Synthesis of gem -difluorinated nitroso compounds

Article abstract of DOI:10.1021/jo5023537

A method for the synthesis of gem-difluorinated nitroso compounds is described. The reaction involves interaction of organozinc reagents with (bromodifluoromethyl)trimethylsilane followed by nitrosation of difluorinated organozinc species with an n-butyl nitrite/chlorotrimethylsilane system.

Full text of DOI:10.1021/jo5023537

Note
pubs.acs.org/joc
Synthesis of gem-Difluorinated Nitroso Compounds
Vladimir O. Smirnov,† Marina I. Struchkova,† Dmitry E. Arkhipov,‡,§ Alexander A. Korlyukov,‡
and Alexander D. Dilman*,†
†N. D. Zelinsky Institute of Organic Chemistry, 119991 Moscow, Leninsky prosp. 47, Russian Federation
‡A. N. Nesmeyanov Institute of Organoelement Compounds, 119991 Moscow, Vavilov str. 28, Russian Federation
§N. I. Pirogov Russian National Research Medical University, 117997 Moscow, Ostrovityanova str. 1, Russian Federation
S
* Supporting Information
ABSTRACT: A method for the synthesis of gem-difluorinated nitroso compounds is
described. The reaction involves interaction of organozinc reagents with (bromo-
difluoromethyl)trimethylsilane followed by nitrosation of difluorinated organozinc
species with an n-butyl nitrite/chlorotrimethylsilane system.
itroso compounds constitute a class of versatile
intermediates which can be involved in cycloaddition
Scheme 2. Transformations of Organozinc 2a
N
and redox processes, as well as in reactions with radicals and
nucleophiles.1 While methods for the preparation of nitroso
arenes2,3 and α-bromo and α-chloro nitroso alkanes4 are well
developed, approaches to fluorinated aliphatic nitroso com-
pounds are scarce. In particular, perfluorinated nitroso alkanes
can be obtained by electrophilic nitrosation of perfluorinated
mercury,5 cadmium,6 and silicon reagents.7 Several other
specific reactions involving harsh conditions and affording
polyfluorinated nitroso alkanes have been reported.8 At the
same time, there is steadily growing interest in partially
fluorinated molecules and reagents due to their utility in drug
design.9 In this regard, herein we describe a general method for
the synthesis of gem-difluorinated nitroso compounds starting
from conventional organozincs, difluorocarbene, and a nitro-
sating reagent (Scheme 1). The approach is based on our
of electrophilic nitroso product 3a with starting organozinc
reagent 2a. Thus, when reagent 2a was treated with half the
amount of the nitrosating system under standard conditions
(−25 °C, 1 h), the crude material contained only small
amounts of an unidentified fluorine-containing product, and no
nitroso compound 3a was detected (according to 19F NMR).
However, when reagent 2a was reacted with presynthesized
nitroso compound 3a at room temperature, product 4 was
obtained in 75% yield14 (Scheme 2, eq b).
Scheme 1. Synthesis of Nitroso Compounds
A series of fluorinated organozinc reagents generated from
organozinc bromides by CF2-insertion were nitrosated using
the n-BuONO/TMSCl system furnishing gem-difluorinated
nitroso compounds 3 in reasonable yields (Table 1). The ester
group, as well as the carbon−boron bond, remained unaffected
upon nitrosation.15
Nitroso compounds 3 appear as blue or green-blue crystals
or oils, with the color being characteristic for the monomeric
nitroso form. For 3f, the structure was confirmed by single
crystal X-ray diffraction analysis.16 However, upon prolonged
storage (from week to month, 0 °C) the crystals have a
tendency to gradually form a colorless microcrystalline powder.
The latter material, being dissolved in CDCl3, affords a blue
recent discovery that treatment of reagents 1 with a
difluorocarbene source leads to difluorinated reagents 2
which can be coupled with various electrophiles.10,11
Treatment of organozinc reagent 2a10a with nitrosonium
tetrafluoroborate (1.1 equiv) in acetonitrile gave the expected
product 3a in 44% yield (Scheme 2, eq a). 19F NMR analysis of
the crude product showed the presence of small amounts of
other fluorinated materials, indicating partial decomposition of
the starting organozinc 2a under the reaction conditions.
Fortunately, by switching to a milder nitrosating system, the
combination of n-butyl nitrite (1.3 equiv) and chlorotrime-
thylsilane (1.2 equiv), which generates nitrosyl chloride,12
allowed isolation of nitroso compound 3a in 63% yield. Further
attempts to improve the product yield were unsuccessful.13
Presumably, the decreased yield is associated with the reaction
Received: October 14, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo5023537 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Table 1. Nitrosation of Organozinc Reagents
Scheme 3. Synthesis of Nitro Compound 5
Scheme 4. Reactions of Compound 3a
Thus, nitroso compound 3a readily reacted at room temper-
ature with diphenylketene affording [2 + 2] cycloaddition
product 8 as a single regioisomer (the structure of 8 was
confirmed by X-ray analysis16). High regioselectivity of the
cycloaddition may be associated with the strong electron-
withdrawing character of a difluorinated substituent adjacent to
the nitroso group.19 At the same time, the reaction of 3a with
aniline was slow, and corresponding azo compound 9 was
obtained in 78% yield after 5 days.20
In summary, a method for the synthesis of gem-difluorinated
nitroso compounds by combining organozinc reagents, a
difluorocarbene source, and a nitrosating electrophile has
been developed. Despite variable yields, the reaction features
straightforward assembly of the nitroso compounds, which are
difficult to access by other means.
a
EXPERIMENTAL SECTION
Isolated yield based on organozinc bromide.
■
General Methods. All reactions were performed in Schlenk flasks
under an argon atmosphere. Column chromatography was carried out
employing silica gel (230−400 mesh). Acetonitrile was distilled from
CaH2 and stored over MS 4A. Organozinc reagents 1a−f,h10a and
(bromodifluoromethyl)trimethylsilane11d were prepared according to
literature procedures.
solution having identical NMR spectra to those of the freshly
prepared product, while evaporation of the solvent leads back
to blue crystals. This behavior is indicative of a monomer/
dimer equilibrium typical for nitroso compounds.17
Preparation of Organozinc Reagents 1g,k. To a stirred
suspension of zinc dust (for 1g, 10.0 mmol, 654 mg; for 1k, 15.0
mmol, 981 mg) in THF (5.0 mL) a drop of 1,2-dibromoethane was
added. The mixture was heated to reflux, and then two drops of
Me3SiCl were added to a hot suspension, and the mixture was
vigorously stirred for 15 min at 60 °C. During this period the
formation of gas was observed and the zinc dust appeared to become a
dark-gray fuzzy material (if this does not happen, an additional drop of
Me3SiCl should be added). Then, the reaction mixture was cooled in
an ice/water bath, and the organic bromide [5 mmol; for 1g, 2-
Similar to nitrosation, we attempted to perform nitration of
fluorinated oragnozinc 2a (Scheme 3). When nitronium
tetrafluoroborate was used, a mixture was formed containing
small amounts of nitro and nitroso compounds, along with
bromination product 6 being a major component (yields were
determined by 19F NMR; compound 6 was previously
described10a). The formation of product 6 is likely due to the
oxidative reactivity of the nitrating agent.18 Nevertheless, the
nitro compound 5 can be isolated in 77% yield after oxidation
of the nitroso group with tert-butyl hydroperoxide, though
azoxy product 7 was also obtained after chromatographic
separation as a minor byproduct.
(bromomethyl)phenyl benzoate; for 1k, 3-bromobutyl benzoate10c
]
was added portionwise within 5 min. The mixture was stirred for 1 h at
0 °C and at room temperature (for 1g, 18 h; for 1k, 72 h). The stirring
was discontinued, and the unreacted zinc was allowed to settle out.
The concentration of the organozinc reagent was determined by
iodometric titration.10a
We also briefly investigated the reactivity of the nitroso
group attached to the gem-difluorinated carbon (Scheme 4).
B
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The Journal of Organic Chemistry
Note
Preparation of Organozinc Reagents 1i,j. To a stirred suspension
of zinc dust (15.0 mmol, 981 mg) in THF (5.0 mL) a drop of 1,2-
dibromoethane was added. The mixture was heated to reflux, and then
two drops of Me3SiCl were added to a hot suspension, which was
followed by vigorous stirring of the mixture for 15 min at 60 °C.
During this period the formation of gas was observed, and zinc dust
appeared as a dark-gray fuzzy material (if this does not happen, an
additional drop of Me3SiCl should be added). Then, the reaction
mixture was cooled to −25 °C, and a solution of the organic bromide
(1.11 g, 5.0 mmol; for 1i, 1-bromomethylnaphthalene; for 1j, 2-
bromomethylnaphthalene) in THF (4.0 mL) was added dropwise
within 20 min. The mixture was allowed to warm gradually (within
approximately 1 h) to 0 °C, followed by cooling in a bath substitued
with ice/water, with continued stirring for 1 h. The cooling bath was
removed, and the mixture was stirred for 18 h at room temperature.
Then the stirring was discontinued, and unreacted zinc was allowed to
settle out. The concentration of organozinc reagent was determined by
iodometric titration.10a
C8H6BrF2NO (250.04): C, 38.43; H, 2.42; N, 5.60. Found: C, 38.62;
H, 2.55; N, 5.41.
1-Bromo-2-(2,2-difluoro-2-nitrosoethyl)benzene (3e). 244 mg
1
(65%). Blue oil. Rf 0.34 (hexane). H NMR (300 MHz, CDCl3) δ:
7.58 (d, J = 7.9 Hz, 1H), 7.35−7.25 (m, 2H); 7.24−7.13 (m, 1H), 3.41
(t, J = 15.3, 2H). 13C{1H} NMR (75 MHz, CDCl3) δ: 133.5, 132.4,
130.0, 129.4 (t, J = 2.4 Hz), 127.8, 125.9 (t, J = 275.8 Hz), 125.8, 35.0
(t, J = 24.0 Hz). 19F NMR (282 MHz, CDCl3) δ: −100.3 (t, J = 15.3
Hz). Anal. Calcd for C8H6BrF2NO (250.04): C, 38.43; H, 2.42; N,
5.60. Found: C, 38.23; H, 2.39; N, 5.43.
4-(2,2-Difluoro-2-nitrosoethyl)phenyl Benzoate (3f). 327 mg
(75%). Blue crystals. Mp 89−92 °C. Rf 0.39 (EtOAc/hexane, 1/8).
1H NMR (300 MHz, CDCl3) δ: 8.21 (d, J = 7.5 Hz, 2H), 7.65 (t, J =
7.4 Hz, 1H), 7.52 (t, J = 7.6 Hz, 2H), 7.31−7.17 (m, 4H), 3.18 (t, J =
15.6 Hz, 2H). 13C{1H} NMR (75 MHz, CDCl3) δ: 165.1, 151.0,
133.8, 131.7, 130.3, 129.5, 128.7, 126.5 (t, J = 2.7 Hz), 125.6 (t, J =
274.8 Hz), 122.2, 34.7 (t, J = 23.9 Hz). 19F NMR (282 MHz, CDCl3)
δ: −100.8 (t, J = 15.6 Hz). Anal. Calcd for C15H11F2NO3 (291.25): C,
61.86; H, 3.81; N, 4.81. Found: C, 61.78; H, 4.01; N, 4.65.
General Procedure. A freshly titrated THF solution of 1 (1.5
mmol) was concentrated under vacuum until a solid or viscous residue
was formed. The residue was dissolved in freshly distilled MeCN (1.5
mL). To the resulting solution was added sodium acetate (148 mg, 1.8
mmol) at room temperature, the reaction flask was immersed in a cold
bath at −25 °C, and the mixture was stirred for 10 min at −25 °C.
Then, Me3SiCF2Br (365 mg, 1.8 mmol) was added dropwise at −25
°C, and the reaction mixture was stirred at this temperature for 18 h.
Then, n-BuONO (200 mg, 1.94 mmol) and Me3SiCl (192 mg, 1.77
mmol) were successively added at −25 °C, and the reaction mixture
was stirred at −25 °C for 1 h. The green-blue reaction mixture was
quenched by addition of methyl tert-butyl ether (5 mL) and saturated
aqueous NaHCO3 (3 mL), and the reaction mixture was allowed to
reach room temperature with stirring. The layers were separated, and
the aqueous layer was washed with methyl tert-butyl ether (2 × 5 mL).
The combined organic phases were dried over Na2SO4 and
concentrated on a rotary evaporator, and the residue was purified by
column chromatography on silica gel.
Methyl 4-(2,2-Difluoro-2-nitrosoethyl)benzoate (3a). 217 mg
(63%). Blue crystals. Mp 44−47 °C. Rf 0.25 (EtOAc/hexane, 1/8).
1H NMR (300 MHz, CDCl3) δ: 7.99 (d, J = 8.2 Hz, 2H), 7.26 (d, J =
8.1 Hz, 2H), 3.91 (s, 3H), 3.19 (t, J = 15.5 Hz, 2H). 13C{1H} NMR
(75 MHz, CDCl3) δ: 166.6, 134.1 (t, J = 2.5 Hz), 130.6, 130.2, 130.1,
125.4 (t, J = 274.8 Hz), 52.3, 35.2 (t, J = 23.8 Hz). 19F NMR (282
MHz, CDCl3) δ: −100.6 (t, J = 15.5 Hz). Anal. Calcd for C10H9F2NO3
(229.18): C, 52.41; H, 3.96; N, 6.11. Found: C, 52.48; H, 4.07; N,
6.04.
2-(2,2-Difluoro-2-nitrosoethyl)phenyl Benzoate (3g). 246 mg
(56%). Blue crystals. Mp 41−43 °C. Rf 0.33 (EtOAc/hexane, 1/8).
1H NMR (300 MHz, CDCl3) δ: 8.21 (d, J = 7.6 Hz, 2H), 7.69 (t, J =
7.3 Hz, 1H), 7.56 (t, J = 7.6 Hz, 2H), 7.41 (td, J = 7.6, 1.7 Hz, 1H),
7.36−7.22 (m, 3H), 3.21 (t, J = 15.1 Hz, 2H). 13C{1H} NMR (50
MHz, CDCl3) δ: 164.7, 149.9, 134.1, 132.5, 130.3, 129.8, 129.1, 128.9,
126.4, 125.9 (t, J = 275.2 Hz), 123.2, 121.5 (t, J = 2.9 Hz), 29.9 (t, J =
24.5 Hz). 19F NMR (282 MHz, CDCl3) δ: −100.3 (t, J = 15.1 Hz).
Anal. Calcd for C15H11F2NO3 (291.25): C, 61.86; H, 3.81; N, 4.81.
Found: C, 61.71; H, 3.94; N, 4.76.
2-[4-(2,2-Difluoro-2-nitrosoethyl)phenyl]-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane (3h). 272 mg (61%). Blue crystals. Mp 76−80
1
°C. Rf 0.42 (EtOAc/hexane, 1/8). H NMR (300 MHz, CDCl3) δ:
7.77 (d, J = 7.9 Hz, 2H), 7.19 (d, J = 7.8 Hz, 2H), 3.18 (t, J = 15.5 Hz,
2H), 1.35 (s, 12H). 13C{1H} NMR (75 MHz, CDCl3) δ: 135.3, 132.0
(t, J = 2.7 Hz), 129.9, 125.8 (t, J = 274.4 Hz), 84.1, 35.5 (t, J = 23.7
Hz), 25.0. 19F NMR (282 MHz, CDCl3) δ: −100.6 (t, J = 15.5 Hz).
Anal. Calcd for C14H18BF2NO3 (297.11): C, 56.60; H, 6.11; N, 4.71.
Found: C, 56.46; H, 5.98; N, 4.73.
1-(2,2-Difluoro-2-nitrosoethyl)naphthalene (3i). 106 mg (32%).
1
Green-blue crystals. Mp 37−41 °C. Rf 0.24 (hexane). H NMR (300
MHz, CDCl3) δ: 7.97−7.80 (m, 3H), 7.61−7.47 (m, 2H), 7.42 (t, J =
7.6 Hz, 1H), 7.33 (d, J = 7.0 Hz, 1H), 3.64 (t, J = 15.4 Hz, 2H).
13C{1H} NMR (75 MHz, CDCl3) δ: 134.1, 132.5, 129.9, 129.3, 129.0,
126.8, 126.5 (t, J = 275.3 Hz), 126.0, 125.33, 125.26 (t, J = 2.3 Hz),
123.7, 31.8 (t, J = 24.1 Hz). 19F NMR (282 MHz, CDCl3) δ: −99.7 (t,
J = 15.4). Anal. Calcd for C12H9F2NO (221.20): C, 65.16; H, 4.10; N,
6.33. Found: C, 65.19; H, 4.04; N, 6.21.
Methyl 3-(2,2-Difluoro-2-nitrosoethyl)benzoate (3b). 251 mg
(73%). Blue crystals. Mp 27−29 °C. Rf 0.27 (EtOAc/hexane, 1/8).
1H NMR (300 MHz, CDCl3) δ: 7.99 (d, J = 6.9 Hz, 1H), 7.88 (s, 1H),
7.50−7.33 (m, 2H), 3.92 (s, 3H), 3.19 (t, J = 15.6 Hz, 2H). 13C{1H}
NMR (75 MHz, CDCl3) δ: 166.6, 134.9, 131.7, 130.9, 129.50, 129.45
(t, J = 2.8 Hz), 129.0, 125.5 (t, J = 274.5 Hz), 52.3, 35.0 (t, J = 23.9
Hz). 19F NMR (282 MHz, CDCl3) δ: −100.8 (t, J = 15.6 Hz). Anal.
Calcd for C10H9F2NO3 (229.18): C, 52.41; H, 3.96; N, 6.11. Found:
C, 52.26; H, 4.01; N, 5.99.
2-(2,2-Difluoro-2-nitrosoethyl)naphthalene (3j). 134 mg (40%).
1
Green-blue crystals. Mp 35−36 °C. Rf 0.25 (hexane). H NMR (300
MHz, CDCl3) δ: 7.87−7.75 (m, 3H), 7.65 (s, 1H), 7.54−7.45 (m,
2H), 7.28 (d, J = 8.4 Hz, 1 H), 3.33 (t, J = 15.6 Hz, 2H). 13C{1H}
NMR (50 MHz, CDCl3) δ: 133.4, 133.0, 130.0, 128.6, 127.9, 127.8,
126.6, 126.5, 126.4 (t, J = 2.8 Hz), 126.0 (t, J = 274.7 Hz), 35.5 (t, J =
23.4 Hz). 19F NMR (282 MHz, CDCl3) δ: −100.4 (t, J = 15.6 Hz).
Anal. Calcd for C12H9F2NO (221.20): C, 65.16; H, 4.10; N, 6.33.
Found: 65.29; H, 4.27; N, 6.27.
Methyl 2-(2,2-Difluoro-2-nitrosoethyl)benzoate (3c). 158 mg
1
(46%). Blue oil. Rf 0.36 (EtoAc/hexane, 1/8). H NMR (300 MHz,
4,4-Difluoro-3-methyl-4-nitrosobutyl Benzoate (3k). 225 mg
(58%). Blue oil. Rf 0.16 (EtOAc/hexane, 1/30). 1H NMR (300
MHz, CDCl3) δ: 8.02 (d, J = 7.4 Hz, 2H), 7.58 (t, J = 7.4 Hz, 1H),
7.45 (t, J = 7.6 Hz, 2H), 4.46−4.31 (m, 2H), 2.68−2.46 (m, 1H),
2.22−2.07 (m, 1H), 1.83−1.67 (m, 1H), 1.08 (d, J = 7.0 Hz,
3H).13C{1H} NMR (75 MHz, CDCl3) δ: 166.4, 133.3, 130.0, 129.7,
128.6, 128.2 (t, J = 276.4 Hz), 61.7, 32.1 (t, J = 22.4 Hz), 28.1 (t, J =
3.1 Hz), 11.7 (t, J = 4.1 Hz). 19F NMR (282 MHz, CDCl3) δ: −107.4
(dd, J = 191.8, 12.3 Hz, 1F), −110.0 (dd, J = 191.8, 14.6 Hz, 1F). Anal.
Calcd for C12H13F2NO3 (257.23): C, 56.03; H, 5.09; N, 5.45. Found:
C, 56.10; H, 5.10; N, 5.46.
CDCl3) δ: 7.97 (d, J = 7.6 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.39 (t, J
= 7.6 Hz, 1H), 7.28 (d, J = 7.6 Hz, 1H), 3.87 (s, 3H), 3.76 (t, J = 15.7
Hz, 2H). 13C{1H} NMR (75 MHz, CDCl3) δ: 167.4, 133.1, 132.3,
131.3, 130.9, 130.8 (t, J = 2.8 Hz), 128.4, 126.0 (t, J = 274.9 Hz), 52.3,
32.6 (t, J = 23.6 Hz). 19F NMR (282 MHz, CDCl3) δ: −100.4 (t, J =
15.7). Anal. Calcd for C10H9F2NO3 (229.18): C, 52.41; H, 3.96; N,
6.11. Found: C, 52.43; H, 4.03; N, 6.09.
1-Bromo-4-(2,2-difluoro-2-nitrosoethyl)benzene (3d). 247 mg
1
(66%). Blue oil. Rf 0.25 (hexane). H NMR (300 MHz, CDCl3) δ:
7.46 (d, J = 8.3 Hz, 2H), 7.05 (d, J = 8.1 Hz, 2H), 3.10 (t, J = 15.5 Hz,
2H). 13C{1H} NMR (75 MHz, CDCl3) δ: 132.2, 132.1, 128.0 (t, J =
2.8 Hz), 125.3 (t, J = 274.8 Hz), 122.6, 34.7 (t, J = 23.9 Hz). 19F NMR
(282 MHz, CDCl3) δ: −100.9 (t, J = 15.5 Hz). Anal. Calcd for
Methyl 4-[2-((Acetyloxy){1,1-difluoro-2-[4-(methoxycarbonyl)-
phenyl]ethyl}amino)-2-oxoethyl]benzoate (4). A solution of organo-
zinc 2a10a (0.41 mmol, 1.0 mL of 0.41 M in MeCN [a stock solution of
C
dx.doi.org/10.1021/jo5023537 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
2a was stabilized with 3 equiv of DMF,10a with the concentration of
organozinc reagent being determined by 19F NMR using PhCF3 as
internal standard]) was added to a solid nitroso compound 3a (93 mg,
0.406 mmol) at room temperature, and the mixture was stirred for 1.5
h. Then, EtOAc (4.0 mL) and a solution of NaHSO4 (240 mg, 2.0
mmol in 2.0 mL of water) were successively added. The organic layer
was separated, and the aqueous phase was washed with EtOAc (4.0
mL). The combined organic phases were dried over Na2SO4 and
concentrated, and the residue was purified by column chromatography
on silica gel to afford 136 mg (75%) of compound 4 as colorless
98−99 °C. Rf 0.23 (EtOAc/hexane, 1/8). 1H NMR (300 MHz,
CDCl3) δ: 8.00 (d, J = 8.2 Hz, 2H), 7.84 (d, J = 6.8 Hz, 2H), 7.60−
7.47 (m, 3H), 7.38 (d, J = 8.0 Hz, 2H), 3.90 (s, 3H), 3.50 (t, J = 14.7
Hz, 2H). 13C{1H} NMR (75 MHz, CDCl3) δ: 166.9, 150.8, 136.9 (t, J
= 2.3 Hz), 133.4, 130.9, 129.8, 129.6, 129.4, 123.6, 123.6 (t, J = 252.8
Hz), 52.2, 39.9 (t, J = 27.1 Hz). 19F NMR (282 MHz, CDCl3) δ:
−90.4 (t, J = 14.7 Hz). Anal. Calcd for C16H14F2N2O2 (304.29): C,
63.15; H, 4.64; N, 9.21. Found: C: 63.11; H: 4.59; N: 9.37.
ASSOCIATED CONTENT
* Supporting Information
Copies of NMR spectra for all compounds, X-ray ellipsoid
plots, and CIF files (for 3f and 8). This material is available free
of charge via the Internet at http://pubs.acs.org.
■
1
crystals. Mp 128−131 °C. Rf 0.13 (EtOAc/hexane, 1/3). H NMR
S
(300 MHz, CDCl3) δ: 7.98 (d, J = 8.1 Hz, 2H), 7.95 (d, J = 8.1 Hz,
2H), 7.33 (d, J = 8.1 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 3.95−3.53 (m,
4H); 3.89 (s, 6H), 2.16 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ:
170.9, 167.3, 166.83, 166.77, 137.6, 136.3 (t, J = 2.5 Hz), 130.7, 130.0,
129.9, 129.7, 129.6, 129.5, 120.2 (t, J = 259 Hz), 52.2, 41.8 (t, J = 26.3
Hz), 41.0 (t, J = 2.1 Hz), 17.9. 19F NMR (282 MHz, CDCl3) δ: −78.2
(br d, J = 198 Hz); −83.1 (br). Anal. Calcd for C22H21F2NO7
(449.40): C, 58.80; H, 4.71; N, 3.12. Found: C, 58.88; H, 4.80; N,
3.22.
AUTHOR INFORMATION
Corresponding Author
*E-mail: adil25@mail.ru.
■
Notes
Oxidation of Nitroso Compounds 3a. tert-Butylhydroperoxide
(1.66 mmol, 214 mg of 70% aqueous solution) was added to a solution
of 3a (185 mg, 0.81 mmol) in acetonitrile (1 mL) at room
temperature, and the mixture was stirred for 52 h. The precipitate
was filtered affording 11 mg of compound 7, the filtrate was
concentrated under vacuum, and the residue was purified by column
chromatography on silica gel (EtOAc/hexane, gradient from 1/10 to
1/3) furnishing nitro compound 5 (153 mg, 77%) and an additional 5
mg of compound 7 (combined yield 16 mg, 9%).
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Ministry of Science (Project
MD-4750.2013.3), Russian Foundation for Basic Research
(Projects 14-03-00293, 13-03-12074, 14-03-31253_mol_a, 14-
03-31265_mol_a), and the Russian Academy of Sciences.
Methyl 4-(2,2-Difluoro-2-nitroethyl)benzoate (5). Colorless crys-
tals. Mp 73−76 °C. Rf 0.39 (EtOAc/hexane, 1/3). H NMR (300
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595−607. (c) The Chemistry of Amino, Nitroso, Nitro and Related
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Mahapatro, S. N.; Broene, R. D.; Guy, J. K. J. Am. Chem. Soc. 1988,
110, 593−599.
MHz, CDCl3) δ: 8.02 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H),
3.90 (s, 3H), 3.70 (t, J = 14.1 Hz, 2H). 13C{1H} NMR (75 MHz,
CDCl3) δ: 166.4, 132.8 (t, J = 2.8 Hz), 131.0, 130.4, 130.3, 123.9 (t, J
= 287.4 Hz), 52.3, 39.5 (t, J = 22.5 Hz). 19F NMR (282 MHz, CDCl3)
δ: −86.3 (t, J = 14.1 Hz). Anal. Calcd for C10H9F2NO4 (245.18): C,
48.99; H, 3.70; N, 5.71. Found: C, 49.11; H, 3.79; N, 5.69.
(2) Gowenlock, B. G.; Richter-Addo, G. B. Chem. Rev. 2004, 104,
3315−3340.
Methyl 4-{2-[{1,1-Difluoro-2-[4-(methoxycarbonyl)phenyl]ethyl}-
NNO-azoxy]-2,2-difluoroethyl}benzoate (7). Colorless crystals. Mp
158−161 °C. Rf 0.23 (EtOAc/hexane, 1/3). 1H (300 MHz, CDCl3) δ:
8.01 (d, J = 8.8 Hz, 2H), 7.98 (d, J = 8.8 Hz, 2H), 7.32 (d, J = 7.7 Hz,
2H), 7.29 (d, J = 7.7 Hz, 2H), 3.93 (s, 3H), 3.92 (s, 3H), 3.68 (t, J =
14.1 Hz, 2H), 3.60 (t, J = 14.5 Hz, 2H). 13C{1H} NMR (50 MHz,
CDCl3) δ: 166.8, 166.5, 135.8 (t, J = 3.0 Hz), 133.4 (t, J = 2.8 Hz),
130.8, 130.6, 130.3, 130.2, 130.1, 129.9, 122.8, 121.1 (t, J = 255.1 Hz),
52.4, 52.3, 39.9 (t, J = 23.1 Hz), 38.6 (t, J = 25.9 Hz). 19F (282 MHz,
CDCl3) δ: −86.6 (t, J = 14.1 Hz, 2F), −87.3 (t, J = 14.5 Hz). Anal.
Calcd for C20H18F4N2O5 (442.36): C, 54.30; H, 4.10; N, 6.33. Found:
C: 54.39; H: 4.19; N: 6.29.
(3) (a) Priewisch, B.; Ruck-Braun, K. J. Org. Chem. 2005, 70, 2350−
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2352. (b) Molander, G. A.; Cavalcanti, L. N. J. Org. Chem. 2012, 77,
4402−4413. (c) Ruck-Braun, K.; Priewisch, B. In Science of Synthesis;
̈
Georg Thieme Verlag: Stuttgart-New York, 2007; Vol. 31b, pp 1321−
1360. (d) Vancik, H. Aromatic C-Nitroso Compounds; Springer: 2013.
(4) For recent literature, see: (a) Bou-Moreno, R.; Luengo-Arratta,
S.; Pons, V.; Motherwell, W. B. Can. J. Chem. 2013, 91, 6−12.
(b) Gupta, A. K.; Acharya, J.; Pardasani, D.; Dubey, D. K. Tetrahedron
Lett. 2007, 48, 767−770. (c) Terent’ev, A. O.; Krylov, I. B.; Ogibin, Y.
N.; Nikishin, G. I. Synthesis 2006, 3819−3824.
(5) Tarrant, P.; O’Connor, D. E. J. Org. Chem. 1964, 29, 2012−2013.
(6) Ludovici, K.; Naumann, D.; Siegemund, G.; Tyrra, W.; Varbelow,
H. G.; Wrubel, H. J. Fluorine Chem. 1995, 73, 273−274.
Methyl 4-[2,2-Difluoro-2-(3-oxo-4,4-diphenyl-1,2-oxazetidin-2-
yl)ethyl]benzoate (8). A solution of diphenylketene21 (0.67 mmol,
0.5 mL of 1.3 M in Et2O) was added dropwise to a solution of 3a (101
mg, 0.44 mmol) in CH2Cl2 at room temperature. The mixture was
stirred for 1 h and then diluted with hexane (5 mL), and the resulting
solution was chromatographed on silica gel (EtOAc/hexane, 1/12)
affording compound 8 as colorless crystals (185 mg, 99%). Mp 66−68
(7) Singh, R. P.; Shreeve, J. M. Chem. Commun. 2002, 1818−1819.
(8) (a) Birchall, J. M.; Bloom, A. J.; Haszeldine, R. N.; Willis, C. J.
Proc. Chem. Soc., London 1959, 367−368. (b) Haszeldine, R. N. J.
Chem. Soc. 1953, 2075−2081.
1
(9) (a) Liang, T.; Neumann, C. N.; Ritter, T. Angew. Chem., Int. Ed.
°C. Rf 0.18 (EtOAc/hexane, 1/8). H NMR (300 MHz, CDCl3) δ:
2013, 52, 8214−8264. (b) Muller, K.; Faeh, C.; Diederich, F. Science
8.00 (d, J = 8.2 Hz, 2H), 7.53−7.37 (m, 12H), 3.91 (s, 3H), 3.63 (t, J
= 13.9 Hz, 2H). 13C{1H} NMR (75 MHz, CDCl3) δ: 170.2, 166.8,
135.5 (t, J = 2.4 Hz), 135.1, 130.7, 130.0, 129.9, 129.6, 128.9, 126.5,
118.3 (t, J = 258.1 Hz), 103.4, 52.2, 40.4 (t, J = 25.0 Hz). 19F NMR
(282 MHz, CDCl3) δ: −85.8 (t, J = 13.9 Hz). Anal. Calcd for
C24H19F2NO4 (423.41): C, 68.08; H, 4.52; N, 3.31. Found: C, 68.05;
H, 4.55; N, 3.31.
Methyl 4-{2,2-Difluoro-2-[(E)-phenyldiazenyl]ethyl}benzoate (9).
Aniline (39 mg, 0.42 mmol) was added to a solution of 3a (92 mg,
0.40 mmol) in THF (2 mL) at 0 °C, and the mixture was stirred at
room temperature for 5 days. The mixture was concentrated under
vacuum, and the residue was purified by column chromatography on
silica gel (EtOAc/hexane, 1/10). 95 mg (78%). Yellow crystals. Mp
̈
́ ́
2007, 317, 1881−1886. (c) Wang, J.; Sanchez-Rosello, M.; Acena, J.
̃
L.; del Pozo, C.; Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.;
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S.; Levin, V. V.; Struchkova, M. I.; Dilman, A. D. J. Org. Chem. 2014,
79, 818−822. (c) Levin, V. V.; Dilman, A. D. Struchkova, M. I. J.
Fluorine Chem. in press, DOI: 10.1016/j.jfluchem.2014.08.021.
(11) For relevant work from our laboratory on the synthesis of CF2-
containing products, see: (a) Kosobokov, M. D.; Levin, V. V.;
Struchkova, M. I.; Dilman, A. D. Org. Lett. 2014, 16, 3784−3787.
(b) Kosobokov, M. D.; Levin, V. V.; Zemtsov, A. A.; Struchkova, M. I.;
D
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The Journal of Organic Chemistry
Note
Korlyukov, A. A.; Arkhipov, D. E.; Dilman, A. D. Org. Lett. 2014, 16,
1438−1441. (c) Tsymbal, A. V.; Kosobokov, M. D.; Levin, V. V.;
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(d) Kosobokov, M. D.; Dilman, A. D.; Levin, V. V.; Struchkova, M. I. J.
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(12) Weiß, R.; Wagner, K.-G. Chem. Ber. 1984, 117, 1973−1976.
(13) Though reagent 2a is expected to be unstable in the presence of
Lewis acids (for example, formed as a result of nitrosation), added zinc
salts did not exhibit a detrimental effect on the nitrosation process.
Thus, the addition of 1 equiv of ZnBr2 to reagent 2a and stirring for 1
h at −25 °C followed by treatment with n-BuONO/TMSCl had
virtually no influence on the yield of nitroso product 3a (60% vs 63%
without ZnBr2). We thank a referee for suggesting this experiment.
(14) For a detailed discussion concerning the mechanism of
formation of product 4 and its structural assignment, see Supporting
Information.
(15) For a rapid nitrosation of the C−B bond, see ref 3b.
(16) See Supporting Information for a CIF file and an ellipsoid plot.
(17) (a) Gowenlock, B. G.; Luttke, W. Quart. Rev. 1958, 12, 321−
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340. (b) Snyder, J. P.; Heyman, M. L.; Suciu, E. N. J. Org. Chem. 1975,
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bromine was reported; see: Hojo, M.; Ueda, T.; Daike, C.; Takezaki,
F.; Furuya, Y.; Miyamoto, K.; Narutaki, A.; Kato, R. Bull. Chem. Soc.
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E
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