Optimization and multigram scalability of a catalytic enantioselective borylative migration for the synthesis of functionalized chiral piperidines

Article abstract of DOI:10.1039/c6ob00685j

The development of new, efficient and economical methods for the preparation of functionalized, optically enriched piperidines is important in the field of drug discovery where this class of heterocycles is often deemed a privileged structure. We have optimized a Pd-catalyzed enantioselective borylative migration of an alkenyl nonaflate derivative of the simple precursor, N-Boc-4-piperidone. This anomalous borylation reaction lends access to a chiral optically enriched piperidinyl allylic boronate that can be employed in carbonyl allylboration and stereoselective cross-coupling to produce substituted dehydropiperidines related to numerous pharmaceutical agents. A systematic fine-tuning of reaction conditions revealed that diethyl ether and the green solvent cyclopentyl methyl ether are suitable reaction solvents providing the highest enantioselectivity (up to 92% ee) under a low catalyst loading of 3 mol%. Optimization of the aldehyde allylboration step led to higher yields with further solvent economy. The multigram-scalability of the entire process was demonstrated under the reaction conditions that provide optimal atom-economy and efficiency.

Full text of DOI:10.1039/c6ob00685j

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Optimization and multigram scalability of a
catalytic enantioselective borylative migration for
Cite this: DOI: 10.1039/c6ob00685j
the synthesis of functionalized chiral piperidines†
You-Ri Kim and Dennis G. Hall*
The development of new, efficient and economical methods for the preparation of functionalized, opti-
cally enriched piperidines is important in the field of drug discovery where this class of heterocycles is
often deemed a privileged structure. We have optimized a Pd-catalyzed enantioselective borylative
migration of an alkenyl nonaflate derivative of the simple precursor, N-Boc-4-piperidone. This anomalous
borylation reaction lends access to a chiral optically enriched piperidinyl allylic boronate that can be
employed in carbonyl allylboration and stereoselective cross-coupling to produce substituted dehydro-
piperidines related to numerous pharmaceutical agents. A systematic fine-tuning of reaction conditions
revealed that diethyl ether and the green solvent cyclopentyl methyl ether are suitable reaction solvents
providing the highest enantioselectivity (up to 92% ee) under a low catalyst loading of 3 mol%.
Optimization of the aldehyde allylboration step led to higher yields with further solvent economy. The
multigram-scalability of the entire process was demonstrated under the reaction conditions that provide
optimal atom-economy and efficiency.
Received 31st March 2016,
Accepted 27th April 2016
DOI: 10.1039/c6ob00685j
www.rsc.org/obc
ring-closing metathesis (RCM) (Fig. 2A).5 These unimolecular
Introduction
approaches employ
a pre-functionalized acyclic substrate
The presence of functionalized piperidine rings in the struc- whose preparation usually requires a multistep sequence.
ture of numerous alkaloids coupled with their prevalence as More convergent approaches include [4 + 2] cycloadditions,
components of pharmaceutical drugs contribute to the impor- which can feature different possible disconnections (Fig. 2B).6
tance of these heterocycles in organic and medicinal chem- With these bimolecular approaches, however, the control of
istry.1 It has been suggested that the piperidine ring is the regio- and diastereoselectivity can be challenging and relatively
most common heterocyclic unit in the structures of commer- few approaches exist for the catalytic control of enantio-
cial pharmaceutical agents.2 The compounds depicted in selectivity.6 A third option consists in using a simple piper-
Fig. 1A represent a few selected examples from a multitude of idine precursor, which can be desymmetrized in a single step
piperidine-containing pharmaceutical agents and clinical can- to provide enantiomerically enriched product (Fig. 2C).7 Alter-
didates. Moreover, a great many classes of alkaloids embed a natively, prochiral pyridine derivatives can be transformed into
piperidine subunit, including iminosugars (Fig. 1B). Conse- chiral dehydropiperidines.8 Although these direct approaches
quently, the development of new methods that enable an are highly advantageous on the standpoint of step- and atom-
efficient and economical preparation of functionalized, opti- economy, it is surprising that only a few methods exist for the
cally enriched piperidines is an important challenge to be desymmetrization of readily available piperidine precursors.
addressed for the field of drug discovery. Current methods for
In this regard, our laboratory described a catalytic enantio-
the stereoselective preparation of polysubstituted piperidines selective borylative migration of pyranyl and piperidinyl tri-
can be classified into three general synthetic approaches flates 1 and 2 (Scheme 1).9 This work was inspired by a report
(Fig. 2).3 Cyclization of a linear precursor may be effected by from Masuda and co-workers on the palladium-catalyzed bory-
N-alkylation4 or through a C–C bond forming process such as lation of the corresponding pyranyl alkenyl triflate 1.10 Instead
of isolating the expected alkenyl boronate 4, the authors
observed allylic boronate 3 as the major product. Intrigued by
Department of Chemistry, 4-010 Centennial Centre for Interdisciplinary Science,
this anomalous borylation process and encouraged by its
University of Alberta, Edmonton, Alberta, Canada, T6G 2G2.
potential as a preparative method for saturated heterocycles,
E-mail: dennis.hall@ualberta.ca
we optimized this formal olefin isomerization11 into a catalytic
enantioselective formation of heterocyclic allylic boronates.
†Electronic supplementary information (ESI) available: 1H and 13C NMR spectra
of new compounds and experimental procedures. See DOI: 10.1039/c6ob00685j
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Scheme 1 Synthetic applications of heterocyclic allylic boronates,
prepared by a catalytic enantioselective borylative migration.
the piperidinyl triflate 2. Compared to the pyranyl analogue
(90–91% ee), the piperidinyl triflate 2 afforded a lower level of
Fig. 1 Examples of piperidine-containing (A) pharmaceutical drugs and
(B) natural products.
enantioselectivity of the allylic boronate
5 (86–87% ee)
(Scheme 1). These reaction conditions were applied to the syn-
thesis and confirmation of absolute stereochemistry of the
antimalarial piperidine drug, mefloquine, using a strategy to
establish the aminoalcohol unit that took advantage of the
ability of the allylic boronate 5 to undergo stereoselective alde-
hyde allylboration.12 Using ultrapure Pd(OAc)2 and carefully
deoxygenated dioxane, we were able to obtain ee’s in the range
of 90–99% in the allylboration of certain aldehydes.12 In 2014,
our laboratory also reported the application of optically
enriched allylic boronates 3 and 5 in stereospecific, catalyst-
controlled regiodivergent sp2–sp3 allylic Suzuki–Miyaura cross-
couplings with aryl and alkenyl halides (Scheme 1).13 This
chemistry provided a highly effective enantioselective synthesis
of the piperidine drug, paroxetine.13
Piperidinyl allylic boronate 5 thus constitutes a very useful
building block for the expedient preparation of enantiomeri-
cally enriched, functionalized piperidine products, which are
of great importance in drug discovery. When using our original
procedure reported in 2009, however, we occasionally encoun-
tered lower yields and enantioselectivity which we attributed to
scale effects, insufficient optimization of reaction parameters,
and other random deleterious factors such as the presence of
trace peroxide in dioxane, insufficiently pure reagents, and
even partially oxidized ligand. With a view to fine-tune the
experimental conditions for the preparation of this useful
chiral allylic boronate and exploit its applications in drug dis-
covery, we aimed to carefully optimize the yield and enantio-
selectivity of the reaction by taking into account a number of
practical factors such as convenience, reliability, cost, and multi-
gram-scalability. To achieve this objective, the current study
examined several parameters: the enol substrate (nature of the
alkenylsulfonate group and the N-protecting group), the source
Fig. 2 Common synthetic strategies for the preparation of chiral
piperidines.
The catalytic enantioselective borylative migration procedure
reported by our group in 2009 employed 5 mol% of Pd(OAc)2,
10 mol% of the chiral diphosphine, Taniaphos, with the base,
dimethylaniline, in dioxane as the solvent.9 Although these
reaction conditions were carefully optimized for the pyranyl
substrate 1, they were transferred without any fine-tuning to
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and stoichiometry of palladium and ligand, solvent, reaction
concentration, temperature, and time. Moreover, the reaction
conditions for the aldehyde allylboration of 5 were briefly re-
examined. Although a mechanism for this unique borylative
migration was proposed in our previous report,9 a detailed
study will be reported in a subsequent account.
Results & discussion
Optimization of the piperidine substrate for the catalytic
enantioselective borylative migration
The initial study of the catalytic enantioselective borylative
migration, as reported in 2009, was performed solely on the
N-Boc-protected alkenyl triflate 2.9 We wondered whether
another sulfonate derivative or N-protecting group would
provide a higher yield and/or enantioselectivity, or present
other advantages such as a more convenient and cost-effective
preparation. Thus, with slightly modified conditions using
diethyl ether as the solvent, we compared the suitability of sub-
strates 2, 8, 9, and 13 by measuring the yield of the desired
allylic boronate along with that of the alkenyl boronate side-
product (Table 1).
Scheme 2 Optimal conditions for the racemic catalytic borylative
migration of 8.
increase of enantioselectivity; however, substrate 8 combining
an alkenyl nonaflate with N-Boc protection led to a higher
yield. Moreover, it is noteworthy that compared to that of sub-
strate 2, the preparation of substrate 8 is higher-yielding and
more cost-effective because perfluorobutanesulfonyl fluoride is
a less expensive reagent than phenyl triflimide, and the chro-
matographic purification is easier. Furthermore, compared to
a N-Cbz group, which is cleaved by catalytic hydrogenation,
removal of a N-Boc protecting group is orthogonal to the
alkene in the allylboration products. Therefore, although
N-Cbz substrate 9 provided a lower proportion of undesired
alkenyl boronate 11, it was decided to employ substrate 8 for
subsequent optimization. The undesired alkenyl boronate
side-product can be removed with ease, unreacted, after the
subsequent aldehyde allylboration step. In the course of deter-
mining the reaction’s substrate of choice, a number of impor-
tant practical and experimental observations were made to
help optimize success and reproducibility. It is preferable to
employ a high grade (>99.95+%) of the palladium source, and
pinacolborane must be employed relatively fresh, and handled
and stored under nitrogen. Additionally, the base, dimethyl-
aniline, is distilled over KOH under reduced pressure. Lastly,
one must also ensure that the chiral diphosphine ligand,
Taniaphos, is not partially oxidized into a phosphine oxide
(which can be revealed by mass spectrometry), as we noted a
detrimental impact on the reaction conversion. For the
purpose of optimizing chiral HPLC separations and other situ-
ations where optically enriched allylic boronate 5 is not
required, we also optimized a racemic variant of the reaction.
It was best achieved with DPEPhos as the achiral diphosphine
ligand and diisopropylethylamine as the base (Scheme 2).
As done previously,9 the yield and enantioselectivity were
measured indirectly using a stable allylboration product (7, 12,
or 16), because the desired allylic boronates tend to decom-
pose when exposed to air or silica gel for a prolonged period of
time. Optimization of the thermal carbonyl allylboration is
described later in this article.
The use of alternate substrates embedding an alkenyl non-
aflate or a carboxybenzyl carbamate did not lead to a significant
Table 1 Optimization of the reaction substratea
Proportion of
6, 11, 15 b (%) (%)
Yieldc eed
Optimization of solvent and temperature
Entry Substrate
R
PG
(%)
One significant concern towards the adoption of this borylative
migration, in larger scales or in a process setting, is the reac-
tion solvent. Specifically, we sought to identify solvents that
would be safer, more efficient, and greener than dioxane.
Thus, using 5 mol% of Pd(OAc)2, we assessed several solvents in
the exploratory scale of 0.5 mmol of substrate 8. The results are
shown in Table 2. When optimized with pyranyl alkenyl triflate
1
2
3
4
2
8
9
13
CF3
t-Boc 10–15%
(CF2)3CF3 t-Boc 10–15%
66
76
60
0
91
91
90
nre
(CF2)3CF3 Cbz
(CF2)3CF3 Bn
<5%
nre
a Scale of reactions: 0.5 mmol. b Separable by flash chromatography.
c Isolated yield of 7, 12, or 16 after flash chromatography. d Determined
by chiral HPLC of 7, 12, or 16. e nr = no reaction.
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Table 2 Broad evaluation of solvents in the borylative migration of 8 a
Scheme 3 Examination of Pd source in the catalytic borylative
migration of 8.
Entry
Solvent
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
Toluene
Chlorobenzene
Dioxane
Diethyl ether
THF
2-MeTHF
Dibutyl ether
Diglyme
MTBE
CPME
CPME (0 °C)
CPME (−10 °C)
<5
<5
78
70
0
0
0
—
—
86
91
—
—
—
—
90
90
92
93
Optimization of chiral ligand
Because a new substrate, alkenyl nonaflate 8, was being used
along with new solvents other than dioxane, we re-evaluated a
small number of common chiral diphosphines and other
ligands in this Pd-catalyzed enantioselective borylative
migration (Fig. 3). The ligands that functioned well in promot-
ing the desired enantioselective reaction were those with a
0
9
60
63
60d
50d
10
11
12
a Scale of reactions: 0.5 mmol. b Isolated yield of 7 after flash chrom-
atography. Accompanied with 10–15% of alkenylboronate 6, separable
by flash chromatography. c Determined by chiral HPLC of 7.
d Reactions failed to reach completion even after a 16 h reaction time.
1, our original screening of reaction conditions identified both
toluene and dioxane as the optimal solvents. It was therefore
surprising to find that toluene and chlorobenzene were
ineffective with piperidinyl substrate 8 (entries 1 and 2). Many
ethereal solvents, however, were found to be suitable, includ-
ing diethyl ether (entry 4) and the green solvents methyl
t-butyl ether (MTBE) and cyclopentyl methyl ether (CPME)
(entries 9 and 10).14 To our satisfaction, these solvents pro-
vided higher and reproducible ee’s of 90–91% compared to the
previously optimal solvent, dioxane (entry 3). The use of lower
temperatures (−10, 0 °C) did not provide significantly higher
enantioselectivity and the product yields were lower due to
incomplete conversion even after 16 hours. Based on these
results, it was decided to continue the optimization process
using diethyl ether and CPME at ambient temperature.
Optimization of palladium source
Although the source of palladium was examined in our orig-
inal communication, we re-examined this important parameter
with the new alkenyl nonaflate substrate 8 (Scheme 3). This
short study confirmed that both Pd(0) and Pd(II) sources were
suitable. Although several other Pd complexes were competent,
including Pd2(dba)3, [PdCl(allyl)]2, [PdCl(cinnamyl)]2, and
XPhos-Pd-G2, palladium diacetate was chosen for further
optimization because of its stability to air and relatively lower
cost.
Fig. 3 Selected chiral ligands evaluated in the borylative migration of 8.
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relatively wider bite angle and chelate size, like Walphos and attempted to increase the reaction concentration. We found it
Taniaphos. The amine-containing diphosphine, Taniaphos, possible to run this borylative migration at a substrate concen-
remained the most effective ligand. As described above tration of 0.33 M, leading to substantial solvent savings
(Table 2), this ligand also provided a significant improvement (entries 8 and 9). Although a decrease in yield was observed
of ee when diethyl ether, MTBE, and CPME were used as the due to a lower conversion when keeping a short reaction time
solvents compared to dioxane.
of 4 hours, increasing the reaction time to 16 hours did
provide the optimal yield of 73% (entry 9). Unfortunately,
further attempts to decrease the catalyst loading to 2 mol% led
to incomplete conversions even after an extended reaction
time of 24 hours (entries 10–11). Finally, we were delighted to
find that these optimal conditions with diethyl ether as the
solvent are also suitable with the greener alternative, CPME,
providing comparable yield and ee (entries 12 and 13).
Optimization of catalyst stoichiometry and concentration
Significant economies can be realized when using a lower cata-
lyst loading, or with a higher reaction concentration to allow
solvent savings. To this end, we examined the impact of
varying these important parameters using diethyl ether as the
model ethereal solvent (Table 3).
The standard conditions from our preliminary communi-
cation, optimized for pyranyl allylic boronate 3, employed a
2 : 1 ligand : Pd ratio.9 Using the same reaction conditions with
diethyl ether as the solvent, a 70% yield of product 7 was
obtained with 91% ee (entry 1). We were delighted to find that
the ligand : Pd ratio can be decreased to near equimolar
(entries 2 and 3), with a slight excess of diphosphine ligand
employed to prevent Pd black out. Although decreasing the
catalyst loading to 3 mol% led to a lower yield (entry 4), it was
possible to make up for this loss by increasing the catalyst’s
concentration (entries 6 and 7). These optimal conditions
employ only about a third of the originally reported amount of
expensive chiral diphosphine, Taniaphos, however at a rela-
tively low concentration of substrate 8. With a view to realize
further solvent economies in multigram scale applications, we
Optimization of the aldehyde allylboration step
Compared to pyranyl allylic boronates, piperidinyl congeners
react more sluggishly. The original reaction conditions for the
aldehyde allylboration reported in 2009 required the use of
microwave heating at 130 °C in toluene (0.2 M) for 2 hours in a
sealed vessel.9 The resulting product yields were moderate,
ranging between 50 to 65%. We suspected that these dis-
appointing yields may be caused by an incomplete conversion
of the allylboration reaction. Indeed, using continuous monitor-
ing of the model reaction via TLC, we found that a significant
proportion of the allylic boronate 5 was left unreacted after
2 hours; hence the reaction time was re-examined, using puri-
fied 5 (Table 4).
To obtain a full conversion and a higher isolated yield of
product 7, we found it necessary to increase the reaction time
to 5 hours (entry 6). No other isomer was observed in this allyl-
boration reaction. Aside for a small standard error margin in
the determination of ee’s by chiral HPLC, the ee of α-hydro-
Table 3 Examination of catalyst loading and concentrationa
Table 4 Optimization of the allylboration stepa,e
Pd loading Ligand loading Pd conc. Conc.
Yieldb eec
Entry (mol%)
(mol%)
(mM)
of 8 (M) (%)
(%)
1
2
3
4
5
6
7
8
5
5
5
3
5
3
3
3
3
2
2
5
3
10
7
1.9
1.9
1.9
1.9
3.1
3.1
4.7
10
0.063
0.063
0.063
0.063
0.063
0.10
70
70
91
91
91
90
91
91
90
90
90
90
90
91
92
5.5
3.3
5.5
3.3
3.3
3.3
3.3
2.2
2.2
5.5
3.3
72
35d
70
Heat
source
Conc.
(M)
T
t
Yieldc eed
50d
65d
66d
73
Entry Solvent
(°C) (h)
(%)
(%)
0.16
0.33
1b
2b
3
4
5
6
7
8
0.2
0.2
0.2
0.2
160
160
130
130
130
130
130
rt
—
—
90
90
91
91
90
92
9
10
0.33e
0.16f
0.33f
0.063
0.33e
10
11
12h
13h
3.1
6.7
1.9
10
64g
64g
70
71
a Scale of reactions: 0.5 mmol. b Isolated yield of 7 after flash chrom-
atography. Accompanied with 10–15% of alkenylboronate 6, separable
by flash chromatography. c Determined by chiral HPLC of 7. a Scale of reactions: 0.5 mmol. b Entries 1 and 2 used racemic allylboro-
d Reactions failed to reach completion after a 4 h reaction time. nate. c Isolated yield of 7 after flash chromatography. d Determined by
e Stirred for 16 h, instead of 4 h. f Stirred for 24 h, instead of 4 h. chiral HPLC of 7. e Allylic boronate 5 was fully purified prior to the
g Reactions failed to reach completion after a 24 h reaction time. allylboration reaction, leading to higher yields in comparison to the
h CPME was used as the reaction solvent.
combined two-step yields of Table 3 utilizing quickly purified 5.
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xyalkylated products is expected to mirror that of allylic boro-
nate 5. The allylic boronate 5 should not be prone to thermally
induced epimerization or allylic migration,15 and the highly
diastereoselective allylboration step occurs from the same face
as the C–B bond.9,16 Thus, we further determined that the heat
source did not affect the yield or ee of the allylboration reac-
tion (entries 4–7). Our next objective was to decrease the reac-
tion temperature. Much to our delight, the reaction underwent
a full conversion at rt after 16 h, however, only under neat con-
ditions (entry 8). Because the use of solvent is essential with
solid aldehyde substrates, we investigated the scope of alde-
hydes at a substrate concentration of 1 M in toluene (Table 5).
Under these conditions, allylboration with the model aldehyde
gave a full conversion at ambient temperature after 16 h (entry
1). The same reaction conditions were successfully applied to
provide product 17 (entry 2). Compared to our previous com-
munication, allylboration with hydrocinnamaldehyde gave an
improved yield and ee (entry 3).9 Encouraged by this result, we
examined heteroaromatic aldehydes. To our satisfaction, these
reactions required a shorter time to achieve full conversion
(entries 4 and 5). Overall, the newly optimized conditions con-
sistently led to higher yields under lower reaction temperature
and a reduced amount of solvent compared to the previous
conditions.9 All attempts to identify alternative conditions
with the use of Lewis acid catalysis (e.g., BF3, Sc(OTf)3),17
Brønsted acid catalysis (e.g., TfOH),18 and conversion to allyldi-
fluoroborane19 were unsuccessful.
Scheme 4 Multigram-scale enantioselective borylative migration/alde-
hyde allylboration using the optimized procedure.
Evaluation of reaction sequence on a multigram-scale
With more robust and economical reaction conditions in
hand, which feature the use of greener and safer industrially
attractive ethereal solvents like CPME, we attempted a multi-
gram scale sequence of borylative migration followed by an
aldehyde allylboration (Scheme 4). Using eight grams of non-
aflate 8 (17 mmol) and only 3 mol% of the catalyst, product 7
was obtained in a 80% yield with an ee of 91% mirroring
that obtained in much smaller reaction scales of our optimiz-
ation studies. The purification process of a large scale reac-
tion was identical to that of
a small scale reaction.
Specifically, the allylic boronate 5 was quickly pre-purified via
a filtration through a short pad of silica gel, followed by con-
centration of solvent. The resulting residue was immediately
subjected to the aldehyde allylboration reaction. The crude
product 7 was then purified directly via silica column chrom-
atography. During this purification, the major side-product,
alkenyl boronate 6, was easily removed to give the desired
pure product 7.
Table 5 . Scope of allylboration of 5 with different aldehydesa
Conclusions
In summary, we optimized a Pd-catalyzed enantioselective bor-
ylative migration of an alkenyl nonaflate derivative of the
simple precursor N-Boc-4-piperidone. Compared to the pre-
vious, unoptimized process employing the corresponding tri-
flate derivative 2, the nonaflate substrate 8 is easier to prepare
and purify. This borylative migration reaction lends access to a
chiral optically enriched piperidinyl allylic boronate 5. This
reagent can be employed in carbonyl allylboration and stereo-
selective cross-coupling to produce functionalized dehydro-
piperidines related to numerous pharmaceutical agents. A
systematic fine-tuning of reaction conditions revealed that
diethyl ether and the green solvent CPME were suitable sol-
vents, providing the highest enantioselectivity (up to 92% ee)
under a low catalyst loading of 3 mol%. Optimization of the
aldehyde allylboration step led to higher yields with further
solvent economy. The gram-scalability of the entire process
was demonstrated under the newly optimized reaction con-
Entry
Reaction time (h)
Product
Yieldb (%)
eec (%)
1
2
3
4
5
16
16
16
3
7
70
70
70
71
72
92
90
90
94
91
17
18
19
20
3
a Scale of reactions: 0.5 mmol. b Isolated yield of 7, 17, 18, 19, or 20
after flash chromatography. c Determined by chiral HPLC of 7, 17, 18,
19, or 20.
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ditions that provide significantly improved atom-economy and using a HPLC Agilent instrument with a Chiralcel-OD or IB or
efficiency.
IC column as specified in the following individual procedures.
Experimental details
Pinacolborane received in a bottle was transferred to a round
bottom flask under a nitrogen atmosphere and stored in a
freezer. DIPEA and DMA were distilled over potassium hydrox-
Experimental
General information
Unless otherwise stated, all reactions were performed under a ide under a nitrogen atmosphere and stored in a refrigerator.
nitrogen atmosphere using flame-dried glassware. THF and Synthesized alkenyl nonaflates were transferred to vials after
toluene were purified using a MBraun MB SPS* solvent system. purification and stored in a refrigerator. Prior to the borylative
Dioxane was distilled over sodium. Diethyl ether (Et2O) was migration reaction, pinacolborane, the base, and the alkenyl
distilled over sodium/benzophenone ketyl. Anhydrous chloro- nonaflate were allowed to warm up to room temperature (ca.
benzene, cyclopentyl methyl ether (CPME), methyl tert-butyl 20 min). Ultrapure (99.95+%) Pd(OAc)2 was used. All the phos-
ether (MTBE), dibutyl ether, 2-methyltetrahydrofuran (2- phine ligands were checked for oxidation via ESI-ToF tech-
MeTHF), and diglyme were purchased from Sigma-Aldrich and nique prior to use. Palladium and ligand were weighed out
used as received. N,N-Diisopropylethylamine (DIPEA) and N,N- carefully and transferred to a reaction flask, which was evacu-
dimethylaniline (DMA) were purchased from Sigma-Aldrich ated and back-filled with nitrogen three times. Due to its
and distilled over potassium hydroxide prior to use. Pinacol- instability to a prolonged exposure to air and silica gel, freshly-
borane and 1,8-diazabicyclo[5.4.0.]undec-7-ene (DBU) were made crude allylic boronate 5 was filtered through a silica plug
purchased from Oakwood Products and Sigma-Aldrich, (silica gel to crude product, 100/1, w/w) very quickly (ca. 30
respectively, and were used without further purification. 1-tert- seconds) and subjected to the allylboration reaction directly
Butoxycarbonyl-4-piperidone,
1-carbobenzoxy-4-piperidone, after concentration of solvent. The major side product, alkenyl
1-benzyl-4-piperidone, and perfluorobutanesulfonyl fluoride boronate, was removed during the purification of final pro-
were purchased from Combi-Blocks Inc. and were used ducts, α-hydroxyalkyl dehydropiperidines.
without further purification. All aldehydes were purified by a
General procedure for the synthesis of alkenyl nonaflates
(Table 1)
bulb-to-bulb distillation under reduced pressure. Taniaphos,
DPEPhos, Walphos, palladium(II) acetate, allylpalladium(II)
chloride dimer, and tris(dibenzylideneacetone)dipalladium(0) N-Protected piperidone (10 mmol, 1.0 equiv.) was dissolved in
were purchased from Strem Chemicals. All other palladium THF (50 mL) under a nitrogen atmosphere. The mixture was
catalysts and ligands were purchased from Sigma-Aldrich. cooled in an ice-water bath (0 °C) and stirred for 5 min. DBU
Thin layer chromatography (TLC) was performed on Merck (1.8 mL, 12 mmol, 1.2 equiv.) and perfluorobutanesulfonyl flu-
Silica Gel 60 F254 plates and visualized with UV light, p-anis- oride (2.2 mL, 12 mmol, 1.2 equiv.) were added respectively
aldehyde stain, and KMnO4 stain. Flash column chromato- and the resulting solution was stirred for 10 min. The reaction
graphy was performed on ultra-pure silica gel 230–400 mesh. was then allowed to warm up to rt and stirred for 16 h. The
Nuclear magnetic resonance (NMR) spectra were recorded on reaction was quenched with a slow addition of water (50 mL)
INOVA-400 or INOVA-500 instruments. The residual solvent and extracted with Et2O (3 × 60 mL). The organic layers were
protons (1H) and the solvent carbons (13C) were used as combined and washed with brine (50 mL), dried (Na2SO4), fil-
internal standards. 1H NMR data are presented as follows: tered, and concentrated in vacuo. The brown oil was then puri-
chemical shift in ppm (δ) downfield from tetramethylsilane fied by flash column chromatography (25% Et2O/pentane).
(multiplicity, coupling constant, integration). The following
tert-Butyl-4-(nonafluorobutylsulfonyloxy)-5,6-dihydropyr-
abbreviations are used in reporting NMR data: s, singlet; br s, idine-1(2H)-carboxylate (8). A colorless oil (4.6 g, 95% yield)
broad singlet; app s, apparent singlet; t, triplet; app t, apparent was obtained according to the general procedure using 1-(tert-
triplet; dd, doublet of doublets; dt, doublet of triplets; m, mul- butoxycarbonyl)-4-piperidone (2.0 g, 10 mmol, 1.0 equiv.) as a
tiplet. Reported J-values are deemed accurate within 0.3 Hz. substrate. Spectral data correspond to that reported.20 Rf = 0.61
NMR data were processed either using VnmrJ from Agilent (15% EtOAc/hextane); 1H NMR (500 MHz, CDCl3) δ (ppm) 5.76
Technologies or MestReNova from Mestrelab Research. High- (app s, 1 H), 4.04 (app s, 2 H), 3.62 (app s, 2 H), 2.43 (app s,
resolution mass spectra were recorded by the University of 2 H), 1.46 (s, 9 H).
Alberta Mass Spectrometry Services Laboratory using electro-
Benzyl-4-(nonafluorobutylsulfonyloxy)-5,6-dihydropyridine-1
spray ionization (ESI) method. Infrared spectra were obtained (2H)-carboxylate (9). A light-yellow oil (4.6 g, 89% yield) was
from a Nicolet Magna-IR machine with frequencies expressed obtained according to the general procedure using 1-carbo-
in cm−1. Optical rotations were measured using a 1 mL cell benzoxy-4-piperidone (2.3 g, 10 mmol, 1.0 equiv.) as a substrate.
with a 1 dm length on a P.E. 241 polarimeter. Regioselectivity Rf = 0.41 (15% EtOAc/hexane); 1H NMR (500 MHz, CDCl3)
of alkenyl to allyl boronate and the diastereomeric ratios for δ (ppm) 7.39–7.32 (m, 5 H), 5.82–5.75 (m, 1 H), 5.16 (s, 2 H),
chiral compounds were determined by integration of relevant 4.14 (app s, 2 H), 3.72 (app s, 2 H), 2.47 (app s, 2 H); 13C NMR
signals on the crude 1H NMR spectra. The enantiomeric excess (100 MHz, CDCl3, 19F decoupled, 60 °C) δ (ppm) 155.1, 147.0,
ratios for optically enriched compounds were determined 136.5, 128.7, 128.3, 128.1, 115.8, 115.4, 114.5, 110.1, 108.7,
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67.8, 42.1, 40.8, 28.2; 19F NMR (376 MHz, CDCl3, 1H mixture was stirred at rt for 16 h. The solvent was concentrated
decoupled, 60 °C) −80.8, −109.4, −120.6, −125.5; IR (Micro- in vacuo, followed by a quick filtration through a silica
scope, cm−1) 3035, 2957, 1711, 1423, 1353, 1280; HRMS plug (100% Et2O). The resulting mixture was concentrated
(ESI-ToF) for C17H14F9NNaO5S (M + Na+): calcd 538.0341; in vacuo and transferred to a pre-dried 5 mL round bottom
found 538.0337.
1-(Benzyl)-4-[(nonafluorobutanesulfonyl)oxy]-1,2,3,6-tetrahy-
flask using dry toluene (1 mL). The flask was flushed
with nitrogen and aldehyde (1.1 mmol, 1.1 equiv.) was
dropyridine (13). A yellow oil (4.3 g, 91% yield) was obtained added. The solution was stirred at rt under nitrogen for
according to the general procedure using 1-benzyl-4-piperi- 3 or 16 h. The mixture was purified directly by flash column
done (1.9 mL, 10 mmol, 1.0 equiv.) as a substrate. Rf = 0.56 chromatography.
(15% EtOAc/hexane); 1H NMR (500 MHz, CDCl3) δ (ppm)
(R)-tert-Butyl 2-[(R)-hydroxy(p-tolyl)methyl]-5,6-dihydropyri-
7.35–7.27 (m, 5 H), 5.75–5.73 (m, 1 H), 3.64 (s, 2 H), 3.15–3.13 dine-1(2H)-carboxylate (7). The title compound (7) was syn-
(m, 2 H), 2.73 (t, J = 5.7 Hz, 2 H), 2.46–2.45 (m, 2 H); 13C NMR thesized by the general procedure using tert-butyl-4-
(100 MHz, CDCl3, 19F Dec) δ (ppm) 147.5, 137.7, 129.0, 128.5, (nonafluorobutylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carb-
127.4, 117.1, 116.3, 114.2, 109.9, 108.5, 61.3, 50.5, 49.1, 28.4; oxylate (8) (481 mg, 1.00 mmol, 1.00 equiv.) and p-tolualde-
19F NMR (376 MHz, CDCl3, 1H decoupled) −80.8, −110.1, hyde (130 µL, 1.10 mmol, 1.10 equiv.); allylboration was
−121.1, −126.0; IR (Microscope, cm−1) 3031, 2926, 2806, 1699, performed for 16 h. The product was obtained as a colorless
1454, 1421; HRMS (ESI-ToF) for C16H15F9NO3S (M + H)+: calcd oil (213 mg, 70% yield) after flash column chromatography
472.0623; found 472.0618.
(50% Et2O/pentane). Rf = 0.50 (20% EtOAc/hexane); [α]D20
+135.0 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3) rotamers
are present: δ (ppm) 7.25–7.23 (m, 2 H), 7.17–7.15 (m, 2 H),
5.89–5.81 (m, 1 H), 5.34–5.17 (m, 1 H), 4.63–4.53 (m, 2 H),
General procedure for the synthesis of optically enriched
allylic boronate (Table 1)
Palladium(II) acetate (6.7 mg, 0.030 mmol, 0.030 equiv.) and 4.18–3.85 (m, 1 H), 3.04–2.78 (m, 1 H), 2.34 (s, 3 H), 2.22–2.17
1
(+)-TANIAPHOS (23 mg, 0.033 mmol, 0.033 equiv.) were added (m, 1 H), 1.95–1.90 (m, 1 H), 1.49 (s, 9 H); H NMR (400 MHz,
to a pre-dried 10 mL round bottom flask equipped with a stir- CDCl3, 65 °C) δ (ppm) 7.24 (d, J = 8.0 Hz, 2 H), 7.14 (d, J = 8.0
bar, which was then evacuated and backfilled with nitrogen Hz, 2 H), 5.85–5.81 (m, 1 H), 5.30–5.28 (m, 1 H), 4.63–4.62 (m,
three times. Et2O (3 mL) was added and the mixture was 2 H), 4.13–4.09 (m, 1 H), 2.92–2.86 (m, 1 H), 2.34 (s, 3 H),
stirred for 30 min. DMA (140 µL, 1.10 mmol, 1.10 equiv.), pina- 2.18–2.14 (m, 1 H), 1.95–1.89 (m, 1 H), 1.49 (s, 9 H); 13C NMR
colborane (160 µL, 1.10 mmol, 1.10 equiv.), and tert-butyl-4- (100 MHz, CDCl3, 60 °C) δ (ppm) 156.8, 138.6, 137.6, 129.1,
(nonafluorobutylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carb- 127.1, 125.1, 80.5, 76.4, 58.5, 37.9, 28.5, 24.8, 21.1; IR (Micro-
oxylate (8) (481 mg, 1.00 mmol, 1.00 equiv.) were respectively scope, cm−1) 3060, 2975, 2930, 1644, 1611, 1512, 1250; HRMS
added. The mixture was stirred at rt for 16 h. The solvent was (ESI-ToF) for C18H25NNaO3 (M + Na)+: calcd 326.1727; found
concentrated in vacuo, followed by a quick filtration through a 326.1724; HPLC (Chiralcel OD): 3.8% i-PrOH/hexane, 6 °C,
silica plug (100% Et2O). The resulting mixture was concen- 0.5 mL min−1, λ = 210 nm, Tmajor = 19.6 min, Tminor
trated in vacuo and purified by flash column chromatography 17.3 min; 92% ee; >96% de.
=
(25% Et2O/pentane).
(4S)-tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- dihydropyridine-1(2H)-carboxylate (17). The title compound
3,4-dihydropyridine-1(2H)-carboxylate (5). colorless oil (17) was synthesized by the general procedure using tert-butyl-
(R)-tert-Butyl
2-[(R)-hydroxy(o-bromophenyl)methyl]-5,6-
A
(155 mg, 50% yield) was obtained according to the general pro- 4-(nonafluorobutylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carb-
cedure. Spectral data correspond to that reported.9 Regio- oxylate (8) (481 mg, 1.00 mmol, 1.00 equiv.) and 2-bromobenz-
selectivity of alkenyl to allyl boronic ester determined by aldehyde (130 µL, 1.10 mmol, 1.10 equiv.); allylboration was
1
integration of relevant signals on the crude H NMR spectrum performed for 16 h. The product was obtained as a colorless
was 1 : 4. Rf = 0.35 (25% Et2O/pentane); 1H NMR (500 MHz, oil (258 mg, 70% yield) after flash column chromatography
CDCl3) rotamers are present: δ (ppm) 6.84–6.71 (m, 1 H), (50% Et2O/pentane). Rf = 0.49 (20% EtOAc/hexane); [α]2D0 +50.5
4.94–4.82 (m, 1 H), 3.58–3.53 (m, 2 H), 1.87–1.83 (m, 3 H), 1.47 (c 1.42, CHCl3); 1H NMR (400 MHz, CDCl3, 65 °C) δ (ppm) 7.57
(s, 9 H), 1.23 (s, 12 H).
(app d, J = 7.7 Hz, 1 H), 7.51 (dd, J = 8.0, 1.2 Hz, 1 H), 7.33 (td,
J = 7.7, 1.1 Hz, 1 H), 7.13 (app td, J = 7.7, 1.8 Hz, 1 H),
5.97–5.91 (m, 1 H), 5.41–5.35 (m, 1 H), 5.25 (d, J = 6.7 Hz, 1 H),
4.73–4.72 (m, 1 H), 4.21–4.14 (m, 1 H), 3.16–3.09 (m, 1 H),
General procedure for the synthesis of optically enriched
α-hydroxyalkyl dehydropiperidines (Table 5)
Palladium(II) acetate (6.7 mg, 0.030 mmol, 0.030 equiv.) and 2.21–2.19 (m, 1 H), 2.01–1.94 (m, 1 H), 1.39 (s, 9 H); 13C NMR
(+)-TANIAPHOS (23 mg, 0.033 mmol, 0.033 equiv.) were added (100 MHz, CDCl3, 60 °C) δ (ppm) 156.0, 140.7, 132.7, 129.1,
to a pre-dried 10 mL round bottom flask equipped with a stir- 129.0, 128.0, 127.7, 124.7, 123.3, 80.3, 75.1, 57.5, 38.2, 28.4,
bar, which was then evacuated and backfilled with nitrogen 24.8; IR (Microscope, cm−1) 3427, 3028, 2976, 2929, 1670,
three times. Et2O (3 mL) was added and the mixture was 1592, 1454; HRMS (ESI-ToF) for C17H23BrNO3 (M + H)+: calcd
stirred for 30 min. DMA (140 µL, 1.10 mmol, 1.10 equiv.), pina- 368.0856; found 368.0850; HPLC (Chiralcel OD): 3.8% i-PrOH/
colborane (160 µL, 1.10 mmol, 1.10 equiv.), and alkenyl non- hexane, 6 °C, 0.5 mL min−1, λ = 210 nm, Tmajor = 26.5 min,
aflate (1.0 mmol, 1.0 equiv.) were respectively added. The Tminor = 19.3 min; 90% ee; >96% de.
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(R)-tert-Butyl 2-[(R)-1-hydroxy-3-phenylpropyl]-5,6-dihydro- 1H NMR (500 MHz, DMSO-d6, 115 °C) δ (ppm) 8.83 (d, J = 4.4 Hz,
pyridine-1(2H)-carboxylate (18). The title compound (18) was 1 H), 8.21 (d, J = 8.4 Hz, 1 H), 8.02 (d, J = 8.4 Hz, 1 H), 7.70 (dt,
synthesized by the general procedure using tert-butyl-4- J = 7.6, 0.91 Hz, 1 H), 7.56–7.51 (m, 2 H), 5.92–5.89 (m, 1 H),
(nonafluorobutylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carb- 5.75–5.72 (m, 1 H), 5.59 (app t, J = 4.5 Hz, 1 H), 5.39 (app s,
oxylate (8) (481 mg, 1.00 mmol, 1.00 equiv.) and hydrocinna- 1 H), 4.74 (app s, 1 H), 3.85–3.84 (m, 1 H), 2.73 (br s, 1 H),
maldehyde (145 µL, 1.10 mmol, 1.10 equiv.); allylboration was 2.01–1.93 (m, 1 H), 1.83–1.80 (m, 1 H), 1.12 (s, 9 H); 13C NMR
performed for 16 h. The product was obtained as a yellow oil (125 MHz, DMSO-d6, 115 °C) δ (ppm) 153.5, 149.0, 147.5,
(222 mg, 70% yield) after flash column chromatography (25% 147.4, 129.1, 127.9, 126.5, 125.7, 125.2, 125.0, 123.1, 119.0,
Et2O/pentane). Spectral data correspond to that reported.9 Rf = 77.9, 69.4, 56.0, 36.9, 27.2, 23.5; IR (Microscope, cm−1) 3405,
0.65 (50% EtOAc/hexane); 1H NMR (400 MHz, CDCl3, 60 °C) 3180, 3041, 2976, 2930, 1687, 1477; HRMS (ESI-ToF) for
δ (ppm) 7.28–7.15 (m, 5 H), 5.96–5.93 (m, 1 H), 5.68–5.66 (m, C20H25N2O3 (M + H)+: calcd 341.1860; found 341.1863; HPLC
1 H), 4.41–4.37 (m, 1 H), 4.16–4.06 (m, 1 H), 3.72–3.68 (m, 1 H), (Chiralcel IC): 50% i-PrOH/hexane, 20 °C, 0.5 mL min−1, λ =
3.02–2.97 (m, 1 H), 2.93–2.88 (m, 1 H), 2.80–2.76 (m, 1 H), 280 nm, Tmajor = 6.1 min, Tminor = 13.2 min; 90% ee; >96% de.
2.21–2.17 (m, 1 H), 1.98–1.85 (m, 2 H), 1.84–1.78 (m, 1 H), 1.48
(S)-Benzyl
2-[(S)-hydroxy(p-tolyl)methyl]-5,6-dihydropyri-
(s, 9 H); HPLC (Chiralcel OD): 10% i-PrOH/hexane, 25 °C, dine-1(2H)-carboxylate (12). The title compound (12) was syn-
0.5 mL min−1, λ = 210 nm, Tmajor = 12.2 min, Tminor = 9.4 min; thesized by the general procedure (modification: use of
90% ee, >96% de.
(−)-TANIAPHOS instead of (+)-TANIAPHOS) using benzyl-4-
(R)-tert-Butyl 2-[(R)-hydroxy(4-pyridyl)methyl]-5,6-dihydro- (nonafluorobutylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carb-
pyridine-1(2H)-carboxylate (19). The title compound (19) was oxylate (9) (515 mg, 1.00 mmol, 1.00 equiv.) and p-tolualde-
synthesized by the general procedure using tert-butyl-4- hyde (130 µL, 1.10 mmol, 1.10 equiv.); allylboration was
(nonafluorobutylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carb- performed for 16 h. The product was obtained as a colorless
oxylate (8) (481 mg, 1.00 mmol, 1.00 equiv.) and 4-pyridine- oil (202 mg, 60% yield) after flash column chromatography
carboxaldehyde (104 µL, 1.10 mmol, 1.10 equiv.); allylboration (50% Et2O/pentane). Rf = 0.41 (20% EtOAc/hexane); [α]D20
was performed for 3 h. The product was obtained as a colorless −109.1 (c 0.32, CHCl3); 1H NMR (500 MHz, CDCl3) δ (ppm)
oil (206 mg, 71% yield) after flash column chromatography 7.38–7.31 (m, 5 H), 7.31–7.12 (m, 4 H), 5.89–5.82 (m, 1 H),
(100% EtOAc). Rf = 0.27 (100% EtOAc); [α]2D0 +131.6 (c 1.07, 5.41–5.38 (m, 1 H), 5.23–5.11 (m, 2 H), 4.70–4.67 (m, 2 H),
CHCl3); 1H NMR (400 MHz, DMSO-d6) rotamers are present: 4.22–3.46 (m, 1 H), 3.03–2.83 (m, 1 H), 2.34 (s, 3 H), 2.23–2.20
δ (ppm) 8.48–8.47 (m, 2 H), 7.25–7.23 (m, 2 H), 5.91–5.88 (m, (m, 1 H), 1.97–1.93 (m, 1 H); 1H NMR (400 MHz, CDCl3, 65 °C)
1 H), 5.71–5.66 (m, 2 H), 4.77 (app t, J = 4.8 Hz, 1 H), 4.52–4.41 δ (ppm) 7.39–7.29 (m, 5 H), 7.23 (app d, J = 7.9 Hz, 2 H), 7.14
(m, 1 H), 3.94–3.68 (m, 1 H), 2.71–2.62 (m, 1 H), 1.94–1.83 (m, (app d, J = 7.9 Hz, 2 H), 5.89–5.84 (m, 1 H), 5.36–5.34 (m, 1 H),
1
2 H), 1.33–1.21 (m, 9 H); H NMR (400 MHz, DMSO-d6, 80 °C) 5.18 (s, 2 H), 4.68–4.66 (m, 2 H), 4.21–4.16 (m, 1 H), 2.98–2.90
δ (ppm) 8.48 (d, J = 5.8 Hz, 2 H), 7.25 (d, J = 5.8 Hz, 2 H), (m, 1 H), 2.35 (s, 3 H), 2.27–2.17 (m, 1 H), 1.97–1.90 (m, 1 H);
5.89–5.88 (m, 1 H), 5.71–5.68 (m, 1 H), 5.45–5.43 (m, 1 H), 4.78 13C NMR (100 MHz, CDCl3, 65 °C) δ (ppm) 156.8, 138.3, 137.8,
(app t, J = 4.8 Hz, 1 H), 4.51 (app s, 1 H), 3.87–3.83 (m, 1 H), 136.9, 129.2, 128.6, 128.1, 128.0, 127.1, 124.9, 76.2, 67.6, 58.7,
2.64–2.57 (m, 1 H), 1.96–1.91 (m, 1 H), 1.83–1.78 (m, 1 H), 1.32 38.0, 24.8, 21.2; IR (Microscope, cm−1) 3438, 3031, 2921, 1697,
(s, 9 H); 13C NMR (100 MHz, DMSO-d6, 80 °C) δ (ppm) 153.6, 1515, 1431, 1391; HRMS (ESI-ToF) for C21H23NNaO3 (M + Na)+:
151.0, 148.6, 126.7, 124.6, 121.8, 78.3, 72.5, 56.3, 37.2, 27.6, calcd 360.1570; found 360.1567; HPLC (Chiralcel IB): 5%
23.7; IR (Microscope, cm−1) 3402, 3189, 2976, 2929, 1691, i-PrOH/hexane, 20 °C, 0.5 mL min−1, λ = 210 nm, Tmajor
1603, 1477, 1455; HRMS (ESI-ToF) for C16H23N2O3 (M + H)+: 15.8 min, Tminor = 18.9 min; 90% ee; >96% de.
calcd 291.1703; found 291.1707; HPLC (Chiralcel IC): 50%
=
i-PrOH/hexane, 20 °C, 0.5 mL min−1, λ = 254 nm, Tmajor
6.3 min, Tminor = 14.2 min; 94% ee; >96% de.
=
Acknowledgements
(R)-tert-Butyl 2-[(R)-hydroxy(4-quinolinyl)methyl]-5,6-di-
hydropyridine-1(2H)-carboxylate (20). The title compound (20)
was synthesized by the general procedure using tert-butyl-4-
(nonafluorobutylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carb-
oxylate (8) (481 mg, 1.00 mmol, 1.00 equiv.) and 4-quinoline-
carboxaldehyde (173 µL, 1.10 mmol, 1.10 equiv.); allylboration
was performed for 3 h. The product was obtained as a colorless
oil (245 mg, 72% yield) after flash column chromatography
(100% EtOAc). Rf = 0.44 (100% EtOAc); [α]2D0 +51.4 (c 1.56,
CHCl3); 1H NMR (500 MHz, DMSO-d6) rotamers are present:
δ (ppm) 8.85–8.82 (m, 1 H), 8.26–8.11 (m, 1 H), 8.04–7.98 (m,
1 H), 7.74–7.71 (m, 1 H), 7.59–7.50 (m, 2 H), 5.98–5.80 (m, 2 H),
5.69–5.60 (m, 2 H), 4.71–4.59 (m, 1 H), 3.99–3.95 (m, 1 H),
3.18–3.12 (m, 1 H), 1.93–1.86 (m, 2 H), 1.30–0.67 (m, 9 H);
This research was supported by the Natural Science and Engin-
eering Research Council (NSERC, Discovery Grant No. 203287-
2012) of Canada and the University of Alberta. The authors
thank Mr Hao Fu for help with chiral HPLC measurements
and Dr Ryan McKay and Mark Miskolzie for help with NMR
spectrometry.
Notes and references
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