C O M M U N I C A T I O N S
Table 2. Diversity of PhP(catechyl) Mediated Pyrrole Synthesisa
challenge in employing 1,3-dipolar cycloaddition to construct
heterocycles (e.g., with M u¨ nchnones), which often generate mix-
tures of isomers. In contrast, these phosphorus-based reagents have
2
5
a large steric discrimination between the carbons at R and R due
to the PR unit. This can allow, for example, the selective synthesis
of isomeric 2,5-substituted pyrroles simply by choice of the correct
3
1
2
imine and acid chloride (entries 2, 3, 7, and 11). Overall,
considering the accessibility, generality, and selectivity of 2, this
provides a straightforward pyrrole synthesis, where any of the five
substituents can be selectively modified.
In conclusion, a new class of 1,3-cycloaddition substrate can be
synthesized from phosphonites, imines, and acid chlorides. These
substrates undergo cycloaddition in a similar fashion to classic 1,3-
dipoles, yet can be generated in a one-pot, modular fashion from
available reagents, suggesting their potential utility in the synthesis
of various heterocycles. Experiments directed toward the latter are
underway.
Acknowledgment. We thank NSERC, FQRNT, and the CFI
for their financial support.
Supporting Information Available: Synthesis of 2 and pyrroles.
This material is available free of charge via the Internet at http://
pubs.acs.org.
References
(
1) (a) Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward
Heterocycles and Natural Products; Padwa, A., William, W. H., Eds.;
Wiley: New York, 2002; Vol. 59. (b) 1,3-Dipolar Cycloaddition
Chemistry; Padwa, A., Ed.; Wiley: New York, 1984; Vol. 1.
(
2) (a) Gribble, G. W. In Oxazoles: Synthesis, Reactions, and Spectroscopy,
A; Palmer, D. C., Ed.; Wiley: New York, 2003; Vol. 60. (b) Gingrich,
H. L.; Baum, J. S. In Oxazoles, Chemistry of Heterocyclic Compounds;
Turchi, I. J., Ed.; Wiley: New York, 1986; Vol. 45.
(
3) (a) Merlic, C. A.; Baur, A.; Aldrich, C. C. J. Am. Chem. Soc. 2000, 122,
7
398. (b) Alper, H.; Tanaka, M. J. Am. Chem. Soc. 1979, 101, 4245.
(
4) (a) Dhawan, R.; Arndtsen, B. A. J. Am. Chem. Soc. 2004, 126, 468. (b)
Dhawan, R.; Dghaym, R.; Arndtsen, B. A. J. Am. Chem. Soc. 2003, 125,
1
4
474. (c) St. Cyr, D. J.; Martin, N.; Arndtsen, B. A. Org. Lett. 2007, 9,
49.
(
5) Kolodiazhnyi, O. I. Phosphorus Ylides: Chemistry and Application in
Organic Synthesis; Wiley-VCH: Weinheim, Germany, 1999.
5
(6) Wittig reagents have been found to react with 1,3-dipoles. In addition,
for the closest related example, a trifluoromethyl-substituted [1,4,2]-
oxazaphospholine has been shown to behave as a dipole precursor (Burger,
K.; Fehn, J.; Moll, E. Chem. Ber. 1971, 104, 1826). However, a simple
phosphorus ylide (e.g., 2′) has not been used as a 1,3-dipole.
a
Table 1 procedure. b LiHMDS at -78 °C. c Imine/acid chloride at -78
d
°
C; AgOTf (1 equiv) added. Imine/acid chloride/PR3 for 16 h prior to
base. At 50 °C. For 33 h.
e
f
(
7) All other data are consistent with the structure shown, including an upfield
3
1
8
P NMR signal (δ -16.9, Handbook of Phosphorus-31 NMR Data;
bipyramidal structure, at least as a reactive intermediate. Overall,
Tebby, J. C., Ed.; CRC Press: Boston, 1991). Nevertheless, a Wittig-
type 2b′ cannot be ruled out, with the reactive form as the 1,3-dipole 2b.
this can allow the rapid intramolecular abstraction of oxygen from
the former acid chloride unit upon reaction with dipolarophiles.
These cycloaddition reagents 2 are both easily generated and
(8) For example: Denmark, S. E.; Sweis, R. F. Acc. Chem. Res. 2002, 35,
35.
8
(
9) PhP(catechyl) can be generated in one step from commercial materials;
see Supporting Information.
9
formed from available materials. As such, they provide the potential
to access heterocyclic products in a modular fashion. These are
illustrated in Table 2, where the formation of 2 and its cycloaddition
has been used to design a one-pot, phosphonite-mediated coupling
of imines, acid chlorides, and alkynes to synthesize pyrroles.10 As
shown, in addition to the reagents employed in Table 1, these 1,3-
dipoles can be generated with an array of imines and acid chlorides.
This includes stabilized C-aromatic and -heteroaromatic imines, as
well as less stable enolizable and formaldehyde-based substrates
(10) Recent pyrrole syntheses: (a) Beck, E. M.; Grimster, N. P.; Hatley, R.;
Gaunt, M. J. J. Am. Chem. Soc. 2006, 128, 2528. (b) Gorin, D. J.; Davis,
N. R.; Toste, R. D. J. Am. Chem. Soc. 2005, 127, 11260. (c) Rivero, M.
R.; Buchwald, S. L. Org. Lett. 2007, 9, 973. (d) Galliford, C. V.; Scheidt,
K. A. J. Org. Chem. 2007, 72, 1811. (e) Shindo, M.; Yoshimura, Y.;
Hayashi, M.; Soejima, H.; Yoshikawa, T.; Matsumoto, K.; Shishido, K.
Org. Lett. 2007, 9, 1963. (f) Yamamoto, Y.; Hayashi, H.; Saigoku, T.;
Nishiyama, H. J. Am. Chem. Soc. 2005, 127, 10804. (g) Binder, J. T.;
Kirsch, S. F. Org. Lett. 2006, 8, 2151. (h) Lu, L.; Chen, G.; Ma, S. Org.
Lett. 2006, 8, 835. (i) Crawley, M. L.; Goljer, I.; Jenkins, D. J.; Mehlmann,
J. F.; Nogle, L.; Dooley, R.; Mahaney, P. E. Org. Lett. 2006, 8, 5837. (j)
Harrison, T. J.; Kozak, J. A.; Corbella-Pane, M.; Dake, G. R. J. Org.
Chem. 2006, 71, 4525. (k) Hiroya, K.; Matsumoto, S.; Ashikawa, M.;
Ogiwara, K.; Sakamoto, T. Org. Lett. 2006, 8, 5349. (l) Tejedor, D.;
Gonzalez-Cruz, D.; Garcia-Tellado, F.; Marrero-Tellado, J. J.; Rodriguez,
M. L. J. Am. Chem. Soc. 2004, 126, 8390. (m) Ramanathan, B.; Keith,
A. J.; Armstrong, D.; Odom, A. L. Org. Lett. 2004, 6, 2957. (n) Wurz, R.
P.; Charette, A. B. Org. Lett. 2005, 7, 2313.
(
entries 5 and 6).11 A similar range of substituents can be used on
the acid chloride, while alkyl, aryl, and common protecting groups
can be incorporated onto the nitrogen. The cycloaddition capability
of 2 also appears to be broad, with electron-poor and even the more
electron-rich alkynes (acetylene, propargyl ethers) generating
pyrrole, albeit in lower yield, as well as chloroalkenes. Together,
this can allow the build up of diverse families of pyrroles.
Interestingly, these reagents also show a high regioselectivity
upon reaction with unsymmetrical alkynes. The latter can be a
(11) In contrast, the palladium-catalyzed pyrrole synthesis from these reagents
is limited to stabilized imines and acid chlorides (ref 4a).
(12) A 2:1 mixture of these pyrroles is generated via M u¨ nchnones.
JA074330W
J. AM. CHEM. SOC.
9
VOL. 129, NO. 41, 2007 12367