Modular access to vicinally functionalized allylic (thio)morpholinonates and piperidinonates by substrate-controlled annulation of 1,3-azadienes with hexacyclic anhydrides

Article abstract of DOI:10.1039/c6ob01526c

A modular substrate-controlled hexannulation of inherently promiscuous 1,3-azadienes with hexacyclic anhydrides, which affords versatile vicinally functionalized allylic lactams, in high yields, regio- and stereoselectivities is described.

Full text of DOI:10.1039/c6ob01526c

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PAPER
Modular access to vicinally functionalized allylic
(thio)morpholinonates and piperidinonates by
substrate-controlled annulation of 1,3-azadienes
with hexacyclic anhydrides†‡
Cite this: DOI: 10.1039/c6ob01526c
Hannah Braunstein, Spencer Langevin, Monique Khim, Jonathan Adamson,
Katie Hovenkotter, Lindsey Kotlarz, Brandon Mansker and Timothy K. Beng*
Received 18th July 2016,
Accepted 30th August 2016
A modular substrate-controlled hexannulation of inherently promiscuous 1,3-azadienes with hexacyclic
anhydrides, which affords versatile vicinally functionalized allylic lactams, in high yields, regio- and stereo-
selectivities is described.
DOI: 10.1039/c6ob01526c
www.rsc.org/obc
nephrine reuptake inhibitor3) as well as their architectural
complexity endear them to the medicinal and synthesis com-
Introduction
Functionalized piperidines, morpholines and thiomorpholines munities, thus, inspiring the development of increasingly
(see highlighted rings in Fig. 1) constitute the core of several more efficient and modular strategies for their construction,
alkaloid natural products, natural or unnatural amino acids, functionalization, and evaluation of their structure–activity
ligands and pharmaceuticals.1
relationships. Toward this end, several elegant systematic
Fittingly, the biological relevance of these N-, N,O-, and N,S- scaffolding strategies have emerged including those employed
heterocycles (e.g., pandoline is an aspidosperma alkaloid with by Bode4,5 (using SnAP reagents), Bosch6 (using bicyclic
anticancer activity2 and viloxazine is a selective norepi- lactams), Comins7–9 and Georg10–15 (using dihydropyridones),
Liebeskind16 (using organometallic scaffolds) Aggarwal17,18
(using α-phenylvinylsulfonium salts), Tiecco19 (using vinyl
selenones), Xia20 (using aziridines), Carreira21,22 (using spiro-
cyclic 3-oxetanones), Wolfe23 (using Pd-catalyzed intra-
molecular carboamination), MacMillan24,25 (using photoredox
catalysis) and Schafer26,27 (using catalytic alkylamination/
reduction).
Circumscribed in these classes of azaheterocycles is a
subset, which bears vicinal stereocenters. However, controlling
the formation of (labile) vicinal stereocenters on the skeleton
of a piperidine or (thio)morpholine poses a considerable chal-
lenge, in part because sequential substitution of a 2- or 3-sub-
stituted cyclic amine derivative is only marginally tolerated in
most of the existing C-2 or C-3 functionalization strategies.
Along these lines, we previously disclosed that the addition of
alkyllithium nucleophiles to the β-position of α-arylated
dehydropiperidines followed by interception of the intermedi-
Fig. 1 Examples of bioactive azaheterocycles.
ate tertiary organolithium with electrophiles furnishes poly-
substituted benzylic piperidine derivatives in excellent
Department of Chemistry, Central Washington University, Ellensburg, WA 98926,
diastereoselectivities (Fig. 2A).28,29 Disappointingly, from the
USA. E-mail: TimothyB@cwu.edu
†Dedication: T. K. B. dedicates this paper to the memory of his former organic
standpoint of generality, dehydromorpholines tended to
undergo undesirable ring opening. Perhaps more dishearten-
chemistry instructor and department chair at the University of Buea, Professor
Samuel Fanso Free. His encouragement and selfless mentorship during those
ing to date is our inability to extend the methodology to
incipient stages will forever be appreciated.
α-alkenyl enecarbamates as we are caught at the crossroads of
‡Electronic supplementary information (ESI) available: Experimental procedures
alkene vs. enecarbamate carbolithiation.
and spectroscopic data. See DOI: 10.1039/c6ob01526c
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Results and discussion
We initiated studies on the construction of vicinally function-
alized allylic lactamoyl acids/esters by assembling a diverse
range of 1,3-azadienes (Fig. 3, see 4a–x).
Foremost among our objectives was to access allylic mor-
pholinonates. Gleaning from recent insightful reports from
the laboratories of Burdzhiev41 and Krasavin42 on the use of
digylcolic anhydride (3b) in a Castagnoli–Cushman reaction
with unconjugated imines, model azadiene 4a and 3b were
engaged in a thermally induced [4 + 2] cycloaddition, using
toluene as the solvent. Pleasingly, after stirring for 12 h at
1
90 °C, GC-MS and H NMR analyses of the methylated crude
mixture revealed the presence of
a single cycloadduct
(Scheme 1, see 5a2). The exclusive and stereodefined for-
mation of E-configured styrene derivative 5a2 indicates a
preference for a Castagnoli–Cushman-type reaction over a
Tamura-like cycloaddition; the latter being the preferred
pathway when homophthalic anhydride was employed (see 10,
Fig. 2C).31 Encouraged by this outcome, and after establishing
that toluene out-performs other solvents (e.g., EtOAc, 2-MeTHF
and 1,4-dioxane), we next moved to evaluate the scope of the
transformation with respect to the N-substituent and the
alkenyl motif. In the event, we have found that electronically
diverse imino dienes are well tolerated. For example, allylic
lactam 5c2, which bears an electron-donating p-methoxy-
Fig. 2 (A) Vicinal functionalization of α-arylated dehydropiperidines by
carbolithation-trapping28,29 (B) proposed plan for accessing vicinally
functionalized allylic morpholinones, thiomorpholinones and piperidi-
nones (C) annulation of homophthalic anhydride with 1,3-azadienes.30,31
Desiring a modular approach to vicinally functionalized and
potentially bioactive N-heterocycles bearing an alkenyl motif at
the α-amino position, and seeking to side-step the aforemen-
tioned limitations, we became interested in investigating the
fate of hexacyclic anhydrides of type 3 in formal [4 + 2] cyclo-
additions with 1,3-azadienes such as 4 (Fig. 2B, see 5–7). We
were fully aware of Haimova’s previous findings that while
homophthalic anhydride (3f) reacts efficiently with simple aro-
matic imines such as 8 to afford azaheterocyclic Castagnoli-
type cycloadducts of type 9,30,31 its reaction with
α,β-unsaturated imines such as 4 proceeds through a plethora
of reaction pathways, including Tamura-like32–34 (see carbocyc-
lic enaminone 10, Fig. 2C), Castagnoli-type and Perkin conden-
sation-type35 pathways. Indeed, the promiscuous nature of 4
has understandably led researchers to the somewhat hasty con-
clusion that its reaction with cyclic anhydrides is ‘synthetically
unattractive’.35 We therefore stoically embraced the challenge
and surmised that the decreased α-CH acidity of anhydrides
3a–e would serve to provide an ideal balance of reactivity and
selectivity. We reasoned that the appendage of an alkenyl
motif on the skeleton of a nitrogen heterocycle would pave the
way for harnessing several reactivity modes, including
hydrogenation,36 hydroarylation,37 oxoamination,38 meta-
thesis,39 or trifluoromethylation.40 It was however recognized
that successful implementation of the planned strategy would
hinge on our ability to (i) achieve substrate-controlled reactivity,
(ii) mitigate E/Z isomerization or double-bond migration, and
(iii) achieve site-selective functionalization of 5–7. Herein,
detailed efforts toward the elicitation of our ideals are
described.
Fig. 3 Examples of hexacyclic anhydrides (i.e., 3) and 1,3-azadienes
(i.e., 4) employed in these studies.
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merits of our strategy given that stereodefined approaches to tri-
substituted styrene derivatives are at a premium.44–47
Knowing that the nature of the N-substituent present on a
morpholine ring can have a dramatic effect on its biological
activity, the amenability of 1,3-azadienes bearing nonaryl
N-substituents to substrate-controlled hexannulation with 3b,
was next explored. Encouragingly, cycloalkyl-, allyl-, benzyl-,
isopropyl- and tert-butyl-containing imino dienes are all com-
petent reactive partners (see 5h2–r2).
The relative configuration of the products depicted in
Scheme 1 was assigned using NOE and coupling constant ana-
lyses, and also by analogy to those of the unambiguously estab-
lished benzylic counterparts.42
Our studies have revealed that thiodiglycolic anhydride (3c),
whose α-CH acidity is close to that of homophthalic anhydride
(3f) displays unproductive reactivity with inherently more
reactive N-alkyl azadienes, even at 60 °C (see 6a1–6b1′).
Encouragingly, 3c undergoes satisfactory annulation with
N-aryl azadienes to afford the allylic thiomorpholinonic acids/
esters depicted in Scheme 2 (see 6c1–6g2).
The aza-hexannulation strategy described herein is not
limited to hexacyclic anhydrides bearing an endocyclic hetero-
atom. This is supported by observations that inert anhydrides
3a/d react satisfactorily with α,β-unsaturated imines, at
elevated temperatures, to afford the corresponding piperidino-
nates depicted in Scheme 3 (see 7a–r). The amenability of 3d
to this hexannulation protocol has set the stage for the instal-
lation of α-amido quaternary centers. In contrast with 3d,
anhydride 3e fails to furnish the desired cycloadducts, even at
150 °C, presumably due to steric congestion.
Not all α,β-unsaturated imines that we have evaluated react
efficiently and stereoselectively with the hexacyclic anhydrides
employed in these studies. For instance, ortho-substituted
Scheme 1 Annulation of 1,3-azadienes with diglycolic anhydride.
phenyl (i.e., PMP) group is affordable in impeccable yield and
in excellent diastereoselectivity. This is a synthetically appeal-
ing result given that in addition to being readily removable
(making it a place-holder for other N-substituents),43 the PMP
group is amenable to further functionalization under several
reaction manifolds, including transition metal-catalyzed cross-
couplings of the aryl ether subunit. The amenability of elec-
tron-poor 1,3-azadienes of type 4e to this hexannulation proto-
col has set the stage for rapid installation of pharmaceutically
relevant motifs such as a trifluoromethylaryl group (see 5d2).
N-Aryl imino dienes derived from substituted cinnam-
aldehydes react stereoselectively with diglycolic anhydride (see
5e1 & 5f1). Importantly, internally substituted N-aryl-1,3-aza-
dienes seamlessly undergo productive hexannulation to afford
cycloadducts such as 5g1, without any complications arising
from E/Z isomerization. This result further highlights the Scheme 2 Annulation of 1,3-azadienes with thiodiglycolic anhydride.
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Scheme 4 Epoxidation of allylic lactamoyl esters.
Trisubstituted alkene 7n2 also undergoes effortless face-
selective oxa-cyclopropanation and gives rise to epoxide 11c,
which contains four contiguous stereocenters, one of which is
tetrasubstituted.
Catalytic hydrogenation of the alkenyl motif resident in
functionalized lactams such as 5 and 7 has paved the way for
α-arylethylation (Scheme 5, see 12a–c). This is noteworthy
since it is well established that imines derived from enolizable
aldehydes such as hydrocinnamaldehyde are incompetent
annulative partners for cyclic anhydrides such as 3, mainly
because the latter preferably serve as acylating agents.42
Scheme 5 Aryl ethylation of allylic lactams.
Scheme 3 Annulation of 1,3-azadienes with either glutaric anhydride
or 2,2-dimethylglutaric anhydride.
We have found that lactamoyl esters of types 5 and 7 are
amenable to substrate-controlled site-selective functionali-
zation with organolithium nucleophiles. For instance, tert-
butyl-bearing morpholinonate 5n2 reacts chemoselectively
N-aryl-azadienes such as 4w/x barely react with 3a/b (see 7s1, with excess methyllithium and phenyllithium to afford tertiary
details are in the ESI‡). Additionally, the importance of having morpholinols 13a and 13b, respectively (Scheme 6). Under
the styrenyl motif is highlighted by observations that aza- identical reaction conditions, indiscriminate attack of both the
dienes derived from trans-crotonaldehyde fail to furnish the ester and lactam motifs resident in the non tert-butyl-bearing
desired allylic lactams (see 7u1). In these cases, hydrolysis of morpholinonates depicted in Scheme 1 is observed. However,
the azadiene and concomitant nucleophilic attack of the anhy- at this temperature, inherently less reactive piperidinonates
dride by the ensuing amine are observed. Performing the reac- react with alkyllithiums exclusively at the ester terminus
tion in the presence of molecular sieves fails to negate the (see 13c–f).
hydrolysis.
The 2-azabicyclic framework constitutes the core and essen-
Desiring to broaden the synthetic utility of the aza-hexannu- tial structural elements of several pharmaceuticals, alkaloid
lation transformation described herein, we have shown that natural products, ligands and amino acids. Additionally, the
further elaboration of the cycloadducts to other synthetically motif offers an excellent platform for systematic scaffolding
important scaffolds is possible. For example, m-CPBA- given that it may be transformed to other bioactive
mediated epoxidation of allylic piperidinonate 7a2, and of N-heterocycles such as quinolones and indoles. We were there-
morpholinonate 5c2 furnishes epoxylactams 11a and 11b, fore elated to find that chemoselective addition of organo-
respectively (Scheme 4).
lithium nucleophiles to lactamoyl esters 5i2, 5o2 and 7p2
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Scheme 8 Sonogashira cross-coupling of iodide 7d2 with 5-chloro-
1-pentyne.
The Vilsmeier–Haack reaction is a notoriously promiscuous
transformation from the standpoint of chemoselectivity.48 It
was therefore gratifying to find that site selective, temperature-
controlled functionalization of the lactam motif present in
allylic lactamoyl ester 7o2, using the conditions described in
Scheme 9 36,49–51 affords α-chloro-β-formyl dehydropiperidine
16a in synthetically attractive yield. Of note, efficiency and
selectivity are maximized when the Vilsmeier–Haack reagent is
generated under refluxing conditions and the lactam is sub-
sequently added at room temperature. In the case of lactam
7q2, the intermediate chloromethylene iminium salt (i.e., 16b)
is isolated simply by reducing the duration of hydrolysis.
Scheme 6 Substrate-controlled addition of organolithium nucleophiles
to allylic lactamoyl esters.
followed by palladium-catalyzed intramolecular etherification
furnishes 2-azabicycles 14a–c in satisfactory efficacy
(Scheme 7). In this C–O bond forming process, hydrogen is the
only byproduct, thus, making the transformation very atom-
economical.
Scheme 9 Regioselective Vilsmeier–Haack reaction of vicinally func-
tionalized allyllic lactamoyl esters.
Scheme 7 Pd-catalyzed dehydrogenative cross-coupling.
Conclusions
Intrinsic to our design of installing a 4-iodophenyl substitu-
ent on nitrogen was the prospect of utilizing the iodo group as In summary, 1,3-azadienes have been successfully employed as
a requisite group for cross-coupling, in view of accessing competent annulative partners with hexacyclic anhydrides,
diversely functionalized arenes. Fittingly, we find that leading to the assembly of a large library of vicinally functiona-
Sonogashira cross-coupling of aryl iodide 7d2 with 5-chloro-1- lized and potentially bioactive allylic piperidinonates, morpho-
pentyne proceeds efficiently and affords tethered alkyne 15 linonates and thiomorpholinolinates. The current work stands
(Scheme 8). The choice of alkyne in this example is guided by as an advance over existing methodology given that the con-
the possibility of utilizing products such as 15 in subsequent struction of 5, 6 and 7 can be achieved in substrate-controlled,
annulative functionalizations, details of which will be dis- atom-economical, stereoselective, high-yielding, and transition
closed shortly. It is notable that dehydrochlorination and epi- metal-free fashions. The synthetic utility of the methodology
merization are not observed under these mild alkynylation has been amply demonstrated through elaboration of the
conditions.
cycloadducts to other versatile azaheterocyclic architectures,
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including epoxylactams bearing up to four contiguous stereo- with brine, dried over Na2SO4 and concentrated in vacuo to
centers and 2-azabicyclic motifs.
give the desired ester.
General procedure D: organolithium addition
To the crude lactamoyl ester (1.0 mmol) dissolved in freshly
distilled THF (5 mL), was slowly added butyllithium (2.0 mL,
2.0 M solution in hexanes, 4 equiv.) under nitrogen at −78 °C.
After complete consumption of the ester (as indicated by TLC
and GC-MS), the mixture quenched by slow addition of sat. aq
NH4Cl. The mixture was diluted with Et2O. The layers were
separated and the aqueous layer was extracted twice with
EtOAc. The combined organic layers were dried over Na2SO4
for 30 min, filtered, and concentrated under reduced pressure
to give the desired product. Purification: flash chromatography
on silica (pretreated with 1% Et3N).
Experimental
All experiments involving air and moisture sensitive reagents
such as palladium precatalysts and organolithium reagents
were carried out under an inert atmosphere of nitrogen and
using freshly distilled solvents. Column chromatography was
performed on silica gel (230–400 mesh). Thin-layer chromato-
graphy (TLC) was performed using Silicycle SiliaplateTM glass
backed plates (250 µm thickness, 60 Å porosity, F-254 indi-
cator) and visualized using UV (254 nm) or CAM, p-anis-
1
aldehyde, or KMnO4 staining. Unless otherwise indicated, H,
13C, and DEPT-135 NMR, COSY 45, HMQC, and NOESY
spectra were acquired using DMSO-d6, CD3OD or CDCl3 as
solvent, at room temperature. Chemical shifts are quoted in
parts per million (ppm). HRMS-EI+ data were obtained using
either electronspray ionization (ESI) or electron impact (EI) tech-
niques. High-resolution ESI was obtained on an LTQ-FT (ion
trap; analyzed using Excalibur). High resolution EI was obtained
on an Autospec (magnetic sector; analyzed using MassLynx).
General procedure E: catalytic hydrogenation
To a round-bottomed flask equipped with a magnetic stir bar
was added EtOAc and 10% Pd/C at room temperature. A solu-
tion of the alkene in EtOAc was added. The flask was degassed
and placed under an inert atmosphere of nitrogen. After com-
plete addition of the alkene, the nitrogen line was cut off.
A balloon of H2 was attached and the reaction mixture was
stirred at r.t. After complete consumption of the allylic lactam
(based on GC-MS or TLC monitoring), the mixture was filtered
through Celite and concentrated under reduced pressure.
General procedure A: synthesis of 1,3-azadienes
To a round-bottom flask equipped with a stir bar was added
the enal (10 mmol), amine (1 to 1.5 equiv.), benzene (50 mL),
and anhydrous MgSO4 (2 g). The cloudy suspension was
allowed to stir at room temperature. After complete consump-
tion of the amine (based on TLC monitoring), the mixture was
filtered through and concentrated under reduced pressure to
obtain the crude enamine, which was used in the next step
without further purification.
General procedure F: epoxidation
To a 10 mL vial, in a 0 °C bath, equipped with a magnetic stir
bar under a N2 atmosphere, was added the allylic lactam
(0.50 mmol) and CH2Cl2 (5 mL). m-CPBA (1.0 mmol, 2 equiv.)
was then added in one portion. After being stirred for 16 h,
during which time the bath was allowed to expire, the reaction
mixture was quenched by the sequential addition of sat.
Na2S2O3(aq) solution (5 mL) along with 10% NaOH solution
(5 mL). The aqueous layer was extracted with CH2Cl2 (2 × 10
mL). The organic layers were combined, washed with 10%
NaOH (2 × 5 mL) and with brine. It was then dried with MgSO4,
filtered, and concentrated in vacuo to afford the crude epoxide.
Note: the azadienes need to be stored in the refrigerator
when not used immediately.
General procedure B: reaction of 1,3-azadienes with hexacyclic
anhydrides
A 5 mL screw-cap vial was flame-dried, evacuated and flushed
with nitrogen. A solution of the 1,3-azadiene (1.0 mL, 0.10 M
in freshly distilled toluene) was added to the vial at room temp-
erature followed by the cyclic anhydride (1 to 1.1 equiv.). The
contents were placed in a pre-heated oil bath thermostatted at
the desired temperature (e.g., 90 °C for diglycolic anhydride).
After complete consumption of the enal (as judged by TLC and
NMR), the mixture/suspension was cooled to room temperature
and washed several times with petroleum ether, then concen-
trated under reduced pressure to afford the crude cycloadducts.
General procedure G: palladium-catalyzed etherification
To an oven dried vial equipped with a stir bar was added the
crude alcohol, prepared using general procedure D (1.0 mmol)
in hexafluorobenzene (5 mL). Pd(OAc)2 (12 mg, 5 mol%),
Li2CO3 (1.5 mmol, 1.5 equiv.), and PhI(OAc)2 (1.5 mmol,
1.5 equiv.) were then added. The contents were then stirred at
100 °C for the indicated length of time prior to cooling to
room temperature. The mixture was filtered through a pad of
Celite and washed with EtOAc. The filtrate was concentrated
under reduced pressure to give the crude product, which was
General procedure C: methyl esterification of cycloadducts
To a stirring suspension of the acid (1 mmol), dissolved in directly subjected to flash column chromatography.
DMF (5 mL), and K2CO3 (6 equiv.) was added methyl iodide
General procedure H: Vilsmeier–Haack reaction of allylic
lactamoyl esters
(3 equiv.) under nitrogen atmosphere. The reaction mixture
was stirred for 12 to 18 h (TLC monitoring). After complete
conversion, it was diluted with water and extracted with EtOAc To a solution of DMF (6 mmol, 6 equiv.) in CH2Cl2 (5 mL) at
(2 × 20 mL). The combined organic extracts were washed 0 °C was added dropwise, phosphorus oxychloride (3 mmol,
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3 equiv.). The resulting pale yellow mixture was refluxed for
Note: all other acids depicted in Scheme 2 were prepared as
40 min. A solution of the lactam (1 mmol, 1 equiv.) in CH2Cl2 described above. Spectroscopic data can be found in the ESI.‡
(5 mL) was added slowly under reflux. After complete addition Synthesis of thiomorpholinonate 6g2. Prepared from thiodi-
of the lactam, the mixture was cooled to room temperature glycolic anhydride (132 mg, 1.0 equiv.) using general pro-
and stirred for the indicated time period (TLC and LC-MS cedures B & C. T = 60 °C, time = 22 h. Yield = 387 mg, 89%.
monitoring was used to follow the extent of the reaction). 1H NMR (400 MHz, CDCl3) δ 7.61 to 7.18 (9H, m), 6.62 (1H, s),
Upon completion, the mixture was poured into a large flask 4.93 (1H, d), 3.93 to 3.87 (4H, m), 3.57 to 3.39 (2H, m), 1.96
containing crushed ice. After stirring at room temperature for (3H, s). 13C NMR (101 MHz, CDCl3) δ 170.37, 165.93, 152.71,
60 min, the layers were separated (note 1). Powdered K2CO3 142.86, 141.45, 136.25, 133.03, 131.15, 130.83, 129.73, 129.70,
was added slowly to the aqueous layer and the flask was 129.54, 128.52, 128.32, 127.40, 124.35, 124.31, 124.06, 122.78,
swirled after each addition (Caution: it bubbles vigorously). 70.83, 53.38, 43.75, 29.05, 18.18. HRMS-EI+ (m/z): calc’d for
The addition/swirling was continued until persistent cloudi- C23H20F3NO3S 435.1116; found 435.1121.
ness was observed. The neutralized/slightly basic mixture was
Synthesis of piperidinonate 7a2. Prepared from imine 4a
extracted three times with CH2Cl2 and washed with brine. The and glutaric anhydride (114 mg, 1 equiv.) using general pro-
combined organic layers were dried over Na2SO4 for 30 min. cedures B and C. Temp = 105 °C, time = 18 h. Purification:
The mixture was filtered and concentrated under reduced flash chromatography on silica eluting with hexane/EtOAc
pressure to give the desired product as an oil.
Note 1: in one instance the organic layer also contained sig- 2 steps, 95 : 5 dr. 1H NMR (400 MHz, CDCl3) δ 7.47 to 7.05
nificant amounts of the product. (10H, m), 6.39 (1H, d), 6.15 to 6.09 (1H, dd), 4.92 to 4.89 (1H,
(50 : 50 to 0 : 100) then 100% MeOH. Yield = 268 mg, 80% over
Synthesis of acid 5e1. Prepared from imine 4f (267 mg, d), 3.79 (3H, s), 2.97 to 2.93 (1H, m), 2.73 to 2.61 (2H, m), 2.42
1.0 mmol) and diglycolic anhydride (128 mg, 1.1 equiv.), using to 2.25 (2H, m). 13C NMR (101 MHz, CDCl3) δ 172.5, 169.3,
general procedure B. T = 90 °C, time = 18 h. Yield = 314 mg, 141.9, 135.8, 134.8, 133.3, 129.1, 128.8, 128.2, 127.7, 127.3,
82%. 1H NMR (400 MHz, CDCl3) δ 11.08 (1H, s, br), 7.51 to 126.5, 124.4, 63.8, 52.5, 44.5, 29.9, 20.4. HRMS-EI+ (m/z): calc’d
6.77 (8H, m), 6.37 to 6.13 (2H, m), 4.81 to 4.20 (4H, m), 3.76 to for C21H21NO3 335.1521; found 335.1525.
3.67 (6H, overlapping singlets). 13C NMR (101 MHz, CDCl3)
Note: all other esters depicted in Scheme 3 were prepared
δ 173.9, 167.5, 159.8, 158.9, 136.2, 134.1, 132.2, 130.0, 129.3, as described above. Spectroscopic data can be found in the
129.1, 128.7, 128.4, 128.3, 128.3, 128.1, 125.4, 122.2, 122.1, ESI.‡
114.2, 114.1, 75.9, 68.1, 64.4, 63.8, 55.4, 55.3. HRMS-EI+ (m/z):
calc’d for C21H21NO6 383.1369; found 383.1376.
Synthesis of epoxylactam 11a. Prepared from allylic lactam
7a2 (0.50 mmol) using general procedure F. Purification: flash
Note: all other acids depicted in Scheme 1 were prepared as chromatography on silica eluting with hexane/EtOAc (50 : 50 to
described above. Spectroscopic data can be found in the ESI.‡
0 : 100). Yield = 155 mg, 88%, >99 : 1 dr. 1H NMR (400 MHz,
Synthesis of morpholinonate 5i2. Prepared from imine 4l CDCl3) δ 7.53 to 7.10 (8H, m), 6.91 to 6.86 (2H, d), 4.01 (1H, d),
(185 mg, 1.0 mmol) and diglycolic anhydride (128 mg, 1.1 3.81 (3H, s), 3.28 to 3.25 (1H, d), 3.17 to 3.15 (1H, dd), 2.69 to
equiv.) using general procedures B and C. T = 90 °C, time = 2.35 (4H, m). 13C NMR (101 MHz, CDCl3) δ 172.4, 168.4, 141.5,
12 h. Yield = 221 mg, 70%, 87 : 13 dr. 1H NMR (400 MHz, 135.5, 133.2, 129.7, 129.6, 129.3, 128.6, 128.5, 128.4, 128.0,
CDCl3) 7.54 to 7.14 (5H, m), 6.65 (1H, s), 4.60 to 4.15 (4H, m), 127.6, 125.3, 63.7, 61.9, 60.3, 52.7, 40.7, 29.5, 20.0. HRMS-EI+
3.79 (3H, s), 2.65 to 2.49 (1H, m), 1.89 (3H, s), 1.07 to 0.54 (4H, (m/z): calc’d for C21H21NO4 351.1471; found 351.1475.
m). 13C NMR (101 MHz, CDCl3) δ 169.9, 168.3, 136.6, 133.4,
Note: epoxides 11b and 11c (see Scheme 4) were prepared
131.6, 130.1, 129.3, 129.0, 128.4, 127.3, 127.2, 126.8, 119.6, as described above. Spectroscopic data can be found in the
76.8, 74.8, 68.2, 67.6, 65.7, 65.6, 65.1, 52.8, 52.6, 28.6, 28.4, ESI.‡
15.2, 14.4, 8.5, 8.3, 5.7, 5.0. HRMS-EI+ (m/z): calc’d for
Synthesis of alkylated lactam 12a. Prepared from alkene 7b2
C18H21NO4 315.1471; found 315.1476.
(0.50 mmol) using general procedure E. Yield = 167 mg, 95%.
Note: all other esters depicted in Scheme 1 were prepared 1H NMR (400 MHz, CDCl3) δ 7.35 to 7.13 (7H, m), 7.02 (2H, d),
as described above. Spectroscopic data can be found in the 4.30 to 4.20 (1H, m), 3.79 (3H, s), 2.80 to 2.71 (1H, t), 2.65 to
ESI.‡
2.16 (9H, m), 2.10 to 1.979 (1H, m), 1.83 to 1.79 (1H, m).
Synthesis of acid 6c1. Prepared from imine 4b (237 mg, 13C NMR (101 MHz, CDCl3) δ 173.2, 169.1, 140.5, 138.9, 137.0,
1.0 mmol) and thiodiglycolic anhydride (132 mg, 1.0 equiv.), 129.9 129.9, 128.5, 128.4, 128.2, 128.1, 127.6, 127.3, 126.2,
using general procedure B. T = 60 °C, time = 12 h. An analytical 126.1, 61.0, 52.5, 41.3, 34.6, 31.9, 29.7, 21.2, 19.9. HRMS-EI+
sample was obtained after a series of washes with cold pet- (m/z): calc’d for C22H25NO3 351.1834; found 351.1839.
roleum ether. Yield = 258 mg, 70%. 1H NMR (400 MHz, CDCl3)
δ 10.96 (1H, br. S), 7.52 to 7.09 (7H, m), 6.91 to 6.79 (2H, d), described above. Spectroscopic data can be found in the ESI.‡
Note: alkanes 12b and 12c (see Scheme 5) were prepared as
6.58 to 6.32 (2H, m), 4.85 to 4.83 (1H, dd), 3.80 to 3.32 (6H,
Synthesis of tertiary alcohol 13a. Prepared from ester 5p2
m). 13C NMR (101 MHz, CDCl3) δ 173.2, 168.3, 158.8, 135.8, (0.50 mmol) and MeLi (1.42 mL, 1.4 M solution in THF,
134.6, 134.1, 130.8, 129.3, 128.1, 126.9, 122.3, 118.9, 66.6, 55.9, 2 mmol, 4 equiv.) using general procedure D. Yield = 151 mg,
1
44.8, 28.3. HRMS-EI+ (m/z): calc’d for C20H19NO4S 369.1035; 87%. H NMR (400 MHz, CDCl3) δ 7.31 (2H, d), 6.84 (2H, d),
found 369.1039.
6.41 (1H, d), 5.97 to 5.91 (1H, dd), 4.69 to 4.66 (1H, dd), 4.17
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(1H, d), 3.95 (1H, d), 3.79 (3H, s), 3.58 (1H, d), 2.29 (1H, s), 2.80 (1H, dd), 1.88 (3H, s), 1.38 to 1.25 (6H, m). 13C NMR
1.44 to 1.24 (9H, m). 13C NMR (101 MHz, CDCl3) δ 171.3, (101 MHz, CDCl3) δ 170.7, 162.3, 157.5, 136.1, 135.4, 128.9,
159.6, 132.0, 130.5, 130.4, 130.0, 128.7, 127.9, 127.8, 127.6, 128.1, 127.9, 127.4, 97.2, 62.3, 58.4, 56.6, 52.8, 41.9, 38.2, 23.2,
+
125.6, 125.0, 114.2, 114.0, 113.7, 85.0, 84.1, 80.0, 77.4, 77.1, 21.4, 20.1, 16.7. HRMS-EI+ (m/z): calc’d for C22H30Cl2N2O2
76.8, 72.9, 71.2, 68.7, 68.0, 57.9, 55.7, 55.4, 55.2, 53.8, 30.4, 381.1990; found 381.1994.
30.0, 28.8, 28.5, 28.4, 28.4, 28.0, 27.3, 26.7, 26.4, 26.2, 25.6,
14.3. HRMS-EI+ (m/z): calc’d for C20H29NO4 347.2097; found
347.2095.
Acknowledgements
Note: alcohols 13b–f (see Scheme 6) were prepared as
described above. Spectroscopic data can be found in the ESI.‡
We are grateful to Central Washington University for financial
Synthesis of bicyclic enol ether 14a. Prepared from ester 5o2 support through the donation of startup funds to T. K. B. H. B.
(0.50 mmol) using general procedures D and G. Yield = is a recipient of the CWU COTS-SURE Fellowship and a Keck
1
149 mg, 79%. H NMR (400 MHz, CDCl3) δ 7.37 to 7.22 (5H, Scholar. S. L. is a Nelson Scholar. We are particularly grateful
m), 4.53 (1H, d), 4.31 to 4.11 (2H, dd), 3.51 (1H, d), 1.88 (3H, to Emil Babik and Jeff Wilcox for NMR and GC-MS assistance.
s), 1.54 to 1.30 (15H, m). 13C NMR (101 MHz, CDCl3) δ 170.7, Miss Lisa Stowe and Mr Ian Seiler are greatly acknowledged for
138.4, 137.0, 128.9, 128.5, 128.4, 128.3, 127.0, 81.5, 77.4, 77.3, ensuring the timely purchase and delivery of laboratory
77.1, 76.8, 73.4, 67.4, 59.1, 58.5, 30.4, 29.8, 28.2, 27.8, 27.2, supplies. Professor Blaise Dondji is thanked for initial assist-
26.3, 15.2. HRMS-EI+ (m/z): calc’d for C20H27NO3 329.1991; ance with logistics. Finally, we are indebted to a reviewer who
found 329.1996.
thoroughly proofed this paper.
Note: cyclic enol ethers 14b and 14c (see Scheme 7) were
prepared as described above. Spectroscopic data can be found
in the ESI.‡
Notes and references
Synthesis of alkyne 15. To an oven-dried, septum-capped
2-neck-round bottom flask equipped with a stir bar, was added
aryl iodide 7d2 (461 mg, 1 mmol, 1.0 equiv.) in DMF/Et3N
(5 : 1 mL) and 5-chloro-1-pentyne (0.212 mL, 2 mmol, 2 equiv.),
under nitrogen atmosphere. After completely degassing the
flask, PdCl2(PPh3)2 (35 mg, 5 mol%) and CuI (10 mg, 5 mol%)
were added rapidly and concurrently. The mixture was then
stirred at room temperature for 22 h (as indicated by TLC and
GC-MS). Upon completion, the mixture was concentrated
under reduced pressure and directly subjected to flash chrom-
atography on silica eluting with hexane/EtOAc. Yield = 396 mg,
91%. 1H NMR (400 MHz, CDCl3) δ 7.40 to 7.16 (9H, m), 6.41 to
6.37 (1H, d), 6.18 to 6.06 (1H, dd), 4.89 to 4.86 (1H, dd), 3.78 to
3.63 (5H, m), 2.93 to 2.86 (2H, m), 2.65 to 2.51 (4H, m), 2.34 to
2.18 (2H, m), 2.03 to 1.97 (2H, m). 13C NMR (101 MHz, CDCl3)
δ 172.4, 169.2, 141.3, 135.7, 134.9, 133.4, 132.3, 128.7, 128.4,
127.5, 127.3, 126.7, 124.3, 122.5, 88.7, 81.1, 63.6, 52.5, 44.7,
43.8, 31.4, 29.7, 21.1, 16.9. HRMS-EI+ (m/z): calc’d for
C26H26ClNO3 435.1601; found 435.1609.
1 E. Vitaku, D. T. Smith and J. T. Njardarson, J. Med. Chem.,
2014, 57, 10257–10274.
2 T.-S. Kam, H.-S. Pang and T.-M. Lim, Org. Biomol. Chem.,
2003, 1, 1292–1297.
3 P. Ghosh, M. J. Deka and A. K. Saikia, Tetrahedron, 2016,
72, 690–698.
4 C.-V. T. Vo, M. U. Luescher and J. W. Bode, Nat. Chem.,
2014, 6, 310–314.
5 C.-V. T. Vo and J. W. Bode, J. Org. Chem., 2014, 79, 2809–
2815.
6 M. Amat, N. Llor, J. Hidalgo, C. Escolano and J. Bosch,
J. Org. Chem., 2003, 68, 1919–1928.
7 D. L. Comins, D. H. LaMunyon and X. Chen, J. Org. Chem.,
1997, 62, 8182–8187.
8 D. L. Comins and Y.-M. Zhang, J. Am. Chem. Soc., 1996,
118, 12248–12249.
9 D. L. Comins, S. P. Joseph and X. Chen, Tetrahedron Lett.,
1995, 36, 9141–9144.
Synthesis of chloro dehydropiperidinal 16a. Prepared from 10 Y.-Y. Yu, L. Bi and G. I. Georg, J. Org. Chem., 2013, 78,
lactam 7o2 (1.0 mmol) using general procedure H. Yield = 6163–6169.
296 mg, 82%. 1H NMR (400 MHz, CDCl3) δ 9.89 (1H, s), 7.34 to 11 Y.-Y. Yu, M. J. Niphakis and G. I. Georg, Org. Lett., 2011, 13,
7.23 (5H, m), 6.47 to 6.44 (1H, d), 6.04 to 5.98 (1H, dd), 5.17 to 5932–5935.
5.07 (1H, dd), 3.78 (3H, s), 2.90 to 2.87 (2H, m), 2.46 to 2.34 12 B. J. Turunen and G. I. Georg, J. Am. Chem. Soc., 2006, 128,
(1H, m), 1.56 (9H, s). 13C NMR (101 MHz, CDCl3) δ 189.0,
8702–8703.
172.4, 150.0, 135.8, 134.2, 132.2, 128.9, 127.1, 126.6, 124.6, 13 H. Seki and G. I. Georg, Org. Lett., 2011, 13, 2147–2149.
110.5, 61.7, 59.3, 52.3, 43.6, 34.8, 31.6, 21.0. HRMS-EI+ (m/z): 14 H. Seki and G. I. Georg, J. Am. Chem. Soc., 2010, 132,
calc’d for C20H24ClNO3 361.1145; found 361.1149.
Synthesis of chloro iminium ion 16b. Prepared from lactam 15 M. J. Niphakis, B. J. Turunen and G. I. Georg, J. Org. Chem.,
7q2 (1.0 mmol) using general procedure H, but hydrolysis was 2010, 75, 6793–6805.
carried out for only 20 min and no basification was necessary. 16 H. Wong, E. C. Garnier-Amblard and L. S. Liebeskind,
Yield = 342 mg, 88%. 1H NMR (400 MHz, CDCl3) δ 8.24 (1H, s),
J. Am. Chem. Soc., 2011, 133, 7517–7527.
7.38 to 7.21 (5H, m), 6.06 (1H, s), 4.98 to 4.90 (1H, m), 4.70 to 17 M. Yar, E. M. McGarrigle and V. K. Aggarwal, Angew. Chem.,
15512–15513.
4.66 (1H, d), 3.76 to 3.61 (9H, m), 3.28 to 3.16 (2H, m), 2.86 to
Int. Ed., 2008, 47, 3784–3786.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2016

View Article Online
Organic & Biomolecular Chemistry
Paper
18 J. V. Matlock, T. D. Svejstrup, P. Songara, S. Overington, 34 T. Imai, T. Tamura, A. Yamamuro, T. Sato, T. A. Wollmann,
E. M. McGarrigle and V. K. Aggarwal, Org. Lett., 2015, 17,
5044–5047.
R. M. Kennedy and S. Masamune, J. Am. Chem. Soc., 1986,
108, 7402–7404.
19 L. Bagnoli, C. Scarponi, M. G. Rossi, L. Testaferri and 35 M. Gonzalez-Lopez and J. T. Shaw, Chem. Rev., 2009, 109,
M. Tiecco, Chem. – Eur. J., 2011, 17, 993–999. 164–189.
20 H. Sun, B. Huang, R. Lin, C. Yang and W. Xia, Beilstein 36 T. K. Beng, S. M. Wilkerson-Hill and R. Sarpong, Org. Lett.,
J. Org. Chem., 2015, 11, 524–529. 2014, 16, 916–919.
21 E. M. Carreira and T. C. Fessard, Chem. Rev., 2014, 114, 37 B. Ye and N. Cramer, Acc. Chem. Res., 2015, 48, 1308–1318.
8257–8322.
38 P. K. Prasad, R. N. Reddi and A. Sudalai, Org. Lett., 2016,
18, 500–503.
22 J. A. Burkhard, G. Wuitschik, M. Rogers-Evans, K. Mueller
and E. M. Carreira, Angew. Chem., Int. Ed., 2010, 49, 9052– 39 S. H. Lim, S. Ma and P. Beak, J. Org. Chem., 2001, 66, 9056–
9067. 9062.
23 M. L. Leathen, B. R. Rosen and J. P. Wolfe, J. Org. Chem., 40 A. Deb, S. Manna, A. Modak, T. Patra, S. Maity and
2009, 74, 5107–5110. D. Maiti, Angew. Chem., Int. Ed., 2013, 52, 9747–9750.
24 A. Noble, S. J. McCarver and D. W. C. MacMillan, J. Am. 41 N. Burdzhiev, E. Stanoeva, B. Shivachev and R. Nikolova,
Chem. Soc., 2015, 137, 624–627. C. R. Chim., 2014, 17, 420–430.
25 Z. Zuo, D. T. Ahneman, L. Chu, J. A. Terrett, A. G. Doyle 42 D. Dar’in, O. Bakulina, M. Chizhova and M. Krasavin, Org.
and D. W. C. MacMillan, Science, 2014, 345, 437–440. Lett., 2015, 17, 3930–3933.
26 H. Zhai, A. Borzenko, Y. Y. Lau, S. H. Ahn and L. L. Schafer, 43 T. W. Greene, Protective Groups in Organic Synthesis, Wiley
Angew. Chem., Int. Ed., 2012, 51, 12219–12223. Interscience, New York, 1981.
27 R. Payne Philippa, P. Garcia, P. Eisenberger, C. H. Yim 44 M.-G. Braun, B. Quiclet-Sire and S. Z. Zard, J. Am. Chem.
Jacky and L. Schafer Laurel, Org. Lett., 2013, 15, 2182–2185. Soc., 2011, 133, 15954–15957.
28 T. K. Beng, H. Takeuchi, M. Weber and R. Sarpong, Chem. 45 A. Deb, S. Bag, R. Kancherla and D. Maiti, J. Am. Chem.
Commun., 2015, 51, 7653–7656. Soc., 2014, 136, 13602–13605.
29 T. K. Beng, N. Fox, D. P. Bassler, A. Alwali, K. Sincavage and 46 Z. He, S. Kirchberg, R. Froehlich and A. Studer, Angew.
A. W. V. Silaire, Org. Biomol. Chem., 2015, 13, 8647–8651. Chem., Int. Ed., 2012, 51, 3699–3702.
30 A. Gerogieva, E. Stanoeva, S. Spassov, M. Haimova, N. De 47 H. Horie, T. Kurahashi and S. Matsubara, Chem. Commun.,
Kimpe, M. Boelens, M. Keppens, A. Kemme and
A. Mishnev, Tetrahedron, 1995, 51, 8407.
31 A. Georgieva, E. Stanoeva, S. Spassov, M. Haimova, N. De
2010, 46, 7229–7231.
48 A. P. Rajput and P. D. Girase, Int. J. Pharm., Chem. Biol. Sci.,
2013, 3, 25–43.
Kimpe, M. Boelens, M. Keppens, A. Kemme and 49 D. P. Bassler, L. Spence, A. Alwali, O. Beale and T. K. Beng,
A. Mishnev, Tetrahedron, 1995, 51, 6099–6114. Org. Biomol. Chem., 2015, 13, 2285–2292.
32 F. Manoni and S. J. Connon, Angew. Chem., Int. Ed., 2014, 50 T. K. Beng, A. W. V. Silaire, A. Alwali and D. P. Bassler, Org.
53, 2628–2632. Biomol. Chem., 2015, 13, 7915–7919.
33 Y. Kita, S. Mohri, T. Tsugoshi, H. Maeda and Y. Tamura, 51 T. K. Beng and D. P. Bassler, Tetrahedron Lett., 2014, 55,
Chem. Pharm. Bull., 1985, 33, 4723–4731.
6662–6664.
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