Formation of Amidinyl Radicals via Visible-Light-Promoted Reduction of N-Phenyl Amidoxime Esters and Application to the Synthesis of 2-Substituted Benzimidazoles

Article abstract of DOI:10.1021/acs.joc.9b01158

We have developed a new method for the synthesis of 2-substituted benzimidazoles via amidinyl radicals generated by visible-light-promoted reduction of N-phenyl amidoxime esters in the presence of an iridium photocatalyst. This is the first report of the use of N-phenyl amidoxime esters as amidinyl radical precursors, and the first use of substituted benzene rings as amidinyl radical acceptors. This method widens the application range of substrates and overcomes the shortcomings of the traditional methods for the synthesis of 2-substituted benzimidazoles, which requires harsh reaction conditions, involves difficult-to-prepare substituted o-phenylenediamine substrates, and produces acidic waste.

Full text of DOI:10.1021/acs.joc.9b01158

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Article
Formation of Amidinyl Radicals via Visible-Light-Promoted Reduction of N-Phenyl
Amidoxime Esters and Application to the Synthesis of 2-Substituted Benzimidazoles
Gang Li, Ru He, Qiang Liu, Ziwen Wang, Yuxiu Liu, and Qingmin Wang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01158 • Publication Date (Web): 14 Jun 2019
Downloaded from http://pubs.acs.org on June 14, 2019
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Formation of Amidinyl Radicals via Visible-Light-Promoted Reduction of N-Phenyl Amidoxime Esters and
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Application to the Synthesis of 2-Substituted Benzimidazoles
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Gang Li,† Ru He,† Qiang Liu,† Ziwen Wang,‡,* Yuxiu Liu,†,* Qingmin Wang†,*
†State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, College of Chemistry,
Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin 300071, China
‡Tianjin Key Laboratory of Structure and Performance for Functional Molecules, MOE Key Laboratory of Inorganic–Organic Hybrid
Functional Material Chemistry, College of Chemistry, Tianjin Normal University, Tianjin Normal University, Tianjin 300387, China
LG
O
N
R2
N
Visible light
R2
N
H
R1
R1
N
PC
H
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ABSTRACT. We have developed a new method for the synthesis of 2-substituted benzimidazoles via amidinyl radicals generated by
visible-light-promoted reduction of N-phenyl amidoxime esters in the presence of an iridium photocatalyst. This is the first report of
the use of N-phenyl amidoxime esters as amidinyl radical precursors, and the first use of substituted benzene rings as amidinyl
radical acceptors. This method widens the application range of substrates and overcomes the shortcomings of the traditional
methods for synthesis of 2-substituted benzimidazoles, which require harsh reaction conditions, involve difficult-to-prepare
substituted o-phenylenediamine substrates, and produce acidic waste.
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INTRODUCTION
Benzimidazole is a privileged structural motif because of its various biological activities, including anticancer,1 antimicrobial,2
antiviral,3 and antidiabetes activities.4 The motif is found in many pharmaceutical and agrochemical products, such as the fungicides
thiabendazole and carbendazim, the anthelmintics albendazole and mebendazole, and the proton pump inhibitor omeprazole (Figure
1).5 Therefore, numerous methods for synthesis of the benzimidazole scaffold have been established. The conventional methods,
which involve condensation of substituted o-phenylenediamines with carboxylic acids and their derivatives6 or condensation via
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oxidative cyclization of o-phenylenediamines with appropriate aldehydes (Figure 2, path a),7 usually require strongly acidic conditions,
high temperatures, or stoichiometric oxidants. Furthermore, the necessary substituted o-phenylenediamines are often difficult to
prepare. An alternative method involving oxidative cyclocondensation of o-phenylenediamines with primary amines,8 alcohols,9
halides,10 and even methylarenes11 was recently reported, but this method also requires harsh reaction conditions. Thus, a mild,
environmentally friendly method for synthesizing benzimidazoles remains to be developed.
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Figure 1. Chemical structures of thiabendazole, carbendazim, albendazole, mebendazole, and omeprazole.
O
N
O
O
O
N
O
S
N
O
N
N
N
O
N
NH
S
NH
NH
N
H
S
N
H
O
O
N
H
N
H
N
H
O
Thiabendazole
Albendazole
Mebendazole
Omeprazole
Carbendazim
Figure 2. Synthesis strategy of benzimidazole.
Path a: Condensation of o-phenylenediamines with carboxylic acids and their derivatives Path b: Synthesis of benzimidazoles via oxidation promoted by phenyliodine(III) diacetate (PIDA)
NH2
H
N
H
N
Z
High temperature, strong acid
N
R2
PIDA (1.1 equiv), Cs2CO3 (1.1 equiv)
R1
R
+
R
R1
R2
R1
R1
X
N
H
NH2
NH
TFE, 25 °C, 1.5 h
N
Path c: Synthesis of benzimidazoles via electrolysis
This work:
LG
O
H
NH
N
N
R3
N
R2
R2
R1
Electrolysis
R3
N
Visible light
R2
N
N
R2
MeOH, Et4NPF6 (1 equiv),
reflux
H
R1
N
H
N
R1
PC
O
N
R1
O
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One possibility that has been explored is the use of nitrogen-centered radicals, such as iminyl and amidinyl radicals. During recent
decades, iminyl radicals have frequently been utilized to synthesize azaheterocycles because the cyclizations of these radicals are
intrinsically faster, and their reductions slower, than those of aminyl radicals.12 Methods for producing iminyl radicals include direct
cleavage of N–X, N–N, N–O, N–S, and even N–H bonds, and indirect generation by the addition of other radical species to cyano
groups.13 In particular, oxime derivatives (e.g., oxime esters and oxime ethers), which have comparatively weak N–O bonds, have
been widely used as precursors of iminyl radicals.14 Recently, the research groups of Leonori,15 Yu,16 Loh,17 and Studer18 carried out
pioneering work on visible-light-promoted electron-transfer reactions that produce iminyl radicals from oxime derivatives and can be
used to construct nitrogen-containing heterocycles in an efficient and environmentally friendly manner.
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Amidinyl radicals, which are analogous to iminyl radicals, are useful intermediates for the synthesis of imidazolines and imidazoles,
as reported by Zard.19 However, to generate amidinyl radicals from amidoxime benzoates, these investigators employed a hazardous
stannane–diazo initiator. Subsequently, Selander carried out a series of transition-metal-catalyzed cascade reactions involving
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intramolecular cyclization/functionalization reactions between amidinyl radicals and C–C double bonds to synthesize functionalized
imidazolines.20 There have been a few reports of the use of amidinyl radicals to synthesize benzimidazoles. For instance, Zhu
reported that benzimidazoles can be synthesized by means of direct C(sp2)–H imidation of N-arylamidines promoted by
phenyliodine(III) diacetate (Figure 2, path b), and these investigators proposed a pathway involving an amidinyl radical
intermediate.21a However, electron-rich groups that are easily oxidized are not suitable for their systems. Punniyamurthy reported the synthesis
of benzimidazoles via iodobenzene catalyzed C-H amination of N-substituted amidines using m-chloroperbenzoic acid.21b This
method can only be used to synthesize N-sulfonyl or N-aryl substituted benzimidazoles and it can't contain nitro group. Finally, Xu
obtained functionalized tetracyclic benzimidazoles by means of efficient, straightforward electrolytic cleavage of N–H bonds via
amidinyl radical intermediates (Figure 2, path c).22 A specific 1-benzyl-4-imino-3-phenyl-3,4-dihydroquinazolin-2(1H)-one structure was used
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for their electrochemical reaction system. When the substrate was changed into 2-fluoro-N-methyl-N-phenylbenzimidamide, the yield decreased
significantly.
However, there are only a few methods for generating amidinyl radicals, and new methods are urgently needed if the their reactions
are to be explored further. In light of the above-described previous work, we hypothesized that visible-light-promoted electron-transfer
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might be an effective strategy for reducing the N–O bonds of N-phenyl amidoxime esters to provide amidinyl radicals, which could
then undergo intramolecular homolytic aromatic substitution, oxidation, and deprotonation to afford benzimidazoles. In fact, this
strategy proved feasible and afforded 2-substituted benzimidazoles. To our knowledge, the generation of amidinyl radicals via visible-
light-promoted reduction of amidoxime esters has not previously been reported.
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RESULTS AND DISCUSSION
We chose N-phenyl-N'-((4-(trifluoromethyl)benzoyl)oxy) benzimidamide (1a, for the preparation scheme see Supporting
Information) as a model substrate for experiments aimed at optimizing the reaction conditions (Table 1). To our delight, we found that
target product 2a could be obtained in 45% yield by irradiation of 1a with a 13 W white LED light for 12 h at room temperature in DMF
in the presence of Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2%) as a photocatalyst (entry 1). None of the other photocatalysts that we evaluated
gave better results (entrys 2–5). When the amount of photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 was decreased, the substrate was
completely consumed; a photocatalyst loading of 1% was sufficient, although the yield was somewhat lower (entry 6). We next
screened a variety of solvents. Polar aprotic solvents (DMSO and CH3CN, entries 7 and 8) and the polar protonic solvent
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(CF3)2CHOH (entry 9) decreased the yield, and the chlorinated solvent 1,2-dichloroethane did not improve the yield (entry 10). To our
surprise, changing the solvent to methyl tert-butyl ether dramatically increased the yield (to 68%, entry 11) and was more suitable
than other ethers (dimethoxyethane, THF, and 1,4-dioxane; entries 12–14). All attempts to improve the yield further by varying the
light source (entries 15–17), increasing the photocatalyst loading (entry 18), or decreasing the substrate concentration (entry 19)
failed. Finally, in the absence of a photocatalyst or light (entries 20 and 21), no reaction occurred, which indicates that both the
photocatalyst and light were indispensable. As a control, we also tried the reaction conditions of Zhu21a and Punniyamurthy21b (entries
22 and 23). Compound 1A was decomposed under the above conditions. Using the optimized reaction conditions (entry 11), we
evaluated other O-acyl amidoxime substrates as potential amidinyl radical precursors (Table 2) and found that the p-
trifluoromethylbenzoate acyl group gave the best yield, which confirmed the wisdom of our choice of p-trifluoromethylbenzoate as a
leaving group. The reaction of 1a is easy to upscale to gram scale, with 2a isolated in 61% yield on a 6 mmol scale under the
optimized reaction conditions (Table 1, entry 11).
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Table 1. Optimization of conditions for the synthesis of 2-substituted benzimidazoles via amidinyl radicals.[a]
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LG
O
photocatalyst (x mol%)
solvent
N
N
5
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N
H
N
H
light, Argon
rt.
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9
1a
2a
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Time
(h)
Yield
(%)[b]
Entry
Photocatalyst
Solvent
Light
1
2
Ir[dF(CF3)ppy]2(dtbbpy)PF6(2%)
Ru(bpy)3(PF6)2(2%)
DMF
DMF
13 W white LED
13 W white LED
13 W white LED
13 W white LED
13 W white LED
13 W white LED
13 W white LED
13 W white LED
12
20
20
20
20
12
36
36
36
36
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36
45
N.R. [c]
N.P.[d]
N.R.
N.R.
31
3
Ir(ppy)3(2%)
DMF
4
Ir(ppy)2(dtbbpy)PF6(2%)
Eosin Y(2%)
DMF
5
DMF
6
Ir[dF(CF3)ppy]2(dtbbpy)PF6(1%)
Ir[dF(CF3)ppy]2(dtbbpy)PF6(1%)
Ir[dF(CF3)ppy]2(dtbbpy)PF6(1%)
DMF
7
DMSO
CH3CN
13
8
21
9
Ir[dF(CF3)ppy]2(dtbbpy)PF6(1%) (CF3)2CHOH 13 W white LED
trace
26
10
11
12
Ir[dF(CF3)ppy]2(dtbbpy)PF6(1%)
Ir[dF(CF3)ppy]2(dtbbpy)PF6(1%)
Ir[dF(CF3)ppy]2(dtbbpy)PF6(1%)
DCE
MTBE
DME
13 W white LED
13 W white LED
13 W white LED
68
31
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Ir[dF(CF3)ppy]2(dtbbpy)PF6(1%)
THF
dioxane
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
TFE
13 W white LED
36
36
36
36
36
36
36
36
36
1.5
12
31
58
Ir[dF(CF3)ppy]2(dtbbpy)PF6(1%)
Ir[dF(CF3)ppy]2(dtbbpy)PF6(1%)
Ir[dF(CF3)ppy]2(dtbbpy)PF6(1%)
Ir[dF(CF3)ppy]2(dtbbpy)PF6(1%)
Ir[dF(CF3)ppy]2(dtbbpy)PF6(2%)
13 W white LED
5 W blue LED
5 W green LED
23 W white CFL
13 W white LED
13 W white LED
13 W white LED
/
63
N.R.
56
9
10
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18
19
20
21
22
23
55
19[e] Ir[dF(CF3)ppy]2(dtbbpy)PF6(2%)
66
20
21
/
N.R.
N.R.
N.P.
N.P.
Ir[dF(CF3)ppy]2(dtbbpy)PF6(1%)
22[f]
23[g]
PIDA
/
mCPBA
HFIP
/
a Reaction conditions, unless otherwise noted: 1a (0.2 mmol, 1 equiv), 1 mL DMF, Ar atmosphere, 13 W white LED, rt, LG = 4-(trifluoromethyl)benzoyl.
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b
c
Abbreviations: DME, dimethoxyethane; HFIP, (CF3)2CHOH; MTBE, methyl tert-butyl ether. Isolated yields are provided. N.R. = no reaction. 2 mL of
MTBE was used. d N.P. = No Product. e 2 mL MTBE. f 1a (0.2 mmol), PIDA (1.1 equiv), Cs2CO3 (1.1 equiv), in TFE (1 mL), at 0 oC under air for 1.5 h.21a
g la (0.5 mmol), iodobenzene (20 mol %), mCPBA (1.5 equiv), HFIP (1 mL), rt.21b
Table 2. Screening of Acyl Groups[a]
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2
CF3
NO2
CN
3
4
O
O
O
5
6
O
O
N
O
N
N
7
8
9
N
N
H
N
H
H
1a
1ba
1ca
68%
F
trace
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20%
O
F
F
F
O
O
O
O
N
O
N
O
F
N
N
H
N
H
N
H
1da
1fa
N.R.
1ea
N.R.
trace
a Conditions: 1 (0.2 mmol, 1 equiv), 1 mL MTBE, Argon atmosphere, 13 W white LED, at room temperature for 36 h, the yields given in the table are all separation
yields.
Next, we investigated the substrate scope of the reaction (Scheme 1) by subjecting various N-phenyl-N'-((4-
(trifluoromethyl)benzoyl)oxy) imidamides to the optimized reaction conditions (Table 1, entry 11). Substrates bearing a variety of
para-substituted phenyl groups at R1 (e.g., alkyl, alkoxyl, cyano, nitro, halogen) were satisfactory (2b–2k). Substrates with electron-
donating para substituents (2b and 2c) gave yields comparable to those obtained with most of the substrates bearing electron-
withdrawing groups (2d, 2e, 2g, 2h, and 2j but not 2f and 2i), which suggests that the electronic nature of the substituent had no
obvious effect on the reaction. The nitro group (2e) and amido group (2p) are also tolerated. The location of the substituent on the
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phenyl ring had a noticeable effect on reactivity. For instance, an ortho-chloro substrate gave a lower yield (2k, 12%) than the
corresponding para- and meta-chloro substrates (2g, 60%; 2j, 53% , respectively). When R1 was a ring-fused phenyl group or some
other aryl group, the corresponding 2-substituted benzimidazoles were obtained in good yields (2n–2o). Furthermore, R1 could be an
electron-withdrawing group such as an ester (2q), although the yield was only moderate. However, when R1 was an alkyl group (2r),
none of the desired product was obtained, perhaps because the oxidation–reduction potential of the substrate was incompatible with
the excited-state potential of Ir[dF(CF3)ppy]2(dtbbpy)PF6 (E1/2IV/*III = −0.96 V vs. SCE).
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Scheme 1. Scope of the reaction with respect to the R1 group of the substrate.
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LG
O
1
2
3
N
N
Ir[dF(CF3)ppy]2(dtbbpy)PF6 (1%)
R1
4
5
6
7
N
H
R1
N
H
MTBE (1 mL)
13W white LED
Argon, rt.
1
2
8
9
N
N
N
N
10
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R
N
H
N
H
H
Cl
Cl
2j 53%
2k 12%
2b R = CH3 57%
2c R = OCH3 59%
2d R = CN 65%
2e R = NO2 63%
2f R = F 18%
2g R = Cl 60%
2h R = Br 60%
2i R = OCF3 33%
O
N
N
O
N
H
N
H
2l 73%
2m 77%
N
O
N
N
N
H
N
H
O
2o R = COOCH3 60%
2p R = NHCOCH3 33%
N
H
2n 72%
2q 39%
2r N.R.
We also evaluated the effects of substituents R2 on the benzene ring of the radical acceptor moiety of the substrate (Scheme 2).
The weak electron-donating para-alkyl substituents (2aa and 2ac) gave better yields than halogens (2ad, 2ae and 2af) or an electron-
donating heteroatom (2ab). The results showed that the para-alkyl substituents were beneficial to the reaction. A substrate with a
meta-methyl group gave an approximately 1:1 mixture of two substituted benzimidazole products (2ag and 2ag. The ortho-methyl-
substituted substrate gave 2ah as the sole product (34%). Substrates with 3,4-dichloro-, 3,5-dimethyl-, and 2,4-dimethoxy-substituted
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benzene rings afforded moderate yields of the desired products, but substrate with a 3,4-dioxamethylene-substituted benzene ring
gave only a trace of desired product 2ai. Due to the influence of ring tension, the power supply capability of oxygen atom decreases
greatly. The results for the lack of 2ai may be attributed to the effect of electronic effect on benzene ring. The 3,4-dichloro-substituted
substrate gave two different benzimidazole products (2aj and 2aj) in a 1:0.9 ratio.
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Scheme 2. Scope of the reaction with respect to the radical acceptor benzene ring.
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LG
O
1
2
3
N
R2
Ir[dF(CF3)ppy]2(dtbbpy)PF6 (1%)
R2
N
4
5
6
7
N
N
MTBE (1 mL)
13W white LED
Argon, rt.
H
H
8
9
O
F
N
N
N
N
10
11
12
13
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N
H
2aa
N
H
2ab
N
H
2ac
N
H
2ad
67%
45%
31%
54%
32%
30%
Cl
Br
N
N
N
N
N
N
H
2af
N
H
2ag'
N
H
2ag''
H
2ae
32%
31%
Cl
N
O
O
N
Cl
Cl
Cl
N
N
N
N
H
trace
H
N
H
N
H
2ai
2ah
34%
2aj'
2aj' 2aj''
2aj''
+
= 23% 1: 0.9
O
N
N
N
H
N
H
O
2ak
2al
20%
49%
Finally, we evaluated the utility of this new method by applying it to the synthesis of the fungicide thiabendazole (8, Scheme 3).
Specifically, thiazole-4-formaldehyde oxime (4) was obtained quantitatively by condensation of thiazole-4-formaldehyde (3) with
hydroxylamine hydrochloride. Intermediate 4 was chlorinated with N-chlorosuccinimide to afford intermediate 5 (83%), which reacted
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with aniline to give compound 6 in 47% yield. Acylation of 6 with 4-trifluoromethyl benzoyl chloride gave key intermediate 7 (82%).
Subjecting 7 to the optimized reaction conditions gave thiabendazole (8) in 40% yield. Current work provides a reference for the
development of the clean production of thiabendazole.
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Scheme 3. Synthesis of the fungicide thiabendazole.
NH2
N OH
H
N OH
Cl
N
N
N
·
NH2OH
HCl
NCS, DMF
rt
CHO
S
S
S
Et3N, THF, 60°C
Py, EtOH, rt
3
5 83%
4 >99%
only one isomer
E/Z = 2:1
CF3
OH
N
O
F3C
COCl
N
N
N
S
Ir[dF(CF3)ppy]2(dtbbpy)PF6 (1%)
N
O
N
Et3N
H
S
N
DCM, rt
MTBE (1 mL)
13W white LED
rt.
6 47%
E/Z = 7.6:1
H
N
S
N
H
Thiabendazole (8)
40%
7 82%
Having explored the substrate scope and utility of the reaction, we turned our attention to the mechanism (Scheme 4). To confirm
that the reaction involved an amidinyl radical, we carried out free-radical-trapping experiments with 1a under the optimal conditions
for 36 h. When TEMPO (either 2 or 0.5 equiv) was added to the system, the formation of product 2a was not detected by TLC,
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indicating that the reaction did not occur in the presence of the radical trap. When BHT was used as a free-radical scavenger, the
reaction did occur, but the yield was markedly reduced. To eliminate the possibility that the process involved chain reactions of free
radicals, we carried out a light/dark experiment with substrate 1i, using trifluorotoluene as an internal standard and 19F NMR to track
product formation. The reaction was carried out under the standard conditions except that the light was turned on or off every 2 h. A
plot of the product yield versus time showed that the reaction proceeded when the light was on but stopped when it was off. This
result indicates that the reaction was a single-electron-transfer process catalyzed by visible light and that it did not involve chain
reactions of free radicals.
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Scheme 4. Mechanistic experiments.
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CF3
O
Ir[dF(CF3)ppy]2(dtbbpy)PF6 (1%)
N
O
+
TEMPO
4
N
MTBE (0.5 mL)
13W white LED
r.t.
N
H
5
6
7
N
H
2a
off
1a
0.1 mmol
A: 2 equiv
A: N.R.
B: 0.5 equiv
B: trace
on
8
off
CF3
9
O
on
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O
Ir[dF(CF3)ppy]2(dtbbpy)PF6 (1%)
N
N
off
BHT
+
MTBE (0.5 mL)
13W white LED
r.t.
N
N
H
2a
H
on
1a
0.1 mmol
2 equiv
31%
CF3
O
O
N
Ir[dF(CF3)ppy]2(dtbbpy)PF6 (1%)
N
OCF3
MTBE (0.5 mL)
13W white LED
r.t.
N
N
H
H
F3CO
1i
0.1 mmol
Figure 3. Possible mechanisms.
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R
O
N
1
2
O
3
4
5
N
H
*
IrIII
I
visible light
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7
SET
•
N
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9
N
H
II
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RCO2
V
IrIII
IrIV
RCO2
SET
H
H
N
N
N
•
N
H
III
N
H
IV
N
H
RCO2
V
IrIV
SET
N
N
•
RCO2H
N
H
IV'
N
H
IrIII
On the basis of the above-described experiments, we propose the possible reaction mechanisms shown in Figure 3. First, visible-
light irradiation converts the photocatalyst to an excited-state (IrIII*) species. Then the excited-state photocatalyst transfers an electron
to substrate I, which undergoes N–O bond cleavage to form amidinyl radical intermediate II and carboxylate ion V. The N-centered
radical II reacts with the adjacent benzene ring to form intermediate III. The electron-deficient photocatalyst, which is strongly
oxidizing, extracts an electron from III to generate cationic intermediate IV. This single-electron transfer restores the photocatalyst to
the ground state, completing the photocatalytic cycle. The benzimidazole product is generated by aromatization of intermediate IV
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accompanied by extraction of a proton by carboxylate ion V. Of course, we cannot rule out the possibility that intermediate III loses a
proton to carboxylate anion V and is then oxidized by the photocatalyst to give the benzimidazole.
CONCLUSION
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In conclusion, we have developed a new method for the synthesis of 2-substituted benzimidazoles from N-phenyl amidoxime esters
via amidinyl radicals generated by visible-light irradiation in the presence of an Ir catalyst. This is the first report of the use of N-aniline
oxime esters as amidinyl radical precursors and the use of substituted benzene rings as amidinyl radical acceptors. The electron-rich
groups that are easily oxidized and nitro group, which are intolerable by reported methods,21 also can give designed products with good
yield. The method described herein does not suffer from the shortcomings of traditional methods for synthesis of 2-substituted
benzimidazoles, which include harsh reaction conditions, the difficulty of preparing the necessary substituted o-phenylenediamine
substrates, and production of acidic waste.
EXPERIMENTAL SECTION
General Methods and Materials. Reagents were purchased from commercial sources and were used as received. The melting points of the
products were determined on an X-4 binocular microscope (Gongyi Yuhua Instrument Co., China) and the thermometer was not corrected. NMR
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spectra were acquired with a Bruker 400 MHz (100 MHz for 13C {1H}) instrument at room temperature. Chemical shifts were measured relative to
residual solvent peaks of CDCl3 (1H: δ = 7.26 ppm; 13C {1H}: δ = 77.0 ppm) with tetramethylsilane as internal standards. The following
abbreviations were used to designate chemical shift multiplicities: s = singlet, d = doublet, t = triplet, m = multiplet, and bs = broad singlet. All
first-order splitting patterns were assigned on the basis of multiplet appearance. Splitting patterns that could not be easily interpreted were
designated multiplet (m) or broad (br). HRMS data were obtained with an FT-ICR MS spectrometer (Ionspec, 7.0 T). Analytical TLC was
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performed on silica gel GF 254. Column chromatographic purification was performed using silica gel. White LED (13 W), blue LED (5 W, λmax
470 nm), green LED (5 W, λmax = 550 nm) and white CFL (5 W) were purchased from JIADENG (LS) and used for light irradiation.
The structures of S-I, S-II and S-III and detailed preparation route of intermediates S-II and S-III can be seen in Support Information.
Preparation of Chloraldoxime S-II.
=
Method 1: To the solution of aldoxime S-I (10 mmol) in dichloromethane and isopropanol (v/v 4:1) 50 mL was added dropwise tert-butyl
o
hypochlorite (15 mmol) at -10 C. The reaction mixture was stirred for 3 h to give the solution of S-II, which was directly used to the next step
without further purification.
Method 2: To the solution of NCS (11 mmol) in DMF (5 mL) was added dropwise the solution of aldoxime (10 mmol) in DMF. And the
solution was heated with oil bath to 50 oC and stirred for 1 h. Then the solution was concentrated. The residue was taken into water (50 mL) and
extracted with ethyl acetate (70 mL×3). The combined organic layer was washed with H2O (25 mL×2), brine (25 mL×2), dried with anhydrous
Na2SO4, and concentrated. The residue was directly used to the next step without further purification.
Preparation of Aminoximes S-III.23
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To the solution of chloraldoxime S-II (10 mmol) in THF (50 mL) was added dropwise corresponding amines and triethylamine. The mixture
2
3
4
5
o
was heated with oil bath to 60 C and stirred at for 12 h, cooled to room temperature, and filtered. The filtrate was concentrated and purified by
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9
flash column chromatography to afford aminoximes S-III.
(E)-N’-Hydroxy-N-phenylbenzimidamide (S-IIIa)
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Chromatography (Petroleum ether:EtOAc 20:1 to 12:1), white solid, 0.95 g, yield 45%, mp. 136−137 ℃ (lit. 23a: mp. 132−134 ℃). 1H NMR (400
MHz, CDCl3) δ 7.47 – 7.41 (m, 2H), 7.37 (t, J = 7.2 Hz, 1H), 7.31 (t, J = 7.2 Hz, 2H), 7.10 (t, J = 7.6 Hz, 2H), 6.92 (t, J = 7.6 Hz, 1H), 6.67 (d, J =
7.6 Hz, 2H).13C {1H} NMR (100 MHz, CDCl3) δ 152.0, 139.7, 131.1, 129.7, 128.8, 128.4, 128.4, 122.7, 121.3.
(E)-N'-Hydroxy-4-methyl-N-phenylbenzimidamide (S-IIIb)
Chromatography (Petroleum ether:EtOAc 20:1 to 12:1), white solid, 0.86 g, yield 38%, mp. 124−125 ℃ (lit. 23a: mp. 119−120 ℃). 1H NMR (400
MHz, CDCl3) δ 7.32 (d, J = 8.0 Hz, 2H), 7.14 – 7.06 (m, 4H), 6.92 (t, J = 7.2 Hz, 1H), 6.67 (d, J = 7.2 Hz, 2H), 2.33 (s, 3H). 13C {1H} NMR (100
MHz, CDCl3) δ 152.0, 139.9, 139.7, 129.2, 128.7, 128.3, 128.0, 122.7, 121.4, 21.4. HR-MS (ESI): Calcd for C14H15N2O [M+H]+ 227.1179, found
227.1180.
(E)-N'-Hydroxy-4-methoxy-N-phenylbenzimidamide (S-IIIc)
Chromatography (Petroleum ether:EtOAc 20:1 to 12:1), white solid, 1.04 g, yield 43%, mp. 120−121 ℃ (lit. 23a: mp. 102−104 ℃). 1H NMR (400
MHz, CDCl3) δ 7.37 (d, J = 8.4 Hz, 2H), 7.11 (t, J = 7.6 Hz, 2H), 6.92 (t, J = 7.6 Hz, 1H), 6.82 (d, J = 8.4 Hz, 2H), 6.68 (d, J = 8.0 Hz, 2H), 3.80
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(s, 3H). C {1H} NMR (100 MHz, CDCl3) δ 160.7, 151.7, 139.9, 129.8, 128.7, 123.4, 122.6, 121.3, 113.8, 55.3. HR-MS (ESI): Calcd for
3
4
5
C14H15N2O2 [M+H]+ 243.1128, found 243.1129.
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(E)-4-Cyano-N'-hydroxy-N-phenylbenzimidamide (S-IIId)
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9
Chromatography (Petroleum ether:EtOAc 10:1 to 6:1), white solid, 1.26 g, yield 53%, mp. 144−145 ℃. 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J
= 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.27 (br, 1H), 7.15 (t, J = 7.6 Hz, 2H), 6.99 (t, J = 7.6 Hz, 1H), 6.66 (d, J = 7.6 Hz, 2H). 13C {1H} NMR
(100 MHz, CDCl3) δ 150.7, 139.0, 135.7, 132.2, 129.1, 128.9, 123.6, 121.7, 118.3, 113.3. HR-MS (ESI): Calcd for C14H12N3O [M+H]+ 238.0975,
found 238.0975.
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(E)-N'-Hydroxy-4-nitro-N-phenylbenzimidamide (S-IIIe)
1
Chromatography (Petroleum ether:EtOAc 20:1 to 10:1), yellow solid, 0.98 g, 38%, mp. 174−176 ℃ (lit. 23a: mp. 166−170 ℃). H NMR (400
MHz, CDCl3) δ 8.71 (s, 1H), 8.16 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.28 (s, 1H, NH), 7.15 (t, J = 7.6 Hz, 2H), 7.00 (t, J = 7.6 Hz, 1H),
6.68 (d, J = 7.6 Hz, 2H). 13C {1H} NMR (100 MHz, CDCl3) δ 150.5, 148.4, 138.9, 137.5, 129.2, 129.2, 123.7, 123.7, 121.8. HR-MS (ESI): Calcd
for C13H12N3O3 [M+H]+ 258.0873, found 258.0874.
(E)-4-Fluoro-N'-hydroxy-N-phenylbenzimidamide (S-IIIf)
Chromatography (Petroleum ether:EtOAc 20:1 to 10:1), white solid, 1.15 g, yield 50%, mp. 135−136 ℃. 1H NMR (400 MHz, CDCl3) δ 7.50 –
7.42 (m, 2H), 7.33 (br, 1H), 7.16 (t, J = 7.6 Hz, 2H), 7.08 – 6.94 (m, 3H), 6.70 (d, J = 7.6 Hz, 2H). 13C {1H} NMR (100 MHz, CDCl3) δ 163.6 (d, J
= 248.2 Hz), 151.2, 139.5, 130.4 (d, J = 8.3 Hz), 128.9, 127.1 (d, J = 3.0 Hz), 123.0, 121.6, 115.6 (d, J = 21.7 Hz). HR-MS (ESI): Calcd for
C13H12FN2O [M+H]+ 231.0928, found 231.0930.
(E)-4-Chloro-N'-hydroxy-N-phenylbenzimidamide (S-IIIg)
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Chromatography (Petroleum ether:EtOAc 20:1 to 10:1), white solid, 1.11 g, yield 45%, mp. 133−135 ℃ (lit. 23a: mp. 132−133 ℃). 1H NMR (400
MHz, CDCl3) δ 7.39 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.15 (t, J = 7.6 Hz, 2H), 6.98 (t, J = 7.6 Hz, 1H), 6.72 – 6.65 (m, 2H). 13C {1H}
NMR (100 MHz, CDCl3) δ 151.2, 139.4, 135.8, 129.7, 129.6, 128.9, 128.8, 123.1, 121.6. HR-MS (ESI): Calcd for C13H12ClN2O [M+H]+
247.0633, found 247.0635.
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(E)-4-Bromo-N'-hydroxy-N-phenylbenzimidamide (S-IIIh)
Chromatography (Petroleum ether:EtOAc 20:1 to 10:1), white solid, 1.37 g, yield 47%, mp. 167−168 ℃. 1H NMR (400 MHz, CDCl3) δ 7.44 (d,
J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.13 (t, J = 7.6 Hz, 2H), 6.96 (t, J = 7.6 Hz, 1H), 6.67 (d, J = 7.6 Hz, 2H). 13C {1H} NMR (100 MHz,
CDCl3) δ 151.2, 139.4, 131.7, 130.1, 129.9, 128.9, 124.1, 123.1, 121.6. HR-MS (ESI): Calcd for C13H12BrN2O [M+H]+ 291.0128, found 291.0124.
(E)-N'-Hydroxy-N-phenyl-4-(trifluoromethoxy)benzimidamide (S-IIIi)
Chromatography (Petroleum ether:EtOAc 20:1 to 15:1), yellow solid, 0.80 g, yield 27%, mp. 99−100 ℃. 1H NMR (400 MHz, CDCl3) δ 9.59 (s,
1H), 7.47 (d, J = 8.4 Hz, 2H), 7.32 (s, 1H), 7.15 – 7.10 (m, 4H), 6.95 (t, J = 7.6 Hz, 1H), 6.66 (d, J = 8.4 Hz, 2H). 13C {1H} NMR (100 MHz,
CDCl3) δ 151.0, 150.2, 139.3, 130.0, 129.6, 128.9, 123.2, 121.6, 120.7. HR-MS (ESI): Calcd for C14H12F3N2O2 [M+H]+ 297.0845, found
297.0846.
(E)-3-Chloro-N'-hydroxy-N-phenylbenzimidamide (S-IIIj)
Chromatography (Petroleum ether:EtOAc 20:1 to 10:1), white solid, 1.31 g, yield 53%, mp. 131−132 ℃. 1H NMR (400 MHz, CDCl3) δ 7.49 (t, J
= 1.6 Hz, 1H), 7.37 – 7.31 (m, 1H), 7.30 – 7.26 (m, 1H), 7.25 – 7.19 (m, 1H), 7.14 (t, J = 7.6 Hz, 2H), 6.97 (d, J = 7.6 Hz, 1H), 6.71 – 6.65 (m,
2H). 13C {1H} NMR (100 MHz, CDCl3) δ 151.0, 139.3, 134.4, 133.0, 129.8, 129.6, 128.9, 128.4, 126.7, 123.3, 121.5. HR-MS (ESI): Calcd for
C13H12ClN2O [M+H]+ 247.0633, found 247.0634.
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(E)-2-Chloro-N'-hydroxy-N-phenylbenzimidamide (S-IIIk)
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Chromatography (Petroleum ether:EtOAc 20:1 to 10:1), white solid, 1.28 g, yield 52%, mp. 124−125 ℃. 1H NMR (400 MHz, CDCl3) δ 7.51 –
7.47 (m, 1H), 7.44 (s, 1H), 7.37 – 7.26 (m, 3H), 7.06 (t, J = 7.6 Hz, 2H), 6.91 (t, J = 7.6 Hz, 1H), 6.65 – 6.59 (m, 2H). 13C {1H} NMR (100 MHz,
CDCl3) δ 150.0, 138.8, 133.9, 131.8, 131.0, 130.5, 130.0, 128.8, 126.9, 123.1, 120.8. HR-MS (ESI): Calcd for C13H12ClN2O [M+H]+ 247.0633,
found 247.0634.
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(E)-N'-Hydroxy-N-phenylbenzo[d][1,3]dioxole-5-carboximidamide (S-IIIl)
Chromatography (Petroleum ether:EtOAc 8:1 to 5:1), white solid, 0.90 g, yield 35%, mp. 151−152 ℃. 1H NMR (400 MHz, CDCl3) δ 7.13 (dd, J
= 8.4, 7.6 Hz, 2H), 6.98 – 6.91 (m, 2H), 6.90 (d, J = 1.6 Hz, 1H), 6.74 (d, J = 8.0 Hz, 1H), 6.72 – 6.67 (m, 2H), 5.96 (s, 2H). 13C {1H} NMR (100
MHz, CDCl3) δ 151.7, 148.9, 147.6, 139.8, 128.8, 124.9, 122.8, 122.7, 121.2, 108.7, 108.4, 101.4. HR-MS (ESI): Calcd for C14H13N2O3 [M+H]+
257.0921, found 257.0923.
(E)-N'-Hydroxy-N-phenyl-[1,1'-biphenyl]-4-carboximidamide (S-IIIm)
Chromatography (Petroleum ether:EtOAc 15:1 to 10:1), yellow solid, 1.32 g, yield 46%, mp. 174−175 ℃. 1H NMR (400 MHz, CDCl3) δ 7.59 –
7.48 (m, 6H), 7.47 – 7.31 (m, 4H), 7.12 (t, J = 7.6 Hz, 2H), 6.94 (t, J = 7.6 Hz, 1H), 6.72 (d, J = 7.6 Hz, 2H). 13C {1H} NMR (100 MHz, CDCl3) δ
151.9, 142.5, 140.2, 139.6, 129.6, 128.9, 128.8, 127.7, 127.1, 127.1, 122.9, 121.5. HR-MS (ESI): Calcd for C19H17N2O [M+H]+ 289.1335, found
289.1335.
(E)-N'-hydroxy-N-phenyl-2-naphthimidamide (S-IIIn)
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Chromatography (Petroleum ether:EtOAc 25:1 to 10:1), yellow solid, 0.71 g, yield 27%, mp. 182−184 ℃. H NMR (400 MHz, DMSO-d6) δ
10.68 (s, 1H), 8.42 (s, 1H), 7.99 (s, 1H), 7.89 (d, J = 8.8 Hz, 2H), 7.84 (d, J = 8.4 Hz, 1H), 7.55 – 7.45 (m, 3H), 7.03 (t, J = 8.0 Hz, 2H), 6.76 (t, J
= 7.2 Hz, 1H), 6.70 (d, J = 7.6 Hz, 2H). 13C {1H} NMR (100 MHz, DMSO-d6) δ 149.6, 142.0, 133.5, 133.0, 131.0, 128.9, 128.7, 128.2, 128.0,
127.4, 127.1, 126.9, 125.7, 121.0, 120.1. HR-MS (ESI): Calcd for C17H15N2O [M+H]+ 263.1179, found 263.1183.
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Methyl (E)-4-(N'-hydroxy-N-phenylcarbamimidoyl)benzoate (S-IIIo)
Chromatography (Petroleum ether:EtOAc 20:1 to 10:1), white solid, 1.27 g, yield 47%, mp. 149−150 ℃. 1H NMR (400 MHz, CDCl3) δ 9.39 (s,
1H), 7.97 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 7.32 (s, 1H), 7.10 (t, J = 7.6 Hz, 2H), 6.94 (t, J = 7.6 Hz, 1H), 65 6. (d, J = 7.6 Hz, 2H),
3.90 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 166.6, 151.3, 139.3, 135.5, 131.1, 129.7, 128.9, 128.4, 123.2, 121.6, 52.3. HR-MS (ESI): Calcd
for C15H15N2O3 [M+H]+ 271.1077, found 271.1079.
(E)-N-(4-(N'-Hydroxy-N-phenylcarbamimidoyl)phenyl)acetamide (S-IIIp)
Chromatography (Petroleum ether:EtOAc 10:1 to 4:1), white solid, 0.97 g, yield 36%, mp. 103−104 ℃. 1H NMR (400 MHz, CDCl3) δ 7.62 (s,
1H), 7.43 (d, J = 8.4 Hz, 2H), 7.34 (br, 1H), 7.33 (d, J = 8.4 Hz, 2H), 7.08 (t, J = 7.6 Hz, 2H), 6.90 (t, J = 7.2 Hz, 1H), 6.64 (d, J = 7.6 Hz, 2H),
2.09 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 168.6, 151.7, 139.6, 139.3, 129.1, 128.8, 126.6, 122.8, 121.4, 119.3, 24.6. HR-MS (ESI): Calcd
for C15H16N3O2 [M+H]+ 270.1237, found 270.1238.
Ethyl (E)-2-(hydroxyimino)-2-(phenylamino)acetate (S-IIIq)
Chromatography (Petroleum ether:EtOAc 10:1 to 6:1), yellow solid, 1.1 g, yield 53%, mp. 107−109 ℃ (lit. 23b: 106−108 ℃). H NMR (400
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MHz, CDCl3) δ 7.31 – 7.24 (m, 2H), 7.09 (t, J = 7.6 Hz, 1H), 6.95 (s, 1H), 6.92 (d, J = 7.6 Hz, 2H), 4.25 (q, J = 7.2 Hz, 2H), 1.21 (t, J = 7.2 Hz,
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3H). 13C {1H} NMR (100 MHz, CDCl3) δ 160.8, 143.3, 139.1, 128.9, 124.0, 121.1, 62.4, 13.8. HR-MS (ESI): Calcd for C10H13N2O3 [M+H]+
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209.0921, found 209.0922.
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(E)-N'-Hydroxy-N-phenylpivalimidamide (S-IIIr)
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Chromatography (Petroleum ether:EtOAc 30:1 to 15:1), white solid, 0.73 g, yield 38%, mp. 118−119 ℃. 1H NMR (400 MHz, CDCl3) δ 8.92 (s,
1H), 7.26 (t, J = 7.6 Hz, 2H), 7.02 (t, J = 7.6 Hz, 1H), 6.93 (d, J = 7.6 Hz, 2H), 5.91 (s, 1H), 1.20 (s, 9H ). 13C {1H} NMR (100 MHz, CDCl3) δ
155.6, 141.2, 128.4, 122.8, 121.6, 36.6, 28.2. HR-MS (ESI): Calcd for C11H17N2O [M+H]+ 193.1335, found 193.1335.
(E)-N'-Hydroxy-N-(p-tolyl)benzimidamide (S-IIIaa)
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Chromatography (Petroleum ether:EtOAc 20:1 to 10:1), white solid, 1.4 g, yield 62%, mp. 165−166 ℃ (lit. 23c: 161.5−163 ℃). H NMR (400
MHz, CDCl3) δ 7.43 (d, J = 7.6 Hz, 2H), 7.36 (t, J = 7.2 Hz, 1H), 7.29 (t, J = 7.2 Hz, 2H), 6.90 (d, J = 8.0 Hz, 2H), 6.57 (d, J = 8.0 Hz, 2H), 2.22
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(s, 3H). C {1H} NMR (100 MHz, CDCl3) δ 152.2, 137.1, 132.4, 131.2, 129.6, 129.3, 128.5, 128.4, 121.7, 20.7. HR-MS (ESI): Calcd for
C14H15N2O [M+H]+ 227.1179, found 227.1181.
(E)-N'-Hydroxy-N-(4-methoxyphenyl)benzimidamide (S-IIIab)
Chromatography (Petroleum ether:EtOAc 20:1 to 8:1), yellow solid, 1.23 g, yield 51%, mp. 129−130 ℃ (lit. 23c: 154.4−157.2 ℃). 1H NMR (400
MHz, CDCl3) δ 7.43 –7.39 (m, 2H), 7.35 – 7.30 (m, 1H), 7.30 – 7.24 (m, 2H), 6.65 (s, 4H), 3.70 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ
155.7, 152.6, 132.8, 131.2, 129.5, 128.6, 128.3, 123.9, 114.0, 55.4. HR-MS (ESI): Calcd for C14H15N2O2 [M+H]+ 243.1128, found 243.1128.
(E)-N-(4-(tert-Butyl)phenyl)-N'-hydroxybenzimidamide (S-IIIac)
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Chromatography (Petroleum ether:EtOAc 20:1 to 15:1), white solid, 1.26 g, yield 47%, mp. 172−173 ℃. 1H NMR (400 MHz, CDCl3) δ 7.48 –
7.42 (m, 2H), 7.39 – 7.28 (m, 3H), 7.11 (d, J = 8.8 Hz, 2H), 6.59 (d, J = 8.8 Hz, 2H), 1.23 (s, 9H). 13C {1H} NMR (100 MHz, CDCl3) δ 152.2,
145.5, 137.1, 131.3, 129.6, 128.5, 128.4, 125.6, 120.9, 34.2, 31.4. HR-MS (ESI): Calcd for C17H21N2O [M+H]+ 269.1648, found 269.1652.
(E)-N-(4-Fluorophenyl)-N'-hydroxybenzimidamide (S-IIIad)
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Chromatography (Petroleum ether:EtOAc 20:1 to 8:1), white solid, 0.69 g, yield 30%, mp. 147−148 ℃ (lit. 23c: 147.5−149 ℃). H NMR (400
MHz, CDCl3) δ 7.46 –7.36 (m, 3H), 7.36 – 7.29 (m, 2H), 6.88 – 6.78 (m, 2H), 6.71 – 6.63 (m, 2H). 13C {1H} NMR (100 MHz, CDCl3) δ 158.88 (d,
J = 242.3 Hz), 152.1, 135.7 (d, J = 2.6 Hz), 130.8, 129.8, 128.5, 123.4 (d, J = 8.0 Hz), 115.50 (d, J = 22.5 Hz). HR-MS (ESI): Calcd for
C13H12FN2O [M+H]+ 231.0928, found 231.0928.
(E)-N-(4-Chlorophenyl)-N'-hydroxybenzimidamide (S-IIIae)
Chromatography (Petroleum ether:EtOAc 20:1 to 15:1), white solid, 0.89 g, yield 36%, mp. 187−188 ℃ (lit. 23c: 182.5−183.6 ℃). 1H NMR (400
MHz, CDCl3) δ 9.05 (br, 1H, 7.48 – 7.29 (m, 5H), 7.06 (d, J = 8.4 Hz, 2H), 6.59 (d, J = 8.4 Hz, 2H). 13C {1H} NMR (100 MHz, CDCl3) δ 151.6,
138.3, 130.7, 130.0, 128.8, 128.6, 128.3, 128.0, 122.4. HR-MS (ESI): Calcd for C13H12ClN2O [M+H]+ 247.0633, found 247.0633.
(E)-N-(4-Bromophenyl)-N'-hydroxybenzimidamide (S-IIIaf)
Chromatography (Petroleum ether:EtOAc 20:1 to 10:1), yellow solid, 0.52 g, yield 18%, mp. 198−200 ℃ (lit. 23c: 192−193.5 ℃). 1H NMR (400
MHz, CDCl3) δ 7.45 – 7.36 (m, 3H), 7.35 – 7.30 (m, 2H), 7.20 (d, J = 8.8 Hz, 2H), 6.52 (d, J = 8.8 Hz, 2H). 13C {1H} NMR (100 MHz, CDCl3) δ
151.5, 138.8, 131.8, 130.6, 130.0, 128.6, 128.3, 122.7, 115.5. HR-MS (ESI): Calcd for C13H12BrN2O [M+H]+ 291.0128, found 291.0119.
(E)-N'-Hydroxy-N-(m-tolyl)benzimidamide (S-IIIag)
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Chromatography (Petroleum ether:EtOAc 20:1 to 10:1), white solid, 0.77 g, yield 34%, mp. 136−137 ℃ (lit. 23d: 133.2−133.7 ℃). 1H NMR (400
MHz, CDCl3) δ 7.47 – 7.41 (m, 2H), 7.39 – 7.27 (m, 3H), 7.23 (br, 1H), 6.96 (t, J = 8.0 Hz, 1H), 6.74 (d, J = 7.6 Hz, 1H), 6.54 (s, 1H), 6.41 (dd, J
= 8.0 Hz, J = 1.6 Hz, 1H), 2.18 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 152.1, 139.6, 138.7, 131.2, 129.6, 128.5, 128.4, 123.5, 121.9, 118.4,
21.3. HR-MS (ESI): Calcd for C14H15N2O [M+H]+ 227.1179, found 227.1183.
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(E)-N'-Hydroxy-N-(o-tolyl)benzimidamide (S-IIIah)
Chromatography (Petroleum ether:EtOAc 20:1 to 10:1), yellow solid, 0.5 g, yield 22%, mp. 147−148 ℃. 1H NMR (400 MHz, CDCl3) δ 7.41 –
7.36 (m, 2H), 7.36 – 7.24 (m, 3H), 7.14 (d, J = 7.2 Hz, 1H), 6.99 (s, 1H), 6.93 –6.81 (m, 1H), 6.45 (dd, J = 7.6, 1.1 Hz, 1H), 2.36 (s, 1H). 13C {1H}
NMR (100 MHz, CDCl3) δ 152.7, 138.1, 131.33, 130.5, 129.8, 129.6, 128.3, 128.2, 126.1, 123.7, 123.5, 18.0. HR-MS (ESI): Calcd for C14H15N2O
[M+H]+ 227.1179, found 227.1181.
(E)-N-(Benzo[d][1,3]dioxol-5-yl)-N'-hydroxybenzimidamide (S-IIIai)
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Chromatography (Petroleum ether:EtOAc 20:1 to 10:1), brown solid, 1.13 g, yield 44%, mp. 201−203 ℃. H NMR (400 MHz, DMSO-d6) δ
10.42 (s, 1H), 8.13 (s, 1H), 7.38 – 7.28 (m, 5H), 6.61 (d, J = 8.4 Hz, 1H), 6.34 (d, J = 2.0 Hz, 1H), 6.07 (dd, J = 8.4, 2.0 Hz, 1H), 5.88 (s, 2H). 13C
{1H} NMR (100 MHz, DMSO-d6) δ 150.2, 147.4, 142.2, 136.4, 133.3, 129.3, 128.6, 128.3, 113.9, 108.1, 103.3, 101.2. HR-MS (ESI): Calcd for
C14H13N2O3 [M+H]+ 257.0921, found 257.0921.
(E)-N-(3,4-Dichlorophenyl)-N'-hydroxybenzimidamide (S-IIIaj)
Chromatography (Petroleum ether:EtOAc 20:1 to 10:1), white solid, 0.39 g, yield 14%, mp. 170−172 ℃. 1H NMR (400 MHz, CDCl3) δ 7.46 –
7.42 (m, 3H), 7.40 – 7.34 (m, 2H), 7.14 (d, J = 8.8 Hz, 1H), 6.81 (d, J = 2.8 Hz, 1H), 6.44 (dd, J = 8.8, 2.8 Hz, 1H). 13C {1H} NMR (100 MHz,
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CDCl3) δ 151.1, 139.3, 132.5, 130.3, 130.2, 130.2, 128.8, 128.2, 126.0, 122.4, 120.3. HR-MS (ESI): Calcd for C13H11Cl2N2O [M+H]+ 281.0243,
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(E)-N-(3,5-Dimethylphenyl)-N'-hydroxybenzimidamide (S-IIIak)
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Chromatography (Petroleum ether:EtOAc 20:1 to 12:1), white solid, 1.13 g, yield 47%, mp. 143−144 ℃. 1H NMR (400 MHz, CDCl3) δ 7.48 –
7.40 (m, 2H), 7.39 – 7.27 (m, 3H), 7.22 (br, 1H), 6.56 (s, 1H), 6.27 (s, 2H), 2.11 (s, 6H). 13C {1H} NMR (100 MHz, CDCl3) δ 152.1, 139.6, 138.3,
131.3, 129.6, 128.4, 128.3, 124.4, 119.1, 21.2. HR-MS (ESI): Calcd for C15H17N2O [M+H]+ 241.1335, found 241.1333.
(E)-N-(2,4-Dimethoxyphenyl)-N'-hydroxybenzimidamide (S-IIIal)
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Chromatography (Petroleum ether:EtOAc 15:1 to 8:1), white solid, 1.25 g, yield 46%, mp. 137−139 ℃. H NMR (400 MHz, CDCl3) δ 7.46 –
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(s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ 156.2, 152.4, 151.7, 131.6, 129.4, 128.4, 128.2, 122.9, 122.4, 103.3, 99.0, 55.6, 55.4. HR-MS (ESI):
Calcd for C15H17N2O3 [M+H]+ 273.1234, found 273.1233.
Preparation of Substrates 1. To the solution of amidoximes S-III (1 mmol) and triethylamine (1.2 mmol) in dichloromethane (10 mL) was
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added dropwise the solution of corresponding benzoyl chlorides (1.1 mmol) in dichloromethane (5 mL). The mixture was stirred at 0 C for 1 h,
added saturated sodium bicarbonate solution (25 mL), and separated. The water phase was extracted with dichloromethane (40 mL × 2). The
combined organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column chromatography to afford
substrates 1.
(E)-N-Phenyl-N'-((4-(trifluoromethyl)benzoyl)oxy)benzimidamide (1a)
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