Chapitre 4 : La fonction cétone comme groupe directeur
IV. Etudes complémentaires
4. Vers des travaux précédents de l’équipe
A partir de ces tetralones, il a également été possible de mettre au point une voie d’accès vers des
structures similaires à celles déjà précédemment étudiées par notre équipe331. Cette étude avait pour sujet des plateformes moléculaires centrées sur un atome de soufre et pouvant se coordinner avec différents métaux alcalins.
Les mêmes plateformes, cette fois ci basées sur un atome d’oxygène ont pu être synthétisées par la méthode décrite dans le Schéma 130.
SCHEMA 130-SYNTHESE DE DIHYDRONAPHTHOBENZOFURANES
Le composé 126 possédant un cycle E à 6 chainons a également pu être obtenu à partir de l’alcool 122
issu de l’aromatisation de la tetralone avec un rendement de 56% en suivant des conditions
expérimentales précédemment décrites par l’équipe de Taylor332.
SCHEMA 131-SYNTHESE DE NAPHTHOCHROMENES
331 H. Boufroura, S. Poyer, A. Gaucher, C. Huin, J.-Y. Salpin, G. Clavier, D. Prim, Chem. - Eur. J.2018, 24, 8656. 332 V. Dimakos, T. Singh, M. S. Taylor, Org. Biomol. Chem.2016, 14, 6703.
122
123 124 125
168
V. Conclusion
Dans le but de développer une nouvelle voie d’accès vers des dérivés du naphthalenes substitués en
position 1 et 8, une nouvelle méthodologie d’arylation des tetralones basée sur l’utilisation d’un
groupe directeur éphémère a été mise au point.
Cette méthodologie a permis l’obtention de trente-quatre dérivés de la tetralone avec des rendements
allant jusqu’à 61% (Schéma 132).
SCHEMA 132-BILAN DE L'ARYLATION DES TETRALONES
Afin d’expliquer le faible rendement de cette réaction, en comparaison avec son analogue réalisée sur
des cétones non cycliques, une étude théorique complète du mécanisme réactionnel a été réalisée. Cette analyse a permis de mettre en évidence l’influence importante de la taille du cycle aliphatique sur le déroulement de cette réaction, et d’expliquer en partie les différences de rendement observées
entre ces différents substrats. L’arylation d’indanone, particulièrement difficile selon ces calculs, a fait
l’objet d’études supplémentaires. D’autres groupes directeurs, en particulier des hydrazones, mais
également la 2-aminopyridine 1-oxide, ont donc été testés, sans succès.
En complément, de cette arylation, plusieurs méthodes de dérivation ont été testées sur ces tetralones arylées en postions 8. Les deux méthodes visant à installer une cétone sur une autre position du cycle benzénique se sont malheureusement révélées infructueuses (Schéma 133).
SCHEMA 133-UNE NOUVELLE CETONE POUR UNE NOUVELLE ARYLATION
Cependant, la possibilité d’aromatiser ces structures vers le naphthalene a pu être vérifiée, ainsi que
deux méthodes permettant la synthèse de polycycles à partir de ces tetralones (Schéma 134).
169
Conclusion générale
Lors de ces travaux de thèse, des méthodologies de C–H activation dédiées au naphthalene, brique moléculaire élémentaire de nombreuses architectures polycycliques aromatiques, ont été développées. Lors de la mise au point de ces méthodes, une régiosélectivité inhérente à ce substrat particulier et au type de groupe directeur utilisé a été observée et étudiée. Après cette étude des conditions expérimentales ont dû être adaptées au socle naphthalene pour que différents groupes fonctionnels, aromatiques ou non, puissent être introduits sur cette plateforme de façon efficace et totalement sélective (Schéma 135).
SCHEMA 135-C–H FONCTIONNALISATION SELECTIVE DU NAPHTHALENE
A partir de ces naphthalenes fonctionnalisés et par des procédés catalytiques, trois types
d’architectures polycycliques étendues ont pu être obtenues : des fluorenones, des phenanthridinones
et, par un procédé monotope unique de double C–H activation, des isoindolinones (Schéma 136). Dans le cas des fluorenones, la sélectivité de la réaction de cyclisation a été étudiée en détails à l’aide de calculs DFT, concordant avec les résultats expérimentaux.
170
Ensuite, une approche différente a été envisagée et la tetralone, précurseur connu du naphthalene, et
devenue le centre de l’étude. Sur ce bicycle, une méthodologie de C–H arylation basée sur l’utilisation
d’un groupe directeur éphémère a été mise au point afin de fonctionnaliser efficacement la position
8, difficilement accessible sur le naphthalene (Schéma 137). Le mécanisme de cette fonctionnalisation
a ensuite été entièrement étudié de façon théorique, ce qui a permis de mettre en évidence l’influence
de la taille du cycle aliphatique sur la réactivité de ce type de substrat.
SCHEMA 137-ARYLATION DE TETRALONES A L'AIDE D'UN GROUPE DIRECTEUR EPHEMERE
Enfin, il a été vérifié que la réaromatisation de ces produits menait bien à des 1-naphthol arylés en position 8 et de nouvelles conditions expérimentales, permettant l’obtention de nouvelles
architectures polycycliques aromatiques à partir de ces tetralones arylées, ont été décrites. Ces méthodologies permettent un accès rapide à des structures aromatiques complexes : des dihydronaphthobenzofuranes et des naphthochromènes (Schéma 138).
171
Parties Expérimentales
General Information
Solvents and reagents were purchased from Aldrich, Alfa Aesar, Acros or TCI and used without further purification except for DCM which was freshly distilled from calcium hydride and stored under Argon. Gerudan Si 60 silica gel 60 (40-63 μm) was used for flash chromatography. 1H NMR spectra were recorded on Bruker AV-I 300 MHz and advance 200 MHz spectrometers at 298 K, referenced to TMS signal and were calibrated using residual CHCl3(δ = 7.26 ppm), DMSO-d6(δ = 2.50 ppm) or MeOD (δ =
3.31 ppm). 19F NMR spectra were recorded on Bruker AV-I 300 MHz spectrometer at 298 K, and were calibrated using CFCl3 (δ = 0.00 ppm). 13C NMR spectra were recorded with a Bruker AV-I 300 MHz spectrometer at 75 MHz and 298 K and were calibrated using CDCl3(δ = 77.16 ppm), DMSO-d6(δ =
39.52 ppm) or MeOD (δ = 49.00 ppm). 1H NMR spectroscopic data are reported as follow: chemical
shift δ [ppm] (multiplicity, coupling constant [Hz], integration). Multiplicities are reported as follow: s
= singlet, d = doublet, t = triplet, q = quadruplet, dd = doublet of doublet, m = multiplet. 13C NMR
spectroscopic data are reported in terms of chemical shifts δ [ppm] and multiplicity and coupling
constant [Hz] are given when adequate. Mass spectra and high-resolution mass spectra were obtained with a Q-TOF spectrometer using electrospray ionisation (ESI). Sonication was performed in a Prolabo Transonic-TS540 ultrasonic cleaner with a frequency of 35 KHz and a power of 320 W.
All calculations were performed in Gaussian 09, revision D.01 Structures were optimized at the B3LYP level of density functional theory in the gas phase. The LanL2 effective core potential (ECP) was used to describe Pd and I along with the associated basis set. The 6-31+G(d,p) basis set was adopted to describe all other atoms. Frequency calculations have been performed to verify the optimized structures as local minima or transition states.
References:
Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, Ö .; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09, revision D.01; Gaussian, Inc.: Wallingford, CT, 2009.
Becke, A. D. J. Chem. Phys. 1993, 98, 5648−5652. Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B: Condens.
Matter Mater. Phys. 1988, 37, 785−787. Becke, A. D. J. Chem. Phys. 1993, 98, 1372−1377. Becke, A. D.
Phys. Rev. A: At., Mol., Opt. Phys. 1988, 38, 3098−3100.
Check, C. E.; Faust, T. O.; Bailey, J. M.; Wright, B. J.; Gilbert, T. M.; Sunderlin, L. S. J. Phys. Chem. A 2001,
172
Partie expérimentale du chapitre 2
GENERALS PROCEDURES
GENERAL PROCEDURE FOR THE PREPARATION OF NAPHTHAMIDES
In an oven-dried round bottom flask filled with argon, thionyl chloride (1.5 eq) was added to a solution of naphthoic acid (1.0 eq), 4-toluene sulfonamide (1.0 eq) and magnesium sulfate (1.0 eq) in o-dichlorobenzene (1.4 M). A condenser was adapted on the flask and the mixture was heated to 120°C and stirred for 24h. The resulting mixture was quickly filtered off in order to remove the magnesium sulfate. After the precipitation of the desired product at r.t. was completed, the solid was recovered by filtration and washed profusely with pentane. The naphthamide was used in the next reaction without further purification.
GENERAL PROCEDURE FOR THE ALKOXYLATION OF NAPHTHAMIDES
Naphthamide (1.0 eq), PIDA (1.0 eq) and palladium trifluoroacetate (0.1 eq) were solubilized in the reacting alcohol (0.1 M) in a round bottom flask and stirred for 24h at 25°C. The resulting mixture was diluted in AcOEt (25 mL), filtered through a pad of celite, and purified by chromatography on silica gel to afford the expected compound.
GENERAL PROCEDURE FOR THE PREPARATION OF NAPHTHALENE PIVALOYL
In a round bottom flask filled with argon, pivaloyl chloride (1 eq) was added to a solution of naphthamine (1 eq) and triethyl amine (1.1 eq) in DCM (0.2 M – 1 v) and stirred at room temperature for 24h. Water (1.4 v) was carefully added to the resulting mixture and the two resulting phases were separated. The organic layer were washed three times with a solution of NaHCO3,sat, dried over MgSO4
and concentrated. The desired product was then purified using chromatography to give the expected product.
GENERAL PROCEDURE FOR THE ARYLATION OF NAPHTHAMIDES
In a 2-dram screw glass tube filled with argon, aryl iodide (2.0 eq) was added to a solution of naphthamide (1.0 eq), silver(I) oxide (1.0 eq), potassium carbonate (4.0 eq), and palladium(II) acetate (0.1 eq) in acetic acid (0.1 M). The reaction mixture was stirred under argon for 24h at 130 °C and then filtered through a pad of celite. The residue was diluted in DCM, and washed with a saturated aqueous solution of NaHCO3, the organic layer was washed with a saturated aqueous solution of NaCl, dried over MgSO4 and concentrated. The desired product was then purified by preparative TLC to afford the expected product.
173
N-TOSYL-2-NAPHTHAMIDE (1)
1
C18H15NO3S M = 325.38 g.mol-1
N-tosyl-2-naphthamide (1) was prepared from 2-naphthoic acid (5.00 g, 29.04 mmol), 4-toluene sulfonamide (4.97 g, 29.04 mmol), thionyl chloride (3.2 mL, 45.56 mmol) and magnesium sulfate (3.50 g, 29.04 mmol) in o-dichlorobenzene (22 mL) following the General procedure for the preparation of naphthamides. The desired product was obtained as a white powder (8.50 g, 90% yield).
1H NMR (200 MHz, CD2Cl2) δ (ppm): 8.90 (s, 1H), 8.31 (s, 1H), 8.04 (d, J = 8.3 Hz, 2H), 7.98 – 7,86 (m, 3H), 7.77 (dd, J = 8.7, 1.9 Hz, 1H), 7.69 – 7.52 (m, 2H), 7.39 (d, J = 8.0 Hz, 2H), 2.45 (s, 3H). 13C NMR (75 MHz, CDCl3) δ (ppm): 164.26, 145.32, 135.55, 135.50, 132.32, 129.68, 129.32, 129.11, 129.05, 128.86, 128.78, 128.36, 127.84, 127.29, 123.34, 21.74. Melting point: 165°C HRMS (ESI):
m/z: Calcd for C18H16NO3S [M+H]+: 326.0851; Found 326.0858.
Data were in concordance with the literature333.
174
N-TOSYL-1-NAPHTHAMIDE (2)
2
C18H15NO3S M = 325.38 g.mol-1
N-tosyl-1-naphthamide (2) was prepared from 1-naphthoic acid (1.01 g, 5.81 mmol), 4-toluene sulfonamide (0.99 g, 5.81 mmol) and thionyl chloride (632 µL, 8.71 mmol) in o-dichlorobenzene (15 mL) following the General procedure for the preparation of naphthamides. The desired product was obtained as white crystals (1.04 g, 55% yield).
1H NMR (300 MHz, CDCl3) δ (ppm):
8.56 (s, 1H), 8.20 (dd, J = 6.2, 3.6 Hz, 1H), 8.08 (d, J = 8.4 Hz, 2H), 7.98 (d, J = 8.2 Hz, 1H), 7.86 (dd, J = 6.1, 3.4 Hz, 1H), 7.67 (d J = 8,2Hz, 1H), 7.57 – 7.50 (m, 2H), 7.48 – 7.42 (m, 1H), 7.39 (d, J = 8.2 Hz, 2H), 2.47 (s, 3H).
Data were in concordance with the literature334.
175
3-METHOXY-N-TOSYL-2-NAPHTHAMIDE (3)
3
C19H17NO4S M = 355.41 g.mol-1
3-methoxy-N-tosyl-2-naphthamide (3) was prepared from N-tosyl-2-naphthamide (1) (71.1 mg, 0.220 mmol) palladium(II) acetate (5.1 mg, 0.022 mmol) and PIDA (75.0 mg, 0.220 mmol) in MeOH (1.9 mL) following the General procedure for the alkoxylation of naphthamides. The crude mixture was purified using column chromatography on silica gel (AcOEt/EP – gradient from 20/80 to 40/60) and the desired product was obtained as a white powder (66.2 mg, 85% yield).
1H NMR (300 MHz, CDCl3) δ (ppm): 10.50 (s, 1H), 8.63 (s, 1H), 8.08 (d, J = 8.3 Hz, 2H), 7.79 (d, J = 8.2 Hz, 1H), 7.72 (d, J = 8.3 Hz, 1H), 7.59 – 7.49 (m, 1H), 7.42 – 7.30 (m, 2H), 7.22 (s, 1H), 4.12 (s, 3H), 2.42 (s, 3H). 13C NMR (75 MHz, CDCl3) δ (ppm): 161.26, 153.02, 143.85, 135.54, 134.93, 134.19, 128.45, 128.42, 128.35, 127.70, 127.01, 125.40, 124.16, 118.41, 106.09, 55.45, 20.64. Melting point: 166°C HRMS (ESI):
176
2-METHOXY-N-TOSYL-1-NAPHTHAMIDE (4)
4
C19H17NO4S M = 355.41 g.mol-1
2-methoxy-N-tosyl-1-naphthamide (4) was prepared from N-tosyl-1-naphthamide (2) (174.6 mg, 0.537 mmol) palladium(II) trifluoroacetate (18.1 mg, 0.054 mmol) and PIDA (179.2 mg, 0.537 mmol) in MeOH (4.5 mL) following the General procedure for the alkoxylation of naphthamides. The crude mixture was purified using column chromatography on silica gel (AcOEt/EP –50/50) and the desired product was obtained as a yellow powder (165.4 mg, 87% yield)
1H NMR (300 MHz, CDCl3) δ (ppm): 9.07 (s, 1H), 8.09 – 7.95 (m, 3H), 7.87 (d, J = 8,0 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.43 (tt, J = 6.8, 3.4 Hz, 1H), 7.35 (m, 3H), 7.18 (d, J = 9.2 Hz, 1H), 3.91 (s, 3H), 2.44 (s, 3H). 13C NMR (75 MHz, CDCl3) δ (ppm): 164.71, 155.09, 144.93, 135.92, 133.77, 131.53, 129.50, 128.85, 128.57, 128.37, 128.17, 124.60, 124.22, 115.67, 112.23, 56.75, 21.73. Melting point: 136°C HRMS (ESI):
177
3-ETHOXY-N-TOSYL-2-NAPHTHAMIDE (5)
5
C20H19NO4S M = 369.44 g.mol-1
3-ethoxy-N-tosyl-2-naphthamide (5) was prepared from N-tosyl-2-naphthamide (1) (66.6 mg, 0.200 mmol) palladium(II) acetate (4.5 mg, 0.020 mmol) and PIDA (66.4 mg, 0.200 mmol) in ethanol (2 mL) following the General procedure for the alkoxylation of naphthamides. The crude mixture was purified on preparative TLC (AcOEt/EP – 50/50) and the desired product was obtained as a gray oil (41.4 mg, 56% yield). 1H NMR (300 MHz, CDCl3) δ (ppm): 10.80 (s, 1H), 8.64 (s, 1H), 8.08 (dd, J = 8.4, 1.6 Hz, 2H), 7.81 (d, J = 8.2 Hz, 1H), 7.71 (d, J = 8.3 Hz, 1H), 7.59 – 7.48 (m, 1H), 7.37 (dd, J = 13.4, 8.0 Hz, 3H), 7.21 (s, 1H), 4.34 (q, J = 7.0 Hz, 2H), 2.43 (s, 3H), 1.70 (bs, 1H), 1.68 (t, J = 6.9 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ (ppm): 162.38, 153.47, 144.89, 136.60, 136.04, 135.11, 129.54, 129.46, 129.43, 128.70, 128.03, 126.41, 125.16, 119.56, 107.99, 65.52, 21.72, 14.67. HRMS (ESI):
178
3-ISOPROPOXY-N-TOSYL-2-NAPHTHAMIDE (6)
6
C21H21NO4S M = 383.46 g.mol-1
3-isopropoxy-N-tosyl-2-naphthamide (6) was prepared from N-tosyl-2-naphthamide (1) (66.1 mg, 0.200 mmol) palladium(II) acetate (5.4 mg, 0.020 mmol) and PIDA (67.7 mg, 0.200 mmol) in isopropanol (2 mL) following the General procedure for the alkoxylation of naphthamides. The crude mixture was purified on preparative TLC (AcOEt/EP – 50/50) and the desired product was obtained as a yellow powder (10.9 mg, 14% yield). 1H NMR (300 MHz, CDCl3) δ (ppm): 10.97 (s, 1H), 8.67 (s, 1H), 8.11 – 8.03 (m, 2H), 7.82 (d, J = 8.2 Hz, 1H), 7.70 (d, J = 8.3 Hz, 1H), 7.54 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H), 7.37 (dd, J = 13.2, 7.9 Hz, 3H), 7.23 (s, 1H), 4.92 (h, J = 6.0 Hz, 1H), 2.43 (s, 3H), 1.59 (d, J = 6.1 Hz, 6H). 13C NMR (75 MHz, CDCl3) δ (ppm): 162.45, 152.31, 144.86, 136.57, 136.07, 135.20, 129.53, 129.46, 129.37, 128.68, 127.99, 126.34, 125.15, 120.27, 109.46, 77.48, 77.05, 76.63, 73.16, 29.73, 22.04, 21.72. HRMS (ESI):
179
3-(2-METHOXYETHOXY)-N-TOSYL-2-NAPHTHAMIDE (7)
7
C21H21NO5S M = 399.46 g.mol-1
3-(2-methoxyethoxy)-N-tosyl-2-naphthamide (7) was prepared from N-tosyl-2-naphthamide (1) (67.4 mg, 0.200 mmol) palladium(II) acetate (5.2 mg, 0.020 mmol) and PIDA (70.3 mg, 0.200 mmol) in 2-methoxyethan-1-ol (2 mL) following the General procedure for the alkoxylation of naphthamides. The crude mixture was purified on preparative TLC (AcOEt/EP – 50/50) and the desired product was obtained as a colorless oil (39.8 mg, 50% yield).
1H NMR (300 MHz, CDCl3) δ (ppm): 10.85 (s, 1H), 8.61 (s, 1H), 8.06 (d, J = 8.4 Hz, 2H), 7.81 (d, J = 8.3 Hz, 1H), 7.70 (d, J = 8.3 Hz, 1H), 7.57 – 7.49 (m, 1H), 7.41 – 7.31 (m, 3H), 7.19 (s, 1H), 4.43 – 4.37 (m, 2H), 3.95 – 3.88 (m, 2H), 3.61 (s, 3H), 2.42 (s, 3H). 13C NMR (75 MHz, CDCl3) δ (ppm): 162.73, 153.38, 144.63, 136.44, 136.35, 135.15, 129.48, 129.45, 129.34, 128.66, 128.26, 126.36, 125.18, 120.29, 108.23, 70.08, 68.49, 59.49, 21.70. HRMS (ESI):
180
N-(NAPHTHALEN-2-YL)PIVALAMIDE (8)
8
C15H17NO M = 227.31 g.mol-1
N-(naphthalen-2-yl)pivalamide (8) was prepared from naphthalen-2-amine (756.1 mg, 5.28 mmol) pivaloyl chloride (650 µL, 5.28 mmol) and triethyl amine (810 µL, 5.81 mmol) in DCM (26.4 mL) following the General procedure for the preparation of naphthalene pivaloyl. The desired product was obtained as a brown powder (1.12 g, 93% yield) and used in the next step without further purification.
1H NMR (200 MHz, CDCl3) δ (ppm):
8.27 (s, 1H), 7.78 (d, J = 8.1 Hz, 3H), 7.45 (dd, J = 19.0, 11.2 Hz, 4H), 1.36 (s, 9H).
Melting point:
176°C
Data were in accordance with the literature335.
181
N-(NAPHTHALEN-1-YL)PIVALAMIDE (9)
9
C15H17NO M = 227.31 g.mol-1
N-(naphthalen-1-yl)pivalamide (9) was prepared from naphthalen-1-amine (1.121 g, 7.83 mmol) pivaloyl chloride (960 µL, 7.83 mmol) and triethyl amine (1.20 mL, 8.61 mmol) in DCM (93.0 mL) following the General procedure for the preparation of naphthalene pivaloyl. The desired product was obtained as a pink powder (1.74 g, 99% yield) and used in the next step without further purification.
1H NMR (200 MHz, CDCl3) δ (ppm):
7.95 (d, J = 7.5 Hz, 1H), 7.91 – 7.73 (m, 2H), 7.70 (d, J = 8.3 Hz, 1H), 7.60 – 7.38 (m, 3H), 1.44 (s, 9H).
Melting point:
147°C
Data were in accordance with the literature336.
182
N-(1-METHOXYNAPHTHALEN-2-YL)PIVALAMIDE (10)
10
C16H19NO2
M = 257.33 g.mol-1
N-(1-methoxynaphthalen-2-yl)pivalamide (10) was prepared from N-(naphthalen-2-yl)pivalamide (8) (102.7 mg, 0.440 mmol) palladium(II) acetate (10.6 mg, 0.044 mmol) and PIDA (150.2 mg, 0.440 mmol) in methanol (3.7 mL) following the General procedure for the alkoxylation of naphthamides. The crude mixture was purified using column chromatography on silica gel (AcOEt/EP – 10/90) and the desired product was obtained as a white powder (29.3 mg, 26% yield).
1H NMR (300 MHz, CDCl3) δ (ppm): 8.52 (d, J = 9.0 Hz, 1H), 8.00 (d, J = 8.3 Hz, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.64 (d, J = 9.0 Hz, 1H), 7.50 (ddd, J = 8.3, 6.8, 1.3 Hz, 1H), 7.41 (ddd, J = 8.1, 6.8, 1.3 Hz, 1H), 3.95 (s, 3H), 1.39 (s, 9H). 13C NMR (75 MHz, CDCl3) δ (ppm): 176.62, 143.06, 131.29, 128.22, 128.16, 127.06, 126.21, 124.81, 124.57, 120.97, 120.11, 61.25, 39.96, 27.64." HRMS (ESI):
183
N-(2-METHOXYNAPHTHALEN-1-YL)PIVALAMIDE (11)
11
C16H19NO2
M = 257.33 g.mol-1
N-(2-methoxynaphthalen-1-yl)pivalamide (11) was prepared from N-(naphthalen-1-yl)pivalamide (9) (100.2 mg, 0.440 mmol) palladium(II) acetate (11.6 mg, 0.044 mmol) and PIDA (150.5 mg, 0.440 mmol) in methanol (3.7 mL) following the General procedure for the alkoxylation of naphthamides. The crude mixture was purified using column chromatography on silica gel (AcOEt/EP – 20/80) and the desired product was obtained as a brown powder (57.0 mg, 50% yield).
1H NMR (300 MHz, CDCl3) δ (ppm): 8.29 (dd, J = 7.5, 2.0 Hz, 1H), 7.70 (dd, J = 7.5, 1.7 Hz, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.57 – 7.44 (m, 3H), 6.76 (d, J = 8.3 Hz, 1H), 3.99 (s, 3H), 1.40 (s, 10H). 13C NMR (75 MHz, CDCl3) δ (ppm): 177.49, 153.81, 129.46, 126.95, 126.01, 125.33, 122.82, 120.90, 103.46, 55.73, 39.66, 27.95. Melting point: 158°C HRMS (ESI):
184
3-METHOXY-N-TOSYL-2-NAPHTHAMIDE PALLADIUM COMPLEX (12)
12
C23H21N3O4PdS M = 541.92 g.mol-1
In a round bottom flask, 3-methoxy-N-tosyl-2-naphthamide (3) (100 mg, 0.281 mmol, 1.0 eq) and palladium acetate (6.59 mg, 0.310 mmol, 1.1 eq) were solubilized in methanol (1.7 mL, 0.17 M).After 19h of stirring at room temperature, the solvent was evaporated and substituted with MeCN (7.0 mL, 0.04 M) and the resulting mixture was stirred at room temperature for 20 minutes. After the removal of the solvent, the resulting brown powder was washed with Et2O and 3-methoxy-N-tosyl-2-naphthamide palladium complex (12) was obtained with a yield of 73%
1H NMR (300 MHz, CD3CN) δ (ppm): 8.17 – 8.07 (m, 1H), 8.00 – 7.83 (m, 2H), 7.66 – 7.57 (m, 1H), 7.43 (ddd, J = 8.1, 6.8, 1.3 Hz, 1H), 7.37 – 7.24 (m, 3H), 6.98 (s, 1H), 3.80 (s, 3H), 2.38 (s, 3H), 1.96 (s, 6H). 13C NMR (75 MHz, CD3CN) δ (ppm): 171.15, 154.85, 141.78, 140.95, 133.55, 131.03, 130.27, 128.39, 127.30, 127.06, 126.24, 122.34, 104.45, 54.62, 20.15, 19.30. HRMS (ESI):
185
1,3-DIMETHOXY-N-TOSYL-2-NAPHTHAMIDE (13)
13
C20H19NO5S M = 385.43 g.mol-1
1,3-dimethoxy-N-tosyl-2-naphthamide (13) was prepared from 3-methoxy-N-tosyl-2-naphthamide palladium complex (12) (34.5 mg, 0.055 mmol) and PIDA (18.3 mg, 0.055 mmol) in MeOH (500 µL) following the General procedure for the alkoxylation of naphthamides. The crude mixture was purified on preparative TLC (AcOEt/EP – 50/50) and the desired product was obtained as a yellow powder (10.0 mg, 41% yield). 1H NMR (300 MHz, CDCl3) δ (ppm): 8.07 (d, J = 8.0 Hz, 2H), 7.99 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 8.3 Hz, 1H), 7.50 (dd, J = 8.3, 6.9 Hz, 1H), 7.45 – 7.31 (m, 3H), 6.88 (s, 1H), 3.86 (s, 3H), 3.80 (s, 3H), 2.47 (s, 3H). 13C NMR (75 MHz, CDCl3) δ (ppm): 162.66, 156.31, 153.99, 144.99, 135.88, 135.78, 129.47, 128.75, 128.69, 126.95, 124.58, 123.12, 122.90, 116.23, 102.28, 63.59, 56.00, 21.75. HRMS (ESI):
186
3-METHOXY-1-(4-METHOXYPHENYL)-N-TOSYL-2-NAPHTHAMIDE (14)
14
C26H23NO5S M = 461.53 g.mol-1
In a round bottom flask flushed with argon, (4-methoxyphenyl)boronic acid (10.4 mg, 0.066 mmol, 1.2 eq) was added to a solution of 3-methoxy-N-tosyl-2-naphthamide palladium complex (12) (30.5 mg, 0.055 mol, 1.0 eq) and potassium carbonate (46.3 mg, 0.332 mmol, 6.0 eq) in anhydrous DMF (700 µL, 0.08 M) and stirred at 50°C, under an argon atmosphere, for 24h. The resulting mixture was diluted in AcOEt, washed with NaHCO3,sat and the combined organic layers were dried over MgSO4, and purified using column chromatography (DCM) to afford 3-methoxy-1-(4-methoxyphenyl)-N-tosyl-2-naphthamide (14) as a white powder (3.1 mg, 12% yield).
1H NMR (300 MHz, CD2Cl2) δ (ppm): 8.19 (s, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.70 (d, J = 8.3 Hz, 2H), 7.56 – 7.43 (m, 2H), 7.38 – 7.26 (m, 3H), 7.24 (s, 1H), 7.13 (d, J = 8.6 Hz, 2H), 6.81 (d, J = 8.7 Hz, 2H), 3.97 (s, 3H), 3.90 (s, 3H), 2.52 (s, 3H). 13C NMR (75 MHz, CD2Cl2) δ (ppm): 164.63, 159.81, 153.46, 145.38, 135.51, 131.39, 129.71, 128.56, 128.10, 127.32, 127.26, 124.91, 113.90, 105.92, 56.24, 55.52, 30.01, 21.82. HRMS (ESI):
187
3-(4-METHOXYPHENYL)-N-TOSYL-2-NAPHTHAMIDE (15)
15
C25H21NO4S M = 431.51 g.mol-1
3-(4-methoxyphenyl)-N-tosyl-2-naphthamide (15) was prepared from N-tosyl-2-naphthamide (1) (322.6 mg, 1.0 mmol), p-iodo anisole (468.01 mg, 2.0 mmol), palladium(II) acetate (22.5 mg, 0.1 mmol), silver(I) oxide (230.5 mg, 1.0 mmol) and potassium carbonate (554.0 mg, 4.0 mmol) in acetic acid (10.0 mL) following the General procedure for the arylation of naphthamides. The crude mixture was washed with pentane and the desired product was obtained as a brown powder (357.7 mg, 83% yield).
1H NMR (300 MHz, CD2Cl2) δ (ppm): 8.20 (s, 1H), 8.15 (s, 1H), 7.93 – 7.82 (m, 2H), 7.79 (d, J = 8.3 Hz, 2H), 7.76 (s, 1H), 7.64 – 7.50 (m, 2H), 7.33 (d, J = 8.1 Hz, 2H), 7.16 (d, J = 8.6 Hz, 2H), 6.79 (d, J = 8.6 Hz, 2H), 3.86 (s, 3H), 2.48 (s, 3H). 13C NMR (75 MHz, CD2Cl2) δ (ppm): 166.67, 159.97, 145.66, 136.49, 135.71, 134.80, 131.70, 131.60, 131.10, 130.37, 130.33, 130.04, 129.85, 128.91, 128.14, 127.41, 114.66, 55.71, 21.87. Melting point: 176°C HRMS (ESI):
188
3-(3-METHOXYPHENYL)-N-TOSYL-2-NAPHTHAMIDE (16)
16
C25H21NO4S M = 431.51 g.mol-1
3-(3-methoxyphenyl)-N-tosyl-2-naphthamide (16) was prepared from N-tosyl-2-naphthamide (1) (326.10 mg, 1.0 mmol), m-iodo anisole (238 µL, 2.0 mmol), palladium(II) acetate (25.8 mg, 0.1 mmol), silver(I) oxide (231.6 mg, 1.0 mmol) and potassium carbonate (555.0 mg, 4.0 mmol) in acetic acid (10.0 mL) following the General procedure for the arylation of naphthamides. The crude mixture was purified using column chromatography on silica gel (DCM/AcOEt – gradient from 99/1 to 90/10) and the desired product was obtained as a yellow powder (303.2 mg, 70% yield).
1H NMR (300 MHz, CDCl3) δ(ppm): 8.29 (s, 1H), 8.02 (s, 1H), 7.92 (d, J = 7.9 Hz, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.83 – 7.74 (m, 3H), 7.68 – 7.52 (m, 2H), 7.36 – 7.27 (m, 3H), 7.06 – 6.96 (m, 1H), 6.93 (d, J = 7.6 Hz, 1H), 6.86 – 6.80 (m, 1H). 13C NMR (75 MHz, CDCl3) δ (ppm): 166.11, 159.89, 144.93, 140.54, 136.17, 135.17, 134.31, 131.71, 130.86, 130.37, 130.31, 129.74, 129.45, 128.75, 128.70, 128.63, 127.85, 127.27, 121.04, 114.70, 113.87, 55.18, 21.74. Melting point: 113°C HRMS (ESI):
m/z: Calcd for C25H22NO4S [M+H]+: 432.1270; Found 432.1288.
Calculated data:
E(RB3LYP) = -1719.181966
Zero-point correction= 0.404736 (Hartree/Particle) Thermal correction to Energy= 0.432186
Thermal correction to Enthalpy= 0.433130
Thermal correction to Gibbs Free Energy= 0.342953 Sum of electronic and zero-point Energies= -1718.777230 Sum of electronic and thermal Energies= -1718.749780 Sum of electronic and thermal Enthalpies= -1718.748836 Sum of electronic and thermal Free Energies= -1718.839013
C 6.18512000 -2.64917500 -0.25454700 C 6.63160000 -1.35299700 -0.62074600 C 5.73702100 -0.30994900 -0.73001000 C 4.35321200 -0.51508400 -0.47550400 C 3.90275800 -1.82261700 -0.10845100
189 C 4.84991300 -2.87891600 -0.00358800 C 3.39543600 0.52554500 -0.58964000 C 2.04776300 0.32835600 -0.34206100 C 1.60851800 -0.97933900 0.06000100 C 2.52381300 -2.01459000 0.14820600 C 0.20664700 -1.35323600 0.47217700 O -0.24176900 -2.47764800 0.29149500 C 1.11296900 1.47100000 -0.57378600 C 1.26886700 2.65925100 0.14659800 C 0.42266500 3.75623900 -0.08624800 C -0.58570700 3.66759500 -1.05301600 C -0.73384400 2.47644600 -1.77516600 C 0.09646300 1.38377100 -1.54493900 N -0.52372800 -0.38107200 1.13610400 C -3.18617400 -0.99632800 0.55494500 C -3.90333000 0.04291000 -0.04040000 C -4.80864700 -0.26037500 -1.05803400 C -5.00739400 -1.58249000 -1.48269600 C -4.26920000 -2.60349900 -0.86178800 C -3.36009900 -2.32418000 0.15639900 C -6.00931500 -1.90969900 -2.56416700 S -2.05248300 -0.61279500 1.88576000 O -2.34674000 0.73576500 2.38513600 O -1.96952900 -1.75998100 2.78324200 O 0.66794900 4.85713600 0.68090900 C -0.17905100 5.99257400 0.53686100 H 6.90237200 -3.46036900 -0.17254800 H 7.68689400 -1.18547100 -0.81549500 H 6.07935900 0.68243300 -1.01132900 H 4.50236100 -3.86916400 0.27814800 H 3.73052100 1.50640300 -0.91626100 H 2.16546400 -2.99617600 0.44215100 H 2.03926200 2.75240400 0.90559200 H -1.24965100 4.50037200 -1.25035200 H -1.51203800 2.41024700 -2.53012100 H -0.02776100 0.47009700 -2.11760500 H -0.18195600 0.57048400 1.22809700 H -3.76256100 1.06311300 0.29910100 H -5.37470300 0.54293900 -1.52208000 H -4.40716200 -3.63377700 -1.17921400 H -2.78519100 -3.11066400 0.62973800 H -5.60117600 -2.63075400 -3.28000300 H -6.91473400 -2.35574300 -2.13464800 H -6.31082200 -1.01484000 -3.11571700 H 0.18808900 6.72798900 1.25332700 H -0.11897600 6.40979000 -0.47604500 H -1.22106600 5.74344300 0.77174000
190
3-(P-TOLYL)-N-TOSYL-2-NAPHTHAMIDE (17)
17
C25H21NO3S M = 415.50 g.mol-1
3-(p-tolyl)-N-tosyl-2-naphthamide (17) was prepared from N-tosyl-2-naphthamide (1) (70.0 mg, 0.215 mmol), p-iodo toluene (96.5 mg, 0.430 mmol), palladium(II) acetate (10.2 mg, 0.043 mmol), silver(I) oxide (51.2 mg, 0.215 mmol) and potassium carbonate (120.0 mg, 0.860 mmol) in acetic acid (2.15 mL) following the General procedure for the arylation of naphthamides. The crude mixture was purified using column chromatography on silica gel (DCM) and the desired product was obtained as a white powder (51.6 mg, 58% yield).
1H NMR (300 MHz, CD2Cl2) δ (ppm): 8.21 (s, 1H), 7.98 – 7.84 (m, J = 16.2, 7.4 Hz, 3H), 7.80 (d, J = 9.8 Hz, 3H), 7.67 – 7.53 (m, 2H), 7.38 (d, J = 8.2 Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 8.1 Hz, 2H), 2.50 (s, 3H), 2.43 (s, 3H). 13C NMR (75 MHz, CD2Cl2) δ (ppm): 166.47, 145.73, 138.40, 136.79, 136.53, 135.67, 134.82, 131.88, 131.15, 130.46, 130.16, 130.01, 129.85, 128.98, 128.21, 127.55, 21.89, 21.39. Melting point: 182°C HRMS (ESI):
191
3-(M-TOLYL)-N-TOSYL-2-NAPHTHAMIDE (18)
18
C25H21NO3S M = 415.50 g.mol-1
3-(m-tolyl)-N-tosyl-2-naphthamide (18) was prepared from N-tosyl-2-naphthamide (1) (326.0 mg, 1.0 mmol), m-iodo toluene (256 µL, 2.0 mmol), palladium(II) acetate (23.4 mg, 0.1 mmol), silver(I) oxide (232.1 mg, 1.0 mmol) and potassium carbonate (554.5 mg, 4.0 mmol) in acetic acid (10.0 mL) following the General procedure for the arylation of naphthamides. The crude mixture was purified using column chromatography on silica gel (DCM/AcOEt – gradient from 100/0 to 90/10) and the desired product was obtained as a white powder (254.4 mg, 61% yield).
1H NMR (300 MHz, CD2Cl2) δ (ppm): 8.20 (s, 1H), 8.14 (s, 1H), 7.94 – 7.83 (m, 2H), 7.78 (d, J = 8.7 Hz, 3H), 7.67 – 7.51 (m, 2H), 7.33 (d, J = 8.2 Hz, 2H), 7.28 – 7.12 (m, 3H), 7.04 (d, J = 7.3 Hz, 1H), 2.47 (s, 3H), 2.33 (s, 3H). 13C NMR (75 MHz, CD2Cl2) δ (ppm): 166.41, 145.64, 139.50, 139.23, 137.04, 135.76, 134.77, 131.89, 130.91, 130.65, 130.26, 130.04, 129.88, 129.21, 129.18, 129.00, 128.93, 128.85, 128.20, 127.56, 126.24, 21.84, 21.53. Melting point: 173°C HRMS (ESI):
m/z: Calcd for C25H22NO3S [M+H]+: 416.1320; Found 416.1329.
Calculated data:
E(RB3LYP) = -1643.965528
Zero-point correction= 0.399424 (Hartree/Particle) Thermal correction to Energy= 0.426171
Thermal correction to Enthalpy= 0.427115
Thermal correction to Gibbs Free Energy= 0.338855 Sum of electronic and zero-point Energies= -1643.566104 Sum of electronic and thermal Energies= -1643.539358 Sum of electronic and thermal Enthalpies= -1643.538414 Sum of electronic and thermal Free Energies= -1643.626673
C 6.46431100 -0.92301900 1.47117300 C 6.45638700 0.48987700 1.60246600 C 5.35998600 1.22291800 1.20203500 C 4.21756500 0.57607000 0.65479900
192 C 4.22725300 -0.84875200 0.52018700 C 5.37379500 -1.57772800 0.94127300 C 3.07571300 1.29311400 0.21416000 C 1.96075900 0.66661500 -0.31920600 C 1.96720800 -0.76650000 -0.41684500 C 3.08437800 -1.48253700 -0.02566000 C 0.81150700 -1.61238000 -0.89354400 O 0.96949100 -2.58878200 -1.60494400 C 0.84397100 1.51089500 -0.83559200 C 0.28778500 2.52185600 -0.03199300 C -0.72280300 3.37040800 -0.50506200 C -1.18552700 3.18535700 -1.81565100 C -0.64857700 2.18222300 -2.62650900 C 0.36049100 1.34850000 -2.14522400 C -1.27708600 4.47278100 0.36841500 N -0.43365800 -1.27157900 -0.36275700 C -3.04256600 -1.16671300 0.19949000 C -3.26663800 -1.70193200 1.47083100 C -4.16487400 -1.06207000 2.32285100 C -4.84713700 0.09853800 1.92158400 C -4.60233400 0.60875400 0.63779700 C -3.70664500 -0.01672700 -0.23070100 C -5.84724700 0.75982100 2.83944000 S -1.90757300 -2.00230000 -0.91269600 O -1.85928800 -3.41994000 -0.56579300 O -2.18580600 -1.56119900 -2.28154100 H 7.33620400 -1.48661300 1.78961700 H 7.32304500 0.99363900 2.02052800 H 5.35578200 2.30543900 1.29938200 H 5.37536300 -2.65936400 0.83705300 H 3.09733700 2.37869800 0.25989100 H 3.07122100 -2.56335400 -0.12950400 H 0.64719100 2.64060200 0.98759800 H -1.97159300 3.82877200 -2.20348600 H -1.01798600 2.04649900 -3.63862000 H 0.77752200 0.57819700 -2.78682000 H -0.72240500 5.40776500 0.21938400 H -2.32691000 4.67750000 0.13648600 H -1.20693300 4.21656000 1.42998200 H -0.55487600 -0.33694100 0.01505700 H -2.75435700 -2.60845000 1.77521300 H -4.34462900 -1.47418200 3.31225000 H -5.12383400 1.50348300 0.30845200 H -3.53052700 0.37025100 -1.22866400 H -5.54677800 0.67241500 3.88794100 H -5.96603200 1.82136100 2.60412100 H -6.83326000 0.28871700 2.74171600
193
3-(3,5-DIMETHYLPHENYL)-N-TOSYL-2-NAPHTHAMIDE (19)
19
C26H23NO3S M = 429.53 g.mol-1
3-(3,5-dimethylphenyl)-N-tosyl-2-naphthamide (19) was prepared from N-tosyl-2-naphthamide (1) (326.5 mg, 1.0 mmol), 1-iodo-3,5-dimethylbenzene (290 µL, 2.0 mmol), palladium(II) acetate (24.2 mg, 0.1 mmol), silver(I) oxide (232.3 mg, 1.0 mmol) and potassium carbonate (551.5 mg, 4.0 mmol) in acetic acid (10.0 mL) following the General procedure for the arylation of naphthamides. The crude mixture was purified using column chromatography on silica gel (DCM/AcOEt – gradient from 100/0 to 90/10) and the desired product was obtained as a pale yellow powder (368.6 mg, 71% yield).
1H NMR (300 MHz, CD2Cl2) δ (ppm): 8.22 (s, 1H), 8.16 (s, 1H), 7.88 (dd, J = 11.6, 8.1 Hz, 2H), 7.82 – 7.74 (m, 3H), 7.65 – 7.51 (m, 2H), 7.33 (d, J = 8.2 Hz, 2H), 7.09 (s, 1H), 6.95 (s, 2H), 2.46 (s, 3H), 2.30 (s, 6H). 13C NMR (75 MHz, CD2Cl2) δ (ppm): 166.38, 145.56, 139.49, 139.09, 137.23, 135.95, 134.79, 131.89, 130.82, 130.20, 130.17, 129.91, 128.98, 128.73, 128.16, 127.48, 127.15, 21.83, 21.42. Melting point: 186°C HRMS (ESI):