Metal-free chemoselective ortho -C(sp2)-F bond hydroxylation and N-trifluoroacylation of fluoroarylamines for domino synthesis of 2-(N-trifluoroacyl)aminophenols

Article abstract of DOI:10.1055/s-0034-1379905

Abstract A novel chemoselective reaction for the formation of C-O bonds by C(sp²)-F bond cleavage and concomitant N-trifluoroacylation of fluoroanilines using trifluoroacetic acid and Oxone is presented. This domino reaction gives o-hydroxy-N-trifluoroacetanilides in good yields under metal-free conditions in a single step. Selective ortho-directed monohydroxylation and N-trifluoroacylation of 2- and 6-fluoro- or 2,6-difluoro-substituted anilines takes place in this transformation.

Full text of DOI:10.1055/s-0034-1379905

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2015, 26, 1258–1262
letter
1258
V. Venkateswarlu et al.
Letter
Synlett
Metal-Free Chemoselective ortho-C(sp2)–F Bond Hydroxylation
and N-Trifluoroacylation of Fluoroarylamines for Domino Synthe-
sis of 2-(N-Trifluoroacyl)aminophenols
F
Applications
Vunnam Venkateswarlua,b
Shilpi Balgotraa,b
K. A. Aravinda Kumara
Ram A. Vishwakarmaa,b
Sanghapal D. Sawant*a,b
- metal-free
X = Y = F
NHCOCF3
- chemoselective
- ortho-directed
- monohydroxylation
N
R
R
CF3
R
O
OH
NHCOCF3
X = H
Y = F
X
NH2
TFA/
NH2
OH
R
X = Y = Cl, Br, I
oxone
no reaction
R
OH
a Medicinal Chemistry Division, CSIR-Indian Institute of Integrative
Medicine, Canal Road, Jammu-180 001, India
b Academy of Scientific and Innovative Research, Anusandhan
Bhawan, 2 Rafi Marg, New Delhi 110 001, India
sdsawant@iiim.res.in
dioxane
Y
X = H; Y = Cl, Br, I
Applications in late-
stage modifications of
natural products or
drug-like molecules in
drug discovery
ref. 7
X
NHCOCF3
OH
X = Cl, Br, I
Y = F
sawant.rrl@gmail.com
R
Received: 31.10.2014
Accepted after revision: 25.02.2015
Published online: 24.03.2015
fluoro arylamines by using an oxidative nonmetallic combi-
nation of TFA and Oxone®; these products can alternatively
be obtained by following a conventional synthetic route us-
ing selective N-trifluoroacylation of aminophenols by using
a protection/deprotection strategy. To our knowledge, there
are no reports on the direct formation of N-trifluoroacyl-2-
aminophenols from fluoroarylamines. Herein, we report
the nucleophilic substitution (SNAr) of a 2-fluoro-substitu-
ent with an OH group to give 2-hydroxy-N-trifluoroacylat-
ed arylamines in good yields.
DOI: 10.1055/s-0034-1379905; Art ID: st-2014-d0907-l
Abstract A novel chemoselective reaction for the formation of C–O
bonds by C(sp2)–F bond cleavage and concomitant N-trifluoroacylation
of fluoroanilines using trifluoroacetic acid and Oxone® is presented.
This domino reaction gives o-hydroxy-N-trifluoroacetanilides in good
yields under metal-free conditions in a single step. Selective ortho-di-
rected monohydroxylation and N-trifluoroacylation of 2- and 6-fluoro-
or 2,6-difluoro-substituted anilines takes place in this transformation.
We recently reported a selective ortho-directed C–H ox-
ygenation of simple anilines, forming N-trifloroacylated o-
hydroxy arylamines.7 During our studies on conversion of
various halo-substituted arylamines, especially fluoro-sub-
stituted compounds, using an oxidative mixture of TFA and
Oxone, we came across an interesting conversion (Scheme
1; solvent = dioxane). Typically, when 2-fluoro-substituted
arylamines were subjected to this oxidation reaction, we
could detect the formation of a mixture of products by GC-
MS analysis (Figure S1 in the Supporting Information), in-
cluding ortho-hydroxylated N-trifluoroacetanilide as a ma-
jor product, with the fluorine having been replaced by a hy-
Key words C–F bonds, chemoselective reactions, C–O bonds, fluoro-
arylamine, hydroxylation
Fluorine forms the strongest single bond to carbon and
is very hard to cleave;1 consequently, chemical modification
of such sites in organic fluorocompounds is not an easy
task.2 Nevertheless, several reports relate to C–F bond cleav-
age for the reduction of fluorocarbons or the transforma-
tion of fluorocarbons into partially fluorinated organic mol-
ecules.3
C–F bond-cleavage reactions, mediated by activation of
this bond, can be achieved by using transition-metal spe-
cies.4 Cleavage of the C–F bond for the formation of phenol
has been little explored, with few reports available on this
conversion.5 Generally, conversions of aryl halides into phe-
nols are limited to iodo-, bromo- and, to some extent,
chloro-aromatic substrates through nucleophilic substitu-
tion. Many methods have been reported for the generation
of phenolic C–O bonds6 and aromatic hydroxylation is at-
tractive for late-stage oxidative derivatization of aromatic
substrates.
H
N
CF3
+
N
F
N
O
NH2
F
OH
F
NO2
F
2a (major)
OH
3
TFA, oxone
solvent
H
N
CF3
1
+
+
O
F
4
5
We now report a simple approach for the hydroxylation
and concomitant N-trifluoroacylation to form N-trifluoro-
acyl-2-aminophenols by nucleophilic substitution of ortho-
Scheme 1 Formation of 2-hydroxy-N-trifluoroacetanilide and by-prod-
ucts from 2-fluoroaniline by using TFA and Oxone
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1258–1262

1259
V. Venkateswarlu et al.
Letter
Synlett
Table 1 Screening of Solvents for Formation of 2-Hydroxy-N-trifluoro-
acetanilide from 2-Fluoroaniline (See Scheme 1)
Our studies then continued by screening a range of fluo-
roaniline substrates to explore the generality of this reac-
tion (Table 1). In all cases, good yields of the respective 2-
hydroxy-N-trifluoroacyl-arylamine products were ob-
tained. Screening of solvents was carried out and dioxane
was found to give the best results (Table 1, entry 4); where-
as with DMSO, THF, DMF, acetonitrile, and MeOH, compara-
tively low or no yields were obtained. Furthermore, the use
of 1.2 equivalents of Oxone and more than 2.0 equivalents
of TFA led to excellent conversion of substrate 1, at 90 °C in
2–3 hours. All subsequent reactions were performed under
these optimized conditions. A wide range of substituted
arylamines underwent reaction smoothly (Table 2).
The conversion was found to be very specific for 2-
and/or 6-fluoro or 2,6-difluoro-substituted arylamine sub-
strates. No product formation was observed when Cl, Br, or I
groups were substituted for fluorine. Some examples of this
chemoselective conversion are presented in Table 3.
Entry
Solvent
Yield (%)a
1b
2a
3
4
5
1
2
3
4
5
6
7
8
toluene
DMF
45
20
–
–
55
20
90
21
–
–
–
10
–
–
–
–
MeOH
dioxane
THF
–
–
67
35
–
9.2
5
3.5
25
–
–
15
10
8
DMSO
CH2Cl2
MeCN
40
–
25
30
45
–
–
10
5
25
a Isolated yield after column chromatography.
b Recovered starting material.
droxyl group. These findings were confirmed by 19F NMR
spectroscopic analysis of the product, which revealed that
the fluorine peak had disappeared.
However, in the case of 2,6-disubstituted fluoroaniline,
only monohydroxy-N-trifluoroacetanilide was obtained,
with no dihydroxy product being observed. Furthermore,
Table 2 Formation of 2-Hydroxy-N-trifluoroacetanilide from Fluoroarylamine Substratesa
H
H
N
H
N
N
CF3
CF3
CF3
O
O
OH
F
OH
O
F3CO
2c 69%
OH
F
2a 66%
2b 63%
H
H
N
H
Cl
Br
CF3
N
CF3
N
CF3
O
O
O
OH
OH
OH
2f 65%
2d 66%
2e 67%
H
N
H
N
H
CF3
CF3
N
CF3
O
O
O
Br
2i 67%
OH
Cl
2g 69%
OH
OH
2h 68%
H
N
H
H
CF3
CF3
N
F
N
CF3
O
OH
O
O
OH
F3C
2l 68%
Br
2k 66%
OH
2j 70%
H
H
H
F
F2HCO
N
CF3
N
CF3
N
CF3
O
O
O
OH
F
OH
OH
2n 69%
2m 68%
2o 67%
OMe
H
N
H
H
N
CF3
MeO
N
CF3
CF3
O
O
O
I
OH
OH
OH
2p 65%
2q 63%
2r 64%
a Isolated yield after column chromatography.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1258–1262

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V. Venkateswarlu et al.
Letter
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Table 3 Screening of Halo-Substituted Arylamine Substrates
F
F
H
N
NH2
F
CF3
X
X
TFA, oxone
dioxane
2w R = H 67%
2x R = 4-F 68%
R
H
N
R
NH2
Y
CF3
O
TFA, oxone
dioxane
OH
R
R
O
Scheme 2 Monohydroxylation of 2,6-difluoro-substituted arylamines
for formation of ortho-hydroxy-N-trifluoroacetanilides
OH
when, X = Cl, Br, I; Y = F
X
NH2
Y
when, X and Y = Cl, Br, I; no reaction
or X = H and Y = Cl, Br, I; ref. 7
or Y = H and X = Cl, Br, I; ref. 7
TFA, oxone
dioxane
To investigate mechanistic aspects, we followed the re-
R
action by using LC-MS analytical techniques. Our observa-
tions lead us to propose that this reaction follows a similar
pathway to that presented in our recent report (Figure 1).7
Intermediate 6 is formed upon mixing of TFA and Oxone
and this is subsequently converted into intermediate 7 by
loss of water. The fluoroaniline adds to intermediate 7, giv-
ing unstable intermediates 8 and 9. During this stage, the
electron lone pair on the oxygen atom of the peroxy linkage
(intermediate 8) undergoes nucleophilic attack on the C–F
bond and forms the weaker C–O bond in cyclic intermediate
10, which finally releases KHSO4 and gives the product 2-
hydroxy-N-trifluoroacetanilide 2a.10
The method has wide applicability and can be an im-
portant tool for bringing in functional moieties to fine-tune
the physicochemical properties of molecules. The tech-
nique could also be useful in late-stage modifications in
drug discovery programs. Mostly in various drug discovery
programs, at the lead optimization stage, introducing the
CF3 group in a compound is often preferred because it plays
an important role in solving issues related to bioavailability
or lipophilicity and physicochemical properties.2b,8,9 The
present method can be applied to biologically active small
molecules such as sparfloxacin and to natural products, and
it can be used as a medicinal chemistry tool. Moreover, this
method provides scope and also offers diversity for obtain-
ing 2-aminophenols or CF3 bearing benzoxazoles deriva-
tives, which are an important class of compounds that are
of great utility.
Entry
Y
X
R
Product[a]
Cl
H
N
CF3
1
2
3
4
5
6
7
F
Cl
Br
Br
Cl
I
H
O
OH
2s 65%
Br
F
H
no reaction
Br
H
N
CF3
4-F
H
O
OH
F
2t 68%
Cl
F
no reaction
I
H
N
CF3
H
O
OH
2u 64%
I
I
H
no reaction
Br
H
N
CF3
F
Br
H
O
OH
2v 68%
a Isolated yield after column chromatography.
In conclusion, we have presented a new approach for
the nucleophilic substitution of a fluoro group with a hy-
droxyl group selectively at the ortho-position and concomi-
tant N-trifluoroacylation of fluoro-substituted anilines.
This is an oxidative reaction under metal-free conditions
offering good yields of 2-hydroxy-N-trifluoroacetanilides.
This method is chemoselective and can be applied on all
kinds of substrates having 2- or 6-fluoro substitutions of-
fering monohydroxylated products, with tolerance of elec-
tron-withdrawing and electron-donating groups. 2,6-
Disubstituted fluoroaniline could be converted into the
monohydroxylated product selectively.
increasing the number of equivalents of TFA and Oxone did
not lead to the dihydroxylated product. In the case of 2,6-
difluorinated substrates, after initial hydroxylation, the
amino group is concomitantly trifluoroacylated. The tri-
fluoroacyl group withdraws electron density from the ni-
trogen and effectively makes the resulting trifluoroacet-
amide incapable of participating in the second hydroxyl-
ation.
A range of 2,6-difluoro-substituted arylamines
underwent this reaction smoothly and representative ex-
amples are shown in Scheme 2.
When the reaction was conducted with fluorobenzene,
conversion into phenol was not observed. Reaction of ani-
line with TFA simply gave the N-trifluoroacylated product
and with Oxone the reaction gave the respective nitroben-
zene product. Thus, the approach is very specific to fluoro-
anilines only.
Acknowledgment
V.V. thanks UGC/CSIR for the award of a Research Fellowship. Funding
support from CSIR sponsored BSC0108 project is gratefully acknowl-
edged. IIIM Communication No. IIIM/1623/2013.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1258–1262

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V. Venkateswarlu et al.
Letter
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Figure 1 Plausible mechanism for the formation of 2-hydroxy-N-trifluoroacetanilide with interpretation of intermediates observed using LC-MS analy-
sis at 30 min reaction time intervals. Mass peaks of intermediate 6 (m/z 246.00), intermediate 10 (m/z 339.10), 2a (m/z 204.00 [M – H+]), and KHSO4
(m/z 134.00 [M – H+])
Supporting Information
(d) Levin, J. I.; Du, M. T. Synth. Commun. 2002, 32, 1401.
(e) Serrano-Plana, J.; Garcia-Bosch, I.; Miyake, R.; Costas, M.;
Company, A. Angew. Chem. Int. Ed. 2014, 53, 9608.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1379905.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
(6) Ohkubo, K.; Fujimoto, A.; Fukuzumi, S. J. Am. Chem. Soc. 2013,
135, 5368.
(7) Venkateswarlu, V.; Aravinda Kumar, K. A.; Balgotra, S.; Reddy, G.
L.; Srinivas, M.; Vishwakarma, R. A.; Sawant, S. D. Chem. Eur. J.
2014, 20, 6641.
References and Notes
(1) (a) Choi, J.; Wang, D. Y.; Kundu, S.; Choliy, Y.; Emge, T. J.; Krogh-
Jespersen, K.; Goldman, A. S. Science 2011, 332, 1545. (b) Arnold,
J.; Gianetti, T.; Bergman, R. G. Chem. Sci. 2014, 5, 2517.
(2) (a) Blanksby, S. J.; Ellison, G. B. Acc. Chem. Res. 2003, 36, 255.
(b) O’Hagan, D. Chem. Soc. Rev. 2008, 37, 308.
(8) Filler, R.; Sahu, R. Future Med. Chem. 2009, 1, 777.
(9) (a) Wong, D. T.; Perry, K. W.; Bymaster, F. P. Nat. Rev. Drug Dis-
covery 2005, 4, 764. (b) Rabasseda, X.; Sorbera, L. A.; Castaner, J.
Drugs Future 1999, 24, 1057. (c) Wouters, J.; Moureau, F.;
Evrard, G.; Koenig, J.-J.; Jegham, S.; George, P.; Durant, F. Bioorg.
Med. Chem. 1999, 7, 1683. (d) Margot, P.; Huggenberger, F.;
Amrein, J.; Weiss, B. BCPC Conf.-Pests. Dis. 1998, 2, 375.
(e) Milne, G. W. A. CRC Handbook of Pesticides; CRC: Boca Raton,
1995. (f) Ren, J.; Milton, J.; Weaver, K. L.; Short, S. A.; Stuart, D. I.;
Stammers, D. K. Structure 2000, 8, 1089. (g) Pedersen, O. S.;
Pedersen, E. B. Synthesis 2000, 479.
(10) Synthesis of 2-Hydroxy-N-trifluoroacetamides; General Pro-
cedure: A Schlenk tube was charged with Oxone (0.398 g, 0.648
mmol) and trifloroacetic acid (0.099 mL, 1.296 mmol) in anhy-
drous dioxane (2 mL) under argon. To this mixture was added 2-
fluoroaniline (0.06 g, 0.54 mmol), and the reaction mixture was
heated to 90 °C under argon until starting material was con-
sumed. As the reaction progressed, the color turned from light
red to dark red. The mixture was then cooled to room tempera-
(3) (a) Amii, H.; Uneyama, K. Chem. Rev. 2009, 109, 2119.
(b) Mazurek, U.; Schwarz, H. Chem. Commun. 2003, 1321.
(4) For recent reviews on metal-mediated aliphatic C–F bond acti-
vation, see: (a) Cárdenas, D. J. Angew. Chem. Int. Ed. 2003, 42,
384. (b) Terao, J.; Kambe, N. Bull. Chem. Soc. Jpn. 2006, 79, 663.
(c) Torrens, H. Coord. Chem. Rev. 2005, 249, 1957.
(5) (a) Del Mar, E. G.; Barmore, R. M.; Sheehan, D.; Van Wagenen, B.
C.; Callahan, J. F.; Keenan, R. M.; Kotecha, N. R.; Lago, M. A.;
Southall, L. S.; Thompson, M. Method of using calcilytic com-
pounds U. S. Patent 6022894, 2000; Chem. Abstr. 2000, 132, 12.
(b) Johansson, H.; Cailly, T.; Rojas, A.; Thomsen, B.; Bräuner-
Osborne, H.; Pedersen, D. S. Beilstein J. Org. Chem. 2013, 9, 1383.
(c) Rogers, J. F.; Green, D. M. Tetrahedron Lett. 2002, 43, 3585.
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ture and washed with a saturated aqueous sodium bicarbonate.
The mixture was extracted with EtOAc (2 × 20 mL) and the com-
bined organic layers were dried over Na2SO4. After filtering and
removal of the solvent under reduced pressure in vacuo, the
residue was purified by silica gel (100–200 mesh) column chro-
matography (hexane–EtOAc, 9:1), to afford a pale-brown solid
(65%) of 2-hydroxy-N-trifluoroacetanilides from 2-fluoroaniline
(2a).
2,2,2-Trifluoro-N-(2-hydroxy-6-methoxyphenyl)acetamide
(2r): Brown solid; mp 221–222 °C. 1H NMR (400 MHz, CDCl3):
δ = 8.48 (s, 1 H), 7.42 (d, J = 7.8 Hz, 1 H), 7.16 (t, J = 7.5 Hz, 1 H),
6.99 (dd, J = 21.3, 7.8 Hz, 1 H), 6.17 (s, 1 H), 3.91 (s, 3 H). 19F
NMR (376.50 MHz, CDCl3): δ = –75.41 (s, 3 F). 13C NMR (100
MHz, CDCl3): δ = 151.4, 145.6, 126.7, 125.8, 121.2, 120.8, 111.1,
96.4, 55.7. MS (ESI): m/z = 234 [M – H]+.
N-(2-Chloro-6-hydroxyphenyl)-2,2,2-trifluoroacetamide
(2s): Reddish brown solid; mp 225–226 °C. IR (CHCl3): 3388,
2-Hydroxy-N-trifluoroacetanilides from 2-Fluoroaniline
(2a): Pale brown solid; mp 155–156 °C. IR (CHCl3): 3389, 3248,
2923, 2851, 1690, 1597, 1562, 1465, 1194, 1159, 1101, 1041,
3220, 2920, 2853, 1687, 1565, 1419, 1199, 1154, 1018, 850 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.21 (s, 1 H), 8.09 (d, J = 8.9 Hz,
851, 749 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 10.51 (br s,
1 H), 7.52 (s, 1 H), 6.96 (s, 1 H), 6.80 (dd, J = 9.0, 2.1 Hz, 1 H). 13
C
1 H), 9.94 (br s, 1 H), 7.31 (dd, J = 7.8, 1.4 Hz, 1 H), 7.16–7.12 (m,
1 H), 6.94 (d, J = 7.1 Hz, 1 H), 6.85–6.81 (m, 1 H). 13C NMR (100
MHz, DMSO-d6): δ = 154.9 (q, J = 36 Hz), 151.2, 127.9, 126.3,
122.2, 118.9, 115.9 (q, J = 287 Hz), 116.0. 19F NMR (376.50 MHz,
CD3OD): δ = –77.16 (s, 3 F). HRMS (ESI): m/z [M – H+]– calcd for
C8H5F3NO2: 204.0275; found: 204.0273.
NMR (100 MHz, CDCl3): δ = 154.0, 130.9, 128.8, 125.2, 125.1,
123.4, 116.4, 114.9. 19F NMR (376 MHz, CDCl3): δ = –75.74.
HRMS (ESI): m/z [M – H+]– calcd for C8H4ClF3NO2: 237.9893;
found: 237.9883.
N-(2-Bromo-4-fluoro-6-hydroxyphenyl)-2,2,2-trifluoroacet-
amide (2t): Reddish brown solid; mp 195–196 °C. IR (CHCl3):
N-(3,4-Difluoro-2-hydroxyphenyl)-2,2,2-trifluoroacetamide
3293, 2923, 2852, 1730, 1432, 1152, 1118, 857 cm–1 1H NMR
.
1
(2b): Brownish semi-solid. H NMR (400 MHz, acetone-d6): δ =
(400 MHz, CDCl3): δ = 8.32 (s, 1 H), 7.81 (s, 1 H), 7.02 (dd, J = 7.3,
2.7 Hz, 1 H), 6.82 (dd, J = 9.5, 2.6 Hz, 1 H). 13C NMR (126 MHz,
CDCl3): δ = 163.1, 161.1, 156.3 (d, J = 38.6 Hz), 152.0 (d,
J = 13.3 Hz), 117.9 (d, J = 12.7 Hz), 115.5 (q, J = 285 Hz), 112.86
(d, J = 26.4 Hz), 107.62 (d, J = 24.5 Hz). 19F NMR (376 MHz,
CDCl3): δ = –74.54 (s, 3 F), –110.09 (dd, J = 9.3, 7.4 Hz, 1 F). GC-
MS: m/z = 301.2 [M]+, 303.2 [M+ + 2] (1:1 ratio).
7.56–7.48 (m, 1 H), 6.89 (ddd, J = 10.0, 9.3, 8.0 Hz, 1 H). 13C NMR
(100 MHz, CD3OD): δ = 152.7, 152.3 (d, J = 24 Hz), 143.2, 133.8,
120.9, 120.2, 117.3 (d, J = 256 Hz), 107.3 (d, J = 18.7 Hz). 19F
NMR (376 MHz, CD3OD): δ = –77.03 (s, 3 F), –141.09 (ddd,
J = 20.3, 10.1, 5.4 Hz, 1 F), –160.66 to –164.19 (m, 1 F). GC-MS:
m/z = 241.2 [M]+.
N-(5-Chloro-2-hydroxyphenyl)-2,2,2-trifluoroacetamide
(2d): Brownish solid; mp 190–191 °C. IR (CHCl3): 3391, 2922,
2,2,2-Trifluoro-N-(2-hydroxy-6-iodophenyl)acetamide (2u):
Light-brown solid; mp 232–233 °C. 1H NMR (400 MHz, CD3OD):
δ = 7.27 (dd, J = 7.4, 1.6 Hz, 1 H), 6.89–6.76 (m, 2 H). 13C NMR
(125 MHz, CD3OD + acetone-d6): δ = 157.5 (q, J = 36.2 Hz),
155.5, 132.0, 130.9, 125.9, 118.9, 117.5, 100.9. 19F NMR (376
MHz, CD3OD): δ = –76.60 (s). HRMS (ESI): m/z [M – H+]– calcd
for C8H4F3INO2: 329.9245; found: 329.9239.
N-(2-Bromo-6-hydroxyphenyl)-2,2,2-trifluoroacetamide
(2v): Light-brown solid; mp 315–316 °C. 1H NMR (400 MHz,
CDCl3): δ = 8.43 (s, 1 H), 7.68 (d, J = 6.0 Hz, 1 H), 7.38 (d,
J = 40.4 Hz, 1 H), 7.20–7.01 (m, 1 H), 6.81 (s, 1 H). 13C NMR (100
MHz, CDCl3): δ = 156.4 (q, J = 38 Hz), 151.1, 134.1, 130.0, 128.2,
125.6, 119.8 (q, J = 277 Hz), 119.5. 19F NMR (376 MHz, CDCl3):
δ = –75.66 (s). HRMS (ESI): m/z [M – H+]– calcd for C8H4BrF3NO2:
283.9365; found: 283.9534.
2852, 1688, 1597, 1158, 1047, 871 cm–1 1H NMR (400 MHz,
.
acetone-d6): δ = 9.97 (s, 1 H), 9.45 (s, 1 H), 7.98 (d, J = 2.4 Hz,
1 H), 7.14 (dd, J = 8.7, 2.5 Hz, 1 H), 7.03 (d, J = 8.7 Hz, 1 H). 13C
NMR (101 MHz, acetone-d6): δ = 155.6 (d, J = 37.6 Hz), 148.2,
127.2, 125.6, 124.4, 123.1, 117.5, 116.8 (q, J = 286 Hz). 19F NMR
(376 MHz, acetone-d6): δ = 101.19 (s). GC-MS: m/z = 239.2 [M]+.
N-(4-Bromo-2,3-difluoro-6-hydroxyphenyl)-2,2,2-trifluoro-
acetamide (2k): Pale brown solid; 187–188 °C. IR (CHCl3):
3391, 2924, 1690, 1594, 1429, 1255, 1122, 1020, 868 cm–1 1H
.
NMR (400 MHz, acetone-d6): δ = 7.92 (d, J = 10.0 Hz, 1 H), 7.25
(d, J = 6.4 Hz, 1 H), 3.04 (s, 1 H), 2.98 (s, 2 H). 13C NMR (126
MHz, CDCl3): δ = 154.1, 151.7, 146.0, 124.9, 119.8, 116.7 (q,
J = 285 Hz), 111.1 (d, J = 35 Hz), 105.1 (d, J = 27.5 Hz). 19F NMR
(376 MHz, CDCl3): δ = –75.68 (s), –119.92 (d, J = 6.8 Hz). HRMS
(ESI): m/z [M – H+]– calcd for C8H3BrF4NO2: 299.9285; found:
299.9284.
2,2,2-Trifluoro-N-(2-fluoro-6-hydroxyphenyl)acetamide
(2w): Light-brown solid; mp 155–156 °C. IR (CHCl3): 3436,
2918, 1619, 1474, 1383, 1200, 1158, 1021, 785 cm–1 1H NMR
.
2,2,2-Trifluoro-N-(5-fluoro-2-hydroxyphenyl)acetamide
(2o): Light-brown solid; mp 192–195 °C. 1H NMR (400 MHz,
CDCl3): δ = 8.94 (s, 1 H), 8.80 (s, 1 H), 7.99 (dd, J = 9.4, 2.0 Hz,
1 H), 6.91 (dd, J = 8.4, 5.0 Hz, 1 H), 6.76 (t, J = 7.0 Hz, 1 H). 13C
NMR (100 MHz, CDCl3 + acetone-d6): δ = 157.4, 154.5 (dd,
J = 72.0, 34.5 Hz), 142.3, 124.7 (d, J = 11.5 Hz), 115.7 (d,
J = 286 Hz), 115.5, 112.1 (d, J = 23.3 Hz), 108.1 (d, J = 29.3 Hz).
19F NMR (376 MHz, CD3OD): δ = –77.23 (s), –122.99 to –128.86
(m). GC-MS: m/z = 223.2 [M]+.
2,2,2-Trifluoro-N-(2-hydroxy-5-methoxyphenyl)acetamide
(2q): Brown solid; mp 168–169 °C. 1H NMR (400 MHz, CDCl3):
δ = 8.45 (s, 1 H), 7.68 (d, J = 2.2 Hz, 1 H), 6.84 (d, J = 8.7 Hz, 1 H),
6.68 (d, J = 2.6 Hz, 1 H), 5.53 (s, 1 H), 3.78 (s, 3 H). 19F NMR (376
MHz, CDCl3): δ = –75.61. 13C NMR (101 MHz, CD3OD): δ = 154.2,
143.9, 124.9, 118.8, 117.0, 116.0, 113.5, 110.0, 56.2. ESI-MS:
m/z = 234 [M – H]+.
(400 MHz, CDCl3): δ = 8.27 (s, 1 H), 7.20 (dd, J = 14.9, 7.6 Hz,
1 H), 6.87 (d, J = 8.0 Hz, 1 H), 6.77 (t, J = 9.1 Hz, 1 H). 13C NMR
(100 MHz, CDCl3): δ = 156.4 (q, J = 39 Hz), 153.9, 150.6, 128.9,
115.6 (q, J = 285 Hz), 116.0, 112.1, 112.0, 107.3. 19F NMR (376
MHz, CDCl3): δ = –74.51 (s, 3 F), –125.35 (d, J = 7.9 Hz, 1 F).
HRMS (ESI): m/z [M – H+]– calcd for C8H4F4NO2: 222.0187;
found: 272.0178.
N-(2,4-Difluoro-6-hydroxyphenyl)-2,2,2-trifluoroacetamide
(2x): Light-brown solid; mp 195–196 °C. IR (CHCl3): 436, 2923,
2852, 1619, 1452, 1384, 1240, 1157, 1054, 1021, 840 cm–1 1H
.
NMR (400 MHz, CDCl3): δ = 8.20 (s, 1 H), 6.62–6.49 (m, 2 H). 13
C
NMR (126 MHz, CDCl3): δ = 163.1 (d, J = 15.7 Hz), 161.4–160.2
(m), 157.2–154.4 (m), 152.1 (dd, J = 14.6, 4.1 Hz), 115.5 (q,
J = 287.1 Hz), 102.7 (dd, J = 25.0, 3.3 Hz), 96.6 (dd, J = 27.5,
24.3 Hz). 19F NMR (376 MHz, CDCl3): δ = –74.5 (s), –109.4 (ddd,
J = 710.6, 163.3, 9.1 Hz), –120.6 (d, J = 6.6 Hz). HRMS (ESI): m/z
[M – H+]– calcd for C8H3F5NO2: 240.0065; found: 240.0084.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1258–1262