An efficient domino approach for the synthesis of multisubstituted pyrroles via gold/silver-catalyzed amination/cycloisomerization of (Z)-2-en-4-yn-1-ols

Article abstract of DOI:10.1002/adsc.200800490

An efficient and one-pot synthesis of multisubstituted pyrroles with high diversity and in a regioselective manner from the reactions of suitably substituted (Z)-enynols with amines or sulfon-amides under mild reaction conditions has been developed. This

Full text of DOI:10.1002/adsc.200800490

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DOI: 10.1002/adsc.200800490
An Efficient Domino Approach for the Synthesis of
Multisubstituted Pyrroles via Gold/Silver-Catalyzed
Amination/Cycloisomerization of (Z)-2-En-4-yn-1-ols
Yuhua Lu,a,b Xiaoping Fu,a Haoyi Chen,a Xiangwei Du,a Xueshun Jia,b
and Yuanhong Liua,*
a
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 354 Fenglin Lu, Shanghai 200032, Peopleꢀs Republic of China
Fax : (+86)-21-6416-6128; e-mail: yhliu@mail.sioc.ac.cn
Department of Chemistry, Shanghai University, Shangda Rd. 99, Shanghai, 200444, Peopleꢀs Republic of China
b
Received: August 6, 2008; Published online: December 19, 2008
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800490.
Abstract: An efficient and one-pot synthesis of mul-
tisubstituted pyrroles with high diversity and in a
regioselective manner from the reactions of suitably
substituted (Z)-enynols with amines or sulfon-
gold-catalyzed cyclization[8] of (Z)-2-en-4-yn-1-ols.[9]
Enynes bearing nitrogen nucleophiles such as (Z)-(2-
en-4-ynyl)amines would represent an important class
of suitable substrates in a metal-catalyzed strategy for
pyrroles due to the structural analogy with (Z)-en-
ACHTUNGTRENNUNGamides under mild reaction conditions has been de-
veloped. This synthesis was realized via a cascade
process in the presence of gold/silver (Au/Ag) or
boron trifluoride·etherate/gold/silver (BF3·Et2O/Au/
Ag) catalysts, which could catalyze amination and
cycloisomerization reactions in the same vessel.
ACHTUNGTRENyNGNU nols. However, there are only limited reports about
the cyclization of (Z)-enynamines to pyrroles. Gabri-
ele et al. have reported that CuCl2 or PdX2/KX could
catalyze cycloisomerizations of these substrates to a
variety of pyrroles under neutral conditions.[7b] They
also disclosed that a spontaneous cyclization occurred
without the use of a metal when specific substrates
(i.e., terminal alkynes) were employed. However, the
reactions were usually carried out in a dipolar aprotic
solvent such as DMA, and, especially with enyn-
Keywords: amination; cycloisomerization; (Z)-en-
ACHTUNGTRENNUNGynols; gold catalysis; pyrroles
AHCTUNGTRENNUNG
Pyrroles are one of the most important classes of het- have shown that a gold(I) complex of Ph3PAuNTf2
erocyclic compounds as they widely occur as key could act as an efficient catalyst in the cyclization of
structural subunits in numerous natural products enynamines (only enynamines unsubstituted at C-1
which exhibit interesting biological activities,[1] and have been tested in this work).[7c] In these methods,
can find a variety of applications in pharmaceutical the substrate enynamines were generally prepared
use[2] and materials science.[3] Furthermore, substitut- from (Z)-enynols through tedious multistep transfor-
ed pyrroles are of significant interest since they are mations involving bromination/amination (for enyn-
useful and versatile synthetic intermediates for fur-
ACHTUNGTRENaNGNU mines unsubstituted at C-1) or through oxidation/
ther structural elaboration.[4] As a consequence, much condensation with amine/addition of organolithiums
attention has been paid to the synthesis of pyrrole de- to the performed imines (for enynamines substituted
rivatives either by classic methods such as the Paal– at C-1) that are usually synthesized prior to such
Knorr[5] and Hantzsch syntheses[6] or by transition usage. An ideal strategy for such cyclizations is
metal-catalyzed reactions.[7] Nevertheless, enhancing through a domino process directly from (Z)-enynols
the efficiency of the synthesis that allows the facile as- and amines catalyzed by a single-pot catalyst to im-
sembly of substituted pyrroles, especially, in a regiose- prove the efficiency. On the other hand, we recently
lective manner, from readily available precursors developed
a straightforward synthesis of allylic
under mild reaction conditions is highly attractive. amines from allylic alcohols[10] through direct amina-
Recently, we have reported a general synthetic ap- tion[11] by utilization of gold as catalyst under mild re-
proach to furans and stereodefined dihydrofurans via action conditions. Based on this work, we envisioned
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Scheme 1.
that pyrroles might be constructed directly from (Z)- Decreasing the amount of amine or the catalyst load-
enynols. Herein, we describe our study of this new ap- ing of AgBF4 resulted in a decreased yield of 3a (66%
proach which combines an initial Au/Ag-catalyzed and 54%, respectively, Table 1, entries 3 and 4).
amination of (Z)-enynols followed by an intramolecu- Ph3P-AuCl could also be used but resulted in a lower
lar hydroACHTUNGTRENNUNG
amination[12] (or cycloisomerization) of the yield of 62% (Table 1, entry 5). A control experiment
alkyne moiety in a one-pot procedure,[13] and there is showed that the silver salt alone could only afford the
no need to isolate the intermediate enynamines substitution product 2a in a high yield of 90%
(Scheme 1).
(Table 1, entry 6). When addition of 5 mol% gold cat-
In the proposed process, two independent reactions alyst to the reaction mixture after formation of 2a cat-
should occur sequentially by a single-set catalyst. Our alyzed by AgBF4, the cyclization product 3a was ob-
initial efforts were made on the optimization of an ef- tained in 83% yield (Table 1, entry 7). The results in-
ficient one-pot catalyst system for pyrrole formation dicated that the pyrrole derivative 3a might be
from the readily available 3-phenyl-substituted (Z)- formed through a cationic Au(I)-catalyzed intramo-
enynol. On the basis of our previous observations, we lecular cycloisomerization of the enynamine inter-
first examined the reaction of 1a with 4-nitroaniline mediate 2a. The structure of the pyrroles was further
in the presence of AuCl3 (Table 1, entry 1). However, confirmed by X-ray crystallographic analysis of 3a.[14]
only amination product 2a was obtained in 65% yield.
The present method could be applied successfully
After much effort, we were delighted to find that the to various enynols 1 and 4, both acyclic and/or bear-
reaction proceeded smoothly and provided an 84% ing a cyclic ring, to provide the corresponding pyr-
yield of the pyrrole 3a at room temperature in 1 h roles in generally good to high yields (Table 2 and
with 5 mol% (p-MeOC6H4)3P-AuCl and 10 mol% Table 3). The domino-type cyclizations of enynols 1a–
AgBF4 as catalysts (Table 1, entry 2). Using TsNH2 in- 1k bearing a substituent at the C-3 position were in-
stead of 4-nitroaniline afforded a low yield of the de- vestigated firstly. It was found that the aromatic ring
sired pyrrole (some other by-products were formed). of R1 at C-1 bearing an electron-withdrawing group
Table 1. Optimization studies for the formation of pyrroles.
[a]
Isolated yields.
2 equiv. of 4-nitroaniline were used.
Not observed.
[b]
[c]
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An Efficient Domino Approach for the Synthesis of Multisubstituted Pyrroles
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Table 2. One-pot synthesis of pyrroles through the reactions of (Z)-enynols with amines.
[a]
Isolated yields.
[b]
In this case, only amination product of 2f was obtained, which was concomitant with
small amount of by-product.
5% BF3·Et2O, room temperature, 2–4 h, then 5% (p-MeOC6H4)3P-AuCl/10% AgBF4,
[c]
room temperature, ca. 5 h.
2 equiv of BF3·Et2O, 50 8C, 4.5 h, then 5% (p-MeOC6H4)3P-AuCl/10% AgBF4, room tem-
[d]
perature, 2 h, in DCE.
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Table 3. Formation of pyrroles fused with carbocycles.
[a]
[b]
Isolated yields.
5% BF3·Et2O, room temperature, 1 h, then 5% (p-MeOC6H4)3P-AuCl/
10% AgBF4, room temperature, 2 h.
(Cl) or an electron-donating group (OMe) were all lysts, the desired pyrrole 3j could be obtained in a
compatible under the reaction conditions, furnishing high yield of 82% (Table 2, entry 11). Analogously,
the corresponding pyrroles 3b and 3c in 72% and enynol 1k unsubstituted at C-1 or 1l unsubstituted
59% yields, respectively (Table 2, entries 2 and 3). both at C-2 and C-3 afforded the corresponding prod-
The aryl substituents on the alkyne moiety had a big ucts 3k and 3l in 46% and 51% yields, respectively
influence on the reaction process, whereas a p-Cl (1d) (Table 2, entries 12 and 13).
or 3,5-dimethoxy-substituted 1e afforded the corre-
The cyclization has also been successfully extended
sponding products 3d and 3e in good yields, the p- to various enynols 4a–f fused with 5- or 6-membered
MeO-substituted 1f only led to amination product 2f carbocycles, and moderate to good yields were realiz-
in 40% yield, along with several by-products (Table 2, ed for all cases. It should be noted that for enynol 4f
entries 4 and 6). The reaction also proceeded smooth- fused with a six-membered ring, the use of BF3·Et2O
ly with C-5 or C-3-alkyl-substituted enynols 1g–i to was required to first achieve the amination (Table 3,
produce the products 3g–i in 62–88% yields (Table 2, entry 7).
entries 7–10). A tosylated pyrrole 3h’ could also be
To further understand the reaction mechanism, the
obtained in 62% yield in the case of enynol 1h cycloisomerization of isolated enynamine 2a was car-
(Table 2, entry 9). Notably, the enynol 1j, bearing an ried out (Scheme 2). Interestingly, it was found that
alkyl-substitutent at C-1, afforded 3j in a low yield of only a 38% yield of 3a was formed along with several
17%, moreover, the furan derivative was isolated as by-products in the absence of any additives. To our
the major product.[15] The results, by comparison with surprise, when 3 equiv. of 4-nitrophenylamine was
the yields obtained from C-1 aryl-substituted enynols, used as an additive, the desired 3a was isolated in
indicated that the reaction rate of amination in this 90% yield. The results showed that the excess amine
case is much slower than the cycloisomerization played an important role in the cycloisomerization of
through an oxygen nucleophile due to the lower sta- 2a, and also in the one-pot process. It may facilitate a
bility of the allylic cation intermediate formed in situ. clean cyclization by serving as a co-ligand to stabilize
It also showed that the substituent effect on C-1 the cationic gold(I) intermediates.
played an important role in the amination. We then
In summary, we have developed an Au/Ag-cata-
tried the reaction of 1j by first addition of 10% lyzed amination/cycloisomerization of (Z)-enynols
AgBF4 to the reaction mixture, to our surprise, no re- with amines or sulfonamides under mild reaction con-
action took place under these conditions. Next, we ditions, which provided an efficient one-pot route to
were pleased to find that BF3·Et2O can remarkably multisubstituted pyrroles with high diversity and in a
promote the amination. Thus, by first stirring the re- regioselective manner. The Lewis acid BF3·Et2O was
action mixture in the presence of 5 mol% BF3·Et2O required in some cases to realize a successful domino
for 2 h, and then subsequent addition of Au/Ag cata- process, depending on the substitution pattern on the
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An Efficient Domino Approach for the Synthesis of Multisubstituted Pyrroles
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Scheme 2.
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enynols. These compounds are potentially useful in
pharmaceutical and materials science. Further studies
to extend the scope of synthetic utility for this
Au/Ag-catalyzed cascade reaction are in progress in
our laboratory.
Experimental Section
General Procedure for the Au/Ag-Catalyzed One-Pot
Synthesis of Pyrroles from (Z)-2-En-4-yn-1-ols
To a solution of (Z)-enynols 1 or 4 (0.3 mmol) in 10 mL
CH2Cl2 was added 4-nitroaniline (1.2 mmol). After the 4-ni-
troaniline had dissolved, (p-MeOC6H4)3P-AuCl (5 mol%)
and AgBF4 (10 mol%, used as a 0.05M solution in toluene)
were added successively. The resulting solution was stirred
at room temperature until the reaction was complete as
monitored by thin-layer chromatography. The solvent was
removed under vacuum and the residue was purified by
chromatography on silica gel to afford the pyrrole deriva-
tives.
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Experimental details and spectroscopic characterization of
all new compounds are given in the Supporting Information
file.
Acknowledgements
We thank the National Natural Science Foundation of China
(Grant No. 20732008), Chinese Academy of Science, Science
and Technology Commission of Shanghai Municipality
(Grant Nos. 08QH14030, 07 JC14063) and the Major State
Basic Research Development Program (Grant No.
2006CB806105) for financial support.
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