stable than diazomethane, it is still toxic6 and therefore still
requires careful handling.
the precursor. Using this reagent in a Vapourtec R2+/R4
combination reactor13 quantitative methylation of benzoic
acid was possible; however, a large excess of reagent was
needed to achieve complete conversion. The reactor config-
uration required two independent injection loops (5 mL
internal volume, PFA, 1 mm id), one loaded with a solution
of benzoic acid (0.35 M in MeOH) and the other loaded
with a solution of TMSCHN2 (0.8 M in Et2O, 3 equiv). The
reagents were mixed at a T-piece and then flowed at a
combined flow rate of 400 µL/min into a 10 mL convection
flow coil (CFC; 10 mL internal volume, 1 mm id, residence
time 25 min) mounted on the Vapourtec R4 unit. Following
careful evaporation of the solvent and the excess TMSCHN2,
clean methyl ester was obtained quantitatively, with no
requirement for further purification.
Flow based synthesis can offer many advantages over
batch sequencing including reduced processing times, precise
parameter control, higher reproducibility, and enhanced
selectivity.7 In addition the application of microreactor
technology gives highly efficient heat and mass transfer and
allows for small reaction volumes which in turn increases
the safety profile of handling exothermic reactions and
reactions involving explosive and toxic materials.8 In this
paper we describe our most recent work toward designing a
safe synthesis of diazoketones in a continuous flow mode.9
In order to evaluate the applicability of diazomethane
precursors in flow, methylation of benzoic acid was used as
a test reaction.10 Various precursors were investigated using
different flow setups. In particular early work was conducted
using a polymer-supported Diazald (PS-Diazald).11 Diaz-
omethane was produced in situ by flowing a solution of
KOtBu in iPrOH through a glass cartridge packed with the
PS-Diazald, using DCM as the system solvent. The output
reaction stream was directed into a mixing chip and
combined with a secondary stream of water. Extraction and
separation of the resulting biphasic mixture was carried out
using a FLLEX membrane device giving an organic flow
which contained the diazomethane.12 The organic stream was
directed into a flask containing benzoic acid, generating the
methyl ester (Scheme 1). Although this procedure showed
Expanding upon this encouraging result, we decided to
investigate the formation of diazoketone in flow using
TMSCHN2 as the preferred diazotizing source. Based upon
on the work of Shiori,14 we designed a flow setup using a
twin injection loop configuration (2 mL internal volume,
PFA, 1 mm id). The first sample loop was loaded with a
solution of an acyl chloride (1 M in MeCN/THF 1:1), and
the second with a solution of TMSCHN2 (1.5 M in Et2O/
MeCN/THF 5.7:1:1). The two reagent streams were com-
bined at a T-piece and passed at a combined flow rate of
200 µL/min through a cartridge containing an immobilized
base (PS-NMe2 A-21, PS-NEt2 or PS-NiPr2, 1-3 equiv). A
back-pressure regulator (BPR) was used to maintain the
system pressure at 8 bar. The exiting solution was collected
and concentrated under reduced pressure prior to analysis.
Using 1-naphthoylchloride as the starting material 62%
conversion to the diazoketone was achieved using polymer-
supported diethylamine (3 equiv) at rt. The only side products
observed were the TMS-protected diazoketone (22%) and
1-chloroacetylnaphthalene (3%) with the remaining material
being unreacted acylchloride (13%).15 Treatment of the crude
reaction mixture with a PS-tetraalkylammonium fluoride
salt16 smoothly transformed all of the TMS-protected diaz-
oketone to the corresponding diazoketone. Indeed, it was
found that, in our flow setup, the amine base could be simply
replaced by the PS-fluoride. The final flow setup was
comprised of two flow streams (each at a flow rate of 200
µL/min) of the acyl chloride and TMSCHN2 which met at a
T-piece and were then directed into a 10 mL CFC. The
incubated reaction mixture was finally passed through a glass
cartridge containing the PS-fluoride (1.5 equiv, 15 mm id)
at rt. The exiting flow stream was collected, and the solvent
evaporated to afford the desired product within 2 h at rt (vs
Scheme 1. Generation of Diazomethane in Flow
promise it was ultimately abandoned due to consistently low
conversion and relatively high pressures being generated by
the solid-supported reagent.
Significantly better results were obtained using com-
mercially available TMSCHN2 (2 M solution in Et2O) as
(7) Anderson, N. Org Process Res. DeV. 2001, 5, 613–621. Kockmann,
N.; Gottsponer, M.; Zimmermann, B.; Roberge, D. M. Chem.sEur. J. 2008,
14, 7470–7477. Hessel, V. Chem. Eng. Technol. 2009, 32, 1655–1681.
Baxendale, I. R.; Deeley, J.; Griffiths-Jones, C. M.; Ley, S. V.; Saaby, S.;
Tranmer, G. K. J. Chem. Soc., Chem. Commun. 2006, 24, 2566–2568.
Baxendale, I. R.; Griffiths-Jones, C. M.; Ley, S. V.; Tranmer, G. K. Synlett
2006, 3, 427–430.
(8) Van Alsten, J. G.; Reeder, L. M.; Stanchina, C. L.; Knoechel, D. J.
Org. Process Res. DeV. 2008, 12, 989–994. Kulkarni, A. A.; Kalyani, V. S.;
Joshi, R. A.; Josh, R. R. Org. Process Res. DeV. 2009, 13, 999–1002.
Baumann, M.; Baxendale, I. R.; Martin, L. J.; Ley, S. V. Tetrahedron 2009,
65, 6611–6625. Baxendale, I. R.; Ley, S. V.; Mansfield, A. C.; Smith, C. D.
Angew. Chem., Int. Ed. 2009, 48, 4017–4021.
(11) PS-Diazald was prepared from a commercially available polymer-
supported tosyl chloride in two steps: see Supporting Information.
(12) Flow Liquid Liquid Extraction machine, available from Syrris,
(9) Industrial scale continuous diazomethane production is carried out
by Phoenix Chemicals: US6962983. This is achieved by feeding a base
and diazomethane precursor into a reactor vessel that generates diazomethane
which can be removed using a diluent gas.
(10) Struempel, M.; Ondruschka, B.; Daute, R.; Stark, A. Green Chem.
2008, 10, 41–43. Struempel, M.; Ondruschka, B.; Stark, A. Org. Process
Res. DeV. 2009, 13, 1014–1021.
(14) Aoyama, T.; Shiori, T. Chem. Pharm. Bull. 1981, 29, 3249–3255.
(15) Similar results were obtained starting from 3-phenyl propionyl
chloride 1a; we observed formation of the expected diazoketone 2a (62%)
and the TMS-protected diazoketone (31%).
(16) A23: 2-3 mmol, commercially available from Sigma-Aldrich.
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