when the phase-transfer
reagent TBAI is incorporated. By combining these accelera-
tion strategies, a very slow methylation that takes up to
several days can be performed efficiently in high yield within
minutes.
°
80-fold (Table 1, entries 1-3). Dramatic rate enhancement
using microwave heating is observed for 2,4,6-trichloro-
phenol (4), an unactivated and congested phenol. Phenol 4
is methylated in only 54 min (93%), which is approximately
2
(
00 times faster than that using conventional thermal heating
192 h, 91%) (entry 4). Furthermore, by adding 1 equiv of
phase-transfer catalyst (PTC) tetrabutylammonium iodide
(
10) (a) Lide, D. R. CRC Handbook of Chemistry and Physics, 75th ed.;
CRC Press: Boca Raton, Ann Arbor, London, Tokyo, 1994; Sec. 8, p 54.
b) Granitza, D.; Beyermann, M.; Wenschuh, H.; Haber, H.; Carpino, L.
A.; Truran, G. A.; Bienert, M. J. Chem. Soc., Chem. Commun. 1995, 2223.
(
Acknowledgment. We appreciate the encouragement of
Drs. Juergen Brokatzky and Thomas Blacklock in pursuing
this study. We thank Dr. Song Xue for a helpful suggestion
and Mr. Mauricio Loo for his assistance in operating the
continuous-flow microwave reactor.
(
(
(
11) Strauss, C. R.; Trainor, R. W. Aust. J. Chem. 1995, 48, 1665.
12) Caddick, S. Tetrahedron 1995, 51, 10403.
13) Kingston, H. M.; Haswell, S. J. MicrowaVe-Enhanced Chemistry.
Fundamentals, Sample Preparation, and Applications; American Chemical
Society: Washington, DC, 1997; Chapter 8.
(
14) Bose, A. K.; Banik, B. K.; Lavlinskaia, N.; Jayaraman, M.; Manhas,
M. S. Chemtech. 1997, 27, 18.
15) Loupy, A.; Petit, A.; Hamelin, J.; Texier-Boullet, F.; Jacquault, P.;
Mathe, D. Synthesis 1998, 1213.
(
OL016949N
(
16) Varma, R. S. Green Chem. 1999, 43.
(
17) Krstenansky, J. L.; Cotterill, I. Curr. Opin. Drug DiscoVery DeV.
(19) For an example of using PTC to accelerate a heterogeneous reaction
under microwave irradiation, see: Bram, G.; Loupy, A. Majdoub, M. Synth.
Comm. 1990, 20, 125.
2
000, 3, 454.
(18) (a) Wang, J.-X.; Zhang, M.; Xing, Z.; Hu, Y. Synth. Comm. 1996,
26, 301. (b) Mitra, A. K.; De, A.; Karchaudhuri, N. Indian J. Chem. 2000,
39B, 387. (c) Bogdal, D.; Pielichowski, J.; Boron, A. Synth. Comm. 1998,
28, 3029. (d) Elder, J. W.; Holtz, K. M. J. Chem. Ed. 1996, 73, A104.
(20) For an example of using PTC to accelerate a homogeneous reaction
under classical thermal conditions, see: Matsui, M.; Yamamoto, H. Bull.
Chem. Soc. Jpn. 1995, 68, 2663.
Org. Lett., Vol. 3, No. 26, 2001
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