Selectfluor-mediated oxidative methylenation of amide with N, N -dimethylpropanamide for N, N ′-methylenebisamide synthesis

Article abstract of DOI:10.1139/cjc-2018-0181

A simple and efficient approach for the synthesis of N,N′-methylenebisamides through a Selectfluor-mediated oxidative reaction of aromatic amides and N,N-dimethylpropanamide (DMP) is described. Remarkable results clearly reveal that DMP plays a dual role in this reaction, as both a one-carbon source and an environment-friendly solvent. Moreover, the process provides new strategies for the synthesis of bisamides with advantages of operationally simple, insensitive to atmospheric conditions, and good to high yields.

Full text of DOI:10.1139/cjc-2018-0181

Canadian Journal of Chemistry
Selectfluor-mediated oxidative methylenation of amide with N,N-dimethylpropanamide for
N,N’-methylenebisamide synthesis
Yue Cao1#, Dongheng Zhou1,2# and Yongmin Ma1*
1College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, P R China,
311402
2Department of Biochemistry and Molecular Biology, School of Medicine, Zhejiang University,
Hangzhou 310058, P R China
*Correspondent. E-mail: yongmin.ma@zcmu.edu.cn
#Yue Cao and Dongheng Zhou contributed equally to this work
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Abstract
A simple and efficient approach for the synthesis of N,N'-methylenebisamides through a
Selectfluor-mediated oxidative reaction of aromatic amides and N,N-dimethylpropanamide (DMP)
is described. Remarkable results clearly reveal that DMP plays a dual role in this reaction, as both
a one-carbon source and an environment-friendly solvent. Moreover, the process provides new
strategies for the synthesis of bisamides with advantages of operationally simple, insensitive to
atmospheric conditions and good to high yields.
Keywords: amides; methylenebisamides; selectfluor; DMP; methylene
1 Introduction
Amides and polyamides, the important biological and medicinal scaffolds, have been widely
occurred among numerous biologically active compounds, natural products1, pharmaceuticals,
polymers2 and peptides3. In particular, symmetrical N,N'-methylenebisamides are critical
functional moieties in the formation of peptidomimetic compounds. It has also been reported that
these compounds can be used as starting materials for the synthesis of inhibitors against HIV-1
integrases4. Among various transformations reported for synthesis of methylenebisamides, the
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coupling of aldehydes with various primary amides at acidic conditions is one of the most broadly
investigated approaches. Such approaches include using different catalysts such as sulfuric acid5,
triflic acid6, p-toluene sulfonic acid7, phosphotungstic acid8 and (SiO2-PPA)9. Extensive
researches over past few years have proved that DMSO can be used as the methylene source in
organic synthesis10. For instance, The synthesis of methylenebisamides can be achieved by using
2,4,6-trichloro[1,3,5]triazine or 2,4-dichloro-6-methoxy[1,3,5]triazine11, ammonium persulfate12,
or Ni-catalyzed system13 to activate DMSO. In fact, DMSO acts in these reactions as both
methylene source and solvent (Scheme 1).
Recently, a few studies of application of N-methylamine compounds as one carbon synthon
under transition-metal or oxidant catalyzed conditions have been reported. Li et al. has introduced
Fe2(CO)9 as an efficient catalyst for the preparation of methylene-bridged bis-1,3-dicarbonyl
derivatives via Fe-catalyzed C-N bond cleavage using N,N’-dimethylaniline as the methylene
source14. In 2012, Zhang et al. reported a Cu(II)-catalyzed, base-switched method for the
synthesis of bisindolylmethanes, 3-formylindoles and diaminodiphenylmethanes using
tetramethylethylenediamine as methylene and formyl donors under external-oxidant-free
conditions15. More recently, methylenebisamides were synthesised from amides using
Na2S2O8/(NH4)2Ce(NO3)6 system in water16. Unfortunately, these methods reported for the
synthesis of methylenebisamides suffer from drawbacks such as expensive catalyst, corrosive
reagent, long reaction time, hazardous organic solvent and low yields. The present work describes
the use of SelectfluorTM, an exceptionally stable, cheap and user-friendly reagent, as an efficient
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oxidant for the synthesis of methylenebisamides. Selectfluor was firstly discovered in 199217 and
soon after became one of the most popular reagents in one-step reactions to introduce fluorine
into organic compounds electrophilically18-21. Its thermal stability, low toxicity, good solubility
and stability in polar and non-polar solvents such as water, methanol, acetonitrile, nitromethane,
tetrahydrofuran and N,N-dimethylformamide are favored by any organic chemistry laboratory22.
Furthermore, its half-wave potential against saturated calomel electrode (SCE) at 0.33 V leads it
to become one of the most powerful oxidants in the N-F fluorinating compounds library21.
Therefore, selectfluor can be served as an oxidant of many functionalizations of organic
compounds other than fluorinations23-25. For example, selectfluor can efficiently oxidize amides
into imides in the presence of copper(I) bromide26 and transform indole into 2-oxindole27. To
explore the C-H/N-H cross-coupling reaction28,29, herein, we report a new approach for the
synthesis of methylenebisamides from primary amides using dimethyl alkylamides as the
methylene source oxidized by selectfluor.
2 Results and Discussion
Permutations and combinations of oxidants and their mole ratios at different temperatures
provided an optimal reaction condition. At the outset, a model reaction of benzamide 1a and a
methylene source (2) was initially investigated at 110°C (Table 1). In the absence of any oxidant
the reaction did not proceed at all, indicating that the oxidant is necessary for this transformation
(entry 1). In order to select the best oxidant, the reaction was investigated at 110°C for 12h with
several oxidants such as N-fluorobenzenesulfonimide, DMSO and Selectfluor (entries 2-4). To
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our delight, selectfluor has showed the best oxidative activity amongst the oxidants examined and
91% yield of the methylenebisamide 3a was obtained (entry 4). However, with a decrease of
reaction temperature, the yield of 3a was correspondingly decreased (entry 5) and the reaction
was not proceed at 50oC and room temperature, respectively (entries 6-7). On the other hand,
further increase of the reaction temperature to 130oC did not enhance the reaction selectivity and
only 81% of the product yield was achieved (entry 8). Therefore, 110oC is an optimal temperature
to process the reaction. The amount of selectfluor was also investigated. When catalytic amounts
of selectfluor were applied (0.1 equiv. and 0.5 equiv., respectively), lower product yields were
achieved compared to that by an equal amount of selectfluor (entries 9-10). On the other side,
when 1.5 equiv. amount of selectfluor was applied for this oxidation reaction, a slightly lower
yield was found, indicating that it may promote a further oxidation of the resulting product and
lead to lower yield (entry 11). Various methylene donors have also been examined and it was
found that when the reaction was carried out in N,N’-dimethylformamide (entry 12), N,N’
-dimethylacetamide (entry 13), DMSO (entry 14) or formaldehyde (entry 15) it was not as
efficient as that in N,N’-dimethylpropanamide (DMP). Interestingly, when N-methylacetamide
was investigated as the methylene donor, the reaction failed (entry 16). Although N-methylamine
compounds such as tetramethylethylenediamine and N,N’-dimethylaniline have been reported to
provide the methylene synthon30, 31, the reaction did not proceed at all using selectfluor as the
oxidant (entries 17-18). Therefore, the standard reaction conditions were built using benzamide
(1.0 equiv.), selectfluor (1.0 equiv.) and DMP (4 mL) at 110°C under air for 12h.
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With the optimized conditions in hand, we decided to explore the substrate scope for
aromatic amide containing both electron-donating and electron-withdrawing groups. The obtained
outcomes are summarized in Table 2. Aromatic amines carrying an electron-donating group
(CH3-, CH3O-) at ortho-, meta- or para- position reacted efficiently to acquire the corresponding
bisamides without significant different yields (85-92%) (entries 2, 3, 8, 11 and 12). In contrast,
the benzamides substituted with an electron-withdrawing group such as p-F, p-Cl, m-F, o-F
furnished the corresponding bisamides in slightly lower yields (78-88%) (entries 4, 5, 9 and 13).
Surprisingly, only 25% yield was achieved when o-chlorobenzamide was used as the reactant
(entry 14). Furthermore, similar product yields were obtained from p-NO2 and m-NO2 substituted
benzamides (entries 6 and 10). This phenomenon indicates that under such protocol the reactivity
of aromatic amides containing an electron-withdrawing group is lower than that with an
electron-donating group. Unfortunately, 4-hydroxybenzamide remained unreactive, which may be
due to an interference of an active proton on the ring (entry 7). The bisamide 3o was obtained in
high yield from 2-naphthamide, similar to that of unsubstituted benzamide (entry 15).
Interestingly, When di-substituted benzamides were examined as the reactants under same
conditions (entries 16-19), only 2,5-difluorobenzamide can be transformed into the corresponding
bisamide 3r in a low yield (17%). Moreover, when 3,5-dimethoxy substituted analogue (1u) was
carried out under same conditions, the desired bisamide was not obtained. Instead, a fluorine
atom was introduced into the aromatic ring to afford 4 with a medium yield (Scheme 2). Apart
from aromatic amides, 2-phenylacetamide can afford the corresponding bisamide 3t under same
conditions in a good yield (entry 20). However, other aliphatic amides such as acetamide, and
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propionamide remain unreactive. In addition, N-methylbenzamide, 2-picolinamide,
2-thiophenecarboxamide, benzothioamide and p-toluenesulfonamide were also investigated for
the reaction but failed. It is noteworthy that when phthalamide was used as the reactant, only
phthalimide (5) was afforded in a good yield under such protocol.
A plausible mechanism has been depicted in Scheme 4 based on literature reports32,33. Firstly
the nitrogen atom of DMP was fluorinated by selectfluor to form an onium ion A, followed by
removal of one molecule of HF to produce iminium ion B. The intermediate B was
nucleophilically attacked by the aromatic amide to obtain intermediate C. Intermediate C was
nucleophilically attacked again by another molecule of aromatic amide to afford the final desired
bisamide 3.
3 Conclusion
In conclusion, we have developed a convenient approach to methylenebisamides through a
selectfluor-mediated oxidation reaction of aromatic amides and DMP. The substrates are easily
available and the method is simple and avoids the use of formaldehyde, transition-metals or
strong acid catalysts. The methylenebisamides are obtained in good to high yields. Further study
of the oxidation of selectfluor in organic synthesis is currently underway.
4 Experimental
All the chemical reagents used in the synthesis were of research grade and were obtained from
commercial sources. All the reactions were monitored by thin-layer chromatography (TLC). All
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target products were characterized by using NMR (BrukerAvance 600 spectrometer) with TMS as
the internal standard in DMSO or CDCl3 and High resolution mass spectra (MicroMass Q-TOF
instrument). The chemical shifts are reported in parts per million (ppm), the coupling constants (J)
are expressed in hertz (HZ). IR spectra are recorded as KBr pellets on a Nicolet IS50 infrared
spectrometer. Melting points are determined using an WRS-1B apparatus and are uncorrected.
General procedure for the preparation ofmethylenebisamides: a mixture of acylamide (1
mmol) and selectfluor (1 mmol) was stirred in DMP (4 mL) at 110°C. After the completion of the
reaction as determined by TLC (Petroleum ether-ethyl acetate, 1:2), the mixture was cooled to
room temperature. Water (20 ml) was added and the mixture was extracted with EtOAc (3×20
ml). The organic layer was separated and dried over Na2SO4. Removal of the solvents produced a
residue which was purified using column chromatography, eluted with a mixture of
EtOAc/petroleum ether (1:1, v/v), to afford the pure symmetrical methylenebisamides.
N,N'-methylenedibenzamide (3a): White solid; yield: 115mg (91%); mp 217-218°C (lit34. mp
216-217°C).IR (ATR): 3308, 2924, 1634,1577, 1527, 1288, 693 cm–1.1H NMR (500 MHz,
CDCl3):δ7.81 (d, J = 7.3 Hz, 4H, ArH), 7.56-7.48 (m, 4H, ArH, NH), 7.43 (m, 4H, ArH), 5.06 (t,
J = 6.2 Hz, 2H, CH2). 13C NMR (151 MHz, CDCl3): δ166.91, 134.40, 131.86, 128.71, 127.88,
45.63. ESI-MS: (M+Na)+ 277.
N,N'-methylenebis(4-methylbenzamide) (3b):White solid; yield: 120mg (85%); mp 211-214°C
(lit13. mp 212-214°C). IR (ATR): 3311, 2967, 2918, 1635, 1530, 1505, 1284, 1110, 757 cm–1.1H
NMR (600 MHz, CDCl3): δ7.71-7.76 (d, 4 H, ArH), 7.48 (t, J = 6.7Hz, 2H, NH), 7.24-7.21 (m, 4
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H, ArH), 5.01 (t, J = 6.4 Hz, 2H, CH2), 2.39 (s, 6H, CH3). 13C NMR (151 MHz, CDCl3): δ168.38,
142.55, 130.60, 129.29, 127.18, 45.52, 21.50. ESI-MS: (M+Na)+ 305.
N,N'-methylenebis(4-methoxybenzamide) (3c): White solid; yield: 143mg (85%); mp
212-213°C (lit34. mp 223-224°C). IR (ATR): 3325, 2965, 2920, 1632, 1505, 1293, 1251, 1185,
1114, 1034, 846, 769 cm–1.1H NMR (600 MHz, CDCl3): δ 7.85-7.74 (d, 4 H, ArH), 7.51 (t, J =
6.3Hz, 2H, NH), 6.95-6.88 (m, 4 H, ArH), 5.00 (t, J = 6.4 Hz, 2H, CH2), 3.84 (s, 6H, OCH3). 13C
NMR (151 MHz, CDCl3): δ 168.00, 162.57, 129.10, 125.73, 113.79, 55.43, 45.59. ESI-MS:
(M+H)+ 315.
N,N'-methylenebis(4-fluorobenzamide) (3d): White solid; yield: 121mg (83%); mp 227-228°C
(lit16. mp 223-224°C). IR (ATR): 3358, 3075, 1646, 1500, 1285, 1239, 850, 767 cm–1.1H NMR
(600 MHz, CDCl3): δ 7.84-7.81 (d, 4 H, ArH), 7.69 (t, J = 6.5Hz, 2H, NH), 7.13-7.09 (m, 4 H,
ArH), 5.00 (t, J = 6.3 Hz, 2H, CH2). 13C NMR (151 MHz, CDCl3): δ 167.55, 131.54, 129.76,
128.89, 115.84, 45.75. ESI-MS: (M+Na)+ 313.
N,N'-methylenebis(4-chlorobenzamide) (3e): White solid; yield: 143mg (88%); mp 245-246°C
(lit13. mp 245-247°C). IR (ATR): 3317, 3179, 3051, 1643, 1526, 1406, 1302, 1093, 847, 789 cm–
1.1H NMR (500 MHz, DMSO-d6): δ 9.17 (t, J = 5.6 Hz, 2H, NH), 7.92 (d, J = 8.1 Hz, 4H, ArH),
7.54 (d, J = 8.1 Hz, 4H, ArH), 4.85 (t, J = 5.6 Hz, 2H, CH2). 13C NMR (151 MHz, DMSO-d6): δ
165.92, 136.72, 133.14, 129.85, 128.83, 45.65. ESI-MS: (M+Na)+ 345.
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N,N'-methylenebis(4-nitrobenzamide) (3f): White solid; yield: 53mg (31%); mp 235-237°C
1
(lit34. mp 234-235°C).IR (ATR): 3294, 1643, 1600, 1536, 1516, 1351, 1289, 1116, 724 cm–1. H
NMR (600 MHz, CDCl3): δ 8.31 (d, J = 8.8 Hz, 4H, ArH), 7.98 (d, J = 8.8 Hz, 4H, ArH), 7.67
(brs, 2H, NH,), 5.06 (t, J = 6.0 Hz, 2H, CH2).13C NMR (126 MHz, DMSO-d6): δ 165.40, 149.62,
139.98, 129.46, 123.97, 45.85. ESI-MS: (M+Na)+ 367.
N,N'-methylenebis(3-methoxybenzamide) (3h): White solid; yield: 123mg (87%); mp
153-154°C (lit34. mp165-166°C). IR (ATR): 3239, 3069, 2971, 2944, 1642, 1529, 1491, 1306,
1240, 1107, 873, 738, 714 cm–1.1H NMR (600 MHz, DMSO-d6): δ δ 9.06 (t, J = 5.7 Hz, 2H, NH),
7.50 – 7.45 (m, 4H, ArH), 7.37 (t, J = 7.9 Hz, 2H, ArH), 7.11 – 7.07 (m, 2H, ArH), 4.85 (t, J =
5.6 Hz, 2H, CH2), 3.80 (s, 6H, OCH3). 13C NMR (126 MHz, DMSO-d6): δ 166.64, 159.59, 135.82,
129.85, 120.19, 117.86, 112.88, 55.74, 45.62. ESI-MS: (M+H)+315.
N,N'-methylenebis(3-fluorobenzamide) (3i):White solid; yield: 113mg (78%); mp 216-218°C
(lit13. mp 222-224°C). IR (ATR): 3300, 3071, 1635, 1533, 1306, 1220, 1110, 765 cm–1.1H NMR
(500 MHz, DMSO-d6): δ 9.18 (t, J = 5.6 Hz, 2H, NH), 7.77 (d, J = 10.1, 2.0 Hz, 2H, ArH), 7.71
(dt, J = 10.1, 2.7, 1.6 Hz, 2H, ArH), 7.53 (m, J = 8.0, 5.9 Hz, 2H, ArH), 7.39 (t, J = 8.5, 2.7, 1.0
Hz, 2H, ArH), 4.86 (t, J = 5.6 Hz, 2H, CH2). 13C NMR (126 MHz, DMSO-d6): δ 165.61, 162.35,
136.73, 130.95, 124.09, 118.86, 114.67, 45.70. ESI-MS: (M+Na)+ 313.
N,N'-methylenebis(3-nitrobenzamide) (3j): White solid; yield: 46mg (27%); mp 227-229°C
1
(lit34. mp225-226°C).IR (ATR): 3300, 3065, 1640, 1524, 1350, 1116, 728 cm–1. H NMR (500
MHz, DMSO-d6): δ 9.59 (t, J = 6.0 Hz, 2H, NH), 8.75 (d, J = 2.2 Hz, 2H, ArH), 8.44 – 8.34 (m,
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4H, ArH), 7.79 (dt, J = 6.0 Hz, 2H, ArH), 4.92 (td, J = 5.6, 2.1 Hz, 2H, CH2).13C NMR (126 MHz,
DMSO-d6): δ 164.95, 148.23, 135.78, 134.38, 130.62, 126.57, 122.70, 45.97. ESI-MS: (M+Na)+
367.
N,N'-methylenebis(2-methoxybenzamide) (3k): White solid; yield: 145mg (92%); mp
157-159°C. IR (ATR): 3387, 2976, 2944, 1644, 1538, 1485, 1302, 1244, 1012, 751 cm–1.1H NMR
(600 MHz, DMSO-d6): δ 8.87 (t, J = 5.8 Hz, 2H, NH), 7.86 (dd, J = 7.7, 1.9 Hz, 2H, ArH), 7.50
(m, 2H, ArH), 7.16 (d, J = 8.3 Hz, 2H, ArH), 7.05 (dt, J = 7.6, 1.0 Hz, 2H, ArH), 4.87 (t, J = 5.8
Hz, 2H, CH2), 3.90 (s, 6H, OCH3).13C NMR (126 MHz, DMSO-d6): δ 165.53, 157.72, 133.34,
131.27, 122.19, 121.09, 112.67, 56.47, 45.52. ESI-MS: (M+Na)+ 337.
N,N'-methylenebis(2-methylbenzamide) (3l): White solid; yield: 120mg (85%); mp 185-186°C
(lit13. mp 204-206°C). IR (ATR): 3293, 2963, 2924, 1639, 1529, 1395, 1304, 1283, 1118, 746,
700 cm–1.1H NMR (500 MHz, DMSO-d6): δ 8.83 (t, J = 5.7 Hz, 2H, NH), 7.36 – 7.31 (m, 4H,
ArH), 7.22 (m, 4H, ArH), 4.76 (t, J = 5.7 Hz, 2H, CH2), 2.35 (s, 6H, CH3).13C NMR (126 MHz,
DMSO-d6): δ 169.70, 137.11, 135.75, 130.85, 129.82, 127.65, 125.86, 44.90, 19.84. ESI-MS:
(M+Na)+ 305.
N,N'-methylenebis(2-fluorobenzamide) (3m): White solid; yield: 115mg (79%); mp 188-189°C
(lit34. mp192-193°C).IR (ATR): 3293, 3069, 1640, 1529, 1306, 1222, 1116, 755 cm–1.1H NMR
(600 MHz, DMSO-d6): δ 8.90 (t, J = 6.1, Hz, 2H, NH), 7.64 (dt, J = 7.6, 1.8 Hz, 2H, ArH),
7.56-7.52 (m , 2H, ArH), 7.31 – 7.26 (m, 4H, ArH), 4.81 (t, J = 6.1 Hz, 2H, CH2).13C NMR (126
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MHz, DMSO-d6): δ 164.45, 160.74, 133.17, 130.64, 124.91, 123.87, 116.61, 45.22. ESI-MS:
(M+Na)+ 313.
N,N'-methylenebis(2-chlorobenzamide) (3n): White solid; yield: 41mg (25%); mp 185-187°C
(lit13. mp189-190°C).IR (ATR): 3283, 3053, 1644, 1529, 1393, 1301, 1111, 751 cm–1.1H NMR
(500 MHz, DMSO-d6): δ 7.63 (d, J = 7.6, Hz, 2H, ArH), 7.43 – 7.32 (m, 8H, NH, ArH), 5.03 (t, J
= 6.3 Hz, 2H, CH2).13C NMR (126 MHz, DMSO-d6): δ 168.60, 136.83, 131.00, 130.06, 129.44,
129.11, 127.46, 44.74. ESI-MS: (M+Na)+ 345.
N,N'-methylenebis(2-naphthamide) (3o): White solid; yield: 154mg (87%); mp 238-239°C (lit12.
mp 235-237°C).IR (ATR): 3299, 3272, 3061, 1641, 1534, 1302, 1114, 781 cm–1.1H NMR (600
MHz, DMSO-d6): δ 9.29 (t, J = 5.7 Hz, 2H, NH), 8.56 (d, J = 1.5 Hz, 2H, ArH), 8.04 – 7.96 (m,
8H, ArH), 7.64-7.57 (m, 4H, ArH), 4.99 (t, J = 5.6 Hz, 2H, CH2).13C NMR (126 MHz, DMSO-d6):
δ 167.00, 134.69, 132.57, 131.74, 129.36, 128.31, 128.30, 128.16, 128.07, 127.20, 124.75, 45.78.
ESI-MS: (M+Na)+ 377.
N,N'-methylenebis(2,5-difluorobenzamide) (3r): White solid; yield: 28mg (17%); mp
200-201°C.IR (ATR): 3330, 2933, 2676, 2489, 1640, 1534, 1283, 1187, 820 cm–1.1H NMR (500
MHz, DMSO-d6): δ 9.03 (t, J = 5.8 Hz, 2H, NH), 7.45 – 7.34 (m, 6H, ArH), 4.79 (t, J = 5.8 Hz,
2H, CH2).13C NMR (151 MHz, DMSO-d6): δ 163.31, 119.73, 119.56, 118.63, 118.45, 116.81,
116.64, 45.24. HRMS calcd for C15H10F4N2O2Na+ 349.0571, found 349.0559.
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N,N'-methylenebis(2-phenylacetamide) (3t): White solid; yield: 103mg (73%); mp 208-209°C
(lit13. mp 213-215°C).IR (ATR): 3305, 3065, 1643, 1537, 1391, 1246, 1114, 697 cm–1.1H NMR
(500 MHz, DMSO-d6): δ 8.71 (t, J = 6.0 Hz, 2H, NH), 7.29 – 7.26 (m, 4H, ArH), 7.25 – 7.21 (m,
6H, ArH), 4.38 (t, J = 6.0 Hz, 2H, CH2), 3.41 (s, 4H, COCH2).13C NMR (151 MHz, DMSO-d6): δ
171.08, 136.63, 129.46, 128.61, 126.78, 43.82, 42.44. ESI-MS: (M+H)+ 283.
2-fluoro-3,5-dimethoxybenzamide (4): White solid; yield: 108mg (53%); mp 121-122°C.
1
IR (ATR): 3383, 3192, 3016, 1655, 1595, 1406, 1213, 1159, 785 cm–1. H NMR (500 MHz,
CDCl3): δ 7.11 (dd, J = 5.1, 3.1 Hz, 1H, ArH), 6.69 (dd, J = 7.2, 3.1 Hz, 1H, ArH), 5.85 (s, 2H,
NH), 3.89 (s, 3H, OCH3), 3.83 (s, 3H, OCH3). 13C NMR (151 MHz, CDCl3): δ 164.86, 155.67,
+
148.59, 146.70, 105.43, 105.38, 103.59, 56.50, 55.89. HRMS calcd for C9H11FNO3 200.0717,
found 200.0711.
Isoindoline-1,3-dione (5): White solid; yield: 113mg (77%); mp 235-236°C. (lit34. mp
236-238°C). IR (ATR): 3197, 3051, 1743, 1599, 1380,1307cm–1.1H NMR (500 MHz, DMSO-d6):
δ 11.35 (s, 1H, NH), 7.83 (s, 4H, ArH).13C NMR (151 MHz, DMSO-d6): δ 169.68, 134.77,
133.06, 123.39. ESI-MS: (M+H)+ 148.
5 Acknowledgements
The financial support from Zhejiang Provincial Natural Science Foundation of China
(LY17H300005) is gratefully acknowledged.
6 References
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1
Duong, T. N.; Edrada, R.; Ebel, R.; Wray, V.; Frank, W.; Duong, A. T.; Lin, W. H.; Proksch,
P. J. Nat. Prod. 2007, 70, (10), 1640-3.
2
3
4
Allen, C. L.; Williams, J. M. Chem. Soc. Rev. 2011, 40, (7), 3405-15.
Glomb, M. A.; Pfahler, C. J. Biol. Chem. 2001, 276, (45), 41638-47.
Sechi, M.; Azzena, U.; Delussu, M. P.; Dallocchio, R.; Dessì, A.; Cosseddu, A.; Pala, N.;
Neamati, N. Molecules 2008, 13, (10), 2442-2461.
5
Magat, E. E.; Faris, B. F.; Reith, J. E.; Salisbury, L. F. J. Am. Chem. Soc. 1951, 73, (3),
1028-1031.
6
7
Fernández, A. H.; Alvarez, R. M.; Abajo, T. M. Synthesis 1996, 1996, (11), 1299-1301.
Anary-Abbasinejad, M.; Mosslemin, M. H.; Hassanabadi, A.; Safa, S. T. Synth. Commun.
2010, 40, (15), 2209-2214.
8
Harichandran; GurusamyAmalraj; Davidshanmugam, S.; Ponnusamy. Indian J. Chem. 2011,
50B, 77-82.
9
Mohammad Shafiee, M. R. J. Saudi Chem. Soc. 2014, 18, (2), 115-119.
10 Wu, X.-F.; Natte, K. Adv. Synth. Catal. 2016, 358, (3), 336-352.
11 Wang, Q.; Sun, L.; Jiang, Y.; Li, C. Beilstein J. Org. Chem. 2008, 4, 51.
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12 Mahajan, P. S.; Tanpure, S. D.; More, N. A.; Gajbhiye, J. M.; Mhaske, S. B. RSC Adv. 2015,
5, (123), 101641-101646.
13 Moghaddam, F. M.; Tavakoli, G.; Saeednia, B. ChemistrySelect 2017, 2, (4), 1316-1322.
14 Li, H.; He, Z.; Guo, X.; Li, W.; Zhao, X.; Li, Z. Org. Let. 2009, 11, (18), 4176-4179.
15 Zhang, L.; Peng, C.; Zhao, D.; Wang, Y.; Fu, H. J.; Shen, Q.; Li, J. X. Chem. Commun
(Camb) 2012, 48, (47), 5928-30.
16 Chen, J.; Mao, J.; Yang, Z. Chinese J. Org. Chem. 2015, 35, (3), 672.
17 Banks, R. E., Fluorinated diazabicycloalkane derivatives. US 5086178, 1992.
18 Nyffeler, P. T.; Duron, S. G.; Burkart, M. D.; Vincent, S. P.; Wong, C.-H. Angew. Chem. Int.
Ed. 2004, 44, (2), 192-212.
19 Champagne, P. A.; Desroches, J.; Hamel, J.-D.; Vandamme, M.; Paquin, J.-F. Chem Rev
2015, 115, (17), 9073-9174.
20 Serguchev, Y. A.; Ponomarenko, M. V.; Ignat'ev, N. V. J. Fluorine Chem. 2016, 185, 1-16;
21 Wolstenhulme, J. R.; Gouverneur, V. Acc. Chem. Res. 2014, 47, (12), 3560-3570.
22 Stavber, S. Molecules 2011, 16, (8), 6432-6464.
23 Laali, K. K.; Nandi, G. C.; Bunge, S. D. Tetrahedron Lett. 2014, 55, (15), 2401-2405.
https://mc06.manuscriptcentral.com/cjc-pubs

Page 15 of 27
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24 Chen, Q.; Zeng, J.; Yan, X.; Huang, Y.; Du, Z.; Zhang, K.; Wen, C. Tetrahedron Lett. 2016,
57, (30), 3379-3381.
25 Bao, H.; Xu, Z.; Wu, D.; Zhang, H.; Jin, H.; Liu, Y. J. Org. Chem. 2017, 82, (1), 109-118.
26 Jin, Z.; Xu, B.; Hammond, G. B. Tetrahedron Lett. 2011, 52, (16), 1956-1959.
27 Jiang, X.; Yang, J.; Zhang, F.; Yu, P.; Yi, P.; Sun, Y.; Wang, Y. Org. Lett. 2016, 18, (13),
3154-7.
28
Karthikeyan, J.; Haridharan, R.; Cheng, C.-H. Angew. Chem. Int. Ed. 2012, 51,
12343-12347.
29 Niu, L.; Yi, H.; Wang, S.; Liu, T.; Liu, J.; Lei, A. Nat. Commun. 2016, 8, 14226.
30 Liu, W.; Liu, J.; Ogawa, D.; Nishihara, Y.; Guo, X.; Li, Z. Org. Lett. 2011, 13, (23), 6272;
29
31 Stephens, D. E.; Nguyen, V. T.; Chhetri, B.; Clark, E. R.; Arman, H. D.; Larionov, O. V.
Org. Lett. 2016, 18, (22), 5808-5811.
32 Daniels, M. H.; Hubbs, J. Tetrahedron Lett. 2011, 52, (28), 3543-3546.
33 Kirihara, M.; Naito, S., Ishizuka, Y.; Hanai, H.; Noguchi, T. Tetrahedron Lett. 2011, 52,
(24), 3086-3089.
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34 Mameda, N.; Marri, M. R.; Peraka, S.; Macharla, A. K.; Kodumuri, S.; Chevella, D.; Naresh,
G.; Nama, N. Catal Commun. 2015, 61, (61), 41-43.
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Page 17 of 27
Canadian Journal of Chemistry
Scheme 1 Traditional routes to methylenebisamides
Scheme 2 Reaction using 3,5-dimethoxybenzamide as the starting material
Scheme 3 Reaction using phthalamide as the starting material
Scheme 4 A plausible mechanism for synthesis of bisamides
Table 1 Optimization of the reaction conditionsa
Table 2 Scope of the substrates a
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Canadian Journal of Chemistry
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Table 1 Optimization of the reaction conditionsa
O
O
O
Oxidant
N
N
NH2
2
+
H
H
3a
1a
Entry
2
Oxidant
Equiv. Temp./°C Yield/%b
1
2
EtCONMe2
EtCONMe2
EtCONMe2
EtCONMe2
EtCONMe2
EtCONMe2
EtCONMe2
EtCONMe2
EtCONMe2
EtCONMe2
HCONMe2
-
-
110
110
110
110
80
NR
48
23
91
83
NR
81
25
40
86
53
NFSI
1.0
1.0
1.0
1.0
1.0
1.0
0.1
0.5
1.5
1.0
3
DMSO
4
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
5
7
r.t.
8
130
110
110
110
110
9
10
11
12
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Page 19 of 27
Canadian Journal of Chemistry
13
14
15
16
17
18
MeCONMe2
DMSO
Selectfluor
Selectfluor
Selectfluor
Selectfluor
1.0
1.0
1.0
1.0
1.0
1.0
110
110
110
110
110
110
75
83
HCHO
72
MeCONHMe
NR
NR
NR
Me2NCH2CH2NMe2 Selectfluor
PhNMe2
Selectfluor
aReaction conditions: 1a (1.0 mmol) and 2 (4 mL) with certain amount of oxidant at the indicated
temperature under air for 12h.
bIsolated yields.
NR, no reaction.
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Canadian Journal of Chemistry
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Table 2 Scope of the substrates a
O
O
O
Selectfluor
N
+
Ar
NH2
Ar
N
N
Ar
110℃/12h
O
H
H
1
3
2
Entry Substrate
Product Yield/%b Entry Substrate
Product Yield/%b
1
2
3
4
5
6
7
8
9
Ph
3a
3b
91
85
91
83
88
31
0
11
12
13
14
15
16
17
18
19
2-MeOC6H4
3k
3l
92
85
79
25
87
0
4-MeC6H4
2-MeC6H4
2-FC6H4
4-MeOC6H4 3c
3m
3n
3o
3p
3q
3r
4-FC6H4
3d
3e
2-ClC6H4
4-ClC6H4
2-naphthyl
2,6-Me2C6H3
2,6-F2C6H3
2,5-F2C6H3
4-NO2C6H4 3f
4-OHC6H4
3g
0
3-MeOC6H4 3h
87
78
17
0
3-FC6H4
3i
3,5-(CF3)2C6H3 3s
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Page 21 of 27
Canadian Journal of Chemistry
10
3-NO2C6H4 3j
27
20
C6H5CH2
3t
73
aReaction conditions: aromatic amide (1 mmol),Selectfluor (1 mmol),DMP (4 mmol).
b Isolated yields.
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Canadian Journal of Chemistry
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Scheme 1 Traditional routes to methylenebisamides
HCHO,H2SO4
Aldehydes,CF3SO3H
Aldehydes,p-TSA
Aldehydes,PTA
O
O
R'
O
Aldehydes,SiO2-PPA
R
NH2
R
N
N
R
H
H
DMSO,cyanuryl chloride
DMSO,(NH4)2S2O8
DMSO,NiCl2•2H2O
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Page 23 of 27
Canadian Journal of Chemistry
Scheme 2 Reaction using 3,5-dimethoxybenzamide as the starting material
O
F
O
MeO
MeO
Selectfluor
N
NH2
NH2
+
℃
110 / 12h
O
OMe
OMe
2
4
, 53% yield
1u
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Canadian Journal of Chemistry
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Scheme 3 Reaction using phthalamide as the starting material
O
O
NH2
NH2
Selectfluor
N
NH
+
℃
110 / 12h
O
O
O
5
, 77% yield
1v
2
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Page 25 of 27
Canadian Journal of Chemistry
Scheme 4 A plausible mechanism for synthesis of bisamides
N
Cl
N
Cl
N
Cl
N
N
N
H
F-
F
O
O
O
N
N F
N
B
A
O
O
O
O
ArCONH2
ArCONH2
-EtCONHMe
N
N
Ar
Ar
Ar
N
N
H
H
H
3
C
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Canadian Journal of Chemistry
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Graphical Abstract
Selectfluor-mediated oxidative
methylenation of amide with N,N-
dimethylpropanamide for
methylenebisamide synthesis
Yue Cao, Dongheng Zhou and Yongmin
Ma*
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