Original Mitsunobu-Triggered Sequence Involved in a One-Pot Domino Process toward Tetracyclic Systems Bearing a Bis-N,O-acetal Junction

Article abstract of DOI:10.1021/acs.joc.6b01523

Herein is reported an efficient, one-pot domino process through a 1,6-aza-Michael addition-triggered sequence and an original Mitsunobu-type concerted sequence for the synthesis of tetracyclic systems containing a bis-N,O-acetal junction. This methodology led to the construction of four new bonds, the cleavage of three C-O bonds, and the generation of an asymmetric center. Mitsunobu activation afforded final ring closure involving the creation of two bonds, which remains unprecedented among reported Mitsunobu-type sequences. The latter occurred in a regioselective fashion at the challenging C₆-position of 2-pyridone intermediates. In the case of adequately substituted enantiopure amino alcohols, up to 95:5 of diastereoisomeric excess was achieved. Computational studies allowed the discrimination of a favored pathway for Mitsunobu sequence and supported the regioselectivity as well as the diastereoselectivity observed for this step.

Full text of DOI:10.1021/acs.joc.6b01523

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Article
Original Mitsunobu triggered sequence involved in a one-pot domino
process toward tetracyclic systems bearing bis-N,O-acetal junction
Thomas Lepitre, Clement Denhez, Morgane Sanselme,
Mohamed Othman, Ata Martin Lawson, and Adam Daïch
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01523 • Publication Date (Web): 07 Sep 2016
Downloaded from http://pubs.acs.org on September 8, 2016
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Original Mitsunobu triggered sequence involved in a one-pot domino
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process toward tetracyclic systems bearing bis-N,O-acetal junction
‡
Thomas Lepitre, Clement Denhez, ,δ Morgane Sanselme,† Mohamed Othman,‡ Ata Martin Lawson,‡ ∗
§
Adam Daïch‡
‡
Normandie Univ, France; UNILEHAVRE, URCOM, Fꢀ76600 Le Havre, France; EA 3221, FR 3038 CNRS, Fꢀ76600 Le
Havre, France
§Universite de Reims Champagne Ardenne, Institut de Chimie Moléculaire de Reims, CNRS UMR 7312, UFR de Pharmacie,
51 rue CognacqꢀJay, 51096 Reims Cedex, France
δ
Multiscale Molecular Modeling Platform, Université de Reims ChampagneꢀArdenne, UFR Sciences Exactes et Naturelles,
Fꢀ51687 Reims Cedex 2, France
†
Normandie Univ, France; UNIROUEN, Laboratoire SMS EA3233, 1 rue Tesniere, France; Fꢀ76821 Mont Saint Aignan,
France
Keywords: 2ꢀPyridones, Chromoneꢀbased Michael acceptor, Mitsunobu reaction, oneꢀpot domino reaction, bisꢀN,Oꢀacetal
junction.
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ABSTRACT: Herein is reported an efficient oneꢀ
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pot domino process through a 1,6ꢀazaꢀMichael
additionꢀtriggered sequence and an original
Mitsunobuꢀtype concerted sequence, for the
synthesis of tetracyclic systems containing a bisꢀ
N,Oꢀacetal junction. This methodology led to the
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construction of four new bonds, the cleavage of three CꢀO bonds and the generation of an asymmetric center. Mitsunobu activation
afforded final ring closure involving the creation of two bonds which remains unprecedented among reported Mitsunobuꢀtype sequences.
The latter occurred in a regioselective fashion at the challenging C6ꢀposition of 2ꢀpyridone intermediates. In case of adequately substituted
enantiopure amino alcohols, up to 95: 5 of diastereoisomeric excess was achieved. Computational studies allowed the discrimination of a
favored pathway for Mitsunobu sequence and supported the regioselectivity as well as the diastereoselectivity observed for this step.
INTRODUCTION
Late 20thꢀearly 21st centuries have witnessed an unprecedented boom of powerful tools such as domino sequences,1,2 or
multicomponent3,4 reactions to access architecturally complex molecular frameworks. Quickly, this modern conception of organic
chemistry is replacing traditional stepwise approach to meet environmental and economic demands, in particular for the highꢀthroughput
screening of novel scaffolds of biological interest.
Fundamental named reactions have reached a privileged place in this new branch of research as they frequently are involved or even
combined5 in such processes. Among these, Michael addition,6 Knoevenagel condensation,7 Mannich reaction,8 Claisen rearrangement9 or
DielsꢀAlder reaction10 are widely used. Remarkable metalꢀcatalyzed reactions such as Heck11 or metathesis12 couplingꢀreactions also have
emerged in a wide range of domino sequences to achieve molecular complexity. Nevertheless, a few popular reactions among this
restricted elite group still remain disregarded despite their high synthetic relevance.
Mitsunobu coupling is a commonly known essential reaction in organic synthesis.13 Its broad synthetic versatility makes it a powerful
strategy for the construction of novel CꢀO,14 CꢀN,15 CꢀS16 or CꢀC17 bonds. Interesting Mitsunobuꢀtriggered concerted sequences which
could be incorporated in domino strategies have been reported in the literature (Scheme 1, examples a and b). Among the very scarce
examples known, one has been reported by Boger et al. in last step of (+)ꢀDuocarmycinꢀA total synthesis,18 to allow the pivotal
cyclopropanation reaction (Scheme 1, example a). More recently Takeya and coꢀworkers also proposed an interesting rearrangement under
Mitsunobu activation for efficient transformation of 7,14ꢀdihydroxyꢀentꢀkaurene diterpenoids, commonly found in Rabdosia plant species,
into entꢀabietanes (Scheme 1, example b).19
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However, Mitsunobu activation remains too rarely involved in domino processes or multicomponent reactions. The first relevant example
has been reported by Goti et al. in (ꢀ)ꢀRosmarinecine total synthesis (Scheme 1, example c).20 Ringꢀfused tricyclic precursor of this
bioactive alkaloid was achieved by an elegant domino Mitsunobu intramolecular nitrone cycloaddition process. Comparatively, Greshock
et al. later reported a Mitsunobu triggered biomimetic pathway involving DielsꢀAlder cycloaddition for the total synthesis of D,Lꢀ
StephacidinꢀA.21 More recently, Berrée and coꢀworkers described the first and unique Mitsunobu transformation involved in a oneꢀpot
multicomponent reaction (Scheme 1, example d)22 to provide enamides and enol benzoates. Finally, cascade/tandem sequences involving
consecutive Mitsunobu activations also were studied by Yan et al. (Scheme 1, example e)23 and Ganesan et al.24 amongst two other
groups.25
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Scheme 1. Modern applications of Mitsunobu activation in domino/multicomponent/concerted sequences
Driven by the high efficiency of such strategies and in keeping with our previous work (Scheme 3),26 we envisioned to develop a oneꢀ
pot domino azaꢀMichael/Mitsunobu process to access tetracyclic frameworks bearing bisꢀN,Oꢀacetal junction. This atypical junction is
found in structurally complex bioactive natural products such as spiramine27 and zoanthamine28 alkaloids (Scheme 2).
Scheme 2. Representative structures of Spiramine and Zoanthamine alkaloids
In this perspective, starting from adequately Nꢀsubstituted 2ꢀpyridone, we anticipated that Mitsunobu activation could be an attractive
solution to achieve bisꢀN,Oꢀacetal junction (Scheme 3, example b), allowing in situ generation of a leaving group on the alcohol moiety
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and phenolic group deprotonation. This activation would not be incompatible with experimental conditions for 2ꢀpyridone intermediate
synthesis (Scheme 3, example a)26 and would thus be suitable for the envisioned oneꢀpot domino strategy (Scheme 3, example c).
Moreover, the easy access to a large panel of amino alcohols and Michael acceptors bearing the chromone core offers an interesting
flexibility in term of reaction scope. Mitsunobuꢀtriggered final ring closure would lead to the intramolecular formation of two new bonds
which has not been reported so far in Mitsunobu type sequences.
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Scheme 3. Domino strategy for the synthesis of nitrogen fused oxazolopyridines analogues.
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RESULTS AND DISCUSSION
We started to investigate Mitsunobu sequence on the 2ꢀpyridone derivative 2 (Table 1) as model substrate, synthesized from 1a
according to our previous work.26 Different conditions were screened and the results are summarized in Table 1.
Table 1. Screening of experimental conditions for Mitsunobu activation.
Conversiona
Diazo
PR3
Ratios
(3a : 4a)
T
reagent
(1.6 eq.)
Entry
/
(°C)
(1.6 eq.)
Yield (%)b
1c
2
3e
DEAD
DEAD
ADDM
ADDM
DDQ
PPh3
t.a
t.a
t.a
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79 (0)d
100 (0)d
100 (86)
100 (88)
0
1 : 0
1 : 0
1 : 0
1 : 0
ꢀ
PPh3
P(nBu)3
P(nBu)3
P(nBu)3
P(nBu)3
P(nBu)3
P(OEt)3
4
5f
6
ADDP
DCAD
ADDP
100 (92)
100 (91)
0
1 : 0
1 : 0
ꢀ
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9f
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11h
ADDP
ADDP
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P(cy)3
P(pꢀmp)3
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0
0
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g
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a Determined by 1H NMR spectroscopy. b Isolated yield. c Reaction carried out for 1h in presence of
1.3 eq. of each Mitsunobu reagents. d Product 3a was inseparable from Mitsunobu byꢀproducts. e The
reaction appeared to be non reproducible. The reaction was carried out for 1h. g P(pꢀmp)3 : Tris(4ꢀ
f
methoxyphenyl)phosphine. h Reaction carried out in presence of 1.1 eq. of NEt3 as a base.
Usual Mitsunobu system (DEAD (diethyl azodicarboxylate) /PPh3) was tested in a first attempt. We were pleased to observe that full
conversion into the desired compound 3a was achieved in only 25 minutes at ambient temperature (entry 2) when 1.6 equivalents of each
Mitsunobu reagents were used. Moreover the reaction proceeded regioselectively at C6ꢀposition of 2ꢀpyridone ring since no traces of 4a
were detected. Unfortunately oxazolopyridine product appeared to be nonꢀisolable from residuals dihydroꢀdiethyl azodicarboxylate
(DEADꢀH2) and triphenylphosphine oxide formed during Mitsunobu reaction.
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In the past few years recurrent post purification problems of Mitsunobu reactions has led to the emergence of a new generation of
Mitsunobu reagents (both phosphines and azidocarboxylates),29 devised to facilitate the reaction workup. We thus turned our attention to
ADDM (azodicarbonyl dimorpholide),30 DDQ (2,3ꢀdichloroꢀ5,6ꢀdicyanoꢀ1,4ꢀbenzoquinone),31 ADDP (1,1′ꢀ(azodicarbonyl)dipiperidine)32
and DCAD (Diꢀpꢀchlorobenzyl azidocarboxylate).33 The latter have been proved to be at least as efficient as DEAD and their dihydro
analogues more easily removable by column chromatography due to their higher polarity.29 Satisfactorily, replacing DEAD/PPh3 by
ADDM/P(nBu)3 afforded the expected product in 86% of isolated yield (entry 3). We then decided to carry out the reaction at 40 °C as the
latter was irreproducible depending on ambient temperature variation. Mitsunobu sequence was positively affected by increasing
temperature since compound 3a was isolated in 88% yield (entry 4). Unfortunately, when ADDM was replaced by DDQ the reaction was
negatively impacted as no conversion was observed (entry 5). To conclude the screening on diazo reagents, ADDP and DCAD were tested
without significant changes observed in the reaction profile in comparison to ADDM (entries 6 and 7). ADDP was finally chosen as most
convenient azido reagent mainly due to its easier and cheaper access in comparison to DCAD. Different phosphines were finally compared
to P(nBu)3 but none of them afforded the desired compound (entries 8ꢀ10). Only starting material was fully recovered. It can be mentioned
that addition of P(nBu)3 in corresponding resulting mixtures afforded full conversion into 3a indicating that all tested phosphines did not
react with ADDP.
Having established optimal reaction conditions for Mitsunobuꢀtriggered sequence we then tested their efficiency in the oneꢀpot domino
process starting from substrate 1a (Scheme 4).
Scheme 4. One-pot domino sequence under optimized Mitsunobu conditions
Pleasingly, starting from ethanolamine, Michael acceptor 1a and 1.8 equivalents of each Mitsunobu reagents, the reaction led to desired
nitrogen fused oxazolopyridine 3a in full conversion and satisfactory 80% of isolated yield.
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Scope and limitations of the reaction were then investigated on different chromone acceptors reacting with diversified amino
alcohols. As it could be anticipated, depending on the chromone moiety substitution, phenolate reactivity of zwitterionic 2ꢀpyridone
intermediate directly impacted Mitsunobu sequence (Table 2).
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Table 2. Impact of Michael acceptors substitution on domino process
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Michael
acceptor
Time Yield
(min) (%)
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acceptor
Time Yield
Entry
Product
Entry
Product
(min)
(%)a
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O
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CO2Et
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H
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CN
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(54)b
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a Isolated Yield. b Achieved by addition of an extra equivalent of Mitsunobu reagents in the reaction mixture after 1 h of reaction time. c The reaction stopped at the zwitterionicꢀ2ꢀpyridone stage. d Only 7% of
conversion into the corresponding cyano oxazolopyridine was observed by 1H NMR.
Electron donating groups (EDG) enhancing phenol nucleophilicity such as 5ꢀsubstituted methylchromone or benzyloxychromone afforded
corresponding oxazoloꢀpyridines 3b and 3c, respectively in 83% and 88% of isolated yields (entries 1 and 2). High reactivity was also
observed for 5ꢀsubstituted isopropylchromone although 3d was isolated in 69% of yield (entry 3). On the other hand, when phenol group
nucleophicility was weakened, the reaction was negatively impacted. A strong electron withdrawing group (EWG) such as nitro group in
para position prevented Mitsunobuꢀdomino sequence. Only the zwitterionic 2ꢀpyridone intermediate was indeed observed after 2 hours of
reaction time. Comparatively, 5ꢀbromo substituted α,βꢀunsaturated chromone afforded desired product 3e in modest 38% of isolated yield.
In this case the decrease of phenolate reactivity also led to an incomplete conversion from corresponding 2ꢀpyridone zwitterionic
intermediate since the latter was detected in the reaction mixture at the end of the reaction. In a second attempt, an extra equivalent of
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ADDP/P(nBu)3 was added to the reaction media after 1 h of reaction time, in order to shift equilibrium in favor of oxazolopyridine
derivative. However, no significant improvement was observed since 3e was isolated in 54% yield. Domino process was then investigated
with diverse electronic withdrawing groups on the Michael acceptor moiety. Interestingly, in case of nonꢀsymmetrical Michael acceptors
bearing cyano/ester or cyano/ketone groups, excellent chemoselectivity was achieved in favor of imidazopyridines derivatives since 3k and
3l were obtained in respectively 93:7 and >99:1 ratios. This chemoselectivity could be explained by the higher reactivity of cyano group in
the first ring closure step of the domino process, and the presence of an intramolecular hydrogen bond involved in formed
imidazopyridines stabilization. It is worth mentioning that in the latter cases Mitsunobu sequence led to the formation of one CꢀO bond and
one CꢀN bond. The structure of 3l was confirmed by Xꢀray diffraction analysis (CCDC 1477526) (Figure 1). One molecule of
dichloromethane appeared to be trapped in each asymmetric unit of the crystal matrix.
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Figure 1. X-ray structure of 3l (asymmetric unit in thermal ellipsoid representation with 50% of probability)
On the other hand, in case of ketoꢀester or nitroꢀester Michael acceptors, no chemoselectivity was observed since desired oxazolopyridines
were obtained in moderate to low ratios among complex mixtures of unidentified byꢀproducts. Finally, diꢀbenzoate substituents afforded
desired compound 3m in 81% of isolated yield. Interestingly, no competitive intermolecular Mitsunobu reaction was observed. The latter
could have occurred with phenol group released in the ring closure step.
The investigation was then focused on the aminoꢀalcohol moiety (Table 3). It was anticipated that substitution in αꢀposition of the nitrogen
atom with sterically hindered groups might have an influence on the formed asymmetric center stereocontrol. Gratifyingly, good
diastereoselectivity was achieved with a variety of enantiopure 2ꢀsubstituted ethanolamines. Hindered substituents such as methyl or ethyl
groups afforded desired compounds 3n and 3o in good yields and satisfactory >80:20 and >85:15 diastereoisomeric excess (Table 3,
entries 1 and 2). Surprisingly, isopropyl group did not enhance diastereoisomeric excess. The best result was obtained for phenyl group
which afforded desired compound 3r in 75% of yield and >95:5 diastereoselectivity (Table 3, entry 5).
Table 3. Impact of amino alcohols substitution on domino process
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Amino
Product
alcohol
Time
(min)
Yield
(%)b
Entry
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60
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a Ratio determined by 1H NMR spectroscopy. b Isolated yield. c Enaminochromanone kinetic product was observed in the crude
mixture. d The reaction stopped at zwitterionic 2ꢀpyridone stage.
Absolute configurations of 3n and 3r asymmetric centers were determined by NOESY experiments (Scheme 5). The results show that Ha
and Hb are transꢀoriented in both cases. Consequently, absolute configurations of the new asymmetric centers were assigned as (S)ꢀ
isomers.
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Scheme 5. NOESY interactions for 3n and 3r
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Finally, when 2ꢀ(benzyl)ethanolamine was used, the corresponding dihydroꢀoxazolopyridine 3s was obtained in 77% yield and >80:20 of
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diastereoisomeric excess (Table 3, entry 6).
Mitsunobu sequence was less tolerant to secondary alcohols since compound 3v was isolated in 35% yield (entry 9). As it could be
envisioned, this substitution did not have any influence on asymmetric center stereocontrol. In case of tertiary alcohol no conversion into
targeted product was observed. The presence of dimethyl group in
αꢀposition of nitrogen atom enhanced the reactivity of Mitsunobu
sequence by Thorpe Ingold effect.34 Nevertheless, beside desired oxazolopyridine, the steric hindrance of 3t led to a substantial proportion
of kinetic enaminochromanone side product as reported in our previous work involving primary amines and Michael acceptors.26 The latter
explains the moderate 52% of isolated yield observed for 3t. In case of cyclohexyl group, only enaminochromanone was observed in the
crude mixture after 2 hours of reaction time. Finally, 6ꢀmembered oxazino ring was attempted but surprisingly domino process stopped at
the zwitterionic 2ꢀpyridone stage.
A plausible mechanism in accordance with previous work and DFT calculations is depicted in Scheme 6. Domino process would be
Scheme 6. Plausible mechanism of domino process
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initiated by a 1,6ꢀazaꢀMichael addition of primary amino alcohols onto chromone acceptors leading first to a nonꢀisolable intermediate A.
The latter would then undergo a ring opening step to provide B1. At this stage, C2 (in Pro4 vs. Pro6 conformation) intermediate would be
accessed via two competitive pathways, both of them involving a ring closure step (B1 to C1 or B2 to C2) and the generation of zwitterion
species by active Mitsunobu reagent (B1 to B2 or C1 to C2). Finally, 2ꢀpyridone zwitterion C2 in favorable Pro6 conformation would
undergo regioselective Mitsunobuꢀtriggered sequence, allowing final ring closure to afford desired tetracyclic nitrogen bridged dihydroꢀ
oxazolopyridines.
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Mechanistic study by DFT calculations
To support the proposed mechanism of Mitsunobu concerted sequence, a complete DFT investigation was conducted using state of the art
M06ꢀ2X functional at the 6ꢀ31G(d,p) level of the theory. The solvent effect was taken into account using the PCM (Polarizable Continuum
Model) formalism during optimization and frequency calculations.35 As further specified the domino process involves a first step leading
to the formation of the 2ꢀpyridone zwitterion intermediate followed by the intramolecular Mitsunobu triggered sequence yielding
tetracyclic nitrogen bridged dihydroꢀoxazolopyridines.
a) Selectivity at C6ꢀ vs. C4ꢀposition. From the first step of the oneꢀpot process, the formation of Nꢀhydroxyethylꢀ2ꢀpyridone (2 ≡ Pyr) could
be anticipated. In order to reduce the computational cost of the study and to simplify the system, we assumed the use of trimethylphosphine
instead of nꢀtributylphosphine. At this point, two positions (C4 and C6) of zwitterionic Pyr could be involved in the intramolecular addition
of phenolate moiety. Therefore, the regioselectivity should be influenced by the conformational preference of zwitterionic Pyr and then by
the energetic barrier level of the cyclization process. The nature of Pyr (neutral or zwitterionic) appeared to have an important impact on
conformational preference. Concerning the neutral state Neutral Pyr, the existence of an intramolecular Hꢀbonding greatly stabilizes the
structure and thus strongly influences the orientation of different conformers (Scheme 7, A). This affirmation is supported by the high
relative free Gibbs energy computed for the two other C6 (Neutral Pyr-Pro6) and C4 (Neutral Pyr-Pro4) conformers, respectively of 5.04
kcal/mol and 4.25 kcal/mol.
Scheme 7. Conformational analysis of 2-pyridone intermediates at the neutral (A) and zwitterionic state (B) calculated at
the PCM/M06-2X/6-31G(d,p) level of theory.36
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On the other hand when zwitterionic Pyr was considered (negative charge on the phenolic moiety and positive charge on the
phosphonium), the conformational analysis of Pyr pointed out two conformers characterized by a tight distance between the phenoxide
moiety and C6 (Pyr-Pro6) or C4 (Pyr-Pro4) positions of the 2ꢀpyridone ring. The computed Boltzmann distribution definitively shows that
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Pyr-Pro6 is quasiꢀexclusively favored (relative ꢀG° of +5.37 kcal/mol calculated for Pyr-Pro4 conformer at room temperature, Scheme 7,
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B). Moreover, calculations clearly revealed that the distance between reactive centers for Pyr-Pro6 (2.665 Å) is slightly closer than Pyr-
Pro4 (2.704 Å) (see SI section). These results are in perfect agreement with the regioselectivity observed experimentally.
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b) Concerted path A vs. path B for Mitsunobu sequence. DFT calculations were pursued with the study of the Mitsunobu sequence
pathway and the localization of possible transition states and intermediates involved in this process leading to final tetracyclic product
(Tetra) and the release of trimethylphophine oxide byꢀproduct (TMP). Herein, from Pyr-Pro6 transition state, two different concerted
pathways can be hypothesized. On the one hand, a concerted pathway A in which phenoxide ion of Pyr-Pro6 induces a nucleophilic attack
at C6ꢀposition of 2ꢀpyridone ring could be envisioned. The latter leads to a chromenopyridone intermediate (Chrom-Pyr) which then
undergoes a nucleophilic substitution of phosphonium group by the oxygen of the 2ꢀpyridone carbonyl group to form final Tetra (Scheme
8, see SI section). On the other hand, another plausible concerted pathway B also was taken into account. The latter is initiated by the
formation of dihydroꢀoxazole ring from Pyr-Pro6, probably due to the impulse of nitrogen atom electron’s lone pair which generates a
furtive pyridinium intermediate (Pyr-Int). Finally, Pyr-Int reacts in a barrierless fashion to yield final Tetra product since several
attempts failed to localize any transition state (Scheme 8, see SI section). The overall processes from Pyr-Pro6 to Tetra was calculated to
be exothermic with a free Gibbs energy variation of ꢀ28.05 kcal/mol (see SI section).
Scheme 8. Energetic profiles of Mitsunobu sequence computed at the PCM/M062X/6-31G(d,p) level of theory.36
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According to these calculations, it was assumed that Mitsunobuꢀtriggered sequence follows the concerted pathway A since TS1a-Pro6
transition state (+3.64 kcal/mol) is highly favored over TS1b-Pro6 (+22.62 kcal/mol) regarding its lower activation barrier (Scheme 8).
Moreover, computed interatomic distance of transition states TS1a-Pro6 (2.089 Å) and Pyr-Int (2.495 Å) also supported the proposed
mechanism (Scheme SI 1, see SI). As calculations proved that concerted pathway A is greatly favored, the latter was applied on βꢀ
substituted amino alcohols in order to justify the diastereoselectivity observed in these cases.
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c) Diastereoselectivity. Since the best diastereoselectivity was observed (> 95:5) for the 2ꢀpyridone derivative bearing a (S)ꢀ1ꢀaminoꢀ2ꢀ
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phenylethanol moiety, the latter was chosen as model structure.37
Scheme 9. Comparison of Pro-(R) and Pro(S) concerted mechanism A of Mitsunobu sequence calculated at the PCM/M06-
2X/6-31G(d,p) level of theory.36
First transition states (TS1a-Pro6) implying the phenolate nucleophilic attack at C6ꢀposition were calculated to be significantly different in
term of energy with +6.33 and +4.07 kcal/mol for Proꢀ(R) and Proꢀ(S) processes, respectively (Scheme 9, see SI section). The calculated
difference in term of energy barriers (ꢀꢀGǂ of 2.19 kcal/mol) favors the Proꢀ(S) process and can already explain the diastereoselectivity
observed when applying the CurtinꢀHammett Principle.38 Moreover, taking into account the last step of Mitsunobu sequence characterized
by a second transition state (TS2-Pro6), the computed free Gibbs energy barrier for Proꢀ(S) (+15.03 kcal/mol) is also favored over Proꢀ(R)
(+16.97 kcal/mol) process. Finally, when considering pathway A, Proꢀ(S) process was modeled to be more favorable in term of energy and
these theoretical results are correlated to the experimentally observed diastereoselectivity for 3r. Despite this good correlation between
both aspects, Proꢀ(R) and Proꢀ(S) processes were also computed through the concerted pathway B. Indeed, on a chemical point of view the
latter was first considered as more plausible to control the newly formed stereogenic center through the furtive chiral oxazolopyridinium
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intermediate (Pyr Int). Nevertheless, the calculations did not support this hypothesis, since this pathway remains improbable regarding the
high activation barriers required (+19.71 kcal/mol for Proꢀ(R) and +19,12 kcal/mol for Proꢀ(S)). Moreover, in this case, no significant
differences were highlighted in term of free Gibbs energy barriers that could explain the diastereoselectivity observed (ꢀꢀGǂ of 0.66
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kcal/mol, see SI section).
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As final conclusion of calculations part, the Mitsunobu triggered sequence pathway was elucidated by DFT calculations. This domino
sequence follows the concerted pathway A in a remarkable C6ꢀregioselective and diastereoselective fashion.
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An interesting application that underlines the potential of this methodology is pointed out in Scheme 10. It was shown that resulting
tetracyclic systems could be useful synthetic intermediates to access a new class of N,3,5ꢀtrisubstituted 2ꢀpyridones bearing oxazoline
group at C3ꢀposition. As illustrated in Scheme 10 (pathway 1), the treatment of compound 3a with benzylamine afforded 2ꢀpyridone 8 in
71% of yield. It is proposed that the latter was achieved through the addition of benzylamine at C11aꢀposition of 3a followed by a ring
opening/azaꢀClaisen rearrangement/ring closure sequence. Oxazoline group could thus been introduced at C3ꢀposition in two steps in 57%
of overall yield starting from Michael acceptor 1a.
Scheme 10. Application of the developed methodology
On the other hand, classical reported methodologies appeared to be much less efficient to access 8 starting from carboxylic acid39 or cyano
precursors.40 The latter was synthetized in three steps in 21% of overall yield via pathway 2 while cyano group failed to provide 8 through
pathway 3 (Scheme 10).
CONCLUSION
In conclusion an original Mitsunobu triggered sequence has been successfully developed and incorporated in a global domino process for
the generation of an interesting class of tetracyclic systems bearing atypical bisꢀN,Oꢀacetal junction. This powerful oneꢀpot methodology
operates in mild conditions and has demonstrated its tolerance to a large scope of Michael acceptors and readily available either racemic or
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chiral amino alcohols. The concerted mechanism proposed for Mitsunobu triggered sequence was corroborated by experimental and
theoretical mechanism studies. From a synthetic point of view Mitsunobu activation has shown its significant interest being incorporated in
domino strategies. Furthermore, this is the first time that Mitsunobu reaction leads to the formation of two bonds. Ultimately, it was
demonstrated that the formed tetracyclic nitrogen bridged dihydroꢀoxazolopyridines can be useful synthetic intermediates to access a new
class of N,3,5ꢀtrisubstituted 2ꢀpyridones of biological interest.
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EXPERIMENTAL SECTION
General Details. Unless otherwise specified, reagents and starting materials were purchased from traditional suppliers and were used
without further purification. Reactions were carried out in standard glassware. NMR spectra were recorded at 300 MHz for 1H and 75 MHz
for 13C in deuterated chloroform (CDCl3) at room temperature, using TMS as internal standard (δ = 0). High resolution ESI mass spectra
were measured on QꢀTOF System spectrometer. Column chromatography purifications were performed using Si2O (40ꢀ63 ꢁm) as solid
phase and a mixture of dichloromethane/ethyl acetate or cyclohexane/ethyl acetate as eluents. Melting points were recorded on a Scientific
analyzer SMP 10 apparatus and are uncorrected. Infrared spectra were performed as neat on FTꢀIR spectrophotometer and only broad or
strong signals are reported.
I. General procedure for α,β-unsaturated chromones synthesis (1)
Michael acceptors bearing the chromone core were prepared by an improved method according to Ghosh’s procedure.41 To a previously
stirred solution of malonate derivative (1.5 eq.) and K2CO3 (0.1 eq.) in acetic anhydride, the appropriate 3ꢀformylchromone was added and
the mixture was heated at adequate temperature until no starting material was observed (TLC analysis). After cooling at room temperature
or at 0°C, the precipitate formed was filtered and washed with cyclohexane to afford the corresponding Michael acceptors.
Diethyl 2ꢀ[(4ꢀoxoꢀ4Hꢀchromenꢀ3ꢀyl)methylene]malonate (1a). White powder (precipitation in Ac2O), Rf = 0.31, eluent (ethyl acetate /
cyclohexane 1:4), mp = 112ꢀ114 °C, 5.00 g scale reaction (in 15 mL of Ac2O) for 3h at 90 °C, 8.81 g was isolated, 97% yield. IR (νmax
/
cmꢀ1): 1716, 1650, 1632, 1460, 1213. 1H NMR (300 MHz, CDCl3): δH 8.34 (s, 1H), 8.26 (dd, J = 8.0, 1.7 Hz, 1H), 7.79 (s, 1H), 7.71 (ddd,
J = 8.6, 7.1, 1.7 Hz, 1H), 7.50 – 7.42 (m, 2H), 4.34 (2xq, J = 7.2 Hz, 4H), 1.50 (t, J = 7.2 Hz, 3H), 1.30 (t, J = 7.2 Hz, 3H). 13C NMR (75
MHz, CDCl3): δC 175.1, 165.9, 163.9, 156.4, 155.9, 134.3, 133.1, 128.12, 126.4, 126.0, 123.8, 119.1, 118.2, 61.8, 61.8, 14.1, 14.0.
Physical and NMR spectral data are in accordance with those previously reported.41
Diethyl 2ꢀ((6ꢀmethylꢀ4ꢀoxoꢀ4Hꢀchromenꢀ3ꢀyl)methylene)malonate (1b). Pale yellow powder (precipitation in cold Ac2O), Rf = 0.33,
eluent (ethyl acetate / cyclohexane 3:7), mp = 67ꢀ69 °C, 5.00 g scale reaction (in 15 mL of Ac2O) for 3h at 90 °C, 5.90 g was isolated, 67%
yield. IR (νmax / cmꢀ1): 1715, 1654, 1620, 1481, 1201. 1H NMR (300 MHz, CDCl3): δH 8.26 (s, 1H), 7.97 (s, 1H), 7.73 (s, 1H), 7.47 (dd, J =
8.6, 2.2 Hz, 1H), 7.33 (d, J = 8.6 Hz, 1H), 4.29 (2xq, J = 7.1 Hz, 4H), 2.42 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H). 13C
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NMR (75 MHz, CDCl3): δC 175.1, 165.9, 163.9, 156.4, 154.1, 136.0, 135.4, 133.2, 127.9, 125.5, 123.3, 118.8, 117.9, 61.7, 61.4, 20.9,
14.1, 14.0. Physical and NMR spectral data are in accordance with those previously reported.41
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Diethyl 2ꢀ((6ꢀ(benzyloxy)ꢀ4ꢀoxoꢀ4Hꢀchromenꢀ3ꢀyl)methylene)malonate (1c). Yellow powder (precipitation in Ac2O), Rf = 0.40, eluent
(ethyl acetate / cyclohexane 1:9), mp = 130ꢀ132 °C, 0.20 g scale reaction (in 4 mL of Ac2O) for 1h at 90 °C, 0.27 g was isolated, 90%
yield. IR (νmax / cmꢀ1): 1724, 1687, 1658, 1483, 1450, 1220. 1H NMR (300 MHz, CDCl3): δH 8.30 (s, 1H), 7.78 (s, 1H), 7.70 (d, J = 2.6 Hz,
1H), 7.31 ꢀ 7.49 (m, 7H), 5.15 (s, 2H), 4.32 (qx2, J = 7.3 Hz, 4H), 1.32 (tx2, J = 7.1 Hz, 6H). 13C NMR (75 MHz, CDCl3): δC 174.9, 165.9,
163.9, 156.6, 156.2, 150.8, 136.0, 133.2, 128.7 (x2), 128.3, 128.0, 127.7 (x2), 124.7, 124.4, 119.7, 118.3, 106.7, 70.7, 61.7 (x2), 14.1, 14.0.
HRMS (ESI+): calcd for C24H23O7 [M+H]+ 423.1444, found 423.1427
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Diethyl 2ꢀ((6ꢀisopropylꢀ4ꢀoxoꢀ4Hꢀchromenꢀ3ꢀyl)methylene)malonate (1d). Pale yellow powder (precipitation in Ac2O at 0 °C), Rf = 0.65,
eluent (ethyl acetate / cyclohexane 3:7), mp = 59ꢀ61 °C, 1.00 g scale reaction (in 4 mL of Ac2O) for 3h at 90 °C, 1.45 g was isolated, 88%
yield. IR (νmax / cmꢀ1): 1723, 1658, 1604, 1487, 1463, 1243. 1H NMR (300 MHz, CDCl3): δH 8.30 (d, J = 1.0 Hz, 1H), 8.08 (d, J = 2.4 Hz,
1H), 7.78 (d, J = 1.0 Hz, 1H), 7.58 (dd, J = 8.5, 2.3 Hz, 1H), 7.41 (d, J = 8.6 Hz, 1H), 4.33 (dq, J = 10.1, 7.1 Hz, 4H), 3.04 (hept, J = 6.9
Hz, 1H), 1.40 – 1.28 (m, 6H), 1.31 (s, 3H), 1.29 (s, 3H). 13C NMR (75 MHz, CDCl3): δC 175.3, 165.9, 163.9, 156.3, 154.3, 147.0, 133.3,
133.1, 127.9, 123.5, 123.1, 118.8, 118.1, 61.7 (x2), 33.8, 23.9 (x2), 14.1, 14.0. HRMS (ESI+): calcd for C20H23O6 [M+H]+ 359.1495, found
359.1508.
Diethyl 2ꢀ((6ꢀbromoꢀ4ꢀoxoꢀ4Hꢀchromenꢀ3ꢀyl)methylene)malonate (1e). White powder (precipitation in cold Ac2O), Rf = 0.56, eluent
(ethyl acetate / cyclohexane 4:6), mp = 89ꢀ91 °C, 1.00 g scale reaction (in 4 mL of Ac2O) for 2h at 90 °C, 1.34 g was isolated, 89% yield.
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IR (νmax / cmꢀ1): 1720, 1643, 1610, 1456, 1235. H NMR (300 MHz, CDCl3): δH 8.34 – 8.38 (m, 1H), 8.32 (s, 1H), 7.79 (dd, J = 8.9, 2.5
Hz, 1H), 7.72 (s, 1H), 7.39 (d, J = 8.9 Hz, 1H), 4.33 (2xq, J = 7.1 Hz, 4H), 1.33 (2xt, J = 7.3 Hz, 6H). 13C NMR (75 MHz, CDCl3): δC
173.8, 165.7, 163.7, 156.5, 154.6, 137.3, 132.5, 128.9, 128.7, 125.0, 120.2, 119.5, 119.2, 61.9 (x2), 14.1, 14.0. HRMS (ESI+): calcd for
C17H16BrO6 [M+H]+ 395.0130, found 395.0138.
Diethyl 2ꢀ((6ꢀnitroꢀ4ꢀoxoꢀ4Hꢀchromenꢀ3ꢀyl)methylene)malonate (1f). Pale yellow powder (precipitation in Ac2O), Rf = 0.66, eluent
(ethyl acetate / cyclohexane 1:1), mp = 158ꢀ160 °C, 3.50 g scale reaction (in 10 mL of Ac2O) for 2h, 3.86 g was isolated, 67% yield. IR
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(νmax / cmꢀ1): 1720, 1657, 1626, 1531, 1465, 1345, 1202. H NMR (300 MHz, CDCl3): δH 9.11 (d, J = 2.7 Hz, 1H), 8.55 (dd, J = 9.2, 2.8
Hz, 1H), 8.40 (d, J = 1.0 Hz, 1H), 7.70 (d, J = 1.0 Hz, 1H), 7.67 (d, J = 9.2 Hz, 1H), 4.34 (qx2, J = 7.1 Hz, 4H), 1.35 (tx2, J = 7.1, 6H).
13C NMR (75 MHz, CDCl3): δC 173.7, 165.5, 163.5, 158.6, 156.5, 145.2, 131.6, 129.8, 128.6, 123.8, 123.0, 120.1, 119.8, 62.0 (x2), 14.1,
14.0. HRMS (ESI+): calcd for C17H16NO8 [M+H]+ 362.0876, found 362.0886.
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Diethyl 2ꢀ((6ꢀchloroꢀ7ꢀmethylꢀ4ꢀoxoꢀ4Hꢀchromenꢀ3ꢀyl)methylene)malonate (1g). Colorless crystals (crystallization in Ac2O), Rf = 0.80,
eluent (ethyl acetate / cyclohexane 1:1), mp = 140ꢀ142 °C, 1.00 g scale reaction (in 4 mL of Ac2O) for 2h at 90 °C, 1.17 g was isolated,
71% yield. IR (νmax / cmꢀ1): 1723, 1646, 1616, 1556, 1458, 1375, 1189. 1H NMR (300 MHz, CDCl3): δH 8.29 (d, J = 1.0 Hz, 1H), 8.20 (s,
1H), 7.74 (d, J = 1.0 Hz, 1H), 7.37 (d, J = 0.9 Hz, 1H), 4.34 (2xq, J = 7.1 Hz, 4H), 2.52 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H), 1.33 (t, J = 7.1
Hz, 3H). 13C NMR (75 MHz, CDCl3): δC 174.0, 165.8, 163.8, 156.3, 154.1, 143.7, 132.7, 132.7, 128.4, 126.0, 122.8, 120.0, 119.0, 61.8
(x2), 20.9, 14.1, 14.0. HRMS (ESI+): calcd for C18H18ClO6 [M+H]+ 365.0792, found 365.0805.
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Diethyl 2ꢀ((7ꢀethoxyꢀ8ꢀmethylꢀ4ꢀoxoꢀ4Hꢀchromenꢀ3ꢀyl)methylene)malonate (1h). White solid (precipitation in Ac2O), Rf = 0.80, eluent
(ethyl acetate / cyclohexane 1:1), mp = 101ꢀ102 °C, 0.63 g scale reaction (in 2 mL of Ac2O) for 3h at 90 °C, 0.83 g was isolated, 82%
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yield. IR (νmax / cmꢀ1): 1723, 1656, 1616, 1460, 1240. H NMR (300 MHz, CDCl3): δH 8.32 (d, J = 1.0 Hz, 1H), 8.08 (d, J = 8.9 Hz, 1H),
7.80 (d, J = 1.0 Hz, 1H), 6.99 (d, J = 8.9 Hz, 1H), 4.34 (2xq, J =7.1 Hz, 4H), 4.19 (q, J = 7.0 Hz, 2H), 2.30 (s, 3H), 1.49 (t, J = 7.0 Hz,
3H), 1.35 (t, J = 7.1 Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δC 175.1, 166.1, 164.0, 161.3, 156.3, 155.1, 133.5,
127.5, 124.8, 118.2, 117.4, 114.4, 110.0, 64.5, 61.7, 61.7, 14.8, 14.2, 14.0, 8.1. HRMS (ESI+): calcd for C20H23O7 [M+H]+ 375.1444, found
375.1458.
Diethyl 2ꢀ((4ꢀoxoꢀ4Hꢀbenzo[h]chromenꢀ3ꢀyl)methylene)malonate (1i). Beige powder (precipitation in cold Ac2O), Rf = 0.52, eluent
(ethyl acetate / cyclohexane 1:2), mp = 140ꢀ142 °C, 4.00 g scale reaction (in 15 mL of Ac2O) for 4h, 4.73 g was isolated, 73% yield. IR
(νmax / cmꢀ1): 1718, 1648, 1569, 1510, 1367, 1206. 1H NMR (300 MHz, CDCl3): δH 8.51 (s, 1H), 8.45 (d, J = 7.9 Hz, 1H), 8.16 (d, J = 8.8
Hz, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.85 (s, 1H), 7.65 – 7.82 (m, 3H), 4.36 (2xq, J = 7.2 Hz, 4H), 1.34 (2xt, J = 7.2 Hz, 6H). 13C NMR (75
MHz, CDCl3): δC 175.0, 165.9, 163.8, 155.5, 153.5, 136.0, 133.0, 129.7, 128.5, 128.2, 127.5, 126.1, 123.7, 122.2, 120.9, 120.3, 120.2,
61.8, 61.8, 14.2, 14.0. Physical and NMR spectral data are in accordance with those previously reported.42
Diethyl 2ꢀ((1ꢀoxoꢀ1Hꢀbenzo[f]chromenꢀ2ꢀyl)methylene)malonate (1j). Pale yellow powder (precipitation in cold Ac2O), Rf = 0.77, eluent
(ethyl acetate / cyclohexane 1:1), mp = 84ꢀ86 °C, 4.00 g scale reaction (in 10 mL of Ac2O) for 5h, 5.10 g was isolated, 78% yield. IR (νmax
/ cmꢀ1): 1715, 1654, 1591, 1514, 1440, 1218. 1H NMR (300 MHz, CDCl3): δH 9.94 (d, J = 8.4 Hz, 1H), 8.33 (s, 1H), 8.02 – 8.11 (m, 1H),
7.84 – 7.95 (m, 2H), 7.70 – 7.82 (m, 1H), 7.57 – 7.69 (m, 1H), 7.40 – 7.53 (m, 1H), 4.35 (2xq, J = 7.2 Hz, 4H), 1.34 (2xt, J = 7.2 Hz, 6H).
13C NMR (75 MHz, CDCl3): δC 176.7, 165.9, 163.8, 157.2, 153.8, 136.1, 133.5, 130.8, 130.4, 129.6, 128.3, 128.3, 127.1, 127.0, 121.4,
117.3, 117.1, 61.8, 61.8, 14.2, 14.0. HRMS (ESI+): calcd for C21H19O6 [M+H]+ 367.1182, found 367.1194.
Ethyl 2ꢀcyanoꢀ3ꢀ(4ꢀoxoꢀ4Hꢀchromenꢀ3ꢀyl)acrylate (1k). Orange powder (precipitation in cold Ac2O), Rf = 0.77, eluent (ethyl acetate /
cyclohexane 1:1), mp = 128ꢀ130 °C, 3.00 g scale reaction (in 8 mL of Ac2O) for 5h at room temperature, 3.23 g was isolated, 70% yield.
IR (νmax / cmꢀ1): 2221, 1726, 1654, 1605, 1557, 1450, 1274. 1H NMR (300 MHz, CDCl3): δH 9.17 (d, J = 0.9 Hz, 1H), 8.67 (d, J = 0.9 Hz,
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1H), 8.30 (ddd, J = 8.0, 1.7, 0.5 Hz, 1H), 7.79 (ddd, J = 8.7, 7.2, 1.7 Hz, 1H), 7.60 – 7.49 (m, 2H), 4.41 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1
Hz, 3H). 13C NMR (75 MHz, CDCl3): δC 174.5, 161.5, 158.3, 155.8, 145.7, 134.9, 126.6, 126.5, 123.6, 118.6, 117.8, 115.4, 103.6, 62.9,
14.2. Physical and NMR spectral data are in accordance with those previously reported.41
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0.31, eluent (ethyl acetate / cyclohexane 1:4), mp = 140ꢀ142 °C, 500 mg scale reaction (in 1 mL of Ac2O) for 2h at room temperature, 507
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mg was isolated, 58% yield. IR (νmax / cmꢀ1): 2220, 1729, 1616, 1560, 1463. H NMR (300 MHz, CDCl3): δH 9.25 (s, 1H), 8.41 (s, 1H),
8.28 (dd, J = 7.9, 1.7 Hz, 1H), 7.88 (d, J = 7.2 Hz, 2H), 7.84 – 7.77 (m, 1H), 7.71 – 7.64 (m, 1H), 7.61 – 7.50 (m, 4H). 13C NMR (75 MHz,
CDCl3): δC 188.5, 174.7, 158.1, 155.9, 146.0, 135.4, 135.0, 133.6, 129.4 (x2), 128.8 (x2), 126.7, 126.5, 123.5, 118.6, 118.1, 116.4, 110.9.
HRMS (ESI+): calcd for C19H12NO3 [M+H]+ 302.0817, found 302.0823.
Diphenyl 2ꢀ((4ꢀoxoꢀ4Hꢀchromenꢀ3ꢀyl)methylene)malonate (1m). Yellow powder (precipitation in cold Ac2O), Rf = 0.77, eluent (ethyl
acetate / cyclohexane 1:1), mp = 123ꢀ124 °C, 3.00 g scale reaction (in 8 mL of Ac2O) for 5h at room temperature, 3.23 g was isolated, 70%
yield. IR (νmax / cmꢀ1): 1756, 1725, 1661, 1614, 1485, 1461, 1239. 1H NMR (300 MHz, CDCl3): δH 8.48 (s, 1H), 8.34 (d, J = 7.9 Hz, 1H),
7.99 (s, 1H), 7.76 (t, J = 7.9 Hz, 1H), 7.57 – 7.41 (m, 6H), 7.39 – 7.24 (m, 6H). 13C NMR (75 MHz, CDCl3): δC 174.7, 163.9, 162.7, 158.1,
155.8, 150.6, 150.6, 136.2, 134.5, 129.6 (x2), 129.6 (x2), 126.9, 126.6, 126.3, 126.2 (x2), 123.8, 121.7 (x2), 121.5 (x2), 118.9, 118.2.
HRMS (ESI+): calcd for C25H17O6 [M+H]+ 413.1025, found 413.1031.
II. General procedure for pyridones synthesis (2)
To a previously stirred solution containing α,βꢀunsaturated chromone and CsF (10.0 mol%) in dichloromethane, the corresponding amine
(1.05 equiv.) was added. The reaction mixture was stirred under reflux until full consumption of substrates was observed (followed by
TLC). After concentration under reduced pressure, the resulting mixture yielded pure N,3,5ꢀtrisubstitutedꢀpyridinꢀ2ꢀone after purification
on silica gel column chromatography.
Ethyl 5ꢀ(2ꢀhydroxybenzoyl)ꢀ1ꢀ(2ꢀhydroxyethyl)ꢀ2ꢀoxoꢀ1,2ꢀdihydropyridineꢀ3ꢀcarboxylate (2). Pale yellow powder (column
chromatography), Rf = 0.24, eluent (ethyl acetate / dichloromethane 1:1), mp = 146ꢀ148 °C, 1.00 g scale reaction (in 5 mL of CH2Cl2) for
1h, 0.75 g was isolated, 71% yield. IR (νmax / cmꢀ1): 3448, 1722, 1625, 1530, 1341, 1218. H NMR (300 MHz, CDCl3): δH 11.39 (s, 1H),
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1H), 6.93 (t, J = 7.5 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 4.20 (t, J = 4.9 Hz, 2H), 4.02 – 3.92 (m, 2H), 3.43 (t, J = 5.2 Hz, 1H), 1.33 (t, J =
7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δC 194.4, 163.9, 162.4, 159.1, 148.6, 144.1, 136.4, 131.8, 119.3, 119.2, 118.7, 118.6, 115.3,
61.6, 59.9, 53.4, 14.2. HRMS (ESI+): calcd for C17H18NO6 [M+H]+ 332.1134, found 332.1142.
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To a previously stirred solution containing α,βꢀunsaturated chromones under reflux in dichloromethane, the corresponding amine (1.05
equiv.), ADDP (1.8 eq.) and P(nBu)3 were added. The reaction mixture was stirred under reflux until full consumption of substrates was
observed (followed by TLC). The resulting mixtures yielded pure tetrahydroꢀoxazolopyridines derivatives after purification on silica gel
column chromatography.
Ethyl 6ꢀoxoꢀ1,2,6,11aꢀtetrahydrochromeno[3,2ꢀe]oxazolo[3,2ꢀa]pyridineꢀ4ꢀcarboxylate (3a). Bright yellow amorphous solid (column
chromatography), Rf = 0.53, eluent (ethyl acetate / dichloromethane 1:1), mp = 168ꢀ169 °C, 100 mg scale reaction (in 3 mL of CH2Cl2) for
40 min, 79 mg were isolated, 80% yield. Product sensitive to CDCl3 acidity. IR (νmax / cmꢀ1): 1657, 1616, 1460, 1279. 1H NMR (300 MHz,
CDCl3): δH 7.97 (dd, J = 7.8, 1.7 Hz, 1H), 7.93 (s, 1H), 7.50 (ddd, J = 8.3, 7.2, 1.8 Hz, 1H), 7.10 (ddd, J = 8.1, 7.3, 1.1 Hz, 1H), 6.95 (dd, J
= 8.3, 1.1 Hz, 1H), 6.57 (s, 1H), 4.98 – 4.89 (m, 1H), 4.84 (q, J = 9.2 Hz, 1H), 4.35 – 4.26 (m, 1H), 4.21 (q, J = 7.1 Hz, 2H), 3.79 (q, J =
9.5 Hz, 1H), 1.29 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δC 179.9, 163.7, 163.5, 155.3, 136.0, 135.6, 127.6, 123.9, 122.6, 117.8,
110.6, 86.6, 81.5, 69.5, 59.8, 45.1, 14.5. HRMS (ESI+): calcd for C17H16NO5 [M+H]+ 314.1028, found 314.1033.
Ethyl 8ꢀmethylꢀ6ꢀoxoꢀ1,2,6,11aꢀtetrahydrochromeno[3,2ꢀe]oxazolo[3,2ꢀa]pyridineꢀ4ꢀcarboxylate (3b). Bright yellow amorphous solid
(column chromatography), Rf = 0.46, eluent (ethyl acetate / dichloromethane 1:1), mp = 91ꢀ92 °C, 100 mg scale reaction (in 3 mL of
CH2Cl2) for 40 min, 82 mg were isolated, 83% yield. Product sensitive to CDCl3 acidity. IR (νmax / cmꢀ1): 1657, 1616, 1487, 1463, 1279. 1H
NMR (300 MHz, CDCl3): δH 7.92 (s, 1H), 7.75 (d, J = 1.9 Hz, 1H), 7.31 (dd, J= 8.3, 1.9 Hz, 1H), 6.85 (d, J = 8.3 Hz, 1H), 6.52 (s, 1H),
4.97 – 4.88 (m, 1H), 4.83 (q, J = 9.2 Hz, 1H), 4.33 – 4.26 (m, 1H), 4.21 (q, J = 7.2 Hz, 2H), 3.77 (q, J = 9.5 Hz, 1H), 2.33 (s, 3H), 1.29 (t,
J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δC 180.1, 163.7, 163.5, 153.3, 136.6, 135.8, 132.2, 127.3, 123.5, 117.6, 110.8, 86.5, 81.3,
69.5, 59.8, 45.1, 20.5, 14.5. HRMS (ESI+): calcd for C18H18NO5 [M+H]+ 328.1185, found 328.1191.
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Ethyl 8ꢀ(benzyloxy)ꢀ6ꢀoxoꢀ1,2,6,11aꢀtetrahydrochromeno[3,2ꢀe]oxazolo[3,2ꢀa]pyridineꢀ4ꢀcarboxylate (3c). Bright yellow amorphous
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solid (column chromatography), Rf = 0.41, eluent (ethyl acetate / dichloromethane 1:1), mp = 199ꢀ200 °C, 100 mg scale reaction (in 3 mL
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of CH2Cl2) for 40 min, 87 mg were isolated, 88% yield. Product sensitive to CDCl3 acidity. IR (νmax / cmꢀ1): 1655, 1616, 1486, 1241. H
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NMR (300 MHz, CDCl3): δH 7.94 (s, 1H), 7.51 (d, J = 3.1 Hz, 1H), 7.47 – 7.34 (m, 5H), 7.17 (dd, J = 8.9, 3.2 Hz, 1H), 6.90 (d, J = 8.9 Hz,
1H), 6.50 (s, 1H), 5.08 (s, 2H), 4.97 – 4.88 (m, 1H), 4.88 – 4.76 (m, 1H), 4.32 – 4.26 (m, 1H), 4.21 (q, J = 7.1 Hz, 2H), 3.76 (q, J = 9.5 Hz,
1H), 1.31 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δC 179.9, 163.7, 163.5, 154.1, 149.8, 136.6, 136.1, 128.6 (x2), 128.1, 127.6
(x2), 124.9, 124.1, 119.1, 110.5, 109.8, 86.5, 81.5, 70.6, 69.5, 59.8, 45.1, 14.5. HRMS (ESI+): calcd for C24H22NO6 [M+H]+ 420.1447,
found 420.1453.
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Ethyl 8ꢀisopropylꢀ6ꢀoxoꢀ1,2,6,11aꢀtetrahydrochromeno[3,2ꢀe]oxazolo[3,2ꢀa]pyridineꢀ4ꢀcarboxylate (3d). Bright yellow amorphous solid
(column chromatography), Rf = 0.60, eluent (ethyl acetate / dichloromethane 1:1), mp = 84ꢀ86 °C, 100 mg scale reaction (in 3 mL of
CH2Cl2) for 40 min, 67 mg was isolated, 68% yield. Product sensitive to CDCl3 acidity. IR (νmax / cmꢀ1): 1655, 1616, 1486, 1461, 1241. 1H
NMR (300 MHz, CDCl3): δH 7.92 (s, 1H), 7.82 (d, J = 2.3 Hz, 1H), 7.37 (dd, J = 8.5, 2.4 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.53 (s, 1H),
4.98 – 4.77 (m, 2H), 4.34 – 4.25 (m, 1H), 4.21 (q, J = 7.2 Hz, 2H), 3.77 (q, J = 9.4 Hz, 1H), 2.92 (hept, J = 6.9 Hz, 1H), 1.30 (t, J = 7.1 Hz,
3H), 1.26 (s, 3H), 1.24 (s, 3H). 13C NMR (75 MHz, CDCl3): δC 180.2, 163.8, 163.5, 153.5, 143.3, 135.7, 134.2, 124.8, 123.5, 117.7, 110.9,
86.5, 81.4, 69.4, 59.8, 45.1, 33.4, 23.9, 23.9, 14.5. HRMS (ESI+): calcd for C20H22NO5 [M+H]+ 356.1498, found 356.1505.
Ethyl 8ꢀbromoꢀ6ꢀoxoꢀ1,2,6,11aꢀtetrahydrochromeno[3,2ꢀe]oxazolo[3,2ꢀa]pyridineꢀ4ꢀcarboxylate (3e). Bright yellow amorphous solid
(column chromatography), Rf = 0.33, eluent (ethyl acetate / dichloromethane 1:1), mp = 193ꢀ194 °C, 100 mg scale reaction (in 3 mL of
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CH2Cl2) for 1 h, 38 mg were isolated, 38 % yield. Product sensitive to CDCl3 acidity. IR (νmax / cmꢀ1): 1657, 1618, 1488, 1459, 1247. H
NMR (300 MHz, CDCl3): δH 8.08 (d, J = 2.4 Hz, 1H), 7.96 (s, 1H), 7.57 (dd, J = 8.7, 2.6 Hz, 1H), 6.86 (d, J = 8.7 Hz, 1H), 6.57 (s, 1H),
5.01 – 4.80 (m, 2H), 4.35 – 4.26 (m, 1H), 4.22 (q, J = 7.1 Hz, 2H), 3.81 (q, J = 9.5 Hz, 1H), 1.31 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz,
CDCl3): δC 178.6, 163.6, 163.5, 154.1, 138.2, 136.9, 130.2, 125.2, 119.9, 115.4, 109.6, 86.8, 81.9, 69.5, 59.9, 45.1, 14.5. HRMS (ESI+):
calcd for C17H15BrNO5 [M+H]+ 392.0134, found 392.0136.
Ethyl 8ꢀchloroꢀ9ꢀmethylꢀ6ꢀoxoꢀ1,2,6,11aꢀtetrahydrochromeno[3,2ꢀe]oxazolo[3,2ꢀa]pyridineꢀ4ꢀcarboxylate (3g). Bright yellow
amorphous solid (column chromatography), Rf = 0.469 eluent (ethyl acetate / dichloromethane 1:1), mp = 192ꢀ193 °C, 100 mg scale
reaction (in 3 mL of CH2Cl2) for 1 h, 59 mg were isolated, 60% yield. Product sensitive to CDCl3 acidity. IR (νmax / cmꢀ1): 1655, 1615,
1497, 1475, 1268. 1H NMR (300 MHz, CDCl3): δH 7.89 (s, 1H), 7.86 (s, 1H), 6.83 – 6.79 (m, 1H), 6.49 (s, 1H), 4.97 – 4.78 (m, 2H), 4.29
– 4.23 (m, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.77 (q, J = 9.4 Hz, 1H), 2.36 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δC
178.7, 163.6, 163.5, 153.5, 144.6, 136.3, 128.7, 127.2, 122.8, 120.0, 109.9, 86.8, 81.6, 69.5, 59.8, 45.1, 20.8, 14.5. HRMS (ESI+): calcd for
C18H17ClNO5 [M+H]+ 362.0795, found 362.0801.
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Ethyl 9ꢀethoxyꢀ10ꢀmethylꢀ6ꢀoxoꢀ1,2,6,11aꢀtetrahydrochromeno[3,2ꢀe]oxazolo[3,2ꢀa]pyridineꢀ4ꢀcarboxylate (3h). Bright yellow
amorphous solid (column chromatography), Rf = 0.37, eluent (ethyl acetate / dichloromethane 1:1), mp = 193ꢀ194 °C, 100 mg scale
reaction (in 3 mL of CH2Cl2) for 1 h, 41 mg were isolated, 41 % yield. Product sensitive to CDCl3 acidity. IR (νmax / cmꢀ1): 1653, 1611,
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1518, 1497, 1267. H NMR (300 MHz, CDCl3): δH 7.90 (s, 1H), 7.85 (d, J = 8.8 Hz, 1H), 6.65 (d, J = 8.8 Hz, 1H), 6.54 (s, 1H), 4.98 –
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4.81 (m, 2H), 4.32 (td, J = 9.3, 6.2 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 4.13 (q, J = 7.0 Hz, 2H), 3.82 (q, J = 9.3 Hz, 1H), 2.10 (s, 3H), 1.46
(t, J = 7.0 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δC 179.9, 163.8, 163.2, 162.8, 154.3, 134.7, 126.4, 117.5, 114.0,
111.0, 106.1, 86.7, 81.2, 69.3, 64.1, 59.7, 45.0, 14.8, 14.5, 8.1. HRMS (ESI+): calcd for C20H22NO6 [M+H]+ 372.1447, found 372.1453.
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Ethyl 6ꢀoxoꢀ1,2,6,13aꢀtetrahydrobenzo[7,8]chromeno[3,2ꢀe]oxazolo[3,2ꢀa]pyridineꢀ4ꢀcarboxylate (3i). Bright yellow amorphous solid
(column chromatography), Rf = 0.48, eluent (ethyl acetate / dichloromethane 1:1), mp = 128ꢀ129 °C, 100 mg scale reaction (in 3 mL of
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CH2Cl2) for 1 h, 44 mg were isolated, 45 % yield. Product sensitive to CDCl3 acidity. IR (νmax / cmꢀ1): 1652, 1617, 1489, 1463, 1239. H
NMR (300 MHz, CDCl3): δH 8.21 (d, J = 8.3 Hz, 1H), 7.98 (d, J = 8.7 Hz, 1H), 7.98 (s, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.66 – 7.60 (m, 1H),
7.57 – 7.50 (m, 2H), 6.76 (s, 1H), 5.03 – 4.90 (m, 2H), 4.55 – 4.43 (m, 1H), 4.24 (q, J = 7.1 Hz, 2H), 3.91 (q, J = 9.4 Hz, 1H), 1.32 (t, J =
7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δC 180.0, 163.7, 163.3, 152.7, 137.5, 129.3, 128.1, 126.2, 124.7, 122.8, 122.6, 122.2, 118.6,
110.3, 87.6, 81.6, 76.8, 69.5, 59.9, 45.2, 14.5. HRMS (ESI+): calcd for C21H18NO5 [M+H]+ 364.1185, found 364.1188.
Ethyl 6ꢀoxoꢀ1,2,6,13aꢀtetrahydrobenzo[5,6]chromeno[3,2ꢀe]oxazolo[3,2ꢀa]pyridineꢀ4ꢀcarboxylate (3j). Bright yellow amorphous solid
(column chromatography), Rf = 0.38, eluent (ethyl acetate / dichloromethane 1:1), mp = 91ꢀ92 °C, 100 mg scale reaction (in 3 mL of
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CH2Cl2) for 1 h, 70 mg were isolated, 71 % yield. Product sensitive to CDCl3 acidity. IR (νmax / cmꢀ1): 1657, 1616, 1486, 1463, 1279. H
NMR (300 MHz, CDCl3): δH 9.39 (dd, J = 8.7, 1.0 Hz, 1H), 7.97 (s, 1H), 7.94 (d, J = 9.0 Hz, 1H), 7.77 (dd, J = 8.1, 1.6 Hz, 1H), 7.65
(ddd, J = 8.6, 6.9, 1.5 Hz, 1H), 7.45 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 7.06 (d, J = 8.9 Hz, 1H), 6.51 (s, 1H), 4.98 – 4.89 (m, 1H), 4.84 (q, J =
9.0, 8.4 Hz, 1H), 4.34 – 4.27 (m, 1H), 4.22 (q, J = 7.1 Hz, 2H), 3.78 (q, J = 9.4 Hz, 1H), 1.32 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz,
CDCl3): δC 180.5, 163.8, 163.2, 156.1, 137.1, 131.8, 130.0, 129.2, 128.3, 126.6, 125.1, 118.3, 116.2, 111.7, 86.4, 81.4, 76.7, 69.5, 59.8,
45.0, 14.5. HRMS (ESI+): calcd for C21H18NO5 [M+H]+ 364.1185, found 364.1192.
Ethyl 6ꢀoxoꢀ2,3,6,11aꢀtetrahydroꢀ1Hꢀchromeno[3,2ꢀe]imidazo[1,2ꢀa]pyridineꢀ4ꢀcarboxylate (3k). Bright yellow amorphous solid
(column chromatography), Rf = 0.16, eluent (ethyl acetate / dichloromethane 1:1), mp = 183ꢀ184 °C, 100 mg scale reaction (in 3 mL of
CH2Cl2) for 1 h, 78 mg were isolated, 67% yield. Product sensitive to CDCl3 acidity. IR (νmax / cmꢀ1): 1648, 1607, 1558, 1501, 1478, 1462,
1360. 1H NMR (300 MHz, CDCl3): δH 7.98 (dd, J = 7.8, 1.8 Hz, 1H), 7.95 (s, 1H), 7.86 (bs, 1H), 7.45 (ddd, J = 8.6, 7.2, 1.8 Hz, 1H), 7.08
(td, J = 7.6, 1.1 Hz, 1H), 6.94 (dd, J = 8.2, 1.0 Hz, 1H), 6.31 (s, 1H), 4.30 – 4.22 (m, 1H), 4.18 (q, J = 7.1 Hz, 2H), 3.91 (t, J = 8.5 Hz, 2H),
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3.75 – 3.57 (m, 1H), 1.30 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δC 179.7, 166.8, 159.0, 155.7, 135.2, 134.8, 127.5, 124.3, 122.2,
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chromatography), Rf = 0.25, eluent (ethyl acetate / dichloromethane 1:1), mp = 219ꢀ221 °C, 100 mg scale reaction (in 3 mL of CH2Cl2) for
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NMR (300 MHz, CDCl3): δH 9.42 (s, 1H), 7.96 (dd, J = 7.8, 1.8 Hz, 1H), 7.76 (s, 1H), 7.56 – 7.39 (m, 6H), 7.10 (td, J = 7.5, 1.1 Hz, 1H),
6.98 (dd, J = 8.3, 1.0 Hz, 1H), 6.32 (s, 1H), 4.32 (td, J = 9.6, 6.5 Hz, 1H), 4.12 – 3.89 (m, 2H), 3.85 – 3.56 (m, 1H). 13C NMR (75 MHz,
CDCl3): δC 191.4, 179.9, 160.2, 155.9, 139.5, 136.7, 135.1, 130.3, 128.4 (x2), 127.9 (x2), 127.6, 124.1, 122.5, 117.7, 109.2, 91.6, 85.4,
45.9, 43.1. HRMS (ESI+): calcd for C21H17N2O3 [M+H]+ 345.1239, found 345.1240.
Phenyl 6ꢀoxoꢀ1,2,6,11aꢀtetrahydrochromeno[3,2ꢀe]oxazolo[3,2ꢀa]pyridineꢀ4ꢀcarboxylate (3m). Bright yellow amorphous solid (column
chromatography), Rf = 0.44, eluent (ethyl acetate / dichloromethane 1:1), mp = 123ꢀ124 °C, 100 mg scale reaction (in 3 mL of CH2Cl2) for
40 min, 71 mg were isolated, 81% yield. Product sensitive to CDCl3 acidity. IR (νmax / cmꢀ1): 1661, 1613, 1522, 1500, 1469, 1284, 1266.
1H NMR (300 MHz, CDCl3): δH 8.06 (s, 1H), 7.98 (dd, J = 7.8, 1.8 Hz, 1H), 7.52 (ddd, J = 8.6, 7.5, 1.8 Hz, 1H), 7.40 – 7.33 (m, 2H), 7.20
(t, J = 7.4 Hz, 1H), 7.15 – 7.08 (m, 3H), 6.98 (d, J = 8.2 Hz, 1H), 6.57 (s, 1H), 4.90 (td, J = 9.1, 5.3 Hz, 1H), 4.81 (q, J = 9.1 Hz, 1H), 4.29
(td, J = 9.4, 6.2 Hz, 1H), 3.79 (q, J = 9.1 Hz, 1H). 13C NMR (75 MHz, CDCl3): δC 179.9, 164.1, 162.1, 155.4, 150.9, 135.8, 135.5, 129.2
(x2), 127.6, 125.3, 123.8, 122.7, 122.0 (x2), 117.9, 111.2, 86.4, 80.6, 69.7, 45.2. HRMS (ESI+): calcd for C21H16NO5 [M+H]+ 362.1028,
found 362.1033.
(1S, 11aS)ꢀEthyl 1ꢀmethylꢀ6ꢀoxoꢀ1,2,6,11aꢀtetrahydrochromeno[3,2ꢀe]oxazolo[3,2ꢀa]pyridineꢀ4ꢀcarboxylate (3n). Bright yellow
amorphous solid (column chromatography), Rf = 0.40, eluent (ethyl acetate / dichloromethane 1:1), mp = 71ꢀ72 °C, 100 mg scale reaction
(in 3 mL of CH2Cl2) for 1 h, 87 mg were isolated, 84% yield. Product sensitive to CDCl3 acidity. IR (νmax / cmꢀ1): 1658, 1610, 1509, 1460,
1280. Major diastereoisomer: 1H NMR (300 MHz, CDCl3): δH 7.97 (dd, J = 7.8, 1.8 Hz, 1H), 7.93 (s, 1H), 7.50 (ddd, J = 8.4, 7.2, 1.8 Hz,
1H), 7.10 (ddd, J = 8.1, 7.3, 1.1 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H), 6.65 (s, 1H), 4.91 (t, J = 8.5 Hz, 1H), 4.66 – 4.54 (m, 1H), 4.48 (dd, J =
8.8, 5.8 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 1.47 (d, J = 6.3 Hz, 3H), 1.30 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δC 180.3, 163.8,
162.9, 155.2, 135.8, 135.6, 127.6, 123.9, 122.6, 117.8, 110.5, 83.4, 81.5, 76.0, 59.8, 51.4, 15.2, 14.5. HRMS (ESI+): calcd for C18H18NO5
[M+H]+ 328.1185, found 328.1190.
(1R)ꢀEthyl 1ꢀethylꢀ6ꢀoxoꢀ1,2,6,11aꢀtetrahydrochromeno[3,2ꢀe]oxazolo[3,2ꢀa]pyridineꢀ4ꢀcarboxylate (3o). Bright yellow amorphous solid
(column chromatography), Rf = 0.49, eluent (ethyl acetate / dichloromethane 1:1), mp = 61ꢀ62 °C, 100 mg scale reaction (in 3 mL of
CH2Cl2) for 1 h, 83 mg were isolated, 77% yield. Product sensitive to CDCl3 acidity. IR (νmax / cmꢀ1): 1659, 1613, 1508, 1458, 1282. Major
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diastereoisomer: 1H NMR (300 MHz, CDCl3): δH 7.97 (dd, J = 7.8, 1.8 Hz, 1H), 7.94 (s, 1H), 7.49 (ddd, J = 8.7, 7.2, 1.8 Hz, 1H), 7.13 –
7.06 (m, 1H), 6.94 (d, J = 8.0 Hz, 1H), 6.62 (s, 1H), 4.85 (t, J = 8.9 Hz, 1H), 4.60 (dd, J = 9.0, 5.4 Hz, 1H), 4.56 – 4.39 (m, 1H), 4.21 (q, J
= 7.1 Hz, 2H), 2.10 – 1.87 (m, 1H), 1.80 – 1.68 (m, 1H), 1.30 (t, J = 7.1 Hz, 3H), 1.00 (t, J = 7.5 Hz, 3H). 13C NMR (75 MHz, CDCl3): δC
180.4, 163.8, 163.3, 155.2, 135.8, 135.6, 127.7, 124.0, 122.6, 117.8, 110.4, 83.7, 81.3, 73.6, 59.8, 56.1, 21.3, 14.5, 8.0. HRMS (ESI+):
calcd for C19H20NO5 [M+H]+ 342.1375, found 342.1348.
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(1S)ꢀEthyl 1ꢀisopropylꢀ6ꢀoxoꢀ1,2,6,11aꢀtetrahydrochromeno[3,2ꢀe]oxazolo[3,2ꢀa]pyridineꢀ4ꢀcarboxylate (3p). Bright yellow amorphous
solid (column chromatography), Rf = 0.52, eluent (ethyl acetate / dichloromethane 1:1), mp = 65ꢀ66 °C, 100 mg scale reaction (in 3 mL of
CH2Cl2) for 1 h, 75 mg were isolated, 67% yield. Product sensitive to CDCl3 acidity. IR (νmax / cmꢀ1): 2963, 1660, 1614, 1509, 1459, 1284.
Major diastereoisomer: 1H NMR (300 MHz, CDCl3): δH 8.01 (dd, J = 7.8, 1.8 Hz, 1H), 7.97 (s, 1H), 7.55 – 7.47 (m, 1H), 7.16 – 7.09 (m,
1H), 6.97 (d, J = 8.3 Hz, 1H), 6.63 (s, 1H), 4.80 – 4.62 (m, 2H), 4.56 – 4.48 (m, 1H), 4.23 (q, J = 7.1 Hz, 2H), 2.42 (hept, J = 6.9, 3.3 Hz,
1H), 1.32 (t, J = 7.1 Hz, 3H), 1.06 (d, J = 7.0 Hz, 3H), 0.92 (d, J = 6.9 Hz, 3H). 13C NMR (75 MHz, CDCl3): δC 180.4, 163.8, 163.4, 155.3,
135.9, 135.6, 127.8, 124.0, 122.6, 117.8, 110.4, 83.9, 81.1, 70.0, 59.8, 59.7, 24.7, 18.0, 14.5, 14.2. HRMS (ESI+): calcd for C20H22NO5
[M+H]+ 356.1498, found 356.1507.
(1R)ꢀEthyl 1ꢀ((methylthio)methyl)ꢀ6ꢀoxoꢀ1,2,6,11aꢀtetrahydrochromeno[3,2ꢀe]oxazolo[3,2ꢀa]pyridineꢀ4ꢀcarboxylate (3q). Bright yellow
amorphous solid (column chromatography), Rf = 0.51, eluent (ethyl acetate / dichloromethane 1:1), mp = 68ꢀ69 °C, 100 mg scale reaction
(in 3 mL of CH2Cl2) for 1 h, 81 mg were isolated, 69% yield. Product sensitive to CDCl3 acidity. IR (νmax / cmꢀ1): 2977, 1658, 1612, 1509,
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1460, 1282. Major diastereoisomer: H NMR (300 MHz, CDCl3): δH 8.01 (dd, J = 7.9, 1.8 Hz, 1H), 7.95 (s, 1H), 7.52 (ddd, J = 8.6, 7.3,
1.8 Hz, 1H), 7.17 – 7.10 (m, 1H), 6.96 (d, J = 8.3 Hz, 1H), 6.72 (s, 1H), 5.03 – 4.87 (m, 1H), 4.82 (dd, J = 9.3, 4.9 Hz, 1H), 4.77 – 4.66 (m,
1H), 4.24 (q, J = 7.1 Hz, 2H), 3.02 (dd, J = 13.5, 3.4 Hz, 1H), 2.81 (dd, J = 13.5, 8.1 Hz, 1H), 2.21 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H). 13C
NMR (75 MHz, CDCl3): δC 180.2, 163.7, 163.1, 155.1, 135.8, 135.7, 127.8, 124.0, 122.7, 117.7, 110.7, 84.0, 81.6, 74.1, 59.9, 54.5, 33.2,
16.1, 14.5. HRMS (ESI+): calcd for C19H20NO5S [M+H]+ 374.1057, found 374.1062.
(1S,11aS)ꢀethyl 1ꢀbenzylꢀ6ꢀoxoꢀ1,2,6,11aꢀtetrahydrochromeno[3,2ꢀe]oxazolo[3,2ꢀa]pyridineꢀ4ꢀcarboxylate (3r). Bright yellow
amorphous solid (column chromatography), Rf = 0.55, eluent (ethyl acetate / dichloromethane 1:1), mp = 83ꢀ84 °C, 100 mg scale reaction
(in 3 mL of CH2Cl2) for 1 h, 97 mg were isolated, 75% yield. Product sensitive to CDCl3 acidity. IR (νmax / cmꢀ1): 1657, 1617, 1488, 1460,
1279. 1H NMR (300 MHz, CDCl3): δH 7.96 (s, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.48 – 7.40 (m, 4H), 7.38 – 7.32 (m, 2H), 7.05 (t, J = 7.5 Hz,
1H), 6.91 (d, J = 8.5 Hz, 1H), 6.15 (s, 1H), 5.44 (dd, J = 9.1, 5.4 Hz, 1H), 5.17 (t, J = 9.2 Hz, 1H), 4.82 (dd, J = 9.3, 5.4 Hz, 1H), 4.26 (q, J
= 7.1 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3): δC 180.4, 163.9, 162.9, 155.3, 135.6, 135.4, 134.2, 130.0, 129.8 (x2),
127.6, 127.5 (x2), 123.9, 122.5, 117.8, 111.2, 83.9, 81.4, 76.9, 59.9, 59.6, 14.6. HRMS (ESI+): calcd for C23H20NO5 [M+H]+ 390.1341,
found 390.1346.
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(1S)ꢀEthyl 6ꢀoxoꢀ1ꢀphenylꢀ1,2,6,11aꢀtetrahydrochromeno[3,2ꢀe]oxazolo[3,2ꢀa]pyridineꢀ4ꢀcarboxylate (3s). Bright yellow amorphous
solid (column chromatography), Rf = 0.57, eluent (ethyl acetate / dichloromethane 1:1), mp = 65ꢀ66 °C, 100 mg scale reaction (in 3 mL of
CH2Cl2) for 1 h, 99 mg were isolated, 77% yield. Product sensitive to CDCl3 acidity. IR (νmax / cmꢀ1): 1661, 1615, 1509, 1460, 1279. Major
diastereoisomer: 1H NMR (300 MHz, CDCl3): δH 8.02 (dd, J = 7.8, 1.7 Hz, 1H), 7.97 (s, 1H), 7.58 – 7.49 (m, 1H), 7.41 – 7.30 (m, 3H),
7.23 (d, J = 6.7 Hz, 2H), 7.14 (t, J = 7.5 Hz, 1H), 7.00 (d, J = 8.2 Hz, 1H), 6.76 (s, 1H), 4.82 – 4.73 (m, 1H), 4.73 – 4.60 (m, 2H), 4.23 (q,
J = 7.1 Hz, 2H), 3.38 (dd, J = 13.7, 4.1 Hz, 1H), 2.79 (dd, J = 13.6, 9.0 Hz, 1H), 1.31 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δC
180.3, 163.7, 163.1, 155.2, 135.8, 135.7, 134.3, 129.3, 129.2, 129.1, 129.0, 127.8, 127.7, 124.0, 122.7, 117.8, 110.7, 83.9, 81.6, 73.7, 59.8,
56.3, 35.1, 14.5. HRMS (ESI+): calcd for C24H22NO5 [M+H]+ 404.1498, found 404.1503.
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Ethyl 1,1ꢀdimethylꢀ6ꢀoxoꢀ1,2,6,11aꢀtetrahydrochromeno[3,2ꢀe]oxazolo[3,2ꢀa]pyridineꢀ4ꢀcarboxylate (3t). Bright yellow amorphous solid
(column chromatography), Rf = 0.47, eluent (ethyl acetate / dichloromethane 1:1), mp = 188ꢀ189 °C, 100 mg scale reaction (in 3 mL of
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CH2Cl2) for 1 h, 56 mg were isolated, 52% yield. Product sensitive to CDCl3 acidity. IR (νmax / cmꢀ1): 1653, 1607, 1488, 1459, 1278. H
NMR (300 MHz, CDCl3): δH 7.98 (dd, J = 7.8, 1.7 Hz, 1H), 7.91 (s, 1H), 7.50 (ddd, J = 8.7, 7.3, 1.8 Hz, 1H), 7.16 – 7.07 (m, 1H), 6.93 (d,
J = 8.2 Hz, 1H), 6.71 (s, 1H), 4.54 (d, J = 8.7 Hz, 1H), 4.45 (d, J = 8.7 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H), 1.73 (s, 3H), 1.52 (s, 3H), 1.31 (t,
J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δC 180.5, 163.9, 163.5, 155.5, 135.6, 127.7, 124.1, 122.6, 117.9, 111.3, 84.5, 81.8, 81.1 (x2),
61.8, 59.8, 27.1, 22.3, 14.5. HRMS (ESI+): calcd for C19H20NO5 [M+H]+ 342.1341, found 342.1348.
(2S)ꢀEthyl 2ꢀmethylꢀ6ꢀoxoꢀ1,2,6,11aꢀtetrahydrochromeno[3,2ꢀe]oxazolo[3,2ꢀa]pyridineꢀ4ꢀcarboxylate (3v). Bright yellow amorphous
solid (column chromatography), Rf = 0.52, eluent (ethyl acetate / dichloromethane 1:1), mp = 78ꢀ79 °C, 100 mg scale reaction (in 3 mL of
CH2Cl2) for 1 h, 36 mg were isolated, 35% yield. Product sensitive to CDCl3 acidity. IR (νmax / cmꢀ1): 1658, 1609, 1516, 1489, 1460, 1279.
Diastereoisomer 1: 1H NMR (300 MHz, CDCl3): δH 7.97 (dd, J = 7.8, 1.8 Hz, 1H), 7.94 (s, 1H), 7.49 (ddd, J = 8.6, 7.3, 1.8 Hz, 1H), 7.10
(ddd, J = 8.0, 7.3, 1.1 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H), 6.53 (s, 1H), 5.35 – 5.16 (m, 1H), 4.37 (t, J = 8.9 Hz, 1H), 4.20 (q, J = 7.1 Hz,
2H), 3.87 (d, J = 8.5 Hz, 1H), 1.69 (t, J = 6.5 Hz, 3H), 1.29 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δC 179.9, 163.7, 163.3, 155.3,
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136.2, 135.6, 127.6, 123.9, 122.6, 117.8, 110.4, 86.7, 81.4, 79.4, 59.7, 51.7, 20.0, 14.5. Diastereoisomer 2: H NMR (300 MHz, CDCl3):
δH 7.97 (dd, J = 7.8, 1.8 Hz, 1H), 7.95 (s, 1H), 7.49 (ddd, J = 8.6, 7.3, 1.8 Hz, 1H), 7.10 (ddd, J = 8.0, 7.3, 1.1 Hz, 1H), 6.94 (d, J = 8.2 Hz,
1H), 6.53 (s, 1H), 5.35 – 5.16 (m, 1H), 4.20 (q, J = 7.1 Hz, 2H), 3.87 (d, J = 8.5 Hz, 1H), 3.36 (t, J = 9.4 Hz, 1H), 1.69 (t, J = 6.5 Hz, 3H),
1.29 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δC 180.0, 163.7, 163.1, 155.3, 136.1, 135.6, 127.6, 123.9, 122.6, 117.8, 110.2, 86.4,
81.3, 79.1, 59.7, 50.9, 20.5, 14.5. HRMS (ESI+): calcd for C18H18NO5 [M+H]+ 328.1185, found 328.1186.
IV. Synthetic pathways for the access of 3-dihydrooxazolopyridin-2-one (8).
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Ethyl 1ꢀbenzylꢀ5ꢀ(2ꢀhydroxybenzoyl)ꢀ2ꢀoxoꢀ1,2ꢀdihydropyridineꢀ3ꢀcarboxylate (5). Synthetized according to general procedure 2 using
1,05 eq. of benzylamine and 1.0 eq. of 1a. Pale orange powder (precipitation in cold diethyl ether), Rf = 0.36, eluent (ethyl acetate /
cyclohexane 1:1), mp = 120ꢀ122 °C, 0.50 g scale reaction (in 5 mL of CH2Cl2) for 1h, 0.57 g was isolated, 95% yield. IR (νmax / cmꢀ1):
3444, 1727, 1650, 1624, 1540, 1340, 1238. 1H NMR (300 MHz, CDCl3): δH 8.53 (d, J = 2.6 Hz, 1H), 8.15 (d, J = 2.7 Hz, 1H), 7.52 (ddd, J
= 8.5, 7.3, 1.6 Hz, 1H), 7.43 – 7.35 (m, 6H), 7.08 (d, J = 8.4 Hz, 1H), 6.90 – 6.83 (m, 1H), 5.25 (s, 2H), 4.40 (q, J = 7.1 Hz, 2H), 1.40 (t, J
= 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δC 194.3, 164.1, 162.6, 158.7, 146.2, 143.6, 136.4, 134.8, 131.4, 129.3 (x2), 128.9, 128.8 (x2),
120.4, 119.0, 118.9, 118.6, 115.9, 61.7, 53.3, 14.3. HRMS (ESI+) calcd for C22H20NO5 [M+H]+ 378.1341, found 378.1336.
1ꢀBenzylꢀ5ꢀ(2ꢀhydroxybenzoyl)ꢀ2ꢀoxoꢀ1,2ꢀdihydropyridineꢀ3ꢀcarboxylic acid (6). A solution of 5 (1.14 g, 3.02 mmol) in 6 mL of Ac2O/
HCl (37%) was heated to 90 °C. After complete consumption of starting material (2 h) the reaction media was allowed to cool at room
temperature. The formed precipitate was filtrated and washed with cyclohexane to yield pure compound 6 as a white powder. Rf = 0.36,
eluent (ethyl acetate / cyclohexane 1:1), mp = 201ꢀ203 °C, 1.01 g was isolated, 94% yield. IR (νmax / cmꢀ1): 3418, 2958, 1722, 1610, 1467,
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1439. H NMR (300 MHz, DMSOꢀd6) : δH 10.39 (s, 1H), 8.92 (d, J = 2.6 Hz, 1H), 8.50 (d, J = 2.6 Hz, 1H), 7.50 – 7.32 (m, 7H), 7.10 –
6.90 (m, 2H), 5.40 (s, 2H). 13C NMR (75 MHz, DMSO): δC 191.4, 164.8, 163.0, 156.3, 149.1, 144.8, 135.9, 133.9, 130.7, 129.2 (x2), 128.5
(x3), 124.8, 119.9, 118.9, 117.2, 117.1, 53.6. HRMS (ESI+) calcd for C20H16NO5 [M+H]+ 350.1028, found 350.1034.
1ꢀBenzylꢀ5ꢀ(2ꢀhydroxybenzoyl)ꢀ2ꢀoxoꢀ1,2ꢀdihydropyridineꢀ3ꢀcarbonitrile (7). Synthetized according to general procedure 2 using 1,05 eq.
of benzylamine and 1.0 eq. of 1k. White powder (column chromatography), Rf = 0.38, eluent (ethyl acetate / cyclohexane 1:1), mp = 89ꢀ91
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°C, 400 mg scale reaction (in 4 mL of EtOH) for 2h, 211 mg was isolated, 43% yield. IR (νmax / cmꢀ1): 3054, 2230, 1731, 1660, 1622,
1541, 1337, 1251. 1H NMR (300 MHz, CDCl3): δH 11.19 (s, 1H), 8.22 (d, J = 2.6 Hz, 1H), 8.18 (d, J = 2.6 Hz, 1H), 7.55 (ddd, J = 8.6, 7.2,
1.7 Hz, 1H), 7.46 – 7.37 (m, 5H), 7.36 – 7.31 (m, 1H), 7.08 (dd, J = 8.4, 1.1 Hz, 1H), 6.93 – 6.86 (m, 1H), 5.25 (s, 2H). 13C NMR (75
MHz, CDCl3): δC 193.1, 162.6, 158.9, 146.6, 146.5, 137.0, 133.9, 131.1, 129.5 (x2), 129.3, 128.9 (x2), 119.3, 119.1, 118.1, 116.6, 114.6,
105.3, 53.8. HRMS (ESI+) calcd for C20H15N2O3 [M+H]+ 331.1083, found 331.1106.
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1ꢀBenzylꢀ3ꢀ(4,5ꢀdihydrooxazolꢀ2ꢀyl)ꢀ5ꢀ(2ꢀhydroxybenzoyl)pyridinꢀ2(1H)ꢀone (8). Pathway 1: To a solution of 3a (120 mg, 0.38 mmol) in
dichloromethane (3 mL) was added benzylamine (46 ꢁL, 0.42 mmol) and the reaction mixture was heated to reflux. After complete
consumption of starting material (40h) the reaction was allowed to cool at room temperature and was concentrated under vacuum.
Selective precipitation in cold diethyl ether afforded pure compound 8 as a white powder. Rf = 0.14, eluent (ethyl acetate /
dichloromethane 9:1), mp = 175ꢀ177 °C, 102 mg were isolated, 71% yield. Pathway 2: To a solution of 5 (300 mg, 0.84 mmol),
ethanolamine (50 ꢁL, 0.84 mmol), Et3N (0.35 mL, 2.52 mmol) and CCl4 (0.33 mL, 3.36 mmol) in MeCN/pyridine (2 mL, 1: 1) was added
dropwise a solution of PPh3 (511 mg, 2.52 mmol) in MeCN/pyridine (2 mL, 1: 1). The mixture was stirred at room temperature for 18h and
the latter was concentrated under reduced pressure. The residue was then dissolved in diethyl ether and basified to pH 8ꢀ9 with
concentrated aqueous NH4OH solution. The organic layer was separated and the organic phase was extracted with diethyl ether (three
times). The combined extracts were dried (MgSO4) and evaporated. Purification by column chromatography afforded pure compound 8 as
a white powder. Rf = 0.14, eluent (ethyl acetate / dichloromethane 9:1), mp = 175ꢀ177 °C, 42 mg were isolated, 23% yield. IR (νmax / cmꢀ1):
1673, 1632, 1541, 1291, 1247. 1H NMR (300 MHz, CDCl3): δH 11.37 (s, 1H), 8.41 (d, J = 2.7 Hz, 1H), 8.12 (d, J = 2.7 Hz, 1H), 7.49 (ddd,
J = 8.6, 7.2, 1.7 Hz, 1H), 7.46 – 7.34 (m, 6H), 7.05 (dd, J = 8.4, 1.1 Hz, 1H), 6.86 (ddd, J = 8.2, 7.2, 1.2 Hz, 1H), 5.24 (s, 2H), 4.36 (td, J =
9.4, 1.3 Hz, 2H), 4.13 (td, J = 9.4, 1.2 Hz, 2H). 13C NMR (75 MHz, CDCl3): δC 194.5, 162.5, 160.8, 158.7, 144.8, 141.4, 136.4, 135.0,
131.5, 129.2 (x2), 128.9 (x2), 128.8, 119.0, 118.8, 118.6, 117.7, 116.1, 67.0, 55.8, 53.5. HRMS (ESI+) calcd for C22H19N2O4 [M+H]+
375.1345, found 375.1347.
ASSOCIATED CONTENT
Supporting Information.
The Supporting Information is available free of charge via the internet at http://pubs.acs.org.
ꢀSingle crystal Xꢀray diffraction data for compound 3l CCDC 1477526 (CIF)
ꢀExperimental procedures, products characterization data including 1H and 13C NMR spectra and Quantum chemical calculation details.
AUTHOR INFORMATION
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Corresponding Author
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* lawsona@univꢀlehavre.fr
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Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGMENT
Authors are grateful to the "Ministère de l’Enseignement Supérieur et de la Recherche" and "Région Haute Normandie" for the Graduate
Fellowship awarded to T. L. The authors are grateful to CS of the University of Le Havre for research facilities.
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