Formal [3+2] Cycloaddition of Nitrosoallenes with Carbonyl and Nitrile Compounds to Form Functional Cyclic Nitrones

Article abstract of DOI:10.1021/acs.joc.6b00758

The synthesis of functional cyclic nitrones via [3+2] cycloadditions of allenamide-derived nitrosoallenes with carbonyl/nitrile compounds, including ketones, esters, and nitriles, is presented herein. Rapid carbon-carbon, carbon-oxygen, and carbon-nitrogen bond formations were achieved with in situ prepared nitrosoallenes, and densely substituted oxacyclic and carbocyclic nitrones containing tetrasubstituted carbon centers were successfully synthesized. The spirocyclic nitrone products synthesized from cyclic dicarbonyl compounds underwent the unique skeletal rearrangements to cyclic α-ketonitrones.

Full text of DOI:10.1021/acs.joc.6b00758

Article
pubs.acs.org/joc
Formal [3+2] Cycloaddition of Nitrosoallenes with Carbonyl and
Nitrile Compounds to Form Functional Cyclic Nitrones
Hiroki Tanimoto,* Takashi Shitaoka, Keiichi Yokoyama, Tsumoru Morimoto, Yasuhiro Nishiyama,
and Kiyomi Kakiuchi
Graduate School of Materials Science, Nara Institute of Science and Technology (NAIST), 8916-5 Takayamacho, Ikoma, Nara
630-0192, Japan
S
* Supporting Information
ABSTRACT: The synthesis of functional cyclic nitrones via [3+2]
cycloadditions of allenamide-derived nitrosoallenes with carbonyl/
nitrile compounds, including ketones, esters, and nitriles, is presented
herein. Rapid carbon−carbon, carbon−oxygen, and carbon−nitrogen
bond formations were achieved with in situ prepared nitrosoallenes,
and densely substituted oxacyclic and carbocyclic nitrones containing
tetrasubstituted carbon centers were successfully synthesized.
The spirocyclic nitrone products synthesized from cyclic dicarbonyl
compounds underwent the unique skeletal rearrangements to cyclic
α-ketonitrones.
Scheme 1. Nitroso Compounds and Their Reactions
INTRODUCTION
■
The development of methodologies that employ reactive species,
which enable the synthesis of valuable molecules because of their
unique reactivity is of great importance in synthetic organic
chemistry. Among them, nitroso compounds are well-known to
be highly fascinating reactive species due to their strong electron-
withdrawing ability.1,2 The behavior of nitroso compounds
has been widely studied because of the ease with which they
form nitrogen-containing compounds as a result of their unique
reactivity (Scheme 1). Thus, to date, a variety of C-nitroso com-
pounds have been applied to the syntheses of various alkaloids
and heterocycles.3−8 Conventional nitroso molecules, including
acyl nitroso compounds, are one of the most studied nitroso
groups to date. These compounds undergo [4+2] cycloadditions
with dienes to afford 3,4-dihydro-2H-oxazines (Scheme 1a).3
Moreover, because of the efficiency of α-hydroxyamino- and
α-aminoxy carbonyl compounds, nitroso compounds, especially
aryl nitroso and alkoxycarbonyl nitroso compounds, have been
utilized in nitroso aldol reactions (Scheme 1b).4 The selective
carbon−nitrogen or carbon−oxygen bond formations can be
carried out in asymmetric metal- and organo-catalyzed reactions.
With nitrosoalkenes as diene units, [4+2] cycloaddition can
deliver 1,2-oxazines (5,6-dihydro-4H-oxazines) that are dif-
ferent from those derived from simple nitroso compounds
(Scheme 1c).5 These nitrosoalkenes also allow the umpolung
α-substitution of ketones and oximes with nucleophiles through
1,4-addition. Thus, these reactions have been applied to the
synthesis of natural products (Scheme 1d).6 Although nitroso
compounds conjugated with sp-carbon atoms are rare,2a−c,7
Kaneko et al. reported a nitrosoketene that undergoes a formal
[3+2] cycloaddition with ketones (Scheme 1e).8a−c Although
the reaction mechanism is still under discussion,8d−f the afforded
butenolide-like cyclic nitrones were also demonstrated as
efficient precursors of α-amino acids through further [3+2]
cycloaddition reactions. Because of the unique molecular
Special Issue: Heterocycles
Received: April 7, 2016
© XXXX American Chemical Society
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Scheme 2. Outline of the Synthetic Pathways, Including Nitrosoallene-Mediated Synthesis, in This Work
transformation ability of nitroso species, we believe that the effect
of their strong reactivity on the synthesis of heterocycles should
be explored. The use of these novel nitroso functional compounds
is envisioned in the development of new synthetic procedures
that supply nitrogen−containing functional molecules, especially
heterocycles toward functional materials and bioactive mole-
cules. Moreover, nitrones have long been known as versatile
intermediates in organic synthesis, and have been in reported
various reactions including concerted cycloadditions.9−12
did not produce any adducts in the presence or absence of base
reagents, as reported in cases with nitrosoalkenes.6f Instead,
cycloaddition reactions forming carbon−oxygen and carbon−
nitrogen bonds proceeded with nitrosoketenes (Scheme 1e).8a,b
On the other hand, with dibenzyl ketone 2, the addition
reaction of nitrosoallene 3 from 1a successfully proceeded
to afford carbocyclic nitrones 4 and 5. These were produced
from 1,4- and 1,2-additions to 3, respectively (Scheme 3). Thus,
Very recently, we reported the nitrosoallene-mediated synthesis
of α-functionalized enoximes representing the umpolung
reactivity of allenamides (Scheme 2).13 These nitrosoallenes
demonstrated very unique reactivities to produce α-functionalized
enoximes and isoxazolines through 1,4-additions of the nucleo-
philes.14 Additionally, the nature of nitrosoallenes were found
to be distinct from those of known nitroso compounds. These
favorable results encouraged us to further investigate other
possible synthetic pathways that these novel reactive species
may undergo to form polycyclic compounds. Thus, following the
outcome of previous research on nitrosoalkenes and nitro-
soketenes,6,8 new reactivity patterns between the current
nitrosoallenes and carbonyl compounds were predicted. Hence,
nitrogen-containing compounds were expected to be formed by
carbon−carbon bond formation through 1,4-additions, and by
nitroso aldol reactions through 1,2-additions, as well as [3+2] and
[4+2] reactions. Moreover, as demonstrated in our previous
study,13 synthetic methods using nitrosoallenes can be performed
under mild conditions, and can be completed in a short period
of time, due to the strong reactivities of these compounds.
To further reveal the potential of these novel nitrosoallenes,
we herein report the addition reactions of nitrosoallenes with
carbonyl/nitrile compounds to produce cyclic nitrones, and
investigate their reaction patterns through DFT calculations.
We also examine the skeletal rearrangement of the afforded
spirooxacyclic nitrones to spiro- and bicyclic α-ketonitrones.
Scheme 3. Cycloaddition Reactions with Ketones
1,4-addition product 4 could be synthesized as a cyclic nitrone
through 4′. The oxacyclic nitrone products afforded with nitro-
soketenes (Scheme 1e)8 were not afforded in this case. Although
the product yields were fair, we accomplished carbon−carbon
bond formation with a ketone and C-nitroso species. We
postulated that this success was due to the pKa values of the
hydrogen atom at the α-position of the ketones (pKa = 19 for 2,
and acetophenone pKa = 25 and 26 for acetophenone and
cyclohexanone in DMSO, respectively).16 Therefore, we opted
to use 1,3-diketones and β-ketoesters because of their more
acidic α-hydrogen atoms (Scheme 4).
RESULTS AND DISCUSSION
■
Based on the preceding examples of nitroso-utilizing reactions,
especially those with nitrosoalkenes and nitrosoketenes
(Scheme 1d,e), we initially tested the reactions of nitrosoallenes
with monoketone compounds. As established in our previous
study,13 the nitrosoallenes were prepared by TBAF in the
presence of the azodicarboxylate reagent dimethoxyethyl azodi-
carboxylate (DMEAD),15 a scavenger of the in situ generated
sulfinates. Acetophenone or cyclohexanone of simple ketones
With 1,3-cyclohexanediones 6a and 6c (pKa = 10 in DMSO
for 1,3-cyclohexanedione),16 when the reaction was performed
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Scheme 4. Cycloaddition Reactions with Cyclic 1,3-Diketones and Their Skeletal Rearrangements
with 1.2 equiv of TBAF, [3+2] product nitrones 7a−c were
afforded in good to excellent yield. However, the afforded
[3+2] products were not carbocyclic nitrones from carbon−
carbon bond formations (as in 2), but oxacyclic nitrones 7a−c
through carbon−oxygen bond formations via enol ether 7′.
It should be noted that 1,3-diketones are reported as failing to
undergo addition reactions with nitrosoalkenes.6e Interestingly,
spirocyclic α-keto nitrone products 8a−b were isolated as
major products when 4.2 equiv of TBAF were used (Scheme 4,
Table 1). The structures of 7a, 7c, and 8a were confirmed by
X-ray crystallography. Oxacyclic nitrones 7a−b were success-
fully converted to 8a−b in good yield under basic conditions.
Thus, α-ketonitrones 8a−b can be afforded from 7a−b via
β-elimination followed by ring closure of 8′ by 1,4-addition of
the resulting enolate. This mechanism is supported by the results
obtained for compounds 7c to 8c via 8′ possessing sterically
repulsive methyl substitute. We also investigated base reagents
to discover whether potassium tert-butoxide and TBAF work
well in this skeletal rearrangement (See Supporting Informa-
tion). Although potassium tert-butoxide afforded the best yields,
C
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Scheme 5. Cycloaddition Reactions with 1,2-Dicarbonyl Compounds
we chose TBAF for its rapid conversion and initial coupling
conditions. Similar to base-treated enolates, the use of enol
ethers 9 or 10 for dienophiles, dipolarophiles, and the in situ-
generated enolates did not produce any coupling products.
A similar transformation was also observed in the reaction with
1,3-cyclopentanedione 11.
nitrosoallenes with carbonyl compounds should be considered
separately from those of the discussed nitrosoketene reactions.8
From the results in Scheme 3, these cycloaddition reactions
should consist of a stepwise pathway via the enolization of
ketones, followed by carbon−oxygen bond formation through
1,4-addition to nitrosoallenes, and finally cyclization with the
oxime nitrogen atoms.
The reaction of 1a with acyclic diketone acetylacetone 14a
(pKa = 13 in DMSO)16 also afforded the [3+2] products
oxacyclic nitrones 16a in moderate yield. The cycloaddition
product 16b was also afforded with α-substituted acetylace-
tone 14b17 in higher yields. With unsymmetrical 1,3-diketone
14c,18 nitrone 16c combined at the less hindered carbonyl
position and was afforded as the major product. The structure
of the minor product 16cc, coupled at the hindered carbonyl
group, was confirmed by X-ray crystallography. β-ketoester
ethyl acetoacetate 15 only afforded cyclic nitrone 17a through
the reaction at the ketone position, while simple 1,4-addition
via carbon−carbon bond formation was reported with nitro-
soalkenes.6e Allenamide with electron-withdrawing arenes 1c
also afforded oxacyclic nitrones 17b in fair yield. Interestingly,
skeletal rearrangements were not observed in the case of acyclic
diketone adducts even in the presence of excess base reagents.
From the crystallographic data of oxacyclic nitrones 7a and 7c
(see Supporting Information), antiperiplanar conformations
and axial directions of carbon−oxygen moieties in the cyclic
dione adducts are expected to favor rapid elimination to form 8′,
followed by a cyclization process. Probably, the conformation of
the enolates of the acyclic dione adducts, suitable for β-elimination,
would be thermodynamically disfavored due to steric repulsion.
In the reported case of nitrosoketene (Scheme 1e),8 for the
structurally similar chemical component nitrosoallenes, [3+2]
reactions with 1,3-dicarbonyl compounds only afforded trace
amounts of cyclic nitrones. On the other hand, simple ketones
produced the desired compound in moderate to good yields
under reflux conditions. These different reactivities showcase
the unique character of nitrosoallenes. Thus, it is suggested
that the reaction mechanisms of the [3+2] cycloaddition of
To compare the reactivity, we next conducted reactions with
1,2-dicarbonyl compounds (Scheme 5). With methyl pyruvate
18a of the α-ketoester, 1a was converted to α-alkenoxy enoxime
19 and bicyclic α-oxonitrone 20. Since pyruvic acid has been
reported to dimerize under base conditions,19 and diacetyl 18b
did not afford the addition product, oxime 19 should have
been formed by the oxa-Michael addition of lactone 21, the
dimerization product from 18a. Excess TBAF gave only 20,
and enol adduct 19 was certainly transformed into 20, probably
through a cascade process including cyclization to spirocyclic
nitrone 20′ followed by β-elimination to 20″ and the 1,4-
addition or 6π electrocyclization/isomerization of nitrone.
The absence of isolable oxacyclic nitrone would be due to the
instability of the carbanion in 20′ when compared to the
carbanions in the 1,3-dicarbonyl adducts. Benzil 18c and methyl
benzoyl formate 18d could not afford carbonyls in the enol
form. Thus, coupling products were not isolated in this case.
A different product was afforded from α-diketone 1,2-cyclo-
hexanedione 18e, and bicyclic oxime ether 22 was afforded
along with enol ether oxime 23 by carbon−oxygen bond forma-
tion through enolization. Because the type of cyclization is
different from that of nitrone 20, 22 is probably formed by a
concerted or stepwise [4+2] reaction with the enol form of 18e.
The reaction with the monomethyl enol ether of 18e did not
afford any addition products.
In the case of ketones, the high electron density of the enolates
tends to be on the electronegative oxygen. This would promote
carbon−oxygen bond formations with the nitrosoallenes.
We therefore introduced malonates and malononitriles to reduce
the contribution of the heteroatom anions, and to encourage
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malonate 26a (pKa = 16 in DMSO)16 did not afford any stable
products (decomposed under concentration during purification),
we propose that the decomposed unstable product is 27e, related
to products 27a−d. Acetonitrile, even when used as solvent, did
not attach to the substrates.
Scheme 6. Cycloaddition Reactions with Malonates and
Malononitriles
We also introduced the substituted malonates 26b,c to the
addition reaction and the coupling products were successfully
afforded in moderate yields. However, the resultant products
were not nitrones from 1,4-addition to nitrosoallenes, but
carbocyclic nitrones 28a,b. These compounds were postulated
to be generated by initial carbon−nitrogen bond formation via
1,2-addition to the nitrosoallenes, and successive Dieckmann
condensation of hydroxyallenamine 28′. With benzyl malono-
nitrile 24b, iminocyclic nitrones 29a,b were isolated in 70% and
22% yields, respectively. The low yield of 29b, whose structure
was determined by X-ray crystallography, would be due to
the large steric repulsion between phenyl groups.13 From these
results, steric repulsion between aryl groups on the allene moiety,
necessary to prepare the nitrosoallene precursor substrates,13
could also enhance regioselectivity. The results from 1,2-addition
to the nitrosoallenes are contrary to those reported for nitrso-
alkene reactions. The latter reactants afforded carbon−carbon
bond formation between nitrosoalkenes and malonates.6
We further investigated benzylated α-cyanoester 25b to test
the chemoselectivity of cyclization where 25b afforded addition
product 30 in ca. 50% yield (Scheme 7). Purification of 30 by
Scheme 7. Cycloaddition Reactions with α-Cyanoester
gel permeation column (GPC) chromatography hydrolyzed
the ester to afford carboxylic acid 31. This was submitted
for X-ray crystallographic analysis. Isoxazoline product 31
was delivered by 1,2-addition to nitrosoallene followed by
Dieckmann condensation of 30′ at the ester moiety. However,
due to the presence of the electron-withdrawing cyano group,
carbon−carbon bond cleavageinstead of elimination of the
alkoxideoccurred, followed by cyclocondensation of C-vinyl
nitrone 30″.
nucleophilic additions at the active methylene positions of the
soft nucleophiles (Scheme 6). Unsubstituted malononitrile 24a
(pKa = 11 in DMSO)16 and ethyl cyanoacetate 25a afforded
2-azafulvene derivatives (cyclic C,N-divinyl nitrones) 27a,b. It is
postulated that these products are afforded by initial carbon−
carbon bond formation through 1,4-addition to nitrosoallenes
followed by cyclization to form nitrones. Cyanoacetate 25a
selectively afforded 3-amino-2-azafulvene 27c by cyclization with
the cyano group. While Weinreb et al. reported a 6-membered
ring 4H-1,2-oxazine product in the reaction with nitrosoalkene
and sulfonylacetonitrile,6e we exclusively created 5-membered
ring products, probably due to the presence of allene moieties.
The structure of aminoazafulvene 27d, afforded from 1b and
25a were confirmed by X-ray crystallography. Although diethyl
As shown above, addition reactions of the diesters occurred
at the carbon atoms. On the other hand, the reaction with
Meldrum’s acid 32 exhibited a different reactivity from those of
malonates and dinitriles (Scheme 8). Similar to 1,3-diketones,
Meldrum’s acid 32 underwent [3+2] cycloaddition reaction
through carbon−oxygen bond formation to afford the very
unique cyclic nitrone 33 containing an orthoamido structure.
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Meldrum’s acid and barbituric acid, the anion population tends
to occur mainly on the oxygen atoms. These atoms are in-
compatible with the nitrogen atoms of nitroso compounds, and
thus, carbon−oxygen bond formation reactions would be
preferred. On the other hand, the negative charges of both
nitriles and esters are mainly on the α-carbon atoms due to the
instability of the ketene acetal and ketenimine anions. For
this reason, the unsubstituted malononitrile achieved carbon−
carbon bond formation on the sp-carbon center. However,
C−N bond formations may occur with α-substituted malonates
and nitriles. Thus, the regioselectivity may also be considered
through steric repulsion with the substituents on the allenes. In
the case of the [3+2] reaction of nitrosoketene under heating
conditions,8 a pericyclic mechanism is proposed. In our study of
nitrosoallenes, the cyclization reaction is expected to proceed
stepwise through enolate formation, as previously discussed.
We also consider the pKa values of the nucleophiles. The pKa
table of tested carbonyl compoundsheteroatom and carbon
nucleophiles including previously tested substrates13is
illustrated in Figure 1, while the addition reactions with the
Scheme 8. Cycloadditions with Meldrum’s Acid and
Dimethyl Barbituric Acid
It can be postulated that the strong acidity of 33 (pKa = 7
in DMSO),16 compared to that of the malonates by orbital
interaction,20 increased the electron density of its anion on
the oxygen atoms to undergo oxa-Michael addition to nitro-
soallenes. 33 also successfully transformed to carbocyclic
α-oxonitrone 34. This latter is analogous to the products afforded
from 1,3-diketones. A similar compound, N,N′-dimethylbarbituric
acid 35, also produced [3+2] adduct orthoimidate 36 that was
similarly converted to 37.
Overall, in conjunction with our previous study,13 the nature
of nitrosoallenes was found to be distinct from that of nitro-
soalkenes and nitrosoketenes. With respect to the reactivities of
nitrosoallenes based on the classical HSAB principle,21 carbon
atoms at the β-position in nitrosoallene seem to be “hard”
and nitrogen atoms “soft” electrophiles.13 On the other hand
in the case of nitrosoalkenes, soft carboanions like malonates
have been reported to generate carbon−carbon bonds at the
β-carbon atoms of the nitrosoalkenes.6 The difference between
nitrosoalkene and nitrosoallene can be partially explained by
DFT calculations (See Table S1 in Supporting Information).
LUMO levels of unsaturated nitroso molecules demonstrate
that they have a much higher reactivity than conjugated carbonyl
compounds. A comparison between the LUMO coefficients
of the nitrogen and β-carbon atoms shows that nitrosoallene
appears between nitrosoalkene and nitrosoketene, while the
value of the nitrogen atom is larger than that of the sp-carbon
atom. On the other hand, the inverse was observed for nitro-
soethene. This could be one of the reasons why there is minimal
carbon−carbon bond formation at the β-carbon centerwhen
compared to nitrosoalkenes. In the case of ketones, including
Figure 1. PKa table of tested carbonyl compounds and other
nucleophiles13 in DMSO.
new azoles (imidazole pKa = 19; benzotriazole pKa = 12)16
are illustrated in Scheme 9. In the case of dibenzylketone 2
(pKa = 19), both 1,2- and 1,4-additions occurred in fair yield,
unselectively. Because it has been reported that nitrosoalkenes
do not afford any adducts with simple ketones, the reactivity
of ketones with a C(sp2)-nitroso compound that have higher
pKa values would simply be reduced, or they would favor
1,2-additions that afford unstable enamine products. The
nucleophilicity of the compounds,22 together with factors, should
also be considered in the assessment of the results obtained
from the addition of base reagents or the use of enol ethers
(Schemes 3−4). However, borderline results of acceptable
and unacceptable nucleophiles are clearly found at a pKa value
between 19 and 20. Because the precursors of nitrosoallenes
to be investigated are limited due to the preparation methods,
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1
2984, 2251, 1743, 1455, 1261, 1207, 1030, 857, 748 cm−1; H NMR
(500 MHz, CDCl3) δ 7.37−7.27 (m, 5H), 4.24 (m, 2H), 3.72 (dd, 1H,
J = 8.5, 6.0 Hz), 3.28 (dd, 1H, J = 13.5, 6.0 Hz), 3.20 (dd, 1H, J = 13.5,
8.5 Hz), 1.27 (t, 3H, J = 6.5 Hz); 13C NMR (126 MHz, CDCl3) δ 165.5,
135.2, 129.0, 128.9, 127.8, 116.1, 62.9, 39.7, 35.7, 13.9; LRMS (EI) m/z
203 (M+, 15%), 130 (20), 91 (100); HRMS (EI) calcd for C12H13NO2
(M+) 203.0946, found 203.0945.
Scheme 9. Synthesis of α-Azole-Attached Enoximes
General Procedure of [3+2] and 1,4-Addition Reactions with
Nitrosoallene Intermediates. A tetrabutylammonium fluoride
(TBAF) THF solution (equivalents used are noted in the section
relevant to each product) was added to a stirred solution of allenamide
and azodicarboxylate (1.5 equiv) in THF (0.05 M for allenamide) at
−60 °C under nitrogen atmosphere. After 5 min, a nucleophile
(equivalents used are noted for each product are noted in the relevant
sections) was added at the same temperature, and the reaction mixture
was warmed up to 0 °C. After 10 min, the reaction was quenched
with water. The mixture was extracted with diethyl ether and washed
with water and brine. The combined organic layers were dried over
sodium sulfate and concentrated in vacuo. The resultant residue was
purified by flash silica gel column chromatography to afford nitrones
or α-substituted enoximes. When necessary, the purified materials
were further treated with GPC.
global research of acceptable nucleophiles on nitrosoallenes
including comparison to the theoretical analyses should be
reported by developing new synthetic methods of aminoallenes,
the nitrosoallene precursors, in near future.
CONCLUSION
■
( )-(2R,3R)-2-Benzyl-5-butyl-4-(diphenylmethylene)-2-hydroxy-
3-phenyl-3,4-dihydro-2H-pyrrole 1-Oxide (4, CCDC 1471114).
The formal [3+2] cycloadditions of nitrosoallenes with carbonyl
compounds including ketones, esters, and nitriles are demon-
strated herein. The synthesis of densely functionalized cyclic
nitrones was achieved along with a further ring rearrange-
ment cascade to form carbocyclic nitrones. From experimental
studies, nitrosoallenes were observed to accept both 1,2- and
1,4-additions to afford cyclic nitrones. The cycloaddition reaction
is thought to have proceeded through a stepwise process.
Our work revealed the reaction behavior of novel chemical
nitrosoallene species, and the [3+2] cycloaddition reaction
mechanism was indicative of a stepwise process. We believe that
our research, based on the synthesis of a characteristic chemical
species and functional carbocyclic nitrones, can further assist the
development of organic chemistry on alkaloid and heterocycle
synthesis.
13.7 mg (27%) of 4 and 5.7 mg (12%) of 5 were afforded from
allenamide 1a (54.8 mg, 0.10 mmol), DMEAD (35.1 mg, 0.15 mmol),
TBAF (420 μL, 1.0 m in THF, 0.42 mmol), and 1,3-diphenyl-2-
propanone (63.1 mg, 0.30 mmol) (silica gel column chromatography:
hexane/ethyl acetate = 3/1 followed by GPC: chloroform).
Recrystallization for X-ray crystallographic analysis was performed
with ethyl acetate. Yellow solid; Rf value 0.28 (hexane/ethyl acetate =
2/1); mp 225.1−226.3 °C; IR (NaCl, neat) νmax 3187, 3060, 2956,
1
1738, 1540, 1494, 1454, 1380, 1291, 1237, 1165, 747 cm−1; H NMR
EXPERIMENTAL SECTION
(500 MHz, CDCl3) δ 7.43−7.41 (m, 3H), 7.36−7.28 (m, 3H), 7.22−
7.16 (m, 7H), 7.11−7.08 (m, 1H), 7.05−7.01 (m, 2H), 6.78−6.77 (m,
2H), 6.49−6.47 (m, 2H), 4.08 (s, 1H), 3.44 (d, 1H, J = 14.0 Hz), 3.06
(d, 1H, J = 14.0 Hz), 2.34−2.28 (m, 1H), 1.76−1.68 (m, 1H), 1.35−
1.25 (m, 3H), 0.99−0.87 (m, 2H), 0.69 (t, 3H, J = 7.5 Hz); 13C NMR
(126 MHz, CDCl3) δ 148.5, 141.3, 140.5, 139.8, 138.9, 134.7, 132.9,
130.5, 128.89, 128.87, 128.82, 128.76, 128.64, 128.53, 128.48, 128.25,
128.1, 127.8, 127.7, 127.6, 127.5, 127.2, 127.0, 99.1, 53.2, 45.1, 26.9,
25.2, 22.8, 13.5; HRMS (ESI) calcd for C34H33NNaO2 [M+Na]+
510.24090, found 510.24086.
■
General Information. 1H, and 13C NMR were recorded at
1
500 MHz for H NMR, 126 MHz for 13C NMR. Chemical shifts
were reported as δ values in ppm and calibrated from residual solvent
1
peaks (CDCl3: δ 7.26 for H NMR, δ 77.00 for 13C NMR, CD2Cl2:
1
δ 5.32 for H NMR, δ 53.84 for 13C NMR), or tetramethylsilane (δ 0
1
for H NMR). Abbreviations are as follows: s (singlet), d (doublet),
t (triplet), q (quartet), br (broad peak), m (complex multiplet). Mass
spectra were realized by EI (70 eV), CI, FAB, or ESI using a double-
focusing mass spectrometer. The materials which were hard to be
purified by silica gel column chromatography were purified by a recycling
preparative gel permeation chromatography (GPC).
( )-(2S,3S)-3-Benzyl-5-butyl-4-(diphenylmethylene)-3-hydroxy-2-
phenyl-3,4-dihydro-2H-pyrrole 1-Oxide (5, CCDC 1471113).
Allenamides of Nitrosoallene Precursors (1a−d). Prepared in
accordance with our previous report.13
Preparation of Ethyl 2-Cyano-3-phenylpropionate (25b).
25b was prepared in accordance with the reported procedure for the
Obtained as above. Recrystallization for X-ray crystallographic analysis
was performed with ethyl acetate. White solid; Rf value 0.28 (hexane/
ethyl acetate = 2/1); mp 188.3−189.4 °C; IR (NaCl, neat) νmax 3176,
synthesis of 1,3-diketones.17 Potassium carbonate (1.11 g, 8.0 mmol)
and benzyl bromide (478 μL, 4.0 mmol) were added to a stirred solution
of ethyl cyanoacetate (1.28 mL, 12 mmol) in acetonitrile (8 mL) at room
temperature. After 2 h, the mixture was extracted with diethyl ether and
the organic layer was washed with 1 N HCl and brine. The combined
organic layers were dried over sodium sulfate and concentrated in vacuo.
The resultant residue was purified by flash silica gel column
chromatography (hexane/ethyl acetate = 10/1) to afford 25b. Colorless
oil; Rf value 0.20 (hexane/ethyl acetate = 10/1); IR (NaCl, neat) νmax
1
2928, 1550, 1494, 1442, 1378, 1230, 1116, 758, 700 cm−1; H NMR
(500 MHz, CDCl3) δ 7.34−7.20 (m, 18H), 6.88−6.86 (m, 2H), 5.08
(s, 1H), 3.28 (d, 1H, J = 14.0 Hz), 3.02 (d, 1H, J = 14.0 Hz), 2.28−
2.22 (m, 1H), 1.93−1.87 (m, 1H), 1.44−1.28 (m, 3H), 1.05−0.98
(m, 2H), 0.73 (t, 3H, J = 7.0 Hz); 13C NMR (126 MHz, CDCl3) δ
150.1, 142.0, 140.8, 140.3, 138.0, 135.4, 132.4, 130.7, 129.5, 129.2,
128.73, 128.68, 128.5, 128.3, 128.14, 128.09, 127.84, 127.79, 127.3,
G
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Article
81.2, 79.3, 47.2, 26.9, 25.3, 22.7, 13.6; HRMS (ESI) calcd for
C34H33NNaO2 [M+Na]+ 510.2409, found 510.2408.
( )-(R)-3-Butyl-2-(diphenylmethylene)-7-oxo-1-oxa-4-azaspiro-
[4.5]dec-3-ene 4-Oxide (7a, CCDC 1471104). 38.1 mg (98%) of 7a
IR (NaCl, neat) νmax 2931, 1720, 1536, 1443, 1258, 1188, 982,
1
703 cm−1; H NMR (500 MHz, CDCl3) δ 7.41−7.36 (m, 3H), 7.30−
7.22 (m, 6H), 7.19−7.16 (m, 1H), 3.34 (q, 1H, J = 6.5 Hz), 2.65 (td,
1H, J = 14.0, 4.5 Hz), 2.58−2.54 (m, 1H), 2.46 (td, 1H, J = 14.0,
6.0 Hz), 2.15−2.09 (m, 1H), 2.06−1.93 (m, 3H), 1.70−1.64 (m, 1H),
1.30−1.09 (m, 2H), 1.01−0.86 (m, 5H), 0.69 (t, 3H, J = 7.5 Hz);
13C NMR (126 MHz, CDCl3) δ 206.9, 146.4, 140.2, 138.2, 137.4,
131.3, 129.3, 128.3, 128.2, 128.0, 127.0, 117.5, 107.8, 50.5, 40.2, 33.5,
26.7, 24.2, 22.6, 20.2, 13.5, 5.9; HRMS (ESI) calcd for C26H29NNaO3
[M+Na]+ 426.2045, found 426.2039.
3-Butyl-2-(diphenylmethylene)-7-oxo-1-oxa-4-azaspiro[4.4]non-
3-ene 4-Oxide (12). 31.4 mg (84%) of 12 was obtained from
was afforded from allenamide 1a (54.8 mg, 0.10 mmol), DMEAD
(35.1 mg, 0.15 mmol), TBAF (120 μL, 1.0 m in THF, 0.12 mmol),
and 1,3-cyclohexanedione (33.6 mg, 0.30 mmol) (silica gel column
chromatography: hexane/ethyl acetate = 2/1). A single crystal for
X-ray analysis was afforded by recrystallization from hexane. White
solid; Rf value 0.28 (hexane/ethyl acetate = 2/1); mp 117−118 °C;
IR (NaCl, neat) νmax 2957, 1725, 1536, 1443, 1258, 1186, 1058, 766,
1
703 cm−1; H NMR (500 MHz, CDCl3) δ 7.41−7.38 (m, 3H), 7.33
(d, 2H, J = 7.5 Hz), 7.29−7.25 (m, 4H), 7.20 (t, 1H), 3.33 (d, 1H, J =
15.0 Hz), 2.67 (d, 1H, J = 15.0 Hz), 2.60−2.53 (m, 2H), 2.45 (ddd,
1H, J = 13.5, 13.5, 6.0 Hz), 2.25−2.19 (m, 1H), 2.07−2.01 (m, 2H),
1.85 (m, 2H), 1.20 (tt, 2H, J = 7.0, 6.0 Hz), 0.95 (td, 2H, J = 7.0,
7.0 Hz), 0.71 (t, 3H, J = 7.0 Hz); 13C NMR (126 MHz, CDCl3)
δ 205.4, 145.2, 139.2, 138.1, 137.3, 131.2, 129.4, 128.3, 128.2, 127.9,
127.0, 118.1, 105.2, 49.2, 39.7, 32.7, 26.8, 24.1, 22.4, 19.8, 13.5; HRMS
(ESI) calcd for C25H27NNaO3 [M+Na]+ 412.1889, found 412.1885.
( )-(R)-3-Cyclohexyl-2-(diphenylmethylene)-7-oxo-1-oxa-4-
azaspiro[4.5]dec-3-ene 4-Oxide (7b). 31.3 mg (75%) of 7c was
allenamide 1a (54.8 mg, 0.10 mmol), DMEAD (35.1 mg, 0.15 mmol),
TBAF (120 μL, 1.0 M in THF, 0.12 mmol), and 1,3-cyclopentanedione
(29.4 mg, 0.30 mmol) (silica gel column chromatography: hexane/ethyl
acetate = 2/1). White solid; Rf value 0.45 (hexane/ethyl acetate = 2/1);
mp 123−124 °C; IR (NaCl, neat) νmax 2956, 1754, 1537, 1492, 1443,
1307, 1262, 1179, 1002, 760, 703 cm−1; 1H NMR (500 MHz, CDCl3)
δ 7.26−7.23 (m, 3H), 7.22−7.20 (m, 2H), 7.16−7.11 (m, 4H), 7.09−
7.06 (m, 1H), 3.04 (d, 1H, J = 18.5 Hz), 2.70−2.45 (m, 4H), 2.30−2.25
(m, 1H), 1.75−1.70 (m, 2H), 1.07 (m, 2H), 0.81 (qt, 2H, J = 7.0 Hz),
0.56 (t, 3H, J = 7.0 Hz); 13C NMR (126 MHz, CDCl3) δ 210.9, 145.6,
139.8, 138.1, 137.3, 131.2, 129.4, 128.4, 128.3, 128.0, 127.2, 118.2,
107.1, 47.0, 37.7, 33.1, 26.8, 24.2, 22.5, 13.5; HRMS (ESI) calcd for
C24H25NNaO3 [M+Na]+ 398.17321, found 398.17322.
4-Butyl-5-(diphenylmethylene)-2-methyl-2-(2-oxopropyl)-2,5-di-
hydrooxazole 3-Oxide (16a). 24.5 mg (65%) of 16a was obtained
afforded from allenamide 1b (57.4 mg, 0.10 mmol), DMEAD
(35.1 mg, 0.15 mmol), TBAF (120 μL, 1.0 m in THF, 0.12 mmol),
and 1,3-cyclohexanedione (33.6 mg, 0.30 mmol) (silica gel column
chromatography: hexane/ethyl acetate = 3/1). White solid; Rf value
0.30 (hexane/ethyl acetate = 2/1); mp 203.9−204.9 °C; IR (NaCl,
neat) νmax 2927, 1721, 1531, 1443, 1297, 1253, 1186, 1061, 753 cm−1;
1H NMR (500 MHz, CDCl3) δ 7.43−7.36 (m, 3H), 7.33−7.31
(m, 2H), 7.27−7.16 (m, 5H), 3.27 (d, 1H, J = 15.0 Hz), 2.63 (d, 1H,
J = 15.0 Hz), 2.53−2.48 (m, 2H), 2.44−2.38 (m, 1H), 2.21−2.08 (m,
3H), 2.04−1.93 (m, 2H), 1.58−1.56 (m, 2H), 1.43−1.41 (m, 1H),
1.28−1.21 (m, 3H), 1.10 (ddt, 1H, J = 3.5, 3.5, 13.0, 13.0 Hz), 0.55
(ddddd, 2H, J = 3.5, 3.5, 13.0, 13.0, 13.0 Hz); 13C NMR (126 MHz,
CDCl3) δ 205.7, 145.3, 140.7, 138.3, 138.0, 130.8, 129.4, 128.4, 128.1,
127.9, 127.0, 118.0, 105.0, 49.3, 39.7, 35.1, 32.8, 25.6, 25.1, 24.2, 24.0,
19.8; HRMS (ESI) calcd for C27H29NNaO3 [M+Na]+ 438.2045, found
438.2042.
from allenamide 1a (54.8 mg, 0.10 mmol), DMEAD (35.1 mg,
0.15 mmol), TBAF (420 μL, 1.0 M in THF, 0.42 mmol), and
acetylacetone (31 μL, 0.30 mmol) (silica gel column chromatography:
hexane/diethyl ether = 3/2). Pale yellow oil; Rf value 0.13 (hexane/
ethyl acetate = 3/1); IR (NaCl, neat) νmax 2957, 1721, 1543, 1259,
1
1185, 1069, 704 cm−1; H NMR (500 MHz, CDCl3) δ 7.39−7.34
(m, 5H), 7.29−7.25 (m, 4H), 7.19 (tt, 1H, J = 7.5, 1.5 Hz), 3.23 (d, 1H,
J = 16.0 Hz), 3.05 (d, 1H, J = 16.0 Hz), 2.19 (s, 3H), 1.93 (ddd, 1H,
J = 13.0, 11.0, 5.0 Hz), 1.78−1.72 (m, 4H), 1.31−1.15 (m, 2H), 1.01−
0.87 (m, 2H), 0.69 (t, 3H, J = 7.0 Hz); 13C NMR (126 MHz, CDCl3)
δ 202.7, 146.4, 139.8, 138.6, 137.7, 131.3, 129.4, 128.2, 128.0, 127.8,
126.8, 117.4, 102.2, 48.1, 31.5, 26.4, 24.8, 24.1, 22.5, 13.4; HRMS (ESI)
calcd for C24H27NO3Na [M+Na]+ 400.18886, found 400.18886.
4-Butyl-5-(diphenylmethylene)-2-methyl-2-(3-oxo-1-phenylbu-
tan-2-yl)-2,5-dihydrooxazole 3-Oxide (16b, 1:1 Inseparable Dia-
stereomixture). 35.5 mg (76%) of 16b was obtained from allenamide
( )-(5R,6R)-3-Butyl-2-(diphenylmethylene)-6-methyl-7-oxo-1-
oxa-4-azaspiro[4.5]dec-3-ene 4-Oxide (7c, CCDC 1471115). 19.3 mg
(48%) of 7c was obtained from allenamide 1a (54.8 mg, 0.10 mmol),
DMEAD (35.1 mg, 0.15 mmol), TBAF (120 μL, 1.0 m in THF,
0.12 mmol), and 2-methyl-1,3-cyclohexanedione (37.8 mg, 0.30 mmol)
(silica gel column chromatography: hexane/ethyl acetate = 4/1 followed
by gel permeation chromatography: chloroform). Recrystallization for
X-ray analysis was performed with hexane/ethyl acetate. White solid;
Rf value 0.30 (hexane/ethyl acetate = 2/1); mp 116.5−117.1 °C;
1a (54.8 mg, 0.10 mmol), DMEAD (35.1 mg, 0.15 mmol), TBAF
(420 μL, 1.0 M in THF, 0.42 mmol), and 3-benzyl-2,4-pentanedione
14b (57.1 mg, 0.30 mmol) (silica gel column chromatography: hexane/
ethyl acetate = 4/1 followed by gel permeation chromatography:
chloroform). Colorless oil; Rf value 0.28 (hexane/ethyl acetate = 4/1);
H
DOI: 10.1021/acs.joc.6b00758
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Article
IR (NaCl, neat) νmax 2957, 1716, 1538, 1495, 1444, 1257, 1190, 1068,
1
968 cm−1; H NMR (500 MHz, CDCl3) δ 7.54 (m, 4H), 7.42−7.17
(m, 26H), 3.61 (dd, 1H, J = 10.5, 5.0 Hz), 3.56 (dd, 1H, J = 12.0,
3.5 Hz), 3.17−3.03 (m, 3H), 2.84 (dd, 1H, J = 13.5, 3.5 Hz), 1.97−1.90
(m, 5H), 1.86 (s, 3H), 1.79−1.66 (m, 8H), 1.31−1.10 (m, 4H), 1.00−
0.85 (m, 4H), 0.69 (t, 3H, J = 7.5 Hz), 0.67 (t, 3H, J = 7.5 Hz);
13C NMR (126 MHz, CDCl3) δ 207.9, 206.9, 146.3, 146.2, 140.0,
139.6, 138.8, 138.3, 138.1, 137.7, 137.5, 137.4, 131.3, 129.6, 129.5,
128.90, 128.87, 128.71, 128.67, 128.4, 128.23, 128.18, 128.0, 127.9,
127.1, 127.0, 126.7, 117.7, 117.4, 104.2, 104.1, 60.1, 58.5, 34.0, 33.5,
33.1, 32.9, 26.7, 26.5, 24.1, 23.9, 23.2, 22.6, 22.5, 22.3, 13.50, 13.48;
HRMS (ESI) calcd for C31H33NO3Na [M+Na]+ 490.2358, found
490.2352.
1543, 1259, 704 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.38−7.36 (m,
5H), 7.28−7.25 (m, 4H), 7.19 (tt, 1H, J = 7.5, 1.5 Hz), 4.21−4.12
(m, 2H), 3.21 (d, 1H, J = 15.5 Hz), 2.97 (d, 1H, J = 15.5 Hz), 1.90
(ddd, 1H, J = 13.0, 10.5, 5.0 Hz), 1.81−1.75 (m, 4H), 1.30−1.17 (m,
5H), 1.00−0.88 (m, 2H), 0.69 (t, 3H, J = 7.5 Hz); 13C NMR (126
MHz, CDCl3) δ 167.5, 146.5, 139.7, 138.6, 137.7, 131.3, 129.5, 128.3,
128.0, 127.9, 127.8, 126.9, 117.2, 102.1, 61.0, 41.4, 26.5, 24.8, 24.2,
22.6, 14.1, 13.5; HRMS (ESI) calcd for C25H29NO4Na [M+Na]+
430.1994, found 430.1992.
4-Butyl-5-(diphenylmethylene)-2-methyl-2-(2-(4-nitrophenyl)-2-
oxoethyl)-2,5-dihydrooxazole 3-Oxide (16c). 27.7 mg (57%) of 16c
5-(Bis(4-chlorophenyl)methylene)-4-butyl-2-(2-ethoxy-2-oxoeth-
yl)-2-methyl-2,5-dihydrooxazole 3-Oxide (17b). 16.2 mg (34%) of
and 8.8 mg (18%) of the isomer 16cc were obtained from allenamide
1a (54.8 mg, 0.10 mmol), DMEAD (35.0 mg, 0.15 mmol), TBAF
(420 μL, 1.0 M in THF, 0.42 mmol), and 1-(4-nitrophenyl)butane-
1,3-dione (62 mg, 0.30 mmol)17 (silica gel column chromatography:
hexane/ethyl acetate = 5/1 to 2/1). Yellow oil; Rf value 0.19 (hexane/
ethyl acetate = 2/1); IR (NaCl, neat) νmax 2957, 1689, 1526, 1345,
1184, 748 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.17 (dd, 2H, J = 8.5,
2.0 Hz), 8.06 (dd, 2H, J = 9.0, 2.0 Hz), 7.38−7.34 (m, 3H), 7.22−7.15
(m, 7H), 3.70 (d, 1H, J = 15.0 Hz), 3.61 (d, 1H, J = 15.0 Hz), 1.87
(s, 3H), 1.85−1.72 (m, 2H), 1.21−1.07 (m, 2H), 0.95−0.85 (m, 2H),
0.67 (t, 3H, J = 7.5 Hz); 13C NMR (126 MHz, CDCl3) δ 193.3, 150.2,
145.8, 141.1, 140.0, 138.1, 137.3, 131.1, 129.4, 129.3, 128.3, 128.2,
127.8, 127.1, 123.6, 117.9, 102.5, 44.5, 26.5, 25.0, 24.1, 22.5, 13.5;
HRMS (ESI) calcd for C29H28N2O5Na [M+Na]+ 507.1896, found
507.1892.
17b was obtained from allenamide 1c (61.7 mg, 0.10 mmol), DMEAD
(35.0 mg, 0.15 mmol), TBAF (320 μL, 1.0 M in THF, 0.32 mmol),
and ethyl acetoacetate (25.5 μL, 0.20 mmol) (silica gel column
chromatography: hexane/diethyl ether = 3/1 to 1/1). Pale yellow oil;
Rf value 0.23 (hexane/ethyl acetate = 3/1); IR (NaCl, neat) νmax 2958,
1739, 1541, 1490, 1259, 1091, 832 cm−1; 1H NMR (500 MHz,
CDCl3) δ 7.37 (d, 2H, J = 8.0 Hz), 7.27−7.22 (m, 4H), 7.18 (d, 2H,
J = 8.0 Hz), 4.15 (q, 2H, J = 7.5 Hz), 3.19 (d, 1H, J = 16.0 Hz), 2.96
(d, 1H, J = 16.0 Hz), 1.97 (ddd, 1H, J = 13.5, 11.0, 5.5 Hz), 1.83 (ddd,
1H, J = 13.5, 11.0, 5.0 Hz), 1.75 (s, 3H), 1.30−1.15 (m, 5H), 1.06−
0.95 (m, 2H), 0.72 (t, 3H, J = 7.5 Hz); 13C NMR (126 MHz, CDCl3)
δ 167.4, 147.2, 139.2, 136.7, 135.8, 134.4, 132.7, 130.7, 128.7, 128.1,
114.5, 102.3, 61.0, 41.1, 26.4, 24.8, 24.2, 22.6, 14.1, 13.4; HRMS (ESI)
calcd for C25H27Cl2NO4Na [M+Na]+ 498.12148, found 498.12146.
Methyl (E)-4-((3-(Hydroxyimino)-1,1-diphenylhept-1-en-2-yl)-
oxy)-2-methyl-5-oxo-2,5-dihydrofuran-2-carboxylate (19). 24.6 mg
4-Butyl-5-(diphenylmethylene)-2-(4-nitrophenyl)-2-(2-oxoprop-
yl)-2,5-dihydrooxazole 3-Oxide (16cc, CCDC 1471116). Yellow
(70%) of 19 was obtained from allenamide 1a (54.8 mg, 0.10 mmol)
and DMEAD (35.1 mg, 0.15 mmol), TBAF (120 μL, 1.0 M in THF,
0.12 mmol), and methyl pyruvate (30.3 μL, 0.30 mmol) (silica gel
column chromatography: hexane/diethyl ether = 2/1 followed by gel
permeation chromatography: chloroform). White solid; Rf value 0.43
(hexane/ethyl acetate = 2/1); mp 129.0−130.8 °C; IR (NaCl, neat)
crystal; recrystallization for X-ray crystallographic analysis was performed
with ethyl acetate/hexane; Rf value 0.29 (hexane/ethyl acetate = 2/1);
mp 138−140 °C; IR (NaCl, neat) νmax 2958, 1728, 1524, 1349, 1187,
1062, 856, 754 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.24 (dd, 2H, J =
9.0, 2.0 Hz), 7.90 (dd, 2H, J = 9.0, 2.0 Hz), 7.45−7.24 (m, 10H), 3.68
(d, 1H, J = 17.5 Hz), 3.43 (d, 1H, J = 17.5 Hz), 2.23 (s, 3H), 1.97 (ddd,
1H, J = 13.0, 11.5, 5.5 Hz), 1.68 (ddd, 1H, J = 13.0, 11.5, 5.0 Hz), 1.30−
1.13 (m, 2H), 0.92 (tq, 2H, J = 7.5, 6.0 Hz), 0.66 (t, 3H, J = 7.5 Hz);
13C NMR (126 MHz, CDCl3) δ 201.4, 148.4, 146.1, 143.5, 140.1, 138.1,
137.1, 131.2, 129.5, 128.3, 128.1, 127.4, 126.3, 123.7, 119.3, 101.1, 48.1,
31.4, 26.3, 24.2, 22.5, 13.4; HRMS (ESI) calcd for C29H28N2O5Na
[M+Na]+ 507.1896, found 507.1898.
4-Butyl-5-(diphenylmethylene)-2-(2-ethoxy-2-oxoethyl)-2-meth-
yl-2,5-dihydrooxazole 3-Oxide (17a). 25.3 mg (62%) of 17a was
obtained from allenamide 1a (54.8 mg, 0.10 mmol), DMEAD
(35.1 mg, 0.15 mmol), TBAF (420 μL, 1.0 M in THF, 0.42 mmol),
and ethyl acetoacetate (38.2 μL, 0.30 mmol) (silica gel column
chromatography: hexane/ethyl acetate = 2/1). Pale yellow oil; Rf value
0.23 (hexane/ethyl acetate = 3/1); IR (NaCl, neat) νmax 2958, 1739,
1
νmax 2957, 1791, 1653, 1444, 1202, 1115, 967, 699 cm−1; H NMR
(500 MHz, CDCl3) δ 7.31−7.24 (m, 7H), 7.19−7.16 (m, 4H), 6.26 (s,
1H), 3.67 (s, 3H), 2.17 (m, 2H), 1.50 (s, 3H), 1.44 (dd, 2H, J = 7.5,
7.0 Hz), 1.23 (qt, 2H, J = 7.5, 7.5 Hz), 0.84 (t, 3H, J = 7.5 Hz);
13C NMR (126 MHz, CDCl3) δ 168.9, 165.3, 156.4, 143.9, 143.2,
138.5, 138.0, 134.3, 130.1, 129.3, 128.3, 128.24, 128.22, 128.1, 122.5,
82.0, 53.2, 27.8, 26.7, 22.8, 22.6, 13.6; HRMS (ESI) calcd for
C26H27NNaO6 [M+Na]+ 472.1736, found 472.1739.
( )-(4aR,8aS)-3-Butyl-4-(diphenylmethylene)-8a-hydroxy-
4a,6,7,8a-tetrahydro-4H-benzo[e][1,2]oxazin-8(5H)-one (22, CCDC
1471110). 11.4 mg of 22 (29%) and 4.1 mg of 23 (11%) were
obtained from allenamide 1a (54.8 mg, 0.10 mmol), DMEAD
(35.1 mg, 0.15 mmol), TBAF (120 μL, 1.0 M in THF, 0.12 mmol),
and 1,2-cyclohexanedione (33.6 mg, 0.30 mmol) (silica gel column
I
DOI: 10.1021/acs.joc.6b00758
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The Journal of Organic Chemistry
Article
0.30 mmol) (silica gel column chromatography: hexane/ethyl acetate =
4/1). Red oil; Rf value 0.50 (hexane/ethyl acetate = 1/1); IR (NaCl,
neat) νmax 3268, 3195, 2925, 2382, 2205, 1680, 1487, 1400, 1292, 1177,
1
755 cm−1; H NMR (500 MHz, CD2Cl2) δ 7.52−7.40 (m, 6H), 7.28
(dd, 2H, J = 7.0, 1.5 Hz), 7.20 (d, 2H, J = 7.0 Hz), 6.00 (brs, 2H), 2.24
(m, 2H), 1.61−1.54 (m, 3H), 1.45−1.10 (m, 4H), 0.587 (m, 2H);
13C NMR (126 MHz, CD2Cl2) δ 156.4, 150.7, 141.5, 140.8, 132.7, 131.6,
130.51, 130.45, 128.7, 128.6, 128.4, 114.7, 67.1, 37.5, 26.5, 25.89, 25.7;
HRMS (ESI) calcd for C24H23N3O [M+Na]+ 392.1739, found 392.1745.
5-Amino-2-butyl-3-(diphenylmethylene)-4-(ethoxycarbonyl)-3H-
pyrrole 1-Oxide (27c). 31.1 mg (80%) of 27c was obtained from
chromatography: hexane/ethyl acetate = 4/1). Single crystal for X-ray
analysis was obtained by recrystallization from diethyl ether. White
solid; Rf value 0.58 (hexane/ethyl acetate = 2/1); mp 127.6−128.9 °C;
IR (NaCl, neat) νmax 2955, 2860, 1732, 1443, 1124, 1075, 906 cm−1;
1H NMR (500 MHz, CDCl3) δ 7.45 (br, 1H), 7.34−7.32 (m, 6H),
7.11 (br, 2H), 6.93 (br, 1H), 4.77 (s, 1H), 2.87 (dt, 1H, J = 14.5, 14.5,
6.5 Hz), 2.60 (dd, 1H, J = 12.0, 5.0 Hz), 2.49 (td, 1H, J = 14.5,
1.5, 1.5 Hz), 2.09−1.82 (m, 4H), 1.69−1.53 (m, 2H), 1.41−1.25
(m, 2H), 1.18−1.00 (m, 2H), 0.73 (t, 3H, J = 7.5 Hz); 13C NMR
(126 MHz, CDCl3) δ 203.2, 157.8, 148.2, 141.5, 140.8, 128.8, 128.3,
128.2, 122.3, 96.7, 43.5, 36.8, 33.1, 30.5, 27.6, 24.1, 22.3, 13.7; HRMS
(ESI) calcd for C25H27NNaO3 [M+Na]+ 412.1889, found 412.1888.
(E)-2-((3-(Hydroxyimino)-1,1-diphenylhept-1-en-2-yl)oxy)-
cyclohex-2-en-1-one (23). Obtained as above. Colorless oil; Rf value
allenamide 1a (54.8 mg, 0.10 mmol), DMEAD (35.1 mg, 0.15 mmol),
TBAF (120 μL, 1.0 M in THF, 0.12 mmol), and ethyl cyanoacetate
(32 μL, 0.30 mmol) (silica gel column chromatography: hexane/ethyl
acetate = 3/2). Red oil; Rf value 0.38 (hexane/ethyl acetate = 1/1);
IR (NaCl, neat) νmax 2954, 2362, 1684, 1487, 1295, 1224, 1104 cm−1;
1H NMR (500 MHz, CDCl3) δ 7.50−7.47 (m, 1H), 7.41−7.29 (m,
5H), 7.27−7.25 (m, 2H), 7.21−7.20 (m, 2H), 6.44 (s, 2H), 3.59 (q,
2H, J = 7.0 Hz), 1.96 (m, 2H), 1.34 (m, 2H), 0.93 (tq, 2H, J = 7.5,
7.5 Hz), 0.75 (t, 3H, J = 7.0 Hz), 0.67 (t, 3H, J = 7.5 Hz); 13C NMR
(126 MHz, CDCl3) δ 164.6, 155.1, 150.9, 147.0, 143.9, 142.0, 132.3,
132.2, 130.0, 129.2, 129.1, 128.1, 127.8, 86.8, 59.6, 28.5, 25.9, 22.8,
13.8, 13.5; HRMS (ESI) calcd for C24H27N2O3 [M+H]+ 391.2022,
found 391.2023.
0.40 (hexane/ethyl acetate = 2/1); IR (NaCl, neat) νmax 3313, 2928,
1691, 1443, 1194, 1122, 963, 756 cm−1; 1H NMR (500 MHz, CDCl3)
δ 7.29−7.14 (m, 10H), 6.31 (t, 1H, J = 4.5 Hz), 2.40 (t, 2H, J =
6.5 Hz), 2.35 (ddt, 2H, J = 6.0, 6.0, 4.5 Hz), 2.22 (dd, 2H, J = 8.0 Hz),
1.86 (tt, 2H, J = 6.5, 6.0 Hz), 1.48 (m, 2H), 1.26 (m, 2H), 0.86 (t, 3H,
J = 7.5 Hz); 13C NMR (126 MHz, CDCl3) δ 192.9, 157.1, 148.8,
143.2, 139.9, 139.0, 132.5, 130.2, 129.5, 128.0, 127.9, 127.5, 127.1,
126.0, 38.6, 27.7, 26.8, 24.6, 23.0, 22.7, 13.7; HRMS (ESI) calcd for
C25H27NNaO3 [M+Na]+ 412.1889, found 412.1880.
5-Amino-2-cyclohexyl-3-(diphenylmethylene)-4-(ethoxycarbon-
yl)-3H-pyrrole 1-Oxide (27d, CCDC 1471112). 31.1 mg (80%) of 27d
5-Amino-2-butyl-4-cyano-3-(diphenylmethylene)-3H-pyrrole 1-
oxide (27a). 21.0 mg (61%) of 27a was obtained from allenamide
was obtained from allenamide 1c (57.4 mg, 0.10 mmol), DMEAD
(35.1 mg, 0.15 mmol), TBAF (120 μL, 1.0 M in THF, 0.12 mmol),
and ethyl cyanoacetate (32 μL, 0.30 mmol) (silica gel column
chromatography: hexane/ethyl acetate = 2/1). Recrystallization for
X-ray analysis was performed with ethyl acetate. Dark yellow solid;
Rf value 0.23 (hexane/ethyl acetate = 2/1); mp 69.4−70.3 °C; IR
(NaCl, neat) νmax 2926, 1683, 1481, 1300, 1191, 1104, 755, 700 cm−1;
1H NMR (500 MHz, CDCl3) δ 7.50 (t, 1H, J = 7.5 Hz), 7.40 (t, 2H,
J = 7.5 Hz), 7.35−7.30 (m, 3H), 7.24−7.23 (m, 4H), 6.45 (brs, 2H),
3.58 (q, 2H, J = 7.5 Hz), 2.30 (dddd, 2H, J = 12.5, 12.5, 12.5, 3.5 Hz),
1.59−1.56 (m, 2H), 1.43−1.39 (m, 2H), 1.29−1.26 (m, 3H), 1.19−
1.12 (m, 1H), 0.76 (t, 3H, J = 7.5 Hz), 0.51 (m, 2H); 13C NMR
(126 MHz, CDCl3) δ 164.6, 155.5, 150.6, 148.9, 144.1, 142.5, 132.4,
132.0, 130.0, 129.4, 129.1, 128.1, 127.8, 87.0, 59.5, 37.1, 26.3, 25.7,
25.2, 13.8; HRMS (ESI) calcd for C26H29N2O3 [M+H]+ 417.2178,
found 417.2179.
1a (54.8 mg, 0.10 mmol), DMEAD (35.1 mg, 0.15 mmol), TBAF
(420 μL, 1.0 M in THF, 0.42 mmol), and malononitrile (19.8 mg,
0.30 mmol) (silica gel column chromatography: hexane/ethyl acetate =
3/2). Red oil; Rf value 0.40 (hexane/ethyl acetate = 1/1); IR (NaCl,
neat) νmax 3268, 3195, 2955, 2203, 1679, 1488, 1381, 1225, 756 cm−1;
1H NMR (500 MHz, CD2Cl2) δ 7.49−7.25 (m, 6H), 7.26−7.22 (m,
2H), 7.210−7.207 (m, 2H), 6.16 (br, 2H), 2.06 (m, 2H), 1.32 (m, 2H),
0.94 (m, 2H), 0.66 (t, 3H, J = 7.5 Hz); 13C NMR (126 MHz, CD2Cl2)
δ 156.1, 150.9, 145.1, 141.0, 140.6, 132.4, 131.7, 130.5, 130.4, 128.7,
128.6, 128.4, 114.7, 66.5, 28.3, 26.0, 23.0, 13.6; HRMS (ESI) calcd for
C22H22N3O [M+H]+ 344.1763, found 344.1762.
5-Butyl-4-(diphenylmethylene)-2-(ethoxycarbonyl)-2-methyl-3-
oxo-3,4-dihydro-2H-pyrrole 1-Oxide (28a). 13.3 mg (44%) of 28a
5-Amino-4-cyano-2-cyclohexyl-3-(diphenylmethylene)-3H-pyr-
role 1-Oxide (27b). 27.0 mg (73%) of 27b was obtained from
was obtained from allenamide 1a (54.8 mg, 0.10 mmol), DMEAD
(35.0 mg, 0.15 mmol), TBAF (620 μL, 1.0 M in THF, 0.62 mmol),
and diethyl methylmalonate (83.0 μL, 0.50 mmol) (silica gel column
chromatography: hexane/diethyl ether = 4/3). Red oil; Rf value 0.23
allenamide 1c (57.4 mg, 0.10 mmol), DMEAD (35.1 mg, 0.15 mmol),
TBAF (420 μL, 1.0 M in THF, 0.42 mmol), and malononitrile (19.8 mg,
J
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Article
(hexane/ethyl acetate = 3/1); IR (NaCl, neat) νmax 2957, 1760, 1730,
for X-ray crystallographic analysis was performed with hexane. Yellow
solid; Rf value 0.48 (hexane/ethyl acetate = 2/1); mp 70.3−71.1 °C;
IR (NaCl, neat) νmax 3288, 3060, 2927, 2360, 1653, 1487, 1444, 1392,
1
1506, 1390, 1256, 699 cm−1; H NMR (500 MHz, CDCl3) δ 7.49−
7.33 (m, 6H), 7.20−7.18 (m, 4H), 4.32−4.22 (m, 2H), 2.34 (ddd, 1H,
J = 13.5, 10.0, 5.5 Hz), 2.12 (ddd, 1H, J = 13.5, 9.5, 5.5 Hz), 1.76 (s,
3H), 1.38−1.25 (m, 5H), 1.06−0.99 (m, 2H), 0.69 (t, 3H, J = 7.5 Hz);
13C NMR (126 MHz, CDCl3) δ 191.4, 164.1, 153.7, 150.2, 139.9,
139.2, 131.2, 130.6, 130.3, 130.2, 128.34, 128.32, 128.30, 127.9,
126.0, 79.5, 63.1, 26.5, 24.9, 22.3, 16.6, 13.9, 13.5; LRMS (EI, M =
C25H27NO4) m/z 405 (M+, 55%), 363 (100), 362 (80); HRMS (EI)
calcd for C25H27NO4 (M+) 405.1940, found 405.1932.
1
1236, 1169, 885, 759, 699 cm−1; H NMR (500 MHz, CDCl3) δ 9.72
(s, 1H), 7.55−7.47 (m, 4H), 7.36−7.27 (m, 8H), 7.05−6.86 (m, 8H),
4.09 (d, 1H, J = 13.0 Hz), 3.58 (d, 1H, J = 13.0 Hz); 13C NMR
(126 MHz, CDCl3) δ 167.2, 147.8, 146.5, 138.8, 138.6, 131.1, 131.0,
130.4, 130.3, 129.4, 129.1, 128.9, 128.7, 128.5, 127.4, 126.4, 123.4,
114.9, 75.4, 42.6; HRMS (ESI) calcd for C31H24N3O [M+H]+
454.1919, found 454.1913.
3-Butyl-2-(1-cyano-2-phenylethyl)-5,5-diphenyl-2,5-dihydroisox-
azole-4-carboxylic Acid (31, CCDC 1471111). 12.9 mg (29%) of 31
2-Allyl-5-butyl-4-(diphenylmethylene)-2-(ethoxycarbonyl)-3-oxo-
3,4-dihydro-2H-pyrrole 1-Oxide (28b). 14.7 mg (45%) of 28b
was obtained from allenamide 1a (54.8 mg, 0.10 mmol), DMEAD
(35.1 mg, 0.15 mmol), TBAF (120 μL, 1.0 M in THF, 0.12 mmol),
and ethyl 2-benzyl-2-cyanoacetate 25b (61.0 mg, 0.50 mmol) (silica
gel column chromatography: hexane/ethyl acetate = 5/1 followed by
gel permeation chromatography:chloroform). Single crystal for X-ray
analysis was obtained by recrystallization from hexane. Pale yellow
solid; Rf value 0.45 (hexane/ethyl acetate = 2/1); mp 149.2−149.7 °C;
IR (NaCl, neat) νmax 2958, 2931, 1661, 1447, 1155, 911, 753 cm−1;
1H NMR (500 MHz, CDCl3) δ 7.50−7.45 (m, 4H), 7.35−7.27 (m,
9H), 7.17−7.16 (m, 2H), 4.45 (t, 1H, J = 7.5 Hz), 3.24 (dq, 2H, J =
14.0, 7.5 Hz), 3.03−2.97 (m, 1H), 2.35 (m, 1H), 1.22−1.13 (m, 4H),
0.76 (t, 3H, J = 7.5 Hz); 13C NMR (126 MHz, CDCl3) δ 159.8, 142.3,
141.3, 134.6, 129.42, 129.37, 128.7, 128.1, 127.84, 127.80, 127.6,
127.5, 116.3, 109.9, 92.7, 54.7, 37.1, 29.8, 24.9, 22.1, 13.5; HRMS
(ESI) calcd for C29H28N2NaO3 [M+Na]+ 475.1998, found 475.1997.
3-Butyl-2-(diphenylmethylene)-7,7-dimethyl-9-oxo-1,6,8-trioxa-
4-azaspiro[4.5]dec-3-ene 4-Oxide (33, CCDC 1471105). 39.5 mg
was obtained from allenamide 1a (54.8 mg, 0.10 mmol), DMEAD
(35.0 mg, 0.15 mmol), TBAF (620 μL, 1.0 M in THF, 0.62 mmol),
and diethyl allylmalonate (99.0 μL, 0.50 mmol) (silica gel column
chromatography: hexane/ethyl acetate = 6/1). Red oil; Rf value 0.29
(hexane/ethyl acetate = 3/1); IR (NaCl, neat) νmax 2958, 1760, 1730,
1
1506, 1389, 1238, 697 cm−1; H NMR (500 MHz, CDCl3) δ 7.49−
7.38 (m, 4H), 7.34 (t, 2H, J = 7.5 Hz), 7.16−7.15 (m, 4H), 5.59
(dddd, 1H, J = 17.5, 10.5, 7.5, 7.5 Hz), 5.28 (dd, 1H, J = 17.5, 2.0 Hz),
5.23 (dd, 1H, J = 10.5, 2.0 Hz), 4.26 (m, 2H), 3.20 (dd, 1H, J = 14.5,
7.5 Hz), 2.96 (dd, 1H, J = 14.5, 7.5 Hz), 2.27−2.13 (m, 2H), 1.37−
1.25 (m, 5H), 1.00 (m, 2H), 0.68 (t, 3H, J = 7.5 Hz); 13C NMR
(126 MHz, CDCl3) δ 190.8, 163.7, 155.3, 149.5, 140.0, 139.2, 131.4,
130.7, 130.4, 130.2, 129.0, 128.3, 127.8, 127.0, 121.8, 82.5, 63.1, 34.2,
26.6, 24.9, 22.4, 13.9, 13.5; LRMS (EI, M = C27H29NO4) m/z 431
(M+, 26%), 389 (50), 388 (42), 83 (53), 57 (100); HRMS (EI) calcd
for C27H29NO4 (M+) 431.2097, found 431.2099.
2-Benzyl-5-butyl-2-cyano-4-(diphenylmethylene)-3-imino-3,4-di-
hydro-2H-pyrrole 1-Oxide (29a). 30.4 mg (70%) of 29a was
obtained from allenamide 1a (54.8 mg, 0.10 mmol), DMEAD (35.1 mg,
0.15 mmol), TBAF (420 μL, 1.0 M in THF, 0.42 mmol), and
2-benzylmalononitrile (46.9 mg, 0.30 mmol)19 (silica gel column
chromatography: toluene/ethyl acetate = 20/1). Single crystal for
X-ray analysis was obtained by recrystallization from ethyl acetate.
Yellow oil; Rf value 0.38 (toluene/ethyl acetate = 20/1); IR (NaCl,
(47%) of 33 was obtained from allenamide 1a (109.6 mg, 0.20 mmol),
DMEAD (70.3 mg, 0.30 mmol), TBAF (840 μL, 1.0 M in THF,
0.84 mmol) and Meldrum’s acid (86.5 mg, 0.60 mmol) (silica gel
column chromatography: hexane/ethyl acetate = 2/1 with 10% toluene).
Single crystal for X-ray analysis was obtained by recrystallization from
hexane. White solid; Rf value 0.38 (hexane/ethyl acetate = 2/1);
mp 137−138 °C; IR (NaCl, neat) νmax 2957, 1768, 1542, 1293, 1039,
1
neat) νmax 3288, 2957, 1654, 1515, 1385, 1250, 702 cm−1; H NMR
(500 MHz, CDCl3) δ 9.70 (s, 1H), 7.49−7.19 (m, 13H), 6.98 (br, 1H),
6.15 (br, 1H), 3.97 (d, 2H, J = 14.0 Hz), 3.49 (d, 2H, J = 14.0 Hz),
1.97−1.84 (m, 2H), 1.24−1.15 (m, 1H), 1.01−0.92 (m, 1H), 0.90−
0.73 (m, 2H), 0.61 (t, 3H, J = 7.5 Hz); 13C NMR (126 MHz, CDCl3)
δ 167.4, 153.0, 145.6, 139.6, 138.7, 131.1, 131.0, 130.1, 129.6, 129.5,
128.41, 128.38, 124.1, 115.0, 74.0, 41.7, 26.2, 25.2, 22.4, 13.3; HRMS
(ESI) calcd for C29H27N3ONa [M+Na]+ 456.2052, found 456.2056.
2-Benzyl-2-cyano-4-(diphenylmethylene)-3-imino-5-phenyl-3,4-
dihydro-2H-pyrrole 1-Oxide (29b, CCDC 1471108). 10.1 mg (22%)
1
703 cm−1; H NMR (500 MHz, CDCl3) δ 7.42−7.24 (m, 10H), 3.64
(d, 1H, J = 18.0 Hz), 3.05 (d, 1H, J = 18.5 Hz), 1.93−1.84 (m, 2H),
1.78 (s, 3H), 1.75 (s, 3H), 1.28−1.18 (m, 2H), 0.96 (tq, 2H, J = 7.5,
7.5 Hz), 0.70 (t, 3H, J = 7.5 Hz); 13C NMR (126 MHz, CDCl3) δ 163.8,
143.5, 139.3, 137.6, 136.8, 130.9, 129.8, 128.6, 128.4, 128.0, 127.9, 121.5,
112.7, 106.3, 34.7, 28.33, 28.27, 26.7, 24.3, 22.5, 13.4; HRMS (ESI)
calcd for C25H27NNaO5 [M+Na]+ 444.1787, found 444.1779.
3-Butyl-2-(diphenylmethylene)-6,8-dimethyl-7,9-dioxo-1-oxa-
4,6,8-triazaspiro[4.5]dec-3-ene 4-Oxide (36). 23.9 mg (55%) of 36
was obtained from allenamide 1a (54.8 mg, 0.10 mmol), DMEAD
(35.1 mg, 0.15 mmol), TBAF (120 μL, 1.0 M in THF, 0.12 mmol),
of 29b was obtained from allenamide 1c (56.8 mg, 0.10 mmol),
DMEAD (35.1 mg, 0.15 mmol), TBAF (420 μL, 1.0 M in THF,
0.42 mmol), and 2-benzyl malononitrile (46.9 mg, 0.30 mmol) (silica gel
column chromatography: hexane/ethyl acetate = 10/1). Recrystallization
K
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and N,N′-dimethyl barbituric acid (46.8 mg, 0.30 mmol) (silica gel
column chromatography: hexane/ethyl acetate = 3/1). Colorless oil;
Rf value 0.38 (hexane/ethyl acetate = 2/1); IR (NaCl, neat) νmax 2957,
1730, 1681, 1544, 1445, 1351, 1178, 1054, 754 cm−1; 1H NMR
(500 MHz, CDCl3) δ 7.41−7.35 (m, 3H), 7.29−7.20 (m, 7H), 3.49
(d, 1H, J = 16.5 Hz), 3.22 (s, 3H), 3.14 (d, 1H, J = 16.0 Hz), 2.90
(s, 3H), 2.01−19.5 (ddd, 1H, J = 13.0, 11.0, 5.5 Hz), 1.73−1.67
(ddd, 1H, J = 13.0, 11.5, 5.0 Hz), 1.27−1.10 (m, 2H), 0.97−0.84 (m,
2H), 0.65 (t, 3H, J = 7.5 Hz); 13C NMR (126 MHz, CDCl3) δ 164.3,
152.6, 143.6, 140.2, 137.4, 136.7, 130.9, 129.7, 128.7, 128.5, 128.2,
128.0, 121.2, 105.3, 39.4, 28.1, 27.7, 26.7, 24.3, 22.5, 13.4; HRMS
(ESI) calcd for C25H27N3NaO4 [M+Na]+ 456.1899, found 456.1900.
General Procedure for Skeletal Rearrangement to Spirocy-
clic Nitrones. A TBAF THF solution (equivalents used are noted in
the section relevant to each product) was added to a stirred THF
solution of oxacyclic nitrone (0.05 M) at 0 °C. After 1 min, the reaction
mixture was concentrated in vacuo, and the residue was purified by
silica gel column chromatography to afford the rearranged carbocyclic
nitrone.
and 1,3-cyclohexanedione (33.6 mg, 0.30 mmol) (silica gel column
chromatography: hexane/ethyl acetate = 6/1 to 4/1).
From Oxacyclic Nitrone. According to the general procedure of
skeletal rearrangement, 17.5 mg (84%) of 8b was afforded from
oxacyclic nitrone 7b (20.8 mg, 0.050 mmol) and TBAF (420 μL, 1.0 M
in THF, 0.15 mmol) (silica gel column chromatography: hexane/ethyl
acetate = 2/1). Colorless oil; Rf value 0.48 (hexane/ethyl acetate =
2/1); IR (NaCl, neat) νmax 2929, 1710, 1550, 1388, 1103, 914, 760,
1
730 cm−1; H NMR (500 MHz, CDCl3) δ 7.44−7.37 (m, 5H), 7.30−
7.24 (m, 3H), 7.12−7.08 (m, 2H), 3.33 (d, 1H, J = 16.0 Hz), 2.86 (tt,
1H, J = 12.0, 3.5 Hz), 2.54 (m, 1H), 2.38 (d, 1H, J = 16.0 Hz), 2.11−
2.05 (m, 1H), 2.00−1.65 (m, 8H), 1.52−1.43 (m, 3H), 1.29−1.21 (m,
3H); 13C NMR (126 MHz, CDCl3) δ 205.8, 194.4, 144.1, 137.3, 136.8,
129.5, 129.4, 128.75, 128.69, 128.1, 127.9, 84.3, 69.5, 44.2, 38.9, 38.7,
33.6, 25.83, 25.79, 25.7, 25.6, 25.4, 20.2; HRMS (ESI) calcd for
C27H29NNaO3 [M+Na]+ 438.2045, found 438.1044.
2-Butyl-3,7-dioxo-4,4-diphenyl-1-azaspiro[4.4]non-1-ene 1-
Oxide (13). From Allenamide. According to the general procedure
2-Butyl-3,7-dioxo-4,4-diphenyl-1-azaspiro[4.5]dec-1-ene 1-Oxide
(8a, CCDC 1471109). From Allenamide. According to the general
for [3+2] reactions with nitrosoallene intermediates, 21.1 mg (56%) of
13 was afforded from allenamide 1a (54.8 mg, 0.10 mmol), DMEAD
(35.1 mg, 0.15 mmol), TBAF (420 μL, 1.0 M in THF, 0.42 mmol),
and 1,3-cyclopentanedione (29.4 mg, 0.30 mmol) (silica gel column
chromatography: hexane/ethyl acetate = 2/1).
procedure of [3+2] reactions with nitrosoallene intermediates, 29.5 mg
(76%) of 8a was afforded from allenamide 1a (54.8 mg, 0.10 mmol),
DMEAD (35.1 mg, 0.15 mmol), TBAF (450 μL, 1.0 M in THF,
0.42 mmol), and 1,3-cyclohexanedione (33.6 mg, 0.30 mmol) (silica
gel column chromatography: hexane/ethyl acetate = 5/1 to 2/1).
From Oxacyclic Nitrone (1). According to the general procedure for
the skeletal rearrangement, 16.2 mg (83%) of 8a was afforded from
oxacyclic nitrone 7a (19.5 mg, 0.050 mmol) and TBAF (150 μL, 1.0 M
in THF, 0.15 mmol) (silica gel column chromatography: hexane/ethyl
acetate = 2/1).
From Oxacyclic Nitrone (2). Potassium t-butoxide (6.2 mg,
0.055 mmol) was added to a stirred solution of 7a (19.5 mg,
0.050 mmol) in THF (1.0 mL) at 0 °C. After 3 h, a saturated ammonium
chloride aqueous solution was added to the reaction mixture. The
mixture was extracted with diethyl ether and washed with brine. The
combined organic layers were dried over sodium sulfate and con-
centrated in vacuo. The residue was purified by flash silica gel column
chromatography (hexane/ethyl acetate = 2/1) to afford 8a (18.8 mg,
96%). Recrystallization for X-ray analysis was performed with ethyl
acetate. White solid; Rf value 0.45 (hexane/ethyl acetate = 2/1);
mp 111−112 °C; IR (NaCl, neat) νmax 2957, 2931, 2873, 1709, 1558,
1387, 1103, 922, 760, 703 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.43−
7.37 (m, 5H), 7.31−7.28 (m, 3H), 7.11−7.10 (m, 2H), 3.32 (d, 1H, J =
15.0 Hz), 2.56−2.49 (m, 3H), 2.40 (d, 1H, J = 15.0 Hz), 2.13−2.06 (m,
1H), 2.02−1.96 (m, 1H), 1.88−1.85 (m, 1H), 1.70−1.65 (m, 1H),
1.56−1.42 (m, 3H), 1.28 (m, 2H), 0.88 (t, 3H, J = 7.0 Hz); 13C NMR
(126 MHz, CDCl3) δ 205.8, 194.7, 142.5, 137.2, 136.8, 129.5, 129.4,
128.8, 128.7, 128.2, 128.0, 84.5, 69.7, 44.6, 38.7, 38.4, 26.1, 22.7, 21.9,
20.3, 13.6; HRMS (ESI) calcd for C25H27NNaO3 [M+Na]+ 412.1889,
found 412.1882.
From Oxyacyclic Nitrone. 19.0 mg (quant) of 13 was obtained
from oxacyclic nitrone 12 (18.8 mg, 0.050 mmol) and TBAF (150 μL,
1.0 M in THF, 0.15 mmol) (silica gel column chromatography:
hexane/ethyl acetate = 3/1). White solid; Rf value 0.58 (hexane/ethyl
acetate = 2/1); mp 146−147 °C; IR (NaCl, neat) νmax 2957, 2931,
1
1751, 1710, 1558, 1495, 1385, 1264, 704 cm−1; H NMR (500 MHz,
CDCl3) δ 7.41−7.37 (m, 3H), 7.33−7.27 (m, 5H), 7.07−7.03 (m,
2H), 3.52 (d, 1H, J = 19.0 Hz), 2.77 (d, 1H, J = 19.0 Hz), 2.57−2.48
(m, 2H), 2.43 (m, 1H), 2.34 (m, 1H), 2.06 (m, 1H), 1.54−1.37 (m,
3H), 1.24 (m, 2H), 0.86 (t, 3H); 13C NMR (126 MHz, CDCl3)
δ 212.6, 194.6, 142.7, 139.4, 136.5, 129.6, 129.3, 128.80, 128.77, 128.4,
128.0, 86.5, 68.7, 44.2, 36.3, 36.1, 26.1, 22.6, 22.0, 13.6; HRMS (ESI)
calcd for C24H25NNaO3 [M+Na]+ 398.1732, found 398.1736.
( )-(4aR,5R,7aS)-2-Butyl-5-(methoxycarbonyl)-5-methyl-3,7-
dioxo-4,4-diphenyl-3,4,4a,5,7,7a-hexahydrofuro[3,4-b]pyridine 1-
Oxide (20, CCDC 1471106). From Allenamide. According to the
general procedure for [3+2] reactions with nitrosoallene intermediates,
16.6 mg (37%) of 20 was obtained from allenamide 1a (54.8 mg,
0.10 mmol), DMEAD (35.1 mg, 0.15 mmol), TBAF (420 μL, 1.0 M in
THF, 0.42 mmol), and methyl pyruvate (30 μL, 0.30 mmol) (silica gel
column chromatography: hexane/ethyl acetate = 10/1 to 5/1 followed
by gel permeation chromatography: chloroform).
From Oxime 19. 5.0 mg (28%) of 20 was afforded from oxime 19
(17.6 mg, 0.040 mmol) and TBAF (120 μL, 1.0 M in THF, 0.12 mmol)
after stirring at 0 °C for 1.5 h followed by rt for 1.5 h (silica gel column
chromatography: hexane/ethyl acetate = 2/1). Single crystal for X-ray
analysis was obtained by recrystallization from hexane. Pale yellow
solid; Rf value 0.40 (hexane/ethyl acetate = 2/1); mp 102.8−104.5 °C;
IR (NaCl, neat) νmax 2955, 1805, 1667, 1529, 1291, 1219, 752 cm−1;
1H NMR (500 MHz, CDCl3) δ 7.51−7.50 (m, 2H), 7.42−7.35 (m,
4H), 7.32−7.25 (m, 3H), 7.22−7.18 (m, 1H), 5.15 (d, 1H, J = 8.0 Hz),
4.80 (d, 1H, J = 8.0 Hz), 3.31 (s, 3H), 2.73 (m, 2H), 1.59
(s, 3H), 1.41−1.21 (m, 4H), 0.85 (t, 3H, J = 7.5 Hz); 13C NMR
2-Cyclohexyl-3,7-dioxo-4,4-diphenyl-1-azaspiro[4.5]dec-1-ene 1-
Oxide (8b). From Allenamide. According to the general procedure for
[3+2] reactions with nitrosoallene intermediates, 21.5 mg (52%) of 8b
was afforded from allenamide 1b (57.4 mg, 0.10 mmol), DMEAD
(35.1 mg, 0.15 mmol), TBAF (150 μL, 1.0 M in THF, 0.42 mmol),
L
DOI: 10.1021/acs.joc.6b00758
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Article
(126 MHz, CDCl3) δ 185.5, 168.6, 163.9, 150.7, 138.2, 137.8, 129.7,
129.2, 128.7, 128.3, 127.6, 126.5, 85.6, 66.6, 53.5, 52.9, 47.5, 26.3,
24.6, 22.7, 19.9, 13.6; HRMS (ESI) calcd for C26H27NNaO6 [M+Na]+
472.1736, found 472.1733.
2-(1H-Benzo[d][1,2,3]triazol-1-yl)-1,1-diphenylhept-1-en-3-one
Oxime (38b). According to the general procedure for [3+2] reactions,
2-Butyl-7,7-dimethyl-3,9-dioxo-4,4-diphenyl-6,8-dioxa-1-
azaspiro[4.5]dec-1-ene 1-Oxide (34, CCDC 1471107). 9.3 mg (44%)
23.4 mg (59%) of 38b was obtained from allenamide 1a (54.8 mg,
0.10 mmol), DMEAD (35.1 mg, 0.15 mmol), TBAF (120 μL, 1.0 M in
THF, 0.12 mmol), and benzotriazole (35.7 mg, 0.30 mmol) (silica gel
column chromatography: hexane/ethyl acetate = 6/1). Colorless oil;
Rf value 0.50 (hexane/ethyl acetate =2/1); IR (NaCl, neat) νmax 3172,
1
2957, 2871, 1491, 1282, 1012 cm−1; H NMR (500 MHz, CDCl3)
δ 8.21 (brs, 1H), 7.91 (d, 1H, J = 8.5 Hz), 7.90−7.21 (m, 8H), 7.01−
6.94 (m, 3H), 6.86−6.84 (m, 2H), 2.07 (m, 2H), 1.41 (m, 2H),
1.16 (tq, 2H, J = 7.5, 7.5 Hz), 0.74 (t, 3H, J = 7.5 Hz); 13C NMR (126
MHz, CDCl3) δ 158.4, 145.2, 145.1, 139.5, 139.1, 133.1, 130.1, 129.1,
128.7, 128.4, 128.3, 128.0, 127.7, 127.6, 123.8, 119.8, 110.1, 27.8, 27.0,
22.8, 13.5; HRMS (ESI) calcd for C25H24N4NaO [M+Na]+ 419.1848,
found 419.1841.
of 34 was afforded from oxacyclic nitrone 33 (21.1 mg, 0.050 mmol)
and TBAF (500 μL, 1.0 M in THF, 0.50 mmol) (silica gel column
chromatography: hexane/ethyl acetate = 2/1). Recrystallization for
X-ray analysis was performed with hexane. White solid; Rf value 0.58
(hexane/ethyl acetate = 2/1); mp 184−185 °C; IR (NaCl, neat) νmax
1
2958, 2359, 1767, 1714, 1563, 1387, 1284, 985, 701 cm−1; H NMR
(500 MHz, CDCl3) δ 7.39−7.35 (m, 3H), 7.30−7.22 (m, 7H), 3.34
(d, 1H, J = 17.5 Hz), 2.81 (d, 1H, J = 17.5 Hz), 2.52 (t, 2H, J =
7.5 Hz), 1.82 (s, 3H), 1.45 (tdd, 2H, J = 7.5, 7.5, 2.5 Hz), 1.34 (s, 3H),
1.20 (m, 2H), 0.84 (t, 3H, J = 7.5 Hz); 13C NMR (126 MHz, CDCl3)
δ 191.8, 163.7, 142.8, 137.1, 136.0, 130.0, 129.5, 129.0, 128.7, 128.2,
127.8, 106.9, 103.8, 69.8, 34.4, 29.0, 28.4, 26.0, 22.5, 21.9, 13.6; HRMS
(ESI) calcd for C25H27NNaO5 [M+Na]+ 444.1787, found 444.1784.
2-Butyl-6,8-dimethyl-3,7,9-trioxo-4,4-diphenyl-1,6,8-triazaspiro-
[4.5]dec-1-ene 1-Oxide (37). 21.1 mg (88%) of 37 was obtained from
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b00758.
1H and 13C NMR spectra (PDF)
Crystallographic data of new compounds (CCDC
numbers 1471114 for 4; 1471113 for 5; 1471104 for
7a; 1471109 for 8a; 1471116 for 16cc; 1471106 for 20;
1471110 for 22; 1471112 for 27c; 1471108 for 29b;
1471111 for 31; 1471105 for 33; 1471107 for 34) (CIF)
Computational data [Gaussian09 B3LYP/6-31G(d,p)]
(XYZ)
oxacyclic nitrone 36 (24.1 mg, 0.056 mmol) and TBAF (168 μL,
1.0 M in THF, 0.168 mmol). Pure material was obtained without
silica gel chromatography. Colorless oil; Rf value 0.43 (hexane/ethyl
acetate = 2/1); IR (NaCl, neat) νmax 2958, 1713, 1674, 1568, 1452,
AUTHOR INFORMATION
Corresponding Author
*tanimoto@ms.naist.jp.
Notes
■
1
1386, 754 cm−1; H NMR (500 MHz, CDCl3) δ 7.72−7.70 (m, 2H),
7.45−7.40 (m, 3H), 7.29−7.24 (m, 3H), 6.81−6.78 (m, 2H), 3.187 (s,
3H), 3.186 (d, 1H, J = 16.5 Hz), 3.11 (d, 1H, J = 16.5 Hz), 2.77−2.66
(m, 2H), 2.34 (s, 3H), 1.65 (ddt, 2H, J = 15.5, 7.5, 7.5 Hz), 1.45
(tq, 2H, J = 7.5, 7.5 Hz), 0.97 (t, 3H, J = 7.5 Hz); 13C NMR
(126 MHz, CDCl3) δ 195.3, 165.2, 153.3, 145.1, 139.1, 134.7, 129.3,
129.0, 128.73, 128.66, 128.5, 128.2, 93.1, 63.7, 36.2, 31.3, 27.9, 26.6,
23.1, 21.9, 13.6; HRMS (ESI) calcd for C25H27N3NaO4 [M+Na]+
456.1899, found 456.1892.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported in part by Grants-in-Aid of MEXT for
Young Scientists (B) (15K17856). We also thank Ms. Yoshiko
Nishikawa, Mr. Kazuo Fukuda (HRMS measurements), and
Mr. Shohei Katao (X-ray crystallographic analysis) of NAIST.
Synthesis of 2-Azolyl Enoximes. 2-(1H-Imidazol-1-yl)-1,1-
diphenylhept-1-en-3-one Oxime (38a). According to the general
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