Asymmetric Synthesis of Multifunctionalized 2,3-Benzodiazepines by a One-Pot N-heterocyclic Carbene/Chiral Palladium Sequential Catalysis

Article abstract of DOI:10.1021/acs.joc.9b02693

We report the first example of the construction of chiral 2,3-benzodiazepine compounds which are of biologic and pharmaceutical relevance by asymmetric catalysis. Catalyzed by a thiazolium-derived carbene and a palladium-chiral bidentate phosphine complex

Full text of DOI:10.1021/acs.joc.9b02693

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Article
Asymmetric Synthesis of Multifunctionalized 2,3-Benzodiazepines by a
One-pot N-Heterocyclic Carbene/Chiral Palladium Sequential Catalysis
Ya-Li Ding, Yun-Long Zhao, Shuang-Shuo Niu, Pei Wu, and Ying Cheng
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02693 • Publication Date (Web): 05 Dec 2019
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Asymmetric Synthesis of Multifunctionalized 2,3-
Benzodiazepines by a One-pot N-Heterocyclic Carbene/Chiral
Palladium Sequential Catalysis
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Ya-Li Ding, Yun-Long Zhao, Shuang-Shuo Niu, Pei Wu and Ying Cheng*
College of Chemistry, Beijing Normal University, Beijing 100875, China
E-mail: ycheng2@bnu.edu.cn
ABSTRACT:
We report the first example of the construction of chiral 2,3-benzodiazepine compounds which are
of biologic and pharmaceutical relevance by asymmetric catalysis. Catalyzed by a thiazolium
derived carbene and a palladium-chiral bidentate phosphine complex in sequence, one-pot reaction
between 1-(2-(2-nitrovinyl)aryl)allyl esters 1 with azodicarboxylates 2 took place efficiently at
ambient temperature to produce 4-nitro-1-vinyl-1H-2,3-benzodiazepine-2,3-dicarboxylates 5 in
good to excellent yields with an enantiomeric ratio up to 95 : 5.
INTRODUCTION
2,3-Benzodiazepine and hydrogenated 2,3-benzodiazepines constitute the core
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skeletons of a large number of biological active compounds. For example, a number of
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7,8-methylenedioxy-2,3-benzodiazepine
derivatives
A-E
including
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dihydrobenzodiazepines and dihydrobenzodiazepinones have been demonstrated to be
noncompetitive AMPA receptor antagonists,1 with compound A (LY 300164,
Talampanel) being clinically studied as an anticonvulsant agent.2 On the other hand, a
series of 1-aryl-4,5-dihydro-2,3-benzodiazepines F were prepared as bromodomain
inhibitors (BET protein-inhibiting and BRD4-inhibiting) useful in the pharmaceutical
agents for hyperproliferative diseases and tumor diseases.3 In addition, various
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synthetic
5-acylamino-2,3-benzodiazepin-4-ones
G
and
5-acylamino-2,3-
benzodiazepin-1,4-diones H have shown inhibition to -amyloidogenic peptide (-
AP) production and have potential application in the treatment of Alzheimer’s
Disease.4
Figure 1. Biological active 2,3-benzodiazepine derivatives.
Due to their broad and powerful pharmacologic activities, the syntheses of 2,3-
benzodiazepine derivatives have attracted continuous interests from both organic and
medicinal chemists. One of the most frequently used strategies to synthesize 2,3-
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benzodiazepine, dihydro- and tetrahydro-2,3-benzodiazepine, 2,3-benzodiazepin-4-one
and 2,3-benzodiazepin-1,4-dione compounds is to construct the 2,3-benzodiazepine
ring by means of the condensation reaction between a hydrazine or substituted
hydrazines with the carbonyl compound including 1-(o-acyl)aryl-2-ketones,3a, 5 2-(o-
acyl)arylacetic acids and esters,1c,4b and 2-(o-carboxy)arylacetic acid anhydride.4a Other
methods such as the Rh-catalyzed coupling reaction between N-boc hydrazones and
diazoketoesters followed by intramolecular condensation,6 the ring expansion reaction
of tetrahydrodiazirino[3,1-a]isoquinoline with sulfonyl chlorides,7 and the reaction of
hydrazine with 2-benzopyrylium or 2-benzoselenopyrylium salts8 have also been
reported. Although most of the bioactive 2,3-benzodiazepine derivatives contain a
stereogenic center, and different enantiomers have considerably different bioactivities
on the physiologic system,1b-1d surprisingly, the asymmetric synthesis of chiral 2,3-
benzodiazepine derivatives remains largely unexplored. Enantiomerically pure 3,5-
dihydro- and 1,2,3,5-tetrahydro-2,3-benzodiazepin-4-ones were obtained by the
resolution of racemates using chiral HPLC.1b-1d Enantioselective synthesis of 3,5-
dihydro-2,3-benzodiazepines was reported once by asymmetric reduction of a C=N
bond of 2,3-benzodiazepines.9 The other examples involved the synthesis of chiral 2,3-
benzodiazepines used optically active 1-arylpropan-2-ols as reactants which were
prepared from the asymmetric reduction of 1-arylpropan-2-ones.10 To the best of our
knowledge, the asymmetric synthesis of dihydro- and tetrahydro-2,3-benzodiazepines
by chiral catalysis has not been reported so far. The development of efficient and
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enantioselective reactions for the synthesis of highly enantiomercally pure 2,3-
benzodiazepine compounds is therefore of great importance.
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We have been interested in developing new synthetic methods by means of N-
heterocyclic carbene (NHC) and transition metal cascade catalysis for many years.
Recently, we reported novel and efficient NHC/Pd cascade catalytic method for the
synthesis of 2,2-disubstituted benzofuran-3-ones11a and NHC/Cu(II) cascade catalytic
method for the synthesis of 2-amido-3-benzylidene-1-indanones.11b In 2013, Ye and co-
workers reported a NHC-catalyzed Morita–Baylis–Hillman (MBH) reaction of β-
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arylnitroalkenes
with
azodicarboxylates,
which
produced
1-(2-aryl-1-
nitrovinyl)hydrazine-1,2-dicarboxylates in excellent yields.12 We envisioned that the
NHC-catalyzed reaction of 1-(2-(2-nitrovinyl)aryl)allyl esters 1 with azodicarboxylates
2 followed by the transition metal-catalyzed intramolecular N-allylation would provide
a new route to 1H-2,3-benzodiazepine derivatives (Scheme 1). Herein we report the
first asymmetrical synthesis of multifunctionalized 1H-2,3-benzodiazepines by a
catalytic cascade reaction.
Scheme 1. Strategy for NHC/Transition Metal Catalyzed Construction of Substituted 2,3-
Benzodiazepines.
RESULTS AND DISCUSSION
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We commenced our study with the investigation of the reaction of (E)-1-(2-(2-
nitrovinyl)phenyl)allyl acetate 1a with dimethyl azodicarboxylate 2a in the presence of
an NHC and a palladium catalyst. Initially, a mixture of substrates 1a and 2a, thiazolium
salt 3a as the NHC precursor, DMAP as a base, Pd(PPh3)4 and BINAP was stirred in
dichloromethane for 24h. Disappointedly, however, only compound 4a that was derived
from the NHC-catalyzed reaction of 1a with 2a was observed. Obviously, the palladium
catalyst did not participate in the reaction under the conditions examined. We then
attempted the cascade reaction of nitroalkene 1a with azodicarboxylate 2a by means of
one-pot sequential catalysis. Thus, a mixture of substrates 1a and 2a (1a : 2a = 1 : 1.8),
the NHC precursor 3 (20 mol %) and DMAP (20 mol %) in dry solvent was first stirred
for 12 h at room temperature. The palladium catalyst and ligand were then added, and
the resulting mixture was kept stirring for another 12 h. This sequential catalytic method
enabled the formation of desired 4-nitro-1-vinyl-1H-2,3-benzodiazepine-2,3-
dicarboxylate 5a. To established an efficient and highly enantioselective synthesis of
5a, the reaction conditions were then optimized by varying NHCs, palladium catalysts,
ligands, solvents and temperature. To trigger the addition of nitroalkene 1a to
azodicarboxylate 2a and to examine the compatibility of N-heterocyclic carbenes with
palladium catalyst, we first surveyed a series of heterocyclic azolium salts such as
thiazolium salts 3a-3d, triazolium salts 3e and 3f as NHC precatalysts. As illustrated in
Table 1, under the conditions using Pd(PPh3)4/(R)-BINAP as a chiral transition metal
catalyst, the reaction of 1a with 2a proceeded smoothly at room temperature in DCM
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to afford 5a in 35-83% yields when a thiazole or a triazole carbene was used (entries 1-
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6). Clearly, the reaction promoted by the triazole carbene 3a' followed by
Pd(PPh3)4/(R)-BINAP catalysis gave the highest chemical yield of 5a (83%) albeit with
low enantioselectivity (63:37 er) (Table 1, entry 1). On the contrary, the combination of
triazole carbene 3c' with Pd(PPh3)4/BINAP led to the formation of product 5a in a low
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yield (41%) but with the highest enantioselectivity (85:15 er) (Table 1, entry 3).
Table 1. Screening of NHC Catalysts.
Entry
NHC
catalyst
3a
Yield of
5a (%)a
83
er of 5ab
Entry
NHC
catalyst
3d
Yield of er of 5ab
5a (%)a
1
2
3
63:37
66:34
85:15
4
5
6
74
58
35
68:32
57:43
65:35
3b
57
3e
3c
41
3f
aIsolated yields. bDetermined by chiral HPLC.
Since the stereogenic center is generated in the second transition metal catalyzed N-
allylation step, we set to optimize the chiral palladium catalysts with the use of
thiazolium salt 3a as an NHC precatalyst. As summarized in Table 2, while using (R)-
BINAP as the chiral ligand, the replacement of Pd(PPh3)4 with Pd2(dba)3CHCl3,
Pd2(dba)3 and [Pd(C3H5)Cl]2 improved the enantioselectivity, albeit the chemical yield
were decreased slightly (entries 1-3). It was notable that Pd(TFA)2 was inactive in this
reaction. The reducing of the loading of [Pd(C3H5)Cl]2 from 20 mol% to 15 mol% and
10 mol% led to the drastic decrease of both the yield and er value of product (entries 5
and 6). Since [Pd(C3H5)Cl]2/BINAP gave higher enantioselectivity than
Pd(PPh3)4/BINAP with comparable chemical yields, the reaction was further optimized
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by varying the ligands with [Pd(C3H5)Cl]2 as palladium source. It was found that,
among the chiral bidentate phosphine ligands L1-L5, the (S)-DIFLUORPHOS (L3)
stood out as the best chiral ligand, which resulted in the formation of 5a in 80% yield
and 87:13 er (Table 2, entry 8). The use of (R)-SEGPHOS (L2) as a ligand gave product
5a in 57% yield with 85:15 er (entry 7). On the contrary, the sterically bulky ligand (S)-
DTBM-SEGPHOS (L4) and 1,1'-spirobiindane ligand (R)-SDP (L5) appeared as less
efficient and enantioselective (entries 9 and 10). It should be noted that the unidentate
phosphine ligand (S)-THQ phos (L6) led to the formation of high yield of product but
displayed no enantiocontrol at all, and the N, P-ligand (L7) and N, N-ligand (L8) were
entirely ineffective ligands (entries 11-13).
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Table 2. Screening of Palladium Catalysts and Chiral Ligands.
Entry
Metal (mol %)
Ligand
Yield of 5a
er of 5ab
(mol %)
(%)a
67
70
76
‒
1
Pd2(dba)3CHCl3 (20) L1 (40)
70:30
75:25
79:21
2
Pd2 (dba)3 (20)
L1 (40)
L1 (40)
L1 (40)
L1 (30)
L1 (20)
L2 (40)
L3 (40)
L4 (40)
L5 (40)
3
[Pd(C3H5)Cl]2 (20)
Pd(TFA)2 (20)
4
5
[Pd(C3H5)Cl]2 (15)
[Pd(C3H5)Cl]2 (10)
[Pd(C3H5)Cl]2 (20)
[Pd(C3H5)Cl]2 (20)
[Pd(C3H5)Cl]2 (20)
[Pd(C3H5)Cl]2 (20)
45
37
57
80
30
37
71:29
76:24
85:15
87:13
76:24
58:42
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[Pd(C3H5)Cl]2 (20)
[Pd(C3H5)Cl]2 (20)
[Pd(C3H5)Cl]2 (20)
L6 (80)
L7 (40)
L8 (40)
78
‒
50:50
‒
7
8
aIsolated yields. bDetermined by chiral HPLC.
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With thiazole 3a' and [Pd(C3H5)Cl]2/(S)-DIFLUORPHOS (L3) as NHC and the chiral
palladium catalyst, respectively, the solvent effect was studied (Table 3). Under the
otherwise identical conditions, the reactions in dichloroethane, acetonitrile, acetone
THF and toluene gave similar enantioselectivity as that in dichloromethane but with
lower yields (Table 3, entries 1-5). Other solvents such as chloroform and 1,4-dioxane
led to both lower yields and lower enantioselectivity (entries 6, 7). To improve
enantioselectivity, different solvents were used in NHC- and palladium-catalyzed
reaction steps. For example, DCM was employed as the solvent for the reaction of 1a
with 2a catalyzed by thiazolium salt 3a/DMAP. After the NHC-catalyzed reaction, the
[Pd(C3H5)Cl]2/DIFLUORPHOS (L3) complex and another solvent including
acetonitrile, acetone and THF were added to the reaction mixture. It was found that,
although the use of a mixture of solvents did not significantly improve the
enantioselectivity, the chemical yield of 5a was increased dramatically to 90% with er
value remaining as 88:12 when the second step was conducted in DCM/acetone (1:1)
(entries 8-10). Finally, the examination of the influence of temperature on the reaction
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o
o
indicated either a higher (60 C) or a lower temperature (0 C) greatly decreased the
chemical yield of product, although the enantioselectivity was only slightly affected
(entries 11 and 12). Thus, the sequential catalytic reaction conducted using thiazolium
3a (20 mol%)/DMAP (20 mol%.) in DCM followed by [Pd(C3H5)Cl]2 (20 mol%)/(S)-
DIFLUORPHOS (L3, 40 mol%) in a mixture of DCM and acetone (1:1) at room
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temperature appeared optimal for the asymmetric synthesis of 1H-2,3-benzodiazepine
derivative 5 from the 1-(2-(2-nitrovinyl)phenyl)allyl acetate 1 with azodicarboxylate 2.
Table 3. Optimization of Reaction Solvent and Temperature.
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Entry
Solvent
Temp. (oC)
Yield of er of 5a
5a (%)
1
2
3
4
5
6
7
8
DCE
rt
rt
rt
rt
rt
rt
rt
rt
70
73
61
51
27
58
39
70
84:16
86:14
87:13
87:13
85:15
77:23
79:21
89:11
CH3CN
acetone
THF
toluene
CHCl3
1,4-dioxane
DCM/(DCM and
CH3CN, 1:1)a
DCM/(DCM and
acetone, 1:1)a
DCM/(DCM and
THF, 1:1)a
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rt
90
78
60
67
88:12
86:14
88:12
85:15
10
11
12
rt
DCM/(DCM and
acetone, 1:1)a
DCM/(DCM and
acetone, 1:1)a
rt /0 oCb
rt /60 oCb
aIn these reactions, the NHC-catalyzed reaction was carried out in DCM, followed by the addition of Pd catalyst and
another solvent. bThe NHC- and Pd-catalyzed reactions were performed at different temperature.
With the optimized conditions established, we examined the substrate scope for the
synthesis of 4-nitro-1-vinyl-1H-2,3-benzodiazepine-2,3-dicarboxylates 5 by employing
various 1-(2-(2-nitrovinyl)phenyl)allyl acetates 1 and azodicarboxylates 2. Under
nitrogen atmosphere and at room temperature, the mixture of allyl acetates 1 (0.2 mmol),
NHC catalyst 3a (20 mol%), DMAP (20 mol%) and azodicarboxylates 2 (0.36 mmol)
in DCM was stirred for 12h. Then the chiral palladium catalyst prepared from
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[Pd(C3H5)Cl]2 (20 mol%) and (S)-DIFLUORPHOS (40 mol%) in DCM was added to
the reaction mixture, followed by the addition of another solvent acetone in a glove box.
The mixture was stirred for another 12 h at room temperature. Pleasingly, as compiled
in Table 4, the sequential catalytic reaction was found to tolerate both electron-donating
and electron-withdrawing groups on the substrates 1. The electronic nature and
substitution pattern of substituents attached to the benzene ring of 1 have marginal
influence on the reaction efficiency and enantioselectivity. For example, 1-(2-(2-
nitrovinyl)phenyl)allyl acetates 1b-1e bearing an electron-donating methoxy and
methyl, or an electron-withdrawing chloro and trifluoromethyl on the para-position of
allyl acetate underwent efficient reaction with dimethyl azodicarboxylate 2a, affording
the corresponding products 5b-5e in 61-81% yields with 85:15-95:5% er. On the other
hand, the substrates 1f-1i substituted by an MeO, Me, Cl or CF3 group on the meta-
position of allyl acetate reacted with 2a to produce products 5f-5i in 65-88% yields with
87:13-92:8 er. The [1,3]dioxolo[4',5':4,5]benzo[1,2-d][1,2]diazepine product 5j that
resembled the key structure of many bioactive 2,3-benzodiazepine derivatives has also
been prepared in 93% yield with 89:11 er from the reaction of 1-(6-(2-
nitrovinyl)benzo[d][1,3]dioxol-5-yl)allyl acetate 1j with 2a. In addition to the 1-(2-(2-
nitrovinyl)phenyl)allyl acetates 1b-1j, heterocyclic aryl substituted allyl acetate
analogues were also included in the study. 1-(3-(2-Nitrovinyl)pyridinyl)allyl acetate
and 1-(3-(2-nitrovinyl)thiophenyl)allyl acetate were prepared readily using the similar
procedures for the synthesis of 1-(2-(2-nitrovinyl)phenyl)allyl acetates. However, the
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1-(3-(2-nitrovinyl)furanyl)allyl acetate was not obtained, because furanyl carbaldehyde
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substrate was unstable under the reaction conditions. It was found that, the reaction of
1-(3-(2-nitrovinyl)pyridin-2-yl)allyl acetate 1k with 2a proceeded equally well to give
the 7H-2,3-pyrido[2,3-d]diazepine-7,8-dicarboxylate 5k in a moderated yield and
enantioselectivity (48% yield, 77:23 er). Unfortunately, no expected thieno[2,3-
d]diazepine product was observed from the reaction of 1-(3-(2-nitrovinyl)thiophen-2-
yl)allyl acetate with 2a. This is most probably due to the fact that the product derived
from the first step of NHC-catalyzed reaction did not undergo the palladium-catalyzed
intramolecular cyclization because of the poisoning effect of thiophene imposed on
palladium catalyst. Other azodicarboxylateas 2 were also accepted as the substrates in
the synthesis of 1H-2,3-benzodiazepine-2,3-dicarboxylates 5. For instance, under the
identical catalytic conditions, diethyl and diisopropyl azodicarboxylate 2b and 2c
reacted analogously with 1a and 1d to furnish products 5l-5o in comparable yields. The
enantioselectivity decreased slightly, probably owing to the increase of steric hindrance
of alkyl group from methyl to ethyl and isopropyl. Finally, the reaction of 1d with 2a
was repeated in 1 mmol scale, which provided product 5d in 74% yield with 92:8 er.
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Table 4. Scope of the NHC and [Pd(C3H5)Cl]2/DIFLUORPHOS Sequentially Catalyzed Reaction
of 1-(o-(2-Nitrovinyl)aryl)allyl Acetates 1 with Azodicarboxylateas 2.a
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a
Reaction conditions: allyl acetates 1 (0.2 mmol), NHC catalyst 3a (20 mol%), DMAP (20 mol%) and
azodicarboxylates 2 (0.36 mmol) in DCM (0.5 mL) reacted at RT for 12h. Then chiral palladium catalyst prepared
from [Pd(C3H5)Cl]2 (20 mol%) and (S)-DIFLUORPHOS (40 mol%) in DCM (0.75 mL) and acetone (1.25 mL) were
added, and the reaction mixture was stirred for another 12 h at RT. bThe yield and er value in the parenthesis were
obtained from the reaction of 1d (1 mmol) with 2a (1.8 mmol).
To extend the substrate scope for the synthesis of multifunctionalized 1H-2,3-
benzodiazepines, we also prepared o-allyl ester substituted cinnamate 1p, chalcone 1q
and sulfonyl styrene 1r as reactants. The first step of the sequential reaction between
electron-deficient styrenes 1p-1r and azodicarboxylate 2a was examined in the
presence of various N-heterocyclic carbene catalysts. Unfortunately, however, the NHC
examined did not triggered the reaction between these electron-deficient styrenes and
azodicarboxylate under different conditions (Scheme 2).
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Scheme 2. The study on the reactions of o-allyl ester substituted sulfonyl styrene, -chalcone and -
cinnamate with azodicarboxylate in the presence of N-heterocyclic carbenes.
The structures of products 5 were elucidated on the basis of spectroscopic data and X-
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ray diffraction analysis. The presence of different conformers led to complicated H
o
NMR spectra of 5 at room temperature. Upon heat to 70 C, due to the rapid
1
interconversion between conformers in relative to H NMR time scale, a single set of
proton signals was observed. Therefore, all NMR spectra of 5 were recorded at 70 oC
in DMSO-d6. X-ray crystallographic analysis of 5d allowed us to unequivocally
confirm the S-configuration of stereocenter (See Figure S1 in Supporting Information).
The mechanism for the formation of 1H-2,3-benzodiazepine derivatives 5 from 1-(2-
(2-nitrovinyl)phenyl)allyl acetates 1 and azodicarboxylates 2 was proposed in Scheme
3. The nucleophilic addition of the NHC catalyst to the nitrovinyl group of substrates 1
initiates the first reaction. The resulting anion intermediate 6 undergoes nucleophilic
addition to azo bond of 2 to form a hydrazine anion 7. Proton transfer and removal of
NHC catalyst result in the formation of intermediates 4. In the presence of a palladium
catalyst, the palladium -allylic complex is generated,13 and it undergoes
intramolecular reaction with the amide moiety derived from deprotonation of the
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hydrazine group of 4 with DMAP to produce the final 2,3-benzodiazepine products 5.
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Scheme 3. Proposed Mechanism for the Formation of 1H-2,3-Benzodiazepine Derivatives 5 from
the Reaction between 1-(2-(2-Nitrovinyl)phenyl)allyl Acetates 1 and Azodicarboxylates 2.
Conclusion
In summary, we have developed a novel NHC/Pd sequentially catalytic method for
the asymmetric synthesis of multifunctionalized 1H-2,3-benzodiazepine derivatives
from the reaction of 1-(2-(2-nitrovinyl)phenyl)allyl acetates and azodicarboxylates.
Under the catalysis of
a
thiazole carbene followed by the chiral
[Pd(C3H5)Cl]2/DIFLUORPHOS catalyst, 1-(2-(2-nitrovinyl)phenyl)allyl acetates and
azodicarboxylates undergo a cascade nucleophilic addition and intramolecular N-
allylation reaction
to produce 4-nitro-1-vinyl-1H-2,3-benzodiazepine-2,3-
dicarboxylates in good to excellent yields with er up to 95:5. This work represents the
first example of catalytic asymmetric construction of 2,3-benzodiazepine core structure,
which occurs widely in a large number of biological active compounds.
Experimental Section
1. Preparation of reactants.
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(1). Preparation of 1-(o-formylaryl)allyl acetates.
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A typical experimental procedure for the synthesis of 1-(2-formylphenyl)allyl
acetate.14
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A mixture of 2-bromobenzaldehyde Ia (1.85 g, 10 mmol), triethyl orthoformate (2.96
g, 20 mmol) and TsOH‧H2O (38 mg, 0.2 mmol) in anhydrous ethanol (20 mL) was
refluxed for 6 h in an oil bath. After removal of the solvent, the residue was
chromatographed on a neutral Al2O3 column eluting with a mixture of petroleum ether
and ethyl acetate (PE : EA = 30 : 1) to give product as a colorless oil. After drying
overnight under vacuum, 1-bromo-2-(diethoxymethyl)benzene IIa was obtained in 95%
yield (2.46 g).
The resulting acetal IIa (2.46 g, 9.5 mmol) was dissolved in anhydrous THF (20 mL),
and n-BuLi (2.5 M in hexane, 4.4 mL, 10.5 mmol) was added dropwise at -78 ˚C under
nitrogen atmosphere. After stirring for 30 min at -78 ˚C, anhydrous DMF (1.7g, 23
mmol) was added dropwise to the solution. The resulting mixture was kept stirring at -
78 ˚C for another 30 min and then at room temperature for 1 h. The reaction was then
quenched by adding a saturated aqueous solution of NH4Cl (20 mL). The resulting
mixture was extracted with ethyl acetate (20 × 3 mL). The combined organic layer was
dried over anhydrous MgSO4. After filtration and removal of solvents, the residue was
chromatographed on a silica gel column eluting with a mixture of petroleum ether and
ethyl acetate (PE : EA = 10 : 1) to give the product as a pale yellow oil. 2-
(Diethoxymethyl)benzaldehyde IIIa was obtained in 92 % yield (1.8 g) after drying
overnight under vacuum.
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Under nitrogen protection and at 0 oC, to a solution of 2-(diethoxymethyl)benzaldehyde
IIIa (1.8 g, 8.7 mmol) in anhydrous THF (20 mL) was added dropwise vinylmagnesium
bromide (1 M in THF, 13 mL, 13 mmol). The reaction mixture was stirred at 0 ˚C for
12 h. After the reaction was quenched by the addition of water (20 mL), the mixture
was extracted with ethyl acetate (20 × 3 mL). The combined organic layer was dried
over anhydrous MgSO4. After filtration and removal of solvents, the residue was
dissolved in acetic anhydride (3.56 g, 34.8 mmol) and pyridine (2.75 g, 34.8 mmol).
The resulting mixture was stirred overnight at ambient temperature. Water (10 mL) was
added, and the resulting mixture was extracted with ethyl acetate (20 × 3 mL) and the
combined organic layer was washed with water (30 mL) and was dried over anhydrous
MgSO4. After filtration and removal of solvents, the residue was chromatographed on
a silica gel column eluting with a mixture of petroleum ether and ethyl acetate (PE : EA
= 10 : 1) to give 1-(2-(diethoxymethyl)phenyl)allyl acetate IVa as pale yellow oil (2 g,
84 %). The obtained acetal IVa was then hydrolyzed with aqueous hydrochloric acid (3
mol/L, 12 mL, 36 mmol) in THF (50 mL) for 4 h at room temperature. The reaction
was terminated by the addition of 30 mL of water and the resulting mixture was
extracted with ethyl acetate (10 × 3 mL). The combined organic layer was washed with
a saturated aqueous solution of NaHCO3 (30 mL) and dried over anhydrous MgSO4.
After evaporation of the solvent, the residue was chromatographed on a silica gel
column eluting with a mixture of petroleum ether and ethyl acetate (PE : EA = 8 : 1) to
give 1-(2-formylphenyl)allyl acetate Va as a pale yellow oil (1.26 g, 85%).
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1-(2-Formylphenyl)allyl acetate Va14: pale yellow oil; IR v (cm-1) 1746, 1697; H
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NMR (400 MHz, CDCl3) δ (ppm) 10.3 (s, 1H), 7.86 (dd, J = 7.6, 1.2 Hz, 1H), 7.55-
7.57 (m, 2H), 7.48 (td, J = 7.6, 1.6 Hz, 1H), 7.03 (dt, J = 5.2, 1.2 Hz, 1H), 6.03-6.12
(m, 1H), 5.23 (dt, J = 9.6, 1.6 Hz, 1H), 5.22 (dt, J = 18.8, 1.6 Hz, 1H), 2.11 (s, 3H).
1-(2-Formylaryl)allyl acetates Vb-Vk were synthesized from the substituted 2-bromo
aromatic aldehydes I using the similar procedures as that for Va. The only difference in
the preparation of different 1-(2-formylaryl)allyl acetates was that the hydrolysis of 1-
(2-(diethoxymethyl)phenyl)allyl acetates IVa-IVi (6.1-8.3 mmol) was performed with
aqueous hydrochloric acid (3 mol/L, 12 mL, 36 mmol) for 4 h in THF (50 mL) at room
temperature, while as the hydrolysis of 1-(6-(diethoxymethyl)benzo[d][1,3]dioxol-5-
yl)allyl acetate IVj (8.5 mmol) and 1-(3-(diethoxymethyl)pyridin-2-yl)allyl acetate
IVk (7.7 mmol) was conducted with TsOH∙H2O (10 mol%) for 3 h in the mixture of
THF (50 mL) and H2O (10 mL) at the refluxing temperature. The reaction scheme for
the preparation of 1-(2-formylaryl)allyl acetates V, and the chemical yields of all
intermediates II, III, IV and products V were summarized in Table S1 in Supporting
Information.
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1-(2-Formyl-4-methoxyphenyl)allyl acetate Vb: pale yellow oil; IR v (cm-1) 1740,
1695; 1H NMR (600 MHz, CDCl3) δ (ppm) 10.3 (s, 1H), 7.45 (d, J = 9.0 Hz, 1H), 7.38
(d, J = 1.2 Hz, 1H), 7.11 (dd, J = 9, 3.6 Hz, 1H), 6.89 (d, J = 4.2 Hz, 1H), 6.05-6.10 (m,
1H), 5.24 (d, J = 11.4 Hz, 1H), 5.18 (d, J = 17.4 Hz, 1H), 3.85 (s, 3H), 2.09 (s, 3H);
13C{1H} NMR (150 MHz, CDCl3) δ (ppm) 191.5, 169.7, 159.7, 136.7, 134.8, 133.1,
130.0, 120.4, 117.2, 114.7, 72.4, 55.6, 21.2; HRMS (TOF-ESI): [M + Na]+ calcd for
C13H14O4Na: 257.0784, found: 257.0780.
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1-(2-Formyl-4-methylphenyl)allyl acetate Vc: pale yellow oil; IR v (cm-1) 1746, 1695;
1H NMR (400 MHz, CDCl3) δ (ppm) 10.26 (s, 1H), 7.67 (s, 1H), 7.44 (d, J = 8.0 Hz,
1H), 7.39 (d, J = 8.4 Hz, 1H), 6.97 (d, J = 5.2 Hz, 1H), 6.02-6.11 (m, 1H), 5.22 (d, J =
10.8 Hz, 1H), 5.19 (d, J = 16.8 Hz, 1H), 2.41 (s, 3H), 2.10 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ (ppm) 192.3, 169.7, 138.5, 138.1, 136.5, 134.8, 133.3, 132.5, 128.0,
117.1, 72.4, 21.2, 20.9; HRMS (TOF-ESI): [M + Na]+ calcd for C13H14O3Na: 241.0843,
found: 241.0838.
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1-(4-Chloro-2-formylphenyl)allyl acetate Vd: pale yellow oil; IR v (cm-1) 1744, 1695;
1H NMR (400 MHz, CDCl3) δ (ppm) 10.25 (s, 1H), 7.83 (d, J = 2.4 Hz, 1H), 7.55 (dd,
J = 8.4, 2.4 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 6.93 (d, J = 5.2 Hz, 1H), 6.01-6.09 (m,
1H), 5.26 (d, J = 10.8 Hz, 1H), 5.21 (d, J = 17.6 Hz, 1H), 2.10 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ (ppm) 190.5, 169.6, 139.3, 135.9, 134.8, 134.7, 133.9, 131.2,
129.7, 117.8, 72.0, 21.1; HRMS (TOF-ESI): [M + Na]+ calcd for C12H11ClO3Na:
261.0288, found: 261.0291.
1-(2-Formyl-4-(trifluoromethyl)phenyl)allyl acetate Ve: pale yellow oil; IR v (cm-1)
1748, 1701; 1H NMR (600 MHz, CDCl3) δ (ppm) 10.3 (s, 1H), 8.12 (s, 1H), 7.83 (d, J
= 7.8 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 5.4 Hz, 1H), 6.03-6.09 (m, 1H),
5.28 (d, J = 10.2 Hz, 1H), 5.24 (d, J = 17.4 Hz, 1H), 2.12 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ (ppm) 190.6, 169.6, 144.7, 135.5, 133.7, 131.0 (q, J = 33.5 Hz), 130.4
(d, J = 3.8 Hz), 128.6, 123.4 (q, J = 271.2 Hz), 118.2, 72.0, 21.0. HRMS (TOF-ESI):
[M + Na]+ calcd for C13H11F3O3Na: 295.0552, found: 295.0551.
1-(2-Formyl-5-methoxyphenyl)allyl acetate Vf: pale yellow oil; IR v (cm-1) 1736,
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1686; 1H NMR (600 MHz, CDCl3) δ (ppm) 10.10 (s, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.07
(d, J = 4.8 Hz, 1H), 7.05 (d, J = 3.0 Hz, 1H), 6.93 (dd, J = 7.8, 2.4 Hz, 1H), 6.02-6.07
(m, 1H), 5.24 (d, J = 18.6 Hz, 1H), 5.21 (d, J = 11.4 Hz, 1H), 3.88 (s, 3H), 2.12 (s, 3H);
13C{1H} NMR (150 MHz, CDCl3) δ (ppm) 190.7, 169.6, 164.1, 143.6, 136.0, 135.5,
126.8, 117.3, 113.6, 112.7, 72.1, 55.7, 21.2; HRMS (TOF-ESI): [M + Na]+ calcd for
C13H14O4Na: 257.0784, found: 257.0782.
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1-(2-Formyl-5-methylphenyl)allyl acetate Vg: pale yellow oil; IR v (cm-1) 1740, 1695;
1H NMR (400 MHz, CDCl3) δ (ppm) 10.2 (s, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.34 (s,
1H), 7.27 (d, J = 8.0 Hz, 1H), 7.01 (dt, J = 5.2，1.6 Hz, 1H), 6.02-6.10 (m, 1H), 5.20-
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5.24 (m, 2H), 2.42 (s, 3H), 2.12 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ (ppm)
191.9, 169.7, 145.2, 140.9, 136.3, 132.6, 131.1, 129.2, 128.4, 117.1, 72.5, 21.9, 21.2;
HRMS (TOF-ESI): [M + Na]+ calcd for C13H14O3Na: 241.0835, found: 241.0831.
1-(5-Chloro-2-formylphenyl)allyl acetate Vh: pale yellow oil; IR v (cm-1) 1744, 1697;
1H NMR (600 MHz, CDCl3) δ (ppm) 10.22 (s, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.54 (s,
1H), 7.45 (dd, J = 7.8, 2.4 Hz, 1H), 7.01 (d, J = 6.0 Hz, 1H), 6.0-6.06 (m, 1H), 5.25 (d,
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J = 7.8 Hz, 1H), 5.24 (d, J = 16.8 Hz, 1H), 2.13 (s, 3H); C{1H} NMR (100 MHz,
CDCl3) δ (ppm) 190.8, 169.6, 142.9, 140.6, 135.6, 133.7, 131.6, 128.7, 127.9, 117.8,
71.6, 21.1; HRMS (TOF-ESI): [M + Na]+ calcd for C12H11ClO3Na: 261.0288, found:
261.0290.
1-(2-Formyl-5-(trifluoromethyl)phenyl)allyl acetate Vi: pale yellow oil; IR v (cm-1)
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1746, 1703; H NMR (400 MHz, CDCl3) δ (ppm) 10.35 (s, 1H), 7.99 (d, J = 7.6 Hz,
1H), 7.81 (s, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 4.4 Hz, 1H), 6.02-6.10 (m, 1H),
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5.29 (d, J = 10.8 Hz, 1H), 5.25 (d, J = 18.4 Hz, 1H), 2.13 (s, 3H); 13C{1H} NMR (150
MHz, CDCl3) δ (ppm) 190.9, 169.6, 142.0, 135.8, 135.5, 135.3 (q, J = 33 Hz), 132.2,
125.4, 124.9, 123.3 (q, J = 271.5 Hz), 118.2, 71.8, 21.1; HRMS (TOF-ESI): [M + Na]+
calcd for C13H11F3O3Na: 295.0552, found: 295.0556.
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1-(6-Formylbenzo[d][1,3]dioxol-5-yl)allyl acetate Vj: pale yellow oil; IR v (cm-1)
1742, 1678; 1H NMR (600 MHz, CDCl3) δ (ppm) 10.18 (s, 1H), 7.32 (s, 1H), 6.98 (s,
1H), 6.94 (d, J = 5.4 Hz, 1H), 6.05 (s, 2H), 6.0-6.04 (m, 1H), 5.24 (d, J = 11.4 Hz, 1H),
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5.22 (d, J = 18.6 Hz, 1H), 2.11 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ (ppm)
189.4, 169.6, 152.6, 148.0, 138.2, 136.2, 128.4, 117.4, 109.4, 108.0, 102.3, 71.9, 21.1;
HRMS (TOF-ESI): [M + Na]+ calcd for C13H12O5Na: 271.0576, found: 271.0580.
1-(3-Formylpyridin-2-yl)allyl acetate Vk: pale yellow oil; IR v (cm-1) 1742, 1699; 1H
NMR (600 MHz, CDCl3) δ (ppm) 10.42 (s, 1H), 8.78 (d, J = 5.2, 2 Hz, 1H), 8.17 (d, J
= 7.6, 1.6 Hz, 1H), 7.42 (dd, J = 7.6, 4.4 Hz, 1H), 6.89 (dt, J = 6, 1.2 Hz, 1H), 6.14-
6.22 (m, 1H), 5.38 (dd, J = 16, 1.2 Hz, 1H), 5.33 (d, J = 10.8 Hz, 1H), 2.13 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 190.6, 170.0, 159.2, 153.4, 138.6, 134.5,
129.3, 123.4, 118.8, 74.4, 21.0; HRMS (TOF-ESI): [M + Na]+ calcd for C11H11NO3Na:
228.0631, found: 228.0628.
(2). Preparation of 1-(o-(2-nitrovinyl)aryl)allyl acetates 1.15
In a flask, 1-(o-formylaryl)allyl acetates V (1 mmol) and NH4OAc (77 mg, 1 mmol)
were mixed with CH3NO2 (10 mL). The reaction mixture was refluxed for 3h and then
the reaction was quenched by the addition of water (10 mL). The resulting mixture was
extracted with DCM (10 × 3 mL). The combined organic layer was dried over
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anhydrous MgSO4. After filtration and removal of solvents, the residue was
chromatographed on a silica gel column eluting with a mixture of petroleum ether and
ethyl acetate (PE : EA = 8 : 1 – 5:1) to give 1-(2-(2-nitrovinyl)aryl)allyl acetates 1
generally as yellow oils (60-76% yield). The products 1 solidified into yellow solids
when kept in refrigerator.
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(E)-1-(2-(2-Nitrovinyl)phenyl)allyl acetate 1a: yellow solid, 175 mg, 71%, mp 51-52
oC (without recrystallization); IR v (cm-1) 1741; 1H NMR (400 MHz, CDCl3) δ (ppm)
8.49 (d, J = 13.7 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.48 (d, J = 4.0 Hz, 2H), 7.43 (d, J
= 13.6 Hz, 1H), 7.35-7.39 (m, 1H), 6.45 (dt, J = 5.2, 1.2 Hz, 1H), 5.96-6.04 (m, 1H),
5.28 (d, J = 10.4 Hz, 1H), 5.20 (d, J = 17.6 Hz, 1H), 2.11 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ (ppm) 169.8 , 139.2, 138.4, 136.6 , 135.6, 131.9 , 129.0 , 128.7, 127.8,
118.2, 74.1, 21.1; HRMS (TOF-ESI): [M + Na]+ calcd for C13H13NO4Na: 270.0736,
found: 270.0740.
(E)-1-(4-Methoxy-2-(2-nitrovinyl)phenyl)allyl acetate 1b: yellow solid, 180 mg,
o
1
65%, mp 54-55 C (without recrystallization); IR v (cm-1) 1742; H NMR (400 MHz,
CDCl3) δ (ppm) 8.46 (d, J = 13.2 Hz, 1H), 7.41 (d, J = 13.2 Hz, 1H), 7.39 (d, J = 7.2
Hz, 1H), 7.00 (d, J = 8.8 Hz, 1H), 6.99 (s, 1H), 6.40 (d, J = 3.6 Hz, 1H), 5.95-6.03 (m,
1H), 5.25 (d, J = 10.8 Hz, 1H), 5.18 (d, J = 17.2 Hz, 1H), 3.82 (s, 3H), 2.08 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 169.8, 159.7, 138.5, 136.6, 136.0, 131.5,
130.7, 130.0, 117.7, 117.4, 112.8, 73.8, 55.6, 21.1; HRMS (TOF-ESI): [M + Na]+ calcd
for C14H15NO5Na: 300.0842, found: 300.0839.
(E)-1-(4-Methyl-2-(2-nitrovinyl)phenyl)allyl acetate 1c: yellow solid, 172 mg, 66%,
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mp 55-56 oC (without recrystallization); IR v (cm-1) 1742; 1H NMR (400 MHz, CDCl3)
δ (ppm) 8.47 (d, J = 13.6 Hz, 1H), 7.43 (d, J = 13.6 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H),
7.33 (s, 1H), 7.29 (d, J = 8.0 Hz, 1H), 6.42 (dt, J = 5.2, 1.6 Hz, 1H), 5.95-6.04 (m, 1H),
5.26 (dd, J = 10.4, 0.8 Hz, 1H), 5.19 (dd, J = 18, 0.8 Hz, 1H), 2.37 (s, 3H), 2.09 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 169.8, 139.0, 138.1, 136.8, 136.5, 135.8,
132.8, 129.1, 128.6, 128.3, 117.9, 74.0, 21.1, 21.1; HRMS (TOF-ESI): [M + Na]+ calcd
for C14H15NO4Na: 284.0893, found: 284.0890.
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(E)-1-(4-Chloro-2-(2-nitrovinyl)phenyl)allyl acetate 1d: yellow solid, 197 mg, 70%,
mp 61-62 oC (without recrystallization); v (cm-1) 1738; 1H NMR (600 MHz, CDCl3) δ
(ppm) 8.40 (d, J = 13.2 Hz, 1H), 7.48 (s, 1H), 7.43-7.45 (m, 2H), 8.41 (d, J = 13.8 Hz,
1H), 6.39 (d, J = 6.6 Hz, 1H), 5.94-6.0 (m, 1H), 5.30 (d, J = 11.4 Hz, 1H), 5.20 (d, J =
13
16.8 Hz, 1H), 2.11 (s, 3H); C{1H} NMR (150 MHz, CDCl3) δ (ppm) 174.5, 145.6,
143.2, 140.9, 139.5, 138.8, 136.7, 135.7, 135.6, 133.2, 123.1, 77.9, 25.9; HRMS (TOF-
ESI): [M + Na]+ calcd for C13H12ClNO4Na: 304.0347, found: 304.0350.
(E)-1-(2-(2-Nitrovinyl)-4-(trifluoromethyl)phenyl)allyl acetate 1e: yellow solid, 221
mg, 70%, mp 118-119 oC(without recrystallization); v (cm-1) 1738;1H NMR (400 MHz,
CDCl3) δ (ppm) 8.45 (d, J = 13.2 Hz, 1H), 7.73 (s, 1H), 7.72 (d, J = 5.2 Hz, 1H), 7.63
(d, J = 8.8 Hz, 1H), 7.46 (d, J = 14.0 Hz, 1H), 6.45 (d, J = 5.6 Hz, 1H), 5.98 (m, 1H),
5.34 (dd, J = 10.4, 0.8 Hz, 1H), 5.23 (dd, J = 17.6, 1.2 Hz, 1H), 2.13 (s, 3H); 13C{1H}
NMR (150 MHz, CDCl3) δ (ppm) 169.6, 142.8, 139.6, 135.0, 134.7, 131.3 (q, J = 33
Hz), 129.6, 129.4, 128.1 (d, J = 2.9 Hz), 124.7 (d, J = 2.9 Hz), 123.4 (q, J = 270 Hz ),
119.0, 73.4, 20.9; HRMS (TOF-ESI): [M + Na]+ calcd for C14H12F3NO4Na: 338.0610,
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(E)-1-(5-methoxy-2-(2-nitrovinyl)phenyl)allyl acetate 1f: yellow solid, 166 mg, 60%,
mp 76-77 oC (without recrystallization); IR v (cm-1) 1739; 1H NMR (400 MHz, CDCl3)
δ (ppm) 8.41 (d, J = 13.2 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.41 (d, J = 14.0 Hz, 1H),
6.99 (d, J = 2.8 Hz, 1H), 6.88 (dd, J = 8.8, 2.8 Hz, 1H), 6.44 (dt, J = 5.2, 1.6 Hz, 1H),
5.94-6.03 (m, 1H), 5.29 (d, J = 10.8 Hz, 1H), 5.22 (d, J = 16.4 Hz, 1H), 3.85 (s, 3H),
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2.12 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ (ppm) 169.7, 162.7, 141.6, 136.4,
136.1, 135.5, 129.6, 120.7, 118.4, 114.5, 114.4, 73.8, 55.7, 21.1; HRMS (TOF-ESI): [M
+ Na]+ calcd for C14H15NO5Na: 300.0842, found: 300.0840.
(E)-1-(5-methyl-2-(2-nitrovinyl)phenyl)allyl acetate 1g: yellow solid, 180 mg, 69%,
mp 75-76 oC (without recrystallization); IR v (cm-1) 1742; 1H NMR (400 MHz, CDCl3)
δ (ppm) 8.47 (d, J = 14.0 Hz, 1H), 7.45 (s, 1H), 7.43 (d, J = 6.0 Hz, 1H), 7.29 (s, 1H),
7.19 (d, J = 7.6 Hz, 1H), 6.44 (dt, J = 5.2, 1.6 Hz, 1H), 5.97-6.05 (m, 1H), 5.29 (dd, J
= 11.2, 0.8 Hz, 1H), 5.21 (dd, J = 18.8, 0.8 Hz, 1H), 2.40 (s, 3H), 2.12 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ (ppm) 169.8 , 142.8, 139.2 , 137.5 , 136.6, 135.7 , 129.8 ,
127.8, 125.8, 118.1, 74.2, 21.7 , 21.2; HRMS (TOF-ESI): [M + Na]+ calcd for
C14H15NO4Na: 284.0893, found: 284.0890.
(E)-1-(5-Chloro-2-(2-nitrovinyl)phenyl)allyl acetate 1h: yellow solid, 206 mg, 73%,
mp 60-61 oC (without recrystallization); IR v (cm-1) 1746; 1H NMR (400 MHz, CDCl3)
δ (ppm) 8.38 (d, J = 13.6 Hz, 1H), 7.47 (s, 1H ), 7.46 (d, J = 6.8 Hz, 2H), 7.42 (d, J =
13.6 Hz, 1H), 7.34 (dd, J = 8.0, 2.0 Hz, 1H), 6.40 (dt, J = 5.6, 1.2 Hz, 1H), 5.91-6.0 (m,
1H), 5.30 (dd, J = 10.4, 0.8 Hz, 1H), 5.23 (dd, J = 16.4, 0.8 Hz, 1H), 2.12 (s, 3H);
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13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 169.7 , 141.0, 138.6, 138.1, 135.2 , 134.9,
129.2, 129.1,128.9,127.1, 118.8, 73.2 , 21.1; HRMS (TOF-ESI): [M + Na]+ calcd for
C13H12ClNO4Na: 304.0347, found: 304.0350.
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(E)-1-(2-(2-Nitrovinyl)-5-(trifluoromethyl)phenyl)allyl acetate 1i: yellow solid, 239
mg, 76%, mp 62-63 oC(without recrystallization);IR v (cm-1) 1746; 1H NMR (400 MHz,
CDCl3) δ (ppm) 8.45 (d, J = 13.6 Hz, 1H), 7.73 (s, 1H), 7.60-7.65 (m, 2H), 7.44 (d, J =
13.6 Hz, 1H), 6.46 (dt, J = 4.8, 1.6 Hz, 1H), 5.94-6.02 (m, 1H), 5.34 (dd, J = 10.8, 1.2
Hz, 1H), 5.24 (dd, J = 17.2, 1.2 Hz, 1H), 2.13 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ (ppm) 169.6, 140.1, 140.0, 135.0, 134.8, 133.4 (q, J = 32.5 Hz), 132.3, 128.4, 125.7
(d, J = 3.9 Hz), 125.6 (d, J = 3.8 Hz), 123.4 (q, J = 271.2 Hz), 119.0, 73.3, 21.0; HRMS
(TOF-ESI): [M + Na]+ calcd for C14H12F3NO4Na: 338.0610, found: 338.0613.
(E)-1-(6-(2-nitrovinyl)benzo[d][1,3]dioxol-5-yl)allyl acetate 1j: yellow solid, 204 mg,
70%, mp 105-106 oC (without recrystallization); IR v (cm-1) 1740; 1H NMR (400 MHz,
CDCl3) δ (ppm) 8.42 (d, J = 13.2 Hz, 1H), 7.37 (d, J = 13.2 Hz, 1H), 6.95 (d, J = 4 Hz,
2H), 6.42 (dt, J = 5.6, 1.6 Hz, 1H), 6.04 (s, 2H), 5.92-6.0 (m, 1H), 5.28 (dt, J = 9.6, 0.8
Hz, 1H), 5.21 (dd, J = 17.2, 1.6 Hz, 1H), 2.11 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ (ppm) 169.7 , 151.3, 148.3 , 136.9 , 135.8, 135.7, 135.6 , 122.2, 118.0, 108.9, 106.4,
102.3, 73.2, 21.1; HRMS (TOF-ESI): [M + Na]+ calcd for C14H13NO6Na: 314.0635,
found: 314.0632.
(E)-1-(3-(2-Nitrovinyl)pyridin-2-yl)allyl acetate 1k: yellow solid, 149 mg, 60%, mp
53-54 oC (without recrystallization); IR v (cm-1) 1744; 1H NMR (400 MHz, CDCl3) δ
(ppm) 8.70 (dd, J = 5.2, 2 Hz, 1H), 8.50 (d, J = 13.6 Hz, 1H), 7.81 (d, J = 8, 2 Hz, 1H),
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7.43 (d, J = 14 Hz, 1H), 7.34 (dd, J = 7.6, 4.4 Hz, 1H), 6.46 (d, J = 6 Hz, 1H), 6.09-
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6.17 (m, 1H), 5.33-5.38 (m, 2H), 2.13 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ
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(ppm) 169.9 , 157.2, 151.9 , 139.5 , 135.6, 134.5 , 134.0 , 124.8, 123.5, 119.0, 75.7,
21.0; HRMS (TOF-ESI): [M + Na]+ calcd for C12H12N2O4Na: 271.0689, found:
271.0692.
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2. General procedure for the enantioselective synthesis of 4-nitro-1-vinyl-1H-2,3-
benzodiazepine-2,3-dicarboxylates
5
from [Pd(C3H5)Cl]2/DIFLUORPHOS
catalyzed reaction of 1-(2-(2-nitrovinyl)aryl)allyl acetates and azodicarboxylates.
Under nitrogen atmosphere and at room temperature, 1-(2-(2-nitrovinyl)aryl)allyl
acetates 1 (0.2 mmol, 1.0 equiv.), thiazolium 3a (0.04 mmol, 20 mol%), DMAP (0.04
mmol, 20 mol%) and dry dichlormethane (0.5 mL) were added successively to a dry
Schlenk tube. After the mixture was stirred for 5 minutes, azodicarboxylates 2 (0.36
mmol, 1.8 equiv.) were added using a microsyringe. In the sealed Schlenk tube, the
reaction mixture was stirred for 12 h at room temperature. On the other hand, the
palladium catalyst was prepared in a glove box by mixing [Pd(C3H5)Cl]2 (14.6 mg, 0.04
mmol, 20 mol%) and (S)-DIFLUORPHOS (54.4 mg, 0.08 mmol, 40 mol%) in dry
DCM (0.75 mL) in an oven-dried test tube and was stirred for 2h at room temperature.
The Schlenk tube was then moved into the glove box, and pre-prepared palladium-
DIFLUORPHOS complex solution was added. The residual palladium catalyst in the
test tube was washed with 1.25 mL of dry acetone and was added to the reaction mixture.
The resulting reaction mixture in the sealed Schlenk tube was kept stirred for another
12 h at ambient temperature. The reaction was then quenched by removal of the solvents.
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The residue was chromatographed on a silica gel column eluting with a mixture of
petroleum ether and ethyl acetate (PE : EA from 5 : 1 to 3 : 1) to give products 5 in 48-
93% yields with er from 77:23 to 95:5.
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(S)-Dimethyl 4-nitro-1-vinyl-1H-2,3-benzodiazepine-2,3-dicarboxylate 5a: pale
yellow solid, 60 mg, 90%, 88:12 er, [α]20 +397.8 (c 0.5, CH2Cl2), mp 147-148oC
D
1
(recrystallization from ethyl ether/n-hexane); IR v (cm-1) 1775, 1736; H NMR (600
o
MHz, DMSO-d6, 70 C) δ (ppm) 7.75 (d, J = 7.2 Hz, 1H), 7.55 (s, 1H), 7.48 (td, J =
7.8, 1.2 Hz, 1H), 7.44 (td, J = 7.8, 1.8 Hz, 1H), 7.41 (d, J=7.8, 1H), 6.22 (d, J = 4.8 Hz,
1H), 5.95-6.00 (m, 1H), 5.31 (d, J = 9.6 Hz, 1H), 4.62 (d, J = 16.8 Hz, 1H), 3.72 (s,
3H), 3.62 (s, 3H); 13C{1H} NMR (150 MHz, DMSO-d6, 70 oC) δ (ppm) 154.5, 152.6,
145.3, 140.4, 136.5, 134.8, 131.5, 130.7, 128.8, 127.4, 123.0, 121.3, 66.2, 54.9, 54.5;
HRMS (TOF-ESI): [M + H]+ calcd for C15H16N3O6: 334.1033, found: 334.1031.
(S)-Dimethyl 7-methoxy-4-nitro-1-vinyl-1H-2,3-benzodiazepine-2,3-dicarboxylate
o
5b: yellow solid, 55 mg, 76%, 92:8 er, [α]20D +415.0 (c 0.5, CH2Cl2), mp 138-139 C
1
(recrystallization from ethyl ether/n-hexane); IR v (cm-1) 1769, 1713; H NMR (400
MHz, DMSO-d6, 70 oC) δ (ppm) 7.55 (s, 1H), 7.37 (d, J = 2.4 Hz, 1H), 7.30 (d, J = 8.4
Hz, 1H), 7.06 (dd, J = 8.8, 2.8 Hz, 1H), 6.16 (d, J = 5.6 Hz, 1H), 5.91-5.99 (m, 1H),
5.29 (d, J = 10 Hz, 1H), 4.62 (d, J = 17.6 Hz, 1H), 3.79 (s, 3H), 3.71 (s, 3H), 3.62 (s,
3H); 13C{1H} NMR (100 MHz, DMSO-d6, 70 oC) δ (ppm) 159.2, 154.5, 152.6, 145.5,
135.2, 132.4, 132.0, 128.5, 122.7, 121.4, 120.8, 117.8, 65.7, 56.1, 54.9, 54.5; HRMS
(TOF-ESI): [M + H]+ calcd for C16H18N3O7: 364.1139, found: 364.1136.
(S)-Dimethyl 7-methyl-4-nitro-1-vinyl-1H-2,3-benzodiazepine-2,3-dicarboxylate
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5c: yellow solid, 56 mg, 81%, 85:15 er, [α]20D +367.0 (c 0.5, CH2Cl2), mp 118-119 oC
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7
1
(recrystallization from ethyl ether/n-hexane); IR v (cm-1) 1767, 1738; H NMR (400
8
9
MHz, DMSO-d6, 70 oC) δ (ppm) 7.56 (s, 1H), 7.49 (s, 1H), 7.27-7.31 (m, 2H), 6.17 (d,
J = 5.6 Hz, 1H), 5.91-6.00 (m, 1H), 5.29 (d, J = 10.4 Hz, 1H), 4.62 (d, J = 17.6 Hz, 1H),
3.71 (s, 3H), 3.61 (s, 3H), 2.31 (s, 3H); 13C{1H} NMR (150 MHz, DMSO-d6, 70 oC) δ
(ppm) 154.5, 152.6, 145.2, 138.3.15, 137.5, 136.8, 135.1, 132.3, 130.7, 127.2, 122.8,
121.5, 65.9, 54.9, 54.5, 20.7; HRMS (TOF-ESI): [M + H]+ calcd for C16H18N3O6:
348.1190, found: 348.1187.
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(S)-Dimethyl 7-chloro-4-nitro-1-vinyl-1H-2,3-benzodiazepine-2,3-dicarboxylate
5d: yellow solid, 54 mg, 73%, 94:6 er, [α]20D +396.4 (c 0.59, CH2Cl2), mp 149-150 oC
1
(recrystallization from ethyl ether/n-hexane); IR v (cm-1) 1767, 1724; H NMR (400
MHz, DMSO-d6, 70 oC) δ (ppm) 7.96 (d, J = 2.4 Hz, 1H), 7.60 (s, 1H), 7.57 (dd, J =
8.4, 2.4 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 6.28 (d, J = 5.2 Hz, 1H), 5.95-6.03 (m, 1H),
5.37 (d, J = 10.0 Hz, 1H), 4.67 (d, J = 17.6 Hz, 1H), 3.76 (s, 3H), 3.67 (s, 3H); 13C{1H}
NMR (150 MHz, DMSO-d6, 70 oC) δ (ppm) 154.4, 152.4, 146.1, 139.2, 135.2, 134.4,
133.3, 132.5, 130.9, 129.5, 123.3, 119.6, 65.6, 55.0, 54.6; HRMS (TOF-ESI): [M + H]+
calcd for C15H15ClN3O6: 368.0643, found: 368.0644.
(S)-Dimethyl
4-nitro-7-trifluoromethyl-1-vinyl-1H-2,3-benzodiazepine-2,3-
dicarboxylate 5e: white solid, 49 mg, 61%, 95:5 er, [α]20D +390.6 (c 0.5, CH2Cl2), mp
o
1
129-130 C (recrystallization from ethyl ether/n-hexane); IR v (cm-1) 1761, 1730; H
NMR (400 MHz, DMSO-d6, 70 oC) δ (ppm) 8.24 (s, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.72
(s, 1H), 7.67 (d, J = 8.4 Hz, 1H), 6.35 (d, J = 6.0 Hz, 1H), 5.91-5.99 (m, 1H), 5.35 (d,
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J = 10.0 Hz, 1H), 4.65 (d, J = 17.2 Hz, 1H), 3.74 (s, 3H), 3.63 (s, 3H); 13C{1H} NMR
(150 MHz, DMSO-d6, 70 oC) δ (ppm) 154.4, 152.4, 146.3, 144.6, 134.1, 132.9, 131.8,
129.7 (q, J = 33 Hz), 128.6, 127.4, 124.2 (q, J = 270 Hz), 123.6, 119.5, 65.9, 55.1, 54.7,
HRMS (TOF-ESI): [M + H]+ calcd for C16H15F3N3O6: 402.0907; found: 402.0905.
(S)-Dimethyl 8-methoxy-4-nitro-1-vinyl-1H-2,3-benzodiazepine-2,3-dicarboxylate
5f: yellow solid, 64 mg, 88%, 92:8 er, [α]20D +397.4 (c 0.5, CH2Cl2), mp 137-138 oC
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(recrystallization from ethyl ether/n-hexane); IR v (cm-1) 1770, 1732; H NMR (400
MHz, DMSO-d6, 70 oC) δ (ppm) 7.71 (d, J = 8.4 Hz, 1H), 7.57 (s, 1H), 7.03 (d, J = 2.8
Hz, 1H), 7.00 (s, 1H), 6.20 (d, J = 5.2 Hz, 1H), 5.91-5.99 (m, 1H), 5.31 (d, J = 10.0 Hz,
1H), 4.70 (d, J = 16.8 Hz,1H), 3.81 (s, 3H), 3.70 (s, 3H), 3.62 (s, 3H); 13C{1H} NMR
(150 MHz, DMSO-d6, 70 oC) δ (ppm) 162.1, 154.6, 152.7, 143.3, 142.7, 138.8, 134.6,
122.8, 122.0, 120.0, 116.4, 114.6, 66.0, 56.2, 54.7, 54.5; HRMS (TOF-ESI): [M + H]+
calcd for C16H18N3O7: 364.1139, found: 364.1141.
(S)-Dimethyl 8-methyl-4-nitro-1-vinyl-1H-2,3-benzodiazepine-2,3-dicarboxylate
5g: yellow solid, 58 mg, 84%, 87:13 er, [α]20D +372.2 (c 0.5, CH2Cl2), mp 117-118 oC
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(recrystallization from ethyl ether/n-hexane); IR v (cm-1) 1769, 1710; H NMR (400
MHz, DMSO-d6, 70 oC) δ (ppm) 7.64 (d, J = 7.6 Hz, 1H), 7.54 (s, 1H), 7.25 (d, J = 7.6
Hz, 1H), 7.23 (s, 1H), 6.16 (d, J = 6.0 Hz, 1H), 5.92-6.00 (m, 1H), 5.31 (d, J = 10.4 Hz,
1H), 4.65 (d, J = 16.8 Hz, 1H), 3.71 (s, 3H), 3.62 (s, 3H), 2.33 (s, 3H); 13C{1H} NMR
(150 MHz, DMSO-d6, 70 oC) δ (ppm) 154.6, 152.6, 144.6, 142.1, 140.4, 136.6, 134.7,
131.3, 129.6, 124.7, 122.9, 121.6, 66.1, 54.8, 54.5, 21.3; HRMS (TOF-ESI): [M + H]+
calcd for C16H18N3O6: 348.1190, found: 348.1192.
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The Journal of Organic Chemistry
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(S)-Dimethyl 8-chloro-4-nitro-1-vinyl-1H-2,3-benzodiazepine-2,3-dicarboxylate
5h: pale yellow solid, 51 mg, 69%, 90:10 er, [α]20D +393.8 (c 0.5, CH2Cl2), mp 114-115
oC (recrystallization from ethyl ether/n-hexane); IR v (cm-1) 1751, 1730; 1H NMR (400
MHz, DMSO-d6, 70 oC) δ (ppm) 7.80 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 2.4 Hz, 2H), 7.51
(dd, J = 8.8, 2.4 Hz, 1H), 6.27 (d, J = 5.6 Hz, 1H), 5.90-5.99 (m, 1H) 5.35 (d, J = 10.4
Hz, 1H), 4.67 (d, J = 16.8 Hz, 1H), 3.72 (s, 3H), 3.63 (s, 3H); 13C{1H} NMR (150 MHz,
DMSO-d6, 70 oC) δ (ppm) 154.4, 152.5, 145.5, 142.5, 138.0, 136.5, 134.3, 130.3, 128.9,
126.5, 123.5, 120.0, 65.5, 55.0, 54.6; HRMS (TOF-ESI): [M + H]+ calcd for
C15H15ClN3O6: 368.0643, found: 368.0643.
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(S)-Dimethyl
4-nitro-8-trifluoromethyl-1-vinyl-1H-2,3-benzodiazepine-2,3-
dicarboxylate 5i: white solid, 52 mg, 65%, 90:10 er, [α]20D + 317.3 (c 0.25, CH2Cl2),
mp 109-110 oC (recrystallization from ethyl ether/n-hexane); IR v (cm-1) 1769, 1732;
1H NMR (400 MHz, DMSO-d6, 70 oC) δ (ppm) 7.99 (d, J = 8.0 Hz, 1H), 7.85 (s, 1H),
7.77 (dd, J = 8.0, 1.2 Hz, 1H), 7.61 (s, 1H), 6.41 (d, J = 6.0 Hz, 1H), 5.92-6.01 (m, 1H),
5.35 (d, J = 10.4 Hz, 1H), 4.63 (d, J = 17.6 Hz, 1H), 3.74 (s, 3H), 3.63 (s, 3H); 13C{1H}
NMR (150 MHz, DMSO-d6, 70 oC) δ (ppm) 154.4, 152.4, 146.7, 141.6, 137.1, 134.3,
131.4, 130.9 (q, J = 31.7 Hz), 127.2 (d, J = 2.9 Hz), 125.3 (d, J = 3 Hz), 124.2 (q, J =
271.5 Hz), 123.5, 119.1, 65.7, 55.1, 54.7; HRMS (TOF-ESI): [M + H]+ calcd for
C16H15F3N3O6: 402.0907, found: 402.0910.
(S)-Dimethyl
8-nitro-5-vinyl-5H-1,3-dioxolo[4,5-h][2,3]benzodiazepine-6,7-
dicarboxylate 5j: yellow solid, 70 mg, 93%, 89:11 er, [α]20D + 426 (c 0.25, CH2Cl2),
mp 135-136 oC (recrystallization from ethyl ether/n-hexane); IR v (cm-1) 1771, 1709;
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