Synthesis of difluoromethylselenoesters from aldehydes: Via a radical process

Article abstract of DOI:10.1039/d0cc02912b

Difluoromethylselenoester compounds, another important kind of organoselenium compounds, are reported herein for the first time. They can be efficiently synthesized from aldehydes and BnSeCF2H. The synthetic method features mild reaction conditions, broad substrate scope, good tolerance of functional groups, and importantly, no metal is involved in the reaction.

Full text of DOI:10.1039/d0cc02912b

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Synthesis of difluoromethylselenoesters from
aldehydes via a radical process†
Cite this:DOI: 10.1039/d0cc02912b
Rui-Li Guo, Xue-Qing Zhu, Xing-Long Zhang and Yong-Qiang Wang
*
Received 22nd April 2020,
Accepted 23rd June 2020
DOI: 10.1039/d0cc02912b
rsc.li/chemcomm
1
0
Difluoromethylselenoester compounds, another important kind of donor than –OH and –NH; (2) it can enhance the binding
1
1
organoselenium compounds, are reported herein for the first time. selectivity while fine-tuning the lipophilicity of the drug; and
They can be efficiently synthesized from aldehydes and BnSeCF H. (3) its electron-withdrawing capability can increase the drug’s
2
1
2
The synthetic method features mild reaction conditions, broad metabolic stability. Recently, there has been considerable
substrate scope, good tolerance of functional groups, and impor- interest in the combination of difluoromethyl group and chal-
1
3
tantly, no metal is involved in the reaction.
cogens, such as difluoromethoxyl (–OCF
2
H) group
H) group. However, less research
The past decade has witnessed tremendous growth of selenium studies on difluoromethylseleno-containing (–SeCF H) com-
chemistry, not only because selenium is an essential micronu- pounds have been reported, probably due to the lack of an
and
1
4
difluoromethylthiol (–SCF
2
2
1
15
trient for plants, microorganisms, animals, and humans, but efficient method to synthesize them.
also because selenium compounds have great biological activ-
ities (e.g. antioxidant, antifatigue, and immunity activities)
According to the Hansch lipophilicity parameter values (p )
R
of XCH (X = O, S) and XCF H (Fig. 1b), it can be speculated
3 2
2
16
and broad applications in materials fields, including alloys, that the Hansch lipophilicity parameter value of the difluoro-
3
photovoltaic products and nanotechnologies. It is foreseeable methylselenyl group (–SeCF
that new selenium compounds and chemistry would emerge to SeCH group (p = 0.74). Therefore, SeCF
2
2
H) is greater than that of the
3
R
H incorporation
reinvigorate these areas. Organoselenium compounds, particu- could increase the lipophilicity of parent compounds. To date,
larly selenoesters (Fig. 1a), are important organic molecules the reports are limited on difluoromethylselenoethers
1
5
which have shown extensive pharmaceutical activities such as (Fig. 1c), while difluoromethylselenoesters (Fig. 1d), which
4
anti-proliferation, anti-tumour and chemoprevention. Seleno- represent another important class of organoselenium com-
esters are also significant synthetic intermediates as acyl-radical pounds, have not been reported yet. In view of the potential
5
6,7
precursors, mild acyl-transfer agents, etc. In addition, due to properties of selenoesters and the difluoromethylselenyl group,
their promising photophysical properties, selenoesters have found
wide applications in emissive LC displays, polarized organic lasers
8
and anisotropic OLEDs. Accordingly, the design and develop-
ment of new selenoester compounds is greatly desirable in
pharmaceutical and materials science.
The incorporation of fluorine atoms into molecules has
become a common tactic to design novel lead compounds and
9
modulate the properties of biologically active substances. Over
the past few decades, the difluoromethyl group has attracted great
attention because: (1) it is a more lipophilic hydrogen-bonding
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry
of Education, College of Chemistry & Materials Science, Northwest University,
Xi’an 710069, People’s Republic of China. E-mail: wangyq@nwu.edu.cn
†
Electronic supplementary information (ESI) available: Detailed experimental
procedures including spectroscopic and analytical data. CCDC compound 3g
1985689) and compound 3ad (1985690). For ESI and crystallographic data in CIF
(
or other electronic format see DOI: 10.1039/d0cc02912b
Fig. 1 Organoselenium compounds.
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the development of a new synthetic method for difluoromethyl- necessity of the initiator (entry 10). Subsequently, the optimization
selenoesters would permit chemical derivatization of novel of the solvents showed that DCE was the best choice (entries 11
bioactive molecules and open a new window for selenium- and 12). By increasing the amount of AIBN to 2.0 equivalents, the
related research and applications.
yield was improved to 84% (entry 13). Finally, the reaction tem-
Aldehydes are abundant and inexpensive chemical materials perature and atmosphere were investigated. It was demonstrated
1
7a
and can easily generate the corresponding acyl radicals.
that a similar result could be obtained by lowering the temperature
Thus, we wondered whether the desired difluoromethylsele- to 50 1C (entry 14). Interestingly, the yield could be improved to
noesters could be directly formed by the coupling of the 90% under an argon atmosphere (entry 15). Accordingly, the
ꢀ
difluoromethylselenyl radical ( SeCF
acyl radicals (Fig. 1e).
2
H) with aldehyde-derived optimized reaction conditions for the synthesis of 3a were identi-
fied as follows: 1a (0.75 mmol), 2b (0.5 mmol), AIBN (1.0 mmol)
The study commenced with p-methylbenzaldehyde as an and DCE (2.5 mL) at 50 1C under an argon atmosphere.
acyl radical precursor and di-tert-butyl peroxide (DTBP) as a With the optimal conditions in hand, the substrate scope of
radical initiator. Firstly, we used the most frequently used difluoro- this transformation was investigated (Scheme 1). A variety of
methylselenolation reagent, ClSeCF
2
H (2a), prepared from aromatic aldehydes bearing either electron-rich groups or
to perform the reaction electron-deficient groups at different positions could react with
1
5d
benzyl(difluoromethyl)selane (2b),
in CH
methylselenoester 3a was not observed. To our delight, instead lenoesters in moderate to excellent yields (3a–3x). The method
of ClSeCF H with Se-(difluoromethyl)-benzenesulfonoselenoate (2c), proved to be compatible with various functional groups, such
3
CN at 80 1C for 24 h. Unfortunately, the desired difluoro- 2b smoothly to generate the corresponding difluoromethylse-
2
the reaction gave the desired product 3a in 25% yield (Table 1, as alkyls (3a–3e and 3u), halides (Cl, Br, I; 3f–3h), phenyl (3i),
entry 2). A similar result was obtained with Se-(difluoromethyl)- ethers (3j, 3k, and 3v–3x), a protected phenolic hydroxyl group
15h
4
-methylbenzenesulfono selenoate (2d) as the difluoromethyl- (3l), ester (3m), and a dimethylamino group (3n), and these
selenolation reagent. To our surprise, the precursor of ClSeCF H, functional groups can be further transformed in the synthesis.
2
simple benzyl(difluoromethyl)selane (2b), afforded a superior The structure of 3g was confirmed by single-crystal X-ray
yield (37%) (entry 4). Then with 1a and 2b as the model diffraction analysis (see ESI†).
substrates, the initiator was screened. It was demonstrated that
AIBN was better than the others, providing 3a in 58% yield difluoromethylselenolation of naphthyl aldehydes. To our satis-
entries 5–9). Meanwhile, the reaction without the initiator was faction, 1-naphthyl, 2-naphthyl and 1-bromine-2-naphthyl alde-
carried out, and it did not afford any product, indicating the hydes successfully provided the desired products in good yields
3aa–3ac). As we know, heteroarenes are pharmaceutically
As illustrated in Scheme 2, we applied this method for the
(
(
1
8
important scaffolds. Pleasingly, the reactions of 2b with
aldehydes containing indole, benzofuran, benzothiophene,
pyrole, furan and thiophene motifs proceeded smoothly under
the standard conditions (3ad–3ai). The structure of difluoro-
methylselenoester 3ad was unambiguously confirmed using
single-crystal X-ray diffraction.
a
Table 1 Optimization of the difluoromethylselenolation reaction
Encouraged by the success of (hetero)aromatic aldehydes,
aliphatic aldehydes and a,b-unsaturated aldehydes were then
b
c
Entry 2 Initiator(equiv.) Solvent
Temp. (1C) Conv. (%) Yield (%)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
2a DTBP(1.0)
2c DTBP(1.0)
2d DTBP(1.0)
2b DTBP(1.0)
2b TBHP(1.0)
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
3
3
3
3
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
80
80
80
80
80
80
80
80
80
80
100
100
100
45
23
0
0
67
61
0
0
25
21
37
15
0
2b H
2b K
2
O
2
O
(1.0)
(1.0)
2
S
2
8
0
2b AIBN(1.0)
2b AMBN(1.0)
2b —
2b AIBN(1.0)
2b AIBN(1.0)
2b AIBN(2.0)
2b AIBN(2.0)
2b AIBN(2.0)
58
54
0
o27
72
84
82
90
0
1
2
3
4
5
d
Other solv. 80
o32
DCE
DCE
DCE
DCE
80
80
50
50
83
100
100
100
e
a
Reaction conditions: 1a (0.75 mmol), 2 (0.5 mmol), initiator, solvent
b
c
(
2.5 mL) and open to air for 24 h. Based on 2. Yields of isolated 3a.
d
Other solv.: CHCl
3
(27%), DMSO (0%), DMF (0%), toluene (18%), and
THF (0%). Under Ar (1 atmosphere). Conv. = conversion. DTBP = di-
tert-butyl peroxide. TBHP = tert-butyl hydroperoxide (70 wt% in H O).
e
Scheme 1 Difluoromethylselenolation of various aromatic aldehydes. Reac-
2
0
H
2
O
2
(30 wt% in H
2
O). DCE = 1,2-dichloroethane. AIBN = 2,2 -azobis tion conditions: 1 (0.75 mmol), 2b (0.5 mmol), AIBN (1.0 mmol), and DCE
0
(2-methylpropionitrile). AMBN = 2,2 -azobis-isovaleronitrile.
(2.5 mL) under Ar at 50 1C for 24 h. Yields shown are those of isolated products.
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Scheme 4 Late-stage difluoromethylselenolation of aldehyde-containing
bioactive molecules. Reaction conditions: 1 (0.75 mmol), 2b (0.5 mmol), AIBN
Scheme 2 Difluoromethylselenolation of naphthyl aldehydes and hetero-
aromatic aldehydes. Reaction conditions: 1 (0.75 mmol), 2b (0.5 mmol),
AIBN (1.0 mmol), and DCE (2.5 mL) under Ar at 50 1C for 24 h. Yields shown
are those of isolated products.
(1.0 mmol), and DCE (2.5 mL) under Ar at 50 1C for 24 h. Yields shown are those
of isolated products.
3a was observed when the radical scavenger 2,2,6,6-tetramethyl
investigated. Pleasingly, the reactivity of aliphatic aldehydes piperidinyloxy (TEMPO), 2,6-di-tert-butyl-4-methylphenol (BHT)
and a,b-unsaturated aldehydes was similar to (hetero)aromatic or 1,1-diphenylethylene was introduced into the reaction sys-
aldehydes. As summarized in Scheme 3, not only linear alipha- tem under standard reaction conditions (eqn (1)). When
tic aldehydes (3ba–3bc) but also branched aliphatic aldehydes TEMPO (1.0 equiv.) was introduced into the standard reaction
(
3bd, 3be) were suitable substrates for this transformation. To system of 1f and 2b, isobutyronitrile (4), tetramethylsuccinoni-
further verify the efficacy of the method, a,b-unsaturated alde- trile (5) and the adduct 6 from the reaction of 1f with TEMPO
19
hydes were examined. (ꢁ)-Myrtenal (1bf) and (E)-dec-2-enal (1bg) were detected using a high-resolution mass spectrometer
worked successfully to give the corresponding products in 72% and (HRMS, see ESI†), while no 3f was detected (eqn (2)). Isobutyr-
6
9% yields, respectively. All the difluoromethylselenoesters synthe- onitrile (4) and tetramethylsuccinonitrile (5) could also be
sized are not sensitive to air, moisture or light at ambient detected in the standard reaction system of 1a and 2b
temperature. The reaction of 1a and 2b was repeated 5 times, and (see ESI†). These experiments indicated that the cyanoisopropyl
the yield of 3a remained in the range of 88–91%, verifying the radical and the acyl radical derived from aldehyde were prob-
stability and the reproducibility of this approach. The products can ably involved in the reaction and the difluoromethylselenola-
be easily purified using flash chromatography on silica gel.
tion should undergo a radical path. Next, visible light-promoted
To demonstrate the synthetic application of this methodology, experiments were implemented. Without the introduction of an
we employed it in the difluoromethylselenolation of complex initiator, the desired product 3a could also be obtained in the
aldehyde-containing molecules (Scheme 4). Known aldehyde- presence of the irradiation of a 23 W white LED bulb or a 10 W
containing bioactive molecules, such as L-menthol derivative blue LED bulb in 13% and 25% yields, respectively (eqn (3)). On
(
1ca), ibuprofen derivative (1cb) and the cholesterol derivative the contrary, no reaction occurred without light. The photo-
(
1cc) were all smoothly converted into their corresponding difluoro- reactions further supported the radical process of the transfor-
methylselenoesters (3ca, 3cb and 3cc), verifying that this approach mation.
can be used in the late-stage modification of drug molecules and
advanced synthetic intermediates.
To gain insights into the reaction mechanism, we carried
out a series of radical-trapping experiments. Firstly, no product
(
(
(
1)
2)
3)
1
7,20
Based on these results and the related literatures,
a
plausible mechanism for the synthesis of difluoromethylsele-
noesters is proposed as shown in Fig. 2. Initially, AIBN is
thermally decomposed into a cyanoisopropyl radical, which
abstracts a hydrogen atom from the aldehyde (1) to generate
2
0b
an acyl radical (A) and isobutyronitrile (4).
radicals can also undergo homocoupling to generate tetra-
Cyanoisopropyl
Scheme 3 Difluoromethylselenolation of aliphatic aldehydes and a,b-
unsaturated aldehydes. Reaction conditions: 1 (0.75 mmol), 2b (0.5 mmol),
AIBN (1.0 mmol), and DCE (2.5 mL) under Ar at 50 1C for 24 h. Yields shown
are those of isolated products.
2
0e
methylsuccinonitrile (5). Then A reacts with 2b to form the
desired product 3. We tried to ascertain the product derived
from the benzyl group of 2b, but complicated results have been
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1
0, 3217.
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We are grateful for financial support from National Natural
Science Foundation of China (No. NSFC-21572178, NSFC-
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1
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Conflicts of interest
There are no conflicts to declare.
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