Origin of the Diastereoselectivity of the Heterogeneous Hydrogenation of a Substituted Indolizine

Article abstract of DOI:10.1021/acs.joc.0c01338

In this work, the stereoselective heterogeneous hydrogenation of a tetrasubstituted indolizine was studied. Partial hydrogenation products were obtained in three steps from a substituted pyridine-2-carboxaldehyde prepared from commercial pyridoxine hydrochloride. The hydrogenation of the indolizine ring was shown to be diastereoselective, forming trans-6b and cis-9. Theoretical calculations (ab initio and DFT) were used to rationalize the unusual trans stereoselectivity for 6b, and a keto-enol tautomerism under kinetic control has been proposed as the source of diastereoselectivity.

Full text of DOI:10.1021/acs.joc.0c01338

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Note
On the Origin of the Diastereoselectivity of the
Heterogeneous Hydrogenation of a Substituted Indolizine
Rodrigo A. Cormanich, Lucas A. Zeoly, Hugo Santos,
Nilton Soares Camilo, Michael Bühl, and Fernando Coelho
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01338 • Publication Date (Web): 11 Aug 2020
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1 On the Origin of the Diastereoselectivity of the Heterogeneous
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Hydrogenation of a Substituted Indolizine
Rodrigo A. Cormanich,[a] Lucas A. Zeoly,[a] Hugo Santos,[a] Nilton S. Camilo,[a]
Michael Bühl,[b] and Fernando Coelho[a],*
[a] University of Campinas, Institute of Chemistry, Department of Organic Chemistry, PO
Box 6154 – 13083-970 – Campinas, São Paulo, Brazil.
[b]
School of Chemistry, University of St Andrews, North Haugh, St Andrews, Fife
KY169ST, UK.
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*E-mail: facoelho@unicamp.br
Table of Contents/Graphical abstract
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Abstract: In this work, the stereoselective heterogeneous hydrogenation of a
tetrasubstituted indolizine was studied. Partial hydrogenation products were obtained in
three steps from a substituted pyridine-2-carboxaldehyde prepared from commercial
pyridoxine hydrochloride. The hydrogenation of the indolizine ring was shown to be
diastereoselective, forming trans-6b and cis-9. Theoretical calculations (ab initio and
DFT) were used to rationalize the unusual trans stereoselectivity for 6b, and a keto-enol
tautomerism under kinetic control has been proposed as the source of diastereoselectivity.
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IINTRODUCTION
Naturally-occurring 5,6,7,8-tetrahydroindolizinones, bicyclic compounds
characterized by a pyrrole ring fused to a 6-membered saturated chain, a
bridgehead nitrogen atom and a ketone moiety, are of rare occurrence in nature,
even though their indolizidine saturated analogues are abundant in alkaloid
chemistry.1
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For instance, the isolation of the first natural 5,6,7,8-tetrahydroindolizinone
was reported only in 1997, when polygonatine B (1) was isolated from the
liliaceous plant Polygonatum sibiricum (Figure 1)2 and from Polygonatum
10 kingianum, along with the homologue kinganone (2).3 Polygonatine A (3), the
11 hydroxymethyl parent of both 1 and 2, was also isolated from P. sibiricum.4 Both
12 1 and 2 exhibited antimicrobial and antifungal activities against a range of
13 microorganisms.3
14
Furthermore, (-)-rhazinicine (4),5,6 an alkaloid containing the 5,6,7,8-
15 tetrahydroindolizin-5-one motif, showed an antitumor activity similar to that of
16 taxol (Figure 1).7
O
O
N
1
8a
7
8
1
2
3
, R = Et, Polygonatine B
, R = Bu, Kinganone
, R = H, Polygonatine A
2
N
6
4
3
5
HN
RO
4
, (-)-Rhazinicine
O
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Figure 1. Naturally occurring 5,6,7,8-tetrahydroindolizinone derivatives.
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Unlike 5,6,7,8-tetrahydroindolizines, whose preparations have been
8,9
21 achieved by efficient procedures in the literature, there are only a few protocols
10,11
22 reported for 5,6,7,8-tetrahydroindolizinone synthesis.
More specifically, the
23 synthesis of compounds containing a 5,6,7,8-tetrahydroindolizin-8-one core (also
24 named 6,7-dihydro-8(5H)-indolizinone) has been scarcely explored,11 with most of
25 the approaches relying on Friedel-Crafts acylation.11a-h To the best of our
26 knowledge, there are no reports on 5,6,7,8-tetrahydroindolizinone preparation
27 directly through partial hydrogenation of an indolizine.
28
In this work, we describe the results of a highly trans diastereoselective
29 heterogeneous hydrogenation reaction of the tetrasubstituted indolizine 5 to
30 prepare polyfunctionalized 5,6,7,8-tetrahydroindolizin-8-one 6 (Scheme 1). This
31 transformation was rationalized by theoretical calculations, which suggested a
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keto-enol tautomerism as the source of the observed stereoselectivity, favoring the
kinetic product.
RESULTS AND DISCUSSIONS
The starting material for our synthetic route was pyridoxine hydrochloride
– also known as vitamin B6 – which, despite its polyfunctionalized structure, is a
low-cost compound (> US$ 1 per gram).12 We envisaged that the presence of
hydroxyl groups of different reactivities in vitamin B6 could potentially be
explored for the preparation of new tetrahydroindolizinone and
10 tetrahydroindolizine motifs.
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The synthetic route developed for the synthesis of the 5,6,7,8-
tetrahydroindolizinone 6 was carefully planned to avoid chromatographic purification in
most of its steps. Furthermore, most of the sequence was carried out on a multigram scale
through low cost and efficient reactions. Thus, functionalized pyridine-2-carboxaldehyde
7 was prepared in 6 steps and 77% overall yield by using a quite robust, modified
procedure reported several decades ago by Korytnyk et al. (Scheme 1).13 The presence of
the seven-membered cyclic acetal in 7 is essential, since it is key to the observed
diastereoselectivity in the heterogeneous hydrogenation step, as will be discussed later.
No chromatographic purification was required for the preparation of 7, which was
sufficiently pure by NMR spectrum to be used in the next reaction step.
O
O
OBn
X
Bn
O
Bn
O
O
O
a
b
c
O
O
O
O
CO2Me
*
*
CO2Me
CO2Me
N
N
N
N
O
OH
7
8
5
6
, X = O
Prepared in 6 steps
(77% overall yield)
from Vitamin B6
OH
H
9
, X =
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Scheme 1. Synthetic approach to tetrahydroindolizinone
6
and
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tetrahydroindolizine 9. Reaction conditions: a) DABCO (0.65 equiv.), methyl acrylate
(20 equiv.), ultrasound, r.t., 64 h (85%); b) Ac2O, 100 °C, 19 h (65%); c) Rh/Al2O3 (10%
w/w), H2 (80 bar), EtOAc, r.t., 48 h (30% for 6b).
The Morita-Baylis-Hillman (MBH) reaction of compound 7 with methyl acrylate,
a key step of our approach, was performed using a protocol developed by our laboratory
involving the use of ultrasound to speed up the reaction.14 Adduct 8 was obtained in 85%
yield after 64 h, and the crude product was used in the next reaction step without further
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purification. Then, we turned our attention to prepare indolizine 5. Several literature
methodologies describe the synthesis of indolizines from MBH adducts.9,15 We initially
opted to test some of them, and the best result was achieved by heating the MBH adduct
to 100 °C in acetic anhydride medium. Some byproducts were formed in this step and
chromatographic purification was necessary to obtain pure 5 in 65% yield.
Once indolizine 5 was prepared, the performance of the partial hydrogenation
reaction was evaluated by screening reaction parameters such as heterogeneous catalysts,
H2 pressures and solvents (see SI for more details).9 When Rh/Al2O3 was used as catalyst
in ethyl acetate at 80 bar of H2 pressure and room temperature, starting material 5 was
fully consumed after 48 h, furnishing a mixture of three main compounds (as determined
by 1H NMR). Compound 6b could be separated and isolated in 30% yield, while alcohol
9 was obtained as an inseparable mixture (see SI for full structural assignment) (Scheme
2).
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O
OH
Rh/Al2O3 (10% w/w)
H2 (80 bar)
OBn
H
H
O
O
O
O
O
O
O
O
O
O
O
O
+
N
N
EtOAc, r.t., 48 h
N
H
H
5
6b
30% yield
9
(as an inseparable mixture
of unassigned compounds)
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Scheme 2. Heterogeneous hydrogenation of indolizine 5.
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Compounds 6b and the mixture containing 9 were fully characterized by H,
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relative stereochemistries were assigned using JHH obtained directly from H NMR
spectra16 and NOE values17 obtained from NOESY experiments (see SI for details).
Curiously, compound 6b was not further reduced under high pressures of H2.
Also, this compound shows a trans relationship between the hydrogen atoms at the 6-7
ring junction, and the other possible diastereomer (6a), which would have a cis
relationship between these hydrogen atoms, was not observed. The hydrogenation of each
individual double bond is expected to occur by cis addition of H2. However, it is intriguing
that the second double bond hydrogenation occurs preferentially at the opposite face of
the first hydrogenation step to furnish 6b.
A plausible mechanistic rationale accounting for the formation of the products of
this reaction is shown in Scheme 3.
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5
OH
O
benzyl
hydrogenolysis
C5-C6
reduction
H
O
O
O
O
O
O
5
6
7
8
OH
N
N
O
O
C7-C8
8
H
reductio
O
O
O
O
11
OH
H
H
6b
7
n
N
H
OH
6
H
C7-C8
reduction
H
C5-C6
reduction
5
O
O
O
O
O
O
10
9
N
N
O
O
H
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Scheme 3. Mechanistic hypothesis for the hydrogenation step using Rh/Al2O3 as catalyst.
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Benzyl hydrogenolysis should occur quickly, even at low hydrogen pressure.18
Indeed, the disappearance of the typical aromatic protons of the benzyl group in the crude
1H NMR spectrum was observed after only 1 hour of reaction at 1 atm of H2 pressure.
Debenzylated intermediate 10 could be hydrogenated in either one of the two double
bonds of the 6-membered ring. Supposing that the double bond in α position to the
nitrogen atom is hydrogenated preferentially (C5-C6 reduction), there is formation of enol
11, which in turn can furnish compound 6b via keto-enol tautomerism. Catalytic
hydrogenation of either 11 or 12, which would come from C7-C8 reduction, could then
furnish alcohol 9. Since formation of the stereogenic center at position 7 occurs with
protonation of 11, we sought to further study this step of the keto-enol equilibrium.
To elucidate the reason for the observed stereoselectivity of the hydrogenation
step, theoretical calculations were carried out for compound 6 for both cis (6a) and trans
(6b) relative stereochemistries (see SI for details).
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For both compounds 6a and 6b, the conformer of type I the most stable at the
B3LYP-D3/aug-cc-pVDZ level in EtOAc. Its geometrical representations are shown in
Figure 2 and considered for further comparative calculations between these two
diastereomers using DFT functionals and ab initio methods (Table S1, SI).
6a-I
6b-I
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Figure 2. Geometrical representations for the global minima of 6a and 6b
obtained at the B3LYP-D3/aug-cc-pVDZ level in EtOAC, using the IEF-PCM implicit
solvent model.
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The ab initio methods show that electron correlation is an important factor to be
taken into account, since the HF method shows the opposite result in comparison to MP2,
Grimme’s Spin-Component-Scaled (SCS)19 MP2 and MP4 methods, which indicate that
6a should be more stable than 6b. Similarly, the B3LYP functional shows the opposite
result, indicating that 6b should be 0.55 kcal·mol-1 more stable than 6a (ΔG values, Table
S1, SI). When Grimme’s D3 dispersion correction19 is applied to the B3LYP method, 6a
becomes more stable, hence indicating both electron correlation and dispersion
corrections should be important parameters to account for the energy difference between
6a and 6b.
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Based on these results, we applied Truhlar’s M06, M06-2X and M11
functionals20,21 and Grimme’s B2PLYP functional22 including D3 dispersion correction
for the latter. These functionals showed a considerable increase in ΔG values favoring 6a
in comparison to B3LYP-D3. By considering the calculated ΔG values for these
functionals, the approximate ratio between 6a and 6b (6a:6b) is calculated to be of 1:1
for B3LYP-D3, 2:1 for M06-2X, 3:1 for M06, 4:1 for M11 and 7:1 for B2PLYP-D3.
Although these functionals show a higher stability for 6a, they are not in complete
agreement with the experimental result, since 6a was not observed in any proportion. The
MP2 ab initio method shows a 6a:6b ratio of 10:1 (1.38 kcal·mol-1; Table S1, SI).
However, the SCS-MP2, which is considered an improvement for the MP2 method,23
shows a smaller 5:1 ratio. Although of high accuracy, SCS-MP2 approach cannot replace
the CCSD(T) model,24 which has been termed as “the gold standard” in the literature,25
mainly when applied together with the CBS approximation.26 The CCSD(T) method,
which scales as N7 (N = basis set), showed to be prohibitively expensive to be applied for
6a and 6b. However, we could apply the MP4(SDQ) method27 and the DLPNO-
CCSDT(T)/aug-cc-pVTZ28,29,30 level, which may be considered the highest levels applied
on this work. The MP4(SDQ) showed a Gibbs free energy preference for 6a of 1.82
kcal·mol-1 (Table S1, SI). Such an energy difference would correspond to a ratio higher
than 20:1. However, the DLPNO-CCSD(T) showed only a slightly preference for 6a of
0.19 kcal·mol-1, which increases to 0.82 kcal·mol-1 when thermal Gibbs free energy
corrections from the M11 functional are added. Thus, even high-level ab initio methods
diverge in the energy difference between 6a and 6b, showing that 6a should be slightly
more stable, even though it could not be observed experimentally. It is worth to mention
that keto-enol tautomerism has shown to be a challenge for high level ab initio methods
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and DFT calculations in the gas phase and implicit solvent even for simpler molecular
systems in previous benchmark studies.31
Thus, although the cis isomer should be the most stable, the keto-enol tautomerism
can have a high barrier in this molecular system, being the formation of the trans isomer
controlled kinetically instead of thermodynamically. Indeed, it was observed that
carboxylic acids can catalyze the keto-enol tautomerism and decrease the Gibbs free
energy barrier of keto-enol interconversion by as much as 45 kcal·mol-1.32,33,34 Because
the reaction in this work is being carried out in EtOAc, some residual acetic acid (AcOH)
may be present in the reaction mixture, catalyzing the reaction, decreasing the barrier
height, and possibly making 6b the favored kinetic product.
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The keto tautomer (6a or 6b, see SI) is more stable than the enol tautomer (11) by
as much as 19 kcal·mol-1 (M11/aug-cc-pVDZ) and the uncatalyzed energy barrier in the
stepwise mechanism can be as high as ~50-60 kcal·mol-1.32,33,34 In order to evaluate the
kinetic product, we obtained the reaction barriers for formation of 6a and 6b from 11
catalyzed by AcOH (Figure 3). These calculations were carried out at the M11/aug-cc-
pVDZ level, since this theoretical level showed similar results to the DLPNO-
CCSD(T)/aug-cc-pVTZ (Table S1, SI). Such calculations showed a G of 15.50 for 6b
and 17.19 kcal·mol-1 for 6a, hence the barrier for 6a is 1.69 kcal·mol-1 higher than for 6b.
Thus, 6b is the kinetic product and 6a is the thermodynamic one. Because 6a is not
observed experimentally, these results suggest that the observed product 6b may be
preferentially formed under kinetic control. Quantitatively, our computed difference in
the activation barriers is probably somewhat underestimated, because it would correspond
to a 6a:6b distribution of 5:95 at room temperature. Qualitatively, however, our results
provide evidence for this reaction being under kinetic control, and this may be the reason
why the diastereomer with cis stereochemistry is not observed experimentally.
17.19
O
TSa
1.423
O
H
O
O
1.263H
1.379
1.274
H
1.229
O1.065
H
15.50
TSb
O1.157
N
1.392
H
O
Ga
O
O
O
O
N
O
O
O
Gb
TSa
H
0.00
11 + AcOH
TSb
-19.08
-19.89
6b
6a
Go = 0.81 kcal mol-1
+ AcOH
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Figure 3. Energy diagram and transition state geometrical representations for the
keto-enol tautomerization step for formation of 6a through TSa and 6b through TSb
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calculated at the M11/aug-cc-pVDZ. The energies are given in kcal·mol-1.
Forming/breaking C=OHO and C=OHC bond distances are showed in angstroms.
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The present work explored the heterogeneous hydrogenation of
a
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polyfunctionalized indolizine (5), which was prepared by using a straightforward two-
steps sequence based on a Morita-Baylis-Hillman reaction with a known pyridine-2-
carboxaldehyde. The partial hydrogenation step was shown to be highly
diastereoselective, forming trans ketone 6b in 30% yield and cis alcohol 9 as an
inseparable mixture of unassigned compounds. The intriguing experimental preference of
trans diastereomer 6b was unveiled by applying high level ab initio and DFT theoretical
calculations, which pointed out the establishment of a keto-enol tautomerism as the key
step of the hydrogenation reaction. Under the experimental conditions, the kinetic (trans,
6b) isomer is favored in detriment of the thermodynamic (cis, 6a) isomer. The transition
state for the trans isomer is more stable by 1.69 kcal·mol-1 in comparison to the cis
isomer. Lastly, the present work may help guiding future experiments for the exploration
of keto-enol tautomerism to efficiently select thermodynamic/kinetic diastereomers in
heterogeneous hydrogenation reactions.
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19 EXPERIMENTAL SECTION
20 General Procedures
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All chemicals and solvents were of analytical grade, purchased from commercial
sources and used without further purification unless otherwise stipulated.
Unless otherwise noted, all reactions were performed under ambient atmosphere
in oven-dried open-flask glassware with magnetic stirring. Reaction progress was
monitored by analytical thin-layer chromatography (TLC) performed on precoated silica
gel 60 F254 (5-40 μm thickness) plates. The TLC plates were visualized with UV light
(254 nm) and/or potassium permanganate or sulfuric vanillin followed by heating. When
necessary, reaction products were purified by flash column chromatography using silica
gel (230-400 mesh).
Nuclear magnetic resonance spectra were recorded in deuterated solvents at room
temperature at 250, 400, 500 and 600 MHz. Data are reported as follows: chemical shift
(δ) in ppm, multiplicity, coupling constant (J) and integrated intensity. Abbreviations to
denote the multiplicity of a particular signal are: s (singlet), bs (broad singlet), d (doublet),
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t (triplet), dd (double doublet), ddd (double double doublet), dddd (double double double
doublet), ddddd (double double double double doublet) and m (multiplet).
The high-resolution mass spectrometric analyses (HRMS) were performed in a Q-
TOF instrument, equipped with ESI ionization source operating in the positive mode
(ESI(+)-MS). The samples were injected by direct infusion in a 40 µL·min-1 flow. The
following parameters were used: 3 kV capillary voltage, 20 V cone voltage, source
temperature of 120 °C and nebulization gas flow of 0.5 L·h-1. Before every analysis, the
instrument was calibrated with an H3PO4 solution (0.005% in H2O/CH3CN 1:1) from m/z
100 to 1000.
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Hydrogenation reactions were carried out in a suitable reactor fitted with a
mechanic stirrer and a system for measuring and controlling both pressure and
temperature (Parr Instruments Series 4590 Micro Stirred Reactor).
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Reactions under ultrasound were carried out in an ultrasonic cleaner UNIQUE
model GA 1000 (1000 W, 25 kHz).
Compounds were named according to IUPAC rules using the MarvinSketch 20.11
software. Compounds S1-S5 are the intermediates for the preparation of aldehyde 7.
Preparation of compound S1.
[5-(Benzyloxy)-4-(hydroxymethyl)-6-methylpyridin-3-yl]methanol (S1):13 To a round-
bottomed flask containing pyridoxine hydrochloride (2.00 g, 9.73 mmol) and anhydrous
potassium carbonate (3.0 equiv., 4.03 g, 29.2 mmol) was added anhydrous acetonitrile
(160 mL) under stirring. The mixture was heated to reflux using a pre-heated silicone oil
bath (at ~90 °C) for 1 h. Then, benzyl bromide (1.0 equiv., 1.16 mL, 9.73 mmol) was
added and the reaction mixture was stirred under reflux for 3 h. After this time, the
reaction was allowed to cool to room temperature and then was quenched by addition of
distilled water (100 mL). The mixture was extracted with EtOAc (4 × 30 mL), and the
combined organic phases were dried with anhydrous Na2SO4, filtered and concentrated
under reduced pressure. The resulting solid was recrystallized from EtOH to afford the
desired product as a brown crystalline solid in 83% yield (2.09 g, 8.06 mmol). M.p. =
1
111-113 °C (lit.13 113-114 °C). H NMR (250 MHz, DMSO-d6): δ 8.27 (s, 1H), 7.54–
7.33 (m, 5H), 5.25 (t, J = 5.5 Hz, 1H, OH), 5.15 (t, J = 5.5 Hz, 1H, OH), 4.89 (s, 2H),
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4.67 (d, J = 5.5 Hz, 2H), 4.60 (d, J = 5.5 Hz, 2H), 2.42 (s, 3H). C{1H} NMR (62.9
MHz, DMSO-d6): δ 151.2, 150.7, 143.7, 139.7, 137.0, 135.4, 128.5 (2C), 128.19 (2C),
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128.18, 75.8, 58.6, 53.9, 19.4. HRMS (ESI/Q-TOF) m/z: Calcd. for C15H18NO3 [M + H]+
260.1281, found 260.1281.
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Preparation of indolizine 5.
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9-(Benzyloxy)-3,3,8-trimethyl-1H,3H,5H-[1,3]dioxepino[5,6-c]pyridine (S2):13 To a
round-bottomed flask, S1 (3.41 g, 13.2 mmol) and 2,2-dimethoxypropane (180 mL) were
added. The mixture was then heated to reflux using a pre-heated silicone oil bath (at ~90
°C) until complete dissolution of the starting material. Then, p-toluenesulfonic acid
monohydrate (0.05 equiv., 125.1 mg, 0.658 mmol) was added to the solution under
stirring, and the reaction mixture was maintained under these conditions for 14 h. After
this time, the reaction mixture was allowed to cool to room temperature and then
quenched by adding distilled H2O (50 mL) and NaHSO4·H2O (75 mg). The resulting
mixture was extracted with CH2Cl2 (4 × 50 mL), and the combined organic phases were
dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to furnish
crude seven-membered cyclic acetal as a viscous brown oil in quantitative yield (4.14 g).
This compound was sufficiently pure to be used in the next step without further
purification. 1H NMR (400 MHz, CDCl3): δ 8.03 (s, 1H), 7.47–7.34 (m, 5H), 4.82 (s, 2H),
4.81–4.77 (m, 4H), 2.51 (s, 3H), 1.45 (s, 6H). 13C{1H} NMR (101 MHz, CDCl3): δ 151.1,
150.1, 141.8, 141.2, 136.4, 133.7, 128.9 (2C), 128.7, 128.2 (2C), 102.8, 75.4, 61.8, 59.4,
23.8, 19.1. HRMS (ESI/Q-TOF) m/z: Calcd. for C18H22NO3 [M + H]+ 300.1594, found
300.1593.
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9-(Benzyloxy)-3,3,8-trimethyl-1H,3H,5H-[1,3]dioxepino[5,6-c]pyridin-7-ium-7-olate
(S3):13 mCPBA (purity ≤ 77%) (1.6 equiv., 4.82 g, 21.5 mmol) was carefully added to a
solution of S2 (4.03 g; 13.4 mmol) in CHCl3 (100 mL) and the reaction mixture was
stirred for 14 h at room temperature in the dark. After this time, the reaction was quenched
by addition of 10% (m/v) aqueous solution of NaHSO4 (90 mL). The phases were
separated, and the organic phase was washed with 10% (m/v) aqueous solution of
NaHSO4 (2 × 90 mL), 10% (m/v) aqueous solution of NaHCO3 (2 × 90 mL) and with
distilled H2O (90 mL). The organic phase was dried with anhydrous NaSO4, filtered and
concentrated under reduced pressure to give desired N-oxide as a viscous yellow oil in
quantitative yield (4.25 g). This compound was sufficiently pure to be used in the next
step without further purification. 1H NMR (400 MHz, CDCl3): δ 7.95 (s, 1H), 7.45–7.33
(m, 5H), 4.81 (s, 2H), 4.74–4.66 (m, 4H), 2.45 (s, 3H), 1.43 (s, 6H). 13C{1H} NMR (101
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MHz, CDCl3): δ 151.6, 143.2, 135.5, 134.7, 133.1, 132.3, 129.02, 128.96 (2C), 128.4
(2C), 103.0, 76.5, 61.4, 59.1, 23.6, 11.8. HRMS (ESI/Q-TOF) m/z: Calcd. for C18H22NO4
[M + H]+ 316.1543, found 316.1543.
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[9-(Benzyloxy)-3,3-dimethyl-1H,3H,5H-[1,3]dioxepino[5,6-c]pyridin-8-yl]methyl
acetate (S4): In a round-bottomed flask, S3 (4.15 g; 13.1 mmol) was dissolved in
anhydrous acetic anhydride (66 mL, 0.20 mol·L-1) under stirring at room temperature and
heated to 70 °C using a pre-heated silicone-oil bath for 1 h. [CAUTION: this
transformation, also known as Boekelheide reaction, may proceed rather exothermically
and vigorously. A reflux condenser should be adapted to the flask.] Then, the reaction
mixture was allowed to reach room temperature and then distilled water (160 mL) was
slowly added to the flask. The resulting mixture was extracted with EtOAc (3 × 50 mL),
and the combined organic phases were dried with anhydrous Na2SO4, filtered and
concentrated under reduced pressure to furnish crude acetate as a viscous yellow oil in
quantitative yield (5.03 g). This compound was sufficiently pure to be used in the next
step without further purification. 1H NMR (500 MHz, CDCl3): δ 8.13 (s, 1H), 7.42–7.33
(m, 5H), 5.19 (s, 2H), 4.85 (s, 2H), 4.81 (s, 4H), 2.06 (s, 3H), 1.44 (s, 6H). 13C{1H} NMR
(126 MHz, CDCl3): δ 170.7, 150.5, 147.7, 142.7, 141.8, 136.0, 135.9, 128.8 (2C), 128.7,
128.2 (2C), 102.8, 76.9, 62.4, 61.7, 58.9, 23.6, 20.9. HRMS (ESI/Q-TOF) m/z: Calcd. for
C20H24NO5 [M + H]+ 358.1649, found 358.1647.
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[9-(Benzyloxy)-3,3-dimethyl-1H,3H,5H-[1,3]dioxepino[5,6-c]pyridin-8-yl]methanol
(S5):13 NaH (60% dispersion in mineral oil) (1.8 equiv., 587 mg; 24.4 mmol) was
weighted in a flame-dried round-bottomed flask under nitrogen atmosphere, carefully
dissolved in 80 mL of dry methanol at -10 °C (ethylene glycol/dry CO2 cryogenic bath)
and left to stir for 45 minutes. This solution was transferred via cannula to a solution of
S4 (4.86 g, 13.6 mmol) in 50 mL of CHCl3 at 0 °C and under stirring. The reaction mixture
was left to warm to room temperature (30 minutes) and then stirred for 2 h. After this
time, the reaction was quenched with saturated aqueous solution of NH4Cl (50 mL), and
the resulting mixture was extracted with EtOAc (4 × 50 mL). The combined organic
phases were dried with anhydrous Na2SO4, filtered and concentrated under reduced
pressure to afford crude primary alcohol as a light brown solid in 93% yield (3.98 g, 12.6
mmol). This compound was sufficiently pure to be used in the next step without further
purification. M.p. = 140-142 °C (lit.13 144 °C). 1H NMR (500 MHz, CDCl3): δ 8.09 (s,
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1H), 7.58–7.30 (m, 5H), 4.95–4.78 (m, 6H), 4.74 (s, 2H), 4.46 (bs, 1H, OH), 1.47 (s, 6H).
13C{1H} NMR (126 MHz, CDCl3): δ 151.3, 148.7, 141.34, 141.32, 136.0, 134.8, 128.8
(2C), 128.7, 128.2 (2C), 102.8, 76.2, 61.7, 60.1, 59.0, 23.6. HRMS (ESI/Q-TOF) m/z:
Calcd. for C18H22NO4 [M + H]+ 316.1543, found 316.1543.
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9-(Benzyloxy)-3,3-dimethyl-1H,3H,5H-[1,3]dioxepino[5,6-c]pyridine-8-carbaldehyde
(7):13 A solution of S5 (1.07 g, 3.38 mmol) in anhydrous CH2Cl2 (70 mL) was prepared
in a round-bottomed flask. The solution was cooled to 0 °C and then trichloroisocyanuric
acid (1.0 equiv., 785 mg, 3.38 mmol) and TEMPO (0.01 equiv., 5.3 mg, 0.338 mmol)
were carefully added to the reaction mixture under stirring. A change in the color of the
reaction mixture was noticed within the first 5 minutes of reaction time (it became an
orange suspension). After 30 minutes, the mixture was filtered through a plug of Celite,
and the filtrate was concentrated under reduced pressure, affording aldehyde 7 as a
viscous yellow oil in quantitative yield (1.13 g). This compound was sufficiently pure to
be used in the next step without further purification. 1H NMR (400 MHz, CDCl3): δ 10.15
(s, 1H), 8.29 (s, 1H), 7.45–7.34 (m, 5H), 5.01 (s, 2H), 4.88 (s, 2H), 4.78 (s, 2H), 1.44 (s,
6H). 13C{1H} NMR (101 MHz, CDCl3): δ 191.1, 153.7, 144.1, 143.6, 143.5, 140.6, 135.9,
129.0, 128.9 (4C), 103.0, 78.2, 61.9, 59.0, 23.6. HRMS (ESI/Q-TOF) m/z: Calcd. for
C18H20NO4 [M + H]+ 314.1387, found 314.1384.
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Methyl
2-{[9-(benzyloxy)-3,3-dimethyl-1H,3H,5H-[1,3]dioxepino[5,6-c]pyridin-8-
yl](hydroxy)methyl}prop-2-enoate (8): Aldehyde 7 (1.47 g, 4.91 mmol) and 1,4-
diazabicyclo[2.2.2]octane (DABCO, 0.65 equiv., 342 mg, 3.05 mmol) were added to a
250 mL round-bottomed flask. Then methyl acrylate (20 equiv., 8.5 mL, 93.8 mmol) was
added to the reaction mixture without magnetic stirring, the reaction flask was fitted with
a rubber septum and connected with a gas bubbler (with silicone oil). [CAUTION: methyl
acrylate has a pungent odor and lachrymatory properties: its manipulation must be carried
out in a well-ventilated fume hood.] The reaction mixture is sonicated in an ultrasound
bath for 64 h (the water bath in the ultrasound equipment was kept at room temperature).
After this time, the excess methyl acrylate was removed under reduced pressure
(alternatively, excess methyl acrylate can be recovered via distillation). The crude product
was redissolved in EtOAc (40 mL), and the solution was washed with saturated aqueous
solution of NH4Cl (4 × 20 mL). The organic phase was dried with anhydrous Na2SO4,
filtered and the solvent was removed under reduced pressure to afford crude MBH adduct
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8 as a yellow oil in 85% yield (1.66 g, 4.17 mmol). Compound 8 was sufficiently pure to
be used in the next step without further purification. 1H NMR (250 MHz, CDCl3): δ 8.10
(s, 1H), 7.42–7.35 (m, 5H), 6.28 (s, 1H), 5.85 (s, 1H), 5.61 (s, 1H), 4.96–4.70 (m, 6H),
3.67 (s, 3H), 1.47 (s, 3H), 1.46 (s, 3H). 13C{1H} NMR (63 MHz, CDCl3): δ 166.7, 152.1,
149.3, 142.2, 142.0, 141.5, 136.3, 135.7, 128.9 (2C), 128.8, 128.3 (2C), 126.7, 103.0,
76.5, 67.8, 62,0, 59.2, 52.1, 23.8. HRMS (ESI/Q-TOF) m/z: Calcd. for C22H26NO6 [M +
H]+ 400.1755, found 400.1740.
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Methyl
11-(benzyloxy)-3,3-dimethyl-1H,3H,5H-[1,3]dioxepino[5,6-f]indolizine-9-
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carboxylate (5): MBH adduct 8 (1.43 g, 3.57 mmol) was dissolved in acetic anhydride
(21.0 mL, 0.17·mol L-1) and heated at 100 °C (silicone oil bath) for 19 h under stirring.
When the reaction was considered finished by TLC, it was allowed to reach room
temperature and then carefully quenched by addition of distilled H2O (250 mL). The
resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic phases
were dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The
crude product was purified by column chromatography (silica gel, EtOAc/hexane 20:80)
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to afford substituted indolizine 5 as a brown oil in 65% yield (0.883 g, 2.32 mmol). H
NMR (250 MHz, CDCl3): δ 7.74 (d, J = 1.5 Hz, 1H), 7.49 (s, 1H), 7.48–7.32 (m, 5H),
6.90 (s, 1H), 5.14 (s, 2H), 4.76 (s, 2H), 4.67 (s, 2H), 3.88 (s, 3H), 1.43 (s, 6H). 13C{1H}
NMR (63 MHz, CDCl3): δ 165.6, 145.7, 136.9, 128.9 (2C), 128.6, 128.47 (2C), 128.45,
125.5, 120.5, 119.8, 117.9, 116.8, 102.7, 98.8, 74.8, 62.0, 59.1, 51.7, 24.1. HRMS
(ESI/Q-TOF) m/z: Calcd. for C22H24NO5 [M + H]+ 382.1649, found 382.1679.
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Heterogeneous Hydrogenation of Indolizine 5.
Indolizine 5 (120 mg, 0.315 mmol) was dissolved in ethyl acetate (5 mL), Rh/Al2O3 (12
mg, 10% w/w) was added to the solution, and the atmosphere was replaced with H2 (80
bar) in a hydrogenation reactor. The reaction mixture was stirred vigorously for 48 h at
room temperature. Then, the reaction medium was purged with N2, filtered through a plug
of Celite® and the filtrate was concentrated. Analysis of the crude by 1H NMR showed
three main products, which were purified by column chromatography (silica gel,
EtOAc/hexane 30:70) to afford product 6b (27 mg, 0.094 mmol) in 30% yield as a
colourless oil and a mixture containing 9 (27 mg, 0.091 mmol) as an oil.
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Methyl
(5aRS,11aSR)‐3,3‐dimethyl‐11‐oxo‐1H,3H,5H,5aH,6H,11H,11aH‐[1,3]dioxepino[5,6‐f]
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indolizine‐9‐carboxylate (6b): H NMR (600 MHz, C6D6): δ 7.71 (d, J = 1.7 Hz, 1H),
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6.94 (d, J = 1.7 Hz, 1H), 4.59 (dd, J = 12.7, 3.5 Hz, 1H), 3.71 (dd, J = 12.7, 9.8 Hz, 1H),
3.55 (s, 3H), 3.14 (dd, J = 11.8, 10.1 Hz, 1H), 2.92 (dd, J = 11.8, 3.1 Hz, 1H), 2.65 (dd,
J = 12.3, 4.2 Hz, 1H), 2.36 (t, J = 12.3 Hz, 1H), 1.88 (ddd, J = 12.3, 9.8, 3.5 Hz, 1H),
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1.56 (tddd, J = 12.3, 10.1, 4.2, 3.1 Hz, 1H), 1.23 (s, 3H), 1.21 (s, 3H). C{1H} NMR
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(126 MHz, C6D6): δ 186.0, 164.2, 130.9, 128.5, 118.2, 114.2, 101.6, 62.3, 60.9, 52.6,
51.0, 46.7, 42.2, 25.0, 24.8. HRMS (ESI/Q-TOF) m/z: Calcd. for C12H15NaNO5 (acetal
deprotection) [M + Na]+ 276.0842, found 276.0829.
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Methyl
(5aSR,11RS,11aSR)-11-hydroxy-3,3-dimethyl-1H,3H,5H,5aH,6H,11H,11aH-
[1,3]dioxepino[5,6-f]indolizine-9-carboxylate (9) – present in mixture of compounds
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(only the signals of 9 were assigned, see SI for details): H NMR (400 MHz, C6D6): δ
7.20 (d, J = 1.8 Hz, 1H), 7.07–7.05 (m, 1H), 4.17 (dd, J = 6.0, 1.3 Hz, 1H), 3.94 (dd, J =
13.0, 11.5 Hz, 1H), 3.83 (ddd, J = 12.7, 3.0, 1.3 Hz, 1H), 3.62 (s, 2H), 3.53 (dd, J = 12.6,
1.7 Hz, 1H), 3.38 (dd, J = 12.6, 10.6 Hz, 1H), 3.13–3.02 (m, 2H), 2.17 (dddd, J = 10.5,
6.1, 3.9, 3.0 Hz, 1H), 1.42–1.35 (m, 1H), 1.26 (s, 3H), 1.09 (s, 3H). 13C{1H} NMR (101
MHz, C6D6): δ 165.5, 131.2, 125.1, 117.6, 107.3, 102.0, 74.1, 62.8, 58.2, 51.0, 43.1, 42.6,
36.2, 25.4, 25.3. HRMS (ESI/Q-TOF) m/z: Calcd. for C15H22NO5 [M + H]+ 296.1492,
found 296.1487.
23 Computational Details
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Conformers of compounds 6a and 6b were located through a Monte Carlo
conformational search at the MMFF level with the Spartan 14 program,35 using a 10
kcal·mol-1 threshold and 5000 K initial temperature in the simulated-annealing algorithm.
Optimizations and frequency calculations were carried out at the B3LYP-D3/aug-cc-
pVDZ level using the Gaussian 09 program, Revision D.0136 for all conformers found in
the Monte Carlo calculations. The lack of negative harmonic vibrational frequencies
confirmed that all conformers are true energy minima, or the observation of a single
negative frequency was used to characterize the geometry as a transition state. The same
frequency calculations were used to evaluate thermodynamic corrections affording
enthalpies and Gibbs free energies at ambient, standard temperature and pressure for each
species. Solvent effects were evaluated by optimizing each conformer using an implicit
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solvent model, namely the IEF-PCM (integral equation formalism variant of the
Polarizable Continuum Model)37. The global minima of 6a and 6b were reoptimized by
using several DFT funcionals and the HF and MP2 ab initio methods and the aug-cc-
pVDZ basis set. MP4 single point calculations were carried out over the M11/aug-cc-
pVDZ optimized geometries and the enthalpy and Gibbs free energies were obtained from
this same functional to add to MP2, MP4, and the B2PLYP-D3 potential energies.
DLPNO-CCSD(T)/aug-cc-pVTZ calculations were ran over the M11/aug-cc-pVDZ
optimized geometries using the ORCA 4.2.1 program and were also corrected with the
enthalpy and Gibbs free energies obtained from this same level.38
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11 ASSOCIATED CONTENT
12 Supporting Information
13
Details for the preparation of aldehyde 7, NMR spectra of all synthesized
1
13
14 compounds, complete attribution of the H and C of compounds 6b and 9 with
15 the analysis for assignment of their relative stereochemistries, cartesian
16 coordinates of compounds 6a and 6b global minima, their relative energies at
17 different levels of theory, and of transition states TSa and TSb obtained at several
18 ab initio and DFT theoretical levels are available.
19
20 AUTHOR INFORMATION
21 Corresponding Author
22
Fernando Coelho – University of Campinas, Institute of Chemistry,
23 Department of Organic Chemistry, PO Box 6154 – 13083-970 – Campinas, São
24 Paulo, Brazil; https://orcid.org/0000-0003-1800-1549
25
26 Authors
27
Rodrigo A. Cormanich – University of Campinas, Institute of Chemistry,
28 Department of Organic Chemistry, PO Box 6154 – 13083-970 – Campinas, São
29 Paulo, Brazil; https://orcid.org/0000-0001-7659-1749
30
Lucas A. Zeoly – University of Campinas, Institute of Chemistry,
31 Department of Organic Chemistry, PO Box 6154 – 13083-970 – Campinas, São
32 Paulo, Brazil; https://orcid.org/0000-0003-2111-3904
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Hugo Santos – University of Campinas, Institute of Chemistry, Department
of Organic Chemistry, PO Box 6154 – 13083-970 – Campinas, São Paulo, Brazil;
https://orcid.org/0000-0002-7411-5180
Nilton S. Camilo – University of Campinas, Institute of Chemistry,
Department of Organic Chemistry, PO Box 6154 – 13083-970 – Campinas, São
Paulo, Brazil; https://orcid.org/0000-0002-3521-2172
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Michael Bühl – School of Chemistry, University of St Andrews, North
Haugh, St Andrews, Fife KY169ST, UK; https://orcid.org/0000-0002-1095-7143
10 ACKNOWLEDGEMENTS
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The authors are grateful to FAPESP for the financial support of this research. The
authors also thank FAPESP for the fellowships to R.A.C. (#2018/03910-1) and F.C.
(#2013/07600-3 and #2018/02611-3) and a scholarship to H.S. (#2015/09205-0), and
CNPq for a scholarship to L.A.Z. and research fellowship for F.C (307840/2014-0 and
301330/2016-2). LAZ also thanks Capes for a scholarship. CENAPAD-SP, CESUP and
SDumont computational resources are also gratefully acknowledged.
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