4796
D. W. Slocum et al. / Tetrahedron Letters 51 (2010) 4793–4796
afford 4.6 g pure product. A second crop of 1.12 g was obtained
from the filtrate after sitting overnight. The resulting overall yield
for the two crops was 5.72 g, 75%. Mp = 52–53 °C.10
separated and back-extracted with 400 mL of ethyl acetate. The
combined organic layers were washed with brine, dried over so-
dium sulfate, and concentrated in vacuo to provide a viscous oil.
The benzhydrol product was isolated as described above for the
batch reaction except employing 200 mL of hexanes for the tritur-
ation to provide 373 g; 82% isolated yield, two crops. Mp = 54–
55 °C.10
2.4. Exchange of p-chlorobromobenzene with 1 equiv THF
(Synthetron™ S3T1 continuous reactor)
A 2.0 M solution of p-chlorobromobenzene in anhydrous cyclo-
hexane including 1 equiv of anhydrous THF was prepared and cou-
pled with a commercial 2.0 M solution of n-BuLi in cyclohexane.
Reagent solutions were delivered through Teflon tubing using
independent SYR-2200 dual programmable syringe pumps ob-
tained from J-KEM Scientific. Initial trials were conducted using
25 mL of each reagent solution being fed into the reactor at room
temperature and directing the exit stream into a stirring 2.0 M
solution of ClTMS in cyclohexane (60 mL) held at 0 °C in an ice
bath. Reagent stream feed rates were 100 mL/min each, providing
a reaction residence time of 0.034 s for the X/Li exchange. A 97%
conversion by ClTMS/GC analysis was attained which was utilized
for the addition of benzaldehyde as described below.
References and notes
1. Wittig, G.; Pockels, U.; Droge, H. Ber. 1938, 71, 1903.
2. (a) Gilman, H.; Jacoby, A. L. J. Am. Chem. Soc. 1938, 3, 108; (b) Gilman, H.;
Langham, W.; Jacoby, A. L. J. Am. Chem. Soc. 1939, 61, 106.
3. (a) Wakefield, B. G. Organolithium Methods; Best Synthetic Methods; Academic
Press: New York, 1988; Wakefield, B. G. The Chemistry of Organolithium
Compounds; Pergamon Press: New York, 1974; (b) Jones, R. G.; Gilman, H. Org.
React. 1951, 6, 339; (c) Parham, W. E.; Bradsher, C. K. Acc. Chem. Res. 1982, 15,
300; (d) Bailey, W. F.; Patricia, J. J. J. Organomet. Chem. 1988, 342, 1; (e)
Wakefield, B. G.. In Comprehensive Organometallic Chemistry; Jones, D. N., Ed.;
Pergamon Press: New York, 1979; Vol. 3,
p 943; (f) Wardell, J. L.. In
Comprehensive Organic Chemistry; Wilkinson, G., Ed.; Pergamon Press: New
York, 1982; Vol. 1, p 43; (g) Brandsma, L.; Veruijsse, H. Preparative Polar
Organometallic Chemistry I; Springer: Berlin, 1987; (h) Slocum, D. W. Metal–
Halogen Exchange Metalations (M–X) of Aryl and Heteroaryl Ring Systems Using
Alkyllithiums; FMC Lithium Link, Winter, 1993.; (i) Bailey, W. F. Metal–Halogen
Exchange (M–X) Involving Aliphatic Substrates Using Organolithiums; FMC
Lithium Link, Spring, 1994.
2.5. Production of (4-chlorophenyl)(phenyl)methanol
(Synthetron™ S3T1 continuous reactor)
4. For concern regarding the use of t-BuLi in the laboratory, cf. Chemical &
Engineering News, Aug 3, 2009, pp 3 and 29. For an article on the safe handling
of organolithium reagents, cf. Schwindeman, J. A.; Woltermann, C. J.; Letchford,
R. J. Chem. Health Safety 2002, 6.
5. (a) Slocum, D. W.; Reed, D.; Jackson, F., III; Friesen, C. J. Organomet. Chem. 1996,
512, 265; (b) Slocum, D. W.; Dietzel, P. Tetrahedron Lett. 1999, 40, 1823; (c)
Slocum, D. W.; Carroll, A.; Dietzel, P.; Eilerman, S.; Culver, J. P.; McClure, B.;
Brown, S.; Holman, R. W. Tetrahedron Lett. 2006, 47, 865.
6. Trepka, W. J.; Sonnenfeld, R. J. J. Organomet. Chem. 1969, 16, 317.
7. (a) Pennemann, H.; Hessel, V.; Löwe, H. Chem. Eng. Sci. 2004, 59, 4789; (b)
Mason, B. P.; Price, K. E.; Steinbacher, J. L.; Bogdan, A. R.; McQuade, D. T. Chem.
Rev. 2007, 107(6), 2300; (c) Schwalbe, T.; Autze, V.; Hohmann, M.; Stirner, W.
8. (a) Synthetron™ model S3T1 reactor available from KinetiChem Inc., Irvine,
CA.; (b) Holl, R. Methods of Operating Surface Reactors and Reactors Employing
Such Methods. U.S. Patent 7125,527, Oct 24, 2006.
Utilizing conditions established for the X/Li exchange in a con-
tinuous fashion, a second S3T1 Synthetron™ reactor was coupled
to the exit stream of the first reactor and chilled to 5 °C with a cir-
culating chiller. A 1.0 M solution of benzaldehyde in THF was pre-
pared and introduced to the second reactor at a flow rate of
200 mL/min (utilizing a Buchi pump, Model C-610). A combined
flow rate of 400 mL/min in the second reactor provided a residence
time of 0.017 s for the nucleophilic addition step. The exit stream
from the second reactor was directed into a 12-L flask containing
1.2 L of aqueous saturated ammonium chloride. 1045 mL of 2.0 M
p-chlorobromobenzene in anhydrous cyclohexane containing
1 equiv THF (170 mL; 2.09 mol), 1045 mL of commercial 2.0 M
n-BuLi in cyclohexane, and 2090 mL of 1.0 M benzaldehyde were
prepared to provide a continuous run time of 10.45 min. GC profil-
ing of the collected reaction stream indicated 94% conversion over
two steps with the crude product being produced at a rate of
43.7 g/min. The biphasic-quenched reaction mixture was trans-
ferred to a separatory funnel where the aqueous layer was
9. For other X/Li exchanges utilizing a continuous reactor, cf. (a) Nagaki, A.;
Takabayashi, N.; Tomida, Y.; Yoshida, J.-I. Org. Lett. 2008, 10, 3937; (b) Usutani,
H.; Tomida, Y.; Nagaki, A.; Okamoto, H.; Nokami, T.; Yoshida, J.-I. J. Am. Chem.
Soc. 2007, 129, 3046; (c) Choe, J.; Seo, J. H.; Kwon, Y.; Song, K. H. Chem. Eng. J.
2008, 135S, S17.
10. (a) Jia, X. Synlett 2009, 495 (reported mp = 55–56 °C); (b) Winstein, S.
Tetrahedron Lett. 1960, 2, 31 (reported mp = 53–55 °C).