PhIO/Et3N ? 3HF-Mediated Formation of Fluorinated 2H-Azirines via Domino Fluorination/Azirination Reaction of Enamines

Article abstract of DOI:10.1002/adsc.201800124

A variety of enamine carboxylic esters and enaminones were converted to the biologically interesting fluorinated 2H-azirines through reactions with PhIF₂ generated in situ by PhIO and Et₃N ? 3HF in 1,2-dichroloethane, which features the hypervalent iodine reagents-mediated introduction of fluorine atom and formation of the 2H-azirine skeleton under metal-free conditions. The domino reaction is postulated to proceed via a PhIF₂-mediated oxidative fluorination and a subsequent azirination of the fluorinated enamine intermediates. (Figure presented.).

Full text of DOI:10.1002/adsc.201800124

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DOI: 10.1002/adsc.201800124
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PhIO/Et3N·3HF-Mediated Formation of Fluorinated 2H-Azirines
via Domino Fluorination/Azirination Reaction of Enamines
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Yong Zhang,a Xiaoyuan Zhao,a Chen Zhuang,a Senlin Wang,a Daisy Zhang-
Negrerie,a and Yunfei Dua, b,*
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a
Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology,
Tianjin University, Tianjin 300072, People’s Republic of China
E-mail: duyunfeier@tju.edu.cn
Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, Peopleꢀs Republic of
China
Tel: +86-22-27406121
b
Received: January 25, 2018; Revised: March 21, 2018; Published online: &&&, &&&&
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.201800124
ring expansion.[5] For example, azirinomycin was
isolated from Streptomyces aureus by Miller and co-
workers in 1970 as the first example of a natural
product containing an azirine ring, which was found to
Abstract: A variety of enamine carboxylic esters
and enaminones were converted to the biologically
interesting fluorinated 2H-azirines through reac-
tions with PhIF2 generated in situ by PhIO and
Et3N·3HF in 1,2-dichroloethane, which features the
hypervalent iodine reagents-mediated introduction
of fluorine atom and formation of the 2H-azirine
skeleton under metal-free conditions. The domino
exhibit a broad range of in vitro antibiotic activities
against both gram-positive and gram-negative bacte-
ria.[4] Other azirine-containing natural products in-
clude (R)-(À)- and (S)-(+)-dysidazirine and (S)-
(+)-antazirine, isolated from dysidea fragilis
reaction is postulated to proceed via a PhIF2-
mediated oxidative fluorination and a subsequent
(Scheme 1).
The predominant synthetic methods developed for
azirination of the fluorinated enamine intermedi-
the construction of this interesting class of compounds
ates.
include the classic Neber rearrangement of proper
imine substrates,[6] azirination of vinyl azides,[7] elimi-
Keywords: enamine; difluoroiodoarene generated
in situ; domino reaction; fluorination; azirination
nation or oxidation of aziridines,[8] ring contraction of
isoxazoles,[9] oxazaphosphole derivatives,[10] and cou-
40 Organofluorine compounds are extremely scarce in
41 natural organohalides, as only five natural fluorinases
42 have been discovered.[1] Fluorine substitution in
43 organic compounds enables many valuable properties,
44 which are applicable to pharmaceuticals, agrochemi-
45 cals, and materials bearing an outstanding property.[2]
46 It has also been well known that the introduction of
47 fluorine atoms into pharmaceuticals can increase their
48 metabolic stability, lipophilicity, and overall biological
49 activity, and thus more than 150 commercially avail-
50 able pharmaceutical agents contain at least one
51 fluorine atom.[3]
Scheme 1. Representatives of naturally-occuring 2H-azirines.
52
2H-azirines, the smallest heterocyclic compounds pling reactions between nitriles and carbenes[11] or
53 with an imino-type C=N bond incorporated into a between nitrenes and acetylenes.[12] In 2009, our group
54 three-membered ring, have been studied extensively reported that 2H-azirines could also be obtained via
55 for their presence in natural products.[4] Furthermore, direct oxidative azirination of enamine compounds
56 2H-azirines have been applied to the synthesis of (Scheme 2a).[13] Although the above approach enables
57 various N-containing heterocycles via strain-driven the synthesis of various 2H-azirine compounds bearing
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different substitution, to the best of our knowledge, logically interesting F atom into the 2H-azirine
there have been scarce reports on the synthesis of F- products by using difluoroiodobenzene, generated
containing 2H-azirines.[14] As both the 2H-azirine in situ from the reaction of PhIO and Et3N·3HF.
4
framework and F atom are important pharmacores in
We began our investigation by choosing compound
5
medicinal chemistry, it should be highly desirable to 1a, a relatively easily prepared product from commer-
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develop methodologies for synthesis of F-containing cially available acetophenone and dimethyl carbonate
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2H-azirines.
in a straightforward two step process, as the model
substrate.
9
We first attempted the reaction by subjecting
enamino ester 1a to various solvents in the presence
of PhIO as oxidant and Et3N·3HF as fluorine reagent
(Table 1). Solvents including CH3CN, DMF and
DMSO were studied, however, TLC analysis indicated
that no desired product was formed in each case
(Table 1, entries 1–3). To our delight, we found that
the reaction in toluene furnished the desired product,
albeit in a low yield of 35% (Table 1, entry 4). DCE
was latter proved to be a more effective solvent as the
reaction gave the desired product in 67% yield
(Table 1, entry 6). The use of other fluorine reagents
including amine·4HF, amine·5HF (amine means the
mixture of Et3N and pyridine) also afforded the
desired products in moderate yield, respectively
(Table 1, entries 8–9), while HF (40% aqueous solu-
tion) and Olah reagent did not provide any desired
product under the conditions (Table 1, entries 7 and
10). Finally, screening of the dosage of Et3N·3HF
showed that when the amount of Et3N·3HF was
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Scheme 2. Formation of 2H-azirines via I(III)-mediated
oxidative azirination of enamines.
Recently, the chemistry of hypervalent iodine increased to 3.0 equiv. or decreased to 1.0 equiv. no
30 compounds has accomplished remarkable progress,[15] improvement was obtained in each case (Table 1,
31 and it has been proven that this class of “green” entries 11–12). Subsequently, the other commonly
32 oxidant compounds have shown many synthetically used I(III) oxidants were also examined, while PIDA
33 useful characteristics, including mild oxidizing prop- gave an even lower yield and PIFA was detected to be
34 erty, similar chemical behaviors to transition metals, ineffective for the reaction (Table 1, entries 13–14).
35 and the environmentally benign feature. Among them, Combining all the testing results, the optimized
36 difluoroiodoarenes (ArIF2), bearing two fluorine conditions are finally determined to be PhIO
37 atoms, have been widely used in synthetic applica- (2.2 equiv.) as oxidant and Et3N·3HF (2.0 equiv.) as
38 tions.[16] For example, difluoroiodoarenes have shown fluorine reagent in DCE (Table 1, entry 6).
39 to be an efficient fluorinating reagent in the fluorina-
Under the optimized reaction conditions, the scope
40 tion reactions of 1,3-dicarbonyl compounds and have and limitation of this cascade fluorination and azirina-
41 been applied to the fluorination of b-ketoesters, b- tion reaction was investigated (Table 2). A series of
42 ketoamides, and b-diketones.[17] Besides, difluoroio- reactions of enamino esters containing electron-rich or
43 doarenes have also been used to fluorinate various electron-deficient aryl groups all reacted smoothly,
44 alkenes and diazocompounds, leading to the synthesis providing the corresponding fluorinated 2H-azirine
45 of various organofluorine compounds.[18] It has also products in moderate to good yields (2a–k, 52–78%).
46 been well documented that the combined use of PhIO Specifically, enamines bearing both electron-donating
47 and amine·HF complex could generate PhIF2 in situ and electron-withdrawing groups in the phenyl ring
48 and the use of such oxidative system could be applied afforded the desired products in good yields while
49 to fluorination reactions.[19]
In 2013, we reported that enaminones and enamine thoxy group at para position could not afford the
substrates possessing a strong electron-donating me-
50
51 carboxylic esters could be converted to the trifluor- products (not shown). Meanwhile, enamines bearing
52 oethoxylated 2H-azirines via PhIO-mediated oxida- substituents at para position gave the products in
53 tive trifluoroethoxylation and the subsequent intra- higher yields than the corresponding meta- and ortho-
54 molecular azirination (Scheme 2b).[20] As this work substituted enamines, except for the meta methoxy
55 allowed the introduction of trifluoromethyl moiety substituted substrates. An enamine bearing a naphthyl
56 into 2H-azirine product to be achieved, we were also group also furnished the corresponding fluorinated
57 interested to realize the introduction of the bio- product (2l) in good yield (81%).
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Table 1. Optimization of reaction conditions.[a]
Table 2. Synthesis of 2-fluoro-2H-azirine derivatives through
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PhIO-mediated fluorination and azirination of Enamines.[a]
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Entry Oxidant F reagent
Solvent
Yield (%)[a]
1
2
3
4
5
6
7
8
PhIO
PhIO
PhIO
PhIO
PhIO
PhIO
PhIO
PhIO
PhIO
PhIO
PhIO
PhIO
PIDA
PIFA
Et3N·3HF
Et3N·3HF
Et3N·3HF
Et3N·3HF
Et3N·3HF
Et3N·3HF
40% HF
CH3CN ND
8
9
DMF
DMSO
toluene
DCM
DCE
ND
ND
35
58
67
10
11
12
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18
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20
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22
23
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35
DCE
DCE
ND
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amine·4HF[c]
9
amine·5HF[d] DCE
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10
11
12
13
14
Olah reagent
Et3N·3HF[e]
Et3N·3HF[f]
Et3N·3HF
DCE
DCE
DCE
DCE
DCE
ND
55
43
15
ND
Et3N·3HF
[a] Reaction conditions: all reactions were carried out by
mixing the I(III) oxidant (2.2 mmol) and F reagent
(2 mmol) in solvent (10 mL) at rt for 15 min and then 1a
was added (1 mmol in 1 mL of solvent) dropwise at rt
unless otherwise stated.
[b] Isolated yield.
[c]
Mixture of pyr · 9HF 0.467 mmol (0.110 mL) and
Et3N·3HF 2.39 mmol (0.390 mL).
Mixture of pyr · 9HF 0.870 mmol (0.205 mL) and
[d]
[a] all reactions were carried out by mixing the oxidant
(2.2 mmol) and F reagent (2 mmol) in DCE (10 mL) at rt
for 15 min and then adding 1a (1 mmol in 1 mL of DCE)
dropwise at rt unless otherwise stated.
Et3N·3HF 1.81 mmol (0.295 mL).
[e] 3.0 equiv. of Et3N·3HF was used.
[f] 1.0 equiv. of Et3N·3HF was used.
[b] Isolated yields.
[c] The structure of 2d was confirmed by X-ray crystal-
lography.[21]
Next, a series of substrates bearing different ester
36 moieties were tested. Enamino esters bearing n-butyl
37 ester, i-propyl ester, t-butyl ester and phenylethyl ester reaction occured and the starting material was recov-
38 also reacted smoothly to afford the corresponding ered in 93% yield (Scheme 3b).
39 fluorinated 2H-azirines in good yields (2m–p). Further
40 experiments showed that this method worked moder-
41 ately for a broad range of enaminones although the
42 corresponding products were obtained in relatively
43 lower yields (2q–t).
44
In order to investigate whether the carbonyl group
45 in the substrate is indispensable for this reaction, we
46 had the carbonyl group in substrate 1d replaced with
47 an electron-withdrawing cyano group and subjected
48 the corresponding 3-amino-3-(4-chlorophenyl)acrylo-
49 nitrile 4[22] to the standard conditions. However, the
50 reaction underwent solely the intramolecular azirina-
51 tion leading to the formation of 3-(4-chlorophenyl)-
52 2H-azirine-2-carbonitrile 5 in 49% yield, without any
Scheme 3. Investigation the reaction scope by changing the
carbonyl group with different electron-withdrawing groups.
One important application of the obtained fluori-
53 detection of the fluorinated 2H-azirine product (Sche- nated-2H-azirine derivatives is their potential to be
54 me 3a). Disappointingly, when enamine substrate transformed into various isoxazole compounds via
55 bearing a strong electron-withdrawing nitro group 6[23] intramolecular ring expansion.[5,13,20] For example,
56 was subjected to the optimal reaction conditions, no upon treatment 2q with FeCl2 in refluxing 1,4-dioxane
57
at 101 8C, fluorinated 2H-azirine 2q could be effi-
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ciently turned into the corresponding isoxazole 3 in with the enamine substrate 1 to give the a-iodo imine
good yield through an intramolecular rearrangement B. The reductive removal of PhI from B affords
3
4
5
6
reaction (Scheme 4).
fluorinated imine C, which tautomerizes into its
enamine isomer D. Further reaction of D with the
second molecule of PhIF2 provides intermediate E,
which undergoes intramolecular azirination to give
the title compound 2.[27]
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Scheme 4. Conversion of fluoronated 2H-azirine 2q to iso-
xazole 3 via FeCl2-mediated intramolecular ring expansion.
In order to gain insights into the reaction mecha-
16 nism, we tried to isolate and confirm the structure of
17 the proposed enamine intermediate. When the
18 amount of PhIO was decreased to 1.1 equiv., the
19 reaction of substrate 1a did not afford any isolable a-
20 fluoro enamine carboxylic ester intermediate 4a
21 (Scheme 5a). This result may indicate that the a-
22 fluoro enamine intermediate may not be stable under
23 the reaction conditions.[24] Fortunately, when the
Scheme 6. Proposed mechanistic pathway.
In conclusion, we have developed an approach to
24 phenyl-protected enamine carboxylic ester 5a[25] was the construction of the fluorinated 2H-azirines
25 used, the corresponding a-fluoro enamine carboxylic through the reaction between the a-unsubstituted
26 ester intermediate 6a could be obtained in 45% yield enamines and PhIF2 which was generated in situ from
27 by using PhIO (1.1 equiv.) and Et3N.3HF (1.0 equiv.) PhIO and Et3N·HF in DCE. The process features a
28 (Scheme 5b). Furthermore, when a-hydrogen 2H- domino reaction of a metal-free intermolecular oxida-
29 azirine 7a prepared by a known procedure[26] was tive CÀF bond formation and a subsequent intra-
30 subjected to the standard conditions, no a-fluorinated molecular oxidative azirination. The significance of
31 2H-azirine 2a could be obtained (Scheme 5c). This the method is tied together with the unique features
32 result obviously ruled out the alternative mechanistic of the products formed, in that they possess not only
33 pathway in which the azirination occurs prior to the the biologically important 2H-azirine skeleton but
34 fluorination.
also the biologically interesting fluorine atom.
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Acknowledgments
We acknowledge the National Science Foundation of China
(#21472136) and Tianjin Research Program of Application
Foundation and Advanced Technology (#15JCZDJC32900)
for financial support.
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[27] It can not be ruled out that intermediate E also
undergoes reductive elimination to give a a,a-difluori-
nated imine intermediate, which undergoes intramolec-
ular SN2 reaction to give the fluorinated 2H-azirine
product 2.
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PhIO/Et3N·3HF-Mediated Formation of Fluorinated
2H-Azirines via Domino Fluorination/Azirination
Reaction of Enamines
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