Stereoselective addition of 2-phenyloxazol-4-yl trifluoromethanesulfonate to N -sulfinyl imines: Application to the synthesis of the HCV protease inhibitor boceprevir

Article abstract of DOI:10.1021/jo301856f

The stereoselective addition of 2-phenyloxazol-4-yl trifluoromethanesulfonate to N-sulfinylimines is described. Vinyl anions derived from enol triflate 2 undergo 1,2-addition with a variety of aldimines to afford the corresponding secondary sulfonamides as single diastereomers. The absolute stereochemistry was confirmed by X-ray crystallography which provides support that the reaction proceeds through an open, nonchelate transition state. This methodology has been applied to the synthesis of the ketoamide fragment of the protease inhibitor boceprevir.

Full text of DOI:10.1021/jo301856f

Note
pubs.acs.org/joc
Stereoselective Addition of 2‑Phenyloxazol-4-yl
Trifluoromethanesulfonate to N‑Sulfinyl Imines: Application to the
Synthesis of the HCV Protease Inhibitor Boceprevir
William J. Morris,* Kiran K. Muppalla,* Cameron Cowden, and Richard G. Ball
Department of Process Research, Merck Research Laboratories, Rahway, New Jersey 07065, United States
S
* Supporting Information
ABSTRACT: The stereoselective addition of 2-phenyloxazol-
4-yl trifluoromethanesulfonate to N-sulfinylimines is described.
Vinyl anions derived from enol triflate 2 undergo 1,2-addition
with a variety of aldimines to afford the corresponding
secondary sulfonamides as single diastereomers. The absolute
stereochemistry was confirmed by X-ray crystallography which
provides support that the reaction proceeds through an open,
nonchelate transition state. This methodology has been
applied to the synthesis of the ketoamide fragment of the protease inhibitor boceprevir.
epatitis C is an infectious disease of the liver caused by
the hepatitis C virus (HCV). Once established, hepatitis
case of boceprevir (5), the amino stereocenter of the β-amino-
α-ketoamide undergoes rapid equilibration under cellular
conditions. Consequently, 5 is prepared commercially as a
mixture of diastereomers at this amino stereocenter. Although
this simplifies the synthesis of 5, preparing a mixture of
diastereomers can introduce problems with respect to process
development as the isolation and characterization of these
diastereomeric mixtures becomes more complex. It is for these
reasons that we sought an alternative approach4 aimed at
maintaining control of the amino stereocenter throughout the
synthesis of hydroxy amide 4.
Our synthetic approach to 4 is shown in Figure 2. In order to
control the outcome at the amino stereocenter, we chose to
employ N-sulfinylimine5 1 as an electrophile and couple it with
enol triflate 2. The product of this addition reaction can be
further converted to hydroxy amide 4 under basic conditions.
H
C can lead to chronic liver disease including cirrhosis, liver
cancer, or liver failure. Approximately 3% of the world’s
population is infected with the HCV including over 4 million
Americans.1 Of those infected, up to 80% develop chronic
infection. The standard of care for hepatitis C has been a
combination therapy of pegylated interferon in conjunction
with ribavirin. Many patients experience undesirable side effects
in response to this therapy including anemia, depression,
fatigue, insomnia, and anxiety. Perhaps of greater significance is
that this combination therapy provides sustained virological
response in approximately 50% of patients with the genotype
1.2 This limited response rate, in combination with the side
effects, has provided the impetus for pharmaceutical companies
to develop alternative therapies for the treatment of hepatitis C.
Two products of these efforts, telaprevir and boceprevir (Figure
1), have recently garnered approval from the US Food and
Figure 1. Boceprevir (5) and telaprevir (6).
Drug administration. These two HCV NS3 protease inhibitors,
which prevent a critical step in HCV genome replication,
represent a significant advancement in the care for patients
infected with HCV.
Each of these protease inhibitors contain a β-amino-α-
ketoamide that binds to the NS3 protease at the S1 pocket and
forms a covalent and reversible complex with Ser139.3 In the
Figure 2. Retrosynthetic analysis.
Received: August 29, 2012
© XXXX American Chemical Society
A
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The Journal of Organic Chemistry
Note
a
The synthesis of hydroxy amide 4 is shown in Scheme 1.
Oxazolone 13 was prepared via known procedures and
Table 1. Reaction Scope
Scheme 1. Synthesis of Hydroxyamide 4
converted to enol triflate 2.6 Enol triflate 2 was treated with
n-BuLi7 at −78 °C followed by addition of the N-sulfinylimine
1. Following an aqueous workup, a single diastereomer was
1
observed by H NMR and was isolated in 70% yield. Exposure
to aqueous NaOH resulted in hydrolysis of the triflate with
concomitant cleavage of the 2-phenyloxazol-4-yl intermediate 3
resulting in the formation of a mixture of diastereomers at the
secondary carbinol stereocenter.8 The sulfinyl group was
removed under acidic conditions furnishing the HCl salt of
hydroxyamide 4.9
Following the successful application of this directed metal-
ation10 reaction to the synthesis of hydroxy amide 4, we chose
to evaluate the scope of this addition reaction. Sulfinyl imines11
derived from aliphatic aldehydes provided addition products as
single diastereomers in moderate to good yields (Table 1,
entries 1−5). Imines with α-alkoxy substitution resulted in no
stereocontrol (Table 1, entries 6 and 7) likely due to the
interruption of the transition state by coordination of the
ethereal oxygen to the aryl lithium reagent.12 It is noteworthy
that α-alkyl substitution of the aldehydes can be tolerated with
minimal loss of conversion and no impact on stereoselectivity
(entries 1, 2, and 5). Imines derived from aromatic aldehydes
also were competent substrates for this reaction. The imine
derived from benzaldehyde provided the addition adduct as a
single diastereomer (entry 8) as did 4-substutituted benzalde-
hydes when the substitution was an electron-withdrawing group
(entries 9 and 10). Imines from aromatic aldehydes with
electron-donating substituents at the para position failed to
react with the aryllithium nucleophile (entry 11). This lack of
reactivity is possibly due to a combination of factors including
the reduced electrophilicity of 4-OMe-substituted sulfinyl
imines in conjunction with the attenuated nucleophilicity of
an aryllithium reagent possessing an electron-withdrawing
triflate substituent and a σ-withdrawing oxygen atom adjacent
to the reactive carbanion. Efforts were made to improve these
results by employing additives such as TMEDA, HMPA, and
Lewis acids such as BF3·OEt2 and AlMe3 without any success.13
The stereochemistry of this addition reaction was confirmed
through X-ray crystallography.14 The stereochemical outcome
observed for the addition is consistent with open transition
state I (Figure 3), which is consistent with previous reports
when employing organolithium reagents in coordinating
solvents such as THF.15
a
b
See the Supporting Information for experimental details. Deter-
1
mined by analysis of unpurified H NMR.
B
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Note
1H), 1.85−1.91 (m, 1H), 1.79−1.83 (m, 1H), 1.70−1.75 (m, 1H),
1.61−1.68 (m, 1H), 1.21 (s, 9H); 13C NMR (400 MHz, CDCl3)
158.1, 141.6, 139.8, 135.4, 130.2, 126.4, 126.1, 69.7, 56.3, 49.6, 41.9,
32.6, 28.1, 22.3, 18.6; HRMS (Micromass Q-Tof Ultima API) mass
calcd for C20H25F3N2O5S2 [M + H], 495.1235, found 495.1240.
4-[[(tert-Butylsulfinyl)amino](cyclopentyl)methyl]-2-phenyl-1,3-
oxazol-5-yl Trifluoromethanesulfonate (15). Purified with 30% ethyl
acetate/hexanes, yielding 1.09g (65%) as yellow oil: IR (KBr, cm−1)
2956, 2869, 1633, 1426, 1451, 1363, 1344, 1205, 1132, 1111, 1047,
1
Figure 3. Model for stereochemical induction.
943, 869, 798, 778, 718, 690, 697; H NMR (400 MHz, CDCl3) δ
7.97−7.99 (dd, J = 1.5 Hz, 1.96 Hz, 2H), 7.45−7.51 (m, 3H), 4.40−
4.44 (dd, J = 3.9 Hz, 1H), 3.53(d, J = 3.8 Hz, 1H), 2.48−2.53 (m, 1H),
1.97−2.04 (m, 1H),1.47−1.73 (m,5H), 1.21−1.34 (m,2H), 1.18 (s,
9H); 13C NMR (400 MHz, CDCl3) 158.1, 141.8, 139.9, 131.4, 128.9,
126.4, 126.1, 56.2, 54.9, 43.9, 30.3, 29.6, 25.2, 22.3; HRMS
(Micromass Q-Tof Ultima API) mass calcd for C20H25F3N2O5S2 [M
+ H] 495.1235, found 495.1232.
In summary, the reaction between the vinyllithium reagent
derived from 2 and N-sulfinyl imines provides 1,2-addition
products in moderate to good yield. In most cases, the addition
products are formed as a single diastereomer. X-ray
crystallography provides support that the reaction proceeds
via an open, nonchelated transition state. This methodology has
been applied to the synthesis of the β-amino-α-hydroxy (4)
fragment of the NS3 protease inhibitor Boceprevir and is being
evaluated as a potential route for commercial manufacturing.
5-[[(tert-Butylsulfinyl)amino](cyclohexyl)methyl]-2-phenyl-1,3-
oxazol-4-yl Trifluoromethanesulfonate (16). Purified with 30% ethyl
acetate/hexanes, yielding 989 mg (57%) as yellow oil: IR (KBr, cm−1)
3128, 2930, 2856, 2323, 1634, 1553, 1487, 1474, 1450, 1419, 1348,
1331, 1317, 1306, 1280, 1214, 1129, 1115, 1077, 1041, 943, 898, 861,
1
800, 778, 760, 745, 722, 690, 638; H NMR (400 MHz, CDCl3) δ
EXPERIMENTAL SECTION
■
7.97−7.99 (dd, J = 1.5 Hz, 2.0 Hz, 2H), 7.45−7.51 (m, 3H), 4.39−
4.43 (q, J = 5 Hz, 1H), 3.51 (d, J = 5 Hz, 1H), 1.99−2.02 (m, 1H),
1.86−1.93 (m, 1H), 1.70−1.85 (m, 2H), 1.61−1.69 (m, 1H), 1.20−
1.35 (m, 3H), 1.19 (s, 9H), 1.05−1.13 (m, 3H); 13C NMR (400 MHz,
CDCl3) 158.2, 142.3, 139.3, 131.4, 129.9, 126.4, 126.1, 56.3, 55.9, 42.4,
30.3, 29.3, 26.1, 25.7, 22.4; HRMS (Micromass Q-Tof Ultima API)
mass calcd for C21H27F3N2O5S2 [M + H], 509.1392, found 509.1392
5-[1-[(tert-Butylsulfinyl)amino]pentyl]-2-phenyl-1,3-oxazol-4-yl
Trifluoromethanesulfonate (17). Purified with 30% ethyl acetate/
hexanes, yielding 1.05g (64%) as yellow oil: IR (KBr, cm−1) 3133,
2961, 2871, 2324, 1639, 1554, 1451, 1425, 1363, 1348, 1318, 1212,
Synthesis of Hydroxyl Amide 4 from 3: (2R)-4-Amino-1-
cyclobutyl-3-hydroxy-4-oxobutan-2-aminium Chloride. To a
round-bottom flask containing 3 (500 mg, 1.01 mmol) was added
EtOH (5 mL). The solution was cooled to 0 °C and treated with
aqueous 1 M NaOH (3 mL, 3.03 mmol) for 4 h. The reaction was
neutralized (pH 7) at 0 °C with aqueous 1 M HCl and diluted with a
1:1 mixture of CH2Cl2/H2O (40 mL). The aqueous layer was split and
extracted with CH2Cl2 (3 × 20 mL). The combined organics were
concentrated to ∼20 mL at which time 2-propanol was added (40
mL). The solution was again concentrated to ∼10 mL at which time
another 40 mL of 2-propanol was added. The mixture was reduced to
a volume of ∼10 mL and treated with 5 M HCl in 2-propanol (1 mL,
5.1 mmol) at room temperature. The mixture was allowed to stir at
room temperature for 3 h. MTBE (10 mL) was added to the mixture
and stirred at room temperature for 30 min. The solid hydrochloride
salt was filtered and washed with MTBE (20 mL). The collected solid
was dissolved in 2-propanol/H2O (9:1, 10 mL) and heated to 80 °C
for 1 h (homogeneous solution). The mixture was cooled to 0−5 °C
over 3 h and held at 0−5 °C for 1 h. The solid was collected by
filtration to afford 168 mg of 4 (80%) as a 1:1 mixture of
diastereomers as a white solid: 1H NMR (400 MHz, CDCl3) δ
4.36−4.31 (m, 1H), 4.22−4.17 (m, 1H), 3.53−3.48 (m, 2H), 3.37−
3.33 (OH, 1H), 2.57−2.49 (m, 2H), 2.13−1.99 (m, 4H), 1.89−1.58
(m, 12H), 13C NMR (400 MHz, CDCl3) 175.0, 174.7, 70.5, 69.1, 51.9,
51.7, 36.1, 34.1, 31.6, 31.5, 27.6, 27.2, 17.8, 17.6; HRMS (Micromass
Q-Tof Ultima API) mass calcd for C8H16N2O2 [M + H], 173.1290,
found 173.1287.
1
1128, 1098, 1077, 1046, 944, 927, 861, 779, 724, 690, 663, 612; H
NMR (400 MHz, CDCl3) δ 7.97−7.99 (dd, J = 1.48 Hz, 1.88 Hz, 2H),
7.45−7.52 (m, 3H), 4.61−4.65 (m, 1H), 3.48 (d, J = 5.32 Hz, 1H),
2.01−2.06 (m, 2H), 1.30−1.48 (m, 4H), 1.20 (s, 9H), 0.89 (t, 3H);
13C NMR (400 MHz, CDCl3) 158.2, 141.7, 139.9, 131.4, 128.9, 126.8,
126.4, 120.1, 116.9, 56.3, 51.1, 34.5, 27.9, 22.2, 13.8; HRMS
(Micromass Q-Tof Ultima API) mass calcd for C19H25F3N2O5S2 [M
+ H] 483.1235, found 483.1229.
5-[1-[(tert-Butylsulfinyl)amino]-3-methylbutyl]-2-phenyl-1,3-oxa-
zol-4-yl Trifluoromethanesulfonate (18). Purified with 30% ethyl
acetate/hexanes, yielding 1.12g (68%) as yellow solid: IR (KBr, cm−1)
3075, 2964, 2876, 2323, 2051, 1640, 1554, 1473, 1451, 1422, 1361,
1347, 1318, 1286, 1213, 1124, 1099, 1080, 1044, 1009, 943, 927, 887,
1
585, 781, 727, 709, 691, 664, 614; H NMR (400 MHz, CDCl3) δ
7.97−7.99 (dd, J = 1.3 Hz, 1.84 Hz, 2H), 7.45−7.51 (m, 3H), 4.68−
4.72 (m, 1H), 3.43 (d, J = 5 Hz, 1H), 1.89−1.94 (m, 2H), 1.59−1.65
(m, 1H), 1.19 (s, 9H), 0.96−1.03 (m, 6H); 13C NMR (400 MHz,
CDCl3) 158.2, 140.1, 131.5, 128.9, 126.4, 126.1, 120.1, 116.9, 56.3,
49.3, 43.7, 24.9, 22.2, 21.9; HRMS (Micromass Q-Tof Ultima API)
mass calcd for C19H25F3N2O5S2 [M + H], 483.1235, found 483.1240.
5-[1-[(tert-Butylsulfinyl)amino]-2,2-dimethylpropyl]-2-phenyl-
1,3-oxazol-4-yl Trifluoromethanesulfonate (19). Purified with 30%
ethyl acetate/hexanes, yielding 650 mg (40%) as yellow solid: IR (KBr,
cm−1) 3328, 2960, 1689, 1631, 1557, 1475, 1427, 1367, 1343, 1322,
1290, 1225, 12121, 1133, 1060, 1025, 943, 911, 868, 802, 779, 725,
692, 659, 604; 1H NMR (400 MHz, CDCl3) δ 7.95−7.98 (dd, J = 1.2
Hz, 1.64 Hz, 2H), 7.48−7.51 (m, 3H), 4.41 (d, J = 4.6 Hz, 1H), 3.62
(d, J = 4.5 Hz, 1H), 1.18 (s, 9H), 1.11 (s, 9H); 13C NMR (400 MHz,
CDCl3) 158.3, 143.2, 138.3, 131.5, 129.1, 126.4, 126.1, 116.9, 59.2,
56.4, 36.3, 26.7, 22.3; HRMS (Micromass Q-Tof Ultima API) mass
calcd for C19H25F3N2O5S2 [M + H], 483.1235, found 483.1232.
5-[2-(Benzyloxy)-1-[(tert-butylsulfinyl)amino]ethyl]-2-phenyl-1,3-
oxazol-4-yl Trifluoromethanesulfonate (20). Purified with 30% ethyl
acetate/hexanes, yielding 559 mg (30%) of 20 as an inseparable1:1
mixture of diastereomers (yellow oil): IR (KBr, cm−1) 3213, 3064,
3031, 2957, 2866, 1737, 1633, 1555, 1452, 1428, 1390, 1363, 1211,
General Procedure for Addition of 2-Phenyloxazol-4-yl
Trifluoromethanesulfonate to N-Sulfinylimines. To a three-
necked round-bottomed flask was added triflate followed by 10
volumes of THF. The mixture was cooled to −78 °C, and n-BuLi (2.5
M in hexanes, 1.2 equiv) was added at a rate such that the internal
temperature did not exceed −70 °C. After 10 min, the sulfinyl imine
was added as a solution in THF (2 volumes of THF) over 3−5 min.
The reaction was stirred for 10 min at −78 °C. The reaction was
quenched with 15 volumes of 10% aqueous NH4Cl, and the aqueous
layer was extracted with CH2Cl2. The combined organic layers were
concentrated and purified by flash column chromatography with
EtOAc/hexanes.
5-[1-[(tert-Butylsulfinyl)amino]-2-cyclobutylethyl]-2-phenyl-1,3-
oxazol-4-yl Trifluoromethanesulfonate (3). Purified with 30% ethyl
acetate/hexanes, yielding 1.09g (70%) as yellow oil: IR (KBr, cm−1)
3110, 2948, 2868, 2323, 1713, 1638, 1553, 1474, 1450, 1362, 1317,
1
1289, 1212, 1128, 1070, 1045, 943, 859, 779, 748, 724, 690, 662; H
NMR (400 MHz, CDCl3) δ 7.99−8.01 (dd, J = 1.5 Hz, 1.96 Hz, 2H),
7.47−7.57 (m, 3H), 4.55−4.6 (m, 1H), 3.53 (d, J = 5 Hz, 1H), 2.32−
2.38 (m, 1H), 2.12−2.19 (m, 1H), 2.09−2.12 (m, 1H), 1.98−2.04 (m,
C
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The Journal of Organic Chemistry
Note
1
1132, 1068, 863, 777, 734, 695, 607; H NMR (400 MHz, CDCl3) δ
AUTHOR INFORMATION
Corresponding Author
*E-mail: william.morris2@merck.com, kiran.muppalla@merck.
com.
■
7.95 (d, J = 6.6 Hz, 2H), 7.44−7.51 (m, 4H), 7.27−7.37 (m, 13H),
4.89−4.92 (q, J = 5.4 Hz, 1H), 4.53−4.66 (m, 6H), 4.4 (d, J = 8.5 Hz,
1H), 4.15−4.18 (m,1H), 3.86−3.95 (m, 3H), 3.67−3.71(m, 1H),
3.59−3.61 (m, 1H), 3.54−3.56 (m, 1H), 3.41−3.48 (m, 1H), 3.36−
3.39 (m, 1H), 1.18−1.25 (m 18H); 13C NMR (400 MHz, CDCl3)
165.9, 159.8, 138.9, 138.4, 131.7, 130.1, 129.1, 127.1, 125.7, 125.1,
87.5, 86.1, 73.4, 72.1, 70.3, 58.3, 57.1, 57.8, 50.6, 22.7, 22.3; HRMS
(Micromass Q-Tof Ultima API) mass calcd for C23H25F3N2O6S2 [M +
H], 547.1184, found 547.1187.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Thomas Novak for HRMS support and Roy Helmy
for IR support.
5-(2,2,9,9,10,10-Hexamethyl-3-oxido-7-oxa-34-thia-4-aza-9-si-
laundecan-5-yl)-2-phenyl-1,3-oxazol-4-yl Trifluoromethanesulfo-
nate (21). Purified with 30% ethyl acetate/hexanes, yielding 558 mg
(28%) of 21 as an inseparable 1:1 mixture of diastereomers (yellow
oil): IR (KBr, cm−1) 3191, 2954, 2928, 2857, 1636, 1605, 1555, 1471,
1430, 1389, 1362, 1345, 1226, 1068, 1006, 937, 833, 776, 719, 689; 1H
NMR (400 MHz, CDCl3) δ 7.96−7.98 (dd, J = 1.4 Hz,1.84 Hz, 2H),
7.45−7.51 (m, 3H), 4.78−4.79 (q, J = 1.1 Hz, 1H), 4.55 (d, J = 3 Hz,
1H) ; 4.42−4.46 (m, 1H), 4.2 (d, J = 5.1 Hz, 1H), 4.02 (m, 1H),
3.85−3.92 (m, 2H), 3.76−3.77 (m, 1H), 3.63- 3.69 (m, 3H), 3.42−
3.45 (m, 1H), 1.24 (s, 9H), 1.22 (s, 9H), 0.89 (m, 18H), 0.11−0.19
(m, 12H); 13C NMR (400 MHz, CDCl3)158.3, 142.7, 137.7, 131.9,
129.1, 126.4, 88.9, 87.4, 68.1, 66.3, 64.3, 56.7, 51.9, 31.9, 25.1, 22.9,
22.4, 18.7, 13.7; HRMS (Micromass Q-Tof Ultima API) mass calcd for
C23H35F3N2O6S2Si [M + H] 571.1580, found 571.1587.
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5-[[(tert-Butylsulfinyl)amino](phenyl)methyl]-2-phenyl-1,3-oxa-
zol-4-yl Trifluoromethanesulfonate (22). Purified with 30% ethyl
acetate/hexanes, yielding 959 mg (56%) as yellow oil: IR (KBr, cm−1)
3176, 2959, 1633, 1554, 1486, 1450, 1427, 1347, 1316, 1209, 1131,
1
1115, 1065, 1026, 923, 864, 795, 777, 728, 714, 688, 663; H NMR
(400 MHz, CDCl3) δ 7.95−7.99 (dd, J = 1.32 Hz, 1.76 Hz, 2H),
7.37−7.53 (m, 8H), 5.86 (d J = 3.7 Hz, 1H), 3.81 (d, J = 3.6 Hz, 1H),
1.26 (s, 9H), 13C NMR (400 MHz, CDCl3) 158.7, 142.2, 138.3, 137.3,
131.6, 129.4, 129.1, 128.9, 127.5, 126.5, 126.1, 120.1, 56.5, 53.8, 22.4;
HRMS (Micromass Q-Tof Ultima API) mass calcd for
C21H21F3N2O5S2 [M + H] 503.0922, found 503.0924.
5-[(4-bromophenyl)[(tert-butylsulfinyl)amino]methyl]-2-phenyl-
1,3-oxazol-4-yl Trifluoromethanesulfonate (23). Purified with 30%
ethyl acetate/hexanes, yielding 753 mg (38%) as yellow oil: IR (KBr,
cm−1) 3174, 2960, 1735, 1633, 1590, 1554, 1487, 1450, 1428, 1346,
1316, 1210, 1131, 1116, 1068, 1009, 944, 865, 841, 78, 765, 716, 688,
Chang, S.; Kim, Y. H. Synlett 2006, 86. (o) Grosjean, F.; Huche,
́
M.;
Larcheveque, M.; Legendre, J. J.; Petit, Y. Tetrahedron 1994, 50, 9325.
̂
(p) Bourzat, J. D.; Commercuon, A. Tetrahedron Lett. 1993, 34, 6049.
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(q) Palomo, C.; Aizpurua, J. M.; Miranda, J. I.; Mielgo, A.; Odriozola,
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1
640; H NMR (400 MHz, CDCl3) δ 7.95−7.99 (dd, J = 1.4 Hz, 1.68
Hz, 2H), 7.39−7.56 (m, 7H), 5.82 (d, J = 4.2 Hz, 1H), 3.79 (d, J = 4.2
Hz, 1H), 1.25 (s, 9H); 13C NMR (400 MHz, CDCl3) 158.9, 142.2,
137.7, 136.3, 132.4, 131.7, 129.7, 129.2, 126.5, 125.9, 123.4, 120.1,
56.7, 53.5, 22.4; HRMS (Micromass Q-Tof Ultima API) mass calcd for
C21H20BrF3N2O5S2 [M + H] 581.0027, found 581.0034.
́
(v) Cativiela, C.; Diaz-de-Villegas, M. D.; Galvez, J. A. Tetrahedron:
Asymmetry 1996, 7, 529. (w) Dondoni, A.; Perrone, D.; Semola, T.
Synthesis 1995, 181.
5-[[(tert-Butylsulfinyl)amino](4-fluorophenyl)methyl]-2-phenyl-
1,3-oxazol-4-yl Trifluoromethanesulfonate (24). Purified with 30%
ethyl acetate/hexanes, yielding 1.05g (59%) as brownish red oil: IR
(KBr, cm−1) 3177, 2962, 2324, 1734, 1633, 1605, 1555, 1509, 1486,
1428, 1347, 1317, 1210, 1160, 1131, 1116, 1064, 944, 843, 779, 767,
730, 689; 1H NMR (400 MHz, CDCl3) δ 7.95−7.97 (dd, J = 1.28 Hz,
1.76 Hz, 2H), 7.47−7.53 (m, 5H), 7.08−7.13 (t, J = 8.6 Hz, 2H), 5.85
(d, J = 4 Hz, 1H), 3.8 (d, J = 4 Hz, 1H), 1.26 (s, 9H), 13C NMR (400
MHz, CDCl3) 164.2, 161.7, 158.8, 142.2, 138.1, 134.4, 131.7, 129.1,
128.1, 126.5, 125.9, 120.1, 56.5, 53.3, 22.4; HRMS (Micromass Q-Tof
Ultima API) mass calcd for C21H20F4N2O5S2 [M + H] 521.0828,
found 521.0830
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as it is ultimately oxidized to a ketone in 5.
1
(9) For H NMR data of 4, see: Chen, M., Green, M. D., Zhang, F.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of 1H and 13C NMR spectra and X-ray data (CIF). This
material is available free of charge via the Internet at http://
pubs.acs.org.
D
dx.doi.org/10.1021/jo301856f | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
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data for this paper. These data can be obtained free of charge from
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uk/data_request/cif
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