readily obtained acceptor substituted propargyl vinyl ethers
1 and aromatic amines 2 are used as starting materials to
produce pyrrole products 3 with high diversity (Scheme 1).
Table 1. Survey of Amines for Pyrrole Synthesisa
Scheme 1. Synthesis of Pyrrole 3 from Propargyl Vinyl Ether
1 and Amine 2
During the envisioned process, three independent reactions
should occur sequentially: a catalytic version of a propargyl-
Claisen rearrangement8,9 to generate allenic ketones, a
condensation with a primary amine,10 and a transition-metal-
catalyzed 5-exo-dig cyclization.7 To realize a single-step
process by subsequent addition of reactants and catalysts,11
we first developed the silver(I)-catalyzed rearrangement route
to the intermediary occurring allenylcarbonyl compounds.
Treatment of propargyl vinyl ethers 1 with several silver(I)
salts at room temperature produced an isomeric mixture of
the corresponding allenes in a remarkably clean reaction. By
far, the best catalyst was AgSbF6, which provided the
rearrangement products rapidly in CH2Cl2. The reaction takes
place at room temperature without the formation of signifi-
cant amounts of any byproducts. Of primary importance, the
a Conditions: (1) 0.2 mmol of 1a, 5 mol % of AgSbF6, 23 °C, CH2Cl2
(0.4 M), 30 min; (2) R4-NH2 (1.5 equiv), 23 °C; (3) 5 mol % (PPh3)AuCl,
38 °C. b Reaction time for the cyclization (step 3). c Yield of pure product
after column chromatography. d Reaction of 1a with 0.5 equiv of 1,4-
phenylenediamine (2k).
slowed markedly when carried out at room temperature. In
the absence of the catalyst, pyrrole formation was not
observed under these conditions. While (PPh3)AuCl was
unreactive, the presence of AgSbF6 in the reaction mixture
led to activation of the Au(I) catalyst by changing the
counterion from chloride to hexafluoroantimonate. With
optimized reaction conditions in hand [(1) substrate 1, 5 mol
% of AgSbF6, 23 °C, 30 min, CH2Cl2 (0.4 M); (2) R4-NH2,
23 °C; (3) 5 mol % of (PPh3)AuCl, 38 °C], pentasubstituted
pyrroles 3a were formed in a one-pot reaction in good yields
from propargyl vinyl ether 1a with R4 being aryl and
heteroaryl substituents (Table 1).15 Unfortunately, reaction
with aliphatic amines (R4 ) Me, iPr, Bn) did not provide
the corresponding pyrroles.
The scope of this domino approach to substituted pyrroles
is summarized in Table 2. A broad variety of propargyl vinyl
ethers 1 with different substituents R1 and R2 was effectively
converted into the corresponding pyrroles. The reaction
tolerated substitution of the substrate with R1 and R2 being
both phenyl and alkyl groups.
1
corresponding furans7 were not seen by H NMR analysis
of crude reaction mixtures. Low catalyst loadings (1-5 mol
%) are sufficient to effect rearrangement in almost quantita-
tive yield.
As the next step, we attempted to combine the Ag(I)-
catalyzed propargyl-Claisen rearrangement with condensation
and heterocyclization.12 After formation of the corresponding
allenylcarbonyl compound from propargyl vinyl ether 1a (R1
) Ph, R2 ) Me, R3 ) H, Y ) OEt), using 5 mol % of
AgSbF6 in CH2Cl2, 1.5 equiv of aniline was added directly
to the reaction mixture followed by 5 mol % of (PPh3)AuCl
to provide pyrrole 3aa in 71% yield after 30 min at 38 °C
(Table 1, entry 1).13,14 The Au(I)-catalyzed cyclization was
(8) Overman, L. E. Angew. Chem., Int. Ed. Engl. 1984, 23, 579.
(9) For a single example of a Ag(I)-catalyzed rearrangement, see: (a)
Grissom, J. W.; Klingberg, D.; Huang, D.; Slattery, B. J. J. Org. Chem.
1997, 62, 603. For a single example of a Au(I)-catalyzed rearrangement,
see: (b) Sherry, B. D.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 15978.
(10) Arcadi, A.; Di Giuseppe, S.; Marinelli, F.; Rossi, E. AdV. Synth.
Catal. 2001, 343, 443.
(11) By performing these steps simultaneously, treatment of a preformed
mixture of 1 and 2 with a variety of transition-metal complexes gave only
traces of the desired pyrroles 3 (<5% yield).
(12) For reviews on the cyclization of allenes, see: (a) Bates, R. W.;
Satcharoen, V. Chem. Soc. ReV. 2002, 31, 12. (b) Hashmi, A. S. K. In
Modern Allene Chemistry; Krause, N., Hashmi, A. S. K., Eds.: Wiley-
VCH: Weinheim, Germany, 2004; p 877.
(13) For reviews on gold catalysis, see: (a) Hashmi, A. S. K. Gold Bull.
2003, 36, 3. (b) Hashmi, A. S. K. Gold Bull. 2004, 37, 51. (c) Hoffmann-
Ro¨der, A.; Krause, N. Org. Biomol. Chem. 2005, 3, 387. (d) Hashmi, A. S.
K. Angew. Chem., Int. Ed. 2005, 42, 6990.
(15) General Procedure. Synthesis of 3af: AgSbF6 (3.4 mg, 5 mol %)
was added to a solution of 1a (50 mg, 0.20 mmol) in CH2Cl2 (0.5 mL),
and the reaction vial was sealed, protected from light, and stirred at room
temperature for 10 min. Then, 3-chloroaniline (39.2 mg, 0.31 mmol, 1.5
equiv) and (Ph3P)AuCl (5.1 mg, 5 mol %) were added subsequently. The
dark reaction mixture was stirred at 38 °C for 1 h (until TLC analysis
indicated complete conversion). The mixture was concentrated under reduced
pressure. Purification of the residue by flash chromatography on neutral
Al2O3 (P/EtOAc ) 98/2) gave pyrrole 3af as a colorless solid (59.0 mg,
0.17 mmol, 83%). Rf 0.73 (P/EtOAc ) 80/20); 1H NMR (360 MHz, CDCl3)
δ 1.04 (t, J ) 7.2 Hz, 3 H), 2.01 (s, 3 H), 2.31 (s, 3 H), 4.08 (q, J ) 7.2
Hz, 2 H), 6.88-6.90 (m, 1 H), 7.05-7.06 (m, 1 H), 7.09-7.12 (m, 2 H),
7.15-7.24 (m, 5 H); 13C NMR (90.6 MHz, CDCl3) δ 10.7, 11.1, 14.1,
59.4, 113.4, 117.2, 127.1, 127.2, 127.5, 127.6, 128.2, 129.1, 129.8, 131.2,
132.5, 134.4, 137.9, 139.6, 165.8; IR (cm-1) 2924 (m), 1700 (vs), 1592
(m), 1481 (s), 1380 (m), 1259 (m), 1147 (s), 1069 (m); LRMS (EI) 353
(100%) [M+], 324 (26%), 308 (26%), 280 (8%), 244 (15%), 152 (12%);
HRMS 353.1182 [353.1183 calcd for C21H20NO2Cl (M+)].
(14) For selected examples on gold-catalyzed cyclizations of allenes,
see: (a) Hashmi, A. S. K.; Schwarz, L.; Choi, J.-H.; Frost, T. M. Angew.
Chem., Int. Ed. 2000, 39, 2285. (b) Morita, N.; Krause, N. Org. Lett. 2004,
6, 4121.
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