Concise Cu (I) catalyzed synthesis of substituted benzofurans via a Tandem SNAr/C-O coupling process

Article abstract of DOI:10.1021/acs.oprd.6b00141

A novel and convergent approach to tetrasubstituted benzofurans was developed from ortho-bromo aryl fluorides and keto-Amides via one-pot SNAr displacement and subsequent Cu(I) catalyzed C-O coupling on the ortho-bromide. The scope of this methodology was demonstrated on several similar substrates.

Full text of DOI:10.1021/acs.oprd.6b00141

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Full Paper
Concise Cu (I) Catalyzed Synthesis of Substituted
Benzofurans via a Tandem SNAr/C-O Coupling Process
Zhiguo Jake Song, Lushi Tan, Guiquan Liu, Honglin Ye, and Jianming Dong
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00141 • Publication Date (Web): 25 May 2016
Downloaded from http://pubs.acs.org on May 26, 2016
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Concise Cu (I) Catalyzed Synthesis of Substituted
Benzofurans via a Tandem SNAr/CꢀO Coupling
Process
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Zhiguo J. Song*, Lushi Tan*,Guiquan Liu †, Honglin Ye †, Jianming Dong†
Department of Process Chemistry, Merck Research Laboratories, P.O. Box 2000, Rahway NJ
07065
†Process R&D, WuXi AppTec Co., Ltd., 288 Fute Zhong Road, Shanghai 200131, China
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Table of Contents Graphic
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ABSTRACT A novel and convergent approach to tetrasubstituted benzofurans was developed
from orthoꢀbromo aryl fluorides and ketoꢀamides via oneꢀpot SNAr displacement and
subsequent Cu(I) catalyzed CꢀO coupling on the orthoꢀbromide. The scope of this methodology
was demonstrated on several similar substrates.
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KEYWORDS Benzofuran, CꢀO Coupling, Nitro Reduction, Aryl fluoride displacement by
enolate.
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Benzofurans are important building blocks for the synthesis of biologically active compounds
in the pharmaceutical industry and compound 3 has been an important intermediate in Merck’s
hepatitis C program.1,2 The introduction of four substituents around the benzofuran ring poses a
significant challenge and the original routes are shown in Scheme 11b,2
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Scheme 1. Previous Synthetic Routes for 3
Two related synthetic strategies have been reported that proceed via the key benzofuran
intermediate 2 which can be prepared by either oxidative coupling of 4ꢀbromophenol with the
keto ester 12,3 or by condensation of bromophenol 4 with 4ꢀfluorobenzoyl chloride.4 While
relatively short, the former route suffers from low yield of the key oxidative coupling step
(15%). A third approach involves the preparation of benzofuran 7 with lateꢀstage introduction of
the 4ꢀfluorophenyl moiety.2 All of these synthetic routes are rather lengthy and impractical,
ranging from 9 to 12 steps. To make compound 3 on large scale, a more efficient synthesis is
desired.
Toward that end we evaluated several potential routes, as illustrated in Scheme 2. One of the
shortest routes envisaged was to preꢀinstall the methyl methanesulfonamide on 3ꢀbromophenol to
make 9 and then form the benzofuran ring via the oxidative coupling of the β−ketoꢀester 12.
While the palladium catalyzed CꢀN coupling between 3ꢀbromophenol and Nꢀmethyl
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methanesulfonamide to make 9 worked well, the oxidative coupling gave low yield of 10 with a
under the reported conditions in dichloroethane.3 The substrate 9 suffered from poor reactivity
and low regio selectivity toward the formation of the desired regio isomer of the substituted
benzofuran 10. We then tested the approach to form the benzofuran via the intramolecular CꢀO
coupling of the βꢀketoꢀester onto the ortho bromide in compound 14.5 This intermediate can be
prepared from 13 by SNAr displacement of aryl fluoride or by Claisen condensation from 15.
We were encouraged by the fact that the Cu (I) catalyzed intramolecular CꢀO coupling worked
well,6 but the two substrates 13 and 15 are not as readily available as we would desire. In
addition, due to difficulties with the bromination of 10 to make 11, a preꢀinstalled bromide at the
5ꢀposition of the benzofuran would be required. We found that the tetrasubstituted benzene 16 is
readily available at very low cost (~$100/kg on scale), providing a raw material with both the
desired bromide and nitrogen functionalities as per the requirement. To make the synthesis yet
more convergent, we would aim to preꢀinstall the Nꢀmethyl carboxamide before the benzofuran
formation by using ketoꢀamide 17, which leads to the overall strategy shown in in Scheme 3.
Gratifyingly, these strategic changes ultimately led to a highly efficient route to compound 3 and
in the next sections, the key process development results for this route will be described.
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Scheme 2. Route Scouting for 3
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Scheme 3. Preferred Route for 3
Benzofuran Formation The substitution of the fluoride on compound 16 by the enolate of 17
o
proved to be very facile, in fact the reaction occurs readily at 0 C in a DMAcꢀwater mixture
(97.5/2.5) in the presence of K3PO4 to generate intermediate 18. This intermediate was proposed
based on consistent LCMS data of a set of two closely eluting peaks on HPLC, presumably the
two enol stereo isomers. A range of commonly used solvents for copperꢀcatalyzed CꢀO
couplings were screened for the cyclization (DMF, DMSO, NMP, MeCN, THF, DMAc and
toluene) and it was found that the CꢀO coupling reaction was compatible with the same DMAcꢀ
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water mixture used for the formation of 18. Addition of common ligands, such as 1,10ꢀ
phenathroline, TMEDA, 2,2’ꢀbypyridyl or N,Nꢀdimethylglycine resulted in much higher levels
of the desꢀbromo side product which significantly reduced the yield.6 Gratifyingly, we found
that a oneꢀpot through process was possible and after formation of intermediate 18, the
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cyclization could be effected by simply adding CuI to the reaction mixture and heating to 55 C
to form the key benzofuran intermediate 19. The crystalline product can be isolated directly from
the reaction mixture in high purity and 69% yield over the 2 steps by addition of water and IPA.
Interestingly, during the preparation of this manuscript, the reaction of 16 and 1 under very
similar conditions to give the ethyl ester analog of compound 19 was reported by the group of
Copley, Xie and coꢀworkers at GlaxoSmithKline.6e The authors also attempted the same
transformation reported here under different conditions and observed unsatifactory results. The
advantage of the sequence reported here is that it is more convergent and higher yielding.
Nitro Reduction and Sulfinamide Formation After successful construction of the
benzofuran ring in 19, we then investigated nitro reduction to form the amine. This reaction is
complicated by the presence of bromide, which is readily reduced under a variety of typical
conditions, such as Pd catalyzed hydrogenation or metal reductions. We screened a number of
more bromideꢀcompatible Pt sources and identified a vanadiumꢀdoped platinum catalyst that
gave clean reduction with <1% bromide reduction.7 The best conditions were identified after
screening solvents and acid additives and we found that THFꢀwater in the presence of 2 eq acetic
acid worked well. It was also observed that while residual Cu from the previous step needs to be
controlled, but 1200 ppm residue Cu was well. The product 20 was crystallized directly after
removal of the catalyst by filtration. Mesylate formation was accomplished using mesyl chloride
and pyridine in DCM to produce 21 in 97% isolated yield. Attempts to replace DCM with other
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solvents such as DMF, THF or MeCN led to much less clean reaction profiles. To complete the
synthesis, the final Nꢀmethyl group was introduced with methyl iodide and K2CO3 in DMF to
make the target compound 3 in 86% yield.
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Scheme 4. Synthesis of Aryl Keto-amide 17
Preparation of keto-amide Although compound 17 is known in the literature, no practical
synthesis has been reported.8a,b,c As this compound was pivotal to our synthetic strategy, we
immediately set out to develop a scalable method for its preparation. As shown in Scheme 4, we
explored two potential routes; one via the Meldrum’s acid, the other from ketoꢀester 24 by
reaction with methylamine. Even though the reaction between Meldrum’s acid and 4ꢀ
fluorobenzoyl chloride gave the desired intermediate 22, the subsequent reaction with
methylamine resulted in very low yield of desired product under wellꢀestablished conditions.8d
An alternative route via the ketoꢀester was more promising based on preliminary data. The ketoꢀ
ester 24 could be readily prepared as the potassium enolate by reaction of the acetophenone 23
with dimethyl carbonate in the presence potassium tertꢀbutoxide.9a,b This potassium enolate 24
was precipitated out from the reaction mixture in MTBE as an amorphous solid in 87% isolated
yield, after correcting for inorganic sideꢀproduct impurities. When this mixture was used
directly in the reaction with excess methylamine,9c it was observed that the excess base carried
over in the crude solid prevented complete conversion to the ketoꢀamide. When the excess base
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was neutralized with 1ꢀ2 equiv HCl, the conversion of the ketoꢀester enolate to the ketoꢀamide 17
proceeded well and the reaction could be conveniently carried out using 30% aqueous
methylamine. Solid formation was observed during the reaction and NMR analysis revealed the
precipitate to be the enamide 25 formed from methylamine and the ketoꢀamide.10 This enamide
was easily hydrolyzed to the ketoꢀamide 17 by adjusting to pH 2 with HCl. The desired ketoꢀ
amide 17 then crystallizes out from the aqueous reaction mixture in 82% isolated yield and
99.3% HPLC purity. This oneꢀpot preparation starts from a commodity building block and is
easily amenable to large scale operation.
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Other Substituted Benzofurans Having established a useful method for preparing our target
benzofuran, we then investigated the scope of this methodology with a range of ketoꢀamides and
bromo fluorobenzenes. The results are listed in Scheme 5. We observed that very strong
electron withdrawing groups para to the fluoride (R4 = NO2, CN) facilitate the SNAr reaction
and subsequent cyclization, so compounds 28a, b and c were prepared under the same
conditions. Less electron withdrawing systems (e.g. R4 = halide or R3 = CN) did not lead to any
reaction for the SNAr step even at elevated temperature. For the ketoꢀamides, only Nꢀmethyl
acetyl acetamide gave moderate yield product 28d. Replacing the Nꢀmethyl group with phenyl
resulted in loss of reactivity.
In conclusion, a practical, concise and scalable synthesis of an important tetrasubstituted
benzofuran core 3 was developed. The key benzofuran formation was achieved through a goodꢀ
yielding oneꢀpot SNAr / intramolecular CꢀO coupling and this methodology was shown to be
amenable to the preparation of several other similarly substituted benzofurans.
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Scheme 5. Preparation of Other Benzofurans
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Notes: Yields were determined by HPLC before isolation.
Experimental Section
1H NMR and C NMR were recorded on 400 MHz spectrometer. Unless specified otherwise,
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all reagents and solvents were used as supplied by the manufacturers. All reactions were
conducted under an inert N2 atmosphere. Melting points are uncorrected.
Potassium (Z)-1-(4-fluorophenyl)-3-methoxy-3-oxoprop-1-en-1-olate (24). Potassium tertꢀ
butoxide (608 g, 5.44 mol) and dimethyl carbonate (2.5 kg) were sequentially charged to a
reactor and temperature adjusted to 20ꢀ30 °C. A solution of 1ꢀ(4ꢀfluorophenyl)ethanone 23 (300
g, 2.17 mol) in dimethyl carbonate (600 g) was charged over 2 h at 20ꢀ30 °C. The reaction
mixture was stirred for 3ꢀ4 h at 20ꢀ25 °C until complete consumption of 23 as indicated by
HPLC, following by the addition of MTBE (450 g) and a slurry was formed. The reaction
mixture was filtered and the product cake was further dried under vacuum at 30ꢀ40 °C to afford
24 as a white solid, 370 g, 63.0 wt% as the K enolate, 87% yield, 98.7% LACP, the rest is likely
KOMe and KOCO2Me based on 1H NMR peaks at 4.17 ppm (s) and 3.20 ppm (s). The wt%
purity was obtained by HPLC against a pure commercial sample. The crude product was used
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directly in the next step without further purification. 1H NMR (400 MHz DMSOꢀd6) δ 7.72 (t, J
= 14.4 Hz, 2H), 7.06 (d, J = 17.6 Hz, 2H), 4.90 (s, 1H), 3.38 (s, 3H), extra peaks 4.17 (br, s, 0.5ꢀ
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1 H), 3.20 (s, 1.5ꢀ2H); C NMR (100 MHz DMSOꢀd6) δ 48.5, 77.6, 114.3 (d, J=10 Hz), 128.6
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(d, J=8 Hz), 141.6, 162.6 (d, J=242.1 Hz), 169.4, 178.5. 19F NMR (376 MHz DMSOꢀd6) δ
114.9.
3-(4-Fluorophenyl)-N-methyl-3-oxopropanamide (17). To a reactor was added 30%
CH3NH2 aqueous solution (550 g x 30%, 5.3 mol) and conc. HCl (42 ml, 12M, 0.54 mol), and
the mixture was agitated for 30 min at 20ꢀ25°C. Intermediate 24 (189 g x63% wt, 0.52 mol) was
charged in portions over 1 h at 20ꢀ25 °C. The resulting slurry was stirred for 4ꢀ6 h until complete
consumption of 24 at 20ꢀ25 °C (sample was quenched with HCl to ensure pH = 1ꢀ2, a sample of
the solid was obtained by filtration and NMR is consistent with 25). The reaction mixture was
cooled to 0ꢀ5 °C, then 6 M HCl (900 g) was charged over 2 h to adjust the pH to 1 while
maintaining the temperature below 0 °C. The resulting slurry was filtered. The cake was washed
with water (100 g) and dried under vacuum at 40ꢀ45 °C to provide 17 as white solid,8b 81.5 g,
99.3% LCAP, 96 wt%, 82% yield. 1H NMR (400 MHz DMSOꢀd6), major ketone form and
minor enol form ratio about 3/1, only the ketone form is listed) δ 8.1ꢀ8.0 (m, 3H), 7.31ꢀ7.40 (m,
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2H), 3.89 (s, 2H), 2.61 (d, J = 4.6 Hz, 3H); C NMR (100 MHz DMSOꢀd6) major only δ 25.6,
47.2, 116.3 (d, J=22Hz), 128.1 (d, J=8Hz), 131.8, 133.6, 165.5 (d, J=247.1Hz), 166.6, 193.8.
19F NMR (376 MHz DMSOꢀd6) major only δ 112.1.
5-Bromo-2-(4-fluorophenyl)-N-methyl-6-nitrobenzofuran-3-carboxamide (19).
3ꢀ(4ꢀ
Fluorophenyl)ꢀNꢀmethylꢀ3ꢀoxopropanamide (17) (46.6 g, 0.24 mol), potassium phosphate
(K3PO4, 109 g, 0.51 mol), DMAc (270 g), water (10.9 g) were sequentially charged in the
reactor, and the mixture was stirred for 30 min. The mixture was purged three times with
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nitrogen, and cooled to 10ꢀ15 °C. A solution of 1,4ꢀdibromoꢀ2ꢀfluoroꢀ5ꢀnitrobenzene (16) (70 g,
0.23 mol) in DMAc (130 g) was charged over 2 h while maintaining the temperature at 10ꢀ15 °C.
The resulting mixture was stirred for 2 h at 10ꢀ15 °C to complete consumption of 16. CuI (0.45
g, 0.023 mol) was charged, and the mixture was purged three times with nitrogen again. The
reaction mixture was warmed to 50ꢀ55 °C, and stirred for 14 h until complete consumption of
intermediate 18. The reaction mixture was cooled to 20ꢀ25 °C, and a solution IPA (350 g) in
water (350 g) was charged dropꢀwise over 2 h. The resulting slurry was filtered and the cake
washed with a solution of IPA (100 g) in water (100 g), and further dried under vacuum at 40ꢀ45
°C to provide 19 as off white solid (63.7 g, 69 % yield, 98.4% LCAP, 95.7 wt%). Mp: 243.5
°C. 1H NMR (400 MHz, DMSOꢀd6) δ 8.73ꢀ8.55 (m, 2H), 8.12 (s, 1H), 8.07ꢀ7.98 (m, 2H), 7.45 (t,
J = 8.9 Hz, 2H), 2.87 (d, J = 4.6 Hz, 3H); 13C NMR (100 MHz, DMSOꢀd6) δ 26.7, 108.2, 110.2,
113.4, 116.6 (d, J=22 Hz), 125.0, 126.2, 130.5 (d, J=8.7 Hz), 132.4, 146.8, 150.8, 157.5, 162.3,
163.8 (d, J=247.9 Hz). 19F NMR (376 MHz, DMSOꢀd6) δ 108.8. AHRꢀFABꢀMS calcd for
C16H10BrFN2O4: MH+, 392.9808. Found: 392.9849 (MH+).
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6-Amino-5-bromo-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (20). 5ꢀbromoꢀ
2ꢀ(4ꢀfluorophenyl)ꢀNꢀmethylꢀ6ꢀnitrobenzofuranꢀ3ꢀcarboxamide (19) (15 g, 0.038 mol), THF
(210 g) and water (60 g) was charged in the reactor. The mixture was stirred for 30 min, and then
purged three times with nitrogen. Pt/V/C catalyst (1.5 g, 3 wt% Pt, 0.6 wt %V on carbon on dry
basis) was charged. The slurry was again purged three times with nitrogen followed by hydrogen
at 50ꢀ60 psi. The reaction mixture was warmed to 40ꢀ45 °C, and stirred for 2 h until complete
consumption of 19. The mixture was cooled to 20ꢀ25 °C and filtered through a Celite bed (15 g)
to remove the insoluble solid. The reactor and Celite cake was rinsed with THF (30 g), and the
combined filtrates was concentrated under reduced pressure below 45 °C to provide crude solid.
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The solid was filtered, washed with nꢀheptane (120 g) and further dried under vacuum at 40ꢀ45
°C to provide 20 as offꢀwhite solid, 13.1 g, 92.1% yield, 97.9% LACP, 95.7 wt%. Mp: 228.0 °C.
1H NMR (400 MHz, DMSOꢀd6) δ 8.32 (t, J = 4.4 Hz, 1H), 7.89 (dt, J = 24.8, 14.1 Hz, 2H), 7.61
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(s, 1H), 7.41ꢀ7.26 (m, 2H), 7.02 (s, 1H), 5.57 (s, 2H), 2.82 (d, J = 4.6 Hz, 3H); C NMR (100
MHz, DMSOꢀd6) δ 26.1, 96.0, 105.0, 113.0, 115.6 (d, J=22Hz), 118.4, 123.4, 126.0, 128.7 (d,
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J=8 Hz), 144.3, 149.9, 153.7, 162.2 (d, J=245.6 Hz), 163.3. F NMR (376 MHz, DMSOꢀd6) δ
111.8. AHRꢀFABꢀMS calcd for C16H12BrFN2O2: MH+, 363.0811. Found: 363.0131 (MH+).
5-Bromo-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide
(21). 6ꢀAminoꢀ5ꢀbromoꢀ2ꢀ(4ꢀfluorophenyl)ꢀNꢀmethylbenzofuranꢀ3ꢀcarboxamide (20) (44.3 kg,
122.4 mol) and DCM (532 kg) was charged into the reactor. The mixture was stirred for 30 min,
and pyridine (48 kg, 607.6 mol) was charged and followed by addition of methanesulfonyl
chloride (24 kg, 210.5 mol) over 2 h while maintaining the temperature at 27ꢀ32 °C. The reaction
mixture was stirred for 15 h to complete consumption of 20. Water (333 kg) was charged, and
the mixture was stirred for 2ꢀ3 h at 27ꢀ32 °C, followed by addition of HCl aqueous solution (1M,
200 kg). The resulting mixture was concentrated under reduced pressure below 40 °C to a
volume of ~530 L, and then cooled to 20ꢀ30 °C. The slurry was stirred for 1 h and was filtered.
The cake was washed with water twice (80 kg x 2). The wet cake and EtOAc (160 kg) was
charged in a reactor. The mixture was warmed to 40ꢀ45 °C and stirred for 2ꢀ3 h to generate a
solution. The solution was cooled to 5ꢀ10 °C slowly over 5 h and filtered. The product cake was
washed with EtOAc (101 kg) and dried by vacuum at 50ꢀ60 °C to afford 21 as offꢀwhite solid
(49.4 kg, 97.5% yield, 98.8% LACP, 97.5 wt%). Mp: >240 °C. 1H NMR (400 MHz, DMSOꢀd6)
δ 9.58 (s, 1H), 8.51 (d, J = 4.6 Hz, 1H), 8.04ꢀ7.91 (m, 2H), 7.93 (s, 1H), 7.79 (s, 1H), 7.41 (t, J =
8.9 Hz, 2H), 3.11 (s, 3H), 2.85 (d, J = 4.6 Hz, 3H); 13C NMR (100 MHz, DMSOꢀd6) δ 26.2, 41.0,
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111.0, 112.7, 115.8 (d, J=8 Hz), 124.0, 125.2 (d, J=3.7 Hz), 127.1, 129.5 (d, J=8.8 Hz), 132.2,
151.8, 153.8, 162.6, 162.9 (d, J=247.1 Hz). 19F NMR (376 MHz, DMSOꢀd6) δ 110.1. AHRꢀ
FABꢀMS calcd for C17H14BrFN2O4S：MH+, 442.2715. Found: 441.9909 (MH+).
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5-Bromo-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-
carboxamide (3). 5ꢀBromoꢀ2ꢀ(4ꢀfluorophenyl)ꢀNꢀmethylꢀ6ꢀ(methylsulfonamido)benzofuranꢀ3ꢀ
carboxamide (21) (3.6 kg, 8.2 mol), potassium carbonate (K2CO3, 2.26 kg, 16.4 mol), were
sequentially charged in the reactor. The mixture was stirred over 20 min at 20ꢀ25 °C. Methyl
iodide (2.3 kg, 16.4 mol) was charged dropꢀwise while maintaining the temperature at 20ꢀ25 °C.
The reaction mixture was warmed to 55ꢀ60 °C and stirred an additional 2 h to complete
consumption of 21. The mixture was cooled to 20ꢀ25 °C, and water (28 kg) was charged dropꢀ
wise over 1 h. The resulting slurry was stirred for 1 h at 20ꢀ25 °C and was filtered. The product
cake was dried under vacuum at 60ꢀ65 °C to afford 1 as pale yellow solid (3.1 kg, 86% yield,
98.8% LACP). Mp: >240 °C. 1H NMR (400 MHz, DMSOꢀd6)δ 8.54 (d, J = 4.5 Hz, 1H), 8.07 (s,
1H), 8.07ꢀ7.94 (m, 3H), 7.42 (t, J = 8.9 Hz, 2H), 3.34 (s, 3H), 3.22 (d, J = 4.1 Hz, 3H), 2.85 (d, J
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= 4.6 Hz, 3H); C NMR (100 MHz, DMSOꢀd6) δ 26.2, 38.2, 112.8, 113.4, 115.9 (d, J=22 Hz),
119.7, 124.2, 125.2, 128.7, 129.6 (d, J=8.8 Hz), 136.9, 151.8, 154.4, 162.4, 162.9 (d, J=247.1
Hz). 19F NMR (376 MHz DMSOꢀd6) δ 109.9 AHRꢀFABꢀMS calcd for C18H16BrFN2O4S：MH+,
455.2980. Found: 455.0055 (MH+).
Other Benzufurans 28 Compounds 28a, b, c, d were prepared similar procedure as 19 and
the pure samples were obtained through silica gel chromatography eluting with ethyl acetate and
heptane. The solution assay yields by HPLC against the pure sample were reported in scheme 5.
28a: 62% Yield, Mp: 220.5 °C. 1H NMR (400 MHz, DMSOꢀd6) δ 8.62 (dd, J = 16.0, 2.8 Hz,
2H), 8.23 (dd, J = 8.7, 1.7 Hz, 1H), 8.00 (dd, J = 8.5, 5.5 Hz, 2H), 7.85 (d, J = 8.7 Hz, 1H), 7.44
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(t, J = 8.8 Hz, 2H), 2.86 (d, J = 4.5 Hz, 3H); 13C NMR (100 MHz, DMSOꢀd6) δ 27.1, 108.6,
114.6, 116.3 (d, J=22.6 Hz), 120.1, 122.1, 125.7, 130.0 (d, J=8.8 Hz), 134.2, 145.8, 152.4, 157.6,
162.3, 163.3 (d, J=248.6 Hz). 19F NMR (376 MHz, DMSOꢀd6) δ 109.0. AHRꢀFABꢀMS calcd for
C16H11FN2O4: MH+, 315.0703. Found: 315.0769 (MH+).
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28b: 58% Yield, Mp: 222.5 °C. 1H NMR (400 MHz, DMSOꢀd6) δ 8.58 (d, J = 4.5 Hz, 1H),
8.33 (s, 1H), 7.92 (dd, J = 8.7, 5.5 Hz, 2H), 7.65 (s, 1H), 7.35 (t, J = 8.8 Hz, 2H), 2.79 (d, J = 4.6
Hz, 3H), 2.55 (s, 3H); 13C NMR (100 MHz, DMSOꢀd6) δ 20.0, 26.2, 108.3, 113.2, 116.2 (d,
J=21.8 Hz), 123.4, 124.9, 128.4, 129.7 (d, J=8.7 Hz), 131.6, 146.0, 149.9, 156.3, 162.5, 163.1 (d,
J=247.9 Hz). 19F NMR (376 MHz, DMSOꢀd6) δ 109.3. AHRꢀFABꢀMS calcd for C17H13FN2O4:
MH+, 329.0859. Found: 329.0947 (MH+).
28c: 67% Yield, Mp: >250 °C. 1H NMR (400 MHz, DMSOꢀd6) δ 8.59 (d, J = 4.7 Hz, 1H), 8.47
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(s, 1H), 8.10 (s, 1H), 8.00 (dd, J = 8.8, 5.4 Hz, 2H), 7.43 (t, J = 8.8 Hz, 2H), 2.51 (s, 3H); C
NMR (100 MHz, DMSOꢀd6) δ 26.2, 109.7, 113.3, 116.2 (d, J=22.6 Hz), 117.6, 118.3 (d, J=12.4
Hz), 124.5, 124.9, 130.0 (d, J=8.7 Hz), 133.2, 150.5, 156.4, 161.9, 162.1, 163.3 (d, J=248.6 Hz).
19F NMR (376 MHz, DMSOꢀd6) δ 109.3. AHRꢀFABꢀMS calcd for C17H10BrFN2O2: MH+,
374.9910. Found: 374.9951 (MH+).
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28d: 63% Yield, Mp: 223.0°C. H NMR (400 MHz, DMSOꢀd6) δ 8.47 (s, 1H), 8.20ꢀ7.98 (m,
2H), 2.83 (d, J = 4.5 Hz, 3H), 2.70 (s, 3H); 13C NMR (100 MHz, DMSOꢀd6) δ 14.0, 26.1, 107.5,
109.3, 112.4, 125.4, 130.8, 145.4, 150.3, 161.9, 163.6. AHRꢀFABꢀMS calcd for C11H9BrN2O4:
MH+, 312.9746. Found: 312.9811 (MH+).
Supporting Information. HPLC analysis conditions for preparation of compounds 17, 19, 21, 3
are listed.
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AUTHOR INFORMATION
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*Corresponding author Eꢀmail: zhiguo_song@merck.com, lushi_tan@merck.com
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ACKNOWLEDGMENT
The authors would like to thank Steven Oliver Oliver, K. Jos Brands, Qinghao Chen, Jing Xu
from Merck and Xianghui Wen, Minyi Feng, Weifeng Chen, Yunchun Dai, Pu Qian, Dong
Miao, Xiaoli Liu, Changjian Yuan from Wuxi Apptec for their helpful discussions and assistance
in preparation of this manuscript.
REFERENCES AND NOTES
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Lett. 2007, 48, 401ꢀ404. (f). Willis, M. C.; Taylor, D.; Gilmore, A. T. Tetrahedron 2006,
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6. (a) Sambiagio, C.; Marsden, S. P.; Blacker, A. J.; McGowan, P. C.; Chem. Soc. Rev.,
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10. Compound 26: H NMR (400 MHz DMSOꢀd6) δ 7.6ꢀ7.8 (m, 1H), 7.3ꢀ7.5 (m, 2H), 7.15ꢀ
7.30 (m, 3H), 4,49 (s, 1H), 2.50ꢀ2.65 (m, 6H).
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