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solution of N,N-bis(p-methoxybenzyl)carbamoyl chloride (0.10m in
THF; flow rate = 9.0 mLminÀ1) and a solution of lithium naphthale-
nide (0.22m in THF; flow rate = 9.0 mLminÀ1) were introduced into
M1 (f = 250 mm) by using a plunger pump and a microfeeder pump,
respectively. The mixture was passed through R1 (f = 1000 mm, l =
100 cm). The resulting solution was mixed with methyl chloroformate
(0.30m in THF; flow rate = 9.0 mLminÀ1) in M2 (f = 250 mm). The
mixture was passed through R2 (f = 1000 mm, l = 100 cm) and was
introduced into M4 (f = 500 mm). A solution of a functionalized
organic compound and
a solution of a lithiating agent were
introduced into M3 (f = 250 mm) by using plunger pumps, and the
mixture was passed through R3. The resulting solution was intro-
duced into M4. After a steady state was reached, the product solution
was collected for 1 min while being quenched with a saturated
aqueous solution of NH4Cl. The aqueous layer was extracted with
EtOAc (3 20 mL) and the combined organic layers were washed
with brine, dried over Na2SO4, and concentrated under reduced
pressure. The crude product was purified by silica gel column
chromatography followed by preparative HPLC.
Figure 4. Formal synthesis of GW356194.
trifluoroacetic acid gave 6 in 62% yield, which can be
converted into 5-amino-1,2,4-triazine derivative GW356194
according to a literature procedure.[22]
Acknowledgements
In conclusion, we have developed a flash method for
harnessing unstable carbamoyl anions, that is, carbamoyl-
lithium, using a flow microreactor system. The extremely fast
mixing in the system renders the method successful. The
method can be applied to the synthesis of various amides,
including a-ketoamides. Functionalized a-ketoamides can be
efficiently synthesized by the three-component reaction of
a carbamoyllithium, methyl chloroformate, and a functional-
ized organolithium reagent. Such transformations are practi-
cally impossible when the conventional batch method is used.
The power of the method was demonstrated by the straight-
forward synthesis of GW356194, a potential sodium channel
blocker. Further work is in progress to explore the full scope
of this useful transformation and its applications in organic
synthesis.
This work was partially supported by a Grant-in-Aid for
Scientific Research (S) (number 26220804), Scientific
Research (S) (number 25220913), Scientific Research (B)
(number 26288049), and Scientific Research on Innovative
Areas 2707 Middle molecular strategy from MEXT (no.
15H05849).
Keywords: amides · carbonyl groups · flow chemistry ·
lithiation · microreactors
How to cite: Angew. Chem. Int. Ed. 2016, 55, 5327–5331
Angew. Chem. 2016, 128, 5413–5417
[1] a) E. J. Corey, Pure Appl. Chem. 1967, 14, 19; b) D. Seebach,
D. Seebach, Synthesis 1977, 357; f) D. Seebach, Angew. Chem.
[3] P. A. Wender, V. A. Verma, T. J. Paxton, T. H. Pillow, Acc.
[5] For books on flow chemistry and flow microreactor synthesis,
see: a) V. Hessel, S. Hardt, H. Lçwe, Chemical Micro Process
Engineering, Wiley-VCH, Weinheim, 2004; b) Micro Process
Engineering; (Eds.: V. Hessel, A. Renken, J. C. Schouten, J.
Yoshida), Wiley-Blackwell, Oxford, 2009; c) Microreactors in
Organic Chemistry and Catalysis, 2nd ed. (Ed.: T. Wirth), Wiley,
Hoboken, 2013.
[6] For reviews on flow chemistry and flow microreactor synthesis,
Experimental Section
Typical procedure for the generation of carbamoyllithium compounds
followed by reaction with electrophiles using a flow microreactor
system: A flow microreactor system consisting of two T-shaped
micromixers (M1 and M2), two microtube reactors (R1 and R2), and
three tube pre-cooling units (P1, P2, and P3; inner diameter f =
1000 mm, length l = 300 cm) was used. A solution of a carbamoyl
chloride (0.10m in THF; flow rate = 9.0 mLminÀ1) and a solution of
lithium naphthalenide (0.22m in THF; flow rate = 9.0 mLminÀ1) were
introduced into M1 by using a plunger pump and a microfeeder pump,
respectively, and the mixture was passed through R1 (f = 1000 mm,
l = 100 cm). The resulting solution was mixed with an electrophile
(0.30m; flow rate = 9.0 mLminÀ1) in M2. The mixture was passed
through R2 (f = 1000 mm, l = 100 cm). After a steady state was
reached, the product solution was collected for 2 min while being
quenched with a saturated aqueous solution of NH4Cl. The aqueous
layer was extracted with EtOAc (3 20 mL) and the combined
organic layers were washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. The crude product was purified
by silica gel column chromatography followed by preparative HPLC.
Typical procedure for three-component coupling using a flow
microreactor system: A flow microreactor system consisting of four T-
shaped micromixers (M1, M2, M3, and M4), four microtube reactors
(R1, R2, R3, and R4), and five tube pre-cooling units (P1, P2, P3, P4,
and P5; inner diameter f = 1000 mm, length l = 300 cm) was used. A
5330
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Angew. Chem. Int. Ed. 2016, 55, 5327 –5331