Synthesis of pyrroles by gold(I)-catalyzed amino-claisen rearrangement of N-propargyl enaminone derivatives

Article abstract of DOI:10.1021/ol902716n

(Figure presented) The cationic N-heterocyclic carbene-gold(I) complex catalyzes the formation of tri- and tetrasubstituted pyrroles via the amino-Claisen rearrangement of N-propargyl β-enaminone derivatives and the cyclization of α-allenyl β-enaminone in

Full text of DOI:10.1021/ol902716n

ORGANIC
LETTERS
2010
Vol. 12, No. 2
372-374
Synthesis of Pyrroles by
Gold(I)-Catalyzed Amino-Claisen
Rearrangement of N-Propargyl
Enaminone Derivatives
Akio Saito,* Tomoyo Konishi, and Yuji Hanzawa*
Laboratory of Organic Reaction Chemistry, Showa Pharmaceutical UniVersity,
3-3165 Higashi-tamagawagakuen, Machida, Tokyo 194-8543, Japan
akio-sai@ac.shoyaku.ac.jp; hanzaway@ac.shoyaku.ac.jp
Received November 24, 2009
ABSTRACT
The cationic N-heterocyclic carbene-gold(I) complex catalyzes the formation of tri- and tetrasubstituted pyrroles via the amino-Claisen
rearrangement of N-propargyl ꢀ-enaminone derivatives and the cyclization of r-allenyl ꢀ-enaminone intermediates.
The pyrrole compound is not only prevalent in a wide variety
of biologically and medicinally important compounds1 but
also used as a building block in organic synthesis.2 The
preparation of the pyrrole compound generally depends on
the classical condensation such as the Paal-Knorr method3
or the Hantzsch method,4 albeit multistep synthetic operation.
Although many studies have been reported on the synthesis
of pyrroles through metal-catalyzed hydroamination or
cycloisomerization of alkyne compounds possessing a ni-
trogen functional group,5,6 a novel and efficient synthetic
method remains an attractive goal.
The ꢀ-enaminone derivative is a versatile synthetic
intermediate, and its utilities have received considerable
attention in the field of heterocyclic synthesis.7 In particular,
the regioselective cyclization of N-propargyl ꢀ-enaminones
(5) Recent examples: (a) Kel’in, A. V.; Sromek, A. W.; Gevorgyan, V.
J. Am. Chem. Soc. 2001, 123, 2074. (b) Kim, J. T.; Gevorgyan, V. Org.
Lett. 2002, 4, 4697. (c) Gabriele, B.; Salerno, G.; Fazio, A. J. Org. Chem.
2003, 68, 7853. (d) Mart´ın, R.; Rivero, M. R.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2006, 45, 7079. (e) Gorin, D. J.; Davis, N. R.; Toste, F. D.
J. Am. Chem. Soc. 2005, 127, 11260. (f) Hiroya, K.; Matsumoto, S.;
Ashikawa, M.; Ogiwara, K.; Sakamoto, T. Org. Lett. 2006, 8, 5349. (g)
Larionov, O. V.; de Meijere, A. Angew. Chem., Int. Ed. 2005, 44, 5664.
(h) Kamijo, S.; Kanazawa, C.; Yamamoto, Y. J. Am. Chem. Soc. 2005,
127, 9260. (i) Arcadi, A.; Di Giuseppe, S.; Marinelli, F.; Rossi, E. AdV.
Synth. Catal. 2001, 343, 443. (j) Arcadi, A.; Di Giuseppe, S.; Marinelli,
(1) For example: (a) Fu¨rstner, A. Angew. Chem., Int. Ed. 2003, 42, 3582.
(b) Hoffmann, H.; Lindel, T. Synthesis 2003, 1753. (c) Agarwal, S.;
Ca¨mmerer, S.; Filali, S.; Fro¨hner, W.; Kno¨ll, J.; Krahl, M. P.; Reddy, K. R.;
Kno¨lker, H.-J. Curr. Org. Chem. 2005, 9, 1601. (d) Walsh, C. T.; Garneau-
Tsodikova, S.; Howard-Jones, A. R. Nat. Prod. Rep. 2006, 23, 517. (e)
Bellina, F.; Rossi, R. Tetrahedron 2006, 62, 7213.
(2) (a) Jones, R. A. Pyrroles, Part II, The Synthesis, ReactiVity and
Physical Properties of Substituted Pyrroles; Wiley: New York, 1992. (b)
Sundberg, R. J. ComprehensiVe Heterocyclic Chemistry II; Katritzky, A. R.,
Rees, C. W., Scriven, E. F. V., Eds.; Elsevier: Oxford, UK, 1996; Vol. 2,
p 119. (c) Pelkey, E. T. Prog. Heterocycl. Chem. 2005, 17, 109.
(3) (a) Knorr, L. Ber. Dtsch. Chem. Ges. 1884, 17, 1635. (b) Paal, C.
Ber. Dtsch. Chem. Ges. 1885, 18, 367. For recent examples, see: (c) Trost,
B. M.; Doherty, G. A. J. Am. Chem. Soc. 2000, 122, 3801. (d) Quiclet-
Sire, B.; Quintero, L.; Sanchez-Jimenez, G.; Zard, S. Z. Synlett 2003, 75.
(e) Tracey, M. R.; Hsung, R. P.; Lambeth, R. H. Synthesis 2004, 918.
(4) (a) Hantzsch, A. Ber. Dtsch. Chem. Ges. 1890, 23, 1474. For recent
examples, see (b) Palacios, F.; Aparico, D.; de los Santos, J. M.; Vicario,
J. Tetrahedron 2001, 57, 1961. (c) Trautwein, A. W.; Su¨ssmuth, R. D.;
Jung, G. Bioorg. Med. Chem. Lett. 1998, 8, 2381.
F.; Rossi, E. Tetrahedron: Asymmetry 2001, 12, 2715
.
(6) Other examples for transition-metal-catalyzed synthesis of pyrroles:
(a) Braun, R.; Zeitler, K.; Mu¨ller, T. J. J. Org. Lett. 2001, 3, 3297. (b)
Balme, G. Angew. Chem., Int. Ed. 2004, 43, 6238. (c) Siriwardana, A. I.;
Kathriarachchi, K. K. A. D. S.; Nakamura, I.; Gridnev, I. D.; Yamamoto,
Y. J. Am. Chem. Soc. 2004, 126, 13898. (d) Wurz, R. P.; Charette, A. B.
Org. Lett. 2005, 7, 2313. (e) Lu, L.; Chen, G.; Ma, S. Org. Lett. 2006, 8,
835. (f) Cadierno, V.; Gimeno, J.; Nebra, N. Chem.sEur. J. 2007, 13, 9973.
(g) Yadav, J. S.; Reddy, B. V. S.; Srinivas, M.; Divyavani, C.; Basha, S. J.;
Sarma, A. V. S. J. Org. Chem. 2008, 73, 3252
.
(7) For reviews: (a) Elassar, A.-Z. A.; El-Khair, A. A. Tetrahedron 2003,
59, 8463. (b) Negri, G.; Kascheres, C.; Kascheres, A. J. J. Heterocycl. Chem.
2004, 41, 461. (c) Stanovnik, B.; Steve, J. Chem. ReV. 2004, 104, 2433.
10.1021/ol902716n  2010 American Chemical Society
Published on Web 12/21/2009

is a divergent construction of highly substituted pyridines
or pyrroles (6-endodig or 5-exo-dig, Scheme 1).8 Although
Table 1. Evaluation of Catalysts for the Formation of 2a from 1a
Scheme 1
.
Formation of Heterocycles from N-Propargyl
ꢀ-Enaminone Derivatives
yield (%)a
entry
catalyst (mol %)c
time (h)
2a
3a 1a
1b
2b
3
4
5
6
7
8
9
[Rh(COD)2]OTf (10)
RhH(CO)(Ph3P)3 (10)
PtCl2 (10)
(Ph3P)AuCl (5)/AgBF4 (5)
AgBF4 (10)
6
3
5
20
20
20
1
1
1
1
3
-
-
-
-
-
-
-
40
6
-
-
1
71
61
48
-
7
87
-
-
-
-
7
(IPr)AuCl (5)
-
(IPr)AuCl (5)/AgBF4 (5)
(IPr)AuCl (5)/AgSbF6 (5)
(IPr)AuCl (5)/AgNTf2 (5)
(IPr)AuCl (5)/AgOTf (5)
AuCl3 (5)
83
73
57
65
60
85d
the catalytic synthesis of pyridines via 6-endodig cyclization
of the propargyl enaminone (path a) has been achieved,
5-exo-dig cyclization (path b) requires an excess amount of
base.8b We recently developed the catalytic approach to the
synthesis of indole compounds through amino-Claisen rear-
rangement of N-propargyl anilines.9 As a part of our studies
on the heterocyclic synthesis, we focused on the metal-catalyzed
formation of pyrroles through the sequential reaction of
amino-Claisen rearrangement and heterocyclization (path c).
A similar approach such as the preparation of furan compounds
from propargyl vinyl ethers was accomplished by cationic
gold(I) catalyst,10,11 which encourages us to examine the
present project for the preparation of pyrroles. We herein
describe the Au(I)-catalyzed formation of highly substituted
pyrroles from N-propargyl ꢀ-enaminone derivatives.
In the preliminary studies on the formation of pyrrole from
N-propargyl ꢀ-enaminone 1a in the presence of Rh(I)-
catalysts (10 mol %) in HFIP (hexafluoroisopropanol), which
are the optimal conditions for the preparation of indole from
N-propargyl anilines,9 the formation of pyrrole was not
observed (entries 1 and 2, Table 1). As our next efforts, the
evaluation of Au catalysts was conducted for the reaction
of 1a in CH2Cl2 (entries 3-12). Although (Ph3P)AuCl/AgBF4
or PtCl2 showed good results for the Claisen rearrangement
of propargyl vinyl ethers,10 3a was obtained through the
6-endo-dig cyclization of 1a (entries 3 and 4). However,
(IPr)AuCl (IPr ) 1,3-bis(2,6-diisopropylphenyl)imidazol-2-
ylidene) with Ag salts or AuCl3 was found to give the pyrrole
2a as a main product after the basic workup (KOH/MeOH-
THF), which brought about the hydrolysis of 4a (entries
7-11).12,13 In particular, by the use of 5 mol % (IPr)AuCl/
AgBF4, 1a was consumed at rt within 1 h giving rise to 2a
2
19
21
13
-
10
11
12
[(IPr)Au(MeCN)]BF4 (5)
1
-
a The yield was determined by 1H NMR analysis using toluene as internal
standard. b Solvent: HFIP (hexafluoroisopropanol). c IPr )N,N′-bis(2,6-di-
isopropylphenyl)-imidazol-2-ylidene. d Isolated yield: 85%.
in 83% yield (entry 7). [(IPr)Au(MeCN)]BF4,14 which is
generated by the mixture of (IPr)AuCl and AgBF4 in CH2Cl2-
MeCN, yielded a similar result to entry 7 (entry 12). It should
be mentioned that other solvents instead of CH2Cl2 showed
inferior results (HFIP-CH2Cl2(1:3):2a 20%, 1 h; HFIP:2a
4%, 1 h; MeCN: 3a 40%, 18 h; THF: 3a 40%, 18 h).
The scope of the Au(I)-catalyzed formation of various
substituted pyrroles is summarized in Tables 2 and 3. The
Table 2. Formation of Pyrroles 2 from Enaminones 1a
1
Y
R1
E/Z
time (h)
yield (%)b
1a
1b
1c
1d
1e
1f
Ph
Ph
Ph
Ph
Ph
Ph
H
67/33
52/48
84/16
74/26
55/45
100/0
1
1
2
4
1
4
2a 85
2b 61
2c 61
2d 72
2e 76
(3f 38)
2-furyl
p-MeO-Ph
p-NO2-Ph
tBu
Me
(8) (a) Abbiati, G.; Arcadi, A.; Bianchi, G.; Giuseppe, S. D.; Marinelli,
F.; Rossi, E. J. Org. Chem. 2003, 68, 6959. (b) Cacchi, S.; Fabrizi, G.;
Filisti, E. Org. Lett. 2008, 10, 2629.
a Au(I): 5 mol % [(IP)Au(MeCN)]BF4. b Isolated yield.
(9) (a) Saito, A.; Kanno, A.; Hanzawa, Y. Angew. Chem., Int. Ed. 2007,
46, 3931. (b) Saito, A.; Oda, S.; Fukaya, H.; Hanzawa, Y. J. Org. Chem.
2009, 74, 1517.
efficiency of [(IPr)Au(MeCN)]BF4 showed in the reactions
of enaminone 1a-e, and the corresponding pyrroles were
obtained in good yields after the basic workup. In all cases,
the dihydropyridines 3a-e were not detected. On the other
(10) (a) Suhre, M. H.; Reif, M.; Kirsch, S. F. Org. Lett. 2005, 7, 3925.
(b) Binder, J. P.; Kirsch, S. F. Org. Lett. 2006, 8, 2151
.
(11) Au(I)-catalyzed Claisen rearrangement of propargyl enol ether:
Sherry, B. D.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 15978
Org. Lett., Vol. 12, No. 2, 2010
.
373

The present pyrrole formation would take part in a process
similar to the furan formation. This is supported by the formation
of deuterated pyrrole 6d-D as shown in Scheme 2. Although 6d-D
Table 3. Formation of Pyrroles 6 from Enaminoesters 5a
Scheme 2
.
Formation of Heterocycles from N-Propargyl
ꢀ-Enaminone Derivatives
1
R1
R2
H
R3
E/Z
time (h) yield (%)b
5a
5a
5a
5b Ph
5c Me
5d Me
CO2Et
H
69/31
22
22
22
2
(7a 86)c
6a 38d
6a 68e
6b 81
6c 93
6d 89
6e 85
6f 87
H
H
Me
Ph
H
H
H
H
H
76/24
100/0
100/0
100/0
1
2
2
1
5e
5f
Me
Me
n-C5H11 100/0
a Au(I): 5 mol % [(IP)Au(MeCN)]BF4. b Isolated yield. c Solvent:
CH2Cl2. d Solvent: CH2Cl2-HFIP (1:1), 7a: 58%. e Solvent: HFIP, 7a: 13%.
was not formed by the treatment of undeuterated 6d with the
present Au(I) catalyst in CH2Cl2-HFIP-d1 [(CF3)2CHOD], the
Au(I)-catalyzed reaction of 5d in CH2Cl2-HFIP-d1 yielded 6d-D
(50% D) quantitatively. The deuterium incorporation into 6d-D
from 5d would be due to the cyclization of intermediate 11-D,
which was generated by the deuterium exchange between HFIP-
d1 and Claisen rearrangement intermediate 11.
In conclusion, we have demonstrated the facile and mild
preparation of tri- and tetrasubstituted pyrrole compounds from
N-propargyl ꢀ-enaminone derivatives by the [(IPr)Au(MeCN)]-
BF4 catalyst. The present catalyst also promoted the formation
of furans from propargyl vinyl ethers efficiently. Since the
propargyl enaminone derivatives or propargyl vinyl ethers as
starting materials are easily available by the reactions of the
corresponding propargyl p-tosylamides or propargyl alcohols
with 2-propynoic acid derivatives (see Supporting Information),
the present procedure would shed new light on the convenient
approach for the preparation of pyrroles and furans. Synthetic
applications and detailed mechanistic studies of the present
reaction are underway.
hand, 1f (R1 ) H) yielded 3f as a main product (Table 2).
Although the reaction of enaminoester 5a in CH2Cl2 under
the Au-catalyzed conditions afforded the dihydropyridine 7a
in 86% yield, the increase in the ratio of HFIP as a cosolvent
improved the yield of pyrrole 6a (Table 3). Thus, the effect
of the employed solvent is very important for the formation
of 6a. In HFIP, the yield of 6a was increased up to 68%.15
Other esters 5b-f (R1 * H and CO2Et) in CH2Cl2-HFIP
(3:1) were converted into the pyrroles 6b-f in good yields
without the formation of 7b-f, respectively (Table 3).16
The present Au(I) catalyst could be applied to the
formation of furan compounds 10 from vinyl ethers 8 (Table
4). On the basis of the previous report about the preparation
Table 4. Formation of Furans 10 from Vinyl Ethers 8a
Acknowledgment. This work was supported by a Grant-
in-Aid for Young Scientists (B), MEXT Japan (No 21790024).
A generous donation of HFIP by Central Glass Co., Ltd. is
gratefully acknowledged.
1
Y
R1
R2
E/Z
yield (%)b
Supporting Information Available: Experimental pro-
cedures and physical data for new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
8a
8b
8c
8d
Ph
Ph
Me
Me
Me
Me
H
Me
Ph
67/33
100/0
100/0
100/0
10a 89
10b 92
10c 97
10d 99
OEt
OEt
OEt
a Au(I): 5 mol % [(IP)Au(MeCN)]BF4. b Isolated yield.
OL902716N
(12) The isolated 4a was hydrolyzed by KOH/MeOH-THF at rt for
1 h to give 2a in 87% yield.
of 10 from 8 catalyzed by (Ph3P)AuCl/AgBF4,10 a plausible
mechanism for such a furan formation would consist of (i)
Au-catalyzed Claisen rearrangement of vinyl ethers 8, which
may proceed through a cyclization-induced rearrange-
ment11,17 (a 6-endo-dig cyclization of 8 through Au(I)-alkyne
complex, followed by the collapse of a six-membered
intermediate into 9), and (ii) the 5-exo-dig cyclization of
allenyl ketone 9 (or its tautomeric enol forms).
(13) Since the treatment of (2,5-dimethyl-1-tosyl-1H-pyrrol-3-yl)-(phen-
yl)-methanone with [(IPr)Au(MeCN)]BF4 in CH2Cl2 showed no reaction,
N-Ts-protected pyrrole may not take part in the formation of 4a.
(14) de Fre´mont, P.; Stevens, E. D.; Fructos, M. R.; D´ıaz-Requejo,
M. M.; Perez, P. J.; Nolan, S. P. Chem. Commun. 2006, 2045.
(15) Although the effect of HFIP remains unclear at present, Brønsted
acid (HBF4), which might be generated from Au catalyst and HFIP during
the reaction, did not catalyze the formation of 6a in HFIP.
(16) In the Au(I)-catalyzed reactions of ester 5, analogues of 4a were
not detected .
(17) Overman, L. E. Angew. Chem., Int. Ed. 1984, 23, 579.
374
Org. Lett., Vol. 12, No. 2, 2010