N. Ambreen, T. Wirth
SHORT COMMUNICATION
were converted into the amides in this two-step process in and concentrated under reduced pressure. The crude mixture was
purified by flash chromatography (silica gel, hexane/ethyl acetate).
good yields.
Procedure for the Large-Scale Conversion of Geraniol into (E)-3,7-
Dimethylocta-2,6-dienamide in Flow: The oxidation reaction was
Table 3. Two-step reaction sequence to amides 2.
performed by using syringe pump PTFE tubing. Geraniol (2.00 g,
1
3 mmol) and (diacetoxyiodo)benzene (4.51 g, 14 mmol) were dis-
solved in THF (60 mL). 2,2,6,6-Tetramethyl-1-piperidinyloxyl
TEMPO; 203 mg, 1.3 mmol) was dissolved in THF (60 mL) and
(
was then loaded into two syringes; both syringes were placed in a
syringe pump (Fusion 100) and connected by a T-piece to a tubing
reactor (PTFE, length: 4 m; internal diameter: 0.75 mm). The tub-
ing reactor was immersed in a thermocontrolled water bath at
–
1
6
0 °C. The total flow rate was adjusted to 0.4 mLmin , which re-
sulted in a residence time of 4.5 min. Another syringe pump set at
–
1
the flow rate of 0.4 mLmin by using a syringe filled with hydrox-
ylamine hydrochloride (0.90 g, 13 mmol) and Cs CO (4.23 g,
3 mmol) in water (120 mL) was connected through a T-piece with
2
3
1
the outlet of the alcohol reaction mixture tube. The mixture was
passed through a flask in which the mixture was stirred to mix.
The reaction was performed as described above with the HPLC
pump feeding from the flask. The amide formation was performed
at 250 °C and 20 MPa back pressure with a flow rate adjusted to
–
1
0
.8 mLmin (residence time: 2.5 min). After a constant flow was
achieved, the reaction solution (120 mL) was collected. The organic
phase was removed, and the aqueous phase was extracted with
EtOAc (3ϫ 20 mL). The combined organic layer was dried with
magnesium sulfate, and the solvents were removed in vacuo. The
crude mixture was purified by flash chromatography (silica gel;
hexane/ethyl acetate, 9:1). The product (E)-3,7-dimethylocta-2,6-di-
One of the reaction sequences shown in Table 3 (entry 3) enamide was isolated in 59% yield (0.65 g, 3.8 mmol).
was also performed on a slightly larger scale. The amide
derived from geraniol [(E)-3,7-dimethylocta-2,6-dienamide]
was isolated in 0.65 g (3.8 mmol) after a total reaction time
Acknowledgments
of 150 min.
The authors thank the Schlumberger Foundation for support
through a Faculty for the Future fellowships (to N. A.) and the
EPSRC National Mass Spectrometry Facility, Swansea, for mass
spectrometric data.
Conclusions
We reported a highly efficient flow synthesis of amides
from aldehydes. The reaction was conducted with different [1] a) C. E. Mabermann, in: Encyclopedia of Chemical Technology
(
Ed.: J. I. Kroschwitz), Wiley, New York, 1991, vol. 1, p. 251;
aldehydes in short reaction times, with high conversions,
and good yields. If combined with an oxidation protocol,
even alcohols can be transformed into amides in a two-step
process, which makes this conversion an attractive approach
with regard to the batch protocol.
b) D. Lipp, in: Encyclopedia of Chemical Technology (Ed.: J. I.
Kroschitz), Wiley, New York, 1991, vol. 1, p. 266; c) R. Opsahl,
in: Encyclopedia of Chemical Technology (Ed.: J. I. Kroschwitz),
Wiley, New York, 1991, vol. 2, p. 346; d) L. J. Gooßen,
K. S. M. Saleh, M. Blanchot, Angew. Chem. Int. Ed. 2008, 47,
8
492; Angew. Chem. 2008, 120, 8620; e) N. Ibrahim, M. Legrav-
erend, J. Org. Chem. 2009, 74, 463; f) Y.-M. Pan, F.-J. Zheng,
H.-X. Lin, Z.-P. Zhan, J. Org. Chem. 2009, 74, 3148.
[2] a) Y. Kang, H. Chung, J. Kim, Y. Yoon, Synthesis 2002, 733;
b) I. Azumaya, T. Okamoto, F. Imabeppu, H. Takayanagi, Tet-
rahedron 2003, 59, 2325; c) X. Wu, L. Hu, J. Org. Chem. 2007,
Experimental Section
General Procedure for the Amide Formation in Flow: A solution of
aldehyde (1 mmol), Cs
2
CO
3
(1.2 mmol, 390 mg), and hydroxyl-
O (1:1, 8 mL)
7
2, 765; d) G. Daniel, B. David, W. Simon, Tetrahedron Lett.
amine hydrochloride (1.2 mmol, 83 mg) in THF/H
2
2008, 49, 5687; e) A. Teichert, K. Jantos, K. Harms, A. Studer,
Org. Lett. 2004, 6, 3477; f) S. Naik, G. Bhattacharjya, B. Ta-
lukdar, B. K. Patel, Eur. J. Org. Chem. 2004, 1254; g) D. M.
Shendage, R. Fröhlich, G. Haufe, Org. Lett. 2004, 6, 3675; h)
D. A. Black, B. A. Arndtsen, Org. Lett. 2006, 8, 1991.
was prepared in a vial. The inlet of the HPLC pump (JASCO) was
placed in the vial and the pump was connected to the steel tubing
reactor (length: 1 m, internal diameter: 1.6 mm) in an oven. The
subsequent cooling zone outside the oven was steel tubing (length:
[
3] a) M. Hashimoto, Y. Obora, S. Sakaguchi, Y. Ishii, J. Org.
Chem. 2008, 73, 2894; b) J. R. Martinelli, T. P. Clark, D. A.
Watson, R. H. Munday, S. L. Buchwald, Angew. Chem. Int. Ed.
6
0
0 cm, internal diameter: 0.5 mm). The flow rate was adjusted to
.4 mLmin , which led to a residence time of 5 min in the steel
–1
tubing reactor in the oven. After reaching a steady state, the reac-
tion mixture (2 mL) exiting the flow reactor was collected,
quenched with water (5 mL), and extracted with EtOAc (3ϫ
2
007, 46, 8460; Angew. Chem. 2007, 119, 8612; c) J. H. Park,
S. Y. Kim, S. M. Kim, Y. K. Chung, Org. Lett. 2007, 9, 2465;
d) S. H. Cho, E. J. Yoo, L. Bae, S. Chang, J. Am. Chem. Soc.
2005, 127, 16046; e) L. Cao, J. Ding, M. Gao, Z. Wang, J. Li,
5
mL). The combined organic layer was dried with MgSO
4
, filtered,
7592
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 7590–7593