Annuloselectivity in Reactions of Diacyl Dichlorides and Imines: Combined Experimental and Theoretical Studies

Article abstract of DOI:10.1021/acs.joc.5b00573

The annuloselectivity defined as the annulation selectivity between [2 + 2] and cascade annulations of diacyl dichlorides and imines in the presence of organic bases to afford bis-β-lactams and 2,3-dihydro-1,3-oxazin-4-ones has been studied extensively wi

Full text of DOI:10.1021/acs.joc.5b00573

Article
pubs.acs.org/joc
Annuloselectivity in Reactions of Diacyl Dichlorides and Imines:
Combined Experimental and Theoretical Studies
Xinyao Li,† Xin Jin,† and Jiaxi Xu*
State Key Laboratory of Chemical Resource Engineering, Department of Organic Chemistry, Faculty of Science, Beijing University of
Chemical Technology, 100029 Beijing, People’s Republic of China
S
* Supporting Information
ABSTRACT: The annuloselectivity defined as the annulation
selectivity between [2 + 2] and cascade annulations of diacyl
dichlorides and imines in the presence of organic bases to
afford bis-β-lactams and 2,3-dihydro-1,3-oxazin-4-ones has
been studied extensively with a combination of experiments
and density functional theory (DFT) calculations. The present
results indicate that it is the preference of diacyl dichlorides in
the formation of cyclic α-oxoketenes in the presence of organic
bases that controls the annuloselectivity. The cascade annulations of hexanedioyl and heptanedioyl dichlorides undergo the
chloride-assisted cyclization of the corresponding ω-chlorocarbonylalkylketenes as the rate-determining step in the presence of
triethylamine, rather than the generation of bisketenes followed by dimerization, affording five- and six-membered cyclic α-
oxoketenes followed by the [4 + 2] annulations with imines to furnish 2,3-dihydro-1,3-oxazin-4-ones. This is an energetically
competitive pathway to the normal Staudinger cycloaddition. Further decreasing (pentanedioyl dichloride) or increasing the
linker length (octanedioyl and nonanedioyl dichlorides) results in the enhanced energetic barriers for the cyclization, which is
less competitive to the direct Staudinger cycloaddition to afford bis-trans-β-lactams as the sole products. The current results
provide an insight into the annuloselective control in the reactions of diacyl dichlorides and imines.
react with imines, and the annuloselectivity of bisketenes with
imines is still a contentious and unclear issue in the
cycloadditions. Sudo and Endo reported that the reaction of
dicarboxylic acid and an imine with pyridinium salt and
triethylamine gives a bis-β-lactam (Scheme 1a).10 Dumas et al.
also developed the synthesis of bis-β-lactams from transition-
metal carbene complexes with a cyclic imine (Scheme 1b).11 In
2008, Allen et al. exploited the annulation of didiazomethyldi-
ketones or diacyl dichlorides with N-benzylideneaniline to
afford bis-β-lactams (Scheme 1c).12 However, Jager achieved
distinct results through the reaction of hexanedioyl dichloride
with an imine to furnish an oxazinone (Scheme 1d).13 Presset
et al. also obtained a similar oxazinone through Wolff
rearrangement of α-diazo-β-diketone with an imine (Scheme
1e).14 Recently, we performed DFT calculations on the
annulations of ketenes and imines, focusing on unraveling the
mechanism of the two tandem reactions of [2 + 2 + 2]
annulations and on in-depth comprehending the origin of the
annuloselectivity in the Staudinger reactions (Scheme 2a).15
We also investigated the influence of base on the
annuloselectivity and found base-switched annuloselectivity in
the reactions of ethyl malonyl chloride and imines.16 However,
to the best of our knowledge, there still lacks a clear
mechanistic investigation on the annuloselectivity in reactions
of bisketenes with imines. Herein, we report the combined
INTRODUCTION
■
The [2 + 2] cycloaddition reaction of imines and ketenes,
referred to as Staudinger reaction or Staudinger cycloaddition,1
has proven to be a powerful tool for the construction of β-
lactams, which serve as key structural figures in a series of
antibiotics.2 Though the numerous reports from our
laboratory3 and others4 have focused on the synthetic
methodologies and the diastereoselectivity of β-lactam
formation in the Staudinger reaction, bisketenes are also
found to be versatile intermediates that react with water,
alcohols, amines, and even alkenes to afford anhydrides, esters,
amides, and Diels−Alder cycloadducts, respectively.5 During
the continuous exploration of the chemistry of bisketenes, a
series of bisketenes has been successfully prepared; even the
unstable ones have be detected and employed in organic
synthesis.6 Among them, there are three representative
methods to give rise to bisketenes: (a) elimination of HCl in
diacyl dichlorides in the presence of base, (b) Wolff
rearrangement of didiazomethyldiketones under photoirradia-
tion or heating conditions, and (c) photolysis of cyclo-
butenediones.6b,7 With the development of the synthetic
methods for bisketenes, their chemical properties and reactions
have been widely investigated.8 Tidwell and co-workers have
focused on this field for several decades and have provided
systematic studies on the nature of bisketenes with a series of
substitutents.9
Ketenes are widely used for construction of β-lactams with
Received: March 13, 2015
imines; however, bisketenes are relatively seldom reported to
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b00573
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experimental and computational studies on the origin of the
annuloselectivity between [2 + 2] and tandem annulations in
the reactions of diacyl dichlorides and imines in the presence of
triethylamine, further unraveling the mechanism of the tandem
annulations (Scheme 2b). We believe that it is critical not only
to our mechanistic understanding of the tandem annulations
and annuloselectivity but also to guiding the further control and
application of the reactions between diacyl dichlorides and
imines in organic synthesis.
Scheme 1. Previous Annulations of Bisketenes with Imines
RESULTS AND DISCUSSION
■
Initially, we employed hexanedioyl dichloride (adipoyl
dichloride) (1) as a bisketene precursor to explore the
annulation with a series of imines 2. As described in Table 1,
a
Table 1. Reaction of Adipoly Chloride (1) and Imines 2
b
entry
R1
R2
3
yield (%)
1
2
Ph
Ph
Ph
3a
3b
3c
3d
3e
3f
68
99
32
72
58
99
89
87
63
42
92
73
65
92
4-NO2C6H4
Ph
3
2,6-Me2C6H3
4
Bn
Ph
5
cHex
allyl
iPr
4-NO2C6H4
Ph
6
7
Ph
3g
3h
3i
8
iPr
4-MeOC6H4
4-MeC6H4
4-NO2C6H4
4-MeO-C6H4
4-NO2C6H4
Ph
9
iPr
10
11
12
13
14
iPr
3j
nPr
nPr
Me
Me
3k
3l
3m
3n
4-NO2C6H4
a
Reaction conditions: 1 (1 mmol), 2 (2 mmol), Et3N (2 mmol) in
b
toluene (5 mL) under N2 at room temperature for 3 h. Isolated yield.
most of the imines react well with 1 in the presence of
triethylamine at room temperature to afford 2,3-dihydro-1,3-
oxazin-4-one derivatives 3 as the sole products in good to
excellent yields. Aryl-substituted imines with electron-with-
drawing and electron-donating groups are fully compatible.
Various aryl and alkyl substituents in imines are well tolerated,
indicative of wide scope. No bis-β-lactam from [2 + 2]
cycloaddition was observed in these cases.
Scheme 2. Annuloselectivity in Reactions of Ketenes/Diacyl
Dichlorides with Imines
By following the mild conditions, the scope of this reaction
with heptanedioyl dichloride (pimeloyl chloride) (4) was next
explored (Table 2). However, reactions of the substrate 4 were
sluggish and afforded 2,3-dihydro-1,3-oxazin-4-one derivatives 5
in low yields under mild conditions. Further increasing the
reaction temperature could improve the yields. Various aryl and
alkyl substituents in imines are well tolerated, indicative of wide
scope, though the yields are still moderate. After scrutiny of the
reaction with 4 and 2a, 2,3-dihydro-1,3-oxazin-4-one 5a was
formed in 27% yield, along with bis-β-lactam 6a in 6% yield (eq
1, Scheme 3). Reducing or increasing the tethered methylene
groups in the diacyl dichlorides 7a−c could not provide 2,3-
dihydro-1,3-oxazin-4-one derivatives at room temperature,
while under reflux conditions, only bis-β-lactams 8a−c were
generated in about 12% yields (eq 2, Scheme 3). Diacyl
B
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a
isomers still exist. The linker 1,5-pentylidene group is so long
so that no difference appears in the NMR spectra for the
different stereoisomers (eqs 1 and 2, Scheme 3). The
diastereomeric bis-β-lactams cannot be separated in most
cases because of similar polarity. Only meso-8a and ( )-8a were
separated on silica gel column chromatography. We attempted
to grow single crystals to distinguish their structures, and we
failed. We assigned their stereostructures on the basis of their
polarity. A less polar diastereomer is a pair of enantiomers
( )-8a, whereas a more polar one is meso-8a.
Computational Methods. All optimized geometries were
calculated at the DFT M06-2X level17 with 6-311+G(d,p) basis
set for all the atoms with the Gaussian 09 suite of programs.18
Frequency calculations at the M06-2X level at 298 K were
performed to confirm each stationary point to be either a
minimum or a transition structure. Solvation energies were
evaluated by a self-consistent reaction field (SCRF) using the
conductor-like polarizable continuum solvation (CPCM)
model,19 where UFF radii were used. Solvation calculations
were carried out at the M06-2X level on the optimized
structures in solution. Unless specifically mentioned, all
discussed relative energies in this paper are referred to
ΔGsol298K. The structures in Figure 2 were prepared using
CYLView.20
DFT Studies on Annuloselectivity. To explore potential
reaction pathways of the annulations, we conducted a density
functional theory (DFT) calculation investigation into the
annuloselectivity of the [2 + 2] cycloaddition (Pathway A) and
cascade annulation (Pathway B) of adipoyl dichloride (1) and
imine 2m in the presence of trimethylamine as a model
reaction. The potential energy profiles in Figure 1 for Pathway
A show that the first step of the cascade process corresponds to
elimination of HCl in 1 by trimethylamine with an activation
free energy of 23.4 kcal/mol to afford monoketene INT1,
which is slightly endergonic by 2.0 kcal/mol. Normally, the
Table 2. Reaction of Pimeloyl Chloride (4) and Imines 2
b
entry
R1
Ph
R2
5
yield (%)
1
2
Ph
5a
5b
5d
5e
5f
27
16
16
13
9
Ph
4-NO2C6H4
Ph
3
Bn
4
cHex
allyl
iPr
4-NO2C6H4
Ph
5
6
Ph
5g
5h
5j
19
8
7
iPr
4-MeOC6H4
4-NO2C6H4
4-MeOC6H4
4-NO2C6H4
Ph
8
iPr
25
14
16
15
14
9
nPr
nPr
Me
Me
5k
5l
10
11
12
5m
5n
4-NO2C6H4
a
Reaction conditions: 4 (1 mmol), 2 (2 mmol), Et3N (2 mmol) in
toluene (5 mL) under N2 at reflux conditions for 3 h. Isolated yield.
b
dichlorides that tethered different numbers of the methylene
group afford distinct annulation products, and the origin of
annuloselectivity is still unclear.
The coupling constants (0−2.3 Hz) of the vicinal protons in
bis-β-lactams 6a and 8 indicate that all β-lactams possess trans
configuration (0−3 Hz for trans-β-lactams and 4−6 Hz for cis-
β-lactams). Except for bis-β-lactam 8c, duplicated peaks were
observed in their H NMR and 13C NMR spectra, indicating
1
that diastereomeric bis-β-lactams, meso-bis-β-lactams and a pair
of enantiomeric bis-β-lactams with double trans-β-lactams, exist
in the products as in a previous observation.12 Although no
duplicated peak was observed in the H NMR and 13C NMR
1
spectra of bis-β-lactam 8c, we believe that diastereomeric
Scheme 3. Annuloselectivity in Reactions of Different Diacyl Dichlorides with N-Benzylideneaniline
C
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Figure 1. Calculated energy profiles for the [2 + 2] cycloaddition and cascade annulations of diacyl dichloride 1 with imine 2m at the M06-
2X(CPCM)/6-311+G(d,p) levels of theory.
monoketene INT1 can be expected to undergo stepwise [2 +
2] Staudinger reaction directly with imine 2m to give rise to the
corresponding cis-β-lactam in which the first step is the
generation of zwitterionic intermediate INT2-E via the
transition-state TS2-E with an activation free energy of 17.5
kcal/mol, and the second step is the ring-closure to form the
corresponding cis-β-lactam product INT3-cis through TS3-E.
The second ring-closure step considered as the rate-
determining step requires an activation free energy of 31.3
kcal/mol, which seems to be a little high under mild conditions.
Alternatively, imine 2m with (E)-configuration could undergo
isomerization to 2m-Z with (Z)-configuration via the TS4-EZ
with an activation free energy of 29.9 kcal/mol. Then 2m-Z
attacks monoketene INT1 via TS2-Z with an activation free
energy of 18.4 kcal/mol to generate zwitterionic intermediate
INT2-Z. The following ring-closure via TS3-Z to form the
corresponding trans-β-lactam INT3-trans requires an activation
free energy of 26.6 kcal/mol, which is more favorable over TS3-
E. Besides, zwitterionic intermediate INT2-E could convert to
INT2-Z via TS5-EZ; however, it suffers from a high energetic
barrier (44.3 kcal/mol).
In Pathway B, after elimination of HCl in 1, the generated
monoketene INT1 could undergo cyclization to deliver α-
oxoketene, followed by [4 + 2] annulation with imine 2m to
yield the 2,3-dihydro-1,3-oxazin-4-one derivative 3m. Two
pathways have been calculated to account for the cyclization of
diacyl dichloride 1. In the previously proposed mechanism,15
monoketene INT1 was regarded to take part in the second
elimination of HCl by trimethylamine via TS6 with an
activation free energy of 24.2 kcal/mol to provide diketene
D
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Figure 2. Transition-state structures in the reaction of adipoyl dichloride (1) and imine 2m optimized at M06-2X(CPCM)/6-311+G(d,p) in the
solution of toluene. The breaking or forming bonds are shown in the gray shaded lines, and the bond distances are shown in Å.
INT4. However, the subsequent dimerization of the diketene
proceeds via TS7 with an activation free energy of 32.7 kcal/
mol to furnish the lactone INT5. This seems to suffer from a
too high energetic barrier to allow the dimerization to proceed
under the conditions used. Alternatively, monoketene INT1
directly undergoes cyclization through TS8 with the C−C bond
formation, and the Cl atom shifts to produce cyclic acyl
chloride INT6. This cyclization between acyl chloride and
ketene readily proceeds with an activation free energy of only
22.3 kcal/mol. In transition-state TS8, the forming C−C bond
distance is 1.91 Å and the breaking and forming C−Cl bond
distances are 2.22 and 2.93 Å, respectively (Figure 2). The
formed acyl chloride INT6 is removed hydrogen chloride by
trimethylamine via TS9 readily to provide α-oxoketene INT7,
which is exergonic by 6.2 kcal/mol. The subsequent step is the
attack of imine 2m to α-oxoketene INT7 with an activation free
energy of 13.5 kcal/mol. In TS10, the forming N−C bond
distance is 2.15 Å. The generation of zwitterionic intermediate
INT8 is slightly endergonic by 3.6 kcal/mol. Finally, the
intermediate INT8 undergoes ring-closure via a six-membered
ring transition state TS11, requiring a low activation free energy
of 2.6 kcal/mol, to give rise to product 3m that is 34.6 kcal/mol
more stable than the starting materials. The forming O−C
bond distance in TS11 is 2.18 Å, which is not far from that in
INT8 (2.96 Å), making the pathway facile.
Reviewing the whole energy profile, we found that Pathway B
is the most likely to take place to afford oxazinone 3m, and the
annuloselectivity-determining step of this cascade annulation
reaction is the cyclization between acyl chloride and ketene
moieties, rather than the generation of bisketene followed by
dimerization, which is very competitive to the direct Staudinger
reaction (22.3 vs 29.9 kcal/mol). Moreover, our mechanistic
understanding provides new insight into the formation of the
dimerization products of diacyl dichlorides in the presence of
organic bases. This is in accord with the previous experimental
result23 and is also supported by our experimental observation
that the reaction of 1,6-diazo-2,5-hexanedione (9) as the
bisketene precursor with imine 2a cannot afford oxazinone 3a
(eq 3, Scheme 3), while adipoyl dichloride (1) can. These
together provide a good proposal for the formation of the
oxazinones as major products from adipoyl dichloride and
imines.
dichlorides on the cyclization (Table 3). When pentanedioyl
dichloride (glutaroyl dichloride) (n = 3) is employed, the Gibbs
Table 3. Energetic Barriers of Cyclization between Acyl
Chloride and Ketene Moieties in Different Diacyl
Dichlorides
diacyl
entry dichloride
ΔG‡(TS)
ΔH‡(TS)
−TΔS‡(TS)
n
(kcal/mol)
(kcal/mol)
(kcal/mol)
1
2
3
4
5
6
7a
3
33.6
22.3
22.8
29.1
33.8
30.9
33.4
21.3
20.4
26.2
30.7
19.8
0.2
1.0
1
4
5
4
2.4
7b
6
2.9
7c
7
3.1
EtCOCl
NA
11.1
free energy of the cyclization is high up to 33.6 kcal/mol with
the four-membered ring strain (33.4 kcal/mol in activation
enthalpy). For adipoyl dichloride (n = 4), the Gibbs free energy
level at its lowest point (22.3 kcal/mol) makes the cyclization
kinetically accessible, corresponding to our successful cascade
annulation reactions in good yields. Heptanedioyl dichloride (n
= 5) requires 22.8 kcal/mol in terms of the Gibbs free energy,
slightly higher than adipoyl dichloride (22.3 kcal/mol), leading
to a decrease in the yields, consistent with our experimentally
observed results. Further increasing the linker length
[octanedioyl dichloride (n = 6) and nonanedioyl dichloride
(n = 7)] results in the enhanced energetic barriers (29.1 and
33.8 kcal/mol in free energy) for the cyclization, which is
unfavorable in comparison with the direct Staudinger reaction
(about 27 kcal/mol, TS3-Z), in good agreement with our
experimental observation of bis-β-lactams as the sole products.
Furthermore, two molecules of propionyl chloride considered
as the simple model for the diacyl dichloride with the longer
linker length undergo the cyclization (herein, dimerization)
with 30.9 kcal/mol in terms of the Gibbs free energy, which is
significantly contributed by the decrease of entropy (−TΔS‡ =
11.1 kcal/mol). This dimerization of propionyl chloride is also
less competitive to the direct Staudinger reaction with imines,
once again in accord with our previous experimental results.3c,24
Given the importance of cyclization between acyl chloride
and ketene moieties as the annuloselectivity-determining step,
we next explore the effect of the linker length of diacyl
E
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For aliphatic diacyl dichlorides, the elimination of HCl by
trimethylamine requires an energetic barrier of about 23 kcal/
mol, and it is slightly endergonic by about 2 kcal/mol. In
addition, the reaction system of 2,2′-(1,2-phenylene)diacetyl
dichloride from Allen et al.12 is compared. It is found from the
calculational results that the elimination of HCl in 2,2′-(1,2-
phenylene)diacetyl dichloride is facile and exergonic by 2.5
kcal/mol to provide the corresponding bisketene possibly
because of the existence of more acidic benzylic α-proton, in
agreement with the experimental observation of bisketene.12
under N2 at room temperature was added adipoyl dichloride
(1) (183 mg, 1 mmol) dropwise. The reaction mixture was
stirred for 3 h at room temperature and was filtered. The filter
cake was washed with dichloromethane. The combined filtrate
was washed with water and brine and was dried over sodium
sulfate. After removal of the solvent under reduced pressure,
the residue was purified by column chromatography on silica
gel and was recrystallized from petroleum ether (30−60 °C)/
ethyl acetate (PE/EA = 8:1, v/v) to afford 3.
2,3,6,7-Tetrahydro-2,3-diphenylcyclopenta[e][1,3]oxazin-
4(5H)-one (3a). White crystals, mp 97−100 °C (lit.13 101−104
°C); 198 mg, yield 68%; 1H NMR (400 MHz, CDCl3) δ 7.52−
7.12 (m, 10H), 6.67 (s, 1H), 2.75−2.52 (m, 2H), 2.52−2.33
(m, 2H), 2.05−1.91 (m, 1H), 1.91−1.77 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 167.7, 161.9, 140.0, 137.3, 129.2, 128.9,
128.5, 127.1, 125.9, 125.4, 111.1, 91.5, 31.6, 25.9, 19.6.
CONCLUSIONS
■
In summary, we have explored the annuloselectivity between [2
+ 2] and cascade annulations of diacyl dichlorides and imines in
the presence of triethylamine to afford bis-β-lactams and 2,3-
dihydro-1,3-oxazin-4-ones, respectively, and have provided
mechanistic investigation with the aid of DFT calculations.
The results indicate that the cascade annulations of hexanedioyl
and heptanedioyl dichlorides with imines in the presence of
organic bases undergo the chloride-assisted cyclization of the
corresponding ω-chlorocarbonylalkylketenes as the rate-deter-
mining step, rather than the generation of bisketenes and
subsequent dimerization, to afford further cyclic α-oxoketenes
followed by the [4 + 2] annulation with imines to furnish 1,3-
oxazin-4-ones. This reaction pathway is very competitive to the
normal Staudinger reaction. Further decreasing (pentanedioyl
dichloride) or increasing the linker length (octanedioyl and
nonanedioyl dichlorides) between the two acyl chloride groups
results in the enhanced energetic barriers for the cyclization,
which is less competitive to the direct Staudinger reaction to
afford bis-β-lactams as the sole products. The annuloselectivity
between [2 + 2] and tandem annulations is controlled
significantly by the linker length between the two acyl chloride
groups. Actually, it is controlled by the preference in the
formation of cyclic α-oxoketenes. Diacyl dichlorides show good
preference in the formation of cyclic α-oxoketenes, generally
five- and six-membered cyclic α-oxoketenes, in the presence of
organic bases, favoring 1,3-oxazin-4-one products in the
reactions with imines. Otherwise, diacyl dichlorides with poor
preference in the formation of cyclic α-oxoketenes generate
predominately bis-trans-β-lactams in the reactions with imines.
The current combined experimental and DFT studies provide
comprehensive understanding on the cascade reaction mech-
anism and the annuloselectivity and even guide the further
application of diacyl dichlorides and imines in the design of
new synthetic strategies for heterocyclic compounds.
2,3,6,7-Tetrahydro-2-(4-nitrophenyl)-3-phenylcyclopenta-
[e][1,3]oxazin-4(5H)-one (3b). Orange crystals, mp 153−154
°C; 387 mg, yield 99%; 1H NMR (400 MHz, CDCl3) δ 8.24 (d,
J = 8.7 Hz, 2H), 7.68 (d, J = 8.6 Hz, 2H), 7.39−7.30 (m, 2H),
7.28−7.17 (m, 3H), 6.74 (s, 1H), 2.74−2.58 (m, 2H), 2.51−
2.36 (m, 2H), 2.08−1.94 (m, 1H), 1.93−1.80 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 167.9, 161.3, 148.5, 144.6, 139.6,
129.2, 128.1, 126.4, 125.2, 123.8, 111.7, 90.4, 31.5, 25.9, 19.6;
IR (cm−1) 1667.8; EI-MS m/z = 336 [M+]; ESI-HRMS calcd
for C19H17N2O4, m/z = 337.1183 [M + H]+; found, 337.1186.
3-(2,6-Dimethylphenyl)-2,3,6,7-tetrahydro-2-phenylcyclo-
penta[e][1,3]oxazin-4(5H)-one (3c). Brown crystals, mp 124−
1
126 °C; 126 mg, yield 32%; H NMR (400 MHz, CDCl3) δ
7.38−7.32 (m, 2H), 7.27−7.15 (m, 3H), 6.97−6.82 (m, 3H),
6.45 (s, 1H), 2.82−2.62 (m, 4H), 2.24 (s, 3H), 2.11 (s, 3H),
2.13−2.01 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 169.8,
162.4, 137.7, 136.8, 136.7, 134.2, 129.6, 128.1, 128.0, 127.9,
127.7, 127.4, 110.8, 92.7, 31.3, 26.2, 20.0, 19.0, 18.9; IR (cm−1)
1667.1; EI-MS m/z = 319 [M+]; ESI-HRMS calcd for
C21H21NO2, m/z = 320.1645 [M + H]+; found, 320.1650.
3-Benzyl-2,3,6,7-tetrahydro-2-phenylcyclopenta[e][1,3]-
1
oxazin-4(5H)-one (3d). Colorless oil; 222 mg, yield 72%; H
NMR (400 MHz, CDCl3) δ 7.40−7.09 (m, 10H), 6.15 (s, 1H),
5.37 (d, J = 15.4 Hz, 1H), 3.82 (d, J = 15.4 Hz, 1H), 2.72−2.60
(m, 1H), 2.60−2.45 (m, 2H), 2.42−2.30 (m, 1H), 2.02−1.81
(m, 2H); 13C NMR (100 MHz, CDCl3) δ 167.5, 163.0, 137.2,
135.9, 129.5, 128.5, 127.8, 127.4, 109.7, 89.4, 46.1, 31.5, 26.0,
19.7; IR (cm−1) 1664.2; EI-MS m/z = 305 [M+]; ESI-HRMS
calcd for C20H20NO2, m/z = 306.1489 [M + H]+; found,
306.1494.
3-Cyclohexyl-2,3,6,7-tetrahydro-2-(4-nitrophenyl)-
cyclopenta[e][1,3]oxazin-4(5H)-one (3e). White crystals, mp
133−134.5 °C; 198 mg, yield 58%; H NMR (400 MHz,
1
EXPERIMENTAL SECTION
■
CDCl3) δ 8.21 (d, J = 8.7 Hz, 2H), 7.63 (d, J = 8.7 Hz, 2H),
6.43 (s, 1H), 4.60−4.48 (m, 1H), 2.66−2.56 (m, 1H), 2.54−
2.43 (m, 1H), 2.37−2.27 (m, 1H), 2.25−2.14 (m, 1H), 1.97−
1.70 (m, 7H), 1.52−1.39 (m, 3H), 1.12−0.93 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 166.3, 161.8, 148.3, 146.1, 128.0,
123.4, 111.8, 84.4, 51.9, 31.8, 31.5, 31.3, 25.8, 25.74, 25.69,
25.3, 19.4; IR (cm−1) 1658.9; EI-MS m/z = 342 [M+]; ESI-
HRMS calcd for C19H23N2O4, m/z = 343.1652 [M + H]+;
found, 343.1655.
General Information. Melting points were obtained on a
melting point apparatus and are uncorrected. 1H NMR and 13
C
NMR spectra were recorded on a 300 or 400 MHz
spectrometer with TMS as an internal standard in CDCl3
solution. IR spectra were taken on an FT-IR spectrometer in
KBr. HRMS data were obtained with an LC/MSD TOF mass
spectrometer. Purification of reaction products was carried out
by column chromatography using silica gel (200−300 mesh).
TLC separations were performed on silica gel G plates with
petroleum ether/ethyl acetate, and the plates were visualized
with UV light.
3-Allyl-2,3,6,7-tetrahydro-2-phenylcyclopenta[e][1,3]-
1
oxazin-4(5H)-one (3f). Colorless oil; 278 mg, yield 99%; H
General Procedure for the Reaction of Adipoyl
Dichloride (1) and Imines 2. To a solution of imine 2 (2
mmol) and Et3N (303 mg, 3 mmol) in dry toluene (5 mL)
NMR (400 MHz, CDCl3) δ 7.40 (s, 5H), 6.22 (s, 1H), 5.76
(dddd, J = 17.2, 10.0, 7.2, 4.8 Hz, 1H), 5.15 (d, J = 17.2 Hz,
1H), 5.10 (d, J = 15.7 Hz, 1H), 4.65 (dd, J = 15.7, 4.8 Hz, 1H),
F
DOI: 10.1021/acs.joc.5b00573
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The Journal of Organic Chemistry
Article
3.35 (dd, J = 15.7, 7.2 Hz, 1H), 2.67−2.57 (m, 1H), 2.55−2.44
(m, 2H), 2.42−2.31 (m, 1H), 2.01−1.80 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 167.4, 162.7, 136.2, 133.1, 129.5, 128.5,
127.3, 117.5, 109.9, 89.3, 45.3, 31.4, 25.9, 19.7; IR (cm−1)
1662.4; EI-MS m/z = 255 [M+]; ESI-HRMS calcd for
C16H18NO2, m/z = 256.1332 [M + H]+; found, 256.1339.
2,3,6,7-Tetrahydro-3-isopropyl-2-phenylcyclopenta[e]-
[1,3]oxazin-4(5H)-one (3g). White crystals, mp 125−127 °C;
IR (cm−1) 1663.5; EI-MS m/z = 287 [M+]; ESI-HRMS calcd
for C17H21NO3, m/z = 288.1594 [M + H]+; found, 288.1599.
2,3,6,7-Tetrahydro-2-(4-nitrophenyl)-3-propylcyclopenta-
[e][1,3]oxazin-4(5H)-one (3l). Brown crystals, mp 97−99 °C;
220 mg, yield 73%; 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J =
8.4 Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H), 6.30 (s, 1H), 4.04−3.93
(m, 1H), 2.91−2.81 (m, 1H), 2.66−2.48 (m, 2H), 2.44−2.25
(m, 2H), 2.00−1.87 (m, 1H), 1.87−1.75 (m, 1H), 1.61 (ddt, J
= 20.0, 13.6, 6.0 Hz, 2H), 0.93 (t, J = 7.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 166.7, 162.2, 148.5, 144.4, 127.9, 123.7,
111.0, 88.5, 45.9, 31.4, 25.8, 22.0, 19.5, 11.2; IR (cm−1) 1665.0;
EI-MS m/z = 302 [M+]; ESI-HRMS calcd for C16H19N2O4, m/
z = 303.1339 [M + H]+; found, 303.1334.
1
228 mg, yield 89%; H NMR (400 MHz, CDCl3) δ 7.47−7.31
(m, 5H), 6.36 (s, 1H), 4.86 (hept, J = 6.9 Hz, 1H), 2.67−2.56
(m, 1H), 2.51−2.30 (m, 2H), 2.25−2.13 (m, 1H), 1.95−1.83
(m, 1H), 1.83−1.66 (m, 1H), 1.29 (d, J = 6.7 Hz, 3H), 1.05 (d,
J = 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.9, 162.3,
138.6, 128.8, 128.2, 127.0, 111.1, 85.1, 43.9, 31.3, 25.8, 21.4,
20.6, 19.5; IR (cm−1) 1658.6; EI-MS m/z = 257 [M+]; ESI-
HRMS calcd for C16H20NO2, m/z = 258.1489 [M + H]+;
found, 258.1491.
2,3,6,7-Tetrahydro-3-isopropyl-2-(4-methoxylphenyl)-
cyclopenta[e][1,3]oxazin-4(5H)-one (3h). Brown crystals, mp
108−112 °C; 250 mg, yield 87%; 1H NMR (400 MHz, CDCl3)
δ 7.34 (d, J = 8.0 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 6.32 (s,
1H), 4.83 (hept, J = 6.9 Hz, 1H), 3.81 (s, 3H), 2.67−2.56 (m,
1H), 2.50−2.32 (m, 2H), 2.24−2.13 (m, 1H), 1.95−1.81 (m,
1H), 1.81−1.68 (m, 1H), 1.27 (d, J = 6.7 Hz, 3H), 1.04 (d, J =
7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.7, 162.3,
160.0, 130.6, 128.4, 113.5, 110.8, 85.0, 55.2, 43.8, 31.4, 25.9,
21.3, 20.6, 19.5; IR (cm−1) 1658.6; EI-MS m/z = 287 [M+];
ESI-HRMS calcd for C17H22NO3, m/z = 288.1594 [M + H]+;
found, 288.1596.
2,3,6,7-Tetrahydro-3-isopropyl-2-(4-methylphenyl)-
cyclopenta[e][1,3]oxazin-4(5H)-one (3i). White crystals, mp
112−114 °C; 170 mg, yield 63%; 1H NMR (400 MHz, CDCl3)
δ 7.32 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 6.34 (s,
1H), 4.86 (hept, J = 6.9 Hz, 1H), 2.68−2.58 (m, 1H), 2.54−
2.38 (m, 2H), 2.26−2.15 (m, 1H), 1.96−1.84 (m, 1H), 1.82−
1.69 (m, 1H), 2.37 (s, 3H), 1.29 (d, J = 6.8 Hz, 3H), 1.06 (d, J
= 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.8, 162.4,
138.8, 135.7, 128.9, 127.0, 111.0, 85.2, 43.9, 31.4, 25.9, 21.4,
21.1, 20.6, 19.5; IR (cm−1) 1659.3; EI-MS m/z = 271 [M+];
ESI-HRMS calcd for C17H22NO2, m/z = 272.1645 [M + H]+;
found, 272.1646.
2,3,6,7-Tetrahydro-3-methyl-2-phenylcyclopenta[e][1,3]-
oxazin-4(5H)-one (3m). Yellow crystals, mp 127−130.5 °C;
1
148 mg, yield 65%; H NMR (400 MHz, CDCl3) δ 7.42 (s,
5H), 6.14 (s, 1H), 2.83 (s, 3H), 2.66−2.40 (m, 4H), 2.01−1.85
(m, 2H); 13C NMR (100 MHz, CDCl3) δ 167.4, 163.7, 136.0,
129.7, 128.7, 127.3, 109.7, 91.6, 31.3, 30.5, 26.0, 19.8; IR
(cm−1) 1665.0; EI-MS m/z = 229 [M+]; ESI-HRMS calcd for
C14H16NO2, m/z = 230.1176 [M + H]+; found, 230.1177.
2,3,6,7-Tetrahydro-3-methyl-2-(4-nitrophenyl)cyclopenta-
[e][1,3]oxazin-4(5H)-one (3n). Yellow crystals, mp 161−164
°C; 253 mg, yield 92%; 1H NMR (400 MHz, CDCl3) δ 8.27 (d,
J = 8.7 Hz, 2H), 7.59 (d, J = 8.6 Hz, 2H), 6.26 (s, 1H), 2.97 (s,
3H), 2.68−2.51 (m, 2H), 2.51−2.45 (m, 1H), 2.42−2.32 (m,
1H), 2.02−1.80 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
167.1, 162.7, 148.6, 143.5, 128.0, 123.9, 110.4, 90.0, 31.3, 31.2,
25.9, 19.6; IR (cm−1) 1665.4; EI-MS m/z = 274 [M+]; ESI-
HRMS calcd for C14H14N2NaO4, m/z = 297.0846 [M + Na]+;
found, 297.0850.
General Procedure for the Reaction of Heptanedioyl
Dichloride (4) and Imines 2. To a solution of imine 2 (2
mmol) and Et3N (303 mg, 3 mmol) in dry toluene (5 mL)
under N2 and reflux was added heptanedioyl dichloride (4)
(197 mg, 1 mmol) dropwise. The reaction mixture was stirred
for 3 h under reflux and was filtered. The residue was washed
with dichloromethane. The combined organic phase was
washed with water and brine and was dried over sodium
sulfate. After removal of the solvent under reduced pressure,
the residue was purified by column chromatography on silica
gel and was recrystallized from petroleum ether (30−60 °C)/
ethyl acetate (PE/EA = 8:1, v/v) to afford 5.
2,3,6,7-Tetrahydro-3-isopropyl-2-(4-nitrophenyl)cyclo-
penta[e][1,3]oxazin-4(5H)-one (3j). Yellow crystals, mp
2,3,5,6,7,8-Hexahydro-2,3-diphenylbenzo[e][1,3]oxazin-4-
1
one (5a).21 Colorless oil; 82 mg, yield 27%; H NMR (400
1
156.5−158 °C; 127 mg, yield 42%; H NMR (400 MHz,
CDCl3) δ 8.22 (d, J = 8.8 Hz, 2H), 7.64 (d, J = 8.6 Hz, 2H),
6.41 (s, 1H), 4.94 (hept, J = 6.9 Hz, 1H), 2.66−2.56 (m, 1H),
2.56−2.44 (m, 1H), 2.38−2.28 (m, 1H), 2.26−2.15 (m, 1H),
1.97−1.85 (m, 1H), 1.80−1.67 (m, 1H), 1.31 (d, J = 6.7 Hz,
3H), 1.09 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
166.4, 161.8, 148.3, 145.9, 128.0, 123.5, 111.8, 83.9, 44.1, 31.3,
25.8, 21.5, 20.7, 19.4; IR (cm−1) 1659.1; EI-MS m/z = 302
[M+]; ESI-HRMS calcd for C16H19N2O4, m/z = 303.1339 [M +
H]+; found, 303.1345.
2,3,6,7-Tetrahydro-2-(4-methoxylphenyl)-3-propylcyclo-
penta[e][1,3]oxazin-4(5H)-one (3k). Colorless oil; 263 mg,
yield 92%; 1H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 8.6 Hz,
2H), 6.90 (d, J = 8.7 Hz, 2H), 6.18 (s, 1H), 3.82 (s, 3H), 3.85−
3.73 (m, 1H), 2.78 (ddd, J = 14.4, 8.4, 6.0 Hz, 1H), 2.65−2.54
(m, 1H), 2.54−2.43 (m, 2H), 2.38−2.27 (m, 1H), 1.99−1.78
(m, 2H), 1.52 (ddt, J = 20.0, 13.6, 6.0 Hz, 2H), 0.85 (t, J = 7.4
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.8, 163.1, 160.3,
128.6, 113.8, 110.0, 89.9, 55.3, 45.1, 31.3, 25.9, 21.8, 19.7, 11.2;
MHz, CDCl3) δ 7.48−7.12 (m, 10H), 6.54 (s, 1H), 2.43−2.32
(m, 1H), 2.32−2.16 (m, 2H), 2.09−1.97 (m, 1H), 1.74−1.56
(m, 3H), 1.44−1.31 (m, 1H); 13C NMR (100 MHz, CDCl3) δ
163.0, 160.9, 139.9, 137.4, 129.1, 128.8, 128.4, 127.1, 125.9,
125.1, 109.0, 89.0, 27.6, 21.84, 21.78, 21.3.
2,3,5,6,7,8-Hexahydro-2-(4-nitrophenyl)-3-phenylbenzo-
[e][1,3]oxazin-4-one (5b). Yellow crystals, mp 192−193.5 °C;
57 mg, yield 16%; 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J =
8.7 Hz, 2H), 7.65 (d, J = 8.7 Hz, 2H), 7.39−7.30 (m, 2H),
7.27−7.17 (m, 3H), 6.61 (s, 1H), 2.43−2.25 (m, 2H), 2.24−
2.13 (m, 1H), 2.10−1.97 (m, 1H), 1.77−1.58 (m, 3H), 1.43−
1.31 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 162.4, 161.2,
148.4, 144.7, 139.5, 129.1, 128.0, 126.4, 124.9, 123.7, 109.5,
87.9, 27.6, 21.71, 21.66, 21.2; IR (cm−1) 1665.2; EI-MS m/z =
350 [M+]; ESI-HRMS calcd for C20H19N2O4, m/z = 351.1339
[M + H]+; found, 351.1342.
3-Benzyl-2,3,5,6,7,8-hexahydro-2-phenylbenzo[e][1,3]-
oxazin-4-one (5d). White crystals, mp 89−90.5 °C; 50 mg,
G
DOI: 10.1021/acs.joc.5b00573
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The Journal of Organic Chemistry
Article
yield 16%; 1H NMR (400 MHz, CDCl3) δ 7.40−7.30 (m, 3H),
7.30−7.20 (m, 5H), 7.14−7.09 (m, 2H), 6.02 (s, 1H), 5.29 (d, J
= 15.4 Hz, 1H), 3.84 (d, J = 15.4 Hz, 1H), 2.43−2.25 (m, 2H),
2.23−2.12 (m, 1H), 2.04−1.91 (m, 1H), 1.67−1.60 (m, 3H),
1.57−1.46 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 164.2,
161.1, 137.2, 136.0, 129.4, 128.48, 128.47, 127.8, 127.4, 127.3,
107.7, 87.1, 46.5, 27.4, 22.0, 21.9, 21.4; IR (cm−1) 1662.7; EI-
MS m/z = 319 [M+]; ESI-HRMS calcd for C21H21NNaO2, m/z
= 342.1465 [M + Na]+; found, 342.1466.
3-Cyclohexyl-2,3,5,6,7,8-hexahydro-2-(4-nitrophenyl)-
benzo[e][1,3]oxazin-4-one (5e). White crystals, mp 171−173
°C; 47 mg, yield 13%; 1H NMR (400 MHz, CDCl3) δ 8.20 (d,
J = 8.8 Hz, 2H), 7.60 (d, J = 8.6 Hz, 2H), 6.28 (s, 1H), 4.52 (tt,
J = 12.1, 3.6 Hz, 1H), 2.39−2.28 (m, 1H), 2.19−2.01 (m, 2H),
1.96−1.89 (m, 1H), 1.86−1.70 (m, 4H), 1.69−1.61 (m, 3H),
1.56−1.34 (m, 4H), 1.25−1.13 (m, 1H), 1.11−0.93 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 162.4, 159.2, 148.2, 146.4,
127.9, 123.4, 109.9, 81.9, 52.1, 31.6, 31.1, 27.5, 25.71, 25.66,
25.3, 21.7, 21.6, 21.2; IR (cm−1) 1660.2; MS m/z = 356 [M+];
HRMS calcd for C20H25N2O4, m/z = 357.1809 [M + H]+;
found, 357.1809.
21.4, 21.1, 20.3; IR (cm−1) 1661.3; EI-MS m/z = 316 [M+];
ESI-HRMS calcd for C17H21N2O4, m/z = 317.1496 [M + H]+;
found, 317.1499.
2,3,5,6,7,8-Hexahydro-2-(4-methoxylphenyl)-3-propyl-
benzo[e][1,3]oxazin-4-one (5k). Colorless oil; 42 mg, yield
14%; 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 8.7 Hz, 2H),
6.90 (d, J = 8.6 Hz, 2H), 6.03 (s, 1H), 3.82 (s, 3H), 3.71 (ddd, J
= 14.4, 8.4, 6.0 Hz, 1H), 2.77 (ddd, J = 14.4, 8.4, 6.0 Hz, 1H),
2.37−2.22 (m, 2H), 2.22−2.10 (m, 1H), 2.02−1.91 (m, 1H),
1.67−1.57 (m, 3H), 1.56−1.43 (m, 3H), 0.83 (t, J = 7.4 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 164.2, 160.31, 160.28,
128.63, 128.58, 113.8, 107.9, 87.6, 55.3, 45.3, 27.3, 21.9, 21.8,
21.6, 21.3, 11.3; IR (cm−1) 1664.3; EI-MS m/z = 301 [M+];
ESI-HRMS calcd for C18H24NO3, m/z = 302.1751 [M + H]+;
found, 302.1758.
2,3,5,6,7,8-Hexahydro-2-(4-nitrophenyl)-3-propylbenzo-
1
[e][1,3]oxazin-4-one (5l). Colorless oil; 51 mg, yield 16%; H
NMR (400 MHz, CDCl3) δ 8.24 (d, J = 8.3 Hz, 2H), 7.57 (d, J
= 8.6 Hz, 2H), 6.17 (s, 1H), 4.00−3.88 (m, 1H), 2.83 (ddd, J =
14.4, 8.4, 6.0 Hz, 1H), 2.38−2.26 (m, 1H), 2.26−2.08 (m, 2H),
1.99−1.88 (m, 1H), 1.70−1.54 (m, 5H), 1.40−1.28, (m, 1H),
0.92 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 163.1,
160.1, 148.4, 144.6, 127.8, 123.7, 108.8, 86.1, 46.2, 27.3, 21.8,
21.7, 21.6, 21.1, 11.2; IR (cm−1) 1665.1; EI-MS m/z = 316
[M+]; ESI-HRMS calcd for C17H21N2O4, m/z = 317.1496 [M +
H]+; found, 317.1497.
3-Allyl-2,3,5,6,7,8-hexahydro-2-phenylbenzo[e][1,3]-
oxazin-4-one (5f).14 Colorless oil; 23 mg, yield 9%; H NMR
1
(400 MHz, CDCl3) δ 7.39 (s, 5H), 6.08 (s, 1H), 5.75 (dddd, J
= 17.2, 10.0, 7.2, 4.8 Hz, 1H), 5.11 (d, J = 17.2 Hz, 1H), 5.07
(d, J = 15.7 Hz, 1H), 4.57 (dd, J = 15.7, 4.8 Hz, 1H), 3.35 (dd, J
= 15.8, 7.2 Hz, 1H), 2.38−2.29 (m, 1H), 2.29−2.13 (m, 2H),
2.06−1.95 (m, 1H), 1.66−1.59 (m, 3H), 1.55−1.43 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 163.8, 160.9, 136.3, 133.0,
129.4, 128.5, 127.3, 117.4, 107.9, 87.0, 45.6, 27.3, 21.9, 21.8,
21.3.
2,3,5,6,7,8-Hexahydro-3-isopropyl-2-phenylbenzo[e][1,3]-
oxazin-4-one (5g). White crystals, mp 110−112 °C; 51 mg,
yield 19%; 1H NMR (400 MHz, CDCl3) δ 7.47−7.30 (m, 5H),
6.21 (s, 1H), 4.80 (hept, J = 6.9 Hz, 1H), 2.40−2.29 (m, 1H),
2.16−2.05 (m, 2H), 1.85−1.73 (m, 1H), 1.69−1.56 (m, 2H),
1.54−1.43 (m, 1H), 1.27−1.20 (m, 1H), 1.30 (d, J = 6.7 Hz,
3H), 1.04 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
163.0, 158.9, 138.7, 128.7, 128.1, 127.0, 109.3, 82.7, 44.2, 27.4,
21.8, 21.7, 21.3, 21.2, 20.2; IR (cm−1) 1661.2; EI-MS m/z =
271 [M+]; ESI-HRMS calcd for C17H22NO2, m/z = 272.1645
[M + H]+; found, 272.1648.
2,3,5,6,7,8-Hexahydro-3-isopropyl-2-(4-methoxylphenyl)-
benzo[e][1,3]oxazin-4-one (5h). Yellow crystals, mp 122.5−
125 °C; 23 mg, yield 8%; 1H NMR (400 MHz, CDCl3) δ 7.31
(d, J = 8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 6.17 (s, 1H), 4.77
(hept, J = 6.9 Hz, 1H), 3.81 (s, 3H), 2.39−2.29 (m, 1H), 2.16−
2.04 (m, 2H), 1.83−1.73 (m, 1H), 1.68−1.57 (m, 2H), 1.54−
1.44 (m, 1H), 1.33−1.21 (m, 1H), 1.29 (d, J = 6.8 Hz, 3H),
1.03 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
163.0, 159.9, 158.7, 130.7, 128.3, 113.4, 109.0, 82.6, 55.2, 44.2,
27.4, 21.9, 21.7, 21.3, 21.2, 20.2; IR (cm−1) 1660.7; EI-MS m/z
= 301 [M+]; ESI-HRMS calcd for C18H24NO3, m/z = 302.1751
[M + H]+; found, 302.1754.
2,3,5,6,7,8-Hexahydro-3-isopropyl-2-(4-nitrophenyl)-
benzo[e][1,3]oxazin-4-one (5j). Yellow crystals, mp 147−148
°C; 79 mg, yield 25%; 1H NMR (400 MHz, CDCl3) δ 8.21 (d,
J = 8.5 Hz, 2H), 7.60 (d, J = 8.7 Hz, 2H), 6.26 (s, 1H), 4.90
(hept, J = 6.9 Hz, 1H), 2.40−2.29 (m, 1H), 2.20−2.01 (m,
2H), 1.85−1.73 (m, 1H), 1.71−1.57 (m, 2H), 1.56−1.42 (m,
1H), 1.24−1.14 (m, 1H), 1.32 (d, J = 6.7 Hz, 3H), 1.07 (d, J =
7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 162.5, 159.3,
148.2, 146.2, 127.9, 123.4, 109.9, 81.5, 44.3, 27.4, 21.7, 21.6,
2,3,5,6,7,8-Hexahydro-3-methyl-2-phenylbenzo[e][1,3]-
1
oxazin-4-one (5m). Colorless oil; 37 mg, yield 15%; H NMR
(400 MHz, CDCl3) δ 7.41 (s, 5H), 5.99 (s, 1H), 2.79 (s, 3H),
2.33−2.26 (m, 2H), 2.20−2.13 (m, 1H), 2.11−2.00 (m, 1H),
1.69−1.62 (m, 2H), 1.62−1.55 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 164.8, 161.1, 136.2, 129.6, 128.7, 127.3, 107.6, 89.2,
30.6, 27.2, 21.93, 21.87, 21.4; IR (cm−1) 1665.6; EI-MS m/z =
243 [M+]; ESI-HRMS calcd for C15H18NO2, m/z = 244.1332
[M + H]+; found, 244.1338.
2,3,5,6,7,8-Hexahydro-3-methyl-2-(4-nitrophenyl)benzo-
[e][1,3]oxazin-4-one (5n). Yellow crystals, mp 207.5−209 °C;
40 mg, yield 14%; 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J =
8.7 Hz, 2H), 7.51 (d, J = 8.6 Hz, 2H), 6.04 (s, 1H), 2.86 (s,
3H), 2.30−2.20 (m, 1H), 2.19−2.07 (m, 2H), 1.98−1.87 (m,
1H), 1.60−1.50 (m, 3H), 1.45−1.34 (m, 1H); 13C NMR (100
MHz, CDCl3) δ 163.8, 160.7, 148.6, 143.6, 128.1, 123.9, 108.2,
87.7, 31.3, 27.2, 21.8, 21.7, 21.2; IR (cm−1) 1665.3; EI-MS m/z
= 288 [M+]; ESI-HRMS calcd for C15H17N2O4, m/z =
289.1183 [M + H]+; found, 289.1185.
General Procedure for the Reaction of Diacyl
Dichlorides and Imine 2a. To a solution of imine 2a (362
mg, 2 mmol) and Et3N (303 mg, 3 mmol) in toluene (5 mL)
under N2 and reflux was added diacyl dichloride 4 or 7 (1
mmol) dropwise. The reaction mixture was stirred for 12 h
under reflux and was filtered. The filter cake was washed with
dichloromethane. The combined filtrate was washed with water
and brine and was dried over sodium sulfate. After removal of
the solvent under reduced pressure, the residue was purified by
column chromatography on silica gel and was recrystallized
from petroleum ether (30−60 °C)/ethyl acetate (PE/EA = 8:1,
v/v) to afford 6a or 8.
meso-3,3′-(1,3-Propylidene)bis(trans-1,4-diphenylazeti-
din-2-one) (meso-6a) and rel(3S,3′S,4R,4′R)-3,3′-(1,3-
propylidene)bis(1,4-diphenylazetidin-2-one) (( )-6a). White
1
crystals, mp 182−185 °C; 26 mg, yield 6%; H NMR (400
MHz, CDCl3) δ 7.45−7.17 (m, 20H), 4.64 (d, J = 2.3 Hz, 2H),
3.09 (ddd, J = 14.4, 6.4, 2.0 Hz, 2H), 2.03−1.84 (m, 4H),
H
DOI: 10.1021/acs.joc.5b00573
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1.84−1.70 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 167.5,
137.9, 137.7, 129.2, 129.0, 128.4, 125.8, 123.8, 116.9, 61.10/
61.07, 60.21/60.13, 28.8/28.5, 24.9/24.6; IR (cm−1) 1660.1;
EI-MS m/z = 486 [M+]; ESI-HRMS calcd for C33H31N2O2, m/
z = 487.2380 [M + H]+; found, 487.2386.
(400 MHz, CDCl3) δ 5.34 (s, 2H), 2.69 (s, 4H); 13C NMR
(100 MHz, CDCl3) δ 193.1, 54.7, 34.8.
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of 1H NMR and 13C NMR spectra of the products and
computational details. The Supporting Information is available
free of charge on the ACS Publications website at DOI:
10.1021/acs.joc.5b00573.
rel(3S,3′S,4R,4′R)-3,3′-(Methylene)bis(1,4-diphenylazeti-
din-2-one) (( )-8a). White crystals, mp 197−199 °C; 28 mg,
1
yield 6%; Rf = 0.56 (silica gel plate, PE/EA = 5:1, v/v). H
NMR (400 MHz, CDCl3) δ 7.35−7.21 (m, 18H), 7.05−7.01
(m, 2H), 4.84 (d, J = 2.1 Hz, 2H), 3.21 (td, J = 7.7, 2.2 Hz,
2H), 2.49 (t, J = 7.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
166.6, 137.5, 137.3, 129.12, 129.06, 128.5, 125.8, 124.0, 117.0,
60.9, 58.8, 28.2. IR (cm−1) 1660.2; EI-MS m/z = 458 [M+];
ESI-HRMS calcd for C31H27N2O2, m/z = 459.2067 [M + H]+;
found, 459.2063.
AUTHOR INFORMATION
Corresponding Author
*Phone: +86-10-6443-5565. Fax: +86-10-6443-5565. E-mail:
jxxu@mail.buct.edu.cn.
■
Author Contributions
meso-3,3′-(Methylene)bis(trans-1,4-diphenylazetidin-2-
†These authors contributed equally.
one) (meso-8a). White crystals, mp 262−264 °C; 24 mg, yield
1
Notes
5%; Rf = 0.55 (silica gel plate, PE/EA = 5:1, v/v). H NMR
The authors declare no competing financial interest.
(400 MHz, CDCl3) δ 7.34−7.19 (m, 18H), 7.05−7.02 (m,
2H), 4.90 (d, J = 2.4 Hz, 2H), 3.38 (td, J = 7.7, 2.4 Hz, 2H),
2.52 (t, J = 7.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 166.5,
137.3, 137.2, 129.2, 129.02, 128.96, 125.5, 124.0, 117.1, 59.9,
57.6, 26.4. IR (cm−1) 1660.3; EI-MS m/z = 458 [M+]; ESI-
HRMS calcd for C31H27N2O2, m/z = 459.2067 [M + H]+;
found, 459.2065.
ACKNOWLEDGMENTS
■
The project was supported by the National Basic Research
Program of China (No. 2013CB328905), the National Natural
Science Foundation of China (Nos. 21372025, 21172017, and
20772005), the specialized Research Fund for the Doctoral
Program of Higher Education, Ministry of Education of China
(No. 20110010110011), and “CHEMCLOUDCOMPUTING”
of Beijing University of Chemical Technology.
meso-3,3′-(1,4-Butylidene)bis(trans-1,4-diphenylazetidin-
2-one) (meso-8b) and rel(3S,3′S,4R,4′R)-3,3′-(1,4-
Butylidene)bis(1,4-diphenylazetidin-2-one) (( )-8b). White
1
crystals, mp 168−174 °C; 60 mg, yield 12%; H NMR (400
REFERENCES
MHz, CDCl3) δ 7.42−7.17 (m, 18H), 7.08−6.96 (m, 2H), 4.60
(s, 2H), 3.07 (t, J = 6.8 Hz, 2H), 2.04−1.76 (m, 4H), 1.61−
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27.1. IR (cm−1) 1659.7; EI-MS m/z = 500 [M+]; ESI-HRMS
calcd for C34H33N2O2, m/z = 501.2537 [M + H]+; found,
501.2545.
■
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solution of succinic dichloride (1.54 g, 10 mmol) in dry diethyl
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1
I
DOI: 10.1021/acs.joc.5b00573
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DOI: 10.1021/acs.joc.5b00573
J. Org. Chem. XXXX, XXX, XXX−XXX