SPECIAL TOPIC
Halogen–Lithium Exchange in a Continuous Flow Reactor
2535
All research chemicals, including anhyd solvents used for reactions,
were supplied by Aldrich Chemical Co. and used as received. GC
analysis was performed on an Agilent 6850 instrument equipped
with a FID detector and GC-MS analysis was performed on an
Agilent 5973 MSD instrument containing a 6890 N Network system
equipped with an FID detector. NMR spectra were performed on a
JEOL Eclipse ECA 500 MHz instrument. Melting points were de-
solubility) at a flow rate of 66.7 mL/min (utilizing a Büchi pump,
Model C-610). Only 33.3 mL of the prepared 50 mL benzophenone
solution was added to ensure essentially a 1:1:1 ratio of n-BuLi/
p-BrA/benzophenone. A combined flow rate of 266.7 mL/min in
the second reactor provided a residence time of 0.026 s for the nu-
cleophilic addition step and an overall production time of 30 s. The
exit stream from the second reactor was directed into a flask con-
taining brine (50 mL). The biphasic-quenched reaction mixture was
transferred to a separatory funnel where the aqueous layer was sep-
arated and back-extracted with MTBE (25 mL). The combined or-
ganic layers were washed with brine (20 mL), dried (Na SO ), and
®
termined using a Mel-Temp apparatus.
Precautions to exclude oxygen and/or moisture were implemented
throughout all processes, save water quenches. All glassware was
2
4
oven-dried, N -purged and fitted with septa under a slight positive
2
concentrated in vacuo to provide a viscous oil. Overnight trituration
at r.t. with cyclohexane (10 mL) and filtration afforded >98% (GC)
pure (4-methoxyphenyl)diphenylmethanol (22.7 g, 80%) as a white
pressure of N before and during any reactant charges; needles and
2
syringes were accordingly handled, including N purge prior to any
2
reactant charge or aliquot sampling. No special handling other than
the above was necessitated during reactor studies.
1
6
solid; mp 80.2–81.4 °C (Lit. mp 82 °C).
1
H NMR (500 MHz, CDCl ): δ = 2.8 (s, OH), 3.8 (s, 3 H), 6.8 (d,
3
Batch Studies; General Procedure
J = 9.2 Hz, 2 H), 7.2 (d, J = 9.1 Hz, 2 H), 7.3 (complex m, 10 H).
Batch studies were performed on an 8 mmol scale. Flasks were
charged with substrate and diluted to 2 M (unless otherwise noted;
see Tables 1, 3) with cyclohexane and doping solvent (if applica-
ble). For competitive runs, defined as those with more than one sub-
strate, 8 mmol of each substrate was added to the flask and
cyclohexane was added to bring the volume to 4 mL (2 M). The sub-
strate(s) solution was placed in a water bath and n-BuLi (4 mL, 8
mmol) was added dropwise over a period of 45 s. Aliquots were tak-
en by withdrawing 0.3 mL from the reaction mixtures; these were
added to vials containing an excess of 2 M ClTMS in cyclohexane
1
3
C NMR (125 MHz, CDCl ): δ = 55.4, 81.8 113.3, 127.3, 127.9,
3
1
28.0, 129.3, 139.3, 147.2, 158.8.
Acknowledgment
Support of this research was under the auspices of NSF, CHE
0
70021. Support of our preliminary studies was provided by the Pe-
troleum Research Fund, PRF 42090-B1. Additional support was re-
ceived from the Western Kentucky University Research
Foundation. Continual consultation with Dr. Jeffrey C. Raber, Pre-
sident of KinetiChem, Inc., re Synthetron™ reactor parameters was
greatly appreciated. Finally, thanks are due to Steven Bush, Brian
Jones, and Maria DiLoreto for their laboratory assistance.
(0.5 mL). After 30 min, the vial solutions were quenched with sat.
aq Na CO (ca. 2 mL) and MTBE (ca. 2 mL to dilute properly for
2
3
GC) was added. After vigorous shaking, the organic layer was re-
1
moved and analyzed by GC and/or GCMS and/or H NMR (for
TMS integration comparison only). Identities of GC and NMR
peaks were confirmed by spiking with authentic samples. Compet-
itive reactions were spiked with products from single-substrate re-
actions to confirm peak identity. Single-substrate results are
contained in Tables 1 and 3, whereas competitive results are de-
scribed in the body of this paper.
References
(1) (a) The SynthetronTM model S3T1 reactor is available from
KinetiChem Inc., Irvine, CA, USA. (b) Holl, R. US Patent
7125527, 2006.
Synthetron Studies; General Procedure
Substrate solutions were prepared identical to the batch studies and
(2) (a) Slocum, D. W.; Kusmic, D.; Raber, J. C.; Reinscheld, T.
K.; Whitley, P. E. Tetrahedron Lett. 2010, 51, 4793.
kept under a slight positive pressure of N during all syringe pump
2
(b) Slocum, D. W.; Tekin, K. C.; Nguyen, Q.; Whitley, P. E.;
Reinscheld, T. K.; Fouzia, B. Tetrahedron Lett. 2011, 52,
withdrawals. A 25 mL solution of substrate(s) (50 mmol of a single
substrate or 50 mmol of each of the two competing substrates, 2.0
M) in cyclohexane or cyclohexane–THF, was prepared and reacted
with commercial 2.0 M n-BuLi in cyclohexane (25 mL). Reagent
solutions were delivered through Teflon tubing using independent
SYR-2200 dual programmable syringe pumps obtained from J-
KEM Scientific. The single reactant or mixture of two reactants was
7
141.
3) (a) Slocum, D. W.; Ray, J.; Shelton, P. Tetrahedron Lett.
002, 43, 6071. (b) Slocum, D. W.; Dumbris, S.; Brown, S.;
(
2
Jackson, G.; LaMastus, R.; Mullins, E.; Ray, J.; Shelton, P.;
Walstrom, A.; Wilcox, J. M.; Holman, R. W. Tetrahedron
2
003, 59, 8275. (c) Slocum, D. W.; Dietzel, P. Tetrahedron
1
fed into the Synthetron S3T1 reactor at 100 mL/min each when in
Lett. 1999, 40, 1823.
neat cyclohexane while 150 mL/min used when THF was employed
(
4) (a) Slocum, D. W.; Moon, R.; Thompson, J.; Coffey, D. S.;
Li, J. D.; Slocum, M. G.; Siegel, A.; Gaytongarcia, R.
Tetrahedron Lett. 1994, 35, 385. (b) Slocum, D. W.; Reed,
D.; Jackson, F.; Friesen, C. J. Organomet. Chem. 1996, 512,
[
(to provide more EoE (see text)] at 12 °C (chilled with a circulating
chiller). The exit streams were directed into 250 mL round-bot-
tomed flasks (immersed in ice baths) containing excess ClTMS (12
mL, 120 mmol) diluted to 60 mL (2 M) with cyclohexane. After 30
min, the solutions were quenched with sat. aq Na CO (ca. 15 mL)
2
65.
5) Bauer, W.; Schleyer, P. v. R. J. Am. Chem. Soc. 1989, 111,
191.
6) (a) Jedlicka, B.; Crabtree, R. H.; Siegbahn, P. E. M.
Organometallics 1997, 16, 6021. (b) Hoffmann, R. W.;
Bronstrup, M.; Muller, M. Org. Lett. 2003, 5, 313.
2
3
(
(
and a sample of the organic layer was diluted and was analyzed by
GC and/or GCMS and/or crude NMR.
7
High-Output Synthesis of (4-Methoxyphenyl)diphenylmeth-
anol in the Synthetron
A 50 mL solution of p-BrA [12.7 mL, 100 mmol (2.0 M)] in THF
was prepared and reacted with commercial 2.0 M n-BuLi in cyclo-
hexane (50 mL). Reagent solutions were fed at 100 mL/min each
into the Synthetron S3T1 reactor at 12 °C. A combined flow rate of
(7) (a) Usutani, H.; Tomida, Y.; Nagaki, A.; Okamoto, H.;
Nokami, T.; Yoshida, J. J. Am. Chem. Soc. 2007, 129, 3046.
(b) Nagaki, A.; Tomida, Y.; Usutani, H.; Kim, H.;
Takabayashi, N.; Nokami, T.; Okamoto, H.; Yoshida, J.
Chem. Asian J. 2007, 2, 1513. (c) Nagaki, A.; Takabayashi,
N.; Tomida, Y.; Yoshida, J. Org. Lett. 2008, 10, 3937.
200 mL/min in the first reactor provided a residence time of 0.034
s for the Br–Li exchange step. The exit stream was directed into a
1
second Synthetron S3T1reactor at 12 °C that was simultaneously
(d) Yoshida, J.; Nagaki, A.; Nokami, T. US Patent
fed a 3 M solution of benzophenone (50 mL solution prepared with
2
008/0194816 A1, 2008.
27.6 g, 150 mmol) in cyclohexane (containing 15 mL of THF for
©
Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2531–2536