Synthesis of Antitricyclic Morpholine Derivatives through Iodine(III)-Mediated Intramolecular Umpolung Cycloaddition of Olefins

Article abstract of DOI:10.1021/acs.joc.0c00286

A (diacetoxyiodo)benzene-mediated intramolecular cycloaddition of olefins to construct tricyclic morpholines is presented. A series of substituted tricyclic morpholines were obtained in one-step simple operation under mild conditions, and the NMR studies

Full text of DOI:10.1021/acs.joc.0c00286

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Article
Synthesis of anti Tricyclic Morpholine Derivatives through Iodine(III)-
Mediated Intramolecular Umpolung Cycloaddition of Olefins
Yangyang Feng, Chenglin Yang, Qingfu Deng, Ruimei Xiong, Xiaohui Zhang, and Yan Xiong
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00286 • Publication Date (Web): 26 Feb 2020
Downloaded from pubs.acs.org on March 2, 2020
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Synthesis of anti Tricyclic Morpholine Derivatives through
Iodine(III)-Mediated Intramolecular Umpolung
Cycloaddition of Olefins
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a
a
a
a
a
Yangyang Feng, Chenglin Yang, Qingfu Deng, Ruimei Xiong, Xiaohui Zhang,
and Yan Xiong*,a,b
aSchool of Chemistry and Chemical Engineering, and Chongqing Key Laboratory of
Theoretical and Computational Chemistry, Chongqing University, Chongqing 401331,
China.
bState Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin
3
00071, China
Email: xiong@cqu.edu.cn
O
HO
O
N
PhI(OAc)2
R
R
MTBE, 25 o
C
N
R'
H
O
R'
18 examples
30-85% yields
ABSTRACT
A (diacetoxyiodo)benzene-mediated intramolecular cycloaddition of olefins to
construct tricyclic morpholines is presented. A series of substituted tricyclic
morpholines were obtained in one-step simple operation under mild conditions, and
the NMR studies were employed to see the interaction of reactants. The studies on
stereochemistry showed that transformation of Z-alkene was inhibited, which is
interpreted by DFT calculations on Z- and E-transition state models, and only
E-alkene resulted in anti cycloaddition product, which is testified by a single-crystal
X-ray diffraction analysis.
INTRODUCTION
Morpholine is the fundamental six-membered heterocycle and acts as an
1
important motif in natural products, drugs, and advanced materials. Particularly,
polycyclic morpholine structures widely exist in pharmaceuticals and natural
products,2 such as ofloxacin, pazufloxacin, levofloxacin carboxylic acid,
3
pollenopyrroside A, shensongine B, and acortatarin B. Therefore, this versatile
framework has been attracting much attention in the field of synthetic organic
4
chemistry. Benzoxazomycin with tricycle unit was assessed approximately in five
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times more likely to possess drug activity than the former natural products (Figure 1).5
Strategies that allow multiple transformations in one-pot process without excessive
prefunctionalization of the substrates to afford substituted tricyclic morpholines as in
benzoxazomycin are especially fascinating.
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OH
O
N
O
HO
OCH3
O
H
N
O
O
benzoxazomycin
Figure 1. Biologically relevant tricyclic morpholine.
With regarding to development of the synthetic methodology, the acquisition of
tricyclic morpholine derivatives in benzoxazomycin has been reported in one-pot
o
process through intramolecular aminoalkylation of olefins (1 , Scheme 1). Li utilized
BF -OEt to promote 9-endo cyclization of various N-(hex-5-enyl)-2-iodoalkanamides
3
2
through radical pathway6 and Yang adopted a Pd-catalyzed intramolecular
7
aminoalkylation of unactivated alkenes. Both works showed that partially positive
carbon and negative nitrogen were added reasonably to two ends of olefin, according
to the polar principle of carbon-carbon double bond electrophilic addition.
Hypervalent iodine compounds possess reactivity similar to transition metals,8
and they have been used successfully as effective umpolung reagents in the
9
10
transformation of alkenes, such as cyanation and aminocyanation. Likewise, we
envisioned that simultaneous addition of both nucleophilic hydroxyl and amino group
of ortho-aminophenol to olefins is greatly feasible and expectable to form tricyclic
1
1
mother structure in the presence of oxidant, especially hypervalent iodine through
o
umpolung aminoxylation process (2 , Scheme 1). For the synthesis of mother core
2
,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazin-1-one, the report has been
traced employing Dess-Martin periodinane (DMP) regent and staring from
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N-phenylpent-4-enamide, where the in situ introduction of oxygen was speculated
from water or oxidant.12 In this work, from commercially available
ortho-aminophenol to synthesize the tricycle morphine is performed in generally
improved yields, presumably due to shortened reaction process.
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Scheme 1. Two Approaches to Tricyclic Morpholine
+
O
O
1o
O
Ph
X
-

NH
1o
N
O
2o
NH
-

O
OH
2o
-

this work
Oxidant is indispensable!
RESULTS AND DISCUSSION
Our investigations
started
with
0.25
mmol
of
(E)-N-(2-hydroxyphenyl)-5-phenylpent-4-enamide (1a) as the model substrate
(Scheme 1), with the results collected in Table 1S in supporting information. When
the reaction mixture of 1a and DMP in DCM was stirred at 25 ℃ for 9 h, the desired
cyclization product (2a) was obtained in 18% yield (entry 1). The structure of 2a was
confirmed convincingly through a single-crystal X-ray diffraction analysis and existed
in a anti-configuration. When relative mild oxidizers such as trivalent
(diacetoxyiodo)benzene (DIB) and PhIO were used as oxidants, 2a was generated in
35% and 9% yields, respectively (entries 2 and 3). Likewise, several other commonly
used hypervalent iodine regents such as IBA, PIFA, and ABX were utilized; however,
no desired product was observed (entries 4-6). Subsequently, various solvents were
screened under oxidation of best DIB. Both nonpolar and strongly polar solvents such
as PhMe, MeCN, EtOAc, MeOH and acetone led to decrease of the yield of desired
product to some extent (entries 7-11). It was worth to note that the yield of 2a was
generally elevated when various ethers with medium polarity were served as solvents
one by one, and especially the best result was obtained in methyl tert-butyl ether
(MTBE) with aliphatic group increased (entries 12-16). With a slight increase in the
amount of DIB from 2.0 to 2.5 equivalents, the yield of 2a increased and reached to
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8% (entries 17-19). However, when the amount of DIB raised further to 2.8
equivalents, the yield of 2a dropped to 77% (entry 20).
Furthermore, the temperature was investigated. Either slightly elevating or
dropping the temperature from initial set temperature (25 ℃) was executed and as a
result dramatic reduction of yields occurred (entries 21 and 22), which suggests that
the reaction was sensitive to temperature. The concentrations of reactants were then
optimized, and as a result increase or decrease of concentration is detrimental to this
reaction (entries 23 and 24). After gathering above conditions, the time was further
optimized, and as a result neither prolonging nor shortening the reaction time is
favorable to this transformation (entries 25 and 26). Therefore, the optimal reaction
conditions were acquired as 2.5 equiv of DIB and 0.25 mmol of substrate in 2.0 mL of
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o
MTBE at 25 C for 9 hours.
O
HO
O
N
oxidant
N
solvent, T oC, t h
H
O
1a
2a
Scheme 1. Condition optimization on transformation of model substrate 1a.
With the optimal conditions in hand, we next investigated the scope of
cycloaddition of substituted ortho-aminophenol and tethered E-olefin moieties, with
results shown in Table 1. Compared with the level of activity of 2a in 85% yield,
electronic effects of substitutions on styryl were investigated, but it was found that
they were unprominent. The neutral styryl substituted by electron-donating groups at
the para-position, such as methyl and methoxy, gave corresponding products in good
yields of 80% (2b) and 66% (2c), respectively. The styryl substituted with
electron-withdrawing groups at the para-position all generated desired products in
good yields (2d, 2e and 2g) and halo-substitution showed increasing reactivities with
the electronegativity decreasing from F to Br. The substrate with strong
electron-withdrawing trifluoromethyl group was able to work as well, albeit with a
moderate yield (2f). It was worth to note that sterically chloroine-hindered substrates
1h and 1i were subjected to the cyclization of alkene, the reactions went smoothly
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affording the corresponding products in 80% and 63% yields, respectively. Compared
with para-chloro substitution (2g), ortho-chloro substitution (2i) showed the largest
inhibition in reactivity and presented relatively less reactivity, while that of
meta-chloro substitution (2h) was placed in the middle. Catalytic transformation of 1h
was attempted with 20% of iodobenzene as catalyst and 2.0 equiv of
m-chloroperbenzoic acid as oxidant, the product 2h was obtained in lower yield of
1
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9%. Moreover, fused 2-naphthyl alkene was also applied to this cyclization
successfully, resulting in good yield of 75% (2j). The benzoheterocyclic group such
as benzotetrahydrofuran and indole moieties manifested good reactivity and gave rise
to the desired products in 61% and 46% yields, respectively (2k and 2l). Referred to
Nicolaou’s
work12,
the
cycloolefine
substrate
N-(2-hydroxyphenyl)cyclohex-3-enecarboxamide was subjected these conditions,
however, no expected polycyclic product was obtained unfortunately.
The scope of o-aminophenols was next examined. Both electron-donating and
electron-withdrawing groups were tolerated in these reactions. It was found that
enlarging the bulkiness of o-aminophenols depressed the reactivity. Substitutions with
methyl or halo (fluorine and bromine) groups on the aryl rings gave rise to
corresponding products in moderate yields ranging from 30 to 52% (2m-p), and
methyl and bromine atom led to lower yields than smallest fluorine atom. Here,
halo-substitution effects demonstrated that stronger electron-withdrawing F resulted
in better yield than bromo-substitution, which is converse to substitution effects on
tethered styryl, and the position of fluorine affects the reactivity of cyclization (2m vs
2
o). Likewise, naphthyl substrate was also employed with the conditions, resulting in
formation of corresponding polycyclic morpholine in 35% yield (2q). When terminal
alkene was used as substrate, no desired product (2r) was detected in spite of starting
material exhaustion, companied some uncertain side-products, which presumably
attributes to its higher activity. The desired pyridinomorpholine (2s) was not acquired
from lengthened carbon chain, which was probably due to relative instability of
six-membered N-heterocycle and the misplacement of olefin in synergistic cyclization.
Additionally, no reaction took place and was presumed resulting from rigid plane and
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the lack of structure flexibility to forming two planes, which is essential to
conjugation addition, when N-(2-hydroxyphenyl)-2-vinylbenzamide (2t) was utilized
in intramolecular cyclization under optimal conditions. Fortunately, when the

-position of carbonyl group was substituted with two methyl groups, the flexibility
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of aliphatic carbon chain was maintained and the cyclization reaction provided
2
,2-dimethylated 2u in 35% yield.
In investigation of substrate scope, the large-scale synthesis and reaction
selectivity need to be underlined. Considering potential application in industrial
production, 1 mmol of (E)-N-(2-hydroxyphenyl)-5-phenylpent-4-enamide (1a) was
subjected to the optimal conditions, a good yield of 61% was obtained yet (Table 1,
footnote b). As a complementary, Z-olefin was expected to afford the syn products,
and the starting material (Z)-N-(2-hydroxyphenyl)-5-phenylpent-4-enamide (1a’) with
Z-olefin was attempted. As a result, no expectable syn product was obtained in the
reaction, accompanied with uncertain side products monitored by thin layer
chromatography, even if the starting material was converted in 93%, which implies a
higher activation energy barrier in transformation of 1a’.
Table 1. Cyclization of Different Alkenesa
O
HO
O
N
O
PhI(OAc)2
R
R
o
N
MTBE, 25 C, 9 h
R'
H
R'
1
2
O
O
O
N
N
N
O
O
O
Me
OMe
2
a, 85% (61%)b
2b, 80%
2c, 66%
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O
O
N
O
N
N
O
O
O
F
Br
CF3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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8
9
0
1
2
3
4
5
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7
8
9
0
2
d, 78%
2e, 84%
2f, 32%
O
O
N
O
N
N
Cl
Cl
O
O
O
Cl
2g, 82%
2h, 80%
2i, 63%
O
O
O
N
N
N
O
O
O
O
N
Boc
2j, 75%
2k, 61%c
2l, 46%c
O
O
O
N
F
N
Br
N
O
O
F
O
2
m, 51%
2n, 40%
2o, 42%
O
O
N
O
N
N
O
Me
O
O
2
p, 30%
2q, 35%
2r, 0%
Me
O
O
N
O
Me
N
O
N
O
O
Cl
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4
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4
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5
5
5
5
5
5
5
6
2
s, 0%
2t, 0%
2u, 35%
a
Conditions: 1 (0.25 mmol) and DIB (0.625 mmol) in MTBE (2 mL) at 25 ℃ (oil bath) for 9 h.
b
c
Yield was isolated by silica gel column chromatography. 1 mmol of synthetic scale. At 30 ℃.
1
In order to glean an insight into the mechanism, H NMR analysis was conducted
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9
0
to
detect
the
interaction
of
electron-deficiency
iodine(III)
and
N-(2-hydroxyphenyl)acetamide 3 simplified from model substrate. There exist six
main active sites, i.e. basic amino, hydroxyl oxygen and their ortho or para aryl
carbons (Figure 2). N-acyl anilines have been reported interacting with hypervalent
iodine(V) at ortho- or para-aryl carbon, and the para-adduct was separated
1
2
1
successfully by Nicolaou. From H NMR spectra, it was found that the signal peaks
for OH and NH in 3 were clearly observed in six-deuterated DMSO (1), the peak
shape of OH broadened, four aryl hydrogens were retained when mixing with DIB (2),
and 30 minutes later, the signal peak of OH was gone (3). It could be concluded that
the DIB attacked firstly with hydroxyl, once both of them were mixed.
O
-
electrophilic attack
six active sites
NH
-
-
-
I(III)

OH
-
-

3
1
Figure 2. H NMR analysis for mechanism insight. (1) Substrate 3; (2) mixing 3 and DIB, no wait;
(
3) mixing 3 and DIB for 30 min.
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A plausible mechanistic pathway for the reaction was proposed (Figure 3).
Firstly, 1a as an nucleophile attacks electron deficient iodine center of PhI(OAc) to
2
generate 4 with the release of one AcOH, following NMR demonstration. Through a
reductive elimination of hypervalent iodine and split of iodobenzene, the intermediate
of o-imidoquinone 5 is formed, similar to previous report, 5a,12,13 which undergoes
intramolecular [4+2] cycloaddition with E-olefin between two conjugate planes like in
E-TS to generate terminal product 2a.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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9
0
O
Ph
OAc
O
Ph
Ph
I
NH
OH
NH
OAc
-
(PhI+AcOH)
Ph
-
AcOH
O
I
OAc
1a
4
O
N
O
O
O
Ph


N
O
N
[4+2]
or
2a
Ph
O
Ph
5
E-TS
favorable
Z-TS
unfavorable
O
N
C
2.23 Å
H
E-TS
0.0]
Z-TS
[3.2]
[
Figure 3. Plausible reaction mechanism.
As above shown, an attempt to use 1a’ with Z-olefin as substrate has been
unsuccessful to furnish the syn product. In mechanistic pathway, similar to formation
of 2a, Z-olefin was assumed reasonably to proceed through a transition states Z-TS to
reach to the syn diastereomer 2a’ (Figure 3). Therefore, both transition state E-TS and
Z-TS were optimized for structure and energy comparison using the hybrid density
functional method B3LYP with 6-31G basis sets, i.e. at the level of B3LYP/6-31G.
The calculations showed that the syn transition state gives 3.2 kcal/mol higher energy
at 25 ℃ than anti transition state, because of the strong repulsion between hydrogens
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of methylene and benzene ring in Z-TS, where the distance of H···H is 2.23 Å,
smaller than the sum of their Van der Waals radius. This delivers the rational
interpretation of no cycloaddition product for Z-alkene and anti products totally in
these transformations.
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CONCLUSION
In summary, we have developed a metal-free oxidized intramolecular cyclization
to synthesize substituted tricyclic morpholine derivatives under mild conditions
through aminoxygenation of olefins, which provides an alternative tool for the
1
synthesis of such polycycle compounds. In mechanistic insight, H NMR analysis
presented an initial interaction between phenolic hydroxyl group and hypervalent
iodine, when electron rich phenolic hydroxyl group, amide and benzene ring were in
coexistence. DFT calculation was employed to interpret the observed energetically
and structurally favorable reaction pathway, i.e. active E-alkenes to anti-tricyclic
morpholines. Further studies about the synthetic utility of this methodology and more
mechanistic details are presently pursued in our laboratory.
EXPERIMENTAL SECTION
1
13
General Information. H- and C-NMR spectra were recorded in CDCl solution on
3
1
a Bruker DRX-400 spectrometer at 20~25 ℃. H NMR spectra were reported in parts
per million using tetramethylsilane TMS (δ = 0.00 ppm) as an internal standard. The
1
data of H NMR are reported as follows: chemical shift, multiplicity (s = singlet, d =
doublet, t = triplet, q = quartet, quin = quintet, m = multiplet), coupling constants (J,
Hz), and integration. 13C NMR spectra were reported in parts per million using
13
solvent CDCl (δ = 77.2 ppm) as an internal standard, The data of C NMR are
3
reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q
= quartet, quin = quintet, m = multiplet), and coupling constants (J, Hz). High
resolution mass spectra (HRMS) were obtained with a Q-TOF MS spectrometer.
Reactions were monitored by TLC and column chromatography was performed using
silica gel. Commercially available reagents were used without further purification
unless otherwise specified. The calculations of E-TS and Z-TS were performed at the
B3LYP/6-31G level using GASSIAN03 system of programs.
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General Procedure for Synthesis of 114-17
For starting materials: 1a-j, 1m-s, or 1u.
i) 4-Pentenoic acid or 5-hexenoic acid (3 mmol), different substituted styrene (6
mmol) and Grubbs II catalyst (0.06 mmol, 51 mg) in CH Cl (9 mL) at 45 °C (oil
(
2
2
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bath) for 12 h. Upon completion the reaction mixture was cooled to room temperature
and solvent was removed under reduced pressure. The resulting residue was
chromatographed to give corresponding carboxylic acid.
(ii) To a round-bottom flask was charged with prepared carboxylic acid (1
mmol), CH Cl (5 mL), aminophenol (1.1 mmol, 120 mg), EDCI-HCl (1.2 mmol, 230
2
2
mg) and DMAP (1.3 mmol, 159 mg) successively. Then the mixture was stirred under
conditions at room temperature for 12 h. Evaporation followed by column
chromatography afforded compound 1a-j, 1m-s, or 1u.
For starting materials: 1k and 1l
(i) To a stirred solution of 1-H-indole (5 mmol) and DMAP (0.05 mmol, 6.1 mg)
in THF (40 mL) was added Boc O (5.5 mmol, 1.2 g) and mixture was stirred at room
2
temperature for 2 h. Evaporation followed by column chromatography afforded
tert-butyl 3-formyl-1H-indole-1-carboxylate with 90% yield.
(ii) t-BuOK (9.5 mmol, 1.07 g) was added to a suspension of MePh PBr (9.5
3
mmol, 3.4 g) in THF (20 mL) at 0 °C for 30 min. The resulting mixture was allowed
to warm to ambient temperature and stirred for additional 1 h. The solution was again
cooled
to
0
ºC,
and
a
solution
of
compound
tert-butyl
3
-formyl-1H-indole-1-carboxylate (8.0 mmol, 1.96 g) in THF (3 mL) was added
dropwise. The reaction was stirred at room temperature for 12 h, quenched with water
and extracted with Et O (20 mL×3). The combined organic layer was washed with
2
brine, dried over MgSO and the solvent was removed under reduced pressure. The
4
crude product was purified by column chromatography to afford tert-butyl
3
-vinyl-1H-indole-1-carboxylate with 80% yield.
iii) The following steps are similar to 1a to prepare 1k and 1l.
(
For starting materials: 1t
To a round-bottom flask was added 2-vinylbenzoic acid (1 mmol, 148 mg),
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CH Cl (5 mL), 2-aminophenol (1.1 mmol, 120 mg), EDCI-HCl (1.2 mmol, 230 mg)
2
2
and DMAP (1.3 mmol, 159 mg) successively. Then the mixture was stirred under
conditions at room temperature for 12 h. Evaporation followed by column
chromatography afforded compound 1t with 75% yield.
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General Procedure for Synthesis of 2
To a round-bottom flask was added 1a-j, or 1m-u (0.25 mmol), MTBE (2 mL)
and DIB (0.625 mmol, 201 mg) successively. Then the resulting mixture was stirred
under conditions at 25 ℃ (oil bath) for 9 h. The reaction was quenched with saturated
solution of Na S O . The organic phase was separated, and the aqueous layer was
2
2
3
extracted with EtOAc (5 mL×3). The combined organic solution was dried with
MgSO and concentrated in vacuo. The resulting residue was purified by a column
4
chromatography to give the corresponding product 2a-j, or 2m-u.
To a round-bottom flask was added 1k or 1l (0.25 mmol), MTBE (2 mL) and
DIB (0.625 mmol, 201 mg) successively. Then the resulting mixture was stirred under
conditions at 30 ℃ (oil bath) for 9 h. The reaction was quenched with saturated
solution of Na S O . The organic phase was separated, and the aqueous layer was
2
2
3
extracted with EtOAc (5 mL×3). The combined organic solution was dried with
MgSO and concentrated in vacuo. The resulting residue was purified by a column
4
chromatography to give the corresponding product 2k or 2l.
Procedure for Synthesis of 2a at the Scale of 1 mmol
To a round-bottom flask was added 1a (1 mmol, 267 mg), MTBE (8 mL) and
DIB (2.5 mmol, 805 mg) successively. Then the resulting mixture was stirred under
o
conditions at 25 C for 9 h. The reaction was quenched with saturated solution of
Na S O . The organic phase was separated, and the aqueous layer was extracted with
2
2
3
EtOAc (10 mL×3). The combined organic solution was dried with MgSO and
4
concentrated in vacuo. The resulting residue was purified by a column
chromatography to give the corresponding product 2a in 61% yield (161.7 mg).
Procedure for Catalytic Synthesis of 2h
To a round-bottom flask was added 1h (0.25 mmol, 75.5 mg), MTBE (2 mL),
iodobenzene (0.05 mmol, 10 mg) and m-CPBA (0.5 mmol, 101 mg) successively.
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o
Then the resulting mixture was stirred under conditions at 25 C for 9 h. The reaction
was quenched with saturated solution of Na S O . The organic phase was separated,
2
2
3
and the aqueous layer was extracted with EtOAc (5 mL×3). The combined organic
solution was dried with MgSO and concentrated in vacuo. The resulting residue was
4
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purified by a column chromatography to give the corresponding product 2h in 29%
yield (22 mg).
1
13
H- and C-NMR Analytical Data
-Phenyl-2,3,3a, 4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazin-1-one (2a):
4
Purification by column chromatography on silica gel (petroleum ether/ethyl acetate =
1
10/1, v/v) afforded 2a as a white solid (56 mg, 85% yield), mp 163-168 ℃; H NMR
(
400 MHz, CDCl ): δ 8.62 (d, J = 8.4 Hz, 1H), 7.47-7.43 (m, 5H), 7.08-6.99 (m, 3H),
3
4
1
1
.61 (d, J = 8.8 Hz, 1H), 3.96-3.90 (m, 1H), 2.58-2.44 (m, 2H), 1.92-1.85 (m, 1H),
1
3
1
.79-1.70 (m, 1H); C{ H} NMR (100 MHz, CDCl ): δ 173.0, 145.5, 135.9, 129.6,
3
29.1, 127.6, 125.1, 124.8, 121.9, 119.2, 117.2, 81.4, 59.5, 31.3, 21.9; HRMS
+
(ESI-TOF) m/z: [M + H] calcd for C H NO , 266.1176; found, 266.1181.
1
7
15
2
4
-(p-Tolyl)-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazin-1-one (2b):
Purification by column chromatography on silica gel (petroleum ether/ethyl acetate =
1
1
0/1, v/v) afforded 2b as a white solid (55 mg, 80% yield), mp 164-167 ℃; H NMR
(
400 MHz, CDCl ): δ 8.61 (d, J = 8.0 Hz, 1H), 7.32-7.24 (m, 4H), 7.08-6.98 (m, 3H),
3
4.57 (d, J = 8.8 Hz, 1H), 3.97-3.90 (m, 1H), 2.63-2.44 (m, 2H), 2.40 (s, 3H),
1
3
1
1
1
2
2
.94-1.86 (m, 1H), 1.77-1.66 (m, 1H); C{ H} NMR (100 MHz, CDCl ): δ 173.1,
3
45.6, 139.5, 133.0, 129.8, 127.5, 125.1, 124.8, 121.8, 119.2, 117.2, 81.3, 59.4, 31.4,
+
2.0, 21.5; HRMS (ESI-TOF) m/z: [M + H] calcd for C H NO , 280.1332; found,
18 17
2
80.1327.
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4-(4-Methoxyphenyl)-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2
d][1,4]oxazin-1-one (2c): Purification by column chromatography on silica gel
(
petroleum ether/ethyl acetate = 8/1, v/v) afforded 2c as a white solid (48 mg, 66%
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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3
4
5
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7
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9
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yield), mp 182-186 ℃; H NMR (400 MHz, CDCl ): δ 8.61 (d, J = 9.6 Hz, 1H), 7.34
3
(
d, J = 8.4, 2H), 7.07-6.96 (m, 5H), 4.55 (q, J = 4.0 Hz, 1H), 3.96-3.89 (m, 1H), 3.84
1
3
1
(s, 3H), 2.63-2.43 (m, 2H), 1.93-1.85 (m, 1H), 1.73-1.66 (m, 1H); C{ H} NMR (100
MHz, CDCl ): δ 173.0, 160.6, 145.6, 128.9, 128.1, 125.1, 124.8, 121.8, 119.2, 117.2,
3
+
1
14.6, 81.1, 59.4, 55.6, 31.4, 22.0; HRMS (ESI-TOF) m/z: [M + H] calcd for
C H NO , 296.1281; found, 296.1293.
1
8
17
3
4
-(4-Fluorophenyl)-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazin-1-o
ne (2d): Purification by column chromatography on silica gel (petroleum ether/ethyl
acetate = 10/1, v/v) afforded 2d as a white solid (55 mg, 78% yield), mp 165-168 ℃;
1
H NMR (400 MHz, CDCl ): δ 8.61 (d, J = 7.6 Hz, 1H), 7.43-7.39 (m, 2H), 7.15 (t, J
3
= 8.8 Hz, 2H), 7.09-7.00 (m, 3H), 4.60 (d, J = 8.8 Hz, 1H), 3.93-3.86 (m, 1H),
1
3
1
2
.64-2.45 (m, 2H), 1.94-1.85 (m, 1H), 1.77-1.65 (m, 1H); C{ H} NMR (100 MHz,
CDCl ): δ 172.9, 163.5 (d, J = 247.0 Hz), 145.3, 131.9 (d, J = 9.0 Hz), 129.4 (d, J =
3
9
.0 Hz), 124.9 (d, J = 17.0 Hz), 122.0, 119.2, 117.2, 116.2 (d, J = 21.0 Hz), 80.7, 59.5,
+
3
1.3, 21.9; HRMS (ESI-TOF) m/z: [M + H] calcd for C H FNO , 284.1083; found,
1
7
14
2
284.1090.
4
-(4-Bromophenyl)-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazin-1-o
ne (2e): Purification by column chromatography on silica gel (petroleum ether/ethyl
acetate = 10/1, v/v) afforded 2e as a white solid (72 mg, 84% yield), mp 166-169 ℃;
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H NMR (400 MHz, CDCl ): δ 8.60 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 8.0 Hz, 2H), 7.30
3
(d, J = 8.4 Hz, 2H), 7.08-6.99 (m, 3H), 4.57 (d, J = 8.4 Hz, 1H), 3.89-3.83 (m, 1H),
13
1
2
.63-2.45 (m, 2H), 1.93-1.85 (m, 1H), 1.77-1.68 (m, 1H); C{ H} NMR (100 MHz,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CDCl ): δ 172.9, 145.2, 135.0, 132.3, 129.2, 125.0, 124.9, 123.7, 122.0, 119.2, 117.2,
3
+
8
0.7, 59.4, 31.3, 21.9; HRMS (ESI-TOF) m/z: [M + H] calcd for C H BrNO ,
1
7
14
2
344.0281; found, 344.0277.
4
-(4-(Trifluoromethyl)phenyl)-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]
oxazin-1-one (2f): Purification by column chromatography on silica gel (petroleum
ether/ethyl acetate = 8/1, v/v) afforded 2f as a white solid (26 mg, 32% yield), mp
1
1
67-170 ℃; H NMR (400 MHz, CDCl ): δ 8.62 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 8.0
3
Hz, 2H), 7.56 (d, J = 8.0 Hz, 2H), 7.10-7.01 (m, 3H), 4.68 (d, J = 8.8 Hz, 1H),
1
3
1
3
.94-3.87 (m, 1H), 2.65-2.47 (m, 2H), 1.95-1.87 (m, 1H), 1.80-1.73 (m, 1H); C{ H}
NMR (100 MHz, CDCl ): δ 172.9, 145.1, 140.0, 132.0, 131.6, 127.9, 126.1 (q, J = 4.0
3
Hz), 124.8(d, J = 5.0 Hz), 122.2, 119.2, 117.2, 80.7, 59.5, 31.2, 29.9, 21.9; HRMS
+
(ESI-TOF) m/z: [M + H] calcd for C H F NO , 334.1053; found, 334.1049.
1
8
14
3
2
4-(4-Chlorophenyl)-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazin-1-
one (2g): Purification by column chromatography on silica gel (petroleum ether/ethyl
acetate = 10/1, v/v) afforded 2g as a white solid (61 mg, 82% yield), mp 162-165 ℃;
1
H NMR (400 MHz, CDCl ): δ 8.61 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 8.0 Hz, 2H), 7.36
3
(d, J = 8.0 Hz, 2H), 7.08-6.99 (m, 3H), 4.58 (d, J = 8.0 Hz, 1H), 3.91-3.83 (m, 1H),
1
3
1
2.64-2.45 (m, 2H), 1.93-1.85 (m, 1H), 1.77-1.68 (m, 1H); C{ H} NMR (100 MHz,
CDCl ): δ 172.9, 145.2, 135.5, 134.5, 129.4, 128.9, 125.0, 124.9, 122.0, 119.2, 117.2,
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+
80.7, 59.4, 31.3, 21.9; HRMS (ESI-TOF) m/z: [M + H] calcd for C H ClNO ,
1
7
14
2
3
5
37
3
00.0786 ( Cl) and 302.0756 ( Cl); found, 300.0788 and 302.0761.
4
-(3-Chlorophenyl)-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazin-1-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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3
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8
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8
9
0
one (2h): Purification by column chromatography on silica gel (petroleum ether/ethyl
acetate = 10/1, v/v) afforded 2h as a white solid (59 mg, 80% yield), mp 189-191 ℃;
1
H NMR (400 MHz, CDCl ): δ 8.61 (d, J = 8.0 Hz, 1H), 7.44-7.29 (m, 4H), 7.09-7.00
3
(
m, 3H), 4.58 (d, J = 8.0 Hz, 1H), 3.92-3.85 (m, 1H), 2.64-2.45 (m, 2H), 1.95-1.88 (m,
13
1
1
H), 1.80-1.71 (m, 1H); C{ H} NMR (100 MHz, CDCl ): δ 172.9, 145.2, 138.0,
3
135.2, 130.4, 129.7, 127.7, 125.7, 125.0, 124.9, 122.1, 119.2, 117.2, 80.7, 59.4, 31.2,
+
35
2
1.9; HRMS (ESI-TOF) m/z: [M + H] calcd for C H ClNO , 300.0786 ( Cl) and
17 14 2
3
7
302.0756 ( Cl); found, 300.0782 and 302.0761.
4
-(2-Chlorophenyl)-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazin-1-
one (2i): Purification by column chromatography on silica gel (petroleum ether/ethyl
acetate = 10/1, v/v) afforded 2i as a white solid (47 mg, 63% yield), mp 169-172 ℃;
1
H NMR (400 MHz, CDCl ): δ 8.61 (d, J = 9.6 Hz, 1H), 7.51-7.45 (m, 2H), 7.42-7.34
3
(m, 2H), 7.08-6.99 (m, 3H), 5.29 (d, J = 8.8 Hz, 1H), 3.96 (q, J = 8.0 Hz, 1H),
1
3
1
2
1
.63-2.46 (m, 2H), 2.05-1.87 (m, 2H); C{ H} NMR (100 MHz, CDCl ): δ 173.1,
3
45.4, 134.0, 133.6, 130.4, 130.0, 129.1, 127.9, 125.1, 124.8, 122.0, 119.3, 117.2,
+
76.4, 60.0, 31.2, 20.7; HRMS (ESI-TOF) m/z: [M + H] calcd for C H ClNO ,
1
7
14
2
3
5
37
3
00.0786 ( Cl) and 302.0756 ( Cl); found, 300.0781 and 302.0760.
4-(Naphthalen-2-yl)-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazin-1-
one (2j): Purification by column chromatography on silica gel (petroleum ether/ethyl
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acetate = 6/1, v/v) afforded 2j as a white solid (59 mg, 75% yield), mp 177-180 ℃; H
NMR (400 MHz, CDCl ): δ 8.64 (d, J = 8.0 Hz, 1H), 7.95-7.88 (m, 4H), 7.56-7.50 (m,
3
3
H), 7.11-7.01 (m, 3H), 4.77 (d, J = 8.0 Hz, 1H), 4.08-4.01 (m, 1H), 2.64-2.46 (m,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
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4
4
4
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4
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5
5
5
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5
5
5
6
0
1
2
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0
1
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9
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8
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1
3
1
2H), 1.91-1.74 (m, 2H); C{ H} NMR (100 MHz, CDCl ): δ 173.1, 145.6, 134.0,
3
1
33.4, 133.3, 129.2, 128.3, 128.0, 127.4, 127.0, 126.8, 125.1, 124.9, 124.5, 121.9,
+
119.3, 117.3, 81.6, 59.5, 31.4, 22.0; HRMS (ESI-TOF) m/z: [M + H] calcd for
C H NO , 316.1332; found, 316.1344.
2
1
17
2
4
-(2,3-Dihydrobenzofuran-5-yl)-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,
4]oxazin-1-one (2k): Purification by column chromatography on silica gel (petroleum
ether/ethyl acetate = 8/1, v/v) afforded 2k as a white solid (47 mg, 61% yield), mp
1
222-225 ℃; H NMR (400 MHz, CDCl ): δ 8.60 (d, J = 7.6 Hz, 1H), 7.25 (s, 1H),
3
7
.14 (d, J = 8.0 Hz, 1H), 7.05-6.98 (m, 3H), 6.83 (d, J = 8.4 Hz, 1H), 4.62 (t, J = 8.8
Hz, 2H), 4.52 (d, J = 8.8Hz, 1H), 3.93 (q, J = 9.2 Hz, 1H), 3.25 (t, J = 8.8 Hz, 2H),
1
3
1
2.63-2.43 (m, 2H), 1.96-1.88 (m, 1H), 1.74-1.68 (m, 1H); C{ H} NMR (100 MHz,
CDCl ): δ 173.0, 161.3, 145.7, 128.2, 128.0, 125.1, 124.8, 124.2, 121.8, 119.2, 117.2,
3
+
109.7, 81.4, 71.7, 59.5, 31.4, 29.8, 22.0; HRMS (ESI-TOF) m/z: [M + H] calcd for
C H NO , 308.1281; found, 308.1281.
1
9
17
3
tert-Butyl
5-(1-oxo-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazin-4-yl)-1H-indole-
-carboxylate (2l): Purification by column chromatography on silica gel (petroleum
1
ether/ethyl acetate = 8/1, v/v) afforded 2l as a white solid (46 mg, 46% yield), mp
1
1
57-159 ℃; H NMR (400 MHz, CDCl ): δ 8.63 (d, J = 7.6 Hz, 1H), 8.23 (d, J = 8.0
3
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5
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Hz, 1H), 7.65 (d, J = 3.6 Hz, 1H), 7.62 (s, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.08-6.99 (m,
3
2
H), 6.60 (d, J = 3.6 Hz, 1H), 4.69 (d, J = 8.8 Hz, 1H), 3.99 (q, J = 9.2 Hz, 1H),
13
1
.62-2.43 (m, 2H), 1.89-1.74 (m, 2H), 1.69 (s, 9H); C{ H} NMR (100 MHz, CDCl ):
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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δ 173.1, 149.7, 145.7, 135.9, 131.1, 130.3, 127.1, 125.1, 124.8, 123.5, 121.8, 120.2,
1
19.2, 117.2, 115.8, 107.4, 84.3, 81.7, 59.7, 31.8, 31.4, 29.9, 28.4, 22.8, 22.0, 14.3;
+
HRMS (ESI-TOF) m/z: [M + H] calcd for C H N O , 405.1809; found, 405.1794.
2
4
24
2
4
8
-Fluoro-4-phenyl-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazin-1-o
ne (2m): Purification by column chromatography on silica gel (petroleum ether/ethyl
acetate = 10/1, v/v) afforded 2m as a white solid (36 mg, 51% yield), mp 146-148 ℃;
1
H NMR (400 MHz, CDCl ): δ 8.43 (dd, J = 2.8, 10.4 Hz, 1H), 7.47-7.40 (m, 5H),
3
6.96 (q, J = 5.2 Hz, 1H), 6.76 (td, J = 2.8, 8.0 Hz, 1H), 4.55 (d, J = 8.8 Hz, 1H),
1
3
1
3
.95-3.89 (m, 1H), 2.63-2.45 (m, 2H), 1.92-1.85 (m, 1H), 1.79-1.68 (m, 1H); C{ H}
NMR (100 MHz, CDCl ): δ 173.2, 157.4 (d, J = 237.0 Hz), 141.7, 135.7, 129.4 (d, J =
3
49.0 Hz), 127.5, 125.3 (d, J = 11.0 Hz), 117.7 (d, J = 9.0 Hz), 111.2 (d, J =23.0 Hz) ,
+
1
06.1 (d, J = 29.0 Hz), 81.2, 59.4, 31.3, 22.0; HRMS (ESI-TOF) m/z: [M + H] calcd
for C H FNO , 284.1082; found, 284.1086.
1
7
14
2
8
-Bromo-4-phenyl-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazin-1-o
ne (2n): Purification by column chromatography on silica gel (petroleum ether/ethyl
acetate = 10/1, v/v) afforded 2n as a white solid (34 mg, 40% yield), mp 182-185 ℃;
1
H NMR (400 MHz, CDCl ): δ 8.80 (d, J = 2.4 Hz, 1H), 7.47-7.39 (m, 5H), 7.15 (q, J
3
= 2.4 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 4.57 (d, J = 8.8 Hz, 1H), 3.94-3.87 (m, 1H),
1
3
1
2
.63-2.45 (m, 2H), 1.94-1.86 (m, 1H), 1.80-1.68 (m, 1H); C{ H} NMR (100 MHz,
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CDCl ): δ 173.1, 144.6, 135.5, 129.7, 129.2, 127.6, 127.5, 126.1, 121.7, 118.6, 114.0,
3
+
8
3
1.4, 59.3, 31.2, 22.0; HRMS (ESI-TOF) m/z: [M + H] calcd for C H BrNO ,
1
7
14
2
44.0281; found, 344.0267.
7-Fluoro-4-phenyl-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazin-1-o
1
1
1
1
1
1
1
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1
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2
2
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2
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0
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0
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0
ne (2o): Purification by column chromatography on silica gel (petroleum ether/ethyl
acetate = 10/1, v/v) afforded 2o as a white solid (30 mg, 42% yield), mp 199-202 ℃;
1
H NMR (400 MHz, CDCl ): δ 8.59 (q, J = 6.0 Hz, 1H), 7.47-7.39 (m, 5H), 6.77-6.71
3
(m, 2H), 4.62 (d, J = 8.8 Hz, 1H), 3.92 (q, J = 8.8 Hz, 1H), 2.63-2.44 (m, 2H),
1
3
1
1.95-1.86 (m, 1H), 1.80-1.68 (m, 1H); C{ H} NMR (100 MHz, CDCl ): δ 172.8,
3
1
59.4 (d, J = 242.0 Hz), 146.5 (d, J = 11.0 Hz), 135.5, 129.5 (d, J = 54.0 Hz), 127.5,
121.5 (d, J = 3.0 Hz), 120.2 (d, J = 9.0 Hz), 108.6 (d, J = 22.0 Hz), 104.6 (d, J = 25.0
+
Hz), 81.9, 59.2, 31.2, 21.8; HRMS (ESI-TOF) m/z: [M+H] calcd for C H FNO ,
1
7
14
2
2
84.1082; found, 284.1090.
7-Methyl-4-phenyl-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazin-1-o
ne (2p): Purification by column chromatography on silica gel (petroleum ether/ethyl
acetate = 10/1, v/v) afforded 2p as a white solid (21 mg, 30% yield), mp 149-152 ℃;
1
H NMR (400 MHz, CDCl ): δ 8.61 (s, 1H), 7.46-7.40 (m, 5H), 6.93-6.84 (m, 2H),
3
4
.57 (d, J = 8.8 Hz, 1H), 3.92 (q, J = 8.8 Hz, 1H), 2.62-2.43 (m, 2H), 2.34 (s, 3H),
1
3
1
1.91-1.83 (m, 1H), 1.78-1.67 (m, 1H); C{ H} NMR (100 MHz, CDCl ): δ 173.0,
3
1
43.4, 136.1, 131.4, 129.5, 129.1, 127.6, 125.5, 124.7, 119.4, 116.9, 81.4, 59.7, 31.4,
+
21.9, 21.2; HRMS (ESI-TOF) m/z: [M+H] calcd for C H NO , 280.1332; found,
1
8
17
2
2
80.1321.
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4-Phenyl-2,3,3a,4-tetrahydro-1H-naphtho[2,3-b]pyrrolo[1,2-d][1,4]oxazin-1-one
(
2q): Purification by column chromatography on silica gel (petroleum ether/ethyl
acetate = 10/1, v/v) afforded 2q as a white solid (27 mg, 35% yield), mp 212-215 ℃;
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
H NMR (400 MHz, CDCl ): δ 9.13 (s, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.66 (d, J = 8.8
3
Hz, 1H), 7.50-7.43 (m, 5H), 7.41 (s, 1H), 7.39-7.33 (m, 2H), 4.70 (d, J = 9.2 Hz, 1H),
1
3
1
4.08-4.02 (m, 1H), 2.68-2.50 (m, 2H),1.95-1.87 (m, 1H), 1.85-1.73 (m, 1H); C{ H}
NMR (100 MHz, CDCl ): δ 173.5, 145.0, 135.9, 131.0, 129.64, 129.56, 129.2, 128.0,
3
1
27.6, 126.5, 125.7, 125.5, 124.6, 116.6, 112.6, 81.6, 59.9, 31.4, 22.1; HRMS
+
(ESI-TOF) m/z: [M + H] calcd for C H NO , 316.1332; found, 316.1322.
2
1
17
2
4
-(4-Chlorophenyl)-2,2-dimethyl-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4
]oxazin-1-one (2u): Purification by column chromatography on silica gel (petroleum
ether/ethyl acetate = 10/1, v/v) afforded 2u as a white solid (28 mg, 35% yield), mp
1
1
62-165 ℃; H NMR (400 MHz, CDCl ): δ 8.62 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 8.4
3
Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.08-7.00 (m, 3H), 4.55 (d, J = 8.8 Hz, 1H),
.84-3.78 (m, 1H), 1.73 (q, J = 6.4 Hz, 1H), 1.60-1.55 (m, 1H), 1.26 (s, 3H), 1.19 (s,
3
1
3
1
3H); C{ H} NMR (100 MHz, CDCl ): δ 177.6, 145.4, 135.5, 134.7, 129.4, 128.8,
3
1
25.1, 124.7, 122.1, 119.2, 117.2, 80.8, 56.3, 41.1, 37.7, 25.2, 24.7; HRMS (ESI-TOF)
+
35
37
m/z: [M+H] calcd for C H ClNO , 328.1099 ( Cl) and 330.1069 ( Cl); found,
1
9
18
2
328.1092 and 330.1068.
ASSOCIATED CONTENT
Supporting Information
Detailed optimization of reaction conditions, crystal structure and crystallographic
1
13
data of 2a, standard orientations and energies of E-TS and Z-TS, and H- and C
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NMR Spectra. Supporting Information is available free of charge on the ACS
Publications website at
ACKNOWLEDGMENTS
We gratefully acknowledge fundings from the National Natural Science Foundation
of China (No. 21372265) and the Natural Science Foundation Project of CQ CSTC
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(cstc2018jcyjAX0155).
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