Palladium-catalyzed ortho -selective C-H fluorination of oxalyl amide-protected benzylamines

Article abstract of DOI:10.1021/jo502365b

A novel and efficient synthetic method for o-fluorobenzylamines via palladium catalyst using an easily accessible oxalyl amide as directing group has been developed. The cheap N-fluorobenzenesulfonimide could be used as an effective [F⁺] source and t-amyl-OH as the solvent with Pd(OAc)₂ as catalyst. Selective mono- or difluorination of oxalyl amide-protected benzylamine derivatives were achieved by modifying the reaction conditions, which presented an efficient method for the preparation of ortho-fluorinated benzylamines.

Full text of DOI:10.1021/jo502365b

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Article
Palladium-Catalyzed ortho-Selective C-H Fluorination
of Oxalyl Amide Protected Benzylamines
Changpeng Chen, Chao Wang, Jingyu Zhang, and Yingsheng Zhao
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 09 Dec 2014
Downloaded from http://pubs.acs.org on December 10, 2014
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Palladium-Catalyzed ortho-Selective C-H Fluorination of
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Oxalyl Amide Protected Benzylamines
Changpeng Chen,a Chao wang,a Jingyu Zhang,b and Yingsheng Zhaoa,*
aKey Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials
Science, Soochow University, Suzhou 215123, China.
bCollege of Physics, Optoelectronics and Energy & Collaborative Innovation Center of Suzhou Nano Science and
Technology, Soochow University, Suzhou 215006, China.
yszhao@suda.edu.cn.
O
N(iPr)2
O
N(iPr)2
HN
O
HN
O
Pd(OAc)2 (5 mol %)
NFSI (3 equiv)
R1
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t-Amyl-OH, 80 oC, 12h
F
R2
R2
23 examples, up to 95% yield
.
ABSTRACT: A novel and efficient synthetic method for orthoꢀfluorobenzylamines via palladium catalyst using an easily
accessible oxalyl amide as directing group has been developed. The cheap NꢀFluorobenzenesulfonimide could be used as the
effective [F+] source and tꢀAmylꢀOH as the solvent with Pd(OAc)2 as catalyst. Selective monoꢀ or difluorination of oxalyl amide
protected benzyl amie derivatives were achieved by modifying the reaction condition which presented an efficient way for the
preparation of orthoꢀfluorinated benzyl amines.
INTRODUCTION
The fluorinated organic compounds mostly have a dramatic change in physical, chemical and biological properties, especially for
the aryl fluorides,1 which are very valuable components in pharmaceutical and agrochemical industries.2 Thus, to develop a
synthetic method for forming CꢀF bonds under mild condition is attractive and significant. In the past few years, important progress
in this field has been achieved,3 and transitionꢀmetalꢀcatalyzed fluorination emerged as powerful method to access partially
fluorinated aromatics.4ꢀ12 However, compared to this successful development in fluorination with the prefunctionalized aromatic
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rings that can lead to the CꢀF bonds under transition catalyst, the direct fluorination of unactived aryl CꢀH bonds still has few
reports.13 In 2006, the pioneering work of CꢀF bond formation was firstly reported by Sanford and coꢀworkers with pyridine as the
directing group via palladium catalyst,14 and the electrophilic fluorinating agents were first applied in CꢀH functionalization as
fluorine sources. Further mechanism studies revealed that the highꢀvalent Pd(IV) complexs might be involved in the catalytic
cycle.15 Later, Yu and coꢀworkers reported the Pdꢀcatalyzed benzylamine triflamide16 and benzoic acid perfluoroaniline amide17
orthoꢀfluorination by electrophilic fluorinating agents. Very recently, a nitrateꢀpromoted selective monofluorination of aromatic and
olefinic C(sp2)ꢀH bonds with electrophilic fluorine reagents were discovered by Xu and coꢀworkers.18 Alternatively, the
combination of nucleophilic fluoride (Fꢀ) and external oxidant as fluorine sources could also be applied in CꢀH fluorination which
was first reported by Sanford and coꢀworkers.19 Later, Daugulis and coꢀworkeres also developed a copperꢀcatalyzed orthoꢀ
fluorination of 8ꢀaminoquinolineꢀcoupled benzoic acid derivatives with nucleophilic fluoride (Fꢀ) and oxidant of NMO (4ꢀ
Methylmorpholine Nꢀoxide ).20 Benzyl amines are broadly synthetic utility which are easily accessible through preparative
methods. However, only one example of ortho-CꢀH fluorination for benzylamine derivatives with triflamide as directing groups via
high loading of Pd(OTf)2·2H2O as catalyst was reported.16 Herein we reported a convenient synthetic method for orthoꢀfluorination
of oxalyl amide protected benzylamine derivatives via palladium(II) acetate as catalyst and the cheap NFSI (Nꢀ
Fluorobis(phenylsulfony)amine) as fluorine source.
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Scheme 1. Oxalyl Amide Assisted Fluorination
RESULTS AND DISCUSSION
Very recently, oxalyl amide was discovered as an easily accessible and efficient directing group for intramolecular
amination by our group.21 We hypothesized that the new developed N,Oꢀbidentated directing group could promote Pdꢀ
catalyzed orthoꢀfluoroation of benzyl amine derivatives by applying the electrophilic fluorinating agents. At the outset of
this study, we first treated oxalyl amide protected 2ꢀ methoxybenzyl amine 1a with electrophilic fluorinating reagent (F1
)
o
with loading of (5 mol %) of Pd(OAc)2 as catalyst in 1,4ꢀdioxane at 80 C under an atmosphere of air in a sealed tube
(entry 1). To our delight, the desired fluorinated product 2a was obtained in 79% yield, along with 5% yield of 1a
recovered. We further screened other [F+] sources (entry 2ꢀ4, 14), in which the fluorinating reagents of F3 gave slightly
higher yield than that of F1. In assessing project cost, we decided to use the inexpensive F1 as the fluorinating reagent for
the further condition optimization. The solvent effect with F1 (entry 5ꢀ8) were subsequently examined. The tꢀAmylꢀOH
turned out to be the best solvent, and excellent yield of 2a (87%, entry 7) was achieved in 12 h. DCE and mꢀxylene gave
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slightly poorer yield. Interestingly, no reaction happened with DMF as solvent. Attempts to further improve the conversion of
starting material, several additives such as NMP, PivOH and PPh3 were added in the reaction respectively. All these additives
displayed suppressive effect in this transformation. Under an air or argon atmosphere, the product of 2a was observed in higher
than 80% yield, implying the oxygen has no promoting effect in this transformation. Combination of AgF and NMO with palladium
acetate (entry 14) or copper salts were also tested, no reaction occurred in general reaction condition, and just starting material was
recovered which was analyzed by GCꢀMS. Controlling experiments confirmed that no reaction happened without using palladium
catalyst, implicating the crucial role of Pd(OAc)2 for the transformation (Table 1, entry 15).
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Table 1. Optimization of the Reaction Conditions.a
aReaction conditions: 1a (0.1 mmol), Pd(OAc)2 (5 mol %), NFSI (0.25 mmol), additive (0.02 mmol), solvent (1 mL), 80 oC, 12 h.
Yield was based on GC using tridecane as the internal standard.
With the optimized conditions in hand, the scope and limitation of this reaction were next explored and repesentative data were
shown in Table 2. To our great surprise, a remarkable broad substrates scope of benzylamines were tolerated. Substrates bearing
electronꢀdonating groups such as methyl or methoxyl substituents were transformed into corresponding fluorinated products in
good to excellent yields (2a-2g). The substrates with electronꢀwithdrawing substituents (2h-2n) were slightly lower activity which
needed 10 mol% loading of Pd catalyst. The useful products containing F, Cl, Br and I were also obtained which were very
important in synthetic elaborations. The high regioselective monofluorination also took place at the less hindered site giving
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excellent yields(2c, 2e, 2f, 2h-2j). Notably, the challenging 2,5ꢀdisubstituted 1o was also fluorinated with slight increase loading of
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the catalyst and temperature.
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Table 2. Palladium-Catalyzed ortho-Fluorination of Benzylaminesa
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aReaction conditions: 1 (0.2 mmol), Pd(OAc)2 (5 mol %), NFSI (0.6 mmol), tꢀAmylꢀOH (2 mL), 80 C. Isolated yields. bPd(OAc)2
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(10 mol%). 1,4ꢀdioxane (2 mL). Nꢀfluoroꢀ2,4,6ꢀtrimethylꢀpyridinium triflate (0.4 mmol), DCE (2 mL). 100 C. 1,4ꢀdioxane:tꢀ
AmylꢀOH = 3:1. gNFSI (1.0 mmol). hDCE:tꢀAmylꢀOH = 1:1.
Monofluorination of oxalyl amide protected benzylamies were also achieved with modified reaction condition which
listed in Table 2. The selective monofluorination of electronꢀrich (1r) and electronꢀpoor (1q, 1s) substituted oxalyl amide
protected benzylamines were observed in moderate yield with shorter reaction time to avoid the difluorinated products,
while the difluorinated products were observed less than 10% yield. To realize the difluorinated products, five equivalent
of F1 and 10 mol% Pd(OAc)2 were applied in the reaction. However, the difluorinated products were obtained less than
60% yield except (1t
,
1u). To reduce the amount of monofluorinated products, several other fluorine sources were
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o
scanned. It is not surprising that F3 yielded the difuorinated products in better yields at 100 C in 24 h (Table 3, 2k, 3b-
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3d).
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Table 3. Difluorination of Benzylamie Derivativesa
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aReaction conditions: 1 (0.2 mmol), Pd(OAc)2 (10 mol %),F3（Nꢀfluoroꢀ2,4,6ꢀtrimethylpyridinium triflate）(0.6 mmol), 1,4ꢀ
dioxane (2 mL), 80 oC, 24 h. Isolated yields. bPd(OAc)2 (15 mol %), ctꢀAmylꢀOH (2 mL), NFSI (5 equiv).
Orthoꢀmonofluorination of substrates 1b was also carried out on gram scale. And excellent yield of 2b was obtained, implicating
the potential excellent versatility for synthetic application (Scheme 2). Due to the low cost of diisopropylamine and oxalyl chloride,
oxalyl amide could be employed as a protecting group for benzyl amine substrates. And the oxalyl amide protected benzylamine
derivative 3a could be activated with NsCl (4ꢀNitrobenze neꢀ1ꢀSulfonyl Chloride) and cleaved by NaH in one pot to give the Nsꢀ
protected amine product 3aa in high yield (Scheme 2, A).22 The oxalyl amide could also be removed through 4 equiv of NaOH in
CH3OH:THF=1:4, giving compound 4 in 86% isolated yield (Scheme 2, B). On the basis of the observed experimental results and
pioneering reports,23 the palladium catalyst would lead to formation of a Pdiv intermediate following CꢀH activation and oxidation
with [F+]. CꢀF reductive elimination afforded to the corresponding product finally (Scheme 3).
Scheme 2. Large Scale Synthesis and Removal of the Directing Group
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Scheme 3. Proposed catalytic cycle
CONCLUSION
In conclusion, we have developed a highly selecive PdIIꢀcatalyzed orthoꢀmonofluorination method for benzylamine derivatives
using an easily accessible oxalyl amide as directing group. The cheap NꢀFluorobenzenesulfonimide could be used as the efficient
[F+] source and tꢀAmylꢀOH as the best solvent. Monoꢀ and difluorination of oxalyl amide protected benzylamie derivatives were
also achieved by modify the fluorine source in moderate to excellent yield with wide functional group tolerance. Oxalyl amide
could be removed under mild condition afording the Ns protected amines. Detailed mechanistic studies are in progress, and the new
application of oxalyl amide as directing group in construction of C–C, C–O or C–Heteroatom bonds are under study in our lab.
EXPERIMENTAL SECTION
Unless otherwise noted, all reagents were purchased from commercial suppliers and used without further purification.
Multiplicities are recorded as: s = singlet, d = doublet, t = triplet, dd = doublet of doublets, br = broad singlet, m = multiplet.
General procedures for the synthesis of products are represented as follows:
Preparation of S1: A solution of Diisopropylamine (7.01 mL, 50 mmol, 1.0 equiv) in CH2Cl2 (50 mL) was added dropwise to a
solution of oxalyl chloride (6.44 ml, 75 mmol, 1.5 equiv) in CH2Cl2 (100 mL) at 0 °C, after stirring for 5 min, triethylamine (7.30
mL, 52.5 mmol, 1.05 equiv) was added dropwise. The solution was warmed to room temperature and stirred for 6 hours. The excess
of oxalyl chloride and the solvent were removed under reduce pressure and CH2Cl2 (30 mL) was added and evaporated. This
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operation was performed twice to give S1 as a pale yellow solid. The crude product was used in the next step without any
purification.
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N, N–Diisopropyloxamoyl chloride S1: Yield 95% (8.4 g), colorless oil; 1H NMR (400 MHz, CDCl3) δ 3.77 (m, 1H), 3.51 (m,
1H), 1.41 (d, J = 6.9 Hz, 6H), 1.24 (d, J = 6.6 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 163.1, 158.8, 51.0, 46.5, 20.3, 19.8; HRMS
(ESIꢀTOF) m/z: [M + Na]+ Calcd for C8H14ClNO2Na 214.0611; Found: 214.0609.
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General procedures for preparation of oxalyl amide protected benzyl amines (1a–1t)21: A solution of amine (20 mmol, 1.0
eq) in CH2Cl2 (40 mL) was added dropwise to a solution of N,N–Diisopropyloxamoyl chloride S1 (25 mmol, 1.25 equiv) in CH2Cl2
(50 mL) at 0 °C. After stirring for 5 min, triethylamine (2.92 ml, 21 mmol, 1.05 equiv) was added dropwise, and then the mixture
was stirred for 6 hours at room temperature before quenched by water (50 mL). The organic layer was separated and the aqueous
layer was extracted with CH2Cl2 (20 mL × 3). The combined organic phase was washed with brine (30 mL), dried over anhydrous
Na2SO4. Evaporation and column chromatography on silica gel afforded corresponding amide substrates as white solid or
colourless liquid with >80% yield.
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N1,N1-diisopropyl-N2-(2-methoxybenzyl)oxalamide (1a): Yield 86% (5.03 g); offꢀwhite solid; mp = 113ꢀ114 °C; H NMR (400
MHz, CDCl3) δ 7.37 (br, 1H), 7.26 (m, 2H), 6.89 (m, 2H), 4.79 – 4.69 (m, 1H), 4.46 (d, J = 5.8 Hz, 2H), 3.85 (s, 3H), 3.53 – 3.45
(m, 1H), 1.41 (d, J = 6.6 Hz, 6H), 1.21 (d, J = 6.5 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 163.1, 162.9, 157.6, 129.7, 129.1, 125.5,
120.6, 110.3, 55.4, 49.6, 46.5, 39.1, 20.9, 20.1. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C16H24N2O3Na 315.1685; Found:
315.1678.
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N1,N1-diisopropyl-N2-(2-methylbenzyl)oxalamide (1b): Yield 88% (4.86 g); offꢀwhite solid; mp = 124ꢀ125 °C; H NMR (400
MHz, CDCl3) δ 7.29 – 7.26 (m, 1H), 7.23 – 7.17 (m, 3H), 7.13 (br, 1H), 4.83– 4.76 (m, 1H), 4.47 (d, J = 5.7 Hz, 2H), 3.57– 3.50
(m, 1H), 2.36 (s, 3H), 1.43 (d, J = 6.8 Hz, 6H), 1.26 (d, J = 6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 163.0, 162.9, 136.5, 135.2,
130.6, 128.6, 128.0, 126.4, 49.8, 46.7, 41.6, 21.0, 20.2, 19.1. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C16H24N2O2Na 299.1735;
Found: 299.1729.
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N1,N1-diisopropyl-N2-(3-methylbenzyl)oxalamide (1c): Yield 92% (5.07 g); offꢀwhite solid; mp = 89ꢀ91 °C; H NMR (400
MHz, CDCl3) δ 7.34 (br, 1H), 7.22 (m, 1H), 7.09 (m, 3H), 4.81 – 4.73 (m, 1H), 4.41 (d, J = 5.9 Hz, 2H), 3.55 – 3.47 (m, 1H), 2.34
(s, 3H), 1.41 (d, J = 6.8 Hz, 6H), 1.24 (d, J = 6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 163.1, 163.0, 138.5, 137.4, 128.7, 128.65,
128.4, 124.9, 49.7, 46.7, 43.4, 21.5, 20.9, 20.1. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C16H24N2O2Na 299.1735; Found:
299.1731.
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N1-(2,3-dimethylbenzyl)-N2,N2-diisopropyloxalamide (1d): Yield 91% (5.28 g); offꢀwhite solid; mp = 93ꢀ95 °C; H NMR (400
MHz, CDCl3) δ 7.16 – 7.02 (m, 3H), 6.97 (br, 1H), 4.82 – 4.76 (m, 1H), 4.47 (d, J = 5.6 Hz, 2H), 3.55 ꢀ 3.48 (m, 1H), 2.29 (s, 3H),
2.22 (s, 3H), 1.41 (d, J = 6.8 Hz, 6H), 1.24 (d, J = 6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 163.0, 162.9, 137.5, 135.2, 135.0,
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129.8, 126.8, 125.8, 49.8, 46.6, 42.3, 21.0, 20.5, 20.1, 14.9. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C17H26N2O2Na 313.1892;
Found: 313.1887.
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N1,N1-diisopropyl-N2-(3-methoxybenzyl)oxalamide (1e): Yield 82% (4.79 g); offꢀwhite solid; mp = 54ꢀ56 °C; H NMR (400
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MHz, CDCl3) δ 7.52 (br, 1H), 7.21 (t, J = 7.8 Hz, 1H), 6.86 (d, J = 7.6 Hz, 1H), 6.79 (m, 2H), 4.74 – 4.64 (m, 1H), 4.39 (d, J = 6.0
Hz, 2H), 3.76 (s, 3H), 3.52 ꢀ 3.45 (m, 1H), 1.38 (d, J = 6.8 Hz, 6H), 1.21 (d, J = 6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 163.2,
163.0, 159.9, 139.1, 129.8, 120.0, 113.3, 113.2, 55.2, 49.7, 46.5, 43.3, 20.9, 20.1. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C16H24N2O3Na 315.1685; Found: 315.1673.
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N1-(3,4-dimethylbenzyl)-N2,N2-diisopropyloxalamide (1f): Yield 92% (5.33 g); offꢀwhite solid; mp = 113ꢀ115 °C; 1H NMR (400
MHz, CDCl3) δ 7.25 (br, 1H), 7.08 – 6.95 (m, 3H), 4.79 – 4.68 (m, 1H), 4.33 (d, J = 5.7 Hz, 2H), 3.50 ꢀ 3.43 (m, 1H), 2.20 (s, 6H),
1.36 (d, J = 6.8 Hz, 6H), 1.19 (d, J = 6.6 Hz, 6H); 13C NMR (151 MHz, CDCl3) δ 163.0, 137.0, 136.0, 134.8, 130.0, 129.26, 125.3,
49.7, 46.6, 43.2, 20.9, 20.1, 19.8, 19.5. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C17H26N2O2Na 313.1892; Found: 313.1877.
N1-(2,4-dimethoxybenzyl)-N2,N2-diisopropyloxalamide (1g): Yield 76% (4.89 g); offꢀwhite solid; mp = 137ꢀ139 °C; 1H NMR
(400 MHz, CDCl3) δ 7.18 (m, 2H), 6.43 (m, 2H), 4.80 ꢀ 4.73 (m, 1H), 4.38 (d, J = 6.0 Hz, 2H), 3.82 (s, 3H), 3.79 (s, 3H), 3.52 ꢀ
3.45 (m, 1H), 1.40 (d, J = 6.8 Hz, 6H), 1.21 (d, J = 6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 163.2, 162.8, 160.7, 158.7, 130.5,
118.1, 103.9, 98.6, 55.4, 55.4, 49.6, 46.5, 38.7, 20.9, 20.1. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C17H26N2O4Na 345.1790;
Found: 345.1783.
N1-(3-chlorobenzyl)-N2,N2-diisopropyloxalamide (1h): Yield 81% (4.80 g); offꢀwhite solid; mp = 96ꢀ98 °C; 1H NMR (400 MHz,
CDCl3) δ 7.28 ꢀ 7.27 (m, 2H), 7.27 ꢀ 7.24 (m, 2H), 7.20 – 7.16 (m, 1H), 4.87 ꢀ 4.80 (m, 1H), 4.44 (d, J = 6.1 Hz, 2H), 3.57 ꢀ 3.50 (m,
1H), 1.43 (d, J = 6.8 Hz, 6H), 1.25 (d, J = 6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 163.2, 162.9, 139.7, 134.6, 130.1, 127.9,
127.8, 125.9, 49.8, 46.7, 42.8, 20.9, 20.1. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C15H21ClN2O2Na 319.1189; Found:
319.1173.
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N1-(3-bromobenzyl)-N2,N2-diisopropyloxalamide (1i): Yield 84% (5.71 g); offꢀwhite solid; mp = 103ꢀ105 °C; H NMR (400
MHz, CDCl3) δ 7.44 (br, 1H), 7.42 ꢀ 7.39 (m, 2H), 7.25 – 7.16 (m, 2H), 4.82 ꢀ 4.75 (m, 1H), 4.42 (d, J = 6.1 Hz, 2H), 3.56 ꢀ 3.49 (m,
1H), 1.41 (d, J = 6.8 Hz, 6H), 1.24 (d, J = 6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 163.2, 163.0, 140.0, 130.8, 130.7, 130.3,
126.4, 122.8, 49.8, 46.7, 42.7, 20.9, 20.1. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C15H21BrN2O2Na 363.0684; Found:
363.0677.
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N1-(3-iodobenzyl)-N2,N2-diisopropyloxalamide (1j): Yield 80% (6.21 g); offꢀwhite solid; mp = 78ꢀ80 °C; H NMR (400 MHz,
CDCl3) δ 7.66 (m, 2H), 7.61 (d, J = 7.9 Hz, 1H), 7.28 (d, J = 6.6 Hz, 1H), 7.07 (t, J = 7.8 Hz, 1H), 4.74 ꢀ 4.67 (m, 1H), 4.39 (d, J =
6.1 Hz, 2H), 3.56 ꢀ 3.49 (m, 1H), 1.41 (d, J = 6.8 Hz, 6H), 1.25 (d, J = 6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 163.2, 163.0,
140.0, 136.7, 130.5, 127.1, 94.6, 49.8, 46.6, 42.5, 20.9, 20.1. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C15H21IN2O2 Na
411.0545; Found: 411.0551.
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N1-(2-fluorobenzyl)-N2,N2-diisopropyloxalamide (1k)：Yield 79% (4.42 g); offꢀwhite solid; mp = 111ꢀ113 °C; 1H NMR (400
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MHz, CDCl3) δ 7.36 ꢀ 7.32 (m, 1H), 7.31 – 7.26 (m, 2H), 7.13 ꢀ 7.09 (m, 1H), 7.07 – 7.02 (m, 1H), 4.83 ꢀ 4.76 (m, 1H), 4.52 (d, J =
6.2 Hz, 2H), 3.55ꢀ3.49 (m, J = 1H), 1.42 (d, J = 6.8 Hz, 6H), 1.23 (d, J = 6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 163.2, 162.7,
135.9, 131.42 (d, JC-F = 222.0 Hz), 128.36 (d, JC-F = 30.0 Hz), 127.9, 126.18 (d, JC-F = 6.0 Hz), 125.98(d, JC-F = 29 Hz), 49.8, 46.8,
39.9, 21.0, 20.1; 19F NMR (376 MHz, CDCl3) δ ꢀ118.63. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C15H21FN2O2Na 303.1485;
Found: 303.1485.
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N1-(2-chlorobenzyl)-N2,N2-diisopropyloxalamide (1l): Yield 83% (4.91 g); offꢀwhite solid; mp = 147ꢀ149 °C; 1H NMR (400
MHz, CDCl3) δ 7.52 (br, 1H), 7.40 – 7.31 (m, 2H), 7.25 – 7.18 (m, 2H), 4.73 – 4.63 (m, 1H), 4.54 (d, J = 6.2 Hz, 2H), 3.53 – 3.44
(m, 1H), 1.38 (d, J = 6.8 Hz, 6H), 1.20 (d, J = 6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 163.2,162.9. 134.9, 133.7, 129.9, 129.6,
129.0, 127.1, 49.7, 46.6, 41.2, 20.9, 20.1. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C15H21ClN2O2Na 319.1189; Found:
319.1188.
N1-(2-bromobenzyl)-N2,N2-diisopropyloxalamide (1m): Yield 82% (5.58 g); offꢀwhite solid; mp = 155ꢀ157 °C; 1H NMR (400
MHz, CDCl3) δ 7.56 – 7.54 (m, 1H), 7.40 – 7.37 (m, 1H), 7.35 (br, 1H), 7.31 – 7.24 (m, 1H), 7.17 ꢀ 7.13 (m, 1H), 4.79 ꢀ 4.73 (m,
1H), 4.54 (d, J = 6.3 Hz, 2H), 3.55 ꢀ 3.48 (m, 1H), 1.41 (d, J = 6.8 Hz, 6H), 1.22 (d, J = 6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ
163.1, 162.8, 136.6, 133.0, 130.1, 129.4, 127.9, 123.8, 49.7, 46.7, 43.7, 21.0, 20.2. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C15H21BrN2O2Na 363.0684; Found: 363.0677.
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N1,N1-diisopropyl-N2-(2-(trifluoromethyl)benzyl)oxala-mide (1n): Yield 73% (4.82 g); offꢀwhite solid; mp = 121ꢀ123 °C; H
NMR (400 MHz, CDCl3) δ 7.66 (d, J = 7.9 Hz, 1H), 7.57 – 7.52 (m, 2H), 7.40 (m, 1H), 7.20 (br, 1H), 4.82 ꢀ 4.75 (m, 1H), 4.66 (d,
J = 6.3 Hz, 2H), 3.56 ꢀ 3.49 (m, 1H), 1.42 (d, J = 6.8 Hz, 6H), 1.24 (d, J = 6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 163.1 ,
162.8, 161.10 (d, JC-F = 245.0 Hz) , 130.19 (d, JC-F = 5.0 Hz), 129.57 (d, JC-F = 8.1 Hz), 124.56 (d, JC-F = 15.0, Hz), 124.44 (d, JC-F
=
4.0 Hz). 115.55 (d, JC-F = 21.0 Hz), 49.7, 46.7, 37.38 (d, JC-F = 4.0 Hz), 21.0, 20.1. 19F NMR (376 MHz, CDCl3) δ ꢀ59.68. HRMS
(ESIꢀTOF) m/z: [M + Na]+ Calcd for C16H21F3N2O2Na 353.1453; Found: 353.1459.
N1-(2,5-dimethylbenzyl)-N2,N2-diisopropyloxalamide (1o): Yield 88% (5.10 g); offꢀwhite solid; mp = 95ꢀ97 °C;1H NMR (400
MHz, CDCl3) δ 7.26 (br, 1H), 7.06 – 7.04 (m, 2H), 7.01 – 6.99 (m, 1H), 4.82 – 4.64 (m, 1H), 4.40 (d, J = 5.7 Hz, 2H), 3.53 ꢀ 3.46
(m, 1H), 2.29 – 2.28 (m, 6H), 1.39 (d, J = 6.8 Hz, 6H), 1.23 (d, J = 6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 163.2. 163.0, 135.7,
134.9, 133.2, 130.4, 129.3, 128.5, 49.7, 46.5, 41.4, 21.0, 20.9, 20.1, 18.6. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C17H26N2O2Na 313.1892; Found: 313.1894.
N1-benzyl-N2,N2-diisopropyloxalamide (1p): Yield 91% (4.77 g); offꢀwhite solid; mp = 102ꢀ103 °C; 1H NMR (400 MHz, CDCl3)
δ 7.39 – 7.27 (m, 5H), 7.20 (br, 1H), 4.87 ꢀ 4.80 (m, 1H), 4.46 (d, J = 6.0 Hz, 2H), 3.56 ꢀ 3.49 (m, 1H), 1.42 (d, J = 6.8 Hz, 6H),
1.24 (d, J = 6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 163.1, 163.0, 137.5, 128.8, 127.9, 127.7, 49.7, 46.7, 43.4, 21.0, 20.1.
HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C15H22N2O2Na 285.1579; Found: 285.1579.
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N1-(4-bromobenzyl)-N2,N2-diisopropyloxalamide (1q): Yield 83% (5.64 g); offꢀwhite solid; mp = 159ꢀ161 °C; 1H NMR (400
MHz, CDCl3) δ 7.45 ꢀ 7.43 (m, 3H), 7.17 (d, J = 8.3 Hz, 2H), 4.78 ꢀ 4.71 (m, 1H), 4.38 (d, J = 6.1 Hz, 2H), 3.55 ꢀ 3.48 (m, 1H),
1.40 (d, J = 6.8 Hz, 6H), 1.23 (d, J = 6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 163.2, 163.0, 136.7, 131.9, 129.6, 121.6, 49.8,
46.7, 42.7, 21.0, 20.1. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C15H21BrN2O2Na 363.0684; Found: 363.0685.
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N1,N1-diisopropyl-N2-(4-methoxybenzyl)oxalamide (1r)
：Yield 87% (5.08 g); offꢀwhite solid; mp = 87ꢀ89 °C; H NMR (400
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MHz, CDCl3) δ 7.34 (br, 1H), 7.20 (d, J = 8.7 Hz, 2H), 6.89 – 6.80 (m, 2H), 4.76 ꢀ 4.69 (m, 1H), 4.36 (d, J = 5.9 Hz, 2H), 3.77 (s,
3H), 3.52 ꢀ 3.45 (m, 1H), 1.38 (d, J = 6.8 Hz, 6H), 1.22 (d, J = 6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 163.1, 163.0, 159.1,
129.6, 129.2, 114.1, 55.3, 49.7, 46.6, 42.8, 20.9, 20.1. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C16H24N2O3Na 315.1685; Found:
315.1686.
N1,N1-diisopropyl-N2-(4-vinylbenzyl)oxalamide (1s): Yield 78% (4.49 g); offꢀwhite solid; mp = 91ꢀ93 °C; 1H NMR (400 MHz,
CDCl3) δ 7.43 – 7.33 (m, 3H), 7.28 – 7.22 (m, 2H), 6.69 (dd, J = 17.6, 10.9 Hz, 1H), 5.73 (d, J = 17.6, 1H), 5.24 (d, J = 10.9, 1H),
4.80 ꢀ 4.73 (m,1H), 4.43 (d, J = 6.0 Hz, 2H), 3.55 ꢀ 3.48 (m, 1H), 1.41 (d, J = 6.8 Hz, 6H), 1.23 (d, J = 6.7 Hz, 6H); 13C NMR (101
MHz, CDCl3) δ 163.2, 137.1, 136.9, 136.4, 128.0, 126.5, 113.9, 49.7, 46.5, 43.0, 20.9, 20.1. HRMS (ESIꢀTOF) m/z: [M + Na]+
Calcd for C17H24N2O2Na 311.1735; Found:311.1731.
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N1,N1-diisopropyl-N2-(1-phenylethyl)oxalamide (1t): Yield 86% (4.75 g); offꢀwhite solid; mp = 142ꢀ144 °C; H NMR (400
MHz, CDCl3) δ 7.73 (br, 1H), 7.37 ꢀ 7.30 (m, 4H), 7.28 – 7.21 (m, 1H), 5.09 – 5.02 (m, 1H), 4.65 (s, 1H), 3.55 – 3.43 (m, 1H), 1.50
(d, J = 7.0 Hz, 3H), 1.41 (dd, J = 9.7, 6.8 Hz, 6H), 1.20 (dd, J = 9.9, 6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 163.3, 162.4,
143.0, 128.7, 127.3, 126.1, 49.7, 49.1, 46.5, 22.0, 20.8, 20.1. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C16H24N2O2Na 299.1735;
Found: 299.1734.
General procedures for preparation of 1u21: The first step using 2ꢀaminoꢀ2ꢀphenylethanol (2.74 g, 20 mmol, 1.0 eq) as starting
material followed the general procedure , affords a white solid which was analyzed by LCꢀMS. The solid (5.25 g) was dissolved in
DCM (30 mL), treated with AcCl (1.56 mL, 22 mmol, 1.1 eq) and Et3N (5.56 mL, 40 mmol, 2.0 eq) at room temperature overnight.
The reaction was quenched with water and extracted with DCM (30 mL× 3). The combined organic layers was washed with water
and brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The resulting residue was purified by column chromatography
on silica gel to give the product 1u 5.55 g, 83%.
2-(2-(diisopropylamino)-2-oxoacetamido)-2-phenylethyl acetate (1u): Yield 82% (5.48 g); offꢀwhite solid; mp = 114ꢀ116 °C;
1H NMR (400 MHz, CDCl3) δ 7.71 (br, 1H), 7.40 – 7.24 (m, 5H), 5.26 ꢀ 5.21 (m, 1H), 4.74 ꢀ 4.67 (m, 1H), 4.35 (d, J = 5.8 Hz, 2H),
3.55 ꢀ 3.48 (m, 1H), 2.03 (s, 3H), 1.42 (dd, J = 9.7, 6.8 Hz, 6H), 1.21 (dd, J = 6.6, 4.2 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ
170.8, 162.8, 137.8, 128.9, 128.1, 126.8, 66.2, 52.4, 49.7, 46.7, 20.9, 20.8, 20.2, 20.1. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C18H26N2O4Na 357.1790; Found: 357.1791.
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General Procedure for Palladium-catalyzed mono-Fluorinationof Benzylamines (Table 2) (2a-2d, 2f): A mixture of
oxalamide (0.2 mmol, 1.0 eq), Pd(OAc)2 (22 mg, 0.05 eq), NFSI (0.6 mmol, 3.0 eq) and tꢀAmylꢀOH (2 mL) in a 25 mL glass vial
(sealed with PTFE cap) was heated at 80 oC. The reaction mixture was cooled to room temperature, and concentrated in vacuo. The
resulting residue was purified by column chromatography on silica gel to give the corresponding product.
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CDCl3) δ 7.25 ꢀ 7.19 (m, 2H), 6.74 – 6.63 (m, 2H), 4.86 ꢀ 4.80 (m, 1H), 4.54 (d, J = 5.9 Hz, 2H), 3.87 (s, 3H), 3.53 ꢀ 3.46 (m, 1H),
1.39 (d, J = 6.8 Hz, 6H), 1.21 (d, J = 6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 162.9, 162.6, 161.51 (d, JC-F = 245.0 Hz), 159.27
(d, JC-F = 7.6 Hz), 129.62 (d, JC-F = 10.7 Hz), 113.03 (d, JC-F = 18.1 Hz), 108.24(d, JC-F =23.0 Hz), 106.35 (d, JC-F = 2.9 Hz), 56.18,
49.6, 46.6, 31.74 (d, JC-F = 5.3 Hz), 21.0, 20.2; 19F NMR (376 MHz, CDCl3) δ ꢀ116.28. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C16H23FN2O3Na 333.1590; Found: 333.1582.
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N1-(2-fluoro-6-methylbenzyl)-N2,N2-diisopropyloxala-mide (2b): Yield 94% (55.3 mg); pale yellow solid; mp = 77ꢀ79 °C; H
NMR (400 MHz, CDCl3) δ 7.18 ꢀ 7.13 (m, 1H), 7.03 (br, 1H), 6.96 (d, J = 7.6 Hz, 1H), 6.89 (t, J = 9.0 Hz, 1H), 4.79 ꢀ 4.72 (m, 1H),
4.53 – 4.51 (m, 2H), 3.52 ꢀ 3.46 (m, 1H), 2.40 (s, 3H), 1.38 (d, J = 6.8 Hz, 6H), 1.22 (d, J = 6.7 Hz, 6H); 13C NMR (101 MHz,
CDCl3) δ, 162.8, 162.8, 161.95 (d, JC-F = 244.0 Hz), 139.72 (d, JC-F = 3.0 Hz), 129.25 (d, JC-F = 9.4 Hz), 126.21 (d, JC-F = 3.0 Hz),
122.69 (d, JC-F = 14.0 Hz), 113.08(d, JC-F = 23.0 Hz) , 49.7, 46.7, 34.21 (d, JC-F = 5.3 Hz), 20.9, 20.1, 19.25 (d, JC-F = 3.0 Hz); 19F
NMR (376 MHz, CDCl3) δ ꢀ118.05. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C16H23FN2O2Na 317.1641; Found:317.1641.
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N1-(2-fluoro-5-methylbenzyl)-N2,N2-diisopropyloxala-mide (2c): Yield 93% (54.7 mg); pale yellow oil; H NMR (400 MHz,
CDCl3) δ 7.30 (br, 1H), 7.11 (d, J = 7.1 Hz, 1H), 7.05 ꢀ 7.01 (m, 1H), 6.96 – 6.86 (m, 1H), 4.79 ꢀ 4.72 (m, 1H), 4.46 (d, J = 6.1 Hz,
2H), 3.52ꢀ3.47 (m, 1H), 2.28 (s, 3H), 1.40 (d, J = 6.8 Hz, 6H), 1.22 (d, J = 6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 163.1, 162.8,
159.29 (d, JC-F = 242.0 Hz), 133.89 (d, JC-F = 3.7 Hz), 130.59 (d, JC-F = 3.9 Hz), 129.92 (d, JC-F = 7.9 Hz), 123.99 (d, JC-F = 15.1 Hz),
115.21(d, JC-F = 21.0 Hz), 49.7, 46.7, 37.42 (d, JC-F = 3.8 Hz), 20.9, 20.7, 20.1; 19F NMR (376 MHz, CDCl3) δ ꢀ124.05. HRMS
(ESIꢀTOF) m/z: [M + H]+ Calcd for C16H23FN2O2H 295.1822; Found: 295.1817.
N1-(6-fluoro-2,3-dimethylbenzyl)-N2,N2-diisopropyloxal-amide (2d): Yield 95% (58.5 mg); pale yellow solid; mp = 114ꢀ116 °C;
1H NMR (400 MHz, CDCl3) δ 7.06 ꢀ 7.03 (m, 1H), 6.95 (br, 1H), 6.80 (t, J = 9.0 Hz, 1H), 4.81 ꢀ 4.74 (m, 1H), 4.54 (dd, J = 5.6, 1.9
Hz, 2H), 3.52ꢀ3.45 (m, 1H), 2.27 (s, 3H), 2.23 (s, 3H), 1.38 (d, J = 6.8 Hz, 6H), 1.22 (d, J = 6.7 Hz, 6H); 13C NMR (101 MHz,
CDCl3) δ 162.8, 162.7, 160.24 (d, JC-F = 242.0 Hz), 137.85 (d, JC-F = 2.9 Hz), 132.86 (d, JC-F = 3.4 Hz), 130.54 (d, JC-F = 8.8 Hz),
122.33 (d, JC-F = 13.9 Hz), 112.29 (d, JC-F = 22.0 Hz), 49.7, 46.6, 34.39 (d, JC-F = 5.8 Hz), 20.9, 20.2, 20.1, 15.63 (d, JC-F = 2.5 Hz);
19F NMR (376 MHz, CDCl3) δ ꢀ120.91. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C17H25FN2O2H 309.1978; Found: 309.1978
N1-(2-fluoro-5-methoxybenzyl)-N2,N2-diisopropyloxala-mide (2e): A mixture of oxalamide 1e (0.2 mmol, 1.0 eq), Pd(OAc)2 (22
o
mg, 0.05 eq), NFSI (0.6 mmol, 3.0 eq) and 1,4ꢀdioxane (2 mL) in a 25 mL glass vial (sealed with PTFE cap) was heated at 80 C
for 10 h. The reaction mixture was cooled to room temperature, and concentrated in vacuo. The resulting residue was purified by
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column chromatography on silica gel to give the product of 2e. Yield 77% (47.8 mg); pale yellow oil; 1H NMR (400 MHz, CDCl3)
δ 7.26 (br, 1H), 6.96 (t, J = 9.1 Hz, 1H), 6.86 – 6.84 (m, 1H), 6.78 ꢀ 6.74 (m,1H), 4.79 ꢀ 4.73 (m, 1H), 4.47 (d, J = 6.1 Hz, 2H), 3.76
(s, 3H), 3.54 ꢀ 3.48 (m, 1H), 1.41 (d, J = 6.8 Hz, 6H), 1.22 (d, J = 6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 163.1, 162.7, 155.90
(d, JC-F = 2.0 Hz), 155.44 (d, JC-F =237.0 Hz), 125.16 (d, JC-F = 16.7 Hz), 116.11(d, JC-F = 23.0 Hz), 114.96 (d, JC-F = 4.0 Hz),
114.42 (d, JC-F = 8.0 Hz), 55.9, 49.7, 46.7, 37.59 (d, JC-F = 3.6 Hz), 20.9, 20.1; 19F NMR (376 MHz, CDCl3) δ ꢀ129.61. HRMS (ESIꢀ
TOF) m/z: [M + H]+ Calcd for C16H23FN2O3H 311.1771; Found: 311.1777.
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N1-(2-fluoro-4,5-dimethylbenzyl)-N2,N2-diisopropyloxa-lamide (2f): Yield 95% (58.5 mg); pale yellow oil; 1H NMR (400 MHz,
CDCl3) δ 7.21 (br, 1H), 7.05 (d, J = 7.7 Hz, 1H), 6.82 (d, J = 10.7 Hz, 1H), 4.80 ꢀ 4.74 (m, 1H), 4.43 (d, J = 6.1 Hz, 2H), 3.53 ꢀ
3.47 (m, 1H), 2.21 (s, 3H), 2.18 (s, 3H), 1.40 (d, J = 6.8 Hz, 6H), 1.22 (d, J = 6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 163.0,
162.8, 159.26 (d, JC-F = 243 Hz), 138.33 (d, JC-F = 7.7 Hz), 132.44 (d, JC-F = 3.4 Hz), 131.08 (d, JC-F = 4.3 Hz), 121.14 (d, JC-F
=
14.0 Hz), 116.47 (d, JC-F = 21.0 Hz) , 49.7, 46.7, 37.23 (d, JC-F = 3.5 Hz), 20.9, 20.1, 19.72 (d, JC-F = 1.4 Hz), 19.0; 19F NMR (376
MHz, CDCl3) δ ꢀ124.24. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C17H25FN2O2H 309.1978; Found: 309.1981.
N1-(2-fluoro-4,6-dimethoxybenzyl)-N2,N2-diisopropylo-xalamide (2g): A mixture of oxalamide 1g (0.2 mmol, 1.0 eq), Pd(OAc)2
(44 mg, 0.10 eq), F3 (0.4 mmol, 2.0 eq) and DCE (2 mL) in a 25 mL glass vial (sealed with PTFE cap) was heated at 80 oC for 6 h.
The reaction mixture was cooled to room temperature, and concentrated in vacuo. The resulting residue was purified by column
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chromatography on silica gel to give the corresponding product. Yield 72% (49.0 mg); pale yellow solid; mp = 125ꢀ127 °C; H
NMR (400 MHz, CDCl3) δ 7.27 (br, 1H), 7.03 (d, J = 11.3 Hz, 1H), 6.51 (d, J = 7.0 Hz, 1H), 4.80 ꢀ 4.74 (m, 1H), 4.36 (d, J = 6.1
Hz, 2H), 3.90 (s, 3H), 3.84 (s, 3H), 3.53 ꢀ 3.47(m, 1H), 1.41 (d, J = 6.8 Hz, 6H), 1.22 (d, J = 6.7 Hz, 6H); 13C NMR (101 MHz,
CDCl3) δ 162.9, 162.9, 153.9, 147.50 (d, JC-F = 11.7 Hz), 146.58(d, JC-F = 237.0 Hz), 117.72 (d, JC-F = 5.5 Hz), 117.29(d, JC-F = 20.0
Hz), 98.2, 56.9, 56.1, 49.6, 46.7, 38.3, 20.9, 20.1; 19F NMR (376 MHz, CDCl3) δ ꢀ145.23. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd
for C17H25FN2O4Na 363.1696; Found: 363.1705.
General Procedure for Palladium-catalyzed mono-Fluorinationof Benzylamines (Table 2) (2h-2n): A mixture of oxalamide
(0.2 mmol, 1.0 eq), Pd(OAc)2 (44 mg, 0.10 eq), NFSI (0.6 mmol, 3.0 eq) and tꢀAmylꢀOH (2 mL) in a 25 mL glass vial (sealed with
PTFE cap) was heated at 80 °C. The reaction mixture was cooled to room temperature, and concentrated in vacuo. The resulting
residue was purified by column chromatography on silica gel to give the corresponding product.
N1-(5-chloro-2-fluorobenzyl)-N2,N2-diisopropyloxala-mide (2h): Yield 81% (50.9 mg); pale yellow solid; mp = 78ꢀ80 °C; 1H
NMR (400 MHz, CDCl3) δ 7.50 (br, 1H), 7.32 (dd, J = 6.4, 2.6 Hz, 1H), 7.24 – 7.17 (m, 1H), 6.98 (t, J = 9.0 Hz, 1H), 4.77 ꢀ 4.71
(m, 1H), 4.47 (d, J = 6.3 Hz, 2H), 3.55 ꢀ 3.48 (m, 1H), 1.40 (d, J = 6.8 Hz, 6H), 1.23 (d, J = 6.7 Hz, 6H); 13C NMR (101 MHz,
CDCl3) δ 163.2, 162.6, 159.50(d, JC-F = 245.0 Hz), 129.81 (d, JC-F = 4.4 Hz), 129.49 (d, JC-F = 3.0Hz), 129.34 (d, JC-F =8.0Hz),
126.52 (d, JC-F = 16.6 Hz), 116.90 (d, JC-F =23.0Hz), 49.8, 46.7, 36.98 (d, JC-F = 3.9 Hz), 20.9, 20.1; 19F NMR (376 MHz, CDCl3)
δ ꢀ121.22. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C15H20ClFN2O2Na 337.1095; Found: 337.1103.
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N1-(5-bromo-2-fluorobenzyl)-N2,N2-diisopropyloxala-mide (2i): Yield 80% (57.3 mg); pale yellow solid; mp = 86ꢀ88 °C;; 1H
NMR (400 MHz, CDCl3) δ 7.46 (dd, J = 6.5, 2.5 Hz, 1H), 7.39 ꢀ 7.35 (m,2H), 6.94 (t, J = 9.1 Hz, 1H), 4.81 ꢀ 4.75 (m, 1H), 4.47 (d,
J = 6.3 Hz, 2H), 3.56 ꢀ 3.49 (m, 1H), 1.41 (d, J = 6.8 Hz, 6H), 1.24 (d, J = 6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 163.1,
162.5, 160.11 (d, JC-F = 246.0Hz), 132.82 (d, JC-F = 4.2 Hz), 132.44 (d, JC-F = 8.2 Hz), 126.92 (d, JC-F = 16.3 Hz), 117.40 (d, JC-F
=22.0 Hz), 116.92 (d, JC-F = 3.5 Hz), 49.7, 46.8, 37.00 (d, JC-F = 3.9 Hz), 21.0, 20.1; 19F NMR (376 MHz, CDCl3) δ ꢀ120.61. HRMS
(ESIꢀTOF) m/z: [M + Na]+ Calcd for C15H20BrFN2O2Na 381.0590; Found: 381.0602.
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N1-(2-fluoro-5-iodobenzyl)-N2,N2-diisopropyloxalamide (2j): Yield 72% (58.5 mg); pale yellow solid; mp = 90ꢀ92 °C; 1H NMR
(400 MHz, CDCl3) δ 7.63 (dd, J = 6.9, 2.2 Hz, 1H), 7.58 ꢀ 7.54 (m, 1H), 7.41 (br, 1H), 6.81 (t, J = 9.5, 1H), 4.79 ꢀ 4.72 (m, 1H),
4.45 (d, J = 6.2 Hz, 2H), 3.55 ꢀ 3.48 (m, 1H), 1.41 (d, J = 6.8 Hz, 6H), 1.23 (d, J = 6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ
163.1, 162.6, 161.03(d, JC-F = 247.0 Hz) , 138.76 (d, JC-F = 4.1 Hz), 138.50 (d, JC-F = 8.0 Hz), 127.31 (d, JC-F = 15.8 Hz), 117.84(d,
JC-F = 22.0 Hz), 87.36 (d, JC-F = 3.7 Hz), 49.7, 46.8, 36.84 (d, JC-F = 4.0 Hz), 21.0, 20.1; 19F NMR (376 MHz, CDCl3) δ ꢀ119.70.
HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C15H20IFN2O2Na 429.0451; Found: 429.0456.
N1-(2,6-difluorobenzyl)-N2,N2-diisopropyloxalamide (2k): Yield 78% (46.5 mg); pale yellow oil; 1H NMR (400 MHz, CDCl3) δ
7.27 – 7.22 (m, 2H), 6.91 – 6.87 (m, 2H), 4.87 ꢀ 4.80 (m, 1H), 4.57 (d, J = 6.0 Hz, 2H), 3.54 ꢀ 3.47 (m, 1H), 1.40 (d, J = 6.8 Hz,
6H), 1.22 (d, J = 6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 162.76 (d, JC-F = 7.8 Hz), 162.6, 162.4, 160.43 (d, JC-F = 8 Hz),
129.91 (t, JC-F = 10.3 Hz), 113.26 (t, JC-F = 19.3 Hz), 111.60 (d, JC-F =25.0 Hz). 111.60 (d, JC-F = 13.0Hz), 49.6, 46.8, 31.2, 20.9,
20.1; 19F NMR (376 MHz, CDCl3) δ ꢀ114.72. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C15H20F2N2O2Na 321.1391;
Found:321.1396.
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N1-(2-chloro-6-fluorobenzyl)-N2,N2-diisopropyloxala-mide (2l): Yield 83% (49.0 mg); pale yellow solid; mp = 78ꢀ80 °C; H
NMR (400 MHz, CDCl3) δ 7.27 (br,1H), 7.25 – 7.18 (m, 2H), 7.05 – 6.97 (m, 1H), 4.85 ꢀ 4.79 (m, 1H), 4.66 (dd, J = 5.9, 1.5 Hz,
2H), 3.54 ꢀ 3.47 (m, 1H), 1.39 (d, J = 6.8 Hz, 6H), 1.22 (d, J = 6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 162.6, 161.74 (d, JC-F
=
249.0 Hz), 135.75 (d, JC-F = 5.2 Hz), 130.00 (d, JC-F = 9.7 Hz), 125.56 (d, JC-F = 3.5 Hz), 123.17 (d, JC-F = 17.9 Hz), 114.47 (d, JC-F
= 22.0Hz), 49.6, 46.7, 34.61 (d, JC-F = 4.1 Hz), 20.9, 20.1; 19F NMR (376 MHz, CDCl3) δ ꢀ112.86. HRMS (ESIꢀTOF) m/z: [M +
Na]+ Calcd for C15H20ClFN2O2Na 337.1095; Found: 337.1102.
N1-(2-bromo-6-fluorobenzyl)-N2,N2-diisopropyloxala-mide (2m): Yield 81% (58.0 mg); pale yellow solid; mp = 98ꢀ100 °C; 1H
NMR (400 MHz, CDCl3) δ 7.38 (d, J = 8.0 Hz, 1H), 7.17 (m, 2H), 7.09 – 7.00 (m, 1H), 4.88 ꢀ 4.81 (m, 1H), 4.66 (dd, J = 5.9, 1.8
Hz, 2H), 3.54 ꢀ 3.47 (m, 1H), 1.40 (d, J = 6.8 Hz, 6H), 1.22 (d, J = 6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 162.5, 162.5,
161.62 (d, JC-F = 250.0 Hz), 130.56 (d, JC-F = 9.4 Hz), 128.87 (d, JC-F = 3.6 Hz), 125.59 (d, JC-F = 4.2 Hz), 124.84 (d, JC-F = 17.5
Hz), 115.17 (d, JC-F = 23.0 Hz), 49.6, 46.7, 37.07 (d, JC-F = 4.0 Hz), 21.0, 20.1; 19F NMR (376 MHz, CDCl3) δ ꢀ111.59. HRMS
(ESIꢀTOF) m/z: [M + Na]+ Calcd for C15H20BrFN2O2Na 381.0590; Found: 381.0591.
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N1-(2-fluoro-6-(trifluoromethyl)benzyl)-N2,N2-diisoprop-yloxalamide (2n): Yield 82% (57.1 mg); pale yellow solid; mp = 85ꢀ
87 °C; 1H NMR (400 MHz, CDCl3) δ 7.50 – 7.48 (m, 1H), 7.46 ꢀ 7.40 (m, 1H), 7.31 (t, J = 8.8 Hz, 1H), 7.05 (br, 1H), 4.86 ꢀ 4.80
(m, 1H), 4.70 (d, J = 5.6 Hz, 2H), 3.54 ꢀ 3.47 (m, 1H), 1.39 (d, J = 6.8 Hz, 6H), 1.23 (d, J = 6.7 Hz, 6H); 13C NMR (101 MHz,
CDCl3) δ 163.4, 163.2, 162.8, 162.5, 162.3, 160.9, 132.5, 131.3, 131.3, 131.0, 131.0, 130.2, 130.1, 130.0, 127.8, 126.1, 126.1,
124.9, 124.9, 123.0, 122.9, 122.2, 122.1, 122.1, 122.0, 122.0, 122.0, 121.9, 121.9, 119.9, 119.6, 49.7, 46.7, 33.6, 33.60 33.5, 33.5,
20.9, 20.1; 19F NMR (376 MHz, CDCl3) δ ꢀ58.87, ꢀ112.75. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C16H20F4N2O2Na 371.1359;
Found: 371.1363.
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N1-(2-fluoro-3,6-dimethylbenzyl)-N2,N2-diisopropyloxa-lamide (2o): A mixture of oxalamide 1o (0.2 mmol, 1.0 eq), Pd(OAc)2
(44 mg, 0.10 eq), NFSI (0.6 mmol, 3.0 eq) and tꢀAmylꢀOH (2 mL) in a 25 mL glass vial (sealed with PTFE cap) was heated at
100 °C for 12 h. The reaction mixture was cooled to room temperature, and concentrated in vacuo. The resulting residue was
purified by column chromatography on silica gel to give the corresponding product. Yield 32% (19.7 mg); pale yellow solid; mp =
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74ꢀ76 °C; H NMR (400 MHz, CDCl3) δ 7.03 – 6.99 (m, 2H), 6.85 (d, J = 7.7 Hz, 1H), 4.82 ꢀ 4.76 (m, 1H), 4.51 (d, J = 5.7 Hz,
2H), 3.53 ꢀ 3.46 (m, 1H), 2.36 (s, 3H), 2.22 (s, 3H), 1.39 (d, J = 6.8 Hz, 6H), 1.22 (d, J = 6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3)
δ 162.7, 160.41(d, JC-F = 243.0 Hz), 136.64 (d, JC-F = 3.3 Hz), 130.73 (d, JC-F = 6.3 Hz), 125.63 (d, JC-F = 3.6 Hz), 122.33 (d, JC-F
=
24 Hz), 122.31 (d, JC-F = 9 Hz) 49.7, 46.7, 34.46 (d, JC-F = 5.7 Hz), 21.0, 20.1, 19.00 (d, JC-F = 2.5 Hz), 14.44 (d, JC-F = 4.1 Hz); 19F
NMR (376 MHz, CDCl3) δ ꢀ122.14. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C17H25FN2O2Na 331.1798; Found: 331.1801.
N1-(2-fluorobenzyl)-N2,N2-diisopropyloxalamide (2p): A mixture of oxalamide 1p (0.2 mmol, 1.0 eq), Pd(OAc)2 (22 mg, 0.05
eq), NFSI (0.6 mmol, 3.0 eq) and 1,4ꢀdioxane : tꢀAmylꢀOH=3:1 (2 mL) in a 25 mL glass vial (sealed with PTFE cap) was heated at
80 °C for 4 h. The reaction mixture was cooled to room temperature, and concentrated in vacuo. The resulting residue was purified
by column chromatography on silica gel to give the corresponding product. Yield 56% (31.4 mg); pale yellow solid; mp = 111ꢀ
113 °C; 1H NMR (400 MHz, CDCl3) δ 7.36 ꢀ 7.32 (m, 1H), 7.31 – 7.26 (m, 2H), 7.13 ꢀ 7.09 (m, 1H), 7.07 ꢀ 7.02 (m, 1H), 4.83ꢀ4.76
(m, 1H), 4.52 (d, J = 6.2 Hz, 2H), 3.55ꢀ3.49 (m, J = 13.6, 6.8 Hz, 1H), 1.42 (d, J = 6.8 Hz, 6H), 1.23 (d, J = 6.7 Hz, 6H); 13C NMR
(101 MHz, CDCl3) δ 163.1, 162.7, 135.9, 131.42 (d, JC-F = 222.0 Hz), 128.36 (d, JC-F = 30.0 Hz), 127.8,126.18 (d, JC-F = 6.0
Hz),125.98(d, JC-F = 29 Hz), 49.7, 46.7, 39.9, 20.9, 20.1; 19F NMR (376 MHz, CDCl3) δ ꢀ118.63. HRMS (ESIꢀTOF) m/z: [M + Na]+
Calcd for C15H21FN2O2 [M+Na]: 303.1485; Found: 303.1485.
N1-(4-bromo-2-fluorobenzyl)-N2,N2-diisopropyloxala-mide (2q): A mixture of oxalamide 1q (0.2 mmol, 1.0 eq), Pd(OAc)2 (44
mg, 0.10 eq), NFSI (1.0 mmol, 5.0 eq) and tꢀAmylꢀOH (2 mL) in a 25 mL glass vial (sealed with PTFE cap) was heated at 80 °C
for 6 h. The reaction mixture was cooled to room temperature, and concentrated in vacuo. The resulting residue was purified by
column chromatography on silica gel to give the corresponding product. Yield 54% (38.7 mg); pale yellow solid; mp = 120ꢀ122 °C;
1H NMR (400 MHz, CDCl3) δ 7.64 (br, 1H), 7.22 ꢀ 7.19 (m, 3H), 4.79 – 4.55 (m, 1H), 4.42 (d, J = 6.2 Hz, 2H), 3.52ꢀ3.45 (m, 1H),
1.36 (d, J = 6.8 Hz, 6H), 1.20 (d, J = 6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 163.3, 163.2, 160.56 (d, JC-F = 250.0 Hz), 131.09
(d, JC-F = 4.7 Hz), 127.52 (d, JC-F = 3.5 Hz), 124.02 (d, JC-F = 14.9 Hz), 121.51 (d, JC-F = 9.3 Hz), 118.99 (d, JC-F = 24.0 Hz), 49.8,
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46.4, 36.5, 20.7, 19.9; 19F NMR (376 MHz, CDCl3) δ ꢀ115.80. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C15H20BrFN2O2Na
381.0590; Found: 381.0593.
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N1-(2-fluoro-4-methoxybenzyl)-N2,N2-diisopropyloxala-mide (2r): A mixture of oxalamide 1r (0.2 mmol, 1.0 eq), Pd(OAc)2 (44
mg, 0.10 eq), NFSI (1.0 mmol, 5.0 eq) and DCE:tꢀAmylꢀOH=1:1 (2 mL) in a 25 mL glass vial (sealed with PTFE cap) was heated
at 80 °C for 4 h. The reaction mixture was cooled to room temperature, and concentrated in vacuo. The resulting residue was
purified by column chromatography on silica gel to give the corresponding product. Yield 61% (37.8 mg); pale yellow solid; mp =
70ꢀ72 °C; 1H NMR (400 MHz, CDCl3) δ 7.23 (d, J = 8.6 Hz, 1H), 7.15 (br, 1H), 6.66 ꢀ 6.59 (m, 2H), 4.81 ꢀ 4.74 (m, 1H), 4.43 (d, J
= 6.0 Hz, 2H), 3.78 (s, 3H), 3.54 ꢀ 3.47 (m, 1H), 1.41 (d, J = 6.8 Hz, 6H), 1.22 (d, J = 6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ
163.0, 162.8, 161.77 (d, JC-F = 245.0 Hz), 160.78 (d, JC-F = 11.0 Hz), 130.96 (d, JC-F = 6.1 Hz), 116.45 (d, JC-F =16.0 Hz), 110.05 (d,
JC-F = 3.1 Hz), 101.93 (d, JC-F =25 Hz), 55.7, 49.7, 46.7, 37.12 (d, JC-F = 3.3 Hz), 21.0, 20.2; 19F NMR (376 MHz, CDCl3) δ ꢀ116.51.
HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C16H23FN2O3Na 333.1590; Found:333.1594.
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N1-(2-fluoro-4-vinylbenzyl)-N2,N2-diisopropyloxalamide (2s): A mixture of oxalamide 1s (0.2 mmol, 1.0 eq), Pd(OAc)2 (22 mg,
0.05 eq), NFSI (0.6 mmol, 3.0 eq) and 1,4ꢀdioxane:tꢀAmylꢀOH=3:1 (2 mL) in a 25 mL glass vial (sealed with PTFE cap) was
heated at 80 °C for 4 h. The reaction mixture was cooled to room temperature, and concentrated in vacuo. The resulting residue was
purified by column chromatography on silica gel to give the corresponding product. Yield 55% (33.7 mg); pale yellow oil; 1H NMR
(400 MHz, CDCl3) δ 7.29 (t, J = 7.8 Hz, 1H), 7.22 (br, 1H), 7.15 – 7.07 (m, 2H), 6.65 (dd, J = 17.5, 10.8 Hz, 1H), 5.73 (d, J = 17.5
Hz, 1H), 5.29 (d, J = 10.9 Hz, 1H), 4.82 ꢀ 4.75 (m, 1H), 4.49 (d, J = 6.2 Hz, 2H), 3.55 ꢀ 3.48 (m, 1H), 1.41 (d, J = 6.8 Hz, 6H), 1.23
(d, J = 6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 163.1, 162.7, 161.31 (d, JC-F =245.0 Hz), 139.67 (d, JC-F = 7.8 Hz), 135.57 (d,
JC-F = 2.3 Hz), 130.28 (d, JC-F = 4.7 Hz), 123.85 (d, JC-F = 15.4 Hz), 122.53 (d, JC-F = 3.1 Hz), 115.5, 112.83(d, JC-F = 22.0 Hz),
49.7, 46.8, 37.33 (d, JC-F = 3.7 Hz), 21.0, 20.1; 19F NMR (376 MHz, CDCl3) δ ꢀ119.04. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C17H23FN2O2Na 329.1641; Found: 329.1630.
N1-(2,6-difluorobenzyl)-N2,N2-diisopropyloxalamide (2k): A mixture of oxalamide1p (0.2 mmol, 1.0 eq), Pd(OAc)2 (66 mg,
0.15 eq), F3 (Nꢀfluoroꢀ2,4,6ꢀtrimethylpyridinium triflate） (0.6 mmol, 3.0 eq) and 1,4ꢀdioxane (2 mL) in a 25 mL glass vial (sealed
with PTFE cap) was heated at 80 °C for 24 h. The reaction mixture was cooled to room temperature, and concentrated in vacuo.
The resulting residue was purified by column chromatography on silica gel to give the corresponding produYield 80% (47.7 mg);
pale yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.27 – 7.22 (m, 2H), 6.91 – 6.87 (m, 2H), 4.87 ꢀ 4.80 (m, 1H), 4.57 (d, J = 6.0 Hz,
2H), 3.54 ꢀ 3.47 (m, 1H), 1.40 (d, J = 6.8 Hz, 6H), 1.22 (d, J = 6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 162.76 (d, JC-F = 7.8
Hz), 162.6, 162.4, 160.43 (d, JC-F = 8 Hz), 129.91 (t, JC-F = 10.3 Hz), 113.26 (t, JC-F = 19.3 Hz), 111.60 (d, JC-F =25.0 Hz). 111.60
(d, JC-F = 13.0Hz), 49.6, 46.8, 31.2, 21.0, 20.1; 19F NMR (376 MHz, CDCl3) δ ꢀ114.72. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C15H20F2N2O2Na 321.1391; Found:321.1396.
N1-(2,6-difluoro-4-vinylbenzyl)-N2,N2-diisopropyloxala-mide (3b): A mixture of oxalamide 1s (0.2 mmol, 1.0 eq), Pd(OAc)2 (44
mg, 0.10 eq), NFSI (1.0 mmol, 5.0 eq) and tꢀAmylꢀOH (2 mL) in a 25 mL glass vial (sealed with PTFE cap) was heated at 80 °C
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for 24 h. The reaction mixture was cooled to room temperature, and concentrated in vacuo. The resulting residue was purified by
column chromatography on silica gel to give the corresponding product. Yield 60% (38.9 mg); pale yellow oil; 1H NMR (400 MHz,
CDCl3) δ 7.21 (br, 1H), 6.97 – 6.89 (m, 2H), 6.60 (dd, J = 17.5, 10.8 Hz, 1H), 5.75 (d, J = 17.5 Hz, 1H), 5.36 (d, J = 10.8 Hz, 1H),
4.86 ꢀ 4.79 (m, 1H), 4.54 (d, J = 6.0 Hz, 2H), 3.54 ꢀ 3.47 (m, 1H), 1.40 (d, J = 6.8 Hz, 6H), 1.22 (d, J = 6.7 Hz, 6H); 13C NMR (101
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MHz, CDCl3) δ 163.0, 162.56(d, JC-F = 16 Hz), 160.47 (d, JC-F = 8.7 Hz), 140.18(t), 134.81(t), 116.9, 112.25 (t), 109.16 (d, JC-F
=
9
26 Hz), 109.16 (d, JC-F = 12.0 Hz), 49.6, 46.8, 31.21(t), 29.8, 21.0, 20.1; 19F NMR (376 MHz, CDCl3) δ ꢀ115.10. HRMS (ESIꢀTOF)
m/z: [M + Na]+ Calcd for C17H22F2N2O2Na 347.1547; Found:347.1534.
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General Procedure for the Preparation of the Difluorination Substrates (Table 3) (3c-3d): A mixture of oxalamide (1t,1u)
(0.2 mmol, 1.0 eq), Pd(OAc)2 (44 mg, 0.10 eq), F3 (Nꢀfluoroꢀ2,4,6ꢀtrimethylpyridinium triflate） (0.6 mmol, 3.0 eq) and 1,4ꢀ
dioxane (2 mL) in a 25 mL glass vial (sealed with PTFE cap) was heated at 80 °C for 24 h. The reaction mixture was cooled to
room temperature, and concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel to give
the corresponding product.
N1-(1-(2,6-difluorophenyl)ethyl)-N2,N2-diisopropyloxala-mide (3c): Yield 81% (50.5 mg); pale yellow solid; mp = 105ꢀ107 °C;
1H NMR (400 MHz, CDCl3) δ 7.56 (br, 1H), 7.23 ꢀ 7.16 (m, 1H), 6.87 (t, J = 8.3 Hz, 2H), 5.61 – 5.43 (m, 1H), 4.81 ꢀ 4.75 (m, 1H),
3.53 ꢀ 3.46 (m, 1H), 1.55 (d, J = 7.1 Hz, 3H), 1.41 (dd, J = 12.9, 6.8 Hz, 6H), 1.19 (dd, J = 11.6, 6.7 Hz, 6H); 13C NMR (101 MHz,
CDCl3) δ 162.4, 162.18 (d, JC-F = 7.8 Hz), 162.1, 159.71 (d, JC-F = 8.4 Hz), 129.10 (t, JC-F = 10.6 Hz), 118.41 (t, JC-F = 17.3 Hz),
111.92 (d, JC-F = 25.0 Hz), 111.92 (d, JC-F = 13.0 Hz),49.5, 46.7, 40.12 (t, JC-F = 2.8 Hz), 20.96 (d, JC-F = 7.0 Hz),20.8, 20.17 (d, JC-F
= 2.9 Hz). 19F NMR (376 MHz, CDCl3) δ ꢀ115.12. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C16H22F2N2O2Na 335.1547; Found:
335.1549.
2-(2,6-difluorophenyl)-2-(2-(diisopropylamino)-2-oxo-acetamido)ethyl acetate (3d): Yield 86% (63.6 mg); pale yellow solid;
mp = 70ꢀ72 °C; 1H NMR (400 MHz, CDCl3) δ 7.76 – 7.66 (m, 1H), 7.34 – 7.21 (m, 1H), 6.92 (t, J = 8.3 Hz, 2H), 5.78 ꢀ 5.73 (m,
1H), 4.80 ꢀ 4.73 (m, 1H), 4.43 (dd, J = 11.2, 7.3 Hz, 1H), 4.31 (dd, J = 11.2, 5.8 Hz, 1H), 3.56 ꢀ 3.49 (m, 1H), 2.04 (s, 3H), 1.42
(dd, J = 14.4, 6.8 Hz, 6H), 1.22 (dd, J = 8.6, 6.8 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 170.7, 162.55 (t, JC-F = 3.9 Hz), 162.1,
160.07 (d, JC-F = 7.9 Hz), 130.00 (d, JC-F = 208.0 Hz), 130.23 (t, JC-F = 10.6 Hz), 113.65 (t, JC-F = 17.5 Hz), 112.03 (d, JC-F = 26.0
Hz), 112.03 (d, JC-F = 13.0 Hz), 64.6, 49.6, 46.8, 43.70, 21.06 (d, JC-F = 9.0 Hz), 20.7, 20.16 (d, JC-F = 9.6 Hz). 19F NMR (376 MHz,
CDCl3) δ ꢀ113.76. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C18H24F2N2O4Na 393.1602; Found: 393.1596.
General Procedure for the Preparation of the Gram scale reaction(Scheme 2) (2b). A mixture of 1b (1.10 g, 4 mmol, 1.0
equiv), Pd(OAc)2 (22 mg, 0.025 eq), NFSI (3.343 g, 2.5 equiv) and tꢀAmylꢀOH (20 mL) in a 100 mL glass vial (sealed with PTFE
o
cap) was heated at 80 C for 12 hours. The reaction mixture was cooled to room temperature, and concentrated in vacuo. The
resulting residue was purified by column chromatography on silica gel to give 2b as pale yellow solid (1.07 g) in 91% yield.
General Procedure for the Preparation of the Gram scale reaction(Scheme 2). (A): A mixture of 3a (0.14 g, 0.5 mmol, 1.0
equiv) in THF (4 mL) was stirred for 5 min at ꢀ10 °C, NaH (60 %) (0.1 g, 2.5 mmol, 5.0 equiv) was slowly added, and then stirred
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for another 1 hour. NsCl (0.1662 g, 7.5 mmol, 1.5 equiv) was added slowly for thirty minutes. The mixture was stirred over night at
room temperature, quenched with water (20 mL), extracted with CH2Cl2 (10 mL × 2). The combined organic phase was washed
with brine (20 mL), dried over anhydrous Na2SO4. Evaporation and column chromatography on silica gel afforded 3aa (110 mg) as
pale yellow solid in 71% yield.
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(B): Compound 3a (0.14 g, 0.5 mmol, 1.0 eq) was dissolved in a mixture of THF/MeOH (0.4/0.1 mL). NaOH (80 mg, 2.0 mmol,
4.0 eq) was added later. The mixture was heated at 100 oC for 12 hours, then diluted with water (10 mL), extracted with DCM(10 m
× 3L ). The combined organic layers was washed with brine (15 mL), dried over anhydrous Na2SO4, and concentrated in vacuo.
The residue was purified by column chromatography on silica gel to give the desired product (2ꢀfluorophenyl)methanamine 4 (47.7
mg) as a colourless oil in 86% yield.
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N-(2-fluorobenzyl)-4-nitrobenzenesulfonamide (3aa): Yield 71% (110 mg); pale yellow solid; mp = 125ꢀ127 °C; 1H NMR (400
MHz, CDCl3) δ 8.22 (d, J = 8.9 Hz, 2H), 7.93 (d, J = 8.8 Hz, 2H), 7.24 – 7.17 (m, 2H), 7.05 – 6.99 (m, 1H), 6.88 (m, 1H), 5.35 (br,
1H), 4.30 (d, J = 5.7 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 160.83 (d, JC-F = 246 Hz), 149.9, 146.1, 130.4, 130.40 (d, JC-F = 12
Hz), 128.3, 124.49 (d, JC-F = 3.6 Hz), 124.2, 122.90 (d, JC-F = 14.4 Hz), 115.57 (d, JC-F = 21 Hz), 41.87 (d, JC-F = 3.5 Hz); 19F NMR
(376 MHz, CDCl3) δ ꢀ118.36. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C13H11FN2O4SNa 333.0321; Found: 333.0325.
(2-fluorophenyl)methanamine (4): Yield 86% (53.8 mg); colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.29 (m, 1H), 7.25 – 7.17
(m, 1H), 7.09 (m, 1H), 7.05 – 6.97 (m, 1H), 3.88 (s, 2H); 1.57 (br, 2H); 13C NMR (101 MHz, CDCl3) δ 160.99 (d, JC-F = 244.0 Hz),
130.30 (d, JC-F = 15.0 Hz), 129.19 (d, JC-F = 4.9 Hz), 128.53 (d, JC-F = 8.1 Hz), 124.22 (d, JC-F = 3.6 Hz), 115.33(d, JC-F = 21.0 Hz),
40.65 (d, JC-F = 3.8 Hz); 19F NMR (376 MHz, CDCl3) δ ꢀ120.06.24
ASSOCIATED CONTENT
Supporting Information
Detailed experimental procedures and characterization data for new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: yszhao@suda.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
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We gratefully acknowledge financial support from the Natural Science Foundation of Jiangsu Province of China (L210903913), a startꢀup
fund (Q410901212) from Soochow University and the Young National Natural Science Foundation of China (NO.21402133). The PAPD
is also gratefully acknowledged.
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