A Scalable, Combined-Batch, and Continuous-Flow Synthesis of a Bio-Inspired UV-B Absorber

Article abstract of DOI:10.1071/CH19252

A new, chromatography-free synthesis for the preparation of an experimental UV-B absorber is reported. A key step of the process is a one-pot partial reduction of a symmetrical imide with a sequential dehydration step. The synthesis uses several continuous-flow steps to increase sample throughput and was used to prepare sufficient material to support further testing activities in >99 % purity.

Full text of DOI:10.1071/CH19252

RESEARCH FRONT
CSIRO PUBLISHING
Aust. J. Chem. 2019, 72, 860–866
Full Paper
https://doi.org/10.1071/CH19252
A Scalable, Combined-Batch, and Continuous-Flow
Synthesis of a Bio-Inspired UV-B Absorber
A C
,
A
A
A
Mark York,
Karen E. Jarvis, Jamie A. Freemont, John H. Ryan,
A
A
B
G. Paul Savage, Stephanie A. Logan, and Larissa Bright
A
CSIRO Manufacturing, CSIRO, Clayton, Vic. 3168, Australia.
B
Coral Sunscreen Pty Ltd, Aitkenvale, Qld 4814, Australia.
C
Corresponding author. Email: mark.york@csiro.au
A new, chromatography-free synthesis for the preparation of an experimental UV-B absorber is reported. A key step of the
process is a one-pot partial reduction of a symmetrical imide with a sequential dehydration step. The synthesis uses several
continuous-flow steps to increase sample throughput and was used to prepare sufficient material to support further testing
activities in .99 % purity.
Manuscript received: 3 June 2019.
Manuscript accepted: 5 July 2019.
Published online: 24 July 2019.
Introduction
readily available sustainable sources of material and, more
importantly, a lack of hydrolytic and oxidative stability of the
parent MAAs.[5,6]
Despite prolonged exposure to the damaging ultraviolet (UV)
radiation of the Australian climate, the shallow-water coral
polyps of the Great Barrier Reef demonstrate resilience to
extended periods of solar irradiation. This resilience is due in
part to the presence of UV-absorbing compounds within the
corals.[1] The presence of UV-absorbing compounds in the
extracts of shallow-water coral species has been known since
they were reported by Shibata in 1969.[2] These compounds
were identified as a family of mycosporine-like amino acids
(MAAs, Fig. 1). Since their identification, there has been
interest in developing these compounds for use as commercial
sunscreens.[3,4] These efforts have been hampered by a lack of
In an attempt to address these shortfalls and improve
synthetic accessibility, a collaboration between groups at the
Australian Institute of Marine Science (AIMS) and Imperial
Chemical Industries (ICI) developed a series of bio-inspired UV-
absorbing compounds. These retained the enaminone chromo-
phore of the MAAs but with a simplified structure, movement of
the enaminone nitrogen from an exocyclic to an endocyclic
position to improve hydrolytic stability, and the addition of a
geminal dimethyl substituent to improve oxidative stability.[3]
The evolution of these compounds can be seen in Fig. 2.
CO2H
Me
N
O
NH
OCH3
OCH3
OCH3
NH
OH
HO
HO
HO
NH
CO2H
NH
CO2H
HO
HO
HO
CO2H
Mycosporine glycine
Palythine
Porphyra 334
Fig. 1. Representative MAAs.
O
O
O
OCH3
OCH3
HO
N
NH
NH
HO
CO2Me
CO2H
Mycosporine glycine
1
Fig. 2. Evolution of bio-inspired UV absorbers.
Journal compilation Ó CSIRO 2019
www.publish.csiro.au/journals/ajc

Synthesis of a Bio-Inspired UV-B Absorber
861
This series of compounds is typified by 1, a tetrahydropyr-
idine derivative. This is a UV-B absorber with a reported
absorbance maximum in methanol of 307 nm and a molar
Results and Discussion
In order to further explore the properties of UV absorber 1, we
required access to .100 g of material and so undertook an
assessment of the published methods for suitability of use at this
(and potentially larger) scales. The synthesis described in
Scheme 1 was discounted owing to the use of excess amounts of
mercury reagents in the key oxidation step and the high risk of
contamination of final products with mercury. The two related
syntheses reported in Scheme 2 were initially judged to be more
suitable; however, several chromatographic separations and
distillations were required to provide pure 1. Owing to the scale
of the work proposed, these operations were not desirable.
Additionally, we experienced considerable difficulty replicating
the reported yields on anything but a very small scale for both the
radical bromination and Rosenmund reduction processes. The
reported reaction of aldehyde 10 with isobutylamine to give
enamine 5 also proved troublesome to perform in a reproducible
fashion owing to the instability of both 5 and 10.
extinction coefficient of 29300 Mꢀ1 cmꢀ1 [7]
Several synthetic
.
pathways to absorber 1 have been reported.[7,8] One reported
synthesis begins with commercially available 3,3-dimethylglu-
taric anhydride, 2, which was treated with isobutylamine fol-
lowed by acetic anhydride to yield the corresponding imide 3.
This was then exhaustively reduced with lithium aluminium
hydride to give piperidine 4, which was oxidised with mercuric
acetate gave the corresponding enamine 5. Finally, acylation of
5 gave UV absorber 1 (Scheme 1).
Alternative approaches to advanced enamine intermediate
5 have also been reported commencing with either methyl
3,3-dimethylpent-4-enoate 6 or 3,3-dimethylpent-4-enal 11
and following a radical bromination approach to yield common
intermediate 10. This intermediate was then cyclised in the
presence of isobutylamine to give 5 (Scheme 2).[7]
A concise approach to enamine 5 from pyranone 13 has also
been reported (Scheme 3).[8] This involved condensation of
13 with isobutylamine to form enaminone 14, followed by
reduction of 14 to the desired advanced intermediate 5.
We were initially drawn to the synthesis outlined in Scheme 3
owing to the brevity and high yields reported. However,
although pyranone starting material 13 was reported to be
readily commercially available at the time of the initial publica-
tion,[8] this was no longer the case for us, with the material being
available only from a limited range of suppliers at prohibitively
high cost from a manufacturing point of view.[9] Syntheses of
13 have been reported but these protocols were judged to be
unsuitable for the desired application. In one report, a Wacker
oxidation process requiring high temperatures and pressures of
oxygen was used.[10] Another synthesis used more accessible
reaction conditions but was a four-step, low-yielding synthesis
from a starting material that was not commercially available.[11]
Nevertheless, for completeness we obtained a small sample of
NH2
LiAlH4
O
N
O
N
Ac2O
Et2O
O
O
O
2
3
94 %
4
82 %
Hg(OAc)2 H2S(g)
O
O
NH2
Cl
LiAlH4
Et3N
CH2Cl2
N
N
O
N
Et2O
N
O
O
p-TsOH
81 %
13
1
5
55 %
14
85 %
5
97 %
Scheme 1. Published synthesis of absorber 1.[7]
Scheme 3. Published synthesis of enamine intermediate 5 from pyranone 13.
HBr(g)
KOH
CO2H
CO2Me
Br
CO2H
77 %
(PhCO2)2
pentane
EtOH
8
>95 %
SOCl2
7
6
H2
NH2
88 %
Pd/BaSO4
COCl
89 %
Br
Br
O
N
9
PhMe
AcOH
EtOH/H2O
10
78 %
5
HBr(g) >95 %
(PhCO)2
pentane
OEt
OEt
HCl(g)
EtOH
O
12
11
Scheme 2. Published syntheses of enamine intermediate 5.

862
M. York et al.
NH2
SOCl2
Ac2O
THF
O
O
O
N
O
HO
OH
O
O
O
CH2Cl2/CHCl3
15
2
3
92 %
99 %
LiAlH4 Et2O
O
O
Cl
LiAlH4
Et2O
N
N
O
Et3N
N
CH2Cl2
72 %
5
14
1
95 %
Scheme 4. Synthesis of UV absorber 1.
89 %
HO
OH
O
O
15
1.95 M in THF
1.2 equiv.
10 mL min–1
O
O
99 %
2
O
Ac2O
10 mL
110°C
10 mL
110°C
10 mL
110°C
10 mL
110°C
Residence time = 4 min
Product throughput = 2.74 g min–1, 165 g h–1
Scheme 5. Continuous-flow approach to anhydride 2.
pyranone 13 to examine the published synthesis (Scheme 3), but
in our hands, the reported procedures did not give adequate
yields of intermediate 14.
of scale-up, rapid mixing and heat transfer, and inherently
higher safety owing to smaller reactor volumes and the con-
tainment of hazardous reaction intermediates.[16] Thus, a
continuous-flow approach to anhydride 2 was developed using
1.2 equiv. of acetic anhydride to effect the transformation over
the course of a 4-min reaction (Scheme 5). Anhydride 2 was
isolated in near-quantitative yield after removal of volatiles. By
utilising a series of four 10-mL reactor coils, the reaction
pumping rate was able to be increased 4-fold over that used with
one coil while maintaining the same residence time. This
allowed the production of 165 g of the product in 1 h.
Given the unsuitability of the previously reported syntheses
for production of material at the desired scale, a new approach
was devised (Scheme 4).[12] Commercially available 3,3-
dimethylglutaric acid, 15, was converted to the corresponding
anhydride 2 in quantitative yield (2 is also commercially
available but expensive on scale). Conversion of the anhydride
to the corresponding glutarimide 3 was achieved in 92 % yield
followed by a partial reduction to enamide 14. This was then
further reduced to enamine 5 and acylated with propionyl
chloride to yield 1.
Formation of Imide 3
The conversion of 2 to 3 has been reported previously by a one-
pot process in 94 % yield whereby 2 is treated with iso-
butylamine followed by an excess of acetic anhydride.[7] The
addition of isobutylamine to 2 under solvent-free conditions as
reported proved to be an extremely exothermic process that was
deemed unsuitable for large-scale application. Additionally, the
reported procedure gave only minor amounts of the desired
product in our hands, with the bulk of the material being a
mixture of intermediate amide 16 and the corresponding mixed
acetic anhydride. With this in mind, a two-step approach to 3
was developed involving initial synthesis of the intermediate
amide 16 over a 3-min reaction time (Scheme 6). The product
was isolated in near-quantitative yield after an aqueous workup.
As the cyclisation of 16 to 3 in the presence of acetic anhydride
had already been found to give only minimal amounts of
Formation of Anhydride 2
The transformation of 3,3-dimethylglutaric acid, 15, to the
corresponding anhydride 2 is a known reaction that has been
reported using either oxalyl chloride in 70 % yield,[13] an 8-fold
excess of acetic anhydride in 79 % yield,[14] or an excess of
thionyl chloride in 96 % yield.[15] In an attempt to avoid the large
excess of acetic anhydride used in the published procedure
and the resulting lengthy distillation and recrystallisation, a
continuous-flow approach was developed. The performance of
synthetic transformations under continuous-flow conditions is
an area of intense current interest. This interest can be explained,
at least in part, by the array of potential advantages that
continuous-flow processing can have over traditional batch
processing. Such advantages include high reproducibility, ease

Synthesis of a Bio-Inspired UV-B Absorber
863
OH
H
N
O
O
O
O
O
16
2
99 %
1.3 M in CH2Cl2
10 mL min–1
10 mL
50°C
10 mL
50°C
10 mL
50°C
10 mL
50°C
NH2
Residence time = 3 min
5 M in CH2Cl2 (1:1 v/v)
3.12 mL min–1
Product throughput = 2.8 g min–1, 168 g h–1
1.2 equiv.
Scheme 6. Continuous-flow synthesis of amide 16.
OH
O
H
N
O
N
O
O
1.63 M in CHCl3
3
2.96 mL min–1
10 mL
95°C
10 mL
95°C
10 mL
95°C
10 mL
95°C
97 %
16
SOCl2
6.85 M in CHCl3 (1:1 v/v)
1.04 mL min–1
Residence time = 10 min
Product throughput = 0.92 g min–1, 55 g h–1
1.5 equiv.
Scheme 7. Continuous-flow synthesis of imide 3.
O
N
O
O
O
O
2
3
1.3 M in CHCl3
2.58 mL min–1
10 mL
100°C
10 mL
100°C
10 mL
100°C
10 mL
50°C
92 %
SOCl2
6.85 M in CHCl3 (1:1 v/v)
0.74 mL min–1
NH2
1.5 equiv.
5 M in CHCl3 (1:1 v/v)
0.67 mL min–1
1 equiv.
Residence time = 10 min
Product throughput = 0.6 g min–1, 36 g h–1
Scheme 8. Telescoped continuous-flow synthesis of imide 3.
product, cyclisation in the presence of thionyl chloride was
attempted. This gave the product in 97 % yield after a reaction
time of 10 min at 958C (Scheme 7) This process allowed the
preparation of 3 in sufficient quantities to complete the synthesis
of absorber 1. In all instances of the continuous-flow reactions,
flow rate was calculated in conjunction with total reactor vol-
ume in order to give the desired reaction and residence time.
A telescoped synthesis of 3 directly from anhydride 2 was
also demonstrated whereby a solution of anhydride 2 was
reacted with isobutylamine at 508C and the resulting solution
of amide 16 further treated with thionyl chloride and reacted at
1008C to give 92 % of the desired product after aqueous workup
and a total reaction time of 10 min (Scheme 8).
Formation of Enamide 14
Previously reported methods for the conversion of imide 3 to
enamine building block 5 involved the complete reduction of 3 to
substituted piperidine 4 followed by oxidation with mercuric
acetate.[7] In order to avoid the need for such a low-yielding and
hazardous oxidationprocess, a reduction approach was developed
whereby 3 was partially reduced to enamide 14 via hemiaminal
intermediate 17 (Scheme 9). Initial attempts to form 17 through a
sodium borohydride reduction weremostly unsuccessful, withthe
major isolated product being ring-opened compound 18. Ring
opening could be avoided by performing the reaction in HCl/
EtOH but a large excess of borohydride was required (8 equiv.)
and the reaction did not proceed to completion, necessitating

864
M. York et al.
evaluation. Using a combination of batch and continuous-flow
steps, the process allowed the chromatography-free preparation
of ,0.5 kg of 1 over several batches in .99 % HPLC purity
(254 nm). The overall yield of the process was 55 %.
N
O
HO
N
O
O
N
O
14
17
3
Experimental
OH
H
N
Methods and Materials
Continuous-flow chemistry was performed on a Vapourtec R-4
flow reactor heater with connected R2þ and R2 pumping
modules. Reagents were used as received from commercial
O
18
1
suppliers. H and 13C NMR scans were performed on Bruker
Scheme 9. Partial reduction approach to enamide 14.
Advance 400 MHz NMR spectrometer at 400 and 100 MHz
respectively. NMR scans were performed with the sample held
at 25 ꢁ 0.18C. Chemical shifts for all experiments are referenced
using the Unified Scale relative to 0.3 % tetramethylsilane in
deuteriochloform. Samples for NMR spectroscopy were pre-
pared by dissolving the analyte in CDCl3. Spectroscopic data are
reported using the following format: (1) chemical shift (ppm);
(2) multiplicity (s, singlet; d, doublet; t, triplet; q, quartet;
m, multiplet; br, broad); (3) J, coupling constant (Hz); (4)
integration. Melting points were determined using a Bu¨chi
melting point B-545 apparatus and are uncorrected. Mass
spectrometric analyses were performed on a Thermo Scientific
Q Exactive mass spectrometer fitted with an atmospheric solids
analysis probe (ASAP) ion source (M&M Mass Spec Consult-
ing).[17] The design and method of ionisation have been
described previously.[18,19] Positive and negative ions were
recorded in an appropriate mass range at 140000 mass resolu-
tion. The atmospheric pressure chemical ionisation (APCI)
probe was used without flow of solvent. The nitrogen nebulising
and desolvation gas used for vaporisation was heated to 3508C in
these experiments. The sheath gas flow rate was set to 25, the
auxiliary gas flow rate to 5, and the sweep gas flow rate to 2 (all
arbitrary units). The discharge current was 4 mA and the cap-
illary temperature was 3208C. HPLC analysis was performed on
an Alliance system comprising a Waters 2695 Separations
module and a 2996 photodiode array detector (scanning from
190 to 700nm). The analysis was performed on a 150 ꢂ 4.6 mm
Alltima C18 column using isocratic 65 % acetonitrile/25 %
water at 1.0 mL minꢀ1 as mobile phase. The chromatograms
were recorded using a wavelength of 254 nm. Data collection
and processing were performed in Waters Empower 3 software.
chromatographic purification. Reduction using sodium bis-
(2-methoxyethoxy)aluminium hydride (1 equiv.) gave ,50 %
conversion to hemiaminal 17 when performed in both
continuous-flow and batch modes. An attempt to increase con-
version by increased reaction temperature or equivalents of
reducing agent resulted in over-reduction to piperidine 4.
In an attempt to avoid over-reduction of 3 to piperidine 4,
reduction with lithium aluminium hydride was attempted in
diethyl ether at low temperature, with the rationale being that the
lower solubility of organoaluminates derived from LiAlH4
would cause the product of the initial reduction to form a
precipitate and disfavour over-reduction. This was borne out,
with 40 % of 17 being isolated by column chromatography after
reduction with LiAlH4. In order to avoid an additional step in the
synthesis, dehydration to 14 was performed in situ by acidifica-
tion of the reaction mixture. Thus, an 89 % yield of 14 could be
obtained from the reduction of 3 with LiAlH4 followed by an
acidic workup (Scheme 4).
Formation of Enamine 5
The reduction of 14 to enamine 5 has been previously reported to
proceed with 97 % yield in the presence of LiAlH4.[8] In the
present work, a slightly modified version of this procedure was
used to provide 5 in 95 % yield. Enamine 5 was found to be par-
ticularly unstable with respect to hydrolysis and oxidation and so
the reduction reaction was quenched with sodium sulfate dec-
ahydrate in place of water. In the majority of cases, the material
was used directly on isolation. Samples of enamine 5 could
be stored in a freezer for up to 3 months if treated with 1 wt-%
dibutylhydroxytoluene (BHT) before removal of solvent.
4,4-Dimethyldihydro-2H-pyran-2,6(3H)-dione 2
Formation of UV absorber 1
Acetic anhydride (265 mL, 2.81mol) was added to a solution of
3,3-dimethylglutaric acid, 15, (375 g, 2.34 mol) in THF (500 mL)
and diluted to a total volume of 1200 mL with THF. The solution
was then pumped at a rate of 10 mL minꢀ1 through a series of
four 10-mL reactor coils (perfluoroalkoxy alkane (PFA) tubing,
1-mm ID) heated to 1108C and fitted with an 8-bar (800 kPa)
acid-resistant backpressure regulator. The combined eluents
were evaporated under vacuum, toluene added (100 mL), and the
solvent evaporated to give the title compound as a colourless
solid (335.0 g, 99 %). Spectroscopic data corresponded to those
reported previously.[14] dH 2.62 (s, 4H), 1.17 (s, 6H).
Acylation of enamine 5 with propionyl chloride was reported to
result in the isolation of 1 in 81 % yield after purification by
column chromatography.[7] In our hands, it was possible to
isolate 1 in 75–88 % yield but the material remained signifi-
cantly coloured even after chromatographic purification (in its
pure state, 1 is an almost colourless oil). It was found that the
final product 1 could be isolated from the reaction mixture in
.99 % HPLC purity (254 nm) and 72 % yield without recourse
to chromatography by formation of the hydrochloride salt,
washing with ethyl acetate and conversion to the free base.
Additionally, it was found that the HCl salt provided a highly
stable form of 1, which was suitable for extended storage at
ambient temperature.
5-(Isobutylamino)-3,3-dimethyl-5-oxopentanoic acid 16
A solution of 4,4-dimethyldihydro-2H-pyran-2,6(3H)-dione, 2,
(1.3 M in CH2Cl2, 1791 mL, 2.33 mol) pumped at a rate of
10 mL minꢀ1 was mixed at ambient temperature with a solution
of isobutylamine (5 M in CH2Cl2, 278 mL, 2.79 mol) pumped at
a rate of 3.12 mL minꢀ1 via a T-piece and passed through a series
Conclusions
An efficient and scalable synthesis of 1, a bio-inspired UV
absorber, has been developed to enable further testing and

Synthesis of a Bio-Inspired UV-B Absorber
865
of four 10-mL reactor coils (PFA tubing, 1-mm ID) heated to
508C and fitted with an 8-bar acid-resistant backpressure regu-
lator. The combined eluents were then washed with dilute HCl
solution (2M, 500 mL), dried with magnesium sulfate, and
evaporated under vacuum to a yellow oil, which on standing
solidified to give the title compound as a cream solid (496.6 g,
99 %). Mp 70–718C. m/z [M þ H]þ 216.1595; C11H22NO3
requires [M þ H]þ 216.1594. dH 6.17 (s, br, 1H), 3.18 (t, J 6.3,
2H), 2.45 (s, 2H), 2.33 (s, 2H), 1.90–1.80 (m, 1H), 1.14 (s, 6H),
0.97 (d, J 6.7, 6H). dc (CDCl3, 400 MHz) 173.92, 173.82, 47.51,
47.22, 46.64, 33.79, 29.37, 28.36, 20.24.
(1g, 30mmol H2O). The cooling bath was removed and the
mixture was stirred for 10 min. The mixture was filtered and the
filtercakewas washedwith three portionsoftoluene. The filtrates
were combined and evaporated under vacuum. The residue was
purified by column chromatography, eluting with 0–100% v/v
light petroleum/ethyl acetate, to give the title compound as a pale
yellow oil, which solidified on standing to a low-melting solid
(0.21 g, 40%). m/z 200.1645 [M þ H]þ; C11H22NO2 requires
[M þ H]þ 200.1645. dH 4.98–4.91 (m, 1H), 3.61–3.58 (m, 1H),
3.12–3.06 (m, 1H), 2.38–1.98 (m, 5H), 1.61–1.54 (m, 1H), 1.07
(s, 3H), 1.01 (s, 3H), 0.91 (d, 3H), 0.85 (d, 3H). dc 170.4, 79.4,
49.3, 46.2, 45.0, 30.2, 29.4, 26.9, 26.6, 20.8, 20.5.
1-Isobutyl-4,4-dimethylpiperidine-2,6-dione
(3,3-Dimethyl-N-isobutylglutarimide) 3
5-Hydroxy-N-isobutyl-3,3-dimethylpentanamide 18
A solution of 5-(isobutylamino)-3,3-dimethyl-5-oxopentanoic
acid, 16, (1.63 M in CHCl3, 935 mL, 1.52 mol) pumped at a rate
of 2.96 mL minꢀ1 was mixed at ambient temperature with a
solution of thionyl chloride (6.85 M in CHCl3, 167mL, 2.29mol)
pumped at a rate of 1.04 mL minꢀ1 via a T-piece and passed
through a series of four 10-mL reactor coils (PFA tubing, 1-mm
ID) heated to 958C and fitted with two 8-bar acid-resistant
backpressure regulators. The combined eluents were evaporated
under vacuum and the residue was dissolved in diethyl ether
(1000 mL), and washed with water (2 ꢂ 500mL) and aqueous
Na2CO3 solution (10 % w/w, 500 mL). The ethereal solution was
dried with magnesium sulfate and evaporatedundervacuum toan
orange oil, which on standing solidified to give the title com-
pound as a pale orange solid (291.3 g, 97 %). Mp 49–508C. m/z
198.1490 [Mþ H]þ; C11H20NO2 requires [M þ H]þ 198.1489.
dH 3.63 (d, J 7.4, 2H), 2.52 (s, 4H), 2.04–1.95 (m, 1H), 1.10
(s, 6H), 0.88 (d, J 6.7, 6H). dc 172.3, 46.6, 29.1, 27.9, 27.3, 20.4.
A solution of 1-isobutyl-4,4-dimethylpiperidine-2,6-dione, 3,
(0.20 g, 1.01 mmol) in EtOH (5 mL) was cooled to 08C, under a
nitrogen atmosphere and treated portion-wise with sodium
borohydride (0.077 g, 2.03 mmol). Once addition was complete,
the reaction mixture was allowed to warm to room temperature
and stirred for 4 h. Analysis showed incomplete reaction and so
the mixture was diluted with EtOH (4 mL) and treated periodi-
cally with sodium borohydride (0.35 g, 9.3 mmol) over a period
of 15 h. The reaction mixture was then cooled to 08C, quenched
with 1 M HCl and water (5 mL), and the mixture stirred for
5 min. The mixture was extracted with ethyl acetate (3 ꢂ 5 mL),
the combined organic extracts were washed with a saturated
brine solution, dried over phase separation paper, and evapo-
rated under vacuum to give the title compound as a colourless oil
(0.17 g, 85 %). m/z 202.1801 [M þ H]þ; C11H24NO2 requires
[M þ H]þ 202.1802. dH 6.00 (s, br, 1H), 3.78 (t, J 5.6, 2H), 3.08
(t, J 6.2, 2H), 2.25 (s, 2H), 1.84–1.73 (m, 1H), 1.67 (t, J 5.8, 2H),
1.02 (s, 6H), 0.91 (d, J 6.7, 6H). dc 172.7, 59.5, 48.2, 47.1, 42.5,
32.8, 29.2, 28.6, 20.3.
One-Pot Preparation of 1-Isobutyl-4,4-dimethylpiperidine-
2,6-dione (3,3-Dimethyl-N-isobutylglutarimide) 3
One-Pot Preparation of 1-Isobutyl-4,4-dimethyl-3,4-
dihydropyridin-2(1H)-one 14
A solution of 4,4-dimethyldihydro-2H-pyran-2,6(3H)-dione,
2, (1.3 M in CHCl3, 7.7 mL, 10 mmol) pumped at a rate of
2.58 mL minꢀ1 was mixed at ambient temperature with a solu-
tion of isobutylamine (5 M in CHCl3, 2 mL, 10 mmol) pumped at
a rate of 0.67 mL minꢀ1 via a T-piece and passed through a
10-mL reactor coil (PFA tubing, 1-mm ID) heated to 508C. The
resulting solution was then mixed at ambient temperature
with a solution of thionyl chloride (6.85 M in CHCl3, 167 mL,
15 mmol) pumped at a rate of 0.74 mL minꢀ1 via a T-piece and
passed through a series of three 10-mL reactor coils (PFA tub-
ing, 1-mm ID) heated to 1008C and fitted with two 8-bar acid-
resistant backpressure regulators. The combined eluents were
then evaporated under vacuum, and the residue dissolved in
diethyl ether (50 mL) and washed with water (2 ꢂ 50 mL) and
aqueous Na2CO3 solution (10 % w/w, 50 mL). The ethereal
solution was then dried with magnesium sulfate and evaporated
under vacuum to an orange oil, which on standing solidified to
give the title compound as a pale orange solid (1.8 g, 92 %).
A solution of 1-isobutyl-4,4-dimethylpiperidine-2,6-dione, 3,
(118 g, 544 mmol) in diethyl ether (590 mL) was cooled on an
ice bath and treated dropwise with lithium aluminium hydride
(1 M in diethyl ether, 283 mL, 283 mmol) under a nitrogen
atmosphere at a rate suitable to keep the temperature below
308C. Once addition was complete (,20 min), the mixture was
stirred for 10 min and quenched by addition of dilute HCl
solution (2 M, 40 mL) followed by addition of further HCl
solution (4 M, 450 mL) until a clear biphasic mixture was
obtained. The cooling bath was removed and the mixture was
stirred for 25 min. The aqueous phase was discarded. The
organic phase was dried with magnesium sulfate and evaporated
under vacuum to give the title compound as a pale orange
oil (87.6 g, 89 %). Spectroscopic data corresponded to those
reported previously.[8] dH 5.90 (d, J 7.8, 1H), 4.95 (d, J 7.8, 1H),
3.28 (d, J 7.4, 2H), 2.36 (s, 2H), 2.04–1.91 (m, 1H), 1.08 (s, 6H),
0.91 (d, J 6.7, 6H).
6-Hydroxy-1-isobutyl-4,4-dimethylpiperidin-2-one 17
1-Isobutyl-4,4-dimethyl-1,2,3,4-tetrahydropyridine 5
A solution of 1-isobutyl-4,4-dimethylpiperidine-2,6-dione, 3,
(0.50 g, 2.53 mmol) in tetrahydrofuran (25 mL) was cooled on
an ice bath and treated dropwise with lithium aluminium hydride
(1 M in THF, 2.53 mL, 2.53 mmol) under a nitrogen atmosphere
at a rate appropriate to keep the temperature below 208C. Once
addition was complete, a large mass of precipitate was formed
that inhibited stirring. The mixture was stirred for 10 min
and quenched by addition of sodium sulfate decahydrate
Lithium aluminium hydride pellets (14.24 g, 375 mmol) were
added to diethyl ether (375 mL) and the resulting mixture was
stirred at ambient temperature for 20 min under a nitrogen
atmosphere. The resulting suspension was then treated dropwise
with a solution of 1-isobutyl-4,4-dimethyl-3,4-dihydropyridin-2-
(1H)-one, 14, (68 g, 375 mmol) in diethyl ether (290 mL) at a
rate suitable to maintain a gentle reflux. Once addition was

866
M. York et al.
complete (,20 min), the mixture was heated at reflux for 1 h.
The mixture was then quenched by portion-wise addition of
sodium sulfate decahydrate (25.6 g, 795 mmol). The resulting
suspension was stirred for 20 min, treated with anhydrous
sodium sulfate (10 g), and stirred for a further 10 min. The
mixture was filtered into a flask containing BHT (0.63 g, 1 wt-%
assuming 100 % yield). The filter pad was washed with diethyl
ether (2 ꢂ 100 mL) and the combined filtrate was evaporated
under vacuum to give the title compound as a pale yellow liquid
(59.5 g, 95 %). Spectroscopic data corresponded to those
reported previously.[6] dH 5.78 (d, J 7.9, 1H), 4.10 (d, J 7.9, 1H),
2.92 (t, J 5.7, 2H), 2.61 (d, J 7.3, 2H), 1.90–1.83 (m, 1H), 1.60
(t, J 5.5, 2H), 1.02 (s, 6H), 0.88 (d, J 6.6, 6H).
Supplementary Material
1H NMR spectra of all synthesised compounds and 13C NMR
spectra of novel compounds (3, 16–18) are available on the
Journal’s website.
Conflicts of Interest
The authors declare no conflicts of interest.
Acknowledgements
This work was supported, in part, by Enterprise Connect’s Researcher in
Business program.
1-(1-Isobutyl-4,4-dimethyl-1,4,5,6-tetrahydropyridin-3-yl)
propan-1-one 1
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