Base-Mediated Cyclization of 3-[2-(2-Oxo-2-phenylethyl)-1-pyrrolidinyl]propanenitrile to 7-Phenyl-1,2,3,7,8,8a-hexahydroindolizine-6-carbonitrile: What Lies Between?

Article abstract of DOI:10.1002/ejoc.201701714

Three intermediates along the reaction path by which 3-[2-(2-oxo-2-phenylethyl)-1-pyrrolidinyl]propanenitrile is converted into the rel-(7R,8aR)- and (7R,8aS)-diastereoisomers of 7-phenyl-1,2,3,7,8,8a-hexahydroindolizine-6-carbonitrile upon treatment with

Full text of DOI:10.1002/ejoc.201701714

A Journal of
Accepted Article
Title: Base-mediated cyclization of 3-[2-(2-oxo-2-phenylethyl)-1-
pyrrolidinyl]propanenitrile to 7-phenyl-1,2,3,7,8,8a-
hexahydroindolizine-6-carbonitrile: what lies between?
Authors: Garreth L. Morgans, Manuel A. Fernandes, Willem A. L. van
Otterlo, and Joseph P. Michael
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701714
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10.1002/ejoc.201701714
European Journal of Organic Chemistry
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Base-mediated Cyclization of 3-[2-(2-Oxo-2-phenylethyl)-1-
pyrrolidinyl]propanenitrile to 7-Phenyl-1,2,3,7,8,8a–
hexahydroindolizine-6-carbonitrile: What Lies Between?
Garreth L. Morgans,[a] Manuel A. Fernandes,[a] Willem A. L. van Otterlo,[a,b] and Joseph P. Michael*[a]
Abstract: Three intermediates along the reaction path by which 3-
[2-(2-oxo-2-phenylethyl)-1-pyrrolidinyl]propanenitrile is converted
into the rel-(7R,8aR)- and (7R,8aS)-diastereoisomers of 7-phenyl-
1,2,3,7,8,8a–hexahydroindolizine-6-carbonitrile upon treatment with
potassium tert-butoxide were isolated and characterized. They
include the rel-(6R,7R,8aR)- and (6R,7S,8aS)-diastereoisomers of 7-
Instead, the indolizinecarbonitrile 10 was obtained as mixture of
diastereoisomers.[13] Intrigued by this outcome, we have now
investigated the reaction in depth in order to ascertain what
intermediates might lie along the reaction pathway. The results
are presented in this article.
hydroxy-7-phenyloctahydroindolizine-6-carbonitrile
(the
former
obtained as monohydrate), and 7-phenyl-1,2,3,5,8,8a-
a
hexahydroindolizine-6-carbonitrile. The alcohol intermediates and
the final products were also characterized by X-ray crystallography.
Introduction
Indolizidine alkaloids and unsaturated analogues bearing
aromatic or heteroaromatic substituents on the bicyclic core are
relatively rare.[1a,1b] Examples include animal alkaloids such as
the Nuphar indolizidine (1),[2,3] the plant alkaloids crepidamine
(2),[4] (+)-ipalbidine (3)[5,6] and (−)-septicine (4),[7,8] and the
sponge metabolite callyimine A (5)[9] (Fig. 1). As part of an
ongoing programme of investigations into the application of
enaminone intermediates in the synthesis of alkaloids,[10,11a-f] we
embarked on a series of model studies in which aromatic
substituents were incorporated into enaminones that could serve
as precursors for arylated indolizidine targets.
Figure 1. Examples of indolizidine alkaloids bearing aromatic substituents.
In studies aimed at the synthesis of Peripentadenia alkaloids
reported over two decades ago, we described the preparation of
the enaminone 6 and its chemoselective reduction to the
saturated ketone 7 with lithium aluminum hydride under carefully
controlled conditions.[12] We subsequently wondered what the
outcome of base-induced cyclisation of 7 might be: would
indolizidinone 8 be formed by reaction of the enolate with the
nitrile; or, alternatively, would the unsaturated indolizidine 9 (a
model for septicine) be formed by condensation of the nitrile
anion with the ketone (Fig. 2)? As it turned out, a trial reaction
showed that neither of the expected products was formed.
Figure 2. Pyrrolidine precursors and possible indolizine products therefrom.
The numbering system used for indolizines is shown on structure 9.
Results and Discussion
[a]
[b]
Molecular Science Institute, School of Chemistry,
University of the Witwatersrand,
PO Wits 2050, Johannesburg,
South Africa
E-mail: Joseph.michael@wits.ac.za
Department of Chemistry and Polymer Science,
Stellenbosch University,
The enaminone 6 was prepared essentially as described
previously[12] by Eschenmoser sulfide contraction[14,15] between
phenacyl bromide and the thiolactam 11 (Scheme 1, upper line).
The reaction could be performed on a six-gram scale, and 6 was
obtained in 86% yield without the need for chromatographic
purification. Although its (E)-geometry, and more specifically the
trans-s-cis conformation, could be inferred from the through-
Matieland 7602, Stellenbosch,
South Africa
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201701714
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space anisotropic deshielding of the pyrrolidine ring’s 3-H
hydrogens at δ 3.40,[14,16] we were able to corroborate the
structure by X-ray crystallography, as shown in the ORTEP
diagram (Figure 3a). The temperamental chemoselective
reduction of the conjugated ketone to 7 was achieved in 86%
yield with fresh lithium aluminum hydride in fairly dilute
tetrahydrofuran solution (0.15 M) at −10 °C provided that the
reaction was worked up within 15 minutes. Formation of the
previously observed[12] by-product of a retro-Michael reaction,
enaminone 12, was less than 3% under these conditions.
equivalents of potassium tert-butoxide in reasonably dilute
tetrahydrofuran solution (ca 0.1 M) for three hours at room
temperature instead of at reflux temperature, a gum was formed
that
proved
to
be
a
mixture
of
7-hydroxy-7-
phenyloctahydroindolizine-6-carbonitrile diastereoisomers (80%),
one of which was dominant (Scheme 2). This major product
could be isolated as
a stable white product after slow
recrystallization from ethyl acetate–hexane (54%). Intriguingly,
the recrystallized product turned out to be the monohydrate of
the rel-(6R,7R,8aR) isomer 13a, as shown by X-ray
crystallography (Fig. 3d). In fact, hydrates of varying composition
were obtained in every attempt at isolating this diastereoisomer
from crude reaction mixtures. For example, an unstable
hemihydrate (as inferred from the NMR spectrum) was produced
when recrystallization was induced rapidly at −10 °C, and this
was converted into the stable monohydrate on further
recrystallization from aqueous acetone. Regrettably, we were
not able to elucidate the true coefficient of hydration by way of
elemental analysis as the results obtained were variable.
Attempts to dehydrate the compound completely by sublimation
or distillation resulted in decomposition.
Scheme 1. Reagents and conditions: (i) PhCOCH2Br, MeCN, rt, 24 h; (ii)
P(OEt)3, NEt3, MeCN, rt, 17 h; (iii) LiAlH4, THF, −10 °C, 15 min; (iv) t-BuOK,
THF, reflux, 3 h.
Our first objective in exploring the outcome of the cyclisation of 7
was to identify the diastereoisomers of the final bicyclic
vinylogous cyanamide 10. Reaction of 7 with two equivalents of
potassium tert-butoxide in boiling tetrahydrofuran for three hours
afforded an approximately 3:1 mixture of the expected
diastereoisomers of 10 in 88% yield, the ratio being determined
by analysis of the NMR spectrum of the mixture (Scheme 1,
lower line). The major isomer could be isolated from the mixture
by careful recrystallization from ethyl acetate–hexane. The
trans-fusion of the junction between the two heterocyclic rings
was suggested by a prominent Bohlmann band at 2870 cm−1 in
the FTIR spectrum.[17] The signal for 7-H appeared as a double
doublet at 3.73 ppm with coupling constants of 5.2 and 1.8 Hz;
this suggested that the phenyl ring occupied an approximately
axial orientation on the half- chair six-membered ring, since the
expected large trans-diaxial coupling to one of the 8-H
hydrogens was not observed. The two 8-H hydrogens appeared
as signals at 2.06 ppm (ddd, J 12.9, 3.6 and 1.9 Hz) and 1.54
ppm (ddd, J 12.8, 11.7 and 5.3 Hz); in addition to the expected
geminal coupling constant of 12.9 Hz between them, the latter
signal also showed a trans-diaxial interaction with the 8a-H
Scheme 2. Reagents and conditions: (i) t-BuOK, THF, rt, 3 h; (ii) t-BuOK, THF,
rt, 21 h; then 40-50 °C, 48 h.
Salient features for the isomer 13a apparent in the crystal
structure were the equatorial arrangement of both the phenyl
and nitrile substituents on the six-membered ring chair, and the
trans-fused junction between the two rings, which was also
suggested by a prominent Bohlmann band at 2826 cm−1 in the
infrared spectrum. Most interestingly, the three atoms in the
water of crystallization showed hydrogen bonding to different
donor or acceptor sites in three neighboring indolizidinol
molecules (Fig. 4): the oxygen atom of the water molecule was
hydrogen-bonded to the hydroxyl terminus of one neighbor,
while the hydrogen atoms interacted with the nitrile substituent
of a second molecule and the tertiary amine of a third.
Isolation
of
other
diastereoisomers
of
7-hydroxy-7-
phenyloctahydroindolizine-6-carbonitrile proved to be very tricky.
One of these, which was shown by thin-layer chromatography to
be formed early and remain rather persistent throughout the
course of the reaction, was eventually isolated not from the
cyclisation of 7, but by epimerization of the indolizidinol 13a.
bridgehead hydrogen at 3.04 ppm (J
> 10 Hz). These
spectroscopic observations pointed to the rel-(7R,8aS)
configuration for the isomer, as shown in 10a. This structure was
subsequently confirmed by single-crystal X-ray crystallography
(Figure 3b).
Reaction of
a
dilute solution of 13a monohydrate in
tetrahydrofuran (ca 0.1 M) with two equivalents of potassium
tert-butoxide at room temperature for three to five days gave a
spread of products, repeated chromatography of which yielded a
sample of the desired compound that was pure enough for both
In order to identify the intermediates en route to the final
unsaturated indolizidines, the cyclisation was carried out under
more carefully controlled conditions. By performing the base-
induced cyclisation of the saturated ketone
7 with two
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10.1002/ejoc.201701714
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Figure 3. ORTEP diagrams of the crystal structures of (a) 3-{2-[(E)-2-oxo-2-phenylethylidene]-1-pyrrolidinyl}propanenitrile (6); (b) rel-(7R,8aS)-7-phenyl-
1,2,3,7,8,8a-hexahydroindolizine-6-carbonitrile (10a); (c) rel-(7R,8aR)-7-phenyl-1,2,3,7,8,8a-hexahydroindolizine-6-carbonitrile (10b); (d) rel-(6R,7R,8aR)-7-
hydroxy-7-phenyloctahydroindolizine-6-carbonitrile monohydrate (13a); and (e) rel-(6R,7S,8aS)-7-hydroxy-7-phenyloctahydroindolizine-6-carbonitrile (13b).
Thermal ellipsoids are at 50% probability.
was recovered unchanged. The crystal structure (Fig. 3e)
proved that this product was the rel-(6R,7S,8aS) indolizidinol
diastereoisomer 13b. The trans-diaxial arrangement of nitrile
and hydroxy substituents on the chair is clearly visible, as is the
trans-fused arrangement of the two heterocyclic rings.
How the reaction progressed further from indolizidinols 13a and
13b to the final bicyclic vinylogous cyanamides 10a and 10b is
the remaining question. At this point, the initially expected
product with unsaturation between the phenyl and nitrile
substituents, i.e. 9, had not been found. However, a relatively
late-forming and rapidly consumed further intermediate was also
apparent by thin-layer chromatography, and this elusive
intermediate proved quite difficult to isolate owing to its transient
nature. It was only by heating the monohydrate of indolizidinol
13a with potassium tert-butoxide in a far more dilute solution of
tetrahydrofuran (ca 0.03 M) that enough of the material could be
obtained for characterization (Scheme 3). This unstable oil,
which rapidly blackened on exposure to air, indeed proved to be
Figure 4. Crystal structure of the monohydrate of 13a showing the interaction
of the water of crystallization with three different indolizidine molecules.
the desired unsaturated compound 9 (56% isolated yield). The
FTIR spectrum indicated a prominent Bohlmann band at 2795
cm−1, which again suggests trans fusion of the bicyclic structure.
In the 13C NMR spectrum the C-6 and C-7 signals of the double
spectroscopic and crystallographic characterization. The same
bond were found at 106.7 ppm and 154.3 ppm respectively. In
the 1H NMR spectrum, the two 5-H protons appeared as a
product was obtained in 34% yield when the monohydrate of
13a was treated with sodium ethoxide in anhydrous ethanol at
room temperature for four days; the remaining starting material
doublet of doublets at 3.79 ppm and a ddd multiplet at 3.11 ppm,
with a geminal coupling constant of 15.9 Hz. The pair of 8-H
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10.1002/ejoc.201701714
European Journal of Organic Chemistry
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protons H8 occurred as a doublet of triplets at 2.76 ppm and a
ddd multiplet at 2.50 ppm, with a geminal coupling constant of
18.0 Hz. An interesting feature is the appearance of homoallylic
coupling between the 5-H signal at 3.79 ppm and the 8-H signal
intermediates shown in Scheme 4. For the ring-closing step itself,
several competitive cyclizations are feasible, but only one leads
to the cyclic vinylogous cyanamides. Clearly, the
chemoselectivity of the cyclisation depends on the relative ease
of deprotonation adjacent to the ketone and nitrile groups as
compared with the electrophilicity of these substituents.
Although ketones are in principle more readily deprotonated
than nitriles, the latter are poorer electrophiles that often resist
nucleophilic attack by organometallic reagents.[18] Ketones, by
contrast, are superior electrophiles that react rapidly with a
plethora of nucleophiles. These contrasting factors thus bias the
keto-nitrile 7 towards cyclisation via the nitrile anion. Although
the ketone enolate 14 is probably formed quite rapidly, inter- or
intramolecular proton transfer is likely to convert this enolate into
the nitrile anion 15, which then cyclizes to the indolizidinols 13a
and 13b in what is presumably the rate-determining step. These
alcohols can equilibrate by epimerization under the basic
reaction conditions. Base-initiated dehydration (presumably from
13a if an E2 mechanism operates) then leads to the unstable
unsaturated indolizidine 9, proton abstraction from which at the
allylic position subsequently gives a carbanion 16a that can be
stabilized by resonance. Protonation of the canonical form 16b
in which the anion is stabilized by additional interaction with the
phenyl substituent finally gives the thermodynamically preferred
indolizidines 10a and 10b in which extended conjugation from
the tertiary amine through to the nitrile (a vinylogous cyanamide)
dictates the final outcome. The intermediates in this Scheme are
consistent with common sense and, gratifyingly, all of them
could be isolated and characterized.
5
at 2.50 ppm, with J = 2.3 Hz. In addition, the remaining 5-H
5
signal at 3.11 ppm shows homoallylic couplings of J ca 3 Hz
and 4.2 Hz to the 8-H protons at 2.76 ppm and 2.50 ppm
respectively. These interactions were confirmed by the
correlations observed in the COSY spectrum.
Scheme 3. Reagents and conditions: (i) t-BuOK, THF, reflux, 24 h; (ii) H2SO4,
CH2Cl2, rt, 90 sec.
The formation of the unstable unsaturated intermediate 9 was
also attempted under acidic conditions. Only one experiment,
performed under somewhat drastic conditions, proved to be
successful. This entailed the addition of fifteen to twenty
equivalents of concentrated sulfuric acid in one portion to a
solution of the indolizidinol hydrate 13a in dichloromethane at
room temperature, followed by careful neutralization with sodium
carbonate after just 90 seconds. In this manner the desired
product could be obtained in 50% yield. Yields decreased when
the reaction was performed over longer time periods (e.g., to
40% after 20 minutes).
Conclusions
The final set of investigations was carried out to demonstrate
that the indolizidinols 13a and 13b and the unsaturated
intermediate 9 indeed lay on the reaction path to the ultimate
vinylogous cyanamides 10a and 10b. In the first instance, the
monohydrate of indolizidinol 13a was heated at reflux
temperature with potassium tert-butoxide in tetrahydrofuran for
four hours to give an 85% combined yield of diastereoisomers.
These could be partially separated by careful column
chromatography to give pure samples of rel-(7R,8aS)-7-phenyl-
1,2,3,7,8,8a-hexahydro-6-indolizinecarbonitrile (10a) (54%) and
rel-(7R,8aR)-7-phenyl-1,2,3,7,8,8a-hexahydro-6-indolizine-
carbonitrile (10b) (15%), as well as a mixed fraction (16%). A
similar reaction of the alternative indolizidinol 13b afforded an
approximately 3:1 mixture of the same two diastereoisomers
(56%). Finally, heating the unstable unsaturated intermediate 9
with potassium tert-butoxide in tetrahydrofuran for no more than
five minutes also gave a 3:1 mixture of the two diastereoisomers
(74%).
The investigations described in this work have demonstrated
that the base-induced cyclisation of a pyrrolidine-containing
keto-nitrile in which the two functional groups are relatively
remote proceeds, perhaps counter-intuitively, via the anion of
the nitrile rather than the ketone enolate. This is not without
precedent, as Fleming et al. have described and rationalized
similar cyclization’s.[18] The cyclisation firstly produces β-
hydroxynitrile indolizidine intermediates, two diastereoisomers of
which could be isolated and characterized. Under the reaction
conditions, dehydration of the initially formed hydroxynitriles
produces yet another characterizable intermediate in which the
double bond is located between the nitrile and the adjacent
phenyl substituent. In the present case, however, the presence
of the indolizidine’s tertiary amine ensures that this unsaturated
intermediate undergoes isomerization of the alkene such that
the final products are vinylogous cyanamides that are stabilized
by extended conjugation from the lone pair on nitrogen through
to the nitrile substituent. The overall course of this reaction has
thus been elucidated.
The sequence of reactions by which 3-[2-(2-oxo-2-phenylethyl)-
1-pyrrolidinyl]propanenitrile (7) is transformed under basic
conditions into the bicyclic vinylogous cyanamides 10a and 10b
can thus be envisaged as occurring through the series of
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10.1002/ejoc.201701714
European Journal of Organic Chemistry
FULL PAPER
Scheme 4. Proposed sequence of reactions by which the pyrrolidine 7 is transformed into the hexahydroindolizines 10a and 10b.
CCDC-1584443, 1584444, 158444,5 1584446 and 1584447 contain the
supplementary crystallographic data for compounds 6, 10a, 10b 13a and
13b, respectively. These data can be obtained free of charge from The
Experimental Section
Cambridge
Crystallographic
Data
Centre
via www.ccdc.cam.ac.uk/data_request/cif.
General remarks: 1H NMR and 13C NMR spectra were recorded in
CDCl3 with TMS as internal standard on
a Bruker AVANCE 300
3-{2-[(E)-2-Oxo-2-phenylethylidene]-1-pyrrolidinyl}propanenitrile (6):
This compound was prepared by
known procedure.[12] Phenacyl
spectrometer at the frequencies indicated. J values are given in Hz.
DEPT, COSY and HSQC spectra were run on some samples to enable
more complete assignments of signals. FTIR spectra were recorded on a
Bruker Vector-22 Fourier Transform spectrometer or a Bruker Tensor 27
Fourier Transform spectrometer. High-resolution mass spectra were
recorded either on a VG70 MS (Mass spectrum CC Pyramid data
system), a VG70 SEQ (VG 11-205J or Marc II data system) or on a DFS
High Resolution Magnetic Sector mass spectrometer. Merck silica gel
(particle size 0.063–0.200 mm) was used for conventional silica gel
chromatography and Merck silica gel (particle size 0.04–0.063 mm) for
flash column chromatography, while thin-layer chromatography was
performed using Merck silica-gel 60 F254 coated on aluminium sheets.
Reactions were performed under a blanket of inert gas (Ar or N2) unless
specified. Tetrahydrofuran (THF) was distilled from Na/benzophenone,
and acetonitrile from calcium hydride. Commercially available chemicals
were used as received.
a
bromide (8.21 g, 41.2 mmol) was added to a solution of 3-(2-thioxo-1-
pyrrolidinyl)propanenitrile (11) (6.00 g, 38.9 mmol) in dry acetonitrile (50
cm3) and stirred under an atmosphere of N2 for 24 h. A solution of
P(OEt)3 (tech. grade 94%, 7.50 cm3, ca 41.2mmol) and Et3N (5.95 cm3,
4.33 g, 42.8 mmol) in dry acetonitrile (20 cm3) was added dropwise over
5 min and stirring was continued for an additional 17 h. The solvent was
evaporated and the residue was taken up into EtOAc (200 cm3) and
washed with H2O (2 × 100 cm3). The organic phase was extracted with
aq. HCl (2 M, 1 × 200 cm3, 2 × 50 cm3) and the aqueous extracts were
combined and back-extracted with EtOAc (100 cm3). The combined
acidic extracts were made basic with aq. NH3 (25%) and extracted with
EtOAc (4 × 50 cm3). The combined organic extracts were washed with
additional H2O (4 × 50 cm3), dried over MgSO4, filtered and finally
evaporated to give the title compound 6 (8.01 g, 86%) as an orange solid,
mp 124–125 °C (MeOH) (lit.,[12] 124.5–125.5 °C); Rf (EtOAc) 0.44; FTIR
(ATR) νmax 3061 (w), 2960, 2930 and 2882 (m), 2244 (w, C≡N), 1624 (s,
C=O), 1597 (s, C=C), 1577 (s), 1539 (s), 1480 (s), 1300 (s), 1218 (s)
cm−1; 1H NMR (300 MHz, CDCl3) δ 7.85 (2H, dd, J 7.4 & 1.9 Hz, Ar o-H),
7.50– 7.33 (3H, m, Ar m- and p-H), 5.70 (1H, s, =CH), 3.66 (2H, t, J 6.7
Hz, chain NCH2), 3.58 (2H, t, J 7.2 Hz, ring NCH2), 3.40 (2H, t, J 7.8 Hz,
CH2C=), 2.69 (2H, t, J 6.7 Hz, CH2CN), 2.06 (2H, quintet, J 7.6 Hz,
CH2CH2CH2); 13C NMR (75 MHz, CDCl3) δ 188.2 (C=O), 166.1 (C=CH),
141.5 (Ar C-1),130.7 (Ar p-C), 128.1 and 127.2 (Ar o- and m-C), 117.5
(C≡N), 87.2 (C=CH), 53.2 (ring NCH2), 42.4 (chain NCH2), 33.5 (CH2C=),
21.1 (CH2CH2CH2), 14.9 (CH2CN). The 1H and 13C NMR spectroscopic
data are in line with those previously reported at 200 MHz and 50 MHz,
respectively.[12] X-ray crystal structure details of compound 6: crystallised
from hexane–EtOAc, formula: C15H16N2O, M=240.30, colour of crystal:
colourless, prisms, crystal size 0.44 × 0.27 × 0.20 mm3, a=5.9532(3) Å,
b=16.4766(10) Å, c=13.0345(8) Å, β=94.127(4)° V=1275.22(13) Å3,
Crystal structure solution and refinement: intensity data were
collected on a Bruker Apex 2 CCD area detector diffractometer with
graphite-monochromated Mo Kα radiation (50kV, 30mA). The collection
method involved ω scans of width 0.5°. Data reduction was carried out
using the program SAINT+.[19] The structure was solved by direct
methods, with non-hydrogen atoms refined isotropically at first, followed
by anisotropic refinement using full matrix least-squares calculations
based on F2 using SHELXL-2017/1.[20] All hydrogen atoms were first
located in the difference-Fourier map then positioned geometrically and
allowed to ride on their respective parent atoms. Software used in this
work was as follows: Data collection: APEX2;[21] cell refinement and data
reduction: SAINT+;[19] program suite used to solve and refine structures:
SHELX-2014;[20] software used to prepare material for publication:
WinGX-2014.1,[22] PLATON,[23] and Mercury.[24]
ρ
calc=1.252 Mg/m3, µ=0.080 mm-1, F(000)=512, Z=4, monoclinic, space
group P21/n, T=173(2) K, 10697 reflections collected, 3071 independent
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10.1002/ejoc.201701714
European Journal of Organic Chemistry
FULL PAPER
reflections, θmax 25.242°, 163 refined parameters, maximum residual
electron density 0.189 and −0.213 e.Å-3. R1=0.0417, wR2=0.1037.
8a-H), 2.40 (1H, br s, OH), 2.31 (1H, q, J 8.8 Hz, 1H, 3-H"), 2.03 (1H, dd,
J 13.8 and 2.7 Hz, 8-H'), 1.95–1.66 (ca 5H, m, 1-H', 2-H', 2-H", 8-H" and
H2O), 1.39 (1H, qd, J 11.1 and 6.6 Hz, 1-H"); 13C NMR (75 MHz, CDCl3)
δ 144.6 (Ar C-1), 128.9 (Ar o- or m-C), 128.1 (Ar p-C), 124.4 (Ar o- or m-
C), 118.5 (C≡N), 73.4 (C-7), 58.6 (C-8a), 53.1 (C-3), 50.7 (C-5), 44.3 (C-
8), 40.2 (C-6), 30.0 (C-1), 21.2 (C-2); HRMS (EI): M+, found 242.1412.
[C15H18N2O]+ requires 242.1414. X-ray crystal structure details of
compound 13a: crystallised from hexane–EtOAc, formula: C15H20N2O2,
M=260.33, colour of crystal: colourless, block, crystal size 0.40 × 0.38 ×
0.18 mm3, a=8.287(1) Å, b=13.2796(14) Å, c=13.3083(15) Å,
3-[2-(2-Oxo-2-phenylethyl)-1-pyrrolidinyl]propanenitrile
(7): This
compound was prepared by adapting a reported procedure.[12] 3-{2-[(E)-
2-Oxo-2-phenylethylidene]-1-pyrrolidinyl}propanenitrile (6) (5.00 g, 20.8
mmol) in THF (150 cm3) was cooled to −10 °C and stirred under an
atmosphere of Ar for 10 min. LiAlH4 (95%, 790 mg, ca 20 mmol) was
added in one portion and stirring was continued for 15 min. EtOAc (20
cm3) was added followed by H2O (3 cm3). Once the solution went white
Na2SO4 was added and stirring was continued for 20 mins. The reaction
mixture was filtered through a pad of Celite and the pad was rinsed with
EtOAc (4 × 50 cm3). Evaporation of the solvents afforded a yellow oil that
was purified by flash chromatography (70% EtOAc/hexane) to afford the
title compound 7 (4.32 g, 86%) as a yellow oil, as well as a small quantity
of (Z)-1-phenyl-2-(2-pyrrolidinylidene)-1-ethanone (12) (100 mg, <3%) as
a colourless solid. Compound 7: Rf (EtOAc) 0.51; FTIR (liquid film) νmax
3060 (w), 2963 (m), 2813 (m), 2248 (w, C≡N), 1682 (s, C=O) 1597 (m),
β=102.566(2)° V=1429.5(3) Å3,
ρ
calc=1.210 Mg/m3, µ=0.081 mm-1,
F(000)=560, Z=4, monoclinic, space group P21/n, T=293(2) K, 8068
reflections collected, 2804 independent reflections, θmax 25.242°, 181
refined parameters, maximum residual electron density 0.124 and −0.191
e.Å-3. R1=0.0386, wR2=0.0936.
Method 2: t-BuOK (2.42 g, 21.5 mmol) was added to a solution of 3-[2-
(2-oxo-2-phenylethyl)-1-pyrrolidinyl]propanenitrile (7) (2.37 g, 9.78 mmol)
in dry THF (50 cm3) and stirred under N2 at room temperature for 3 h.
Workup and chromatography as described above afforded an orange
solid (2.15 g). Rapid recrystallization from chilled (−10 °C) EtOAc/hexane
1580 (m), 1449 (m), 1210 (m) cm−1 1H NMR (300 MHz, CDCl3) δ 7.97
;
(2H, d with fine coupling, J ca 7.2 Hz, Ar o-H), 7.57 (1H, t with fine
coupling, J ca 7.3 Hz, Ar p-H), 7.47 (2H, t with fine coupling, J ca 7.4 Hz,
Ar m-H), 3.26 (1H, dd, J 16.1 and 4.1 Hz, CHaHbC=O), 3.20–3.07 (3H, m,
ring 2-H, ring NCH, ring NCHaHb, chain NCHaHb), 3.02 (1H, dd, J 16.1
and 7.8 Hz, CHaHbC=O), 2.61 (1H, ddd, J 12.1, 6.8 and 5.5 Hz, chain
NCHaHb), 2.50 (2H, dd, J 7.5 and 5.9 Hz, CH2CN), 2.30 (1H, q, J 8.5 Hz,
ring NCHaHb), 2.13 (1 H, ddt, J 12.6, 8.9 and 7.3 Hz, ring 3-Ha), 1.90–
1.75 (2H, m, ring 4-H), 1.50 (1H, ddt, J 12.6, 8.6 and 6.2 Hz, ring 3-Hb);
13C NMR (75 MHz, CDCl3) δ 199.3 (C=O), 137.1 (Ar C-1), 133.2 (Ar p-C),
128.6 and 128.0 (Ar o- and m-C), 118.9 (C≡N), 60.1 (ring NCH), 53.3
(ring NCH2), 49.8 (chain NCH2), 44.1 (CH2C=O), 31.4 (ring C-3), 22.8
(ring C-4), 17.7 (CH2CN). The 1H and 13C NMR spectroscopic data are in
line with those previously reported at 200 MHz and 50 MHz,
respectively.[12] Compound 12: mp 114–116 °C (acetone) (lit.,[12] 115.5–
117.5 °C); 1H NMR (300 MHz, CDCl3) δ 10.28 (1H, br s, NH), 7.92–7.82
(2H, m, Ar-H), 7.44–7.34 (3H, m, Ar-H), 5.81 (1H, s, =CH), 3.65 (2H, t, J
7.0 Hz, NCH2), 2.74 (2H, t, J 7.8 Hz, CH2C=), 2.12–1.96 (2H, m, ring 4-
H); 13C NMR (75 MHz, CDCl3) δ 188.03 (C=O), 169.15 (C=CH), 140.33
(Ar C-1), 130.68 (Ar p-C), 128.09 and 126.95 (Ar o- and m-C), 86.47
(C=CH), 47.67 (NCH2), 32.83 (CH2C=), 21.36 (CH2CH2CH2). The 1H and
13C NMR spectroscopic data agree with those previously reported at 200
MHz and 50 MHz, respectively.[12]
mixtures
afforded
rel-(6R,7R,8aR)-7-hydroxy-7-
phenyloctahydroindolizine-6-carbonitrile that appeared to be
a
hemihydrate by NMR spectroscopy (1.72 g, ca 70%). This hydrate could
be converted into the crystalline monohydrate by recrystallization from
aqueous acetone.
rel-(6R,7S,8aS)-7-Hydroxy-7-phenyloctahydroindolizine-6-
carbonitrile (13b)
Method 1: t-BuOK (277 mg, 2.47 mmol) was added to a solution of the
monohydrate of rel-(6R,7R,8aR)-7-hydroxy-7-phenyloctahydroindolizine-
6-carbonitrile hydrate (13a) (536 mg, 2.06 mmol) in dry THF (25 cm3),
and the mixture was stirred under argon at room temperature for 21 h,
and then at 40–50 °C for an additional 48 h. The solvent was evaporated
and the residue was taken into EtOAc (25 cm3) and washed with H2O (10
cm3) and brine (10 cm3). The organic extract was dried over Na2SO4,
filtered and evaporated to afford an orange gum. Flash chromatography
(50% EtOAc/hexane) afforded the title compound 13b (79 mg, 16%) as a
solid. Further elution of the column afforded recovered starting material
(237 mg, 44% mass recovery). Compound 13b: mp 136–138 °C; Rf
(EtOAc) 0.75; FTIR (ATR) νmax 3472 (s, H-bonded OH), 2843 and 2826
(s, Bohlmann bands), 2248 (w, C≡N), 1665 (m), 1493 (s), 1336 (s), 1045
rel-(6R,7R,8aR)-7-Hydroxy-7-phenyloctahydroindolizine-6-
carbonitrile monohydrate (13a)
(s) cm−1 1H NMR (300 MHz, CDCl3) δ 7.57 (2H, d, J 7.6 Hz, Ar o-H),
;
7.43–7.32 (3H, m, Ar m- and p-H), 3.19 (1H, dd, J 11.4 and 2.1 Hz, 5-H'),
3.13 (1H, td, J 8.6 and 2.5 Hz, 3-H'), 2.98 (1H, q, J 2.3 Hz, 6-H), 2.80 (1H,
dd, J 11.2 and 2.8 Hz, 5-H"), 2.47 (1H, td, J 11.1 and 5.6 Hz, 8a-H), 2.34
(1H, t, J 12.0 Hz, 8-H'), 2.25 (1H, t, J 8.7 Hz, 3-H"), 2.01 (1H, dt, J 12.0
and 2.3 Hz, 8-H"), 1.98–1.85 (3H, m, 1-H', 2-H' and OH), 1.82–1.68 (1H,
m, 2-H"), 1.57 (1H, qd, J 10.9 and 6.1 Hz, 1-H"); 13C NMR (75 MHz,
CDCl3) δ 144.3 (Ar C-1), 128.7 (Ar o- or m-C), 128.5 (Ar p-C), 125.3 (Ar
o- or m-C), 120.0 (C≡N), 73.0 (C-7), 58.3(C-8a), 53.0 (C-3), 50.1 (C-5),
41.0 (C-6), 38.9 (C-8), 30.3 (C-1), 21.3 (C-2); HRMS (EI): M+, found
242.1421. [C15H18N2O]+ requires 242.1414. X-ray crystal structure details
of compound 13b: crystallised from hexane–EtOAc, formula: C15H18N2O,
M=242.31, colour of crystal: colourless, plate, crystal size 0.36 × 0.32 ×
0.11 mm3, a=6.412(2) Å, b=13.228(4) Å, c=7.460(2) Å, β=90.017(7)°,
V=632.7(3) Å3, ρcalc=1.272 Mg/m3, µ=0.081 mm-1, F(000)=260, Z=2,
monoclinic, space group P21, T=173(2) K, 5573 reflections collected,
2713 independent reflections, θmax 25.242°, 165 refined parameters,
maximum residual electron density 0.138 and −0.154 e.Å-3. R1=0.0311,
wR2=0.0753.
Method 1: t-BuOK (3.64 g, 32.3 mmol) was added to a solution of 3-[2-
(2-oxo-2-phenylethyl)-1-pyrrolidinyl]propanenitrile (7) (3.85 g, 15.9 mmol)
in dry THF (100 cm3) and stirred under N2 at room temperature for 3 h.
The solvent was evaporated and the residue partitioned between brine
(100 cm3) and EtOAc (200 cm3) and stirred for 15 min. The organic
extracts were combined and washed with additional brine (4 × 100 cm3),
and then dried over Na2SO4, filtered and evaporated to afford an orange
oil. Column chromatography (60% EtOAc/hexane) afforded impure
product as an orange solid (3.065 g, ca 80%). Slow recrystallization from
hot 30% EtOAc/hexane afforded the monohydrate of the title compound
13a (2.23 g, 8.57 mmol, 54%) as a colourless solid. Attempts to isolate
additional products from the mother liquors resulted in decomposition to
a black tar. Compound 13a monohydrate: mp 118–119 °C (30%
EtOAc/hexane); Rf (EtOAc) 0.51; FTIR (ATR) νmax 3508 (s, H-bonded
OH), 3192 (br, m, OH), 2946 (s), 2874 (s), 2826 (s), 2256 (w, C≡N), 1447
(m), 1383 (m), 1343 (m), 1217 (s) cm−1; 1H (300 MHz, CDCl3) δ 7.50 (2H,
d, J 7.5 Hz, Ar o-H), 7.41 (2H, t, J 7.4 Hz, Ar m-H), 7.33 (1H t, J 7.1 Hz,
Ar p-H), 3.36–3.28 (2H, m, 5-H' and 6-H), 3.10 (1H, td, J 8.6 and 2.5 Hz,
3-H'), 2.79 (1H, t, J 12.4 Hz, 5-H"), 2.48 (1H, tdd, J 10.9, 5.8 and 2.6 Hz,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701714
European Journal of Organic Chemistry
FULL PAPER
Method 2: The hydrate of rel-(6R,7R,8aR)-7-hydroxy-7-phenyl-
octahydroindolizine-6-carbonitrile (13a) (251 mg, 1.00 mmol) was added
to a solution of NaOEt (prepared from Na, 28 mg, 1.22 mmol) in absolute
EtOH (5 cm3) and stirred at room temperature for 4 d under Ar. H2O (15
cm3) was added and the aqueous reaction mixture was extracted with
CH2Cl2 (3 × 15 cm3). The organic extracts were dried over Na2SO4,
filtered and evaporated to give an orange gum. Flash chromatography
rel-(7R,8aS)-10a as
a
white solid, mp 120–122 °C (EtOAc/hexane
mixtures); [Found: C, 80.00; H, 7.58; N, 12.21. C15H16N2 requires C,
80.32; H, 7.19; N, 12.49%]; Rf (20% EtOAc/hexane) 0.21; Rf (EtOAc)
0.90; FTIR (ATR) νmax 2968 (w), 2870 (Bohlmann band), 2182 (m, C≡N),
;
1614 (s, C=C), 1408 (m), 1355 (m), 1082 (w) cm−1 1H NMR (300 MHz,
CDCl3) δ 7.35–7.28 (2H, m, Ar o-H), 7.25–7.20 and 7.19 (4H, overlapping
m and s, Ar-H and 5-H3.73 (1H, dd, J 5.2 and 1.8 Hz, 7-H), 3.53 (1H, td,
J 9.2 and 2.5 Hz, 3-H'), 3.33 (1H, td, J 9.7 and 6.9 Hz, 3-H"), 3.04 (1H,
tdd, J 10.2, 5.7 and 3.4 Hz, 8a-H), 2.06 (1H, ddd, J 12.9, 3.6 and 1.9 Hz,
8-H'), 2.02–1.87 (2H, m, 1-H' and 2-H'), 1.87–1.73 (1H, m, 2-H"), 1.54
(1H, ddd, J 12.8, 11.7 and 5.3 Hz, 8-H"), 1.46 (1H, ddd, J 11.6, 7.1 and
1.8 Hz, 1-H"); 13C NMR (75 MHz, CDCl3) δ 145.3 (C-5), 144.2 (Ar C-1),
128.4 and 127.8 (Ar o- and m-C), 126.5 (Ar p-C), 123.4 (C≡N), 74.1 (C-6),
51.6 (C-8a), 50.2 (C-3), 39.4 (C-7), 34.9 (C-8), 31.9 (C-1), 23.7 (C-2);
HRMS (EI): M+, found 224.1326. [C15H16N2]+ requires 224.1308. X-ray
crystal structure details of compound 10a: crystallised from hexane–
(50%
EtOAc/hexane)
afforded
rel-(6R,7S,8aS)-7-hydroxy-7-
phenyloctahydroindolizine-6-carbonitrile (13b) (83 mg, 0.34 mmol, 34%).
Further elution of the column afforded quantitative return of unreacted
starting material as the hydrate (172 mg).
7-Phenyl-1,2,3,5,8,8a-hexahydroindolizine-6-carbonitrile (9)
Method 1: The monohydrate of rel-(6R,7R,8aR)-7-hydroxy-7-phenyl-
octahydroindolizine-6-carbonitrile (13a) (84 mg, 0.32 mmol) was added to
a solution of t-BuOK (78 mg, 0.70 mmol) in dry THF (25 cm3) and stirred
under N2 at room temperature for 24 h. As no discernible reaction was
occurring, the reaction was heated at reflux temperature for 24 h. The
solvent was evaporated and the residue was taken up into CH2Cl2 (50
cm3) and washed with H2O (20 cm3) and brine (25 cm3). The organic
extract was dried over Na2SO4, filtered and evaporated to give an orange
gum. Column chromatography (80% EtOAc/hexane) afforded the title
compound 9 (39 mg, 56%) as a yellow oil that turned black rapidly on
exposure to air; Rf (EtOAc) 0.46; FTIR (liquid film) νmax 2967 (s), 2877
and 2795 (Bohlmann bands), 2210 (s, C≡N), 1622 (w, C=C), 1444 (s),
EtOAc, formula: C15
irregular, crystal size 0.41
b=8.6108(16) Å, c=12.439(2) Å, β=102.292(3)°, V=633.9(2) Å3,
calc=1.175 Mg/m3, µ=0.070 mm-1, F(000)=240, Z=2, monoclinic, space
H
16N2, M=224.30, colour of crystal: colourless,
×
0.24
×
0.17 mm3, a=6.0568(11) Å,
ρ
group P21, T=293(2) K, 3930 reflections collected, 1929 independent
reflections, θmax 25.242°, 154 refined parameters, maximum residual
electron density 0.109 and −0.140 e.Å-3. R1=0.0392, wR2=0.0927.
Method 2: The monohydrate of rel-(6R,7R,8aR)-7-hydroxy-7-phenyl-
octahydroindolizine-6-carbonitrile (13a) (502 mg, 1.93 mmol) was added
to a solution of t-BuOK (542 mg, 4.83 mmol) in dry THF (25 cm3) and
1416 (s), 1314(s), 1033 (m) cm−1 1H NMR (300 MHz, CDCl3) δ 7.45–
;
stirred under N2 at reflux temperature for
4 h. The solvent was
7.30 (5H, m, Ar-H), 3.79 (1H, dd, J 15.9 and 2.3 Hz, 5-H'), 3.27 (1H, td, J
8.6 and 2.6 Hz, 3-H'), 3.11 (1H, ddd, J 15.9, 4.2 and 2.9 Hz, 5-H"), 2.76
(1H, dt, J 17.6 and 3.1 Hz, 8-H'), 2.50 (1H, ddd, J 10.0, 4.2 and 2.5 Hz, 8-
H"), 2.45–2.30 (1H, m, 8a-H), 2.27 (1H, q, J 8.9 Hz, 3-H"), 2.09 (1H, tdd,
J 10.9, 7.9 and 4.3 Hz, 1-H'), 2.05–1.75 (2H, m, 2-H' and 2-H"), 1.52 (1H,
tdd, J 11.4, 9.1 and 6.4 Hz, 1-H"); 13C NMR (75 MHz, CDCl3) δ 154.3 (C-
7), 138.8 (Ar C-1), 129.2 (Ar p-C), 128.6 and 127.1 (Ar o- and m-C),
118.2 (C≡N), 106.7 (C-6), 59.3 (C-8a), 53.9 (C-5), 53.8 (C-3), 38.1 (C-8),
30.6 (C-1), 21.4 (C-2); HRMS (EI): M+, found 224.1299. [C15H16N2]+
requires 224.1308.
evaporated and the residue was taken up into EtOAc (50 cm3) and
washed with H2O (20 cm3) and brine (25 cm3). The organic extract was
dried over Na2SO4, filtered and evaporated to afford an orange gum.
Partial separation of the diastereoisomers was achieved by flash
chromatography (20% EtOAc/hexane). The first eluting fraction afforded
title compound rel-(7R,8aS)-10a (236 mg, 54%) as
a white solid
(characterisation as described above), a mixed fraction (68 mg, 16%),
and finally title compound rel-(7R,8aR)-10b (63 mg, %) as a brown solid
that darkened to black on standing in air; mp 111–113 °C (EtOAc/hexane
mixtures); Rf (20% EtOAc/hexane) 0.16; Rf (EtOAc) 0.90; FTIR (ATR)
νmax 3027 (w), 2945 (w), 2869 (Bohlmann band), 2182 (s, C≡N), 1608 (s,
Method 2: The monohydrate of rel-(6R,7R,8aR)-7-hydroxy-7-phenyl-
octahydroindolizine-6-carbonitrile (13a) (299 mg, 1.15 mmol) was added
to CH2Cl2 (20 cm3) and stirred under N2 until dissolved. Concentrated
H2SO4 (2.03 g, 1.10 cm3, ca 20.7 mmol) was added in one portion and
stirring was continued for 90 sec, after which solid Na2CO3 (5.00 g) was
cautiously added to the red reaction mixture. The reaction mixture was
filtered and the filtered solids were washed with CH2Cl2 (20 cm3).
C=C), 1408 (m), 1329 (m), 1066 (m) cm−1 1H NMR (300 MHz, CDCl3) δ
;
7.38–7.28 (2H, m, Ar o-H), 7.28–7.19 (3H, m, Ar m- and p-H), 7.09 (1H, s,
5-H), 3.64 (1H, dd, J 11.7 and 5.2 Hz, 7-H), 3.57–3.42 (2H, m, 8a-H and
3-H'), 3.31 (1H, td, J 9.6 and 7.0 Hz, 3-H"), 2.26 (1H, ddd, J 12.9, 5.2 and
3.3 Hz, 8-H'), 2.15 (1H, dtd, J 12.5, 6.3 and 1.8 Hz, 1-H'), 2.05–1.95 and
1.95–1.80 (2H, 2 × m, 2-H' and 2-H"), 1.49 (1H, ca qd, J ca 11.6 and 7.5
Hz, 1-H"), 1.41 (1H, q, 11.8 Hz, 8-H"); 13C NMR (75 MHz, CDCl3) δ 145.4
(C-5), 142.4(Ar C-1), 128.7 and 127.6 (Ar o- and m-C), 127.0 (Ar p-C),
122.7 (C≡N), 78.2 (C-6), 56.7(C-8a), 49.8 (C-3), 40.6 (C-7), 38.1 (C-8),
32.3 (C-1), 24.0 (C-2); HRMS (EI): M+, found 224.1305. [C15H16N2]+
requires 224.1308. X-ray crystal structure details of compound 10b:
crystallised from hexane–EtOAc, formula: C15H16N2, M=224.30, colour of
crystal: brown, needle, crystal size 0.48 × 0.24 × 0.15 mm3, a=19.8800(3)
Å, b=5.9696(1) Å, c=22.7218(5) Å, β=113.739(1)°, V=2468.37(8) Å3,
Evaporation afforded
a red oil that was subjected to column
chromatography (80% EtOAc/hexane) to afford the title compound 9 (130
mg, 50%) as a yellow oil that rapidly turned black on standing in air;
characterisation as described above.
rel-(7R,8aS)-7-Phenyl-1,2,3,7,8,8a-hexahydroindolizine-6-carbonitrile
(10a) and rel-(7R,8aR)-7-phenyl-1,2,3,7,8,8a-hexahydroindolizine-6-
carbonitrile (10b):
ρ
calc=1.207 Mg/m3, µ=0.072 mm-1, F(000)=960, Z=8, monoclinic, space
group C2/c, T=173(2) K, 16884 reflections collected, 3038 independent
reflections, θmax 25.242°, 154 refined parameters, maximum residual
electron density 0.269 and −0.191 e.Å-3. R1=0.0397, wR2=0.1044.
Method 1: t-BuOK (745 mg, 6.64 mmol) was added to a solution of 3-[2-
(2-oxo-2-phenylethyl)pyrrolidin-1-yl]propanenitrile (7) (805 mg, 3.32
mmol) in dry THF (15 cm3) and stirred under N2 at reflux temperature for
3 h. The solvent was evaporated and taken up into brine (50 cm3) and
extracted with EtOAc (3 × 50 cm3). The combined organic extracts were
dried over MgSO4, filtered and evaporated to afford an orange oil that
solidified on standing. Column chromatography (20% EtOAc/hexane)
afforded 7-phenyl-1,2,3,7,8,8a-hexahydroindolizine-6-carbonitrile (10), a
white solid, as a mixture of diastereoisomers in a 3:1 ratio (656 mg, 88%).
Recrystallization from EtOAc/hexane mixtures afforded title compound
Method 3: t-BuOK (84 mg, 0.75 mmol) was added to a solution of rel-
(6R,7S,8aS)-7-hydroxy-7-phenyloctahydroindolizine-6-carbonitrile (10b)
(83 mg, 0.34 mmol) in dry THF (5 cm3) and stirred at reflux for 3 h under
argon. The reaction mixture was poured into a saturated solution of
NH4Cl (15 cm3) and extracted with EtOAc (3 × 15 cm3). The organic
extract was dried over Na2SO4, filtered and evaporated to give an orange
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701714
European Journal of Organic Chemistry
FULL PAPER
gum. Column chromatography (50% EtOAc/hexane) afforded a mixture
of 10a and 10b (42 mg, 0.19 mmol, 56%) in an approximate ratio of 3:1
(by NMR spectroscopy) as a brown solid.
[6]
Z.-J. Liu, R.-R. Lu, Q. Chen, H. Hong, Acta Chim. Sinica (Engl. Ed.)
1985, 3, 262-265.
[7]
[8]
J. H. Russel, Naturwissenschaften 1963, 50, 443-444.
D. L. Comins, X. Chen, L. A. Morgan, J. Org. Chem. 1997, 62, 7435-
7438.
Method 4: 7-Phenyl-1,2,3,5,8,8a-hexahydroindolizine-6-carbonitrile (9)
(53 mg, 0.24 mmol) was added to a solution of t-BuOK (74 mg, 0.66
mmol) in dry THF (5 cm3) and stirred under N2 at reflux temperature for 5
mins. The solvent was evaporated and the residue was taken up into
EtOAc (20 cm3) and washed with H2O (20 cm3) and brine (20 cm3). The
organic extract was dried over Na2SO4, filtered and evaporated to afford
an orange gum. Column chromatography (20% EtOAc/hexane) afforded
a mixture of 10a and 10b (39 mg, 0.18 mmol, 74%) in an approximate
ratio of 3:1 (by NMR spectroscopy) as a cream solid.
[9]
B. Yang, H. Tao, X. Zhou, X.-P. Liu, Y. Liu, Nat. Prod. Res. 2013, 27,
433-437.
[10] Review: J. P. Michael, C. B. de Koning, D. Gravestock, G. D. Hosken,
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J. P. Michael, C. B. de Koning, Beilstein J. Org. Chem. 2016, 12, 2609-
2613.
Acknowledgements
This work was supported by the National Research Foundation
(NRF), Pretoria (Grants 85964 and 93447) and the University of
the Witwatersrand. We wish to thank Dr A. S. Parsons for
preliminary investigations, Mr T. van der Merwe and Mr M. Brits
for mass spectrometry, and Dr R. Mampa for assistance with
NMR spectroscopy.
[12] J. P. Michael, A. S. Parsons, Tetrahedron 1996, 52, 2199-2216.
[13] A. S. Parsons, PhD Thesis, University of the Witwatersrand,
Johannesburg, 1992.
[14] M. Roth, P. Dubs, E. Götschi, A. Eschenmoser, Helv. Chim. Acta 1971,
54, 710-734.
[15] S. R. Hussaini, R. R. Chamala, Z. Wang, Tetrahedron 2015, 71, 6017-
6086.
[16] J. P. Célérier, E. Deloisy-Marchalant, G. Lhommet, J. Heterocyclic
Chem. 1984, 21, 1633-1635.
Keywords: Cyclization • Reaction mechanisms• X-ray diffraction
• Heterocycles • Indolizines
[17] F. Bohlmann, Chem. Ber. 1958, 91, 2157-2167.
[18] F. F. Fleming, L. A. Funk, R. Altundas, V. Sharief, J. Org. Chem. 2002,
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10.1002/ejoc.201701714
European Journal of Organic Chemistry
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Key Topic*
Garreth L. Morgans, Manuel A.
Fernandes, Willem A. L. van Otterlo, and
Joseph P. Michael*
Page No. – Page No.
Intermediates formed during the base-mediated conversion of the pyrrolidine-
containing keto-nitrile into the title indolizine were isolated and characterized.
Base-mediated Cyclization of 3-[2-(2-
Oxo-2-phenylethyl)-1-
pyrrolidinyl]propanenitrile to 7-
Phenyl-1,2,3,7,8,8a–
hexahydroindolizine-6-carbonitrile:
What Lies Between?
Three intermediates formed during the base-mediated conversion of the
pyrrolidine-containing keto-nitrile into two diastereoisomers of the title
indolizine were isolated and characterized.
*Cyclization; nitrogen heterocycles
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