One-step conversion of azine N -oxides to α-N -aryltriflamidoazines

Article abstract of DOI:10.1021/jo302014c

Various pyridine, quinoline, isoquinoline, and pyrimidine N-oxides were converted to their corresponding α-N-aryltriflamidoheteroarenes in good yield by treatment with N-aryltriflimides, both neat and in solution, at temperatures ranging from rt to 100 °C

Full text of DOI:10.1021/jo302014c

Note
pubs.acs.org/joc
One-Step Conversion of Azine N‑Oxides to α‑N‑Aryltriflamidoazines
John M. Keith*
Janssen Research and Development, LLC, 3210 Merryfield Row, San Diego, California 92121, United States
S
* Supporting Information
ABSTRACT: Various pyridine, quinoline, isoquinoline, and
pyrimidine N-oxides were converted to their corresponding α-N-
aryltriflamidoheteroarenes in good yield by treatment with N-
aryltriflimides, both neat and in solution, at temperatures ranging
from rt to 100 °C.
zine N-oxides have proven to be versatile synthetic
components, but an excellent yield of product was obtained.
Aintermediates for the drug discovery process. Methods The reaction conducted in acetonitrile took place at a lower
allowing direct α-arylation1,2 and substitution3 as well as
temperature (50 °C), but the reaction time was significantly
deoxygenative introduction of halide,4 carbon,5−7 oxygen,8
longer (8.5 h vs 3 h) and, in this particular example, the yield
sulfur,9 and nitrogen10−12 nucleophiles have all been developed.
was a bit lower (74% vs 97%). With these promising results in
hand, we expanded the scope of N-oxides subjected to our
reaction conditions.
Our particular interest in N-oxides is with regard to
deoxygenative substitutions reactions (Reissert−Henze ap-
proach)13,14 with nitrogen nucleophiles. Recently, we have
disclosed new or optimized methods for the introduction of
azides,15 imidazoles,16 1,2,3-triazoles, 1,2,4-triazoles, and
electron-deficient pyrazoles17 (Figure 1) utilizing such an
approach. A key feature of the Reissert−Henze mechanism is
that reactivity of the N-oxide is enhanced by the presence of
suitably positioned electron-donating groups. This is in contrast
to SNAr and transition metal mediated couplings where the
more electron-deficient ring-systems are expected to be more
reactive. In this way, the Reisert−Henze approach is
mechanistically complementary to SNAr and transition-metal-
mediated couplings and should be considered when the
electronics of the system do not favor direct substitution or
coupling.
More recently, we turned our attention to the possibility of
introducing protected aniline functionality via a Reissert−
Henze strategy. Methods exist for the introduction of
unprotected anilines either through preactivation of the N-
oxide (alkylation)18 or the use of peptide coupling reagents19
and for protected anilines using TsCl and PhNHTs.20 We were
interested in whether or not N-aryltriflimides, either preformed
or prepared in situ, would be suitable reagents for the
introduction of N-aryltriflamido functionality to the α-position
of azines. We focused on triflimides because, in many instances,
the same reagents can be used to affect the removal of
triflamides as are used to remove other sulfonyl groups, but the
reaction times tend to be much shorter when nucleophilic or
reductive methods are utilized.21
Simple electron neutral to slightly electron rich pyridine N-
oxides were generally good substrates for this transformation
(Table 1). Methyl groups in the 3-position neither hindered the
reaction nor influenced the regioselectivity of nucleophilic
attack (entries 3 and 4). Likewise, a 2-methyl (entry 5) was not
noticeably detrimental to the reaction rate, although the
reaction did slow somewhat with a 2-aryl ring (entry 8).
Quinoline N-oxide (entry 6) and pyrimidine N-oxide (entry 7)
both underwent this transformation, albeit under different
conditions. Quinoline N-oxide reacted readily in heated
acetonitrile solutions to give only one regioisomeric product
(7), whereas pyrimidine N-oxide was unreactive in hot
acetonitrile solutions. However, when heated neat in the
presence of PhN(Tf)2 and DIPEA, pyrimidine N-oxide gave a
mixture of 2- and 4-substituted products (8 and 9,
respectively), slightly favoring 2-substitution (1.35:1). The
highly electron-deficient 3- and 4-cyanopyridine N-oxides were
unreactive at moderate temperatures and yielded complex
reaction mixtures at 130 °C (neat reaction).
Strongly electron-rich N-oxides are quite reactive in the
presence of PhNTf2. 4-Methoxypyridine N-oxide underwent
reaction readily at rt, but not cleanly. It appears 4-
methoxypyridine N-oxide reacts to a significant degree through
a cationic mechanism (Scheme 2). There was evidence of
solvent trapping, formation of the 2-triflate, dimerization of the
substrate, and many other unidentifiable species. Running the
reaction in a solvent with a lower dielectric constant (0.20 M in
toluene, 50 °C, 2 h) yielded somewhat better, though still
modest, results (42%). It may be that lower polarity solvents
will be generally required for reactions involving highly
electron-rich N-oxides.
We began our study using commercial N-phenyltriflimide
and 4-phenylpyridine N-oxide as the substrate in the presence
of an excess of diisopropylethylamine (DIPEA). The initial
reactions were run both in solution (acetonitrile) and neat for
comparison (Scheme1, Table 1). The neat reaction required a
higher temperature (100 °C) simply to melt the solid
Received: September 22, 2012
© XXXX American Chemical Society
A
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Note
Figure 1. Possible mechanisms for generation of side products.
could be prepared and used in situ. Three substituted anilines
were treated with 2 equiv of Tf2O at 0 °C in the presence of
DIPEA. After 2.5 h, the substrate was added and the mixture
heated at 70 °C for 19 h (Scheme 4). Interestingly, the
electron-rich aniline gave the highest yield of final product
(18), whereas the yields of the other two decreased in step with
their electron deficiency. HPLC and TLC analysis suggest the
triflimides of the two electron-deficient anilines are not forming
efficiently, and we thought this may be a limitation of preparing
triflimides of electron-deficient anilines in situ.
The notion that the triflimide reagents were not being
formed efficiently in situ was at least partially supported by the
yields obtained in the preparation and isolation of 21 and 22
(Scheme 5). But the yields of 21 and 22 did not explain the
yields of 19 and 20. When 4-phenylpyridine N-oxide was
treated with 21 or 22 in CH3CN at rt or 70 °C, the only
product obtained in either case was the triflate 23. It would
appear that in CH3CN, formation of the triflate is faster when
there is not a large excess of ArTfN− present as would be the
case if the reaction to form the reagents in situ did not go to
completion. Interestingly, the product distribution could be
changed to favor the pyridyltriflamide simply by utilizing a low
dielectric solvent. Yields of 65% and 59% were obtained for 19
and 20, respectively, when toluene22 was used as the solvent at
rt, though there was still some 23 generated under these
conditions. Running the reactions neat (with heating) did not
afford any advantage over the use of toluene.
In conclusion, we have developed a simple procedure for the
introduction of N-aryltriflimides to the α-position of azine
nitrogens starting from the corresponding azine N-oxides. The
method is complementary to transition metal mediated and
SNAr reactions because it favors electron-neutral to moderately
electron-rich N-oxide substrates. A highly electron-rich
substrate appeared to yield products suggestive of cationic
mechanisms in acetonitrile but gave a moderately improved
yield in the less polar solvent toluene. Substituted N-
phenyltriflimides can be prepared and used in situ, but when
the substituent is electron-withdrawing, preformed and isolated
triflimide reagents appear to be more efficient, especially in
Scheme 1. Neat and Solution Reaction Conditions
Two other substrates, isoquinoline N-oxide and 4,6-
dimethylpyrimidine N-oxide gave unusual products as well
(Scheme 3). Isoquinoline N-oxide, in addition to the two
expected regioisomeric products (12 and 13), gave a product
that appeared to have undergone the desired substitution plus
incorporation of a triflate moiety (14). This unusual
substitution pattern was mirrored when 4,6-dimethylpyrimidine
N-oxide was the substrate, although in this case, we also
obtained the 5-substituted product (17).
Our suspicion is that the initial two steps of the reaction
pathway (activation of the N-oxide and nucleophilic attack of
the α-position) take place as expected, but from there,
competing pathways intervene (Figure 1). Typically, the
tetrahedral intermediate A would be deprotonated to eliminate
triflate and afford the desired product, in this case 15. However,
one can imagine that in competition with deprotonation, a
nucleophile, either N-oxide or PhTfN−, could attack the 5-
position, thereby eliminating triflate and giving an intermediate
with two tetrahedral centers (intermediates B and D). What
happens next depends on where deprotonation takes place and
which nucleophile attacked the ring. If deprotonation takes
place at the 2-position, then the desired product 15 should
form. However, if deprotonation occurs at the 5-position, then
intermediate B would be expected to eliminate 4,6-
dimethylpyrimidine to give intermediate C. Intermediate C
would tautomerize to the phenol, which would be rapidly
converted to 16 under the reaction conditions. In contrast to
the pathway proposed to be followed by intermediate B,
deprotonation of intermediate D in the 5-position will likely
lead to elimination of the 2-substituent to give 17.
Having verified that PhNTf2 is a competent reagent for
converting azine N-oxides to α-phenyltriflamidoazines, we
wanted to determine whether substituted variants of PhNTf2
B
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Note
a
Table 1. Substrate Scope
a
Reaction conditions: (a) isolated; (b) 58.6 mmol (10 g) scale.
mixture was diluted with Et2O and washed with 1 N NaOH followed
by brine. The ethereal solution was dried over MgSO4, filtered, and
evaporated to dryness to give the crude product. Chromatographic
purification on silica gel was typically performed using a low polarity
gradient of EtOAc/hexanes. For those samples not analytically pure
after silica gel chromatography, an additional HPLC purification step
was performed using a preparative (250 mm × 50 mm) C18 column,
eluting with 25−100% acetonitrile/water with 0.05% trifluoroacetic
acid at 80 mL/min. High-resolution mass spectra were obtained using
a quadrupole detector.
Scheme 2. Reaction of 4-Methoxypyridine N-Oxide with
PhN(Tf)2
General Method for Preparing α-Phenyltriflamidoazines
(Neat Reaction). To a microwave vial were added a small stirbar,
azine N-oxide substrate (limiting reagent), 2 equiv of PhNTf2, and 3.0
equiv of DIPEA. The vial was purged with nitrogen and then heated in
an oil bath until the solids melted (the mixture never became
homogeneous; DIPEA is immiscible with the melted solids). The
reaction progress was monitored by TLC or HPLC and the
temperature adjusted to optimize reaction rate. Once the N-oxide
was consumed, the workup and purification procedures described
above were used.
nonpolar solvents. Strongly electron-poor N-oxides are not
productively reactive under the described reaction conditions.
EXPERIMENTAL SECTION
■
General Method for Preparing α-Phenyltriflamidoazines in
Solution. To a round-bottomed flask were added a stirbar, azine N-
oxide substrate (limiting reagent), 2 equiv of PhNTf2, dry acetonitrile
(0.1 M in substrate), and DIPEA (3.0 equiv). The flask was purged
with nitrogen and the mixture warmed until reaction progression was
evident by TLC or HPLC. Once the N-oxide was consumed, the
1,1,1-Trifluoro-N-phenyl-N-(4-phenylpyridin-2-yl)methane-
sulfonamide (1): neat reaction 228 mg, 97%; solution reaction 169
mg, 74%; 10 g scale solution reaction 16.005 g, 72%; white solid; mp =
C
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Note
Scheme 3. Products Derived from Isoquinoline N-Oxide and 4,6-Dimethylpyrimidine N-Oxide
N-(3,5-Dimethylpyridin-2-yl)-1,1,1-trifluoro-N-phenylmetha-
nesulfonamide (3): solution reaction 502 mg, 89%; colorless oil; 1H
NMR (600 MHz, acetone-d6) δ 8.301−8.297 (m, 1H), 7.79−7.77 (m,
2H), 7.562−7.558 (m, 1H), 7.47−7.44 (m, 2H), 7.41−7.38 (m, 1H),
2.38 (s, 3H), 2.30 (s, 3H); 13C NMR (151 MHz, acetone-d6) δ 149.4,
148.3, 142.3, 138.9, 136.4, 133.0, 130.2, 129.9, 129.4, 121.6 (q, J =
322.8 Hz), 17.8, 17.7; MS (ESI+), found 331.2 (M + H)+; HRMS
(ESI+) m/e calcd for C14H13F3N2O2S 331.0723 (M + H)+, found
331.0719.
N-(4,5-Dimethylpyridin-2-yl)-1,1,1-trifluoro-N-phenylmetha-
nesulfonamide (4): 199 mg, 36%; white solid; 1H NMR (600 MHz,
CDCl3) δ 8.22 (br s, 1H), 7.57−7.55 (m, 2H), 7.40−7.34 (m, 3H),
7.15 (s, 1H), 2.26 (s, 3H), 2.22 (s, 3H); 13C NMR (151 MHz, CDCl3)
δ 150.5, 149.5, 149.3, 138.6, 133.2, 129.7, 129.39, 129.37, 123.0, 120.6
(q, J = 322.3 Hz), 19.6, 16.2; MS (ESI+), found 331.2 (M + H)+;
HRMS (ESI+) m/e calcd for C14H13F3N2O2S 331.0723 (M + H)+,
found 331.0723.
Scheme 4. In Situ Generation and Use of N-Aryltriflimides
Scheme 5. Evaluation of 4-Cyanophenyl and 4-
Trifluoromethyl Triflimides
N-(3,4-Dimethylpyridin-2-yl)-1,1,1-trifluoro-N-phenylmetha-
nesulfonamide (5): 216 mg, 39%; white solid; 1H NMR (600 MHz,
CDCl3) δ 8.28 (d, J = 4.8 Hz, 1H), 7.71−7.69 (m, 2H), 7.37−34 (m,
2H), 7.33−7.29 (m, 1H), 7.12 (d, J = 4.8 Hz, 1H), 2.33 (s, 3H), 2.27
(s, 3H); 13C NMR (151 MHz, CDCl3) δ 150.8, 150.0, 146.4, 138.3,
132.1, 129.4, 128.8, 128.4, 126.5, 120.7 (q, J = 323.5 Hz), 20.2, 14.3;
MS (ESI+), found 331.2 (M + H)+; HRMS (ESI+) m/e calcd for
C14H13F3N2O2S 331.0723 (M + H)+, found 331.0721.
1,1,1-Trifluoro-N-(6-methylpyridin-2-yl)-N-phenylmethane-
sulfonamide (6): neat reaction 201 mg, 72%; solution reaction 251
mg, 80%; white solid; mp = 91−92 °C; 1H NMR (600 MHz, acetone-
d6) δ 7.75 (t, J = 7.8 Hz, 1H), 7.66−7.65 (m, 2H), 7.51−7.45 (m, 3H),
7.27 (d, J = 7.2 H, 1H), 7.22 (d, J = 7.8 Hz, 1H), 2.51 (s, 3H); 13C
NMR (151 MHz, acetone-d6) δ 160.5, 153.7, 141.3, 140.3, 131.4,
131.3, 125.7−119.2 (q, J = 322.0 Hz), 125.0, 120.3, 25.0; MS (ESI+),
found 317.3 (M + H)+; HRMS (ESI+) m/e calcd for C13H11F3N2O2S
317.0566 (M + H)+, found 317.0570.
1,1,1-Trifluoro-N-phenyl-N-(quinolin-2-yl)methane-
1
sulfonamide (7): 192 mg, 87%; white solid; mp = 57−59 °C; H
120−121 °C; 1H NMR (600 MHz, acetone-d6) δ 8.59 (d, J = 5.4 Hz,
1H), 7.86 (d, J = 1.2 Hz, 1H), 7.78−7.75 (m, 4H), 7.74−7.73 (dd, J =
1.8, 5.4 Hz, 1H), 7.53−7.46 (m, 6H); 13C NMR (151 MHz, acetone-
d6) δ 155.1, 153.4, 151.6, 140.2, 138.5, 131.6, 131.5, 131.4, 131.1,
128.9, 125.6−119.1 (q, J = 321.9 Hz), 123.6, 121.6; MS (ESI+), found
379.1 (M + H)+; HRMS (ESI+) m/e calcd for C18H14F3N2O2S
379.0728 (M + H)+, found 379.0735.
1,1,1-Trifluoro-N-phenyl-N-(pyridin-2-yl)methane-
sulfonamide (2): neat reaction 298 mg, 81%; solution reaction 210
mg, 66%; white solid; mp = 114−116 °C; 1H NMR (600 MHz,
acetone-d6) δ 8.54−8.53 (m, 1H), 7.94−7.91 (dt, J = 1.8, 8.4 Hz, 1H),
7.69−7.68 (m, 2H), 7.53−7.46 (m, 4H), 7.44−7.41 (ddd, J = 1.2, 4.8,
7.2 Hz, 1H); 13C NMR (151 MHz, acetone-d6) δ 154.3, 151.0, 141.3,
140.1, 131.5, 131.4, 125.8, 125.5−119.1 (q, J = 321.8 Hz), 123.8; MS
(ESI+), found 303.1 (M + H)+; HRMS (ESI+) m/e calcd for
C12H10F3N2O2S 303.0415 (M + H)+, found 303.0421.
NMR (600 MHz, acetone-d6) δ 8.39 (d, J = 8.4 Hz, 1H), 8.03 (d, J =
8.4 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.83−7.80 (m, 1H), 7.71 (d, J =
7.8 Hz, 2H), 7.64−7.62 (m, 1H), 7.55−7.48 (m, 3H), 7.37 (d, J = 9.0
Hz, 1H); 13C NMR (151 MHz, acetone-d6) δ 152.5, 147.5, 140.7,
138.9, 131.7, 130.74, 130.66, 130.62, 129.6, 128.8, 128.4, 128.1, 121.6
(q, J = 322.3 Hz), 119.3; MS (ESI+), found 353.2 (M + H)+; HRMS
(ESI+) m/e calcd for C16H11F3N2O2S 353.0566 (M + H)+, found
353.0563.
1,1,1-Trifluoro-N-phenyl-N-(pyrimidin-2-yl)methane-
1
sulfonamide (8): 147 mg, 46%; white solid; mp = 114−115 °C; H
NMR (600 MHz, acetone-d6) δ 8.75 (d, J = 4.8 Hz, 2H), 7.55−7.48
(m, 5H), 7.44 (t, J = 4.8 Hz, 1H); 13C NMR (151 MHz, acetone-d6) δ
159.95, 159.92, 138.2, 131.2, 130.5, 130.4, 121.4 (q, J = 322.3 Hz),
120.4; MS (ESI+), found 304.1 (M + H)+; HRMS (ESI+) m/e calcd for
C11H8F3N3O2S 304.0362 (M + H)+, found 304.0358.
D
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Note
1,1,1-Trifluoro-N-phenyl-N-(pyrimidin-4-yl)methane-
N-(4,6-Dimethylpyrimidin-5-yl)-1,1,1-trifluoro-N-phenylme-
thanesulfonamide (17): 163 mg, 19%; pale yellow solid, mp =
76.5−78 °C; H NMR (600 MHz, acetone-d6) δ 9.0 (s, 1H), 7.53−
7.50 (m, 2H), 7.46−7.44 (m, 2H), 7.42−7.39 (m, 1H), 2.59 (s, 6H);
13C NMR (151 MHz, acetone-d6) δ 168.4, 158.1, 139.6, 131.0, 128.8,
124.8, 122.9 (q, J = 321.4 Hz), 22.2; MS (ESI+), found 332.2 (M +
H)+; HRMS (ESI+) m/e calcd for C13H12F3N3O2S 332.0675 (M +
H)+, found 332.0679.
1
sulfonamide (9): 109 mg, 34%; white solid; mp = 69−71 °C; H
1
NMR (600 MHz, acetone-d6) δ 9.04 (s, 1H), 8.81 (br s, 1H), 7.62−
7.59 (m, 5H), 7.14 (d, J = 5.4 Hz, 1H); 13C NMR (151 MHz, acetone-
d6) δ 160.8, 159.9, 158.8, 137.1, 131.33, 131.25, 131.0, 121.2 (q, J =
322 Hz), 114.6; MS (ESI+), found 304.1 (M + H)+; HRMS (ESI+) m/
e calcd for C11H8F3N3O2S 304.0362 (M + H)+, found 304.0361.
1,1,1-Trifluoro-N-(6-(4-methoxyphenyl)pyridin-2-yl)-N-phe-
nylmethanesulfonamide (10): 206 mg, 83%; white solid; mp = 82−
1,1,1-Trifluoro-N-(4-methoxyphenyl)-N-(4-phenylpyridin-2-
1
83 °C; H NMR (600 MHz, acetone-d6) δ 8.09 (dd, J = 2.1, 6.7 Hz,
1
yl)methanesulfonamide (18): 451 mg, 88%; viscous oil; H NMR
2H), 7.89 (t, J = 7.8 Hz, 1H), 7.84 (dd, J = 0.9, 7.8 Hz, 1H), 7.74−7.72
(m, 2H), 7.54−7.51 (m, 2H), 7.49−7.47 (m, 1H), 7.26 (dd, J = 0.8,
7.8 Hz, 1H), 7.07 (dd, J = 2.1, 6.8 Hz, 2H), 3.86 (s, 3H); 13C NMR
(151 MHz, acetone-d6) δ 162.3, 157.5, 153.2, 141.1, 139.3, 131.2,
130.65, 130.60, 130.5, 129.3, 121.6 (q, J = 322.2 Hz), 119.8, 119.6,
115.2, 55.8; MS (ESI+), found 409.5 (M + H)+; HRMS (ESI+) m/e
calcd for C19H15F3N2O3S 409.0828 (M + H)+, found 409.0824.
1,1,1-Trifluoro-N-(4-methoxypyridin-2-yl)-N-phenylmetha-
nesulfonamide (11): in CH3CN 16 mg, 6%; in PhCH3 119 mg, 42%;
colorless film; 1H NMR (400 MHz, acetone-d6) δ 8.03 (d, J = 7.2 Hz,
1H), 7.04 (d, J = 2.4 Hz, 1H), 6.75 (dd, J = 4.2, 7.2 Hz, 1H), 4.02 (s,
3H); 13C NMR (151 MHz, acetone-d6) δ 172.4, 158.7, 138.9, 122.0
(q, J = 321.0 Hz), 107.0, 99.7, 57.3; MS (ESI+), found 333.1 (M +
H)+; HRMS (ESI+) m/e calcd for C13H11F3N2O3S 333.0515 (M +
H)+, found 333.0512.
(600 MHz, acetone-d6) δ 8.55 (d, J = 5.4 Hz, 1H), 7.81 (d, J = 0.6 Hz,
1H), 7.73−7.70 (m, 4H), 7.63 (dd, J = 1.2, 4.8 Hz, 1H), 7.49−7.44
(m, 3H), 7.04−7.01 (m, 2H), 3.78 (s, 3H); 13C NMR (151 MHz,
acetone-d6) δ 161.4, 154.5, 152.4, 150.5, 137.6, 132.0, 131.6, 130.6,
130.1, 127.9, 122.3, 121.5 (q, J = 322 Hz), 120.2, 115.6, 55.9; MS
(ESI+), found 409.2 (M + H)+; HRMS (ESI+) m/e calcd for
C19H15F3N2O3S 409.0828 (M + H)+, found 409.0815.
1,1,1-Trifluoro-N-(4-phenylpyridin-2-yl)-N-(4-(trifluoro-
methyl)phenyl)methanesulfonamide (19): 337 mg, 51%; waxy
1
solid, mp = 83−85 °C; H NMR (600 MHz, CDCl3) δ 8.61 (dd, J =
0.6, 5.4 Hz, 1H), 7.73−7.69 (m, 5H), 7.64−7.62 (m, 3H), 7.55−7.50
(m, 3H); 13C NMR (151 MHz, CDCl3) δ 153.7, 151.7, 149.3, 141.1,
136.4, 131.7 (q, J = 33.0 Hz), 130.6, 129.71, 129.66, 127.4, 127.1 (q, J
= 3.6 Hz), 123.6 (q, J = 270.9 Hz), 122.7, 120.9, 120.4 (q, J = 321.9
Hz); MS (ESI+), found 447.1 (M + H)+; HRMS (ESI+) m/e calcd for
C19H12F6N2O2S 447.0596 (M + H)+, found 447.0583.
1,1,1-Trifluoro-N-(isoquinolin-1-yl)-N-phenylmethanesulfo-
namide (12): neat reaction 101 mg, 40%; solution reaction 243 mg,
1
48%; white solid; mp = 118−119 °C; H NMR (600 MHz, acetone-
N-(4-Cyanophenyl)-1,1,1-trifluoro-N-(4-phenylpyridin-2-yl)-
1
d6) δ 8.56 (d, J = 6.0 Hz, 1H), 8.51−8.50 (m, 1H), 8.05−8.03 (m,
1H), 7.97 (d, J = 5.4 Hz, 1H), 7.94−7.93 (m, 2H), 7.83−7.79 (m,
2H), 7.48−7.46 (m, 2H), 7.41−7.40 (m, 1H); 13C NMR (151 MHz,
acetone-d6) δ 152.0, 143.2, 140.8, 140.1, 133.3, 131.4, 131.2, 131.1,
130.3, 129.2, 127.7, 126.4, 125.9−119.4 (q, J = 322.0 Hz), 125.2; MS
(ESI+), found 353.3 (M + H)+; HRMS (ESI+) m/e calcd for
C16H11F3N2O2S 353.0566 (M + H)+, found 353.0568.
methanesulfonamide (20): 204 mg, 32%; tan solid; H NMR (600
MHz, acetone-d6) δ 8.61 (dd, J = 0.6, 5.4 Hz, 1H), 7.97−7.93 (m, 5H),
7.78−7.75 (m, 3H), 7.54−7.48 (m, 3H); 13C NMR (151 MHz,
acetone-d6) δ 153.4, 152.9, 151.0, 143.1, 137.5, 134.6, 131.2, 130.9,
130.3, 128.1, 123.2, 121.4 (q, J = 321.8 Hz), 121.2, 118.2, 114.2; MS
(ESI+), found 404.1 (M + H)+; HRMS (ESI+) m/e calcd for
C19H12F3N3O2S 404.0675 (M + H)+, found 404.0666.
1,1,1-Trifluoro-N-(isoquinolin-3-yl)-N-phenylmethanesulfo-
1,1,1-Trifluoro-N-(4-(trifluoromethyl)phenyl)-N-((trifluoro-
methyl)sulfonyl)methanesulfonamide (21). To a 250 mL round-
bottomed flask were added a stir bar, 2.734 g (17.0 mmol) of 4-
trifluoromethylaniline, 70 mL of dry DCM, and 12.0 mL (69.6 mmol)
of diisopropylethylamine. The mixture was then cooled to 0 °C and
slowly treated with 10.0 g (35.4 mmol) of Tf2O over the course of 5
min. The resultant mixture darkened considerably. The mixture was
stirred for 19 h with gradual warming to rt after which time the solvent
was removed in vacuo and the residue subjected to silica gel
chromatography (eluting with 0−10% EtOAc/hexanes) to give the
desired product as a crystalline white solid (4.979 g, 69%): mp = 95−
96 °C; 1H NMR (600 MHz, CDCl3) δ 7.82−7.78 (m, 1H), 7.58−7.54
(d, J = 8.3 Hz, 1H); 13C NMR (151 MHz, CDCl3) δ 135.08, 134.3 (q,
J = 33.2 Hz), 131.78, 127.3 (q, J = 3.0 Hz), 123.0 (q, J = 271.8 Hz),
119.5 (q, J = 324.7 Hz); MS (ESI+), found 423.9 (M + H)+; HRMS
(ESI+) m/e calcd for C9H3F9NO4S2 423.9365 (M − H)−, found
423.9365.
namide (13): neat reaction 31 mg, 12%; solution reaction 34 mg, 7%;
1
white solid; mp = 126−127 °C; H NMR (600 MHz, acetone-d6) δ
9.42 (s, 1H), 9.05 (s, 1H), 8.44 (d, J = 8.4 Hz, 1H), 8.25 (d, J = 8.4
Hz, 1H), 8.02−8.00 (m, 1H), 7.91 (d, J = 7.8 Hz, 2H), 7.82−7.79 (m,
1H), 7.52−7.48 (m, 2H), 7.44−7.41 (m, 1H); 13C NMR (151 MHz,
acetone-d6) δ 156.5, 146.2, 141.3, 135.4, 134.3, 133.5, 131.74. 131.70,
131.1, 130.4, 130.3, 130.1, 125.6−119.2 (q, J = 321.9 Hz), 123.8; MS
(ESI+), found 353.3 (M + H)+; HRMS (ESI+) m/e calcd for
C16H11F3N2O2S 353.0566 (M + H)+, found 353.0569.
1-(1,1,1-Trifluoro-N-phenylmethylsulfonamido)isoquinolin-
4-yl trifluoromethanesulfonate (14): neat reaction 62 mg, 17%;
1
solution reaction 156 mg, 22%; white solid; mp =116−117 °C; H
NMR (600 MHz, acetone-d6) δ 8.78 (s, 1H), 8.66 (d, J = 8.4 Hz, 1H),
8.21 (d, J = 8.4 Hz, 1H), 8.18−8.15 (m, 1H), 8.06−8.04 (m, 1), 7.93−
7.92 (d, J = 8.4 Hz, 2H), 7.52−7.49 (m, 2H), 7.47−7.44 (m, 1H); 13C
NMR (151 MHz, acetone-d6) δ 151.6, 145.0, 139.6, 135.7, 135.6,
133.6, 133.0, 131.64, 131.58, 130.4, 129.0, 127.5, 122.5 (q, J = 323.0
Hz), 122.5, 120.2 (q, J = 318.7 Hz,); 19F NMR (376 MHz, acetone-d6)
δ −71.4, −73.9; MS (ESI+), found 501.3 (M + H)+; HRMS (ESI+) m/
e calcd for C17H10F6N2O5S2 501.0008 (M + H)+, found 500.9990.
N-(4,6-Dimethylpyrimidin-2-yl)-1,1,1-trifluoro-N-phenylme-
thanesulfonamide (15): 162 mg, 30%; tan solid, mp = 88−89 °C;
1H NMR (600 MHz, acetone-d6) δ 7.52−7.47 (m, 5H), 7.15 (s, 1H),
N-(4-Cyanophenyl)-1,1,1-trifluoro-N-((trifluoromethyl)-
sulfonyl)methanesulfonamide (22). Compound 22 was prepared
under conditions identical to those used to prepare compound 21 and
was isolated as a crystalline white solid (1.686 g, 26%): mp = 70.5−
1
71.5 °C; H NMR (600 MHz, CDCl3) δ 7.86−7.81 (m, 2H), 7.58−
7.53 (m, 2H). 13C NMR (151 MHz, CDCl3) δ 135.6, 133.8, 132.1,
119.4 (q, J = 324.7 Hz), 116.9, 116.6. MS (ESI+), found 382.9 (M +
H)+; HRMS (ESI+) m/e calcd for C9H5F6N2O4S2 382.9595 (M + H)+,
found 382.9580.
2.39 (s, 6H); 13C NMR (151 MHz, acetone-d6) δ 170.1, 159.3, 138.4,
131.1, 130.3, 121.5, (q, J = 322.6 Hz), 119.0, 23.6; MS (ESI+), found
332.2 (M + H)+; HRMS (ESI+) m/e calcd for C13H12F3N3O2S
332.0675 (M + H)+, found 332.0668.
4-Phenylpyridin-2-yl trifluoromethanesulfonate (23): pale
4,6-Dimethyl-2-(1,1,1-trifluoro-N-phenylmethylsulfon-
amido)pyrimidin-5-yl trifluoromethanesulfonate (16): 158 mg,
20%; white solid; mp = 116−116.5 °C (needles obtained from slow
1
yellow semisolid; H NMR (600 MHz, CDCl3) δ 8.46−8.41 (dd, J
= 5.2, 0.6 Hz, 1H), 7.67−7.62 (m, 2H), 7.61−7.58 (dd, J = 5.1, 1.5 Hz,
1H), 7.56−7.48 (m, 3H), 7.38−7.35 (dd, J = 1.5, 0.6 Hz, 1H); 13C
NMR (151 MHz, CDCl3) δ 156.9, 154.3, 149.0, 136.4, 130.3, 129.6,
127.3, 122.5, 118.8 (q, J = 321.6 Hz), 112.9; MS (ESI+), found 304.0
(M + H)+; HRMS (ESI+) m/e calcd for C12H9F3NO3S 304.0255 (M +
H)+, found 304.0249.
1
evaporation of acetone); H NMR (600 MHz, acetone-d6) δ 7.56−
7.53 (m, 3H), 7.50−7.48 (m, 2H), 2.53 (s, 6H); 13C NMR (151 MHz,
acetone-d6) δ 163.6, 156.7, 141.2, 137.7, 131.1, 130.7, 130.4, 121.3 (q,
J = 292.4 Hz), 119.2 (q, J = 287.2 Hz), 20.0; HRMS (ESI+) m/e calcd
for C14H11F6N3O5S2 480.0117 (M + H)+, found 480.0101.
E
dx.doi.org/10.1021/jo302014c | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra and HPLC chromatograms for all
described compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: jkeith@its.jnj.com
■
Notes
The authors declare no competing financial interest.
REFERENCES
■
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dx.doi.org/10.1021/jo302014c | J. Org. Chem. XXXX, XXX, XXX−XXX