A. L. Dunn et al.
Cambridge Isotope Laboratories, Inc. Tewksbury, MA, USA in
0.75-ml ampules and was used without further purification.
temperature. 1H, 13C, HSQC and HMBC data were recorded for char-
acterization of the reaction components.
Reaction of 3-methylpentanoyl chloride 9 with Meldrum’s acid 2 to produce 5-
(1-hydroxy-3-methylpentylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione 8b
Online NMR spectroscopy
3-Methylpentanoyl chloride 9 (0.24 mmol) in 0.75 ml acetonitrile-d3
was synthesized as described previously. A large excess of 1-
methylimidazole 4 (2.5mmol) was added to the solution of 9. A
bright yellow solid formed immediately upon addition and was fil-
tered off. Meldrum’s acid 2 was added to the filtrate via a micropi-
pette at room temperature (36 mg, 0.24 mmol). The reaction was
monitored at 25 °C with 1H NMR.
The online NMR system was used as previously described with
the needle splitting valve removed.[7] The reaction vessel
(Mettler-Toledo AutoChem Inc. Columbia, MD, USA), sample loop
and spectrometer were all temperature controlled to 25 °C using a
heating circulator (Julabo FP-50-HE) with Syltherm XLT tempera-
ture regulation fluid. The flow rate through the system was
3 ml/min regulated by a dual piston pump (Lab Alliance Prep
100, Scientific Systems, Inc. State College, PA, USA), and spectra
were acquired on the flowing solution on a 400-MHz spectrome-
ter. 1H NMR spectra were acquired with four scans, 30° pulse
angle and 10 s relaxation delay. 3-Methylpentanoic acid 1b
(3.5 ml, 28 mmol), 1-methylimidazole 4 (7.4ml, 92mmol) and
Meldrum’s acid 2 (4.5g, 31 mmol) were added to 30 ml anhydrous
acetonitrile in a reaction vessel under an atmosphere of N2. Re-
agents were circulated through a system to achieve temperature
(25 °C) and concentration equilibration. Pivaloyl chloride 3 (4.1ml,
34 mmol) was added to reaction vessel over the course of 10 min
via dosing syringe. 1H NMR spectra were obtained on the flowing
sample at 2 min intervals for the first 20 spectra, 6 min intervals
until reaction time reached 185 min and then every 16min until
reaction completion was observed.
Reaction of 3-methylpentanoic pivalic anhydride 6b and 3-methylpentanoic anhy-
dride 7b with Meldrum’s acid 2 to produce 5-(1-hydroxy-3-methylpentylidene)-2,2-
dimethyl-1,3-dioxane-4,6-dione 8b
Meldrum’s acid 2 (72 mg, 0.5 mmol) was added to the crude reaction
mixture of 3-methylpentanoic acid 1b, 3-methylpentanoic anhydride
7b and 3-methylpentanoic pivalic anhydride 6b in an NMR tube at
room temperature. The reaction was monitored at 25 °C with 1H NMR.
References
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Offline NMR tube characterization
Synthesis of 3-methylpentanoyl chloride 9
3-Methylpentanoic acid 1b (60 μl, 0.48 mmol) and three drops DMF
were added to 0.75 ml acetonitrile-d3. Oxalyl chloride (42μl,
0.48 mmol) was added via a micropipette in two portions over
15 min at room temperature. 1H, 13C, HSQC and HMBC data were re-
corded for characterization of the reaction components.
Synthesis of 3-methylpentanoic anhydride 7b
To crude reaction mixture of synthesized 3-methylpentanoyl chlo-
ride 9 in an NMR tube, 3-methylpentanoic acid 1b (50 μl,
0.40 mmol) and triethylamine (50 μl, 0.36 mmol) were added via a
micropipette. 1H, 13C, HSQC and HMBC data were recorded for char-
acterization of the reaction components.
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Synthesis of 3-methylpentanoic pivalic anhydride 6b
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To a crude reaction mixture of 3-methylpentanoic anhydride 6b, 3-
methylpentanoyl chloride 9 and 3-methylpentanoic acid 1b, 5 mg
pivalic acid 10 in an NMR tube at room temperature was added.
The reaction was monitored at 25 °C with 1H NMR.
Synthesis of 3-methylpentanoic pivalic anhydride 6b and 3-methylpentanoic
anhydride 7b
Supporting information
3-Methylpentanoic acid 1b (62 μl, 0.5mmol), pivalic anhydride 5
(102 μl, 0.5mmol) and 1-methylimidazole 4 (131 μl, 1.65mmol)
were added to 0.75ml acetonitrile-d3 in an NMR tube at room
Additional supporting information may be found in the online ver-
sion of this article at the publisher’s web-site.
wileyonlinelibrary.com/journal/mrc
Copyright © 2015 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2016, 54, 477–484