Regiodivergent Stereoselective Access to Fused Alkylideneazetidines

Article abstract of DOI:10.1021/acs.joc.7b02786

Following recent advances in the generalization and simplification of 2H-azetine synthesis, a regiodivergent approach to fused 2- and 3-alkylideneazetines was designed via the intermediate formation of unprecedented vinylazetine structures. Concise sequen

Full text of DOI:10.1021/acs.joc.7b02786

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Article
Regiodivergent Stereoselective Access to Fused Alkylideneazetidines
Arif Music, Andreas Nicolas Baumann, Michael Eisold, and Dorian Didier
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02786 • Publication Date (Web): 20 Dec 2017
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The Journal of Organic Chemistry
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Regiodivergent Stereoselective Access to Fused Alkylideneazetidines
Arif Music†, Andreas N. Baumann†, Michael Eisold, Dorian Didier*
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Department of Chemistry and Pharmacy, LudwigꢀMaximiliansꢀUniversity, Butenandtstraße 5ꢀ13, 81377 Munich, Germany
Supporting Information Placeholder
ABSTRACT: Following recent advances on the generalization and simplification of 2Hꢀazetine synthesis, a regiodivergent apꢀ
proach to fused 2ꢀ, and 3ꢀalkylideneazetines was designed via the intermediate formation of unprecedented vinylazetine structures.
Concise sequences to the latter are described, from which expected unsaturated fused ring system were isolated with very high
yields,
regioꢀ
and
stereoselectivities
by
[4+2]ꢀcycloadditions.
Scheme 1. Past and present work on the formation of un-
saturated four-membered N-heterocycles.
Introduction
Nitrogenꢀcontaining heterocycles are essential motifs in orꢀ
ganic and medicinal chemistry1 as their incorporation in drugs
has been leading a number of synthetic studies.2 As βꢀlactams
have become important in pharmacology after the discovery of
penicillin, a part of medicinal chemistry research has been
dedicated to exploring the synthesis and biological activities of
such strained fourꢀmembered heterocycles. More than antibiꢀ
otic properties, azetidineꢀderived fused systems present a wide
range of applicability, showing for example antiꢀviral and
antifungal activities (Figure 1).3ꢀ5
Figure 1. Selected examples of fused N-containing four-
membered rings.
a) organolithium (M = Li) or organomagnesium (M = MgBr) were
employed (1.2 eq.); reactions were performed in THF at ꢀ30 °C.
b) NaH, MeI, THF, 0°C to rt. c) sꢀBuLi (2 eq.), TMEDA (1 eq.),
THF, ꢀ78 °C.
Moreover, a relatively restrained library of fused azetidines
found in the literature points out the importance of these moꢀ
tifs as potential candidates for the treatment of a variety of
diseases, including antitumor agents.6 While smaller and larger
Nꢀcontaining heterocycles have been intensively studied, the
general formation of azetines7 and alkylideneazetines8 remains
a challenge in organic chemistry.
En route to developing new accesses to sophisticated azetꢀ
idine structures, we recently generalized the synthesis of 3,4ꢀ
disubstituted 2ꢀazetines 3 through the key formation of an
azetinyllithium intermediate 2 (Scheme 1).9 While direct elecꢀ
trophilic trapping furnished alkylated, silylated and carbinol
derivatives, transmetalation to boron followed by inꢀsitu Suꢀ
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zuki coupling opened an unprecedented access to 4ꢀarylated strates also furnished expected product 6d in good yields.
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derivatives. Importantly, desired structures could be obtained
in only three steps and after a sole purification. Starting from a
commercial source of 3ꢀazetidinone 1,10 the introduction of the
substituent at position 3 can be simply done by nucleophilic
1,2ꢀaddition of an organometallic and subsequent methylation
of the resulting tertiary alcohol giving then adequate substrates
for the double αꢀlithiation / trapping sequence pioneered by
Hodgson.9,11 Employing either vinylmetal species (eq. 1) or
performing the subsequent crossꢀcoupling with vinyl halides
(eq. 2) respectively furnishes 3ꢀ, and 2ꢀvinylazetines 4 and 7
(Scheme 1). Upon addition of a dienophile 5, a stereoselective
[4+2]ꢀcycloaddition takes place, leading to fused alkyliꢀ
deneazetidines (AAz) 6 and 8. The regiodivergence of the
strategy simply comes from the nature of the embedded diene
initially employed (3ꢀvinylazetine 4 or 4ꢀvinylazetine 7).
Using Feringa’s deprotonation for the formation of lithiated
vinyl ether13 resulted in the formation of tetracyclic AAz 6e
and Oꢀethyl substituted AAz 6f in 77 to 88% yield. Following
the double deprotonation, subsequent addition of TMSCl in
the formation of 4 led to quaternary stereocenter containing
AAz 6h and 6i in good yields and stereoselectivities.15
Scheme 3. Three-step sequence towards fused AAz.a
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Results and Discussion
In Scheme 2, we detail the twoꢀstep preparation of 3ꢀ
vinylazetidine building blocks 9a-f.12,13 Upon addition of an
alkenylmetal species on 1, tertiary alcohols are intermediary
formed and further methylated without need for purification.
Diverse alkenyl groups and vinylethers13 were introduced,
giving access to the desired substrates 9a-f in moderate to high
yields (46 to 95%).
Scheme 2. Preparation of 3-vinylazetidine building blocks.
Starting from these vinylazetidines 9a-f, αꢀlithiation in the
presence of sꢀBuLi promotes a βꢀelimination and an excess
amount of sꢀBuLi yields the key azetinyllithium intermediate
10 that can then be trapped by the appropriate electrophile
(H2O or TMSCl, Scheme 3).12 Resulting dienes 4 were subseꢀ
quently engaged in a [4+2]ꢀcycloaddition with electron defiꢀ
cient dienophiles 5 to afford fused AAz 6a-i with excellent
control over the stereochemical outcome of the transformation
in all cases (dr = 97:3).14 While isopropenylmetal species (R1
= Me) led to 6a and 6b with good yields employing respecꢀ
tively maleic anhydride or Nꢀmethylmaleimide, the possibility
of adding a stereocenter was explored by using an inꢀsitu
generated transꢀ2ꢀbutenyllithium as the starting organometalꢀ
lic species. 6c and 6g (from Nꢀphenylmaleimide) containing
four consecutive stereocenters were obtained with an excellent
diastereomeric ratio and up to 96% yield. A decrease in stereꢀ
oselectivity was however observed when employing Nꢀ
phenylmaleimide (6g, dr = 86:14). Interestingly, bulky subꢀ
a Indicated yields are calculated from compound 9 after the threeꢀ
step sequence, including the extraction step, see supporting inꢀ
formation.
With an efficient exꢀsitu preparation of functionalized
dienes embedded in the azetine structures in hands, we enviꢀ
sioned that a chiral substrate 11 (Scheme 4) – obtained by
intermediate addition of an aldehyde – could lead to a diaꢀ
stereocontrolled [4+2]ꢀcycloaddition. Benzaldehyde was first
used on 4ꢀazetinyllithium species, furnishing the correspondꢀ
ing azetine carbinol 11a which was engaged crude in the cyꢀ
cloaddition with Nꢀmethylmaleimide. Delightfully, 12a was
isolated in good yields and with an excellent diastereomeric
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diene (from 9a) only gave moderate regioselectivities
ratio (dr = 97:3). We propose to explain this exceptional stereꢀ
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oselectivity by an intramolecular Hꢀbonding between the
hydroxyl moiety and the Boc group, placing the aromatic
group – coming initially from the aldehyde – on one of the two
diastereotopic faces. Potential allylic strain reinforces this
selectivity, placing the larger group (aromatic) out of the
plane. As a result, the dienophile preferentially approaches
from the less hindered face of the diene. Xꢀray measurements
on product 12g showed a Hꢀbonding and we assume that this
interaction plays a determining role in the diastereoselectivity
of the reaction, as proposed in the transition state (Scheme
4).16 Aromatic as well as heteroaromatic substrates furnished
12b-d and 12e,f, respectively, with similarly high yields and
diastereoselectivities.
(14a:14b = 75:25), the most substituted one (from 9c) furꢀ
nished exclusively 17a in 89% yield
Scheme 5. Synthesis of AAz using 3-methylfuran-2,5-
dione.a
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Scheme 4. Diastereoselective approach toward AAz.a
a Indicated yields are calculated from compound 9 after the threeꢀ
step sequence, including the extraction step, see supporting inꢀ
formation.
Scheme 6. Access to fused 2-alkylideneazetidines.a
1. s-BuLi (2 eq.)
TMEDA / THF
2. B(Oi-Pr)3
NBoc
NBoc
O
4. extraction
5.
Me
R1
R3
MeO
3. Pd(dppf)Cl2
N
R1
N
R2
O
O
5
Me
(4 mol %)
18
R3
O
X
8
R2
Li Li
toluene, 80 °C
B
Pd 4+2
NBoc
Me
NBoc
Me
NBoc
Ph
Ph
Ph
O
O
O
N
N
N
Me
Me
Me
Me
4 Cl
O
O
O
8a, X = Br (91%)
8b, X = Br (62%)
8c, X = I (65%)
(dr > 97:3)
(dr > 97:3)
(dr > 97:3)
MeO
MeO
NBoc
Me
NBoc
O
O
N
N
Me
Me
Me
4 Cl
O
O
8d, X = Br (64%)
8e, X = I (64%)
(dr > 97:3)
(dr > 97:3)
Ph
NBoc
NBoc
Et
O
O
Me
Me
a Indicated yields are calculated from compound 9 after the threeꢀ
step sequence, including the extraction step, see supporting inꢀ
formation.
N
N
Me
Me
O
O
8f, X = Br (86%)
8g, X = Br (67%)
(dr > 97:3)
(dr > 97:3)
In order to introduce a quaternary stereocenter α to a carꢀ
bonyl position, we next employed citraconic anhydride 13 as
dienophile. Dienes 4g-i and 4l obtained after quenching with
either H2O or D2O were employed without further purification.
Interestingly, different regioselectivities were observed deꢀ
pending on the bulkiness of the diene engaged in the cycloadꢀ
dition reaction (Scheme 5). While the less bulky terminal
Boc
N
proposed endo-
transition state for
the [4+2]-cycloaddition
R1
R2
R3
O
NMe
O
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1
a Indicated yields are calculated from compound 9 after the threeꢀ
step sequence, including the extraction step, see supporting inꢀ
formation.
ated chloroform (CDCl3: δ 7.26 ppm for HꢀNMR and δ 77.16
ppm for 13CꢀNMR). Abbreviations for signal coupling are as
follows: s (singlet), d (doublet), t (triplet), q (quartet), quint (quinꢀ
tet), m (multiplet) and br (broad). Reaction endpoints were deterꢀ
mined by GC monitoring of the reactions. Gas chromatography
was performed with machines of Agilent Technologies 7890,
using a column of type HP 5 (Agilent 5% phenylmethylpolysiloxꢀ
ane; length: 15 m; diameter: 0.25 mm; film thickness: 0.25 ꢁm) or
HewlettꢀPackard 6890 or 5890 series II, using a column of type
HP 5 (HewlettPackard, 5% phenylmethylpolysiloxane; length: 15
m; diameter: 0,25 mm; film thickness: 0.25 ꢁm). High resolution
mass spectra (HRMS) and low resolution mass spectra (LRMS)
were recorded on Finnigan MAT 95Q or Finnigan MAT 90 inꢀ
strument or JEOL JMSꢀ700. Infrared spectra were recorded on a
Perkin 281 IR spectrometer and samples were measured neat
(ATR, Smiths Detection DuraSample IR II Diamond ATR). The
absorption bands were reported in wave numbers (cmꢀ1) and
abbreviations for intensity are as follows: vs (very strong; maxiꢀ
mum intensity), s (strong; above 75% of max. intensity), m (meꢀ
dium; from 50% to 75% of max. intensity), w (weak; below 50%
of max. intensity) and br (broad). Melting points were determined
on a Büchi Bꢀ540 apparatus and uncorrected. Single crystals were
grown in small quench vials with a volume of 5.0 mL from slow
evaporation of dichloromethane/hexanes mixtures at room temꢀ
perature. Suitable single crystals were then introduced into perꢀ
fluorinated oil and mounted on top of a thin glass wire. Data
collection was performed at 100 K with a Bruker D8 Venture
TXS equipped with a Spellman generator (50 kV, 40 mA) and a
Kappa CCD detector operating with MoꢀKα radiation (l = 0.71071
Å).
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As this variable regioselectivity can be easily explained by
steric repulsion between the methyl group of the dienophile
and the substituents at the vinylic position, cisꢀ, and transꢀ
dimethylvinyl substrates (respectively from 9d and 9b) led to
intermediate regioselectivities (79:21 and 83:17, respectively).
Importantly, regioisomers could be isolated separately via
chromatography.
9
Finally, a regiodivergent approach toward fused 2ꢀAAz was
designed starting form aryl, alkyl and alkynylꢀsubstituted
azetidines 18 (Scheme 6). Following the aboveꢀdescribed
lithiation sequence led to the corresponding azetinylboronate
upon addition of boron isopropoxide. Subsequent addition of
vinyl iodide or bromide furnished dienes 7 (not depicted in
Scheme 6) through an inꢀsitu Suzuki crossꢀcoupling catalyzed
by Pd(dppf)Cl2·CH2Cl2. These 4ꢀvinylazetines were then
directly engaged in the DielsꢀAlder cycloaddition with Nꢀ
methylmaleimide 5 without further purification, but after
extracting switching the solvent to toluene. In all cases, a
perfect control over the diastereoselective outcome was
achieved (dr > 97:3). 3ꢀaryl, alkyl and alkynyl substituted
substrates led to fused ring systems 8aꢀg in good to excellent
yields (up to 91%) containing up to four consecutive stereoꢀ
centers.
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Conclusion
sꢀBuLi and tꢀBuLi were purchased as solutions in cyclohexꢀ
ane/hexanes mixtures from Rockwood Lithium GmbH. The
commercially available Grignard reagents MeMgCl, PhMgCl and
nꢀBuMgCl were also purchased from Rockwood Lithium GmbH,
as solutions in THF.
The concentration of organometallic reagent from commercially
purchased and synthesized reagents was determined either by
titration of isopropyl alcohol using the indicator 4ꢀ
(phenylazo)diphenylamine in THF for Grignard reagents or using
the indicator Nꢀbenzylbenzamide in THF for organolithium reaꢀ
gents.
In conclusion, we assembled highly stereoselective threeꢀ
step sequences in which successive αꢀmetallation, electroꢀ
philic addition and [4+2]ꢀcycloaddition led to unprecedented
fused triꢀ and tetracyclic alkylideneazetidines with up to four
consecutive stereocenters. Both regioisomers could be acꢀ
cessed independently through this simple and efficient strateꢀ
gy, taking advantage of an easy and straightforward substrate
preparation. Paths allowing the formation of these interesting
patterns surely represent important advances in the chemistry
of nitrogenꢀcontaining fourꢀmembered rings and their potential
implications in drugꢀdiscovery processes.
[sꢀBuLi] = 1.31
1,10ꢀphenanthroline), purchased from Rockwood Lithium GmbH.
[tꢀBuLi] = 2.00 in hexane (titration with isopropanol / 1,10ꢀ
M in cyclohexane (titration with isopropanol /
Experimental Section
M
General considerations. Commercially available starting materiꢀ
als were used without further purification unless otherwise stated.
All reactions were carried out under N2 atmosphere in flameꢀdried
glassware. Syringes, which were used to transfer anhydrous solꢀ
vents or reagents, were purged with nitrogen prior to use. CH2Cl2
was predried over CaCl2 and distilled from CaH2. THF was reꢀ
fluxed and distilled from sodium benzophenone ketyl under nitroꢀ
gen. Et2O was predried over CaCl2 and passed through activated
Al2O3 (the solvent purification system SPSꢀ400ꢀ2 from Innovative
Technologies Inc.). Toluene was predried over CaCl2 and distilled
from, CaH2. Chromatography purifications were performed using
silica gel (SiO2, 0.040ꢀ0.063 mm, 230ꢀ400 mesh ASTM) from
Merck. The spots were visualized under UV (254 nm) or by stainꢀ
ing the TLC plate with KMnO4 solution (K2CO3, 10 g – KMnO4,
1.5 g – H2O, 150 mL – NaOH 10% in H2O, 1.25 mL), pꢀ
anisaldehyde solution (conc. H2SO4, 10 mL – EtOH, 200 mL –
AcOH, 3 mL – pꢀanisaldehyde, 4 mL). Diastereoisomeric ratios
phenanthroline), purchased from Rockwood Lithium GmbH.
General procedure A for the synthesis of organomagnesiumꢀ
vinyl reagents:[13]
In a Schlenk flask, two equivalents of magnesium turnings were
layered with either diethyl ether or THF. One seed of iodine was
added for activation and one drop of concentrated corresponding
vinylbromide was added. After ensuring that the reaction had
started, the corresponding bromides were solubilised in the approꢀ
priate solvent and added dropwise at a constant rate that would
keep the reaction constantly refluxing. After completed addition,
the reaction was stirred for three more hours at room temperature
and the organomagnesium reagents stored under nitrogen.
General procedure B for the synthesis of 3ꢀsubstituted 1ꢀBocꢀ3ꢀ
methoxyazetidines (9a-f, 18a-d): Commercially available tertꢀ
butyl 3ꢀoxoazetidineꢀ1ꢀcarboxylate (1) (1.0 eq., 5.0 mmol) was
dissolved in THF (20 mL) and cooled to ꢀ30 °C. The correspondꢀ
ing vinylꢀGrignard (1.3 eq., 6.5 mmol) or vinyllithium species[13]
was added dropwise and the solution stirred for one hour before
warming to room temperature. The reaction mixture was
quenched with saturated NH4Cl and extracted twice with diethyl
1
1
were determined by H NMR and 13C NMR. 13C and H NMR
spectra were recorded on VARIAN Mercury 200, BRUKER ARX
300, VARIAN VXR 400 S and BRUKER AMX 600 instruments.
Chemical shifts are reported as δ values in ppm relative to residuꢀ
al solvent peak (1HꢀNMR) or solvent peak (13CꢀNMR) in deuterꢀ
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ether (2x 20 mL). The combined organic layers were dried over
(d, J = 9.0 Hz, 2H), 3.85 (d, J = 9.1 Hz, 2H), 3.06 (s, 3H), 1.67 (s,
3H), 1.44 ppm (s, 9H). 13C NMR (101 MHz, CDCl3) δ 156.7,
142.0, 114.9, 79.7, 77.8, 58.3, 56.3, 51.0, 28.5, 17.2 ppm. LRMS
(ESIꢀquadrupole pos): m/z (%): 212.1 (1), 170.1 (32), 154.1 (8).
MgSO4 and the solvents were evaporated under vacuum. The
crude alcohol was then redissolved in THF (10 mL) and cooled to
0 °C. After adding sodium hydride (1.3 eq., 6.5 mmol) portionꢀ
wise, the reaction mixture was allowed to reach room temperature
and stirred for one hour. Methyl iodide (1.3 eq., 6.5 mmol) was
then added and the mixture stirred for two more hours at room
temperature. The reaction was quenched with methanol and the
solvents were evaporated. Purification by column chromatography
on silica gel gave substituted 3ꢀsubstituted 1ꢀbocꢀ3ꢀ
methoxyazetidines 9a-f.
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2
3
4
5
6
7
8
+
HRMS (ESIꢀquadrupole pos): calcd for C11H18NO3 : 212.1287;
found: 212.1301. IR (DiamondꢀATR, neat) ꢀȬ(ꢁ3: 2976 (w), 2946
(w), 2884 (w), 2826 (vw), 1704 cmꢀ1 (vs).
tert-Butyl-(Z)-3-(but-2-en-2-yl)-3-methoxyazetidine-1-
carboxylate (9b): Using tertꢀbutyl 3ꢀoxoazetidineꢀ1ꢀcarboxylate
(1) and vinyllithium according to general procedure B, provided
9b after purification on silica gel (hexane/ethyl acetate 9:1),
(3.70 mmol, 900 mg, 55%) as a colourless crystalline solid. 1H
NMR (400 MHz, CDCl3) δ 5.56 (q, J = 7.2, 6.8 Hz, 1H), 4.02 (d, J
= 9.3 Hz, 2H), 3.92 (d, J = 9.3 Hz, 2H), 3.14 (s, 3H), 1.66 (s, 3H),
1.57 (d, J = 7.2 Hz, 3H), 1.42 ppm (s, 9H). 13C NMR (101 MHz,
CDCl3) δ 156.7, 132.0, 126.7, 79.6, 76.8, 58.6, 50.8, 28.5, 21.2,
14.7 ppm. LRMS (ESIꢀquadrupole pos): m/z (%): 184.1 (16),
168.1 (6), 153.1 (4), 112.1 (68). HRMS (ESIꢀquadrupole pos):
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General procedure C for the synthesis of alkylideneazetidines
(6a-i/12a-g): Azetidines 9a-f (0.50 mmol, 1.0 eq.) were dissolved
in THF (5.0 mL) and the solution was cooled down to ꢀ78 °C.
After the addition of TMEDA (1.3 mmol, 2.5 eq.), sꢀBuLi
(1.3 mmol, 1.31 M, 2.5 eq.) was added dropwise and the mixture
stirred for one hour. The reaction was then quenched with the
corresponding electrophile (H2O, TMSCl, D2O, aldehydes),
stirred for 30 minutes and warmed up to room temperature. After
workup with saturated NH4Cl and extraction with diethyl ether
(2x 10 mL), the organic phases were combined and dried over
Na2SO4. The crude dienes were then redissolved in toluene
(3.0 mL) and transferred into a pressure tube. The dienophile was
added (1.0 mmol, 2.0 eq.) and the sealed pressure tube was heated
between 80 °C for 10 ꢀ24 h. Evaporation of the solvent and purifiꢀ
cation by column chromatography led to compounds 6a-i/12a-g.
+
calcd for C9H14NO3 [MꢀtꢀBu]+: 184.0974; found: 184.0984. IR
(DiamondꢀATR, neat) ꢀȬ(ꢁ3: 2978 (w), 2944 (w), 2884 (w), 2824
(vw), 1694 cmꢀ1 (vs).
tert-Butyl-3-methoxy-3-(3-methylbut-2-en-2-yl)azetidine-1-
carboxylate (9c): Using tertꢀbutyl 3ꢀoxoazetidineꢀ1ꢀcarboxylate
(1) and vinyllithium according to general procedure B, provided
9c after purification on silica gel (hexane/ethyl acetate 9:1),
(3.00 mmol, 760 mg, 46%) as a colourless oil. 1H NMR (400
MHz, CDCl3) δ 4.01 (d, J = 9.4 Hz, 2H), 3.92 (d, J = 9.4 Hz, 2H),
3.14 (s, 3H), 1.71 (s, 3H), 1.61 (d, J = 6.4 Hz, 6H), 1.43 ppm (s,
9H). 13C NMR (101 MHz, CDCl3) δ 156.7, 133.1, 124.9, 79.6,
78.3, 58.9, 50.9, 28.5, 21.6, 16.5 ppm. LRMS (ESIꢀquadrupole
pos): m/z (%): 198.2 (9), 184.2 (3). HRMS (ESIꢀquadrupole pos):
General procedure D for the synthesis of alkylideneazetidines
(14aꢀ17a/14bꢀ17b): Azetidines 9a-d (0.50 mmol, 1.0 eq.) were
dissolved in THF (5.0 mL) and the solution was cooled down to ꢀ
78 °C. After the addition of TMEDA (1.3 mmol, 2.5 eq.), sꢀBuLi
(1.3 mmol, 1.31 M, 2.5 eq.) was added dropwise and the mixture
+
calcd for C10H16NO3 [MꢀtꢀBu]+: 198.1130; found: 198.1123. IR
stirred for one hour. The reaction was then quenched with the
corresponding electrophile (H2O or D2O), stirred for 30 minutes
and warmed up to room temperature. After workup with saturated
NH4Cl and extraction with diethyl ether (2x 10 mL), the organic
phases were combined and dried over Na2SO4. The crude dienes
were then redissolved in toluene (3.0 mL) and transferred into a
pressure tube. The dienophile was added (1.0 mmol, 2.0 eq.) and
the sealed pressure tube was heated between 80 °C for 16 h.
Evaporation of the solvent and purification by column chromatogꢀ
raphy led to compounds 14aꢀ17a/14bꢀ17b.
(DiamondꢀATR, neat) ꢀȬ(ꢁ3: 2978 (w), 2942 (w), 2880 (w), 2822
(vw), 2244 (vw), 1704 cmꢀ1 (vs).
tert-Butyl-(E)-3-(but-2-en-2-yl)-3-methoxyazetidine-1-
carboxylate (9d): Using tertꢀbutyl 3ꢀoxoazetidineꢀ1ꢀcarboxylate
(1) and vinyllithium according to general procedure B, provided
9d after purification on silica gel (hexane/ethyl acetate 9:1),
(2.00 mmol, 482 mg, 50%) as colorless oil. Rf = 0.5 (hexꢀ
ane/EtOAc 8:2, UV, KMnO4, PAA). 1H NMR (400 MHz, CDCl3)
δ 5.61 – 5.53 (m, 1H), 3.99 – 3.91 (m, 2H), 3.81 (d, J = 9.0 Hz,
2H), 3.01 (s, 3H), 1.68 (d, J = 7.5 Hz, 3H), 1.53 (s, 3H), 1.43 ppm
(s, 9H). 13C NMR (101 MHz, CDCl3) δ 156.8, 132.5, 123.7, 79.6,
78.9, 50.7, 28.5, 13.4, 11.0 ppm. LRMS (ESIꢀquadrupole pos):
m/z (%): 242.2 (40), 227.1 (35), 186.1 (60), 154.0 (5). HRMS
General procedure E for the synthesis of alkylideneazetidines
(8a-g): Azetidines (0.50 mmol, 1.0 eq.) were dissolved in THF
(5.0 mL) and the solution was cooled down to ꢀ78 °C. After the
addition of TMEDA (1.3 mmol, 2.5 eq.), sꢀBuLi (1.3 mmol,
+
1.31 M, 2.5 eq.) was added dropwise and the mixture stirred for
(ESIꢀquadrupole pos): calcd for C13H24NO3 : 242.1751, found
one hour. The reaction was then quenched with 2.0 eq B(OiꢀPr)3,
stirred for 60 minutes at 0 °C. After this time, Pd(dppf)Cl2.DCM
(4 mol%) as well as the corresponding vinylꢀhalogenide (X = I or
Br) was added and let stirr for 24 h. After workup with saturated
NH4Cl and extraction with diethyl ether (2x 10 mL), the organic
phases were combined and dried over Na2SO4. The crude dienes
were then redissolved in toluene (3.0 mL) and transferred into a
pressure tube. The dienophile was added (1.0 mmol, 2.0 eq.) and
the sealed pressure tube was heated between 80 °C for 10 ꢀ24 h.
Evaporation of the solvent and purification by column chromatogꢀ
raphy led to compounds 8a-g.
242.1751. IR (DiamondꢀATR, neat) ꢀȬ(ꢁ3: 2976 (w), 2934 (w),
2882 (w), 2824 (vw), 1702 cmꢀ1 (vs).
tert-Butyl-3-(4,5-dihydrofuran-2-yl)-3-methoxyazetidine-1-
carboxylate (9e): Using tertꢀbutyl 3ꢀoxoazetidineꢀ1ꢀcarboxylate
(1) and vinyllithium according to general procedure B, provided
9e after purification on silica gel (hexane/ethyl acetate 9:1),
(3.80 mmol, 980 mg, 95%) as a colourless oil. 1H NMR (400
MHz, CDCl3) δ 5.03 (t, J = 2.5 Hz, 1H), 4.41 (t, J = 9.4 Hz, 2H),
3.98 (d, J = 0.8 Hz, 2H), 3.93 (d, J = 9.6 Hz, 2H), 3.21 (s, 3H),
2.71 (td, J = 9.4, 2.5 Hz, 2H), 1.43 ppm (s, 9H). 13C NMR (101
MHz, CDCl3) δ 156.5, 155.4, 99.7, 79.8, 72.0, 70.8, 58.6, 57.3,
52.1, 30.2, 28.5 ppm. LRMS (ESIꢀquadrupole pos): m/z (%):
198.1 (16), 182.1 (6), 154.1 (5), 126.1 (75), 96.1 (44), 85.1 (11),
67.1 (9), 57.1 (100). HRMS (ESIꢀquadrupole pos): calcd for C
C9H12NO4+ [MꢀtꢀBu]+: 198.0766; found: 198.0754. IR (Diamondꢀ
ATR, neat) ꢀȬ(ꢁ3: 2976 (m), 2884 (w), 2836 (vw), 1702 cmꢀ1 (vs).
Experimental Data
tert-Butyl-3-methoxy-3-(prop-1-en-2-yl)azetidine-1-
carboxylate (9a): Using tertꢀbutyl 3ꢀoxoazetidineꢀ1ꢀcarboxylate
(1) and isopropenylmagnesium bromide according to general
procedure B, provided 9a (4.40 mmol, 1.00 g, 88%) as colorless
oil. 1H NMR (400 MHz, CDCl3) δ 5.15 (s, 1H), 5.04 (s, 1H), 3.97
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 11
carboxylate (6d): Using tertꢀbutyl 3ꢀ(3ꢀmethylbutꢀ2ꢀenꢀ2ꢀ
tert-Butyl 3-(1-ethoxyvinyl)-3-methoxyazetidine-1-carboxylate
(9f): Using tertꢀbutyl 3ꢀoxoazetidineꢀ1ꢀcarboxylate (1) and vinylꢀ
lithium according to general procedure B, provided 9f after purifiꢀ
cation on silica gel (hexane/ethyl acetate 9:1), (2.33 mmol,
600 mg, 58%) as colorless oil. Rf = 0.5 (hexane/EtOAc 8:2, UV,
yl)azeteꢀ1(2H)ꢀcarboxylate and 1ꢀmethylꢀ1Hꢀpyrroleꢀ2,5ꢀdione
according to general procedure C, provided 6d (0.36 mmol,
120 mg, 72%) as a yellow sticky foam. 1H NMR (400 MHz,
CDCl3) δ 4.94 (dq, J = 9.9, 2.4 Hz, 1H), 4.40 (dt, J = 11.8, 2.1 Hz,
1H), 4.12 – 4.05 (m, 1H), 3.42 (dd, J = 9.7, 7.9 Hz, 1H), 2.85 (s,
3H), 2.67 (d, J = 7.7 Hz, 1H), 1.56 (d, J = 1.4 Hz, 3H), 1.51 (s,
3H), 1.44 (s, 9H), 0.99 ppm (s, 3H). 13C NMR (101 MHz, CDCl3)
δ 177.4, 173.6, 157.8, 135.6, 124.4, 80.4, 77.2, 63.9, 56.3, 54.2,
43.6, 37.8, 28.5, 28.2, 24.8, 24.2, 14.1 ppm. LRMS (DEP/EIꢀ
Orbitrap): m/z 278.1 (16), 261.1 (9), 234.2 (20), 219.2 (52), 202.1
1
2
3
4
5
6
7
8
1
KMnO4, PAA). H NMR (400 MHz, CDCl3) δ 4.28 – 4.22 (m,
2H), 4.05 (d, J = 9.2 Hz, 2H), 3.89 (d, J = 9.2 Hz, 2H), 3.79 (q, J =
7.0 Hz, 2H), 3.21 (s, 3H), 1.44 (s, 9H), 1.33 ppm (t, J = 7.0 Hz,
3H). 13C NMR (101 MHz, CDCl3) δ 158.8, 156.6, 84.3, 79.7,
76.0, 63.5, 51.8, 28.5, 28.5, 14.5 ppm. LRMS (ESIꢀquadrupole
pos): m/z (%): 258.2 (100), 202.1 (50), 170.1 (10), 126.6 (2).
9
+
+
HRMS (ESIꢀquadrupole pos): calcd for C13H24NO4 : 258.1700,
(5), 167.1 (92). HRMS (EIꢀOrbitrap): calcd for C18H26N2O4 :
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
found 258.1702. IR (DiamondꢀATR, neat) ꢀȬ(ꢁ3: 2978 (w),
334.1893; found: 334.1895. IR (DiamondꢀATR, neat) ꢀȬ(ꢁ3: 2978
2934 (w), 2886 (w), 1704 (vs), 1628 cmꢀ1 (w).
(w), 2934 (vw), 2872 (vw), 2254 (vw), 1778 (w), 1696 cmꢀ1 (s).
tert-Butyl-(4aR*,7aR*,7bR*)-3-methyl-5,7-dioxo-
tert-Butyl-(5aS,5bR,8aR,8bR)-7-methyl-6,8-dioxo-
4,4a,5,7,7a,7b-hexahydroisobenzofuro[4,5-b]azete-1(2H)-
carboxylate (6a): Using tertꢀbutyl 3ꢀ(propꢀ1ꢀenꢀ2ꢀyl)azeteꢀ1(2H)ꢀ
carboxylate and maleic anhydride according to general procedure
C, provided 6a (0.20 mmol, 60 mg, 51%) as a light yellow solid.
1H NMR (400 MHz, CDCl3) δ 4.72 (d, J = 9.4 Hz, 1H), 4.55 (d, J
= 11.3 Hz, 1H), 4.33 (d, J = 12.2 Hz, 1H), 3.71 (t, J = 8.5 Hz, 1H),
3.41 (ddd, J = 8.9, 5.5, 1.9 Hz, 1H), 2.60 (dd, J = 15.2, 1.9 Hz,
1H), 2.25 (d, J = 16.1 Hz, 1H), 1.71 (s, 3H), 1.49 ppm (s, 9H). 13C
NMR (101 MHz, CDCl3) δ 173.9, 167.8, 136.6, 127.8, 125.7,
80.9, 77.2, 62.6, 56.4, 43.1, 42.2, 29.0, 28.4, 18.5 ppm. LRMS
(DEP/EIꢀOrbitrap): m/z 293.3 (2), 237.2 (4), 195.2 (9). HRMS
2,4,5,5a,5b,6,7,8,8a,8b-decahydro-1H-azeto[2,3-e]furo[2,3-
g]isoindole-1-carboxylate (6e): Using tertꢀbutyl 3ꢀ(4,5ꢀ
dihydrofuranꢀ2ꢀyl)azeteꢀ1(2H)ꢀcarboxylate and 1ꢀmethylꢀ1Hꢀ
pyrroleꢀ2,5ꢀdione according to general procedure C, provided 6e
1
(0.44 mmol, 150 mg, 88%) as a white solid. H NMR (400 MHz,
CDCl3) δ 4.89 (dd, J = 6.5, 4.4 Hz, 1H), 4.43 (t, J = 9.4 Hz, 2H),
3.86 (t, J = 7.3 Hz, 1H), 3.46 (d, J = 7.1 Hz, 1H), 3.30 – 3.25 (m,
1H), 3.24 – 3.20 (m, 1H), 2.90 (s, 3H), 2.88 – 2.80 (m, 2H), 2.74
– 2.71 (m 1H), 1.34 ppm (s, 9H). 13C NMR (101 MHz, CDCl3) δ
176.6, 175.3, 158.1, 153.6, 100.1, 80.7, 77.2, 70.1, 61.0, 53.2,
44.0, 41.1, 32.4, 28.1, 27.4, 25.1.ppm. LRMS (DEP/EIꢀOrbitrap):
m/z 234.2 (8), 205.1 (42), 177.1 (11). HRMS (EIꢀOrbitrap): calcd
+
(EIꢀOrbitrap): calcd for C15H19NO5 : 293.1263; found: 293.1255.
+
IR (DiamondꢀATR, neat) ꢀȬ(ꢁ3: 2984 (w), 2933 (w), 2869 (vw),
for C17H22N2O5 : 334.1529; found: 334.1518. IR (DiamondꢀATR,
1837 (w), 1773 (s), 1685 (vs), 1645 cmꢀ1 (w). mp (°C): 170 – 175.
neat) ꢀȬ(ꢁ3: 2976 (w), 2932 (w), 2898 (w), 2254 (vw), 1780 (w),
1696 cmꢀ1 (vs). mp (°C): 170 – 174.
tert-Butyl-(4aR*,7aR*,7bR*)-3,6-dimethyl-5,7-dioxo-
2,4,4a,5,6,7,7a,7b-octahydro-1H-azeto[2,3-e]isoindole-1-
carboxylate (6b): Using tertꢀbutyl 3ꢀ(propꢀ1ꢀenꢀ2ꢀyl)azeteꢀ
1(2H)ꢀcarboxylate and 1ꢀmethylꢀ1Hꢀpyrroleꢀ2,5ꢀdione according
to general procedure C, provided 6b (0.23 mmol, 70 mg, 58%) as
tert-Butyl-(4aR*,7aR*,7bR*)-3-ethoxy-6-methyl-5,7-dioxo-
2,4,4a,5,6,7,7a,7b-octahydro-1H-azeto[2,3-e]isoindole-1-
carboxylate (6f): Using tertꢀbutyl 3ꢀ(1ꢀethoxyvinyl)azeteꢀ1(2H)ꢀ
carboxylate and 1ꢀmethylꢀ1Hꢀpyrroleꢀ2,5ꢀdione according to
general procedure C, provided 6f (0.39 mmol, 130 mg, 77%) as
1
a white solid. H NMR (400 MHz, CDCl3) δ 4.71 (d, J = 9.1 Hz,
1
1H), 4.50 (d, J = 11.3 Hz, 1H), 4.23 (d, J = 12.2 Hz, 1H), 3.44 (t, J
= 8.5 Hz, 1H), 3.06 (t, J = 8.5 Hz, 1H), 2.96 (s, 3H), 2.60 (dd, J =
15.1, 1.5 Hz, 1H), 2.17 (d, J = 15.6 Hz, 1H), 1.64 (s, 3H),
1.51 ppm (s, 9H). 13C NMR (101 MHz, CDCl3) δ 179.4, 174.5,
156.7, 126.7, 125.2, 77.2, 63.9, 55.6, 42.1, 41.2, 28.8, 28.5, 25.4,
18.4 ppm. LRMS (DEP/EIꢀOrbitrap): m/z 306.1 (1), 250.1 (31),
233.1 (8), 206.1 (38), 191.0 (11). HRMS (EIꢀOrbitrap): calcd for
white solid. Rf = 0.1 (hexane/EtOAc 7:3, UV, KMnO4, PAA). H
NMR (400 MHz, CDCl3) δ 4.75 – 4.71 (m, 1H), 4.63 (dt, J = 11.2,
2.6 Hz, 1H), 4.42 – 4.37 (m, 1H), 3.72 (qd, J = 7.1, 4.1 Hz, 2H),
3.35 (s, 1H), 3.05 (t, J = 6.7 Hz, 1H), 2.95 (s, 3H), 2.62 (d, J =
15.5, 1H), 2.29 – 2.19 (m, 1H), 1.46 (s, 9H), 1.17 ppm (t, J = 7.0
Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 178.8, 174.4, 156.0,
145.2, 95.6, 80.2, 64.6, 64.1, 55.1, 41.8, 40.9, 28.4, 27.5, 25.3,
14.8 ppm. LRMS (ESIꢀquadrupole pos): m/z (%): 337.2 (40),
281.1 (100), 253.0 (5), 237.1 (2). HRMS (ESIꢀquadrupole pos):
+
C16H22N2O4 : 306.1580; found: 306.1588. IR (DiamondꢀATR,
neat) ꢀȬ(ꢁ3: 2972 (w), 2944 (w), 2926 (w), 2881 (w), 2866 (w),
+
1776 (w), 1698 cmꢀ1 (vs). mp(°C): 110 – 115.
calcd for C17H25N2O5 : 337.1758, found 337.1761. IR (Diamondꢀ
ATR, neat) ꢀȬ(ꢁ3: 2982 (w), 2932 (w), 2874 (w), 2252 (vw),
2154 (vw), 1778 (w), 1696 (s), 1560 cmꢀ1 (vw). mp (°C): 120 –
125.
tert-Butyl-(4R*,4aR*,7aR*,7bR*)-3,4,6-trimethyl-5,7-dioxo-
2,4,4a,5,6,7,7a,7b-octahydro-1H-azeto[2,3-e]isoindole-1-
carboxylate (6c): Using tertꢀbutyl (Z)ꢀ3ꢀ(butꢀ2ꢀenꢀ2ꢀyl)azeteꢀ
1(2H)ꢀcarboxylate and 1ꢀmethylꢀ1Hꢀpyrroleꢀ2,5ꢀdione according
to general procedure C, provided 6c (0.38 mmol, 120 mg, 75%) as
tert-Butyl-(4R*,4aR*,7aR*,7bR*)-3,4-dimethyl-5,7-dioxo-6-
phenyl-2,4,4a,5,6,7,7a,7b-octahydro-1H-azeto[2,3-e]isoindole-
1-carboxylate (6g): Using tertꢀbutyl (Z)ꢀ3ꢀ(butꢀ2ꢀenꢀ2ꢀyl)azeteꢀ
1(2H)ꢀcarboxylate and 1ꢀphenylꢀ1Hꢀpyrroleꢀ2,5ꢀdione according
to general procedure C, provided 6g (0.48 mmol, 190 mg, 96%)
1
a sticky oil. H NMR (400 MHz, CDCl3) δ 4.89 (dq, J = 9.5, 2.3
Hz, 1H), 4.53 – 4.42 (m, 1H), 4.18 (ddd, J = 12.0, 2.7, 1.2 Hz,
1H), 3.45 (t, J = 8.9 Hz, 1H), 2.93 (s, 3H), 2.88 (ddd, J = 11.9,
7.6, 1.7 Hz, 2H), 1.62 (q, J = 1.8 Hz, 3H), 1.49 (s, 9H), 1.08 ppm
(d, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 179.0, 174.2,
157.2, 132.3, 123.9, 80.4, 63.2, 56.4, 48.4, 42.3, 36.2, 28.4, 25.3,
18.7, 17.6 ppm. LRMS (DEP/EIꢀOrbitrap): m/z 264.1 (29), 247.2
(9), 220.2 (40), 205.1 (27), 153.1 (45). HRMS (EIꢀOrbitrap):
1
as a yellowish solid. H NMR (400 MHz, CDCl3) δ 7.43 – 7.36
(m, 2H), 7.34 (t, J = 7.4 Hz, 1H), 7.18 – 7.15 (m, 2H), 5.05 – 4.94
(m, 1H), 4.55 (d, J = 12.1 Hz, 1H), 4.26 (d, J = 11.4 Hz, 1H), 3.61
(t, J = 9.0 Hz, 1H), 3.08 (dd, J = 8.3, 1.6 Hz, 1H), 3.01 (q, J = 7.3
Hz, 1H), 1.67 (s, 3H), 1.48 (s, 9H), 1.13 (d, J = 7.3 Hz, 3H). 13C
NMR (101 MHz, CDCl3) δ 177.8, 173.1, 157.3, 132.9, 132.1,
129.2, 128.6, 126.5, 123.9, 80.5, 77.2, 63.4, 56.3, 48.6, 42.5, 36.4,
28.4, 18.3, 17.7, 14.0 ppm. LRMS (DEP/EIꢀOrbitrap): m/z 282.1
(62), 265.1 (83), 248.1 (10), 237.2 (34), 221.2 (16), 207.1 (16),
194.1 (13), 172.2 (8). HRMS (EIꢀOrbitrap): calcd for
+
calcd for C17H24N2O4 : 320.1736; found: 320.1730. IR (Diamondꢀ
ATR, neat) ꢀȬ(ꢁ3: 2970 (w), 2932 (w), 2872 (vw), 1778 (w), 1694
cmꢀ1 (vs).
tert-Butyl-(4aS*,7aR*,7bR*)-3,4,4,6-tetramethyl-5,7-dioxo-
2,4,4a,5,6,7,7a,7b-octahydro-1H-azeto[2,3-e]isoindole-1-
+
C22H26N2O4 : 382.1893; found: 382.1897. IR (DiamondꢀATR,
ACS Paragon Plus Environment

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The Journal of Organic Chemistry
neat) ꢀȬ(ꢁ3: 2972 (w), 2932 (w), 2872 (w), 1780 (w), 1704 (vs),
(0.47 mmol, 227 mg, 93%) as white solid. Rf = 0.2 (hexꢀ
ane/EtOAc 7:3, UV, KMnO4, PAA). 1H NMR (400 MHz, CDCl3)
δ 7.62 (d, J = 7.7 Hz, 2H), 7.56 (d, J = 8.0 Hz, 2H), 7.45 (t, J = 7.5
Hz, 2H), 7.36 (dd, J = 7.7, 5.8 Hz, 3H), 6.51 (s, 1H), 4.75 (s, 1H),
4.32 (d, J = 8.4 Hz, 1H), 3.88 (d, J = 12.1 Hz, 1H), 3.32 (t, J = 7.7
Hz, 1H), 3.27 – 3.21 (m, 1H), 2.99 (s, 3H), 2.71 (dd, J = 15.7, 1.6
Hz, 1H), 2.60 (dd, J = 16.3, 7.1 Hz, 1H), 1.60 (s, 3H), 1.51 ppm
(s, 9H). 13C NMR (101 MHz, CDCl3) δ 179.4, 175.3, 157.3,
140.7, 140.4, 139.2, 129.0, 127.5, 127.3, 127.1, 127.1, 126.9,
126.5, 81.3, 79.5, 74.7, 55.7, 43.5, 41.7, 29.5, 28.5, 25.6,
18.4 ppm. LRMS (DEP/EIꢀOrbitrap): m/z 489.3 (2). 447.3 (2),
374.2 (10), 306.2 (20). HRMS (EIꢀOrbitrap): calcd for
1
2
3
4
5
6
7
8
1598 cmꢀ1 (w). mp (°C): 145 – 149
tert-Butyl-(4aR*,7aS*,7bS*)-3-ethoxy-6-methyl-5,7-dioxo-7b-
(trimethylsilyl)-2,4,4a,5,6,7,7a,7b-octahydro-1H-azeto[2,3-
e]isoindole-1-carboxylate (6h): Using tertꢀbutyl 3ꢀ(1ꢀ
ethoxyvinyl)ꢀ4ꢀ(trimethylsilyl)azeteꢀ1(2H)ꢀcarboxylate and 1ꢀ
methylꢀ1Hꢀpyrroleꢀ2,5ꢀdione according to general procedure C,
provided 6h (0.34 mmol, 140 mg, 67%) as white solid. Rf = 0.3
(hexane/EtOAc 7:3, UV, KMnO4, PAA). 1H NMR (400 MHz,
CDCl3) δ 4.53 (dd, J = 11.5, 2.7 Hz, 1H), 4.46 (d, J = 12.1 Hz,
1H), 3.74 (q, J = 7.0 Hz, 2H), 3.49 – 3.35 (m, 1H), 2.98 (t, J = 8.6
Hz, 1H), 2.95 (s, 3H), 2.49 (d, J = 16.5 Hz, 1H), 2.31 (dd, J =
16.1, 7.4 Hz, 1H), 1.47 (d, J = 17.9 Hz, 9H), 1.17 (t, J = 7.0 Hz,
3H), 0.18 ppm (s, 9H). 13C NMR (101 MHz, CDCl3) δ 180.5,
176.5, 156.8, 145.2, 102.2, 81.9, 80.8, 65.9, 58.0, 56.7, 45.2, 42.8,
30.0, 26.8, 16.5, 0.0 ppm. LRMS (ESIꢀquadrupole pos): m/z (%):
363.4 (1), 351.4(50), 307.3 (100), 263.2 (20). HRMS (ESIꢀ
quadrupole pos): calcd for C16H23N2O5Si+ [M–tꢀBu]+: 351.1376;
found: 351.1388. IR (DiamondꢀATR, neat) ꢀȬ(ꢁ3: 2978 (w),
2900 (vw), 2868 (vw), 1778 (w), 1700 cmꢀ1 (vs). mp (°C): 130 –
132.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
C29H33N2O5 : 489.2384, found 489.2410 IR (DiamondꢀATR,
neat) ꢀȬ(ꢁ3
: 3300 (vw), 2978 (vw), 2932 (vw), 2868 (vw),
2252 (vw), 1776 (w), 1700 (s), 1660 (m), 1600 (vw), 1520 cmꢀ
1 (vw). mp (°C): 165 – 170.
tert-Butyl-(4aR*,7aR*,7bR*)-7b-((S*)-(4-cyanophenyl)
(hydroxy)methyl)-3,6-dimethyl-5,7-dioxo-2,4,4a,5,6,7,7a,7b-
octahydro-1H-azeto[2,3-e]isoindole-1-carboxylate (12c): Using
tertꢀbutyl 4ꢀ((4ꢀcyanophenyl)(hydroxy)methyl)ꢀ3ꢀ(propꢀ1ꢀenꢀ2ꢀ
yl)azeteꢀ1(2H)ꢀcarboxylate and 1ꢀmethylꢀ1Hꢀpyrroleꢀ2,5ꢀdione
according to general procedure C, provided 12c (0.4 mmol,
175 mg, 80%) as yellow solid. Rf = 0.1 (hexane/EtOAc 7:3, UV,
1
KMnO4, PAA). H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 8.0
tert-Butyl-(4aR*,7aS*,7bS*)-3,6-dimethyl-5,7-dioxo-7b-
(trimethylsilyl)-2,4,4a,5,6,7,7a,7b-octahydro-1H-azeto[2,3-
e]isoindole-1-carboxylate (6i): Using tertꢀbutyl 3ꢀ(propꢀ1ꢀenꢀ2ꢀ
yl)ꢀ4ꢀ(trimethylsilyl)azeteꢀ1(2H)ꢀcarboxylate and 1ꢀmethylꢀ1Hꢀ
pyrroleꢀ2,5ꢀdione according to general procedure C, provided 6i
(0.37 mmol, 140 mg, 74%) as white solid. Rf = 0.3 (hexꢀ
ane/EtOAc 7:3, UV, KMnO4, PAA). 1H NMR (400 MHz, CDCl3)
δ 4.37 (d, J = 12.5 Hz, 1H), 4.23 (d, J = 12.3 Hz, 1H), 3.54 – 3.40
(m, 1H), 2.98 (t, J = 6.9 Hz, 1H), 2.94 (s, 3H), 2.46 (d, J = 15.9,
1H), 2.30 – 2.19 (m, 1H), 1.62 (s, 3H), 1.57 – 1.41 (m, 9H),
0.19 ppm (s, 9H). 13C NMR (101 MHz, CDCl3) δ 179.7, 174.9,
128.9, 123.7, 80.7, 60.5, 44.4, 41.7, 29.4, 28.6, 25.4, 21.2, 18.6,
18.6, ꢀ1.4 ppm. LRMS (DEP/EIꢀOrbitrap): m/z 333.3 (2), 321.8
(15), 277.2 (100), 263.2 (30). HRMS (EIꢀOrbitrap): calcd for
C19H30N2O4Si+: 378.1975, found 378.1963 IR (DiamondꢀATR,
neat) ꢀȬ(ꢁ3: 2974 (w), 2948 (w), 2934 (w), 2902 (vw), 2864 (vw),
1778 (w), 1698 cmꢀ1 (vs).
Hz, 2H), 7.38 (d, J = 8.1 Hz, 2H), 6.62 (d, J = 10.4 Hz, 1H), 4.72
(d, J = 8.6 Hz, 1H), 4.24 (d, J = 8.4 Hz, 1H), 3.87 (d, J = 12.2 Hz,
1H), 3.30 (t, J = 7.7 Hz, 1H), 3.13 (d, J = 12.3 Hz, 1H), 2.95 (s,
3H), 2.69 (d, J = 15.7, 1H), 2.54 (dd, J = 15.9, 7.4 Hz, 1H), 1.58
(s, 3H), 1.46 ppm (s, 9H). 13C NMR (101 MHz, CDCl3) δ 179.0,
174.9, 157.1, 145.8, 131.6, 128.3, 127.5, 126.2, 118.8, 111.6,
81.6, 79.1, 74.3, 55.5, 43.3, 41.4, 29.6, 28.4, 25.5, 18.4 ppm.
LRMS (DEP/EIꢀOrbitrap): m/z 379.4 (2), 321.3 (5). HRMS (EIꢀ
+
Orbitrap): calcd for C24H28N3O5 : 438.2023, found 438.2013 IR
(DiamondꢀATR, neat) ꢀȬ(ꢁ3: 3286 (vw), 2980 (vw), 2254 (vw),
2230 (vw), 1776 (vw), 1700 (m), 1658 (w), 1610 cmꢀ1 (vw). mp
(°C): 160 – 165.
tert-Butyl-(4aR*,7aR*,7bR*)-7b-((S*)-hydroxy(4-nitrophenyl)
methyl)-3,6-dimethyl-5,7-dioxo-2,4,4a,5,6,7,7a,7b-octahydro-
1H-azeto[2,3-e]isoindole-1-carboxylate (12d): Using tertꢀbutyl
(S*)ꢀ4ꢀ(hydroxy(4ꢀnitrophenyl)methyl)ꢀ3ꢀ(propꢀ1ꢀenꢀ2ꢀyl)azeteꢀ
1(2H)ꢀcarboxylate and 1ꢀmethylꢀ1Hꢀpyrroleꢀ2,5ꢀdione according
to general procedure C, provided 12d (0.42 mmol, 190 mg, 83%)
as yellow solid. Rf = 0.1 (hexane/EtOAc 7:3, UV, KMnO4, PAA).
1H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 8.6 Hz, 2H), 7.46 (d, J
= 8.5 Hz, 2H), 6.71 (s, 1H), 4.79 (s, 1H), 4.28 (d, J = 8.4 Hz, 1H),
3.91 (d, J = 12.2 Hz, 1H), 3.33 (t, J = 7.2 Hz, 1H), 3.18 (d, J =
11.9 Hz, 1H), 2.99 (s, 3H), 2.73 (d, J = 15.7, 1H), 2.59 (dd, J =
15.3, 7.3 Hz, 1H), 1.61 (s, 3H), 1.50 ppm (s, 9H). 13C NMR (101
MHz, CDCl3) δ 179.0, 174.9, 157.2, 147.9, 147.6, 128.5, 127.8,
126.2, 123.0, 81.9, 79.2, 74.3, 55.6, 43.3, 41.5, 29.7, 28.4, 25.6,
18.5 ppm. LRMS (ESIꢀquadrupole pos): m/z (%): 458.2 (100),
402.1 (20), 251.1 (10). HRMS (ESIꢀquadrupole pos): calcd for
tert-Butyl-(4aR*,7aR*,7bR*)-7b-((S*)-
hydroxy(phenyl)methyl)-3,6-dimethyl-5,7-dioxo-
2,4,4a,5,6,7,7a,7b-octahydro-1H-azeto[2,3-e]isoindole-1-
carboxylate (12a): Using tertꢀbutyl 4ꢀ(hydroxy(phenyl)methyl)ꢀ
3ꢀ(propꢀ1ꢀenꢀ2ꢀyl)azeteꢀ1(2H)ꢀcarboxylate and 1ꢀmethylꢀ1Hꢀ
pyrroleꢀ2,5ꢀdione according to general procedure C, provided 12a
1
(0.44 mmol, 180 mg, 62%) as colorless oil. H NMR (400 MHz,
CDCl3) δ 7.16 – 7.07 (m, 5H), 6.32 (s, 1H), 4.56 (s, 1H), 4.14 (d,
J = 8.4 Hz, 1H), 3.69 (d, J = 12.0 Hz, 1H), 3.15 (t, J = 7.4 Hz,
1H), 2.97 (d, J = 11.9 Hz, 1H), 2.83 (s, 3H), 2.53 (d, J = 15.3 Hz,
1H), 2.42 (dd, J = 15.5, 6.5 Hz, 1H), 1.43 (s, 3H), 1.35 ppm (s,
9H). 13C NMR (101 MHz, CDCl3) δ 179.4, 175.3, 157.2, 140.0,
127.8, 127.7, 126.9, 126.8, 81.1, 79.4, 77.2, 74.8, 55.6, 43.4, 41.6,
29.4, 28.4, 25.5, 18.3 ppm. LRMS (DEP/EIꢀOrbitrap): m/z 294.1
(100), 279.1 (48), 222.2 (8), 208.2 (23). HRMS (EIꢀOrbitrap):
+
C23H28N3O7 : 458.1922, found 458.1922. IR (DiamondꢀATR,
neat) ꢀȬ(ꢁ3: 3276 (vw), 2978 (w), 2934 (w), 2868 (vw), 1776 (w),
1698 (s), 1658 (m), 1606 (w), 1520 cmꢀ1 (m). mp (°C): 152 – 155.
+
calcd for C23H29N2O5 : 413.2071; found: 413.2054. IR (Diamondꢀ
ATR, neat) ꢀȬ(ꢁ3: 3306 (vw), 2976 (w), 2932 (w), 2868 (vw),
tert-Butyl-(4aR*,7aR*,7bR*)-7b-((R*)-furan-2-yl(hydroxy)
methyl)-3,6-dimethyl-5,7-dioxo-2,4,4a,5,6,7,7a,7b-octahydro-
1H-azeto[2,3-e]isoindole-1-carboxylate (12e): Using tertꢀbutyl
4ꢀ(furanꢀ2ꢀyl(hydroxy)methyl)ꢀ3ꢀ(propꢀ1ꢀenꢀ2ꢀyl)azeteꢀ1(2H)ꢀ
carboxylate and 1ꢀmethylꢀ1Hꢀpyrroleꢀ2,5ꢀdione according to
general procedure C, provided 12e (0.35 mmol, 140 mg, 70%) as
a white solid. 1H NMR (400 MHz, CDCl3) δ 7.34 (s, 1H), 6.40 (d,
J = 9.2 Hz, 1H), 6.35 (s, 1H), 6.28 (d, J = 3.1 Hz, 1H), 4.65 (d, J =
7.7 Hz, 1H), 4.20 (d, J = 8.5 Hz, 1H), 3.96 (d, J = 11.9 Hz, 1H),
1776 (w), 1698 (vs), 1662 cmꢀ1 (s).
tert-Butyl-(4aR*,7aR*,7bR*)-7b-((S*)-[1,1'-biphenyl]-4-
yl(hydroxy)methyl)-3,6-dimethyl-5,7-dioxo-2,4,4a,5,6,7,7a,7b-
octahydro-1H-azeto[2,3-e]isoindole-1-carboxylate (12b): Using
tertꢀbutyl (S*)ꢀ4ꢀ([1,1'ꢀbiphenyl]ꢀ4ꢀyl(hydroxy)methyl)ꢀ3ꢀ(propꢀ
1ꢀenꢀ2ꢀyl)azeteꢀ1(2H)ꢀcarboxylate and 1ꢀmethylꢀ1Hꢀpyrroleꢀ2,5ꢀ
dione according to general procedure C, provided 12b
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 11
3.61 (d, J = 11.9 Hz, 1H), 3.20 (t, J = 7.4 Hz, 1H), 2.96 (s, 3H),
308.1482; found: 308.1479, found 322.1651 IR (DiamondꢀATR,
2.61 (d, J = 15.6 Hz, 1H), 2.41 (dd, J = 15.5, 6.0 Hz, 1H), 1.58 (s,
3H), 1.47 ppm (s, 9H). 13C NMR (101 MHz, CDCl3) δ 179.3,
175.0, 157.5, 153.6, 142.1, 127.3, 125.8, 110.5, 107.8, 81.2, 78.1,
77.2, 69.8, 55.7, 43.2, 41.6, 28.9, 28.4, 25.5, 18.5 ppm. LRMS
(ESIꢀquadrupole pos): m/z (%): 284.1 (100), 269.1 (21), 241.2
(5), 210.0 (6), 198.1 (12), 184.1 (67), 170.1 (8). HRMS (ESIꢀ
neat) ꢀȬ(ꢁ3: 2977 (w), 2935 (w), 2873 (vw), 1847 (w), 1779 (vs),
1
2
3
4
5
6
7
8
1697 cmꢀ1 (s). mp (°C): 151 – 155.
tert-Butyl-(4aR*,7aR*,7bR*)-3,4a-dimethyl-5,7-dioxo-
4,4a,5,7,7a,7b-hexahydroisobenzofuro[4,5-b]azete-1(2H)-
carboxylate-7b-d (14b): Using tertꢀbutyl 3ꢀ(propꢀ1ꢀenꢀ2ꢀ
yl)azeteꢀ1(2H)ꢀcarboxylateꢀ4ꢀd and 3ꢀmethylfuranꢀ2,5ꢀdione
according to general procedure D, provided 14b (0.7 mmol,
+
quadrupole pos): calcd for C21H27N2O6 : 403.1864; found:
403.1926. IR (DiamondꢀATR, neat) ꢀȬ(ꢁ3: 3298 (vw), 2974 (w),
2930 (w), 2870 (w), 1778 (w), 1698 (vs), 1668 cmꢀ1 (s). mp (°C):
157 – 160.
1
20 mg, 14%) as colorless crystals. H NMR (400 MHz, CDCl3) δ
4.52 (d, J = 12.4 Hz, 1H), 4.30 (d, J = 12.4 Hz, 1H), 3.31 (s, 1H),
2.51 (d, J = 15.0 Hz, 1H), 2.04 (d, J = 14.9 Hz, 1H), 1.68 (s, 3H),
1.48 (s, 9H), 1.46 ppm (s, 3H). 13C NMR (101 MHz, CDCl3) δ
176.8, 167.3, 156.4, 128.4, 125.9, 80.8, 77.2, 63.2, 55.7, 50.5,
49.1, 37.9, 28.4, 24.2, 18.1 ppm. LRMS (DEP/EIꢀOrbitrap): m/z
(%): 196.2 (15), 140.1 (49). HRMS (EIꢀOrbitrap): calcd for
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
tert-Butyl-(4aR*,7aR*,7bR*)-7b-((S*)-hydroxy(1-methyl-1H-
indol-3-yl)methyl)-3,6-dimethyl-5,7-dioxo-2,4,4a,5,6,7,7a,7b-
octahydro-1H-azeto[2,3-e]isoindole-1-carboxylate (12f): Using
tertꢀbutyl
(S*)ꢀ4ꢀ(hydroxy(1ꢀmethylꢀ1Hꢀindolꢀ3ꢀyl)methyl)ꢀ3ꢀ
and 1ꢀmethylꢀ1Hꢀ
+
(propꢀ1ꢀenꢀ2ꢀyl)azeteꢀ1(2H)ꢀcarboxylate
C16H20DNO5 : 308.1482; found: 308.1479. IR (DiamondꢀATR,
pyrroleꢀ2,5ꢀdione according to general procedure C, provided 12f
(0.41 mmol, 191 mg, 82%) as brown oil. Rf = 0.1 (hexane/EtOAc
7:3, UV, KMnO4, PAA). 1H NMR (400 MHz, CDCl3) δ 7.30 (d, J
= 8.3 Hz, 2H), 7.22 – 7.17 (m, 2H), 7.02 (t, J = 7.5 Hz, 1H), 6.29
(d, J = 11.0 Hz, 1H), 5.09 (d, J = 11.0 Hz, 1H), 4.40 (d, J = 8.5
Hz, 1H), 3.84 (d, J = 11.9 Hz, 1H), 3.79 (s, 3H), 3.36 – 3.26 (m,
2H), 3.00 (s, 3H), 2.78 – 2.65 (m, 2H), 1.52 ppm (s, 12H). 13C
NMR (101 MHz, CDCl3) δ 179.5, 175.5, 157.7, 136.9, 128.2,
127.0, 126.9, 126.9, 121.5, 119.2, 119.1, 114.6, 109.3, 80.7, 79.7,
69.7, 56.3, 43.6, 41.8, 33.0, 29.3, 28.5, 25.5, 18.4 ppm. LRMS
(DEP/EIꢀOrbitrap): m/z 447.3 (2), 374.2 (10), 306.2 (20), 250.1
neat) ꢀȬ(ꢁ3: 2977 (w), 2935 (w), 2873 (vw), 1847 (w), 1779 (vs),
1697 cmꢀ1 (s). mp (°C): 151 – 155.
tert-Butyl-(4S*,4aR*,7aR*,7bS*)-3,4,7a-trimethyl-5,7-dioxo-
4,4a,5,7,7a,7b-hexahydroisobenzofuro[4,5-b]azete-1(2H)-
carboxylate (15a): Using tertꢀbutyl (E)ꢀ3ꢀ(butꢀ2ꢀenꢀ2ꢀyl)azeteꢀ
1(2H)ꢀcarboxylate and 3ꢀmethylfuranꢀ2,5ꢀdione according to
general procedure D, provided 15a (0.18 mmol, 58 mg, 36%) as
white solid. Rf = 0.5 (hexane/EtOAc 7:3, UV, KMnO4, PAA). 1H
NMR (400 MHz, CDCl3) δ 4.50 – 4.42 (m, 1H), 4.32 (s, 1H), 4.25
(d, J = 12.5 Hz, 1H), 2.77 (d, J = 3.1 Hz, 1H), 2.48 – 2.36 (m,
+
1H), 1.68 (s, 3H), 1.60 (s, 3H), 1.52 (s, 3H), 1.49 ppm (s, 9H). 13
C
(100). HRMS (EIꢀOrbitrap): calcd for C26H31N3O5 : 465.2264,
found 465.2258. IR (DiamondꢀATR, neat) ꢀȬ(ꢁ3: 3324 (vw),
2946 (vw), 2934 (vw), 2926 (vw), 2894 (vw), 2884 (vw),
2254 (vw), 1776 (vw), 1700 (m), 1662 (w), 1616 (vw), 1548 cmꢀ
1 (vw).
NMR (101 MHz, CDCl3) δ 171.3, 171.0, 157.1, 133.0, 126.0,
81.2, 71.4, 57.2, 55.5, 51.0, 32.6, 28.4, 21.7, 14.3, 14.2 ppm.
LRMS (ESIꢀquadrupole pos): m/z (%): 322.2 (85), 266.1 (100).
+
HRMS (ESIꢀquadrupole pos): calcd for C17H24NO5 : 322.1649,
found 322.1651 IR (DiamondꢀATR, neat) ꢀȬ(ꢁ3
: 2998 (w),
tert-Butyl-(4aR*,7aR*,7bR*)-7b-((S*)-1-hydroxy-2-methyl
propyl)-3,6-dimethyl-5,7-dioxo-2,4,4a,5,6,7,7a,7b-octahydro-
1H-azeto[2,3-e]isoindole-1-carboxylate (12g): Using tertꢀbutyl
4ꢀ(1ꢀhydroxyꢀ2ꢀmethylpropyl)ꢀ3ꢀ(propꢀ1ꢀenꢀ2ꢀyl)azeteꢀ1(2H)ꢀ
carboxylate and 1ꢀmethylꢀ1Hꢀpyrroleꢀ2,5ꢀdione according to
general procedure C, provided 12g (0.29 mmol, 110 mg, 58%) as
2978 (w), 2946 (w), 2920 (w), 1846 (m), 1774 (s), 1676 cmꢀ1 (vs).
mp(°C): 169ꢀ173.
tert-Butyl-(4R*,4aR*,7aR*,7bR*)-3,4,4a-trimethyl-5,7-dioxo-
4,4a,5,7,7a,7b-hexahydroisobenzofuro[4,5-b]azete-1(2H)-
carboxylate (15b): Using tertꢀbutyl (E)ꢀ3ꢀ(butꢀ2ꢀenꢀ2ꢀyl)azeteꢀ
1(2H)ꢀcarboxylate and 3ꢀmethylfuranꢀ2,5ꢀdione according to
general procedure D, provided 15b (0.05 mmol, 14 mg, 9%) as
white solid. Rf = 0.45 (hexane/EtOAc 7:3, UV, KMnO4, PAA).
1H NMR (400 MHz, CDCl3) δ 4.71 (d, J = 7.1 Hz, 1H), 4.54 (d, J
= 12.5, 1H), 4.35 (d, J = 12.5 Hz, 1H), 3.37 (s, 1H), 2.25 (d, J =
7.7 Hz, 1H), 1.63 (s, 3H), 1.48 (s, 12H), 1.36 ppm (d, J = 7.5 Hz,
3H). 13C NMR (101 MHz, CDCl3) δ 174.3, 167.7, 156.1, 131.4,
128.0, 80.7, 62.9, 56.0, 52.2, 39.8, 29.8, 28.5, 22.3, 14.0,
11.0 ppm. LRMS (ESIꢀquadrupole pos): m/z (%): 322.2 (85),
1
a crystalline white solid. H NMR (400 MHz, CDCl3) δ 5.19 (s,
1H), 4.41 (d, J = 12.5 Hz, 1H), 4.26 – 4.12 (m, 2H), 3.28 (d, J =
4.1 Hz, 1H), 3.15 (t, J = 7.7 Hz, 1H), 2.94 (s, 3H), 2.48 (d, J =
15.5 Hz, 1H), 2.32 (d, J = 7.2 Hz, 1H), 1.98 – 1.85 (m, 1H), 1.58
(s, 3H), 1.48 (s, 9H), 1.02 (d, J = 6.7 Hz, 3H), 0.98 ppm (d, J = 6.8
Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 179.5, 175.6, 156.6,
127.8, 126.9, 81.1, 79.4, 77.2, 76.5, 55.6, 44.1, 41.5, 30.9, 30.0,
28.5, 25.4, 22.5, 18.4, 17.7 ppm. LRMS (DEP/EIꢀOrbitrap): m/z
305.2 (8), 250.2 (56), 217.2 (8), 205.2 (100). HRMS (EIꢀ
+
+
Orbitrap): calcd for C20H31N2O5 : 379.2227; found: 379.2227. IR
266.1 (100). HRMS (ESIꢀquadrupole pos): calcd for C17H24NO5 :
(DiamondꢀATR, neat) ꢀȬ(ꢁ3: 3332 (vw), 2962 (w), 2934 (w),
2870 (w), 1776 (w), 1702 (vs), 1670 cmꢀ1 (m). mp (°C): 134 –
138.
322.1649, found 322.1651 IR (DiamondꢀATR, neat) ꢀȬ(ꢁ3:
2978 (m), 2936 (m), 2872 (m), 1854 (m), 1780 (vs), 1738 (m),
1698 (s), 1658 cmꢀ1 (m).
tert-Butyl-(4aR*,7aR*,7bS*)-3,7a-dimethyl-5,7-dioxo-
tert-Butyl-(4R*,4aR*,7aR*,7bS*)-3,4,7a-trimethyl-5,7-dioxo-
4,4a,5,7,7a,7b-hexahydroisobenzofuro[4,5-b]azete-1(2H)-
carboxylate-7b-d (16a): Using tertꢀbutyl (Z)ꢀ3ꢀ(butꢀ2ꢀenꢀ2ꢀ
yl)azeteꢀ1(2H)ꢀcarboxylateꢀ4ꢀd and 3ꢀmethylfuranꢀ2,5ꢀdione
according to general procedure D, provided 16a (0.25 mmol,
4,4a,5,7,7a,7b-hexahydroisobenzofuro[4,5-b]azete-1(2H)-
carboxylate-7b-d (14a): Using tertꢀbutyl 3ꢀ(propꢀ1ꢀenꢀ2ꢀ
yl)azeteꢀ1(2H)ꢀcarboxylateꢀ4ꢀd and 3ꢀmethylfuranꢀ2,5ꢀdione
according to general procedure D, provided 14a (0.20 mmol,
1
1
62 mg, 40%) as colorless crystals. H NMR (400 MHz, CDCl3) δ
80 mg, 50%) as white solid. H NMR (400 MHz, CDCl3) δ 4.50
4.48 (ddd, J = 12.3, 3.0, 1.8 Hz, 1H), 4.24 (d, J = 12.3 Hz, 1H),
2.97 (dd, J = 4.4, 2.7 Hz, 1H), 2.57 (dd, J = 15.2, 2.7 Hz, 1H),
2.20 (d, J = 14.1 Hz, 1H), 1.72 – 1.68 (s, 3H), 1.62 (s, 3H),
1.48 ppm (s, 9H). 13C NMR (101 MHz, CDCl3) δ 172.6, 171.3,
157.1, 128.9, 125.8, 81.1, 77.2, 70.8, 56.1, 50.7, 49.8, 28.6, 28.3,
22.6, 18.5 ppm. LRMS (DEP/EIꢀOrbitrap): m/z (%): 196.2 (15),
(d, J = 12.1 Hz, 1H), 4.25 (d, J = 12.1 Hz, 1H), 2.97 (qd, J = 7.3,
2.1 Hz, 1H), 2.85 (d, J = 2.2 Hz, 1H), 1.69 (s, 6H), 1.50 (s, 9H),
1.12 ppm (d, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ
172.3, 171.3, 157.4, 134.0, 124.6, 81.2, 77.2, 70.1, 56.5, 50.0,
37.7, 31.1, 28.3, 24.8, 17.7, 17.3 ppm. LRMS (DEP/EIꢀOrbitrap):
m/z (%): 222.0 (3), 210.2 (25). HRMS (EIꢀOrbitrap): calcd for
+
+
140.1 (49). HRMS (EIꢀOrbitrap): calcd for C16H20DNO5 :
C17H22DNO5 : 322.1639; found: 322.1630. IR (DiamondꢀATR,
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The Journal of Organic Chemistry
neat) ꢀȬ(ꢁ3: 2972 (w), 2932 (w), 2874 (w), 1854 (w), 1780 (vs),
added dropwise and the solution stirred for one hour before addꢀ
ing dropwise a solution of tertꢀbutyl 3ꢀoxoazetidineꢀ1ꢀcarboxylate
(1) (0.8 eq, 16 mmol, in 10 mL THF). The reaction mixture was
quenched with saturated NH4Cl and extracted twice with diethyl
ether (2x 40 mL). The combined organic layers were dried over
MgSO4 and the solvents were evaporated under vacuum. The
crude alcohol was then redissolved in THF (60 mL) and cooled to
0 °C. After adding sodium hydride (1.0 eq., 20 mmol) portionꢀ
wise, the reaction mixture was allowed to reach room temperature
and stirred for one hour. Methyl iodide (1.0 eq., 20 mmol) was
then added and the mixture stirred for two more hours at room
temperature. The reaction was quenched with methanol and the
solvents were evaporated. Purification by column chromatography
on silica gel gave substituted 3ꢀsubstituted 1ꢀbocꢀ3ꢀ
methoxyazetidines 18c (11.8 mmol, 3.398 g, 74%) as yellow
solid. Rf = 0.80 (hexane/EtOAc 8:2, UV, KMnO4, PAA). 1H
NMR (400 MHz, CDCl3) δ 7.48 – 7.42 (m, 2H), 7.38 – 7.31 (m,
3H), 4.18 (d, J = 9.0 Hz, 2H), 4.08 (d, J = 9.0 Hz, 2H), 3.41 (s,
3H), 1.45 ppm (s, 9H). 13C NMR (101 MHz, CDCl3) δ 156.3,
131.9, 129.0, 128.5, 122.0, 87.7, 86.2, 80.1, 68.4, 61.8, 52.8,
28.5 ppm. LRMS (ESIꢀquadrupole pos): m/z (%): 288.1 (30),
273.1 (85), 232.1 (100). HRMS (EIꢀOrbitrap): calcd for
1
2
3
4
5
6
7
8
1706 cmꢀ1 (s). mp (°C): 170 – 173.
tert-Butyl-(4S*,4aR*,7aR*,7bR*)-3,4,4a-trimethyl-5,7-dioxo-
4,4a,5,7,7a,7b-hexahydroisobenzofuro[4,5-b]azete-1(2H)-
carboxylate-7b-d (16b): Using tertꢀbutyl (Z)ꢀ3ꢀ(butꢀ2ꢀenꢀ2ꢀ
yl)azeteꢀ1(2H)ꢀcarboxylateꢀ4ꢀd and 3ꢀmethylfuranꢀ2,5ꢀdione
according to general procedure D, provided 16b (0.06 mmol,
1
20 mg, 12%) as white solid. H NMR (400 MHz, CDCl3) δ 4.50
(d, J = 12.4 Hz, 1H), 4.25 (d, J = 12.0 Hz, 1H), 3.27 (s, 1H), 2.62
(q, J = 7.3 Hz, 1H), 1.69 (s, 3H), 1.48 (s, 9H), 1.42 (s, 3H),
1.01 ppm (d, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ
176.8, 167.6, 157.3, 136.0, 123.5, 81.0, 77.2, 62.8, 53.6, 51.4,
40.8, 31.1, 28.5, 22.7, 17.7, 13.7 ppm. LRMS (DEP/EIꢀOrbitrap):
m/z (%): 222.0 (3), 210.2 (25). HRMS (EIꢀOrbitrap): calcd for
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
C17H22DNO5 : 322.1639; found: 322.1630. IR (DiamondꢀATR,
neat) ꢀȬ(ꢁ3: 2954 (m), 2924 (s), 2854 (m), 1852 (w), 1782 (vs),
1706 cmꢀ1 (s). mp (°C): 170 – 173.
tert-Butyl-(4aR*,7aR*,7bS*)-3,4,4,7a-tetramethyl-5,7-dioxo-
4,4a,5,7,7a,7b-hexahydroisobenzofuro[4,5-b]azete-1(2H)-
carboxylate (17a)
+
C17H22NO3 [2M+H]+: 288.1594, found 288.1595. IR (Diamondꢀ
Using
tertꢀbutyl
3ꢀ(3ꢀmethylbutꢀ2ꢀenꢀ2ꢀyl)azeteꢀ1(2H)ꢀ
ATR, neat) ꢀȬ(ꢁ3
: 2996(vw), 2974(w), 2952(w), 2932(w),
carboxylate and 3ꢀmethylfuranꢀ2,5ꢀdione according to general
procedure D, provided 17a (0.45 mmol, 150 mg, 89%) as a yelꢀ
lowish solid. Only one regioisomer was isolated (ratio greater
than 10:1 in crude 13C NMR): 1H NMR (400 MHz, CDCl3) δ 4.62
– 4.57 (m, 1H), 4.46 (d, J = 11.9 Hz, 1H), 4.20 (d, J = 11.8 Hz,
1H), 2.64 (s, 1H), 1.68 (s, 3H), 1.64 (s, 3H), 1.56 (s, 3H), 1.49 (s,
9H), 1.08 ppm (s, 3H). 13C NMR (101 MHz, CDCl3) δ 171.1,
170.5, 157.6, 137.2, 125.5, 81.2, 77.2, 71.2, 61.8, 56.2, 51.1, 39.5,
28.5, 28.3, 27.6, 24.3, 14.2 ppm. LRMS (DEP/EIꢀOrbitrap): m/z
(%): 235.1 (3), 223.2 (23), 167.1 (100). HRMS (EIꢀOrbitrap):
2880(w), 2230(vw), 1692(s).
tert-Butyl-3-ethyl-3-methoxyazetidine-1-carboxylate
(18d):
Using ethylmagnesium chloride according to general procedure B
afforded 18d (7.38 g, 69%). Colorless oil, Rf = 0.24 (10% EtOAc
1
in hexane, PAA, KMnO4). H NMR (400 MHz, CDCl3): δ: 3.84
(d, J = 9.0 Hz, 2H), 3.66 (d, J = 8.9 Hz, 2H), 3.20 (s, 3H), 1.78 (q,
J = 7.3 Hz, 2H), 1.44 (s, 9H), 0.88 ppm (t, J = 7.3 Hz, 3H). 13C
NMR (101 MHz, CDCl3): δ: 156.7, 79.7, 75.4, 58.0, 50.5, 28.5,
27.2, 7.1 ppm. LRMS (ESIꢀquadrupole pos) m/z (%): not found.
HRMS (ESIꢀquadrupole pos): not found. IR (DiamondꢀATR,
neat) ꢀȬ(ꢁ3: 2976 (w), 2938 (w), 2882 (w), 1740 (m), 1704 cmꢀ1
(vs).
+
calcd for C18H24NO5 [MꢀH]+: 334.1654; found: 334.1646. IR
(DiamondꢀATR, neat) ꢀȬ(ꢁ3: 2976 (w), 2938 (w), 2874 (w), 1844
(w), 1780 (vs), 1702 cmꢀ1 (vs). mp (°C): 121 – 125.
tert-Butyl-3-methoxy-3-phenylazetidine-1-carboxylate (18a):
Using tertꢀbutyl 3ꢀoxoazetidineꢀ1ꢀcarboxylate (1) and phenylꢀ
magnesium bromide according to general procedure B, provided
18a (7.80 mmol, 2.101 g, 98%) as colorless oil. 1H NMR (400
MHz, CDCl3) δ 7.52 – 7.26 (m, 5H), 4.17 (s, 4H), 3.08 (s, 3H),
1.45 (s, 9H) ppm. 13C NMR (101 MHz, CDCl3) δ 156.7, 140.0,
128.8, 128.2, 126.2, 79.9, 76.8, 59.2, 51.7, 28.5 ppm. LRMS
(ESIꢀquadrupole pos): m/z (%): 190.1 (6), 175.1 (12). HRMS
tert-Butyl-(4aS*,7aS*,7bS*)-3,6-dimethyl-5,7-dioxo-7b-
phenyl-1,4,4a,5,6,7,7a,7b-octahydro-2H-azeto[3,2-e]isoindole-
2-carboxylate (8a): Using 18a and 2ꢀbromopropꢀ1ꢀene according
to general procedure E, provided 8a (0.46 mmol, 174 mg, 91%) as
a yellowish oil. Rf = 0.6 (hexane/EtOAc 7:3, UV, KMnO4, PAA).
1H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 4.3 Hz, 4H), 7.33 –
7.27 (m, 1H), 4.82 (d, J = 7.9 Hz, 1H), 3.64 (d, J = 7.9 Hz, 1H),
3.50 (d, J = 8.5 Hz, 1H), 3.05 (s, 3H), 2.96 (t, J = 7.3 Hz, 1H),
2.40 (d, J = 15.1 Hz, 1H), 2.23 (dd, J = 15.3, 6.4 Hz, 1H), 2.02 (s,
3H), 1.43 ppm (s, 9H). 13C NMR (101 MHz, CDCl3) δ 179.6,
177.4, 151.6, 142.2, 137.4, 129.5, 127.5, 126.1, 106.8, 81.0, 61.3,
47.4, 46.9, 42.3, 29.1, 28.4, 25.6, 18.0 ppm. LRMS (DEP/EIꢀ
Orbitrap): m/z (%): 382.3 (20), 326.2 (90), 281.2 (100). HRMS
+
(ESIꢀquadrupole pos): calcd for C15H22NO3 : 264.1594; found:
264.1594. IR (DiamondꢀATR, neat) ꢀȬ(ꢁ3: 2978 (w), 2950 (w),
2884 (w), 2828 (vw), 1702 cmꢀ1 (vs).
tert-Butyl-3-methoxy-3-(4-methoxyphenyl)azetidine-1-
carboxylate (18b): Using tertꢀbutyl 3ꢀoxoazetidineꢀ1ꢀcarboxylate
(1) and (4ꢀmethoxyphenyl)magnesium bromide according to
general procedure B, provided 18b (3.75 mmol, 1.100 g, 75%) as
colorless oil. Rf = 0.5 (hexane/EtOAc 9:1, UV, KMnO4, PAA).
1H NMR (400 MHz, CDCl3) δ 7.25 (d, J = 8.5 Hz, 2H), 6.88 (d, J
= 8.5 Hz, 2H), 4.11 (s, 4H), 3.77 (s, 3H), 3.00 (s, 3H), 1.41 ppm
(s, 9H). 13C NMR (101 MHz, CDCl3) δ 159.3, 156.5, 131.7,
127.5, 113.9, 79.6, 76.3, 60.4, 58.4, 55.2, 51.3, 28.3 ppm. LRMS
(ESIꢀquadrupole pos): m/z (%): 294.2 (85), 279.1 (45). HRMS
+
(EIꢀOrbitrap): calcd for C22H26N2O4 [M]+: 382.1893 found
382.1890. IR (DiamondꢀATR, neat) ꢀȬ(ꢁ3: 2976 (vw), 2930 (vw),
2858 (vw), 1774 (w), 1730 (w), 1700 cmꢀ1 (vs).
tert-Butyl-(4R*,4aS*,7aS*,7bS*)-3,4,6-trimethyl-5,7-dioxo-7b-
phenyl-1,4,4a,5,6,7,7a,7b-octahydro-2H-azeto[3,2-e]isoindole-
2-carboxylate (8b): Using 18a and (E)ꢀ2ꢀbromobutꢀ2ꢀene accordꢀ
ing to general procedure E, provided 8b (0.31 mmol, 123 mg,
62%) as a yellowish oil. Rf = 0.6 (hexane/EtOAc 7:3, UV,
+
(ESIꢀquadrupole pos): calcd for C16H24NO4 : 294.1700, found
1
KMnO4, PAA). H NMR (400 MHz, CDCl3) δ 7.43 – 7.35 (m,
294.1702. IR (DiamondꢀATR, neat) ꢀȬ(ꢁ3: 2974 (w), 2938 (w),
2882 (w), 2836 (vw), 1698 (vs), 1612 cmꢀ1 (m).
4H), 7.33 – 7.27 (m, 1H), 4.72 (d, J = 8.0 Hz, 1H), 3.58 (dd, J =
8.1, 5.8 Hz, 2H), 3.01 (s, 3H), 2.90 (dd, J = 8.2, 5.0 Hz, 1H), 2.49
(p, J = 7.0 Hz, 1H), 1.99 (s, 3H), 1.43 (s, 9H), 1.36 ppm (d, J = 7.5
Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 177.6, 177.2, 151.6,
142.1, 138.1, 129.5, 127.5, 125.8, 111.1, 80.9, 61.5, 48.6, 48.3,
47.4, 31.8, 28.4, 25.2, 14.3, 12.8 ppm. LRMS (DEP/EIꢀOrbitrap):
tert-Butyl-3-methoxy-3-(phenylethynyl)azetidine-1-
carboxylate (18c): Commercially available phenylacetylene
(1.0 eq., 20 mmol) was dissolved in THF (60 mL) and cooled to ꢀ
78 °C. After cooling, nꢀBuLi (1.0 eq., 2.44 M, 20 mmol) was
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m/z (%): 355.0 (5), 295.1 (100), 265.1 (20), 182.1 (85). HRMS
(EIꢀOrbitrap): calcd for C23H28N2O4 [M]+: 396.2049 found
3H), 2.94 (d, J = 8.6 Hz, 1H), 2.44 (d, J = 2.6 Hz, 2H), 1.87 (s,
+
3H), 1.74 – 1.64 (m, 2H), 1.45 (s, 9H), 1.00 ppm (t, J = 7.3 Hz,
3H). 13C NMR (101 MHz, CDCl3): δ: 179.8, 177.7, 151.7, 138.4,
105.3, 80.8, 56.1, 44.1, 44.0, 42.3, 28.7, 28.5, 28.3, 25.5, 18.0,
8.4 ppm. LRMS (ESIꢀquadrupole pos) m/z (%): 335.2 (95), 279.1
1
2
3
4
396.2040. IR (DiamondꢀATR, neat) ꢀȬ(ꢁ3: 2976(w), 2906(vw),
1770(w), 1692 cmꢀ1 (vs).
+
(100). HRMS (ESIꢀquadrupole pos): calcd for C18H27N2O4 :
tert-Butyl-(4S*,4aS*,7aS*,7bS*)-4-(4-chlorobutyl)-6-methyl-
5,7-dioxo-7b-phenyl-1,4,4a,5,6,7,7a,7b-octahydro-2H-
5
335.1965, found 335.1968.
6
7
8
9
azeto[3,2-e]isoindole-2-carboxylate (8c): Using 18a and (E)ꢀ6ꢀ
chloroꢀ1ꢀiodohexꢀ1ꢀene according to general procedure E, providꢀ
ed 8c (0.33 mmol, 149 mg, 65%) as a yellowish oil. Rf = 0.5
(hexane/EtOAc 7:3, UV, KMnO4, PAA). 1H NMR (400 MHz,
CDCl3) δ 7.45 – 7.37 (m, 4H), 7.34 – 7.28 (m, 1H), 5.25 (s, 1H),
4.88 (s, 1H), 3.69 (d, J = 7.8 Hz, 1H), 3.60 (d, J = 8.1 Hz, 1H),
3.52 (t, J = 6.6 Hz, 2H), 3.02 – 2.97 (m, 4H), 2.30 (dtd, J = 9.9,
6.0, 3.9 Hz, 1H), 1.88 – 1.70 (m, 4H), 1.57 – 1.47 (m, 2H),
1.44 ppm (s, 9H). 13C NMR (101 MHz, CDCl3) δ 176.9, 152.2,
145.0, 141.2, 134.3, 129.6, 127.7, 125.9, 100.1, 81.5, 47.8, 46.9,
46.2, 45.1, 34.5, 32.6, 31.2, 28.3, 25.6, 25.2 ppm. LRMS
(DEP/EIꢀOrbitrap): m/z (%): 458.4 (10), 402.2 (60), 357.3 (25),
323.3 (65), 291.2 (70), 267.2 (100), 247.2 (50), 194.1 (5). HRMS
tert-Butyl-(4aS*,7aS*,7bS*)-3,6-dimethyl-5,7-dioxo-7b-
(phenylethynyl)-1,4,4a,5,6,7,7a,7b-octahydro-2H-azeto[3,2-
e]isoindole-2-carboxylate (8g): Using 18c and 2ꢀbromopropꢀ1ꢀ
ene according to general procedure E, provided 8g (0.34 mmol,
136 mg, 67%) as a yellowish oil. Rf = 0.5 (hexane/EtOAc 7:3,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
UV, KMnO4, PAA). H NMR (400 MHz, CDCl3) δ 7.45 – 7.38
(m, 2H), 7.36 – 7.28 (m, 3H), 4.84 (d, J = 8.0 Hz, 1H), 4.11 (d, J =
8.0 Hz, 1H), 3.39 (d, J = 8.5 Hz, 1H), 3.23 (ddd, J = 8.3, 6.3, 1.7
Hz, 1H), 3.01 (s, 3H), 2.87 – 2.77 (m, 1H), 2.51 (dd, J = 15.0, 1.7
Hz, 1H), 1.92 (s, 3H), 1.47 ppm (s, 9H). 13C NMR (101 MHz,
CDCl3) δ 179.2, 175.8, 151.2, 135.7, 131.9, 128.7, 128.5, 122.4,
105.8, 88.5, 82.8, 81.4, 58.6, 46.3, 41.6, 36.8, 29.0, 28.4, 25.6,
+
17.8 ppm. HRMS (EIꢀOrbitrap): calcd for C24H26N2O4 [M]+:
+
(EIꢀOrbitrap): calcd for C25H31ClN2O4 [M]+: 458.1972 found
406.1893 found 406.1895. IR (DiamondꢀATR, neat) ꢀȬ(ꢁ3
:
458.1969. IR (DiamondꢀATR, neat) ꢀȬ(ꢁ3: 2976 (w), 2936 (w),
2866 (vw), 1770 (w), 1694 cmꢀ1 (vs).
2976(w), 2960(w), 2932 (w), 2874 (vw), 1790 (w), 1776 (w),
1756 (w), 1698 cmꢀ1 (vs).
tert-Butyl-(4R*,4aS*,7aS*,7bS*)-7b-(4-methoxyphenyl)-3,4,6-
trimethyl-5,7-dioxo-1,4,4a,5,6,7,7a,7b-octahydro-2H-azeto[3,2-
e]isoindole-2-carboxylate (8d): Using 18b and (E)ꢀ2ꢀbromobutꢀ
2ꢀene according to general procedure E, provided 8d (0.32 mmol,
156 mg, 64%) as a yellowish oil. Rf = 0.45 (hexane/EtOAc 7:3,
ASSOCIATED CONTENT
Supporting Information
1H and 13C NMR spectra for all new compounds and Xꢀray crysꢀ
tallographic data of compound 12g can be found in the Supporting
Information.
1
UV, KMnO4, PAA). H NMR (400 MHz, CDCl3) δ 7.30 (d, J =
8.5 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 4.69 (d, J = 8.0 Hz, 0H),
3.79 (s, 1H), 3.53 (t, J = 8.6 Hz, 1H), 2.98 (s, 1H), 2.87 (dd, J =
8.1, 5.0 Hz, 1H), 2.48 (p, J = 7.0 Hz, 1H), 1.96 (s, 1H), 1.42 (s,
4H), 1.34 ppm (d, J = 7.5 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ
176.9, 176.9, 159.0, 152.2, 145.3, 133.0, 127.0, 114.8, 99.9, 81.4,
55.4, 47.8, 46.1, 45.1, 34.4, 32.6, 31.1, 28.3, 25.6, 25.2 ppm.
LRMS (DEP/EIꢀOrbitrap): m/z (%): 426.3 (5), 370.3 (100), 325.3
The Supporting Information is available free of charge on the
ACS Publications website.
AUTHOR INFORMATION
+
Corresponding Author
(90), 311.2 (80). HRMS (EIꢀOrbitrap): calcd for C24H30N2O5
[M]+: 426.2155 found 426.2155. IR (DiamondꢀATR, neat) ꢀȬ(ꢁ3
:
*dorian.didier@cup.uniꢀmuenchen.de
2976 (w), 2936 (vw), 1770 (w), 1698 (vs), 1610 cmꢀ1 (vw).
Author Contributions
†These authors contributed equally.
tert-Butyl-(4S*,4aS*,7aS*,7bS*)-4-(4-chlorobutyl)-7b-(4-
methoxyphenyl)-6-methyl-5,7-dioxo-1,4,4a,5,6,7,7a,7b-
octahydro-2H-azeto[3,2-e]isoindole-2-carboxylate (8e)
ACKNOWLEDGMENT
Using 18b and (E)ꢀ6ꢀchloroꢀ1ꢀiodohexꢀ1ꢀene according to general
procedure E, provided 8e (0.32 mmol, 156 mg, 64%) as a yellowꢀ
ish oil. Rf = 0.4 (hexane/EtOAc 7:3, UV, KMnO4, PAA). 1H
NMR (400 MHz, CDCl3) δ 7.32 (d, J = 8.5 Hz, 2H), 6.90 (d, J =
8.5 Hz, 2H), 5.21 (s, 1H), 4.85 (s, 1H), 3.79 (s, 3H), 3.64 (d, J =
7.7 Hz, 1H), 3.55 (d, J = 8.2 Hz, 1H), 3.51 (t, J = 6.6 Hz, 2H),
3.04 – 2.92 (m, 4H), 2.34 – 2.24 (m, 1H), 1.77 (dqq, J = 19.3,
12.5, 6.0, 5.4 Hz, 4H), 1.57 – 1.45 (m, 2H), 1.43 ppm (s, 9H). 13C
NMR (101 MHz, CDCl3) δ 177.6, 177.2, 158.9, 151.6, 138.4,
133.9, 126.9, 114.7, 110.8, 80.8, 61.7, 60.5, 55.4, 48.6, 47.6, 47.4,
31.6, 28.3, 25.1, 21.1, 14.3, 12.8 ppm. LRMS (DEP/EIꢀOrbitrap):
m/z (%): 488.4 (2), 459.2 (2), 432.3 (100), 387.3 (80), 377.3 (50).
D.D. and A.N.B. are grateful to the Fonds der Chemischen Indusꢀ
trie, the Deutsche Forschungsgemeinschaft (DFG grant: DI
2227/2ꢀ1) and to the SFB749 for PhD funding and financial supꢀ
port. We thank Prof. David M. Hodgson (University of Oxford)
for fruitful discussion on the preparation of azetinyllithium speꢀ
cies. Dr. Peter Mayer is kindly acknowledged for Xꢀray measureꢀ
ments, as well as I. R. Alonso Benito and G. Haas for helpful
experimental support.
REFERENCES
[1] For a general review on Nꢀcontaining fourꢀmembered rings:
Rousseau G.; Robin, S. Four-membered Heterocycles: Structure and
Reactivity in Modern Heterocyclic Chemistry, First Edition (Eds:
AlvarezꢀBuilla, J.; Vaquero, J. J.; Barluenga, J.) 2011, pp. 163ꢀ268,
WileyꢀVCH Verlag.
[2] (a) Gianatassio, R.; Lopchuk, J. M.; Wang, J.; Pan, C.ꢀM.; Maꢀ
lins, L. R.; Prieto, L.; Brandt, T. A.; Collins, M. R.; Gallego, G. M.;
Sach, N. W.; Spangler, J. E.; Zhu, H; Baran, P. S. Science 2016, 351,
241. (b) Lopchuk, J. M.; Fjelbye, K.; Kawamata, Y.; Malins, L. R.;
Pan, C.ꢀM.; Gianatassio, R.; Wang, J.; Prieto, L.; Bradow, J.; Brandt,
T. A.; Collins, M. R.; Elleraas, J.; Ewanicki, J.; Farrell, W.; Fadeyi,
O. O.; Gallego, G. M.; Mousseau, J. J.; Oliver, R.; Sach, N. W.;
Smith, J. K.; Spangler, J. E.; Zhu, H.; Zhu, J.; Baran, P. S. J. Am.
HRMS (EIꢀOrbitrap): calcd for C26H33ClN2O5 [M]+: 488.2078
+
found 488.2059. IR (DiamondꢀATR, neat) ꢀȬ(ꢁ3: 2972 (w), 2954
(w), 2936 (w), 1770 (w), 1696 cmꢀ1 (vs).
tert-Butyl-(4aS*,7aS*,7bR*)-7b-ethyl-3,6-dimethyl-5,7-dioxo-
1,4,4a,5,6,7,7a,7b-octahydro-2H-azeto[3,2-e]isoindole-2-
carboxylate (8f): Using 18d and 2ꢀbromopropꢀ1ꢀene according to
general procedure E, provided 8f (0.43 mmol, 144 mg, 86%) as a
yellowish oil. Yellow oil, Rf = 0.29 (20% EtOAc in hexane, UV,
1
PAA, KMnO4). H NMR (400 MHz, CDCl3): δ: 4.27 (d, J = 8.4
Hz, 1H), 3.65 (d, J = 8.4 Hz, 1H), 3.12 – 3.04 (m, 1H), 3.00 (s,
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The Journal of Organic Chemistry
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[8] For recent examples of alkylideneazetidines: (a) Cainelli, G.;
Galletti, P.; Garbisa, S.; Giacomini, D.; Sartor, L.; Quintavalla, A.
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[12] See fully detailed procedure in supporting information.
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Feringa, B. L. Chem. Sci. 2015, 6, 1394.
[14] Diastereoisomeric ratios were determined by 1H NMR and GC
and the relative configuration was determined by Xꢀray measureꢀ
ments.
[15] Baumann, A. N.; Eisold, M.; Didier, D. Org. Lett. 2017, 19,
2114.
[16] CCDC 1548836 (12g) contains the supplementary crystalloꢀ
graphic data for this paper
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