placement of fluoride by phenoxides in the preparation of
thermally stable polymers.4
Table 1. Intramolecular Replacement of the
Benzimidazole-Activated Nitro Groupa
Although the nitro group is most frequently utilized to
activate SNAr reactions in fluoroarenes, a wide range of
electron-withdrawing substituents5,6 (e.g., -CF3,6a,b -NO2,6c-e
-CN,6f -COR,6e -CO2R,6f etc.) have been reported to
facilitate its replacement.
Various electron-withdrawing heterocyclic functionalities7
(e.g., oxadiazoles,7a benzoxazoles,7b benzothiazoles,7c triazoles,7d
phenylquinoxalines,7e,f triazines,7g etc.), that are also capable
of stabilizing the negative charge developed during SNAr
reactions (Meisenheimer complex), have been successfully
used as activating groups (especially for fluoride).
The new transformation depicted in Scheme 1 proved to
be quite general, and a series of structurally diverse analogues
of alcohol 18 were shown to be competent substrates (Table
1).9 As can be noted, the steric hindrance on the nucleophilic
arm is well tolerated, and both moderately (entries 1 and 2)
and severely (entries 3-6) sterically hindered secondary
alcohols undergo the cyclization in high yield. In addition,
tertiary alcohol 14 (entry 7) undergoes a smooth nitro group
displacement to give the cyclized product 15 in good yield.
Substitution ortho to the nitro group, however, gives mixed
results. Although the nitro group in benzimidazole 16 (entry
8) undergoes the displacement with high yield, replacement
of the chloro substituent with a methyl group (entry 9) has
a detrimental effect on the yield of the cyclized product 19.
This result can be attributed to both the unfavorable steric
(3) (a) Pratt, W. B. Chemotherapy of Infection; Oxford University
Press: New York, 1977. (b) White, A. W.; Almassy, R.; Calvert, A. H.;
Curtin, N. J.; Griffin, R. J.; Hostomsky, Z.; Maegley, K.; Newell, D. R.;
Srinivasan, S.; Golding, B. T. J. Med. Chem. 2000, 43, 4084-4097. (c)
Bostock-Smith, C. E.; Searle, M. S. Nucleic Acid Res. 1999, 27, 1619-
1624. (d) Roth, T.; Morningstar, M. L.; Boyer, P. L.; Hughes, S. H.;
Buckheit, Jr., R. W.; Michejda, C. J. J. Med. Chem. 1997, 40, 4199-4207.
(4) Twieg, R.; Matray, T.; Hedrick, J. L. Macromolecules 1996, 29,
7335-7341.
(5) For a review on SNAr of the nitro group, see: Beck, J. R. Tetrahedron
1978, 34, 2057-2068.
a Reactions were performed in DMF in the presence of NaH (1.1 equiv).
For details, see Supporting Information. b Isolated yield of spectroscopically
(1H NMR) pure products.
(6) (a) Chung, I. S.; Kim, S. Y. J. Am. Chem. Soc. 2001, 123, 11071-
11072. (b) Park, S. K.; Kim, S. Y. Macromolecules 1998, 31, 3385-3387.
(c) Kornblum, N.; Cheng, L.; Kerber, R. C.; Kestner, M. M.; Newton, B.
N.; Pinnick, H. W.; Smith, R. G.; Wade, P. A. J. Org. Chem. 1976, 41,
1560-1564. (d) Zlotin, S. G.; Kislitsin, P. G.; Samet, A. V.; Serebryakov,
E. A.; Konyushkin, L. D.; Semenov, V. V.; Buchanan, A. C., III; Gakh, A.
A. J. Org. Chem. 2000, 65, 8430-8438. (e) Knudsen, R. D.; Snyder, H. R.
J. Org. Chem. 1974, 39, 3343-3346. (f) Beck, J. R. J. Org. Chem. 1973,
38, 4086-4087.
and electronic contributions of the methyl group that hinders
formation of the intermediate Meisenheimer complex and
also decreases its stability.
(7) (a) Hedrick, J. L.; Twieg, R. Macromolecules 1992, 25, 2021-2025.
(b) Hilborn, J. G.; Labadie, J. W.; Hedrick, J. L. Macromolecules 1990,
23, 2854-2861. (c) Hedrick, J. L. Macromolecules 1991, 24, 6361-6364.
(d) Carter, K. R.; Miller, R. D.; Hedrick, J. L. Macromolecules 1993, 26,
6, 2209-2215. (e) Hedrick, J.; Twieg, R, Matray, T.; Carter, K. Macro-
molecules 1993, 26, 4833-4839. (f) Hedrick, J. L.; Labadie, J. W.
Macromolecules 1990, 23, 1561-1568. (g) Fink, R.; Frenz, C.; Thelakkat,
M.; Schmidt, H.-W. Macromolecules 1997, 30, 8177-8181.
(8) Most of the alcohols used in these studies were prepared by the Cu-
(OTf)2-catalyzed ring opening of epoxides with 1-unsubstituted benzimi-
dazoles. This reaction had previously been successfully applied to the
epoxide ring opening with poorly nucleophilic nitroanilines; see: Sekar,
G.; Singh, V. K. J. Org. Chem. 1999, 64, 287-289.
(9) Typical Experimental Procedure (Table 1, entry 3). To a solution
of alcohol 8 (100 mg, 0.29 mmol) in anhydrous DMF (2 mL) was added
NaH (60% w/w, 12.8 mg, 0.32 mmol) to give a dark-green solution. After
11 h at room temperature, the reaction mixture was quenched with water
and diluted with EtOAc. The organic phase was washed repeatedly with
water, dried (MgSO4), and evaporated in vacuo to give a yellow solid.
Purification by flash chromatography (silica gel, CH2Cl2 f CH2Cl2/EtOAc
(10/1)) gave the title compound 9 (74 mg, 86%) as a white solid.
Single crystals of the cyclic ether 9 suitable for X-ray
analysis were grown by slow evaporation of its CH2Cl2-
petroleum ether solution. As anticipated (Figure 1), the three-
atom bridge spanning the two aromatic subunits forces them
into a nearly perfect coplanarity (the dihedral angle N2-
C7-C8-C9: 1.4 and 10.9°, respectively, for the two enan-
tiomeric molecules in the asymmetric unit). This conforma-
tional constraint, common to all the studied seven-membered
1
cyclization products, has a marked effect on the H NMR
chemical shift of the aromatic proton located ortho to the
aryl-heteroaryl axis.10 As this proton is placed directly within
1
(10) For a recent controversy concerning the ring current effects on H
NMR chemical shifts, see: Wannere, C. S.; Schleyer, P. v. R. Org. Lett.
2003, 5, 605-608.
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