Intramolecular 1,6-addition to 2-pyridones. Mechanism and synthetic scope

Article abstract of DOI:10.1021/jo100514a

Figure presented The scope and limitations of the intramolecular 1,6-addition of an enolate to a 2-pyridone moiety, a reaction that has found application in the synthesis of the lupin alkaloids, have been probed. This nucleophilic addition process has been shown to be reversible and favored in the case of (less stabilized) amide and lactam enolates, which readily form five- and six-membered bi-/tricyclic products. Alternative enolates (ketone, ester, thiolactam) and a variety of different acceptors (isoquinolinone, pyrimidinone, pyrazinone, pyridopyrazinone) have been evaluated, and a range of competing side reactions have been identified and characterized using various techniques, including in situ IR.

Full text of DOI:10.1021/jo100514a

pubs.acs.org/joc
Intramolecular 1,6-Addition to 2-Pyridones.
Mechanism and Synthetic Scope.
Timothy Gallagher,*,† Ian Derrick,‡ Patrick M. Durkin,† Claire A. Haseler,†
†
Christoph Hirschhauser, and Pietro Magrone
†
€
†School of Chemistry, University of Bristol, Bristol, BS8 1TS, United Kingdom, and
‡AstraZeneca, Process Research and Development, Avlon Works, Bristol, BS10 7ZE,
United Kingdom
t.gallagher@bristol.ac.uk
Received March 18, 2010
The scope and limitations of the intramolecular 1,6-addition of an enolate to a 2-pyridone moiety, a
reaction that has found application in the synthesis of the lupin alkaloids, have been probed. This
nucleophilic addition process has been shown to be reversible and favored in the case of (less
stabilized) amide and lactam enolates, which readily form five- and six-membered bi-/tricyclic
products. Alternative enolates (ketone, ester, thiolactam) and a variety of different acceptors
(isoquinolinone, pyrimidinone, pyrazinone, pyridopyrazinone) have been evaluated, and a range
of competing side reactions have been identified and characterized using various techniques,
including in situ IR.
Introduction
Hiroya2 and co-workers have employed a carboxy ester to
direct and control the Lewis acid catalyzed reaction of an
ester-based silyl enol ether with 2-pyridones. Hiroya demon-
strated a significant change of selectivity by repositioning the
activating ester moiety; while 5-carboxy ester-2-pyridones
were attacked predominantly at C(6), the corresponding
3-carboxy ester isomers reacted mainly at the 4-position.
Given this background, it is perhaps more appropriate to
rationalize these profiles as 1,4-additions with respect to the
conjugated ester or nitro substituent rather than to focus on
Pyridones and pyridone-like heterocycles are key subunits
in many biologically important molecules, so the develop-
ment of novel methodologies to access this class of com-
pounds is of value. Our interest has focused on the use of
pyridones as electrophiles (Michael acceptor), and there
have been very few examples of nucleophilic attack at the
6-position of 2-pyridones reported. In 1983, Tohda1 de-
scribed the addition of amine or enolate nucleophiles to
highly activated 3,5-dinitro-2-pyridones. More recently,
(1) Tohda, Y.; Ariga, M.; Kawashima, T.; Matsumura, E. Chem. Lett.
1983, 12, 715–718.
(2) Hiroya, K.; Kawamoto, K.; Inamoto, K.; Sakamoto, T.; Doi, T.
Tetrahedron Lett. 2009, 50, 2115–2118.
3766 J. Org. Chem. 2010, 75, 3766–3774
Published on Web 04/30/2010
DOI: 10.1021/jo100514a
r
2010 American Chemical Society

Gallagher et al.
JOCArticle
the pyridone carbonyl as the predominating electrophilic
influence.
SCHEME 1. Lupin Alkaloid Synthesis via Intramolecular
1,6-Addition of Lactam Enolates
involved a lactam enolate, and this chemistry has been applied
effectively to provide an efficient and convergent entry to
representative lupin alkaloids,6 including (þ)-cytisine 3
(the unnatural enantiomer), (()-anagyrine 4a, and (()-
thermopsine 4b (Scheme 1).
(-)-Cytisine 3 is a potent and selective partial agonist for
the R4β2 neuronal nicotinic acetylcholine receptor,7 and
while structural details of the receptor-ligand interaction
have yet to be defined, cytisine nevertheless provided the
inspiration for the design of varenicline (Chantix), Pfizer’s
smoking cessation agent.8
There are, however, pyridone addition processes that are more
readily rationalized and recognizable as 1,6-addition reactions.
Thomas3 reported that 2-pyridone reacted with 2 equiv of
butyllithium to give the 1,6-addition adduct in 55% yield;
however, the use of other alkyllithium reagents was less success-
ful. Joule4 found that when N-methyl-2-pyridone was treated
with butyllithium, formation of a dimer was observed, which
can be attributed to the 1,6-addition of a C-lithiated N-methyl-
5
ꢀ
2-pyridone to another mole of N-methyl-2-pyridone. Sosnicki
has described the addition of alkyllithium-modified Grignard
reagents to unsubstituted (or alkyl substituted) N-alkyl-2-pyr-
idones which led predominantly to attack at C(6), but C(4)
adducts were also observed. The analogous thiopyridones,
though more reactive, displayed a similar regioselectivity trend.
Access to novel structural variants of cytisine (and indeed
other lupin alkaloids) offers an important and timely vehicle
with which to probe both the nicotinic pharmacophore9 and,
of particular interest in terms of cytisine (vs other well-
known full agonists such as nicotine), those structural char-
acteristics that contribute to the partial agonist profile
associated with cytisine.
This paper describes studies which have explored the scope
of this intramolecular 1,6-enolate addition process and
provided insights into the mechanistic detail of this process.
This work was also pursued with a view to downstream
(3) Thomas, E. W. J. Org. Chem. 1986, 51, 2184–2191.
(4) Meghani, P.; Joule, J. J. Chem. Soc., Perkin Trans. 1 1988, 1, 1–8.
ꢀ
ꢀ
(5) Sosnicki, J. G. Tetrahedron Lett. 2005, 46, 4295–4298. Sosnicki, J. G.
Tetrahedron Lett. 2006, 47, 6809–6812.
(6) Gray, D.; Gallagher, T. Angew. Chem., Int. Ed. 2006, 45, 2419–2423.
Botuha, C.; Galley, C. M. S.; Gallagher, T. Org. Biomol. Chem. 2004, 2,
1825–1826.
(7) Jensen, A. A.; Frølund, B.; Liljefors, T.; Krogsgaard-Larsen, P.
J. Med. Chem. 2005, 48, 4705–4745.
(8) (a) Coe, J. W.; Brooks, P. R.; Vetelino, M. G.; Wirtz, M. C.; Arnold,
E. P.; Huang, J. H.; Sands, S. B.; Davis, T. I.; Lebel, L. A.; Fox, C. B.;
Shrikhande, A.; Heym, J. H.; Schaeffer, E.; Rollema, H.; Lu, Y.; Mansbach,
R. S.; Chambers, L. K.; Rovetti, C. C.; Schulz, D. W.; Tingley, F. D.; O’Neill,
B. T. J. Med. Chem. 2005, 48, 3474–3477. (b) Coe, J. W.; Brooks, P. R.; Wirtz,
M. C.; Bashore, C. G.; Bianco, K. E.; Vetelino, M. G.; Arnold, E. P.; Lebel,
L. A.; Fox, C. B.; Tingley, F. D.; Schulz, D. W.; Davis, T. I.; Sands, S. B.;
Mansbach, R. S.; Rollema, H.; O’Neill, B. T. Bioorg. Med. Chem. Lett. 2005,
15, 4889–4897.
We recently reported the first examples of the intra-
molecular nucleophilic 1,6-addition to a 2-pyridone, which
(9) Glennon, R. A.; Dukat, M. Bioorg. Med. Chem. Lett. 2004, 14, 1841–
1844.
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Gallagher et al.
SCHEME 3. Non-Lactam Cyclization Precursors
JOCArticle
SCHEME 2. Cyclization Mechanism and Oxidation-Based
Side Reactions
application of this chemistry to generate core variants of
cytisine 3.
istry will be reported in due course. More importantly
though, pyridone 5b was a key intermediate in our previous
route6 to cytisine 3 and was obtained by MnO2 oxidation of
2r. Thus, the ability to generate 5b directly without any need
for isolation and conversion of 2r was clearly advantageous,
and once this pathway had been characterized, 5b was
obtained in 60% conversion (by 1H NMR) when the tricyclic
enolate 7 was trapped with bis(trimethylsilyl)peroxide (i.e.,
E=Me3SiOOSiMe3, Scheme 2) followed (effectively) by loss
of HOSiMe3.11
Results and Discussion
We previously reported that under thermodynamic (THF,
reflux) conditions, intramolecular 1,6-addition of the enolate
derived from 1 afforded tricyclic adduct 2r exclusively and in
high (94%) yield.6 When lactam deprotonation/cyclization
was carried out at lower temperatures (-78 °C, 0 °C, or rt) a
mixture of diastereomeric adducts 2r and 2β were observed
(Scheme 2).
Initially, the reproducibility of this sequence was an issue
as varying amounts of adducts 2r and 2β, which depended
on the reaction conditions/solvent used, and several other
products were observed. Conducting enolate formation and
cyclization at lower temperatures (-78 °C, 2 h) produced a
∼1:1 ratio of 2r/2β in excellent yield, but at higher tempera-
tures (from rt to reflux) and longer reaction times, 2r was
obtained as either the predominant (at rt) or the exclusive (at
reflux) product. These observations suggested that the 1,6-
addition (enolate 6 f 7) is a reversible process, and when
pure 2β was resubjected to these basic reaction conditions,
isomerization occurred to afford 2r/2β in a 7:10 ratio after
3 h at -78 °C. In addition, a small amount (5%) of the ring-
opened lactam 1 was also obtained under these isomerization
conditions which demonstrated (i) a thermodynamic and a
kinetic preference for 2r and 2β, respectively, and (ii) that
(most reasonably) this equilibration involves ring-opening
and reclosure, i.e., 2r/β f 7 f ring-opened 6 (which is
trapped on workup to give 1) f 7 f 2r/β.
Minor reaction products, the yields of which depended on
scale and other difficult-to-define variables, were identified
as the tricyclic R-hydroxypyridone 5a and pyridone 5b which
would be accounted for by the trapping of the initially
formed adduct 7 by trace (but variable) levels of peroxides/
oxygen present in alumina dried THF.10 Fragmentation of
adducts 8a/b could occur via two different pathways leading to
5a and 5b with the driving force being restoration of the
aromatic pyridone moiety. Oxidation products such as 5a
and 5b were, however, completely suppressed by use of freshly
distilled (from Na/benzophenone) THF, affording 2r and 2β
cleanly, reproducibly, and in excellent yields (85-95%).
R-Hydroxypyridone 5a is an attractive and potentially
useful cytisine analogue, and the exploitation of this chem-
Variation of the Nucleophilic Component
We have already demonstrated the versatility of the
intramolecular 1,6-addition outlined in Scheme 1 in terms
of related bicyclic lactam substrates which led to the synth-
esis of (()-anagyrine 4a and (()-thermopsine 4b, but the
presence of a lactam/amide appears to be critical for success-
ful 1,6-addition to a pendant 2-pyridone.
Using a simple model system, the ability of range of
alternative enolate precursors to achieve 1,6-addition to a
2-pyridone has been evaluated (Scheme 3). Ester 12 and
ketone 13 were prepared by N-alkylation of 2-pyridone with
bromides 9 and 10, respectively, and the “carbocytisine”
keto-based precursor 14 was synthesized from the known
acetal 11.12 A thioamide variant 15 was prepared from
lactam 1 using Lawesson’s reagent.13
Exposure of ester 12 to LiHMDS in THF resulted in
formation of the corresponding intermolecular Claisen con-
densation adduct in 22% yield. Ketones 13 and 14 failed to
cyclize, even when exposed to a range of different tempera-
tures (-78 °C, 0 °C, refluxing THF), and thiolactam 15 also
proved ineffective as a substrate for cyclization; in this latter
case, a D2O quench confirmed that thioenolate formation
did occur. Given the equilibration process observed in the
conversion of 1 to 2r/2β, our conclusion is that cyclization
of 1 (Scheme 2) occurs because the product, the extended
lactam enolate 7, is more stable than the simple lactam
enolate 6. Therefore, the enhanced stability of enolates
derived from 12-15 (compared to an extended lactam
enolate) favors the ring-opened form.
(11) Adam, W.; Korb, M. N. Tetrahedron 1996, 52, 5487–5494.
(12) De Loos, W. A. J.; van den Berg-Van Kuijk, A. J. W.; van Iersel, H.;
de Haan, J.; Buck, H. Recl. Trav. Chim. Pay. B. 1980, 99, 53–57.
(13) Full details of the synthesis of these compounds is described in the
Supporting Information.
(10) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.;
Timmers, F. J. Organometallics 1996, 15, 1518–1520.
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SCHEME 4. Cyclization Precursors for 5-, 6-, and 7-Membered
Ring Formation
amounts of 17c were observed, despite screening a range of
bases and temperatures.14
Given the success of the formation of the 5-membered
adduct 17a, this method was extended to the synthesis of nor-
bispidine 23 (Scheme 5). Following a procedure described by
Stanetty,15 reaction of itaconic acid 18 with benzylamine
yielded lactam 19 in excellent yield. Subsequent esterifica-
tion, reduction, and bromination yielded bromide 20, which
underwent N-alkylation with 2-pyridone, providing the
cyclization precursor 21. Conversion of 21 to diastereomers
22r and 22β (as a 1:3 ratio) occurred in essentially quanti-
tative yield, and MnO2 oxidation of this mixture yielded
norbispidine 23 (seven steps, 19% overall yield). Analogous
to the bispidine system (Scheme 2), a direct quench of the
enolate resulting from cyclization of 21 with bis(trimethylsilyl)-
peroxide led to the one-pot formation of pyridone 23 in 60%
conversion (by 1H NMR).
Variation of Ring Size
Since the intramolecular 1,6-addition had only been used
to make six-membered rings, the question remained as to
whether other ring sizes (which provide the opportunity to
access, for example, nor- or homobispidines) were accessible
by this method. A series of amide-based precursors 16a-c
were synthesized by N-alkylation of 2-pyridone with the
commercially available ω-bromoester and subsequent expo-
sure to pyrrolidine (Scheme 4).13
Variation of the Heterocyclic Acceptor
As expected, the six-membered cyclization product 17b
formed readily and in good yield. Differing from the cytisine
analogues 2r/2β, 17b formed as a single diastereomer which
was also resistant to subsequent oxidation (MnO2) to form
the corresponding pyridone. Five-ring formation was also
facile, and 16a cyclized readily upon treatment with
LiHMDS to provide adduct 17a. However, and as might
be anticipated, formation of a seven-membered ring via this
method, though achieved, was inefficient, and only small
While lactam enolates added readily to pyridones to form
five- or six-membered rings, 1,6-addition to other “acceptor”
electrophiles, such as those shown in Scheme 6, have proven
more challenging. The lactam-precursors 25a/b and 26a/b
were synthesized directly by N-alkylation of the appropriate
heterocycles with bromide 246 and substrates 27a/b were
synthesized by N-alkylation with 9 and subsequent amino-
lysis with pyrrolidine. The requisite heterocyclic precursors
were commercially available16 except for pyridopyrazinone
SCHEME 5. Application of a Five-Membered Cyclization to Nor-bispidine 23
SCHEME 6. Synthesis of Cyclization Precursors with Different “Acceptor” Heterocycles
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SCHEME 7. In Situ IR Profile of the Cyclization of 1a
aKey: (A) solvent background (individual spectrum not shown); (B) lactam 1 in THF; (C) addition of LiHMDS; (D) quench NH4Cl(s) then MeOH.
30, which was prepared from the literature known pyrido-
pyrazine 28.17 N-Oxidation of 28 gave 2918 which, following
acetylation and rearrangement, gave the target pyridopyr-
azinone 30 in good yield.13
25b and 27b proved to be highly reactive and underwent
rapid decomposition when exposed to basic conditions, even
at low temperatures. To establish if this reactivity was
associated with formation and reaction of a lactam enolate,
the n-butyl analogue 31 was exposed to LiHMDS at -78 °C.
This substrate also underwent rapid decomposition suggest-
ing that these highly electron-deficient heterocycles are
themselves excessively susceptible to nucleophilic attack.
More interestingly, because of the potential of this chem-
istry to provide access to fundamentally different core
variants of cytisine, pyrimidinone 26a and pyrazinone 26b
also proved problematic. In neither case was any reaction
(apparently) observed at -78 °C, and at higher temperatures
degradation of both 26a and 26b occurred according to 1H
NMR analysis of the crude reaction product.
This observation was, however, at odds with our rationale
of the 1,6-addition equilibrium, since the more electron-
deficient heterocycle was anticipated to stabilize the addition
adduct (cf. the earlier work of Tohda1 and Hiroya2). We
suspected a competing and reversible reaction, for example,
formation of an unstable (with respect to the protic quench)
1,2-addition, and in situ IR spectroscopy provided a flexible
means by which to probe the nature of the enolate/cyclized
species generated under these basic conditions.
To provide a baseline for the study of these problematic
cases, initial spectroscopic studies focused on the conversion
of 1 (via enolates 6 and 7) to 2r/β since these latter products
had already been fully characterized. After addition of
LiHMDS to a solution of 1 in THF, distinctive shifts for
the carbonyl moieties were observed and assessed (a) as
indicators of formation of the lactam enolate 6, (b) as
indicators that a reaction was occurring (via perturbation
of the heteroarene carbonyl functionality), and (c) to support
generation of the product lactam enolate 7. In situ IR profiles
of the cyclization of 1 were collected to compare the behavior
of this well-understood substrate with that of pyrimidinone
26a under the same reaction conditions. Due to instrument
limitations, reactions involving both 1 and 26a were carried
out at -20 °C at which temperature formation of reaction
Isoquinolone analogues 25a and 27a were unreactive
toward cyclization at lower temperatures and decomposed
under more forcing reflux conditions. Clearly, some disrup-
tion of aromaticity within the isoquinolone moiety would
be associated with nucleophilic addition to these systems,
which may have the effect of favoring the ring-open eno-
late (cf. 6 vs 7, Scheme 2). This, again points to the 1,6-
addition as a relatively finely balanced process that may
require an additional factor(s) to stabilize/favor the cyclized
product.19
More electron-deficient pyridone variants might be ex-
pected to promote cyclization; however, pyridopyrazinones
(14) LiHMDS/THF (-78 °C, 0 °C, rt, reflux), n-BuLi/THF (-78 °C),
KO-t-Bu/DMF (110 °C).
(15) Stanetty, P.; Turner, M.; Mihovilovic, M. D. Molecules 2005, 10,
367–375.
(16) 2-Pyrazinone, though commercially available, has been synthesized
from serine ethyl ester by aminolysis with ammonia and subsequent con-
densation with glyoxal.
(17) Pyridopyrazine 28 was synthesized in two steps by (i) catalytic
hydrogenation of 4-amino-3-nitropyridine and (ii) subsequent condensation
with glyoxal as described by: (a) Clark-Lewis, J. W.; Singh, R. J. Chem. Soc.
1962, 2379–2382. (b) Clark-Lewis, J. W.; Singh, R. J. Chem. Soc. 1962,
3162–3167.
(18) Oxidation of pyridopyrazine 28 with p-nitroperbenzoic acid has been
described in: Boutte, D.; Queguiner, G.; Pastour, P. C. R. Seances Acad. Sci.
C 1971, 273, 1529–1532.
(19) A plausible alternative explanation for the apparent “lack of reac-
tion” associated with 25a is that this substrate undergoes preferentially 1,2-
addition (to the isoquinolone CdO); see intermediate 33, Scheme 8. This
would not result in a disruption of the benzenoid aromaticity that would
accompany 1,6-addition. Two experiments were carried out to probe possible
fates of 25a. Exposure of 25a to LiHMDS followed by a D2O quench showed
no incorporation of D in recovered 25a. Second, in the event that lactam
enolate formation and cyclization were facile processes, we used (TMSO)2 to
trap the putative extended enolate (and cyclized) product (compare
7f8f5a/b, Scheme 2). No evidence for an oxidized product analogous to
5a (or a regioisomer) or 5b was obtained, and only 25a was recovered. It is
difficult to understand why enolization should be particularly inhibited in the
case of lactam 25a, and these experiments cannot exclude the possibility that
cyclization of 25a does, nevertheless, occur (1,2- or 1,6-addition) but that the
product is unstable with respect to ring opening on work up.
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SCHEME 8. In Situ IR Profile of the Attempted Cyclization of 26aa
aKey: (A/B) solvent with undissolved 26a; (C) addition of LiHMDS; (D) quench NH4Cl(s) then MeOH.
intermediates occurred immediately. Schemes 7 and 8 outline
the chemistry associated with 1 and 26a, respectively, as well
as the snapshot in situ IR spectra of the intermediates (as
assigned) that formed during each reaction.20
1522 cm-1 [LiO-C(2)dC(3)],22 and 1244 cm-1 (HMDS)23
(Spectrum C). After 25 min, a slow quench was initiated with
solid ammonium chloride, which was then accelerated by
addition of methanol. At this point, IR signals associated
with 7 were replaced by a broad peak at 1638 cm-1, attrib-
uted to the two similar lactam carbonyls in 2 [C(13)dO] and
[C(2)dO] (Spectrum D).24 NMR analysis of the crude reac-
tion mixture subsequently confirmed clean formation of a
3:1 mixture of 2r and 1. (The relatively larger amount of 1
isolated likely reflects the nature of the quench conditions
used as compared to the more usual synthetic procedure).
The same reaction conditions were then applied to the
pyrimidinone substrate 26a (Scheme 8). No IR signals were
observed for pyrimidinone 26a prior to addition of base as
this substrate was only sparingly soluble in THF at -20 °C.
However, following addition of 2 equiv of LiHMDS, dis-
solution of 26a occurred to give a bright yellow solution (as
was observed with 1), but and surprisingly, no sharp/strong
Background spectra of the solvent provided a window
(1500-1800 cm-1) to monitor changes in the carbonyl
functionalities during reaction. Lactam 1 displayed two
carbonyl signals (1647 and 1682 cm-1) which were identified
as the piperidinone lactam [C(13)dO] and pyridone
[C(2)dO]21 carbonyls, respectively (Scheme 7, Spectrum B).
After the system containing 1 had reached steady state, 2
equiv of LiHMDS was added over 1 min, and the initially
colorless solution instantly turned bright yellow. Both car-
bonyl signals associated with 1 diminished to be replaced by
new peaks that were assigned to 7: 1645 cm-1 [C(13)dO],
(20) Instrumentation and Software. The in situ IR reaction spectra were
collected using a MCT (mercury cadmium telluride) detector; diamond
composite probe connected via AgX 9.5 mm x 2 m fiber (silver halide);
sampling 2000 to 650 at 8 cm-1 resolution. The MCT detector operates at
liquid nitrogen temperature.
IR signals were observed in the region of 1500-1800 cm-1
.
The absence of CdO signals leads us to deduce that (a) an
enolate derived from lactam 26a had formed and (b) a
(21) These IR signals were consistent with the neat IR spectrum of
lactam 1.
(22) The frequencies for simple nonconjugated amide enolates have been
reported as 1575, 1540, 1604 cm-1. See: McWilliams, C.; Reamer, R. Process
Chemistry in the Pharmaceutical Industry, 1st ed.; Gadamasetti, K., Braish,
T., Eds.; CRC Press: Boca Raton, 2007; Vol. 2, Chapter 20, p 320.
(23) An IR spectrum of HMDS is available at http://www.Acros.com.
(24) These IR signals were consistent with the neat IR spectrum of
lactam 2r.
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SCHEME 9. Isolation of the HMDS Adduct 35
1,6-addition process now more clearly defined, open the way
to tuning the process (via subtle changes to the precise
structure of the heteroaromatic component) to broaden the
applicability of this chemistry.
Experimental Section
General experimental procedures are described in the Sup-
porting Information.
(()-(2R,1S,9S)-11-Benzyl-7,11-diazatricyclo[7.3.1.02,7]tridec-3-
ene-6,12-dione (2β) and (()-(2S,1S,9S)-11-Benzyl-7,11-diazatr-
icyclo[7.3.1.02,7]tridec-3-ene-6,12-dione (2r). To a solution of
cyclization precursor 1 (130 mg, 0.44 mmol)6 in THF (5 mL,
freshly distilled from sodium and benzoquinone) at -78 °C was
added LiHMDS (1.0 M THF solution, 0.84 mL, 0.84 mmol)
dropwise. The reaction solution was stirred at -78 °C for 2 h and
then quenched by the addition of saturated aq NH4Cl (5 mL).
The aqueous phase was extracted with EtOAc (5 mL) and
CH2Cl2 (5 mL), and then the combined organic washings were
dried (Na2SO4) and concentrated in vacuo. Purification by flash
chromatography [CH2Cl2/MeOH (99:1)] yielded 2β (15 mg,
11%) as a colorless oil: Rf 0.45 [CH2Cl2/MeOH (10:1)]; 1H
NMR (400 MHz, CDCl3) δH 7.21-7.46 (5H, m), 5.84 (1H, dtd,
J=10.0, 3.0, 2.0 Hz), 5.79 (1H, dtd, J=10.0, 2.0, 1.5 Hz), 4.99
(1H, dd, J=14.0, 10.5 Hz), 4.93 (1H, d, J=14.0 Hz), 4.32 (1H, d,
J=14.0 Hz), 4.28 (1H, ddt, J=7.5, 5.5, 2.0 Hz), 3.36 (1H, dd, J=
12.0, 3.5 Hz), 2.99-3.04 (2 H, m), 2.97 (1H, dt, J=12.0, 2.0 Hz),
2.72 (1H, td, J=3.5, 2.0 Hz), 2.43-2.52 (1H, m), 2.10 (1H, dd,
J = 14.0, 6.0 Hz), 1.58-1.76 (2H, m); 13C NMR (101 MHz,
CDCl3) δC 171.8, 167.2, 136.7, 128.7, 128.4, 127.7, 126.4, 122.8,
59.5, 51.8, 49.9, 43.3, 40.8, 31.6, 25.3, 21.2; IR νmax/cm-1 (film)
2934 (s), 2239 (w), 1635 (s), 1454 (m), 1262 (s), 1075 (m), 726 (s);
MS m/z ESIþ 297 ([M þ H]þ, 100), 319 ([M þ Na]þ, 100);
reaction had occurred that involved the pyrimidinone CdO
but (c) no new bispidine-like lactam, such as the expected
intermediate 32 or the 1,2-addition-product 33, was gener-
ated. After 40 min, the reaction was quenched (solid ammo-
nium chloride followed by methanol) which led to rapid
generation of a series of carbonyl signals, among which
were those associated with 26a (1663 cm-1 [C(13)dO] and
1635 cm-1 [C(2)dO]). NMR analysis of the crude reaction
mixture confirmed the presence of 26a as the major compo-
nent as well as several unidentified but minor degradation
products.
From these observations, we conclude that although
deprotonation of the piperidinone lactam 26a occurred, a
competing process, involving nucleophilic addition of
HMDS to the electron-deficient pyrimidinone, was preferred
leading to adducts (some or all) of type 34. Although most of
the signals associated with these possible intermediates
appear to be masked by the solvent background, an increa-
sed intensity of the broad solvent signal around 1461 cm-1
suggests the presence of more signals in this region. Based on
recovery of 26a, we suggest that adducts 34a-c are unstable
with respect to loss of HMDS upon protic quench.
HRMS C18H21N2O2 requires 297.1598, found [M þ H]þ
=
Credible support for a process involving addition of
HMDS to the pyrimidinone moiety was provided by the
isolation of adduct 35 after reaction of 26a with NaHMDS at
-78 °C (Scheme 9). Adduct 35 was obtained as a 1:1 mixture
of diastereomers in 30% yield and was characterized by
1H/13C NMR; this adduct proved to be relatively unstable
with respect to reversion in solution to 26a.
297.1597. NOE interactions outlined in the Supporting Infor-
mation confirmed the relative stereochemistry of 2β.
Continued elution [CH2Cl2/MeOH (99:1)] yielded 2r (30 mg,
22%) as a colorless oil: Rf 0.35 [CH2Cl2/MeOH (10:1)]; 1H
NMR (400 MHz, CDCl3) δH 7.19-7.33 (5H, m), 5.75-5.84
(2H, m), 4.89 (1H, dt, J=13.5, 2.5 Hz), 4.55 (1H, d, J=14.5 Hz),
4.48 (1H, d, J=14.5 Hz), 4.13-4.17 (1H, m), 3.35 (1H, dd, J=
13.0, 6.5 Hz), 3.24 (1H, d, J = 13.0), 2.84-2.93 (1H, m),
2.77-2.81 (2H, m), 2.72-2.75 (1H, m), 2.23-2.28 (1H, m),
2.18 (1H, ddd, J=13.0, 5.5, 3.5 Hz), 2.00-2.05 (1H, m); 13C
NMR (101 MHz, CDCl3) δC 167.9, 166.9, 136.7, 128.6, 128.2,
127.5, 123.6, 121.9, 60.2, 51.2, 50.0, 47.2, 43.9, 31.3, 28.9, 27.6.
Spectroscopic data for this compound were consistent with
those reported previously.6 Intermediary fractions collected
afforded a 1:1 mixture of diastereomers (∼50% yield by mass).
Complete separation of these isomers required multiple chroma-
tography.
Conclusion
In conclusion, the intramolecular 1,6-addition of a lactam
enolate to a pyridone, which is highly effective as the basis of
a strategy for the synthesis of the lupin alkaloids, is a finely
balanced process. Equilibration of adducts 2r/β occurs via a
reversible ring-opening/1,6-addition, and although this re-
action will tolerate variation of the lactam unit,25 other more
stabilized enolates (derived from an ester, ketone, or
thiolactam) shift this equilibrium toward the ring-opened
form. Further, it has been shown that this chemistry is
applicable in the synthesis of five-membered as well as six-
membered rings, and this has been extended to the synthesis
of a nor-bispidine core (23). Changes associated with the
electrophilic heteroarene “acceptor” component have a ma-
jor impact on the reaction outcome. Although attempts to
promote cyclization by use of a more electron-deficient
acceptor failed, alternative preferred pathways have been
identified and validated by IR studies. The insights garnered
from these studies, and with the scope and limitations of this
(()-11-Benzyl-7,11-diazatricyclo[7.3.1.02,7]tridec-2,4-diene-
6,12-dione (5b) via Tandem Cyclization-Oxidation. To a solu-
tion of cyclization precursor 1 (170 mg, 0.57 mmol)6 in THF
(10 mL, freshly distilled from sodium and benzoquinone) at -78 °C
was added LiHMDS (1.0 M THF solution, 1.00 mL, 1.00 mmol)
dropwise. The reaction solution was heated at reflux for 2 h and
then cooled to rt. Freshly distilled bis(trimethylsilyl)peroxide
(200 mg, 1.12 mmol, bp 42-44 °C/30 mmHg, lit.11 bp 40 °C/30
mmHg) was then added via a glass pipet, and the reaction
solution was stirred for 18 h at rt. After this time, the reaction
was quenched by the addition of saturated aq NH4Cl (10 mL)
and extracted with EtOAc (3 ꢀ 10 mL) and CH2Cl2 (10 mL).
The combined organic washings were dried (Na2SO4) and
concentrated in vacuo. The crude reaction mixture was analyzed
by 1H NMR to show ∼60% conversion to 5b: Rf 0.15 [CH2Cl2/
MeOH (19:1)]; 1H NMR (400 MHz, CDCl3) δH 7.33 (1H, dd, J=
9.0, 7.0 Hz), 7.25-7.32 (3H, m), 7.10 (2H, dd, J=7.5, 2.0 Hz),
(25) In addition to the substrates shown, a series of 4-substituted pyri-
dones variants of 1, leading to the corresponding 4-substituted cytisine
analogues, have also been successfully employed in this chemistry.
3772 J. Org. Chem. Vol. 75, No. 11, 2010

Gallagher et al.
JOCArticle
6.52 (1H, dd, J=9.0, 1.5 Hz), 6.36 (1H, dd, J=7.0, 1.5 Hz), 4.64
(1H, d, J=14.5 Hz), 4.41 (1H, d, J=14.5 Hz), 4.07 (1H, dt, J=
15.5, 1.0 Hz), 3.97 (1H, ddd, J=15.5, 6.5, 1.0 Hz), 3.77 (1H, dd,
J=4.5, 3.0 Hz), 3.56 (1H, ddd, J=13.0, 6.0, 1.0 Hz), 3.20 (1H, dt,
J = 13.0, 1.5 Hz), 2.75-2.83 (1H, m), 2.20-2.28 (1H, m),
2.06-2.16 (1H, m); 13C NMR (101 MHz, CDCl3) δC 167.3,
163.4, 144.0, 139.2, 136.1, 128.8, 127.9, 127.7, 118.3, 106.5, 52.9,
50.0, 49.7, 43.2, 25.7, 23.1. Spectroscopic data for this com-
pound were consistent with those reported previously.6
(()-(1S,8aR)-1-(Pyrrolidine-1-carbonyl)-1,2,3,8a-tetrahydro-
indolizin-5(6H)-one (17a). To a solution of cyclization precursor
16a (300 mg, 1.27 mmol) in THF (15 mL, freshly distilled from
sodium and benzoquinone) at -78 °C was added LiHMDS
(1.0 M THF solution, 2.55 mL, 2.55 mmol). The reaction
solution was stirred at -78 °C for 4 h and then quenched by
the addition of saturated aq NH4Cl (50 mL). The aqueous phase
was extracted with CH2Cl2 (4 ꢀ 50 mL), and then the combined
organic washings were dried (Na2SO4) and concentrated in
vacuo. Purification by flash chromatography [CH2Cl2/MeOH
(49:1-24:1)] yielded 17a (219 mg, 73%) as a colorless oil: Rf 0.27
[CH2Cl2/MeOH (9:1)]; 1H NMR (500 MHz, CDCl3) δH
5.74-5.85 (2H, m), 4.41-4.50 (1H, m), 3.87 (1H, dt, J=12.0,
9.0 Hz), 3.39-3.56 (5H, m), 2.94-3.03 (1H, m), 2.89 (1H, dt,
21.5, 4.0 Hz), 2.69 (1H, dt, J=11.0, 7.5 Hz), 2.16-2.26 (1H, m),
2.02-2.12 (1H, m), 1.98 (2H, quin, J=6.5 Hz), 1.89 (2H, quin,
J=7.0 Hz); 13C NMR (125 MHz, CDCl3) δC 169.3, 166.0, 123.4,
solid: Rf 0.23 [CH2Cl2/MeOH (19:1)]; mp 148-152 °C (benzene/
n-hexane); 1H NMR (500 MHz, CDCl3) δH 5.83-5.89 (1H, m),
5.77 (1H, ddd, J=10.0, 4.0, 3.0 Hz), 4.45 (1H, ddd, J=14.0, 7.0,
2.5 Hz), 4.32 (1H, ddt, J = 9.5, 5.0, 2.5 Hz), 3.44 (4H, m),
2.96-3.02 (2H, m), 2.92 (1H, m, J=14.0, 11.0, 6.0 Hz), 2.43 (1H,
td, J = 9.5, 4.5 Hz), 2.12 (1H, dtt, J = 13.5, 11.0, 7.0 Hz),
1.74-2.01 (7H, m), 1.57-1.67 (1H, m), 1.38-1.49 (1H, m); 13
NMR (126 MHz, CDCl3) δC 171.7, 168.0, 126.8, 122.9, 62.8,
C
53.6, 46.8, 46.6, 45.7, 32.4, 29.3, 26.0, 25.5, 24.3, 24.0; IR νmax
/
cm-1 (film) 2935 (w), 1635 (s), 1592 (m), 1539 (w), 1471 (m), 1432
(m), 1401 (w), 1345 (w), 1320 (w), 1257 (w), 1065 (w), 808 (w),
706 (w); MS m/z EIþ 126 (100%), 262 ([M]þ, 60); HRMS
C15H22N2O2 requires 262.1681, found [M]þ=262.1680. NOE
interactions outlined in the Supporting Information confirmed
the relative stereochemistry of 17c.
(()-1-Benzyl-4-bromomethylpyrrolidin-2-one (20). To a solu-
tion of 1-benzyl-4-(hydroxymethyl)pyrrolidin-2-one (6.11 g,
29.77 mmol)15 in toluene (100 mL) at 0 °C was added PBr3
(2.93 mL, 31.26 mmol) dropwise. The reaction mixture was
heated at reflux for 5 h, cooled to 0 °C, and quenched by
dropwise addition of H2O (5 mL). Concentration in vacuo aff-
orded an orange gum which was dissolved in EtOAc (50 mL)
and sonicated to aid dissolution. The solution was then parti-
tioned between H2O (30 mL) and EtOAc (3 ꢀ 20 mL). The
combined organic extracts were dried (Na2SO4) and concen-
trated in vacuo to afford bromide 20 (5.11 g, 64%) as a colorless
oil: Rf 0.35 (EtOAc); 1H NMR (400 MHz, CDCl3) δH 7.22-7.45
(5H, m), 4.52 (1H, d, J=14.5 Hz), 4.44 (1H, d, J=14.5 Hz), 3.46
(1H, dd, J=10.0, 0.5 Hz), 3.44 (1H, dd, J=10.0, 3.0 Hz), 3.37
(1H, dd, J = 10.0, 7.5 Hz), 3.11 (1H, dd, J = 10.0, 6.0 Hz),
2.73-2.86 (1H, m), 2.68 (1H, ddd, J=17.0, 9.0, 0.5 Hz), 2.35
(1H, dd, J=17.0, 7.0 Hz); 13C NMR (101 MHz, CDCl3) δC
172.9, 136.1, 128.8, 128.2, 127.7, 51.1, 46.6, 36.6, 35.7, 33.5; IR
123.0, 61.4, 48.2, 46.5, 45.9, 43.2, 32.5, 26.3, 25.9, 24.1; IR νmax
/
cm-1 (film) 2972 (w), 2881 (w), 1632 (s), 1447 (m), 1411 (w), 1346
(w), 691 (w); MS m/z ESIþ 257 ([M þ Na]þ, 100); HRMS C13H18-
N2O2Na requires 257.1260, found [M þ Na]þ=257.1266. NOE
interactions outlined in the Supporting Information confirmed the
relative stereochemistry of 17a.
(()-(1S,9aR)-1-(Pyrrolidine-1-carbonyl)-3,4,7,9a-tetrahydro-
1H-quinolizin-6(2H)-one (17b). To a solution of cyclization
precursor 16b (200 mg, 0.81 mmol) in THF (5.0 mL) at -78 °C
was added LiHMDS (1.0 M THF solution, 1.61 mL, 1.61 mmol).
The reaction solution was stirred at -78 °C for 1 h then quenched
via the addition of saturated aq NH4Cl solution (25 mL). The
aqueous phase was extracted with EtOAc (4 ꢀ 25 mL) and
CH2Cl2 (4 ꢀ 25 mL), and then the combined organic washings
were dried (Na2SO4), filtered, and concentrated in vacuo. Pur-
ification by column chromatography [CH2Cl2/MeOH (49:1)]
yielded 17b (165 mg, 83%) as an off-white solid: Rf 0.27
[CH2Cl2/MeOH (19:1)]; mp 121 °C (benzene/n-hexane); 1H
NMR (500 MHz, CDCl3) δH 5.62-5.78 (2H, m), 4.90 (1H, ddt,
J=13.0, 4.0, 2.0 Hz), 4.16-4.26 (1H, m), 3.44-3.54 (3H, m), 3.39
(1H, dt, J=10.0, 6.5 Hz), 2.88-3.04 (2H, m), 2.56 (1H, td, J=
13.0, 3.0 Hz), 2.39 (1H, ddd, J=12.0, 10.5, 4.0 Hz), 1.77 - 2.03
(7H, m), 1.50 (1H, qt, J=13.0, 4.0 Hz); 13C NMR (101 MHz,
CDCl3) δC 171.2, 166.0, 123.6, 122.4, 59.6, 49.1, 46.7, 45.7, 41.9,
31.7, 28.3, 26.0, 24.31, 24.30; IR νmax/cm-1 (film) 2951 (m), 2885
(m), 1635 (s, br), 1478 (s), 1440 (s), 1407 (m), 1341 (m), 1322 (m),
1265 (m), 1092 (m); MS m/z EIþ 150 ([C9H12NO]þ, 100), 248
([M]þ, 50); HRMS C14H20N2O2 requires 248.1525, found [M]þ=
248.1537. NOE interactions outlined in the Supporting Informa-
tion confirmed the relative stereochemistry of 17b.
(()-(10S,10aR)-10-(Pyrrolidine-1-carbonyl)-6,7,8,9,10,10a-
hexahydropyrido[1,2-a]azepin-4(3H)-one (17c). To a solution of
cyclization precursor 16c (112 mg, 0.42 mmol) in THF (5.0 mL)
at -78 °C was added LiHMDS (1.0 M solution in THF, 850 μL,
0.85 mmol). The reaction solution was stirred at -78 °C for 5 h
and then quenched via the addition of saturated aq NH4Cl
solution (40 mL). The aqueous phase was extracted with CH2Cl2
(4 ꢀ 40 mL), and then the combined organic washings were
dried (Na2SO4), filtered, and concentrated in vacuo. Purifica-
tion by column chromatography [CH2Cl2/MeOH (9:1)] fol-
lowed by secondary purification by column chromatography
[EtOAc/MeOH (19:1)] yielded 17c (15 mg, 14%) as an off-white
ν
max/cm-1 (film) 2922 (m), 1685 (s), 1496 (m), 1445 (m), 1420
(m), 1358 (w), 1296 (m); MS m/z ESIþ 268 ([M{79Br} þ H]þ, 77),
270 ([M{81Br} þ H]þ, 80), 290 ([M{79Br} þ Na]þ, 100), 292
([M{81Br}þNa]þ, 90); HRMS C12H15NO79Br requires 268.0331,
found [M þ H]þ=268.0343.
(()-1-((1-Benzyl-5-oxopyrrolidin-3-yl)methyl)pyridin-2(1H)-
one (21). A stirred mixture of 2-pyridone (2.61 g, 27.40 mmol),
bromide 20 (7.99 g, 30.14 mmol), K2CO3 (8.33 g, 60.30 mmol),
and tetrabutylammonium bromide (0.89 g, 2.75 mmol) in water
(1 mL) and toluene (100 mL) was heated at reflux overnight.
After being cooled to rt, the reaction mixture was filtered and
concentrated in vacuo. Flash chromatography [CH2Cl/MeOH
(19:1)] yielded 21 (5.15 g, 61%) as a colorless oil: Rf 0.40
[CH2Cl2/MeOH (19:1)]; 1H NMR (400 MHz, CDCl3) δH
7.20-7.41 (6H, m), 6.82 (1H, dd, J =7.0, 1.5 Hz), 6.54 (1H,
dd, J=9.0, 0.5 Hz), 6.05 (1H, td, J=7.0, 1.5 Hz), 4.54 (1H, d, J=
14.5 Hz), 4.36 (1H, d, J=14.5 Hz), 3.87 (1H, dd, J=13.0, 7.0
Hz), 3.79 (1H, dd, J=13.0, 8.0 Hz), 3.33 (1H, dd, J=10.0, 7.0
Hz), 2.93-3.06 (2H, m), 2.62 (1H, dd, J=17.0, 8.0 Hz), 2.24 (1H,
dd, J=17.0, 5.5 Hz); 13C NMR (101 MHz, CDCl3) δC 179.0,
172.9, 139.7, 137.6, 136.4, 128.8, 128.4, 127.8, 121.3, 106.0, 53.1,
48.9, 46.5, 35.3, 30.8; IR νmax/cm-1 (film) 2918 (s), 2851 (s),
1681 (s), 1657 (s), 1586 (s), 1541 (m), 1429 (s), 1255 (m), 1155 (m);
MS m/z ESIþ 283 ([M þ H]þ, 10), 305 ([M þ Na]þ, 100); HRMS
C17H18N2O2Na requires 305.1267, found [MþNa]þ=305.1260.
(()-(3aS,9aR,9bS)-2-Benzyl-2,3,3a,7,9a,9b-hexahydro-1H-
pyrrolo[3,4-a]indolizine-1,6(4H)-dione (22β) and (()-(3aS,9aS,
9bS)-2-Benzyl-2,3,3a,7,9a,9b-hexahydro-1H-pyrrolo[3,4-a]indo-
lizine-1,6(4H)-dione (22r). To a solution of cyclization precur-
sor 21 (786 mg, 2.78 mmol) in THF (30 mL, freshly distilled from
sodium and benzoquinone) at -78 °C was added LiHMDS (1.0 M
THF solution, 5.6 mL, 5.60 mmol) dropwise. The reaction
solution was stirred at -78 °C for 2 h and then quenched by
the addition of saturated aq NH4Cl (10 mL). The aqueous phase
was extracted with EtOAc (2 ꢀ 15 mL) and CH2Cl2 (15 mL), and
J. Org. Chem. Vol. 75, No. 11, 2010 3773

Gallagher et al.
JOCArticle
then the combined organic washings were dried (Na2SO4) and
concentrated in vacuo. Purification by flash chromatography
[CH2Cl2/MeOH (19:1)] yielded adduct 22β (200 mg, 28%) as a
colorless oil: Rf 0.25 [CH2Cl2/MeOH (19:1)] 1H NMR: (500
MHz, CDCl3) δH 7.28-7.38 (3H, m), 7.22-7.26 (2H, m),
6.09-6.13 (1H, m), 5.84-5.89 (1H, m), 4.58 (1H, dd, J=12.0,
8.5 Hz), 4.54 (1H, d, J=14.5 Hz), 4.41 (1H, d, J=14.5 Hz),
4.24-4.31 (1H, m), 3.49 (1H, dd, J=10.5, 8.0 Hz), 3.09 (1H, dd,
J=10.5, 3.5 Hz), 3.03 (1H, dd, J=10.0, 7.5 Hz), 2.84-3.00 (3H,
m), 2.79 (1H, dd, J=12.0, 7.5 Hz); 13C NMR (125 MHz, CDCl3)
δC 172.9, 165.7, 135.7, 128.7, 128.0, 127.8, 124.8, 123.0, 60.1,
52.9, 49.6, 49.2, 46.6, 32.8, 32.1; IR νmax/cm-1 (film) 2922 (m),
2851 (m), 1684 (s), 1646 (s), 1496 (m), 1446 (s), 1314 (m), 1261
(m), 729 (w); MS m/z ESIþ 283.1 ([MþH]þ, 33), 305.1 ([Mþ
Na]þ, 100); HRMS C17H18N2O2Na requires 305.1260, found
[MþNa]þ =305.1267, C17H19N2O2 requires 283.1441, found
[MþH]þ=283.1449.
THF (10 mL, freshly distilled from sodium and benzoquinone)
at -78 °C was added LiHMDS (1.0 M THF solution, 0.82 mL,
0.82 mmol) dropwise. The reaction solution was stirred at -78 °C
for 2 h, and then freshly distilled bis(trimethylsilyl)peroxide
(146 mg, 0.82 mmol, bp 42-44 °C/30 mmHg, lit.11 bp 40 °C/
30 mmHg) was added via a glass pipet. The reaction solution
was stirred for a further 18 h at rt and then quenched by the
addition of NH4Cl (50 mg, 0.93 mmol) and MeOH (5 mL) and
concentrated in vacuo. The crude reaction mixture was analyzed
1
by H NMR to show ∼60% conversion by comparison with
starting material 21 and oxidized product 23.
(()-(R)-3-(((R)-1-Benzyl-6-oxopiperidin-3-yl)methyl)-4-(bis-
(trimethylsilyl)amino)-3,4-dihydropyrimidin-2(1H)-one and (()-(S)-
3-(((R)-1-Benzyl-6-oxopiperidin-3-yl)methyl)-4-(bis(trimethylsilyl)-
amino)-3,4-dihydropyrimidin-2(1H)-one (35). To a solution of
NaHMDS (124 mg, 0.67 mmol) in THF (3 mL) at -78 °C was
added a solution of 26a (100 mg, 0.34 mmol) in THF (3 mL,
freshly distilled from sodium and benzoquinone) dropwise. The
reaction solution was stirred at -78 °C for 2 h, quenched by
the addition of saturated aq NH4Cl (0.5 mL), and further
diluted with water (3 mL). The aqueous phase was extracted
with CH2Cl2 (3 ꢀ 3 mL), and then the combined organic
washings were dried (MgSO4) and concentrated in vacuo.
Purification by flash chromatography [CH2Cl2/MeOH (49:1)]
yielded adduct 35 (46 mg, 30%) as a 1:1 mixture of diastereo-
mers and as a pale yellow oil: Rf 0.45 [CH2Cl2/MeOH (19:1)];
1H NMR (400 MHz, CDCl3) δH 7.37 (1H, m), 7.23-7.34 (5H,
m), 5.96 (1H, m), 5.23 (1H, dd, J=19.0, 3.5 Hz), 4.79 (0.5H, d,
J = 15.0 Hz), 4.60 (1H, m), 4.56 (1H, m), 4.42 (0.5H, d, J =
15.0 Hz), 3.53-3.66 (1H, m), 3.13-3.26 (1H, m), 2.94-3.09
(2H, m), 2.54-2.70 (1H, m), 2.36-2.50 (1H, m), 2.10-2.30
(1H, m), 1.84-1.94 (1H, m), 1.49-1.63 (1H, m), 0-0.25 (18H,
br m); 13C NMR (101 MHz, CDCl3) δC 169.7, 169.5, 153.1,
152.9, 137.1, 136.9, 128.6, 128.5, 128.0, 128.0, 127.3, 127.3,
122.8, 122.8, 102.8, 69.1, 68.8, 50.8, 50.6, 50.4, 50.1, 44.1, 43.7,
32.7, 32.5, 31.5, 31.3, 25.5, 25.3, 2.5-3.1 (br), 2.4, 1.3. This
material was subjected to NMR analysis immediately after iso-
lation, and was found to be unstable, undergoing slow decom-
position to regenerate 26a (as judged by 1H NMR) over a period
of hours.
Continued elution [CH2Cl2/MeOH (9:1)] yielded diastereomer
22r (100 mg, 14%) as a colorless oil: Rf 0.50 [CH2Cl2/MeOH
(9:1)]; 1H NMR (400 MHz, CDCl3) δH 7.07-7.38 (5H, m),
6.30-6.36 (1H, m), 5.81-5.90 (1H, m), 4.44 (1H, d, J=15.0 Hz),
4.35 (1H, d, J=15.0 Hz), 4.08-4.17 (1H, m), 3.48 (1H, dd, J=
11.0, 9.0 Hz), 3.34 (1H, dd, J=12.5, 7.5 Hz), 3.27 (1H, t, J=
8.0 Hz), 2.92-3.04 (4H, m), 2.66 (1H, q, J=7.5 Hz); 13C NMR
(125 MHz, CDCl3) δC 171.4, 166.0, 135.7, 128.7, 128.3, 127.9,
127.8, 122.2, 60.0, 52.2, 50.1, 50.0, 46.6, 32.4, 32.1; IR νmax/cm-1
(film) 3152 (m), 3055 (m), 2925 (m), 1684 (s), 1647 (s), 1585 (m),
1496 (m), 1447 (s), 1322 (m), 1279 (m), 1077 (w); MS m/z ESIþ
283 ([M þ H]þ, 100); HRMS C17H19N2O2 requires 283.1441,
found [M þ H]þ = 283.1449. Note: Intermediary fractions
collected afforded a 3:1 mixture of diastereomers 22β and 22r
(∼60% yield by mass).
(()-2-Benzyl-2,3,3a,9b-tetrahydro-1H-pyrrolo[3,4-a]indolizine-
1,6(4H)-dione (23) via MnO2 Oxidation. To adducts 22β and 22r
(930 mg, 3.29 mmol, as a 3:1 mixture of 22β/r) in DCE (50 mL)
was added MnO2 (2.86 g, 32.9 mmol). The reaction mixture was
heated at 90 °C for 18 h and then cooled to rt, filtered through a
plug of Celite, and concentrated in vacuo to afford pyridone 23
(627 mg, 68%) as a pale brown microcrystalline solid: Rf 0.35
1
[CH2Cl2/MeOH (19:1)]; mp 203-206 °C (toluene); H NMR
(500 MHz, CDCl3) δH 7.41 (1H, dd, J=9.0, 7.0 Hz), 7.27-7.35
(3H, m), 7.17-7.20 (2H, m), 6.50 (1H, dt, J=7.0, 1.0 Hz), 6.48
(1H, dt, J=9.0, 1.0 Hz), 4.48 (1H, d, J=14.5 Hz), 4.43 (1H, d, J=
14.5 Hz), 4.42 (1H, dd, J=13.5, 8.5 Hz), 4.14 (1H, dt, J=9.0,
1.0 Hz), 3.92 (1H, dd, J=13.5, 5.0 Hz), 3.62 (1H, dd, J=10.5,
Acknowledgment. We thank Mr. Richard Hart and Astra-
Zeneca for supporting the in situ IR experiments described
here, and funding from EPSRC (to C.A.H. and P.M.D.) and
the Rotary Foundation (to C.H.) is acknowledged.
8.0 Hz), 3.28-3.36 (1H, m), 3.15 (1H, dd, J=10.5, 4.0 Hz); 13
C
NMR (125 MHz, CDCl3) δC 169.2, 162.1, 147.9, 135.3, 128.8,
Supporting Information Available: Additional synthetic
procedures for new compounds not described in the Experi-
127.9, 127.7, 118.8, 102.6, 54.3, 52.4, 50.8, 47.3, 31.2; IR νmax
/
cm-1 (film) 2924 (m), 1695 (s), 1662 (s), 1582 (s), 1543 (w), 1496
(w), 1447 (s), 1262 (m), 1154 (m); MS m/z ESIþ 281 ([MþH]þ,
100); HRMS C17H17N2O2 requires 281.1284, found [MþH]þ=
281.1290.
mental Section, characterization data and copies of 1H and 13
C
NMR spectra of new compounds, descriptions of NOE inter-
actions for 2β, 17a, 17b, 17c and 22β, as well as expanded
versions of the in situ IR data shown in Schemes 4 and 5. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(()-2-Benzyl-2,3,3a,9b-tetrahydro-1H-pyrrolo[3,4-a]indolizine-
1,6(4H)-dione (23) via Tandem Cyclization Oxidation. To a
solution of cyclization precursor 21 (116 mg, 0.41 mmol) in
3774 J. Org. Chem. Vol. 75, No. 11, 2010