Copper-Catalyzed Four-Component Reaction for the Synthesis of N-Difluoroethyl Imides

Article abstract of DOI:10.1002/ejoc.201801334

A general and efficient method for the synthesis N-difluoroethyl imides has been developed. This copper-catalyzed four-component reaction proceeds via in-situ generated difluorodiazomethane, which does not require prior formation and transferring. The reaction is scalable, tolerant toward a range of functional groups, and also suitable for the late-stage functionalization of drugs and drug-like molecules.

Full text of DOI:10.1002/ejoc.201801334

A Journal of
Accepted Article
Title: Copper-Catalyzed Four Component Reaction for the Synthesis of
N-Difluoroethyl Imides
Authors: Yu Gao, shanqing peng, deyong Liu, Peixin Rui, and Xiang-
Guo Hu
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801334
Link to VoR: http://dx.doi.org/10.1002/ejoc.201801334
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10.1002/ejoc.201801334
European Journal of Organic Chemistry
FULL PAPER
Copper-Catalyzed Four Component Reaction for the Synthesis of
N-Difluoroethyl Imides
Yu Gao, Shan-Qing Peng, De-Yong Liu, Pei-Xin Rui, Xiang-Guo Hu *[a]
Abstract: A general and efficient method for the synthesis N-
scarce, and the access to this kind of compounds is mainly
relied on multi-step syntheses.[11]
difluoroethyl imides has been developed. This copper-catalyzed four
component
reaction
proceeds
via
in-situ
generated
difluorodiazomethane，which does not require the prior formation
and transferring. The reaction is scalable, tolerant a range of
functional groups, and also suitable for the late-stage
functionalization of drugs and drug-like molecules.
Introduction
An imide is a basic functional group that is structurally related
to an acid anhydride but more resistant towards hydrolysis. For
this reason, imides have been frequently used as key
intermediates in organic synthesis. They are also important
structural motifs found in a great number of bioactive molecules
and pharmaceuticals. Notable examples such as Thalidomide,[1]
Ethosuximide,[2] Penimide,[3] Captan,[4] Aniracetam[5] and
Palau’imide[6] are shown in Figure 1. At the same time, a
difluoromethyl group (CF2H) is an attractive entity from drug
development perspective.[7-8] The slightly acidic C–H bond of the
difluoromethyl group (CF2H)[9] can act both as a lipophilic
hydrogen-bond donor and a bioisostere for hydroxyl and thiol
groups.[10] Furthermore, as a fluoroalkyl group, it can possibly
improve the metabolic stability, oral bioavailability and solubility
of molecules if incorporated.[7]
Scheme 1. Reactions that involve difluoromethyl diazomethane (CF2HCHN2).
Difluoromethyl diazomethane (HCF2CHN2), first reported by
Mykhailiuk, has emerged as a versatile building block for the
synthesis of difluoromethylated compounds.[12] Compared to its
well-known trifluorinated counterparts,[13] the reaction of
HCF2CHN2 is still underdeveloped and largely limited to [2+3]-
cycloaddition with alkynes and alkenes,[14] cyclopropanation with
alkenes[15] and esterification of carboxylic acids[16] (Scheme 1).
Herein, we report a copper-catalyzed four component reaction
for the facile synthesis imides bearing a CF2H group, employing
all commercially available reagents (Scheme 1). The reaction
proceeds
from
the
in-situ
generated
difluoromethyl
diazomethane (HCF2CHN2) that does not need prior formation
and transferring. The optimization, the generality with respect to
both the carboxylic acid and nitrile, and the application of this
reaction for late-stage functionalization are discussed.
Results and Discussion
Figure
compounds
1 Selected examples of imide containing drugs and bioactive
Based on our recent work on the formation of trifluoroethyl
imides
from
carboxylic
acids
with
trifluoromethyl
diazomethane,[16b] we envisioned that an efficient synthesis of
difluoromethyl imides could be developed if proper conditions
could be identified. Challenges, however, exist: (1) as the
activation barrier for the esterification of carboxylic acids with
HCF2CHN2 is quite low (22.6 kJ/mol), [16b] how to suppress this
uncatalyzed esterification is a big problem; (2) reactions with
CF2HCHN2 (possibly due to its instable nature)[12] disclosed are
generally less efficient than those with CF3CHN2, 【 12-15 】 so the
efficacy and generality would be another issue to address.
Considering the aforementioned two aspects, the combination of
an imide and a CF2H moiety would offer much possibility in the
searching of novel bioactive compounds. However, the literature
surveying shows that the research on CF2H-containing imides is
[a]
Yu Gao, Shan-Qing Peng, De-Yong Liu, Pei-Xin Rui,
Dr. Xiang-Guo Hu
National Engineering Research Center for Carbohydrate Synthesis,
Jiangxi Normal University, Nanchang 330022, China.
E-mail: huxiangg@iccas.ac.cn.
To address the second issue raised above, we determined to
use HCF2CHN2 generated in-situ from 2, 2-difluoromethylamine
(HCF2CH2NH2) and tert-butyl nitrite (TBN) without discrete
operation. Thus, the optimization was carried out by mixing all
Homepage:http://www.escience.cn/people/xiangguohu/index.html;js
essionid=1EF1BEAF74C7A6D13C9ADE9C1FF99ECE-n2
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201801334
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[14h, 16b]
With the optimized reaction conditions in hand (Entry 13, Table
1), we next examined the substrate scope of this copper-
catalyzed 4-component reaction with respect to the carboxylic
acid (Scheme 2). For aromatic acids, different substituents
including alkyl, alkyloxyl, ester, and phenyl were all tolerated
(2a-2h). It is noteworthy that halide substituents, especially
bromo group, were intact under the reaction conditions (2e-2g),
which allows further functionalization via transitional-metal
catalyzed coupling reactions. However, the efficacy of this
reaction decreased sharply with the substrate bearing an
electron-withdrawing nitro group. In particular, the corresponding
ester 2ia (structure not shown) was isolated in 46% yield along
with 2i. Nevertheless, the ester side products are much less
polar than the corresponding imide products, thus causing no
difficulties for the purification. The structure of 2i was confirmed
unambiguously by means of X-ray crystallographic analysis
(CCDC 1862470).14 Compounds with bicycloaryl and heteroaryl
ring systems were also viable substrates, affording the desired
products (2j−2l) in 60-85% yields. The double bond of cinnamic
acid 1m was unaffected under the reaction conditions, thus
delivering the desired products (2m) in 63% yield. Aliphatic acids
1n-1o also underwent the reaction successfully, and 2n-2o were
obtained in 82% and 71% yield, respectively. These two results
also highlighted that the reaction is not sensitive to the steric
hindrance of carboxylic acid, given the congested nature of the
starting carboxylic acids 1n-1o. Finally, the practicality of this
reaction was demonstrated by running the reaction of 1a on
gram scale and the corresponding imide 2a was obtained in
78%.
the reagents together at once (Table 1).
The ester
formation was indeed
a problem as anticipated, and the
previously established thermal conditions for CF3CHN2 yielded
completely ester 2aa from 2a, while copper-catalyzed conditions
afforded the imide product 2a as the minor product (33%
yield).[16b] The selectivity in Entries 1-2 indicates that the
formation of imide 2a may have a larger activation barrier than
that of the esterification. To overcome this kinetic preference, we
performed the reaction at 80 oC and 2a was obtained in 46%
yield. Increasing the amount of the HCF2CH2NH2 and TBN
slightly enhanced the yield, giving 2a in 52% yield (Entry 4).
Diluting the concentration was very beneficial to the reaction and
a higher yield was obtained in 86% at the concentration of 0.05
mmol/mL (Entries 4-6); presumably, this positive result was
ascribed to the increased amount of acetonitrile that only
participates in the imide formation, relative to other reagents.
Comparison experiments proved that high temperature was
indeed advantageous for the formation of imide products
(Entries 7-9). Catalyst screening showed that copper salts were
generally effective for the reaction, with Cu(OTf)2 giving the best
result (Entries 10–20). Under this optimized conditions, 2a was
obtained in 90% yield, and ester product 2aa was decreased to
4% yield (Table 1, entry 12). Lowering or increasing the amount
of Cu(OTf)2 resulted in a slightly lower yield (Entries 21–22).
Overall, the first issue raised previously, that is, the ester
formation, was also addressed through the reaction optimization.
Table 1. Optimization of the reaction conditions.
Entry
Catalyst (x mol%)
Concentration of 1a Yield (%)a,b
(mmol/mL) / T (oC)
1c
2c
/
CuI (5)
CuI (5)
CuI (5)
CuI (5)
0.2/80
0.2/ 25
0.2/80
Trace (69)
33 (42)
46 (23)
52 (13)
81 (9)
86 (7)
7 (3)
3c
4
5
6
7
0.2/80
0.1/80
CuI (5)
CuI (5)
0.05/80
0.05/0
8
9
CuI (5)
CuI (5)
0.05/40
0.05/60
0.05/80
0.05/80
0.05/80
0.05/80
0.05/80
0.05/80
0.05/80
0.05/80
0.05/80
0.05/80
0.05/80
0.05/80
0.05/80
38 (21)
59 (9)
67 (13)
71 (12)
87 (8)
90 (4)
83 (9)
86 (8)
77 (4)
82 (3)
79 (5)
76 (7)
87 (4)
82 (7)
87 (4)
10
11
12
13
14
15
16
17
18
19
20
21
22
CuCl2 (5)
CuBr2 (5)
Cu(acac)2 (5)
Cu(OTf)2 (5)
Cu(NO3).3H2O (5)
.
Cu(OAc)2 H2O (5)
CuCl (5)
CuBr (5)
Cu(MeCN)4PF6 (5)
Cu(OTf).toluene (5)
CuTc (5)
Cu(OTf)2 (1)
Cu(OTf)2 (10)
Scheme 2. Substrate scope of Cu-catalyzed four component reaction with
carboxylic acids; Conditions: carboxylic acids (0.2 mmol,
1 equiv), 2,2-
difluoroethylamine (0.5 mmol, 2.5 equiv), tert-butyl nitrite (0.5 mmol, 2.5 equiv),
Cu(OTf)2 (5 mol%), acetonitrile (4 mL), 80oC, 20 h; [a] 78% is Gram scale yield;
[b] yields in the parentheses are the yields for the corresponding esters.
Conditions: 1a (0.2 mmol, 1.0 equiv), CF2HCH2NH2 (0.5 mmol, 2.5 equiv),
TBN (0.5 mmol, 2.5 equiv), catalyst (x mol%), acetonitrile (4 mL), 20 h.
[a]Yields determined by 19F-NMR spectroscopy using PhCF3 as an internal
Next, we investigated reaction further with other kinds of nitriles
under the established conditions (Scheme 3). To our delight, the
reaction of three representative aromatic acids 1a-c underwent
reaction successfully using isobutyl nitrile 3 as the reaction
component and similar yields were obtained with those when
acetonitrile was used at a longer reaction time (Scheme 3).
These experiments suggest that the reaction can tolerate the
steric hindrance of the nitrile component to some extent. Other
[b]
[c]
standard;
values in the parentheses are the yields of ester 2aa;
CF2HCH2NH2 (0.4 mmol, 2.0 equiv), TBN (0.4 mmol, 2.0 equiv).
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10.1002/ejoc.201801334
European Journal of Organic Chemistry
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three nitriles with a phenyl, benzyl and long alkyl chain were also
found as good substrates and the reaction occurred successfully
in 79- 83% yields (Scheme 3).
relatively high temperature and dilute concentration in the
presence of a copper catalyst.
Scheme 5. Plausible reaction mechanism for this copper-catalyzed four
component reaction.
Conclusions
A copper-catalyzed four component reaction for the efficient
synthesis difluoroethyl imides (imides containing a HCF2 moiety)
has been developed. The reaction proceeds via the in-situ
generated difluoromethyl diazomethane (HCF2CHN2), without
the requirement for the prior formation and transferring of this
potentially dangerous reagent. The kinetically favored,
uncatalyzed background reaction, the esterification of acids with
HCF2CHN2, was successfully suppressed. This imide formation
tolerates a range of functional groups and is insensitive to the
steric effect of the carboxylic acids and nitriles. Furthermore, the
reaction is scalable and suitable for the late-stage
functionalization of drugs and drug-like molecules in a protecting
group free fashion, which should make it valuable in the
searching of novel imide-based bioactive compounds in future.
Scheme 3. Substrate scope of Cu-catalyzed four component reaction with
various nitriles; Conditions: carboxylic acids (0.2 mmol,
1 equiv), 2,2-
difluoroethylamine (0.5 mmol, 2.5 equiv), TBN (0.5 mmol, 2.5 equiv), Cu(OTf)2
(5 mol%), nitrile (4 mL), 80 oC.
Experimental Section
To examine the synthetic utility of this reaction in medicinal
chemistry, we have applied this method for late-stage
functionalization[17] of drugs and drug-like molecules (Scheme
4).. The imide 7 derived from gibberellic acid (1p) was obtained
in 70% yield, again showcasing the reaction works well with
stereochemically hindered acids and tolerates sensitive
functionalities such as ester, alkene and hydroxyl groups.
Reaction with shikimic acid (1q), and cholic acid (1r), bearing
multiple hydroxyl groups, further demonstrated the utility of this
reaction in building molecular complexity in a protecting group
free fashion (Scheme 4).
General Information: All purchased reagents were used without further
purification unless otherwise noted. All solvents were dried over 4Å
molecular sieves before used unless stated. Reactions were stirred using
Teflon-coated magnetic stirrers. Analytical TLC was performed with 0.20
mm silica gel 60F plates with 254 nm fluorescent indicator. TLC plates
were visualized by ultraviolet light or by treatment with a spray of
Pancaldi reagent {(NH4)6MoO4, Ce(SO4)2, H2SO4, H2O} or a solution
0.5% ninhydrin in n-butanol. Chromatographic purification of products
was carried out by flash column chromatography on silica gel (230-400
mesh). Melting points were determined using a WRX-4 visual melting
point apparatus. Both melting points and boiling points are uncorrected.
Infrared spectra were recorded on an IR Affinity-1. NMR spectra were
measured in CDCl3 (with TMS as internal standard) or DMSO-d6 or
CD3OD on a Bruker AV400 (1H at 400 MHz, 13C at 100 MHz, 19F at 376
MHz) magnetic resonance spectrometer. High-resolution mass spectra
(HRMS) were recorded on a SYNAPT G2Si High Definition MS System.
Chemical shifts (δ) are reported in ppm, and coupling constants (J) are in
Hz. The following abbreviations were used to explain the multiplicities: s
= singlet, d = doublet, t = triplet, q = quartet, m = multiplet. The HRMS
were measured under ESI model (specified in the section of
characterization data).
Scheme 4. late stage-functionalization of complex molecules; [a] yields in the
parentheses are for the corresponding ester.
General procedure for the synthesis of TBN:
Based on our work with CF3CHN2,[16b] a plausible reaction
mechanism for this copper-catalyzed four component reaction is
depicted as the following (Scheme 5). The in-situ generated
HCF2CHN2 I[12] reacts with the copper catalyst to form the
carbenoid II[18] which yields the nitrilium salt III after attacking by
the acetonitrile. Addition of the carboxylic acid onto the nitrilium
III, followed by the Mumm rearrangement,[19] affords the imide
product IV. The unproductive but kinetically favored esterification
to yield IV was suppressed successfully by reaction at a
It is important to use freshly prepared TBN to get reproducible yields,
which was synthesized according to a reported procedure.[20] t-BuOH
was added (38 mL, 0.4 mol) dropwise to an ice-cold solution of
con.H2SO4 (22 mL, 0.4 mol) in H2O (25.0 mL), followed by the addition of
a solution of sodium nitrite (42.0 g in 100 mL of H2O). The reaction
mixture was kept at approximately 0 C during the addition. After the
addition, the reaction mixture was allowed to warm to room temperature
and stirred overnight. After the separation of the aqueous layer, the
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10.1002/ejoc.201801334
European Journal of Organic Chemistry
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organic portion was washed with saturated aq. NaHCO3 solution and
saturated aq. NaCl solution successively. The organic layer was then
dried over anhydrous Na2SO4 and purified by distillation. The TBN is a
light yellow liquid that was collected at about 80C (ca. 25 mL). It was
stored in a refrigerator and used for the four-component reaction directly.
Pale yellow oil (37 mg, 76% yield); 1H NMR (400 MHz, CDCl3) δ 7.81 –
7.61 (m, 2H, Ar-H), 7.26 – 7.08 (m, 2H, Ar-H), 6.07 (tt, J = 56.7, 4.4 Hz,
1H, CF2H), 4.13 (td, J = 13.6, 4.4 Hz, 2H, CH2CF2H), 2.17 (s, 3H,
COCH3); 13C NMR (100 MHz, CDCl3) δ 173.0, 172.6, 166.8, 164.2, 131.4
(d, J = 9.3 Hz), 130.8 (d, J = 3.3 Hz), 116.5, 116.3, 113.2 (t, J = 242.6 Hz,
CF2H), 47.8 (t, J = 28.3 Hz, CCF2H), 25.7; 19F NMR (376 MHz, CDCl3) δ -
104.1~ -104.26 (m, 1F, Ar-F), -122.24 (dt, J = 57.1, 13.7 Hz, CF2H); 19
F
Copper-Catalyzed Four Component reaction:
{1H}NMR (376 MHz, CDCl3) δ -104.22 (s, Ar-F), -122.24 (s, CF2H);
HRMS (ESI) m/z calcd for C11H11F3NO2 [M+H]+ 246.0742, found
+
The carboxylic acid (0.2 mmol, 1 equiv) was dissolved in acetonitrile (4
mL), and stirred at room temperature. Tert-butyl nitrite (60 μL, 0.5 mmol,
2.5 equiv.) and 2, 2-difluoroethylamine (36 μL, 0.5 mmol, 2.5 equiv.) were
added dropwise, then the reaction temperature was warmed to 80 °C.
When the reaction was completed (Monitored by TLC), the crude product
was evaporated and purified by column chromatography on silica gel
using petroleum–AcOEt as eluent to afford the desired adduct 2.
246.0736.
N-acetyl-4-chloro-N-(2, 2-difluoroethyl) benzamide (2f)
Pale yellow oil (43 mg, 79% yield); 1H NMR (400 MHz, CDCl3) δ 7.62 –
7.48 (m, 2H, Ar-H), 7.44 – 7.36 (m, 2H, Ar-H), 5.99 (tt, J = 56.7, 4.4 Hz,
1H, CF2H), 4.05 (td, J = 13.5, 4.4 Hz, 2H, CH2CF2H), 2.11 (s, 3H,
COCH3); 13C NMR (100 MHz, CDCl3) δ 172.0, 171.7, 138.5, 132.0, 129.0,
128.4, 112.1 (t, J = 242.7 Hz, CF2H), 46.8 (t, J = 28.3 Hz, CCF2H), 24.7;
19F NMR (376 MHz, CDCl3) δ -122.24 (dt, J = 56.4, 13.2 Hz, CF2H); 19F
{1H}NMR (376 MHz, CDCl3) δ -122.24 (s, CF2H); HRMS (ESI) m/z calcd
for C11H11ClF2NO2+ [M+H]+ 262.0446, found 262.0441.
N-acetyl-N-(2, 2-difluoroethyl) benzamide (2a)[16b]
Colorless oil (40 mg, 89% yield); 1H NMR (400 MHz, CDCl3) δ 7.66 –
7.62 (m, 2H, Ar-H), 7.61 – 7.56 (m, 1H, Ar-H), 7.48 (dd, J = 8.2, 6.8 Hz,
2H, Ar-H), 6.07 (tt, J = 56.8, 4.4 Hz, 1H, CF2H), 4.14 (td, J = 13.6, 4.5 Hz,
2H, CH2CF2H), 2.13 (s, 3H, COCH3); 13C NMR (100 MHz, CDCl3) δ
173.7, 173.2, 134.7, 133.0, 129.0, 128.6, 113.3 (t, J = 242.5 Hz, CF2H),
47.6 (t, J = 28.4 Hz, CCF2H), 25.7; 19F NMR (376 MHz, CDCl3) δ -122.30
(dt, J = 56.7, 13.7 Hz, CF2H); 19F {1H} NMR (376 MHz, CDCl3) δ -122.30
(s, CF2H); HRMS (ESI) m/z calcd for C11H11F2NO2Na+ [M+Na]+ 250.0650,
found 250.0654.
N-acetyl-4-bromo-N-(2, 2-difluoroethyl) benzamide (2g)
Pale yellow oil (48 mg, 77% yield); 1H NMR (400 MHz, CDCl3) δ 7.71 –
7.59 (m, 2H, Ar-H), 7.56 – 7.47 (m, 2H, Ar-H), 6.06 (tt, J = 56.7, 4.4 Hz,
1H, CF2H), 4.12 (td, J = 13.5, 4.4 Hz, 2H, CH2CF2H), 2.19 (s, 3H,
COCH3); 13C NMR (100 MHz, CDCl3) δ 173.0, 172.8, 133.5, 132.4, 130.1,
128.0, 113.1 (t, J = 242.7 Hz, CF2H), 47.8 (t, J = 28.3 Hz, CCF2H), 25.8;
19F NMR (376 MHz, CDCl3) δ -122.22 (dt, J = 56.4, 13.1 Hz, CF2H); 19F
{1H}NMR (376 MHz, CDCl3) δ -122.22 (s, CF2H); HRMS (ESI) m/z calcd
for C11H11BrF2NO2+ [M+H]+ 305.9941, found 305.9936.
N-acetyl-N-(2, 2-difluoroethyl)-4-methoxybenzamide (2b)[16b]
Pale yellow oil (45 mg, 87% yield); 1H NMR (400 MHz, CDCl3) δ 7.77 –
7.57 (m, 2H, Ar-H), 7.06 – 6.92 (m, 2H, Ar-H), 6.08 (tt, J = 56.7, 4.4 Hz,
1H, CF2H), 4.15 (td, J = 13.7, 4.4 Hz, 2H, CH2CF2H), 3.89 (s, 3H, OCH3),
2.11 (s, 3H, COCH3); 13C NMR (100 MHz, CDCl3) δ 173.13, 173.06,
163.8, 131.4, 126.6, 114.4, 113.4 (t, J = 242.5 Hz, CF2H), 55.6, 47.8 (t, J
= 28.4 Hz, CCF2H), 25.5; 19F NMR (376 MHz, CDCl3) δ -122.19 (dt, J =
57.1, 13.8 Hz, CF2H); 19F {1H}NMR (376 MHz, CDCl3) δ -122.19 (s,
methyl 4-(acetyl (2, 2-difluoroethyl)carbamoyl) benzoate (2h)
White solid (38 mg, 67% yield); 1H NMR (400 MHz, CDCl3) δ 8.19 – 8.11
(m, 2H, Ar-H), 7.71 – 7.65 (m, 2H, Ar-H), 6.07 (tt, J = 56.7, 4.4 Hz, 1H,
CF2H), 4.12 (td, J = 13.4, 4.4 Hz, 2H, CH2CF2H), 3.96 (s, 3H, CO2CH3),
2.21 (s, 3H, COCH3); 13C NMR (100 MHz, CDCl3) δ 173.0, 172.9, 138.6,
133.7, 130.1, 128.3, 113.1 (t, J = 242.7 Hz, CF2H), 52.5, 47.7 (t, J = 28.4
Hz, CCF2H), 25.8; 19F NMR (376 MHz, CDCl3) δ -122.28 (dt, J = 56.6,
13.5 Hz, CF2H).; 19F {1H}NMR (376 MHz, CDCl3) δ -122.28 (s, CF2H);
CF2H); HRMS (ESI) m/z calcd for C12H14F2NO3 [M+H]+ 258.0936, found
258.0938.
+
N-acetyl-4-methyl-N-(2, 2-difluoroethyl) benzamide (2c)
+
HRMS (ESI) m/z calcd for C13H14F2NO4 [M+H]+ 286.0885, found
Pale yellow oil (44 mg, 91% yield); 1H NMR (400 MHz, CDCl3) δ 7.62 –
7.51 (m, 2H, Ar-H), 7.35 – 7.22 (m, 2H, Ar-H), 6.07 (tt, J = 56.8, 4.5 Hz,
1H, CF2H), 4.15 (td, J = 13.6, 4.5 Hz, 2H, CH2CF2H), 2.44 (s, 3H, Ar-
CH3), 2.12 (s, 3H, COCH3); 13C NMR (100 MHz, CDCl3) δ 173.7, 173.2,
144.2, 131.8, 129.7, 129.0, 113.3 (t, J = 242.6 Hz, CF2H), 47.8 (t, J =
28.5 Hz, CCF2H), 25.8, 21.7; 19F NMR (376 MHz, CDCl3) δ -122.27 (dt, J
= 57.0, 13.8 Hz, CF2H); 19F {1H}NMR (376 MHz, CDCl3) δ -122.27 (s,
286.0888.
N-acetyl-N-(2, 2-difluoroethyl)-4-nitrobenzamide (2i)[16b]
Pale yellow oil (29 mg, 48% yield); 1H NMR (400 MHz, CDCl3) δ 7.64 –
7.56 (m, 2H, Ar-H), 7.50 – 7.43 (m, 2H, Ar-H), 6.06 (tt, J = 56.7, 4.4 Hz,
1H, CF2H), 4.12 (td, J = 13.5, 4.4 Hz, 2H, CH2CF2H), 2.19 (s, 3H,
COCH3); 13C NMR (100 MHz, CDCl3) δ 172.8, 171.8, 149.8, 140.4, 129.1,
124.1, 113.0 (t, J = 242.9 Hz, CF2H), 47.7 (t, J = 28.0 Hz, CCF2H), 25.5;
19F NMR (376 MHz, CDCl3) δ -122.23 (dt, J = 56.6, 13.6 Hz, CF2H); 19F
{1H} NMR (376 MHz, CDCl3) δ -122.23 (s, CF2H); HRMS (ESI) m/z calcd
for C11H11F2N2O4+ [M+H]+ 273.0681, found 273.0680.
CF2H); HRMS (ESI) m/z calcd for C12H14F2NO2 [M+H]+ 242.0993, found
242.0987.
+
N-acetyl-N-(2, 2-difluoroethyl)-[1, 1'-biphenyl]-4-carboxamide (2d)
White solid (51 mg, 84% yield); 1H NMR (400 MHz, CDCl3) δ 7.78 – 7.68
(m, 4H, Ar-H), 7.66 – 7.59 (m, 2H, Ar-H), 7.54 – 7.46 (m, 2H, Ar-H), 7.45
– 7.37 (m, 1H, Ar-H), 6.10 (tt, J = 56.8, 4.5 Hz, 1H, CF2H), 4.18 (td, J =
13.6, 4.5 Hz, 2H, CH2CF2H), 2.20 (s, 3H, COCH3); 13C NMR (100 MHz,
CDCl3) δ 173.5, 173.2, 146.0, 139.4, 133.2, 129.4, 129.1, 128.5, 127.7,
127.3, 113.3 (t, J = 242.6 Hz, CF2H), 47.9 (t, J = 28.5 Hz, CCF2H), 25.8;
19F NMR (376 MHz, CDCl3) δ -122.19 (dt, J = 57.0, 13.6 Hz, CF2H); 19F
{1H}NMR (376 MHz, CDCl3) δ -122.19 (s, CF2H); HRMS (ESI) m/z calcd
for C17H16F2NO2+ [M+H]+ 304.1149, found 304.1144.
N-acetyl-N-(2, 2-difluoroethyl)-1-naphthamide (2j)
Pale yellow oil (47 mg, 85% yield); 1H NMR (400 MHz, CDCl3) δ 8.13 –
7.98 (m, 2H, Ar-H), 7.92 (dd, J = 8.0, 1.5 Hz, 1H, Ar-H), 7.67 – 7.55 (m,
3H, Ar-H), 7.51 (dd, J = 8.2, 7.1 Hz, 1H, Ar-H), 6.10 (tt, J = 56.9, 4.5 Hz,
1H, CF2H), 4.12 (td, J = 13.4, 4.5 Hz, 2H, CH2CF2H), 2.20 (s, 3H,
COCH3); 13C NMR (100 MHz, CDCl3) δ 173.5, 172.9, 133.7, 132.6, 132.3,
129.9, 128.8, 128.2, 127.1, 126.7, 124.8, 124.3, 113.1 (t, J = 242.6 Hz,
CF2H), 47.3 (t, J = 28.9 Hz, CCF2H), 26.2; 19F NMR (376 MHz, CDCl3) δ -
122.38 (d, J = 57.0 Hz, CF2H); 19F {1H}NMR (376 MHz, CDCl3) δ -122.39
N-acetyl-N-(2, 2-difluoroethyl)-4-fluorobenzamide (2e)
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10.1002/ejoc.201801334
European Journal of Organic Chemistry
FULL PAPER
+
(s, CF2H); HRMS (ESI) m/z calcd for C17H16F2NO2 [M+H]+ 278.0993,
Colorless oil (43 mg, 84 % yield); 1H NMR (400 MHz, CDCl3) δ 7.67 –
7.63 (m, 2H, Ar-H), 7.62 – 7.57 (m, 1H, Ar-H), 7.53 – 7.46 (m, 2H, Ar-H),
6.11 (tt, J = 56.9, 4.5 Hz, 1H, CF2H), 4.12 (td, J = 13.4, 4.5 Hz, 2H,
CH2CF2H), 2.74 (hept, J = 6.7 Hz, 1H, CH), 1.06 (d, J = 6.7 Hz, 6H,
2CH3); 13C NMR (100 MHz, CDCl3) δ 181.8, 173.8, 135.0, 133.0, 129.1,
128.7, 113.4 (t, J = 242.7 Hz, CF2H), 48.3 (t, J = 28.6 Hz, CCF2H), 36.2,
19.5; 19F NMR (376 MHz, CDCl3) δ -122.19 (dt, J = 56.7, 13.5 Hz, CF2H);
19F {1H}NMR (376 MHz, CDCl3) δ -122.19 (s, CF2H); HRMS (ESI) m/z
calcd for C13H16F2NO2+ [M+H]+ 256.1144, found 256.1150.
found 278.0987.
N-acetyl-N-(2, 2-difluoroethyl) furan-2-carboxamide (2k)
Pale yellow oil (26 mg, 60 % yield); 1H NMR (400 MHz, CDCl3) δ 7.63 (dd,
J = 1.7, 0.8 Hz, 1H, Ar-H), 7.33 (dd, J = 3.6, 0.8 Hz, 1H, Ar-H), 6.63 (dd,
J = 3.6, 1.7 Hz, 1H, Ar-H), 6.07 (tt, J = 56.8, 4.5 Hz, 1H, CF2H), 4.21 (td,
J = 13.4, 4.6 Hz, 2H, CH2CF2H), 2.23 (s, 3H, COCH3); 13C NMR (100
MHz, CDCl3) δ 172.9, 162.1, 146.9, 146.6, 120.7, 113.3 (t, J = 242.7 Hz,
CF2H), 113.1, 47.2 (t, J = 29.0 Hz, CCF2H), 24.7; 19F NMR (376 MHz,
CDCl3) δ -122.25 (dt, J = 56.5, 13.1 Hz, CF2H); 19F {1H}NMR (376 MHz,
N-(2, 2-difluoroethyl)-N-isobutyryl-4-methoxybenzamide (4b)
+
CDCl3) δ -122.25 (s, CF2H); HRMS (ESI) m/z calcd for C9H10F2NO3
[M+H]+ 218.0629, found 218.0616.
Colorless oil (47 mg, 80 % yield); 1H NMR (400 MHz, CDCl3) δ 7.70 –
7.59 (m, 2H, Ar-H), 7.03 – 6.87 (m, 2H, Ar-H), 6.11 (tt, J = 56.9, 4.5 Hz,
1H, CF2H), 4.11 (td, J = 13.6, 4.6 Hz, 2H, CH2CF2H), 3.89 (s, 3H, OCH3),
2.73 (hept, J = 6.7 Hz, 1H, CH), 1.06 (d, J = 6.7 Hz, 6H, 2CH3); 13C NMR
(100 MHz, CDCl3) δ 181.5, 173.2, 163.7, 131.3, 126.9, 114.4, 113.5 (t, J
= 242.7 Hz, CF2H), 55.6, 48.4 (t, J = 28.5 Hz, CCF2H), 35.9, 19.6; 19F
NMR (376 MHz, CDCl3) δ -122.08 (dt, J = 57.1, 13.6 Hz, CF2H); 19F {1H}
NMR (376 MHz, CDCl3) δ -122.08 (s, CF2H); HRMS (ESI) m/z calcd for
C14H18F2NO3+ [M+H]+ 286.1249, found 286.1248.
N-acetyl-N-(2, 2-difluoroethyl) thiophene-2-carboxamide (2l)
Pale yellow oil (26 mg, 57 % yield); 1H NMR (400 MHz, CDCl3) δ 7.74 (dd,
J = 5.0, 1.2 Hz, 1H, Ar-H), 7.59 (dd, J = 3.8, 1.2 Hz, 1H, Ar-H), 7.17 (dd,
J = 5.0, 3.8 Hz, 1H, Ar-H), 6.09 (tt, J = 56.8, 4.4 Hz, 1H, CF2H), 4.19 (td,
J = 13.5, 4.4 Hz, 2H, CH2CF2H), 2.22 (s, 3H, COCH3); 13C NMR (100
MHz, CDCl3) δ 172.7, 167.0, 137.6, 134.6, 133.6, 128.1, 113.2 (t, J =
242.7 Hz, CF2H), 48.3 (t, J = 28.6 Hz, CCF2H), 25.2; 19F NMR (376 MHz,
CDCl3) δ -122.03 (dt, J = 57.1, 13.8 Hz, CF2H); 19F {1H}NMR (376 MHz,
CDCl3) δ -122.03 (s, CF2H); HRMS (ESI) m/z calcd for C9H10F2NO2S+
[M+H]+ 234.0400, found 234.0395.
N-(2, 2-difluoroethyl)-N-isobutyryl-4-nitrobenzamide (4c)
Colorless oil (35 mg, 58 % yield); 1H NMR (400 MHz, CDCl3) δ 8.38 –
8.28 (m, 2H, Ar-H), 7.87 – 7.65 (m, 2H, Ar-H), 6.10 (tt, J = 56.6, 4.4 Hz,
1H, CF2H), 4.11 (td, J = 13.3, 4.4 Hz, 2H, CH2CF2H), 2.90 (hept, J = 6.8
Hz, 1H, CH), 1.15 (d, J = 6.7 Hz, 6H, 2CH3); 13C NMR (100 MHz, CDCl3)
δ 181.1, 171.9, 149.8, 140.7, 129.0, 124.2, 113.1 (t, J = 243.0 Hz, CF2H),
47.9 (t, J = 28.2 Hz, CCF2H), 35.5, 19.4; 19F NMR (376 MHz, CDCl3) δ -
122.13 (dt, J = 56.6, 13.3 Hz, CF2H); 19F {1H}NMR (376 MHz, CDCl3) δ -
122.13 (s, CF2H); HRMS (ESI) m/z calcd for C13H14F2N2O4Na+ [M+Na]+
323.0814, found 323.0811.
N-acetyl-N-(2, 2-difluoroethyl) cinnamamide (2m)
White soild (32 mg, 63 % yield); 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J =
15.5 Hz, 1H, Ar-H), 7.52 – 7.46 (m, 2H, Ar-H), 7.37 – 7.30 (m, 3H, Ar-H),
7.01 (d, J = 15.5 Hz, 1H, Ar-H)), 5.97 (tt, J = 56.7, 4.6 Hz, 1H, CF2H),
4.03 (td, J = 13.0, 4.6 Hz, 2H, CH2CF2H), 2.41(s, 3H, COCH3); 13C NMR
(100 MHz, CDCl3) δ 172.3, 168. 1, 145.1, 133.3, 129.8, 128.0, 127.4,
118.4, 112.4 (t, J = 242.6 Hz, CF2H), 46.0 (t, J = 28.6 Hz, CCF2H), 24.8;
19F NMR (376 MHz, CDCl3) δ -121.92 (dt, J = 56.5, 12.8 Hz, CF2H); 19F
{1H} NMR (376 MHz, CDCl3) δ -121.92 (s, CF2H); HRMS (ESI) m/z calcd
for C17H16F2NO2+ [M+H]+ 254.0993, found 254.0987.
N-benzoyl-N-(2, 2-difluoroethyl) benzamide (6a)
Colorless oil (48 mg, 83% yield); 1H NMR (400 MHz, CDCl3) δ 7.40 –
7.29 (m, 4H, Ar-H), 7.23 – 7.16 (m, 2H, Ar-H), 7.14 – 7.04 (m, 4H, Ar-H),
6.28 (tt, J = 56.8, 4.6 Hz, 1H, CF2H), 4.33 (td, J = 13.5, 4.6 Hz, 2H,
CH2CF2H); 13C NMR (100 MHz, CDCl3) δ 172.9, 134.7, 131.2, 127.9,
127.3, 112.6 (t, J = 243.0 Hz, CF2H), 47.3 (t, J = 28.5 Hz, CCF2H); 19F
NMR (376 MHz, CDCl3) δ -122.24 (dt, J = 57.0, 13.5 Hz, CF2H); 19F
{1H}NMR (376 MHz, CDCl3) δ -122.24 (s, CF2H); HRMS (ESI) m/z calcd
for C16H14F2NO2+ [M+H]+ 290.0987, found 290.0989.
N-acetyl-N-(2, 2-difluoroethyl)-2-methyl-2-phenylpropanamide (2n)
Pale yellow oil (44 mg, 82 % yield); 1H NMR (400 MHz, CDCl3) δ 7.40 –
7.34 (m, 2H, Ar-H), 7.30 – 7.26 (m, 1H, Ar-H), 7.24 – 7.20 (m, 2H, Ar-H),
5.85 (tt, J = 57.4, 4.7 Hz, 1H, CF2H), 3.45 (td, J = 12.7, 4.6 Hz, 2H,
CH2CF2H), 2.35 (s, 3H, COCH3), 1.65 (s, 6H, 2CH3); 13C NMR (100 MHz,
CDCl3) δ 181.3, 173.9, 143.6, 129.1, 127.2, 125.2, 112.8 (t, J = 242.8 Hz,
CF2H), 49.9, 46.9 (t, J = 29.6 Hz, CCF2H), 28.8, 25.4; 19F NMR (376 MHz,
CDCl3) δ -121.89 (dt, J = 57.4, 12.7 Hz, CF2H); 19F {1H}NMR (376 MHz,
N-(2, 2-difluoroethyl)-N-(2-phenylacetyl)benzamide (6b)
Colorless oil (48 mg, 79 % yield); 1H NMR (400 MHz, CDCl3) δ 7.50 (td, J
= 7.2, 1.4 Hz, 1H, Ar-H), 7.47 – 7.43 (m, 2H, Ar-H), 7.40 – 7.34 (m, 2H,
Ar-H), 7.21 – 7.15 (m, 3H, Ar-H), 7.04 (dd, J = 7.7, 1.7 Hz, 2H, Ar-H),
5.98 (tt, J = 56.8, 4.5 Hz, 1H, CF2H), 3.99 (td, J = 13.4, 4.5 Hz, 2H,
CH2CF2H), 3.77 (s, 2H, PhCH2); 13C NMR (100 MHz, CDCl3) δ 174.9,
173.7, 134.3, 133.7, 133.1, 129.3, 129.1, 128.7, 128.6, 127.3, 113.2 (t, J
= 242.7 Hz, CF2H), 48.5 (t, J = 28.7 Hz, CCF2H), 44.0; 19F NMR (376
MHz, CDCl3) δ -122.03 (dt, J = 57.0, 13.7 Hz, CF2H); 19F {1H}NMR (376
+
CDCl3) δ -121.89 (s, CF2H); HRMS (ESI) m/z calcd for C14H18F2NO2
[M+H]+ 270.1306, found 270.1300.
N-acetyl-2-(4-chlorophenyl)-N-(2,
methylbutanamide (2o)
2-difluoroethyl)-3-
Pale yellow oil (44 mg, 71 % yield); 1H NMR (400 MHz, CDCl3) δ 7.33 –
7.28 (m, 2H, Ar-H), 7.28 – 7.23 (m, 2H, Ar-H), 5.92 (dddd, J = 57.3, 56.0,
5.6, 3.6 Hz, 1H, CF2H), 4.10 – 3.97 (m, 1H, CHCF2H), 3.96 (d, J = 10.0
Hz, 1H, CHCH3), 3.92 – 3.79 (m, 1H, CHCF2H), 2.48 – 2.31 (m, 4H,
COCH3 and CH-iPr), 1.02 (d, J = 6.5 Hz, 3H, CH3), 0.67 (d, J = 6.8 Hz,
3H, CH3); 13C NMR (100 MHz, CDCl3) δ 176.8, 173.4, 136.0, 133.5,
130.0, 129.0, 113.2 (t, J = 242.7 Hz, CF2H), 59.0, 46.6 (dd, J = 30.7, 26.4
Hz, CCF2H), 33.1, 26.2, 21.5, 20.1; 19F NMR (376 MHz, CDCl3) δ -120.26
– -123.19 (m, CF2H); 19F {1H}NMR (376 MHz, CDCl3) δ -120.37 – -123.27
MHz, CDCl3)
δ -122.03 (s, CF2H); HRMS (ESI) m/z calcd for
C17H16F2NO2+ [M+H]+ 304.1144, found 304.1147.
N-(2, 2-difluoroethyl)-N-pentanoylbenzamide (6c)
Colorless oil (43 mg, 81% yield); 1H NMR (400 MHz, CDCl3) δ 7.66 –
7.62 (m, 2H, Ar-H), 7.62 – 7.57 (m, 1H, Ar-H), 7.49 (dd, J = 8.2, 6.8 Hz,
2H, Ar-H), 6.09 (tt, J = 56.9, 4.5 Hz, 1H, CF2H), 4.13 (td, J = 13.5, 4.5 Hz,
2H CH2CF2H), 2.52 – 2.21 (m, 2H, COCH2), 1.56 (p, J = 7.5 Hz, 2H,
COCH2CH2), 1.21 (h, J = 7.2 Hz, 2H, CH2CH3), 0.81 (t, J = 7.3 Hz, 3H,
CH3); 13C NMR (100 MHz, CDCl3) δ 176.9, 173.8, 134.9, 133.0, 129.1,
128.6, 113.3 (t, J = 242.6 Hz, CF2H), 47.9 (t, J = 28.5 Hz, CCF2H), 37.8,
+
(m, CF2H); HRMS (ESI) m/z calcd for C15H19ClF2NO2 [M+H]+ 318.1072,
found 318.1067.
N-(2, 2-difluoroethyl)-N-isobutyrylbenzamide (4a)
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10.1002/ejoc.201801334
European Journal of Organic Chemistry
FULL PAPER
27.5, 22.5, 13.6; 19F NMR (376 MHz, CDCl3) δ -122.23 (dt, J = 56.8, 13.6
Hz, CF2H); 19F {1H}NMR (376 MHz, CDCl3) δ -122.23 (s, CF2H); HRMS
(ESI) m/z calcd for C14H18F2NO2+ [M+H]+ 270.1300, found 270.1303.
Keywords: imide • diazomethane • multicomponent • Copper •
difluoromethyl
[1]
Thalidomide: (a) T. Hideshima, D. Chauhan, Y. Shima, N. Raje, F. E.
Davies, Y. T. Tai, S. P. Treon, B. Lin, R. L. Schlossman, P. Richardson,
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J. B. Bartlett, K. Dredge, A. G. Dalgleish, Nat. Rev. Cancer, 2004, 4,
314-322.
(1S,2S,4aR,4bR,7S,9aS,10S,10aR)-N-acetyl-N-(2,2-difluoroethyl)-2,7-
dihydroxy-1-methyl-8-methylene-13-oxo-1,2,4b,5,6,7,8,9,10,10a-
decahydro-4a,1-(epoxymethano)-7,9a-methanobenzo[a]azulene-10-
carboxamide (7)
[2]
Ethosuximide: (a) T. R. Browne, F. E. Dreifuss, P. R. Dyken, D. J.
Goode, J. K. Penry, R. J. Porter, B. G. White, P. T. White, Neurology,
1975, 25, 515-524; (b) N. Leresche, H. R. Parri, G. Erdemli, A. Guyon,
J. P. Turner, S. R. Williams, E. Asprodini, V. Crunelli, J. Neurosci., 1998,
18, 4842-4853; (c) M. Z. Goren, F. Onat, Cns Drug Rev., 2007, 13,
224-239.
Colorless oil (71 mg, 70 % yield); 1H NMR (400 MHz, CDCl3) δ 6.34 (d, J
= 9.2 Hz, 1H), 5.99 (tt, J = 56.6, 4.3 Hz, 1H, CF2H), 5.88 (dd, J = 9.2, 3.6
Hz, 1H), 5.22 (t, J = 2.3 Hz, 1H), 4.97 (t, J = 2.1 Hz, 1H), 4.16 – 4.05 (m,
2H), 4.05 – 3.91 (m, 2H), 3.33 (d, J = 9.1 Hz, 1H), 2.52 (s, 2H), 2.41 (s,
3H), 2.26 – 2.06 (m, 3H), 2.04 – 1.88 (m, 3H), 1.83 (d, J = 10.9 Hz, 1H),
1.79 – 1.68 (m, 2H), 1.20 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 179.0 (d,
J = 1.7 Hz), 176.8, 173.4, 155.4, 132.7, 132.5, 113.0 (t, J = 242.9 Hz,
CF2H), 107.7, 91.0, 78.3, 70.0, 55.8, 53.3, 52.29, 50.28, 50.22, 47.5 (t, J
= 27.9 Hz, CCF2H), 45.9, 43.3, 38.2, 25.5, 17.3, 14.5; 19F NMR (376 MHz,
CDCl3) δ -121.66 (ddt, J = 56.0, 27.8, 13.0 Hz, CF2H); 19F {1H}NMR (376
MHz, CDCl3) δ -121.66 (d, J = 28.0 Hz, CF2H); HRMS (ESI) m/z calcd for
C23H28F2NO6+ [M+H]+ 452.1879, found 452.1882.
[3]
[4]
[5]
[6]
[7]
Penimide: T. Pacher, A. Raninger, E. Lorbeer, L. Brecker, P. P.-H., H.
Greger, J. Nat. Prod. 2010, 73, 1389-1393.
Captan: D. F. Rawn, S. C. Quade, W. F. Sun, A. Fouguet, A. Belanger,
M. Smith, Food chem., 2008, 109, 790-796.
Aniracetam: K. Nakamura, M. Kurasawa, Eur. J. Pharmacol., 2001, 420,
33-43.
Palau’imide: H. Luesch, W. Y. Toshida, R. E. Moore, V. J. Paul,
Tetrahedron, 2002, 58, 7959-7966.
(3R,4S,5R)-N-acetyl-N-(2,2-difluoroethyl)-3,4,5-trihydroxycyclohex-1-
ene-1-carboxamide (8)
For the application in pharmaceutical area: (a) S. Purser, P. R. Moore, S.
Swallow, V. Gouverneur, Chem. Soc. Rev. 2008, 37, 320–330; (b) J.
Wang, M. Sánchez-Roselló, J. L. Aceña, C. del Pozo, A. E.
Sorochinsky, S. Fustero, V. A. Soloshonok, H. Liu, Chem. Rev., 2014,
114, 2432-2506; (c) E. P. Gillis, K. J. Eastman, M. D. Hill, D. J.
Donnelly, N. A. Meanwell, J. Med. Chem., 2015, 58, 8315-8359.
Colorless oil (41 mg, 74 % yield); 1H NMR (400 MHz, Methanol-d4) δ 6.11
(dd, J = 3.5, 1.8 Hz, 1H), 5.94 (tt, J = 56.6, 4.3 Hz, 1H, CF2H), 4.29 (dt, J
= 3.9, 1.9 Hz, 1H, CHCF2H), 4.07 – 3.93 (m, 3H), 3.65 (dd, J = 7.0, 4.1
Hz, 1H), 2.63 (ddt, J = 18.0, 4.4, 2.0 Hz, 1H), 2.22 (dt, J = 5.2, 1.6 Hz,
1H), 2.18 (s, 3H); 13C NMR (100 MHz, Methanol-d4) δ 177.9, 177.6, 139.5,
138.0, 117.7 (t, J = 241.2 Hz, CF2H), 74.9, 70.8, 69.7, 50.5 (t, J = 27.9 Hz,
CCF2H), 34.3, 28.5; 19F NMR (376 MHz, Methanol-d4) δ -123.70 (dq, J =
56.5, 14.7 Hz, CF2H); 19F {1H}NMR (376 MHz, Methanol-d4) δ -123.70 (d,
[8] For review of the syntheses: (a) C. F. Ni, M. Y. Hu, J. B. Hu, Chem. Rev.,
2015, 115, 765-825; (b) J. Hu, W. Zhang, F. Wang, Chem. Commun.,
2009, 7465-7478; (c) Z. Feng, Y.-L. Xiao, X. Zhang, Acc. Chem. Res.,
2018, DOI: 10.1021/acs.accounts.8b00230; For selected examples: (d)
Z. Feng, Q. Q. Min, X. P. Fu, L. An, X. G. Zhang, Nat. Chem. 2017, 9,
918-923; (e) C. Xu, W.-H. Guo, X. He, Y.-L. Guo, X.-Y. Zhang, X.
Zhang, Nat. Commun. 2018, 9, 1170; (f) X. Yang, Z. Chen, Y. Cai, Y.-Y.
Huang, N. Shibata, Green Chem. 2014, 16, 4530-4534; (f) X. Yang, F.
Cheng, Y.-D. Kou, S. Pang, Y.-C. Shen, Y.-Y. Huang, N. Shibata,
Angew. Chem. Int. Ed. 2017, 56, 1510-1514; (g) S. M. Banik, J. W.
Medley, E. N. Jacobsen, Science 2016, 353, 51-54.
+
J = 15.8 Hz, CF2H); HRMS (ESI) m/z calcd for C11H16F2NO5 [M+H]+
280.0991, found 280.0993.
(R)-N-acetyl-N-(2,2-difluoroethyl)-4-
((3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3,7,12-trihydroxy-10,13-
dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)
pentanamide (9)
[9]
J. A. Erickson, J. I. McLoughlin, J. Org. Chem., 1995, 60, 1626-1631.
[10] N. A. Meanwell, J. Med. Chem., 2011, 54, 2529-2591.
Colorless oil (78 mg, 65 % yield); 1H NMR (400 MHz, CDCl3) δ 5.95 (tt, J
= 56.8, 4.6 Hz, 1H, CF2H), 4.03 (td, J = 13.0, 4.6 Hz, 2H, CHCF2H), 3.97
(d, J = 2.9 Hz, 1H), 3.84 (d, J = 2.9 Hz, 1H), 3.64 (s, 3H), 3.42 (dt, J =
11.1, 6.4 Hz, 1H), 2.79 (ddd, J = 14.7, 10.1, 4.3 Hz, 1H), 2.66 (ddd, J =
15.8, 9.2, 5.7 Hz, 1H), 2.44 (s, 3H), 2.20 (dtd, J = 12.8, 9.0, 5.0 Hz, 2H),
1.96 – 1.71 (m, 8H), 1.65 (d, J = 13.5 Hz, 2H), 1.62 – 1.48 (m, 4H), 1.48
– 1.35 (m, 4H), 1.32 – 1.21 (m, 1H), 1.10 (td, J = 12.3, 11.5, 4.8 Hz, 1H),
1.00 (d, J = 5.9 Hz, 3H), 0.88 (s, 3H), 0.68 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 176.7, 173.4, 113.4 (t, J = 242.5 Hz, CF2H), 73.1, 71.8, 68.4,
47.0, 46.8 (t, J = 28.5 Hz, CCF2H), 46.4, 41.6, 41.5, 39.5, 35.4, 35.2,
[11] (a) D. Schirlin, F. Gerhart, J. M. Hornsperger, M. Hamon, J. Wagner, M.
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Acknowledgments
We thank the National Natural Science Foundation of
China(21502076) Natural Science Foundation of Jiangxi
province (20161BAB213068), and Outstanding Young Talents
Scheme of Jiangxi Province (20171BCB23039) for funding this
research.
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difluoromethyl, copper-catalyzed*
Yu Gao, Shan-Qing Peng, De-Yong Liu,
Pei-Xin Rui, Xiang-Guo Hu *[a]
Page No. – Page No.
Copper-Catalyzed Four Component
Reaction for the Synthesis of N-
Difluoroethyl Imides
A general and efficient method for the synthesis N-difluoroethyl imides has been
developed. This copper-catalyzed four component reaction proceeds via in-situ
generated difluorodiazomethane，which does not require the prior formation and
transferring. The reaction is scalable, tolerant a range of functional groups, and also
suitable for the late-stage functionalization of drugs and drug-like molecules.
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