A High-Yield, General Method for the Catalytic Formation of Oxygen Heterocycles

Full text of DOI:10.1021/ja005698v

J. Am. Chem. Soc. 2000, 122, 12907-12908
12907
Scheme 1
A High-Yield, General Method for the Catalytic
Formation of Oxygen Heterocycles
Karen E. Torraca, Shin-Itsu Kuwabe, and
Stephen L. Buchwald*
Department of Chemistry
Massachusetts Institute of Technology
Cambridge, Massachusetts 02139
ReceiVed October 16, 2000
Table 1. Palladium-Catalyzed Synthesis of Cyclic Aryl Ethers
Several years ago we reported on the intramolecular cyclization
of tertiary alcohols to form five- and six-membered oxygen
heterocycles (Scheme 1).1,2 The optimal cyclization conditions
involved the use of either DPPF or Tol-BINAP as the bidentate
ligand, K2CO3 or NaOt-Bu as the base, and toluene as the solvent
at 80-100 °C. Application of this method for the cyclization of
primary and secondary alcohol substrates was largely unsuccessful
due to the formation of the debrominated ketone or aldehyde B.
For example, efforts to cyclize 2-bromophenethyl alcohol under
these conditions resulted in the formation of phenylacetaldehyde
as the major product. To overcome this problem it was necessary
to discover a new ligand that would interchange the relative rates
of reductive elimination and â-hydride elimination of the key
intermediate A.
We recently showed that bulky, electron-rich o-biphenyl
phosphines were effective in a variety of Pd-catalyzed cross-
coupling reactions.3 Attempts were made to apply these and
related ligands to cyclize 2-bromophenethyl alcohol and it was
found that the ligands containing a di-tert-butylphosphino moiety
tended to be much more effective than others. The most general
catalyst system found was the binaphthyl ligand 1. In addition,
both a novel phenanthrene-based ligand 2 and dimethylamino-
phosphine 3 were found to be useful in many cases. Our
previously reported ligand, commercially available 2-di-tert-
a Reaction conditions: 2-3 mol % Pd(OAc)2, 1.5 equiv of Cs2CO3,
2.5-3.5 mol % ligand 1 in toluene. Yields in parentheses were obtained
by using 4 and were carried out at 80 °C. b Yields refer to average
isolated yields of 2 runs.
(1) Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1996,
118, 10333-10334.
butylphosphinobiphenyl (4), could be successfully employed in
several instances, but catalysts based on it were less generally
effective than the others.
(2) For recent reports on palladium-catalyzed C-O bond formation, see:
(a) Aranyos, A.; Old, D. W.; Kiyomori, A.; Wolfe, J. P.; Sadighi, J. P.;
Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 4369-4378. (b) Mann, G.;
Incarvito, C.; Rheingold, A.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121,
3224-3225. (c) Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem.
Soc. 1997, 119, 3395-3396. (d) Mann, G.; Hartwig, J. F. Tetrahedron Lett.
1997, 38, 8005-8008. (e) Mann, G.; Hartwig, J. F. J. Am. Chem. Soc. 1996,
118, 13109-13110. For examples of copper-catalyzed C-O bond formation,
see: (f) Zhu, J.; Price, B. A.; Zhao, S. X.; Skonezny, P. M. Tetrahedron Lett.
2000, 41, 4011-4014 and references therein. (g) Fagan, P. J.; Hauptman, E.;
Shapiro, R.; Casalnuovo, A. J. Am. Chem. Soc. 2000, 122, 5043-5051 and
references therein. (h) Watanabe, M.; Nishiyama, M.; Koie, Y. Tetrahedron
Lett. 1999, 40, 8837-8840 and references therein. (i) Marcoux, J. F.; Doye,
S.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 10539-10540 and references
therein. (j) Lee, S.; Frescas, S. P.; Nichols, D. E. Synth. Commun. 1995, 25,
2775-2780 and references therein.
As shown in Table 1, five-, six- and seven-membered oxygen
heterocycles were formed in good yield. Both aryl bromides and
aryl chlorides were effectively transformed, although reactions
of aryl bromides were more rapid and proceeded more cleanly
than those of the corresponding aryl chlorides. Primary alcohols
cyclized more easily than secondary alcohols which required
higher temperatures and higher quantities of catalyst to go to
completion.
The most general catalyst system was that derived from the
novel binaphthyl ligand, 1. Reactions using 1 also proceeded at
consistently lower temperatures than when other ligands were
employed. While 4 was efficient for the cyclization of primary
and secondary alcohols to five- and six-membered heterocycles,
its use for the cyclization to seven-membered oxocycles was
ineffective.
(3) For C-N coupling reactions employing these ligands, see: (a) Harris,
M. C.; Buchwald, S. L. J. Org. Chem. 2000, 65, 5327-5333. (b) Zhang, X.
X.; Sadighi, J. P.; Mackewitz, T. W.; Buchwald, S. L. J. Am. Chem. Soc.
2000, 122, 7606-7607. (c) Plante, O. J.; Buchwald, S. L.; Seeberger, P. H.
J. Am. Chem. Soc. 2000, 122, 7148-7149. (d) Old, D. W.; Harris, M. C.;
Buchwald, S. L. Org. Lett. 2000, 2, 1403-1406. (e) Wolfe, J. P.; Tomori,
H.; Sadighi, J. P.; Yin, J. J.; Buchwald, S. L. J. Org. Chem. 2000, 65, 1158-
1174. (f) Wolfe, J. P.; Buchwald, S. L. Angew. Chem., Int. Ed. 1999, 38,
2413-2416. (g) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc.
1998, 120, 9722-9723. For C-O coupling reactions employing these ligands,
see ref 2a. For R-arylation of ketones employing these ligands, see: (h) Fox,
J. M.; Huang, X. H.; Chieffi, A.; Buchwald, S. L. J. Am. Chem. Soc. 2000,
122, 1360-1370. For C-C coupling reactions employing these ligands, see:
(i) Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J. Am. Chem.
Soc. 1999, 121, 9550-9561. (j) Wolfe, J. P.; Buchwald, S. L. Angew. Chem.,
Int. Ed. 1999, 38, 2413-2416. For the synthesis of these ligands, see: (k)
Tomori, H.; Fox, J. M.; Buchwald, S. L. J. Org. Chem. 2000, 65, 5334-
5341.
10.1021/ja005698v CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/06/2000

12908 J. Am. Chem. Soc., Vol. 122, No. 51, 2000
Table 2. Palladium-Catalyzed Synthesis of Heterocycles
Communications to the Editor
Scheme 2
Scheme 3
a Reaction conditions: 2 mol % Pd(OAc)2, 1.5 equiv of Cs2CO3,
2.5 mol % ligand in toluene. b Yields refer to average isolated yields
of 2 runs.
A major incentive for this work was the preparation of
heterocycles that contain multiple heteroatoms in the ring that is
undergoing construction. The importance of such compounds is
apparent from their numerous applications.4,5 As such, we
undertook a study to ascertain whether our newly developed
process could be applied to the synthesis of this type of
heterocycle. As is evident from the results presented in Table 2,
the method is effective in a number of instances.
In addition, as shown in Scheme 2, we were able to cyclize
optically active alcohols to optically active cyclic ethers with
complete conservation of enantiomeric purity. In the case of
reaction 2, the use of higher temperatures or less catalyst led to
formation of product with a decreased ee. Presumably this occurs
by a pathway analogous to the situation in the related C-N bond-
forming process.6
An important issue in this work was the development of ligands
for which kr.e. . kâ-H (Scheme 3). It is interesting to note that
with L ) 4 for n ) 1, 2 this requirement is met, but not when
n ) 3. In the latter case the intermediate is an eight-membered
palladacycle. These results are in accord with previous work in
which â-hydride elimination shows a strong dependence on the
ring size of the metallacycle.7 In the case of larger metallacycles,
the energy price paid to achieve the necessary conformation for
â-hydride elimination is considerably reduced.
In conclusion, we have developed a palladium-catalyzed
synthesis of aryl ethers involving primary and secondary alcohols.
In addition, cyclization of enantiopure alcohols results in cycliza-
tion without racemization under these reaction conditions. Further
studies are underway to extend the scope of these and related
metal-catalyzed processes and to ascertain the reasons for the
special efficacy of catalyst systems employing 1.
(4) For recent reports involving 1,4-benzodioxane derivatives, see: (a)
Czompa, A.; Dinya, Z.; Antus, S.; Varga, Z. Arch. Pharm. 2000, 333, 175-
180. (b) Gu, W. X.; Jing, X. B.; Pan, X. F.; Chan, A. S. C.; Yang, T. K.
Tetrahedron Lett. 2000, 41, 6079-6082. (c) Ward, R. S. Nat. Prod. Rep. 1999,
16, 75-96. (d) Bolognesi, M. L.; Budriesi, R.; Cavalli, A.; Chiarini, A.; Gotti,
R.; Leonardi, A.; Minarini, A.; Poggesi, E.; Recanatini, M.; Rosini, M.;
Tumiatti, V.; Melchiorre, C. J. Med. Chem. 1999, 42, 4214-4224.
(5) For recent reports involving 1,4-benzoxazine derivatives, see: (a)
Matsumoto, Y.; Uchida, W.; Nakahara, H.; Yanagisawa, I.; Shibanuma, T.;
Nohira, H. Chem. Pharm. Bull. 2000, 48, 428-432. (b) Kuroita, T.;
Marubayashi, N.; Sano, M.; Kanzaki, K.; Inaba, K.; Kawakita, T. Chem.
Pharm. Bull. 1996, 44, 2051-2060. (c) Largeron, M.; Lockhart, B.; Pfeiffer,
B.; Fleury, M. J. Med. Chem. 1999, 42, 5043-5052. (d) Buon, C.; Chacun-
Lefevre, L.; Rabot, R.; Bouyssou, P.; Coudert, G. Tetrahedron 2000, 56, 605-
614. (e) Bourlot, A.; Sa´nchez, I.; Dureng, G.; Guillaumet, G.; Massingham,
R.; Monteil, A.; Winslow, E.; Pujol, M. D.; Me´rour, J. J. Med. Chem. 1998,
41, 3142-3158.
Acknowledgment. We gratefully acknowledge the National Institute
of Health (GM58160) for financial support of this work. We also thank
Pfizer and Merck for additional unrestricted funds. K.E.T. thanks the NIH
for a postdoctoral fellowship (GM20346), and S.K. thanks Ono Phar-
maceutical for support. We are grateful to Prof. Eric N. Jacobsen for
helpful discussions.
Supporting Information Available: Complete experimental proce-
dures and spectral data for ligands 1 and 2 and the compounds listed in
Tables 1 and 2 and Scheme 2 (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
JA005698V
(6) Wagaw, S.; Rennels, R. A.; Buchwald, S. L. J. Am. Chem. Soc. 1997,
119, 8451-8458.
(7) McDermott, J. X.; White, J. F.; Whitesides, G. M. J. Am. Chem. Soc.
1976, 98, 6521-6528.