Direct approach to multi-substituted pyrroles from 2-propynylamine and 1,3-diketone or β-keto ester using Bi(OTf)3 catalyst

Article abstract of DOI:10.1246/cl.2009.224

Bi(OTf)₃was found to be a good catalyst for the direct synthesis of multisubstituted pyrroles from the readily accessible 2-propynylamine and activated methylene compounds in which the bismuth played two roles: σ-and π-activations. Copyright

Full text of DOI:10.1246/cl.2009.224

224
Chemistry Letters Vol.38, No.3 (2009)
Direct Approach to Multi-substituted Pyrroles from 2-Propynylamine
and 1,3-Diketone or ꢀ-Keto Ester Using Bi(OTf)3 Catalyst
Kimihiro Komeyama,ꢀ Motoyoshi Miyagi, and Ken Takakiꢀ
Department of Chemistry and Chemical Engineering, Graduate School of Engineering,
Hiroshima University, 1-4-1 Kagamiyama, Higashi-Hiroshima 739-8527
(Received December 18, 2008; CL-081188; E-mail: kkome@hiroshima-u.ac.jp)
Bi(OTf)3 was found to be a good catalyst for the direct syn-
Table 1. Direct synthesis of pyrroles 3 and 4 from the reaction
of 2-propynylamine 1a and various diketones and ꢂ-keto esters 2
thesis of multisubstituted pyrroles from the readily accessible
2-propynylamine and activated methylene compounds in which
the bismuth played two roles: ꢀ- and ꢁ-activations.
Ts
Ts
N
N
R1
C(O)R2
R1
10 mol%Bi(OTf)3
O
O
+
+
TsHN
R1
R2
toluene, 100 °C
(2 equiv)
1a
3
4
2
New synthetic strategies for multisubstituted pyrroles are
of continuous interest due to the ubiquity of this heterocycle in
natural products1 and pharmaceuticals.2 For their construction,
there are a number of classic methods and modified processes,
such as the Paal–Knorr,3 and Hantzsch syntheses.4 Recently,
these methods have been improved and partly altered into cycli-
zations such as hetero-annulation and cycloisomerization to
achieve more complex pyrrole skeletons.5 However, these meth-
odologies typically require the initial synthesis of the correctly
adjusted precursors prior to the cyclization, which makes struc-
tural modifications of substituted pyrroles complicate. There-
fore, the development of more practical and efficient approaches
to the pyrroles from readily available and easily diversified
building blocks remains an active research area.6 In this commu-
nication, we report a new direct synthesis of multisubstituted
pyrroles from 2-propynylamine and 1,3-diketones and ꢂ-keto
esters with a bismuth catalyst.7
Ketone 2
R1
Total yield
(3/4)/%a
Entry
Time/h
R2
1
2
2a
2b
2c
2d
2e
2f
Me
Ph
Me
Ph
9
6
74 (36/64)
64 (42/58)
57 (45/55)
67 (54/46)
58 (81/19)
55 (100/0)
41 (100/0)
55 (100/0)
34 (100/0)
54 (100/0)
36 (100/0)
3
4-ClC6H4
4-MeC6H4
4-MeOC6H4
Me
4-ClC6H4
4-MeC6H4
4-MeOC6H4
OEt
6
4
8
5
6
6
6
7
2g
2h
2i
Ph
Ph
OMe
OEt
12
10
6
8
9
4-ClC6H4
4-MeC6H4
2-MeC6H4
OEt
OEt
10
11
2j
2k
12
12
OEt
aIsolated yield.
The present reaction could be applied to various ꢂ-keto esters
(Entries 6–11). It is noteworthy that the reaction with ꢂ-keto
esters afforded 3-acylpyrroles 3 only, albeit with slightly lower
conversions to the product in comparison with the diketone.
Unfortunately, the alternation of the terminal proton of the
alkyne 1 with aryl and alkyl groups caused the substitution
reaction of the TsNH moiety of 1 by the methylene compound
2, exclusively. Additionally, when the protecting group on nitro-
gen was replaced to benzyl and H, no reaction was observed.
We envisioned two possible processes of the present reac-
tion as illustrated in Scheme 1. In path a, the addition of the
methylene compound 2 to the alkyne part of 1 would provide
the intermediate A, whose amine and ketone functions would in-
tramolecularly condensed to afford the pyrroles 3 and/or 4, and
H2O. However, it seems less likely, because the C–C bond for-
mation did not proceed in a similar reaction of 5 with 2h under
the present reaction conditions (eq 1). Another plausible process
(path b), involves the formation of 3-aza-1,5-enyne B from the
amine 1 and the methylene compound 2,10 which is followed
When N-tosyl-2-propynylamine (1a) was treated with two
equivalents of 2,4-pentanedione (2a) and Bi(OTf)3 (10 mol %)
in toluene at 100 ꢁC for 9 h, the substituted pyrrole 3a and 4a
were isolated in 74% total yield (3a/4a = 36/64) (Entry 1,
Table 1). The high catalytic performance of the bismuth on the
reaction was specific. Thus, any other Lewis acid catalysts like
.
BF3 OEt2, AlCl3, Sc(OTf)3, La(OTf)3, Zn(OTf)2, and TfOH
showed negligible or no catalytic activities. Although complete
conversions of 1a were observed by means of noble metal cata-
lysts, PdCl2 and PtCl2, insoluble white polymeric materials were
obtained instead of the pyrrole. In contrast, Fe(OTf)2or3
,
Ni(OTf)2, and Cu(OTf)2 catalysts were slightly effective for
the transformation (3–12% yield of 3a and 4a). Another bismuth
catalysts Bi(ClO4)3 was moderately active (38% yield), but
Bi(BF4)3 was useless.8 1,2-Dichloroethane was suitable solvent
as well as toluene, whereas tetrahydrofuran and acetonitrile pre-
vented the reaction.
Next, we investigated the scope and limitation of the
Bi(OTf)3-catalyzed reaction of 2-propynylamine 1 with the ac-
tive methylene compounds 2 (Entries 2–11, Table 1). With opti-
mized conditions in hand,9 the reaction with 1,3-diphenyl-1,3-
propanedione (2b) provided the corresponding pyrroles in 64%
total yield (3b/4b = 42/58) as well as with 1a (Entry 2). Elec-
tron-deficient aromatic diketone 2c was also permitted to par-
ticipate at the transformation (Entry 3). Notably, electron-rich
diketones, 2d (R ¼ 4-MeC6H4) and 2e (R ¼ 4-MeOC6H4), were
mainly converted to the 3-acylpyrroles 3 (Entries 4 and 5).
Ts
TsHN
R1
N
R1
path a
R2
−H2O
TsHN
C(O)R2
O
A
O
1a
3
+
or
O
O
Ts
N
Ts
R1
N
R1
R1
R2
path b
2
−H2O
C(O)R2
4
B
Scheme 1.
Copyright ꢀ 2009 The Chemical Society of Japan

Chemistry Letters Vol.38, No.3 (2009)
225
References and Notes
1
Angew. Chem., Int. Ed. 2003, 42, 3582.
by the enyne-cycloisomerization and the subsequent olefinic iso-
merization to yield the desired pyrroles.11 Evidence to support
definitely the latter process was obtained in eq 2. When aza-
enyne (E)-6, independently prepared, was treated with Bi(OTf)3
catalyst in the presence of one equivalent of water for 5 h at
100 ꢁC, the product 3h was obtained in 80% yield. It was note-
worthy that the presence of water and the stereochemistry of 6
drastically affected the present reaction. Thus, the product yield
decreased under anhydrous conditions and in the reaction of
azaenyne (Z)-6.
a) J. T. Gupton, Heterocycl. Chem. 2006, 25, 53. b) A. Furstner,
¨
2
a) J. L. Bullington, R. R. Wolff, P. F. Jackson, J. Org. Chem. 2002,
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Chem. Soc. 1996, 118, 7117. d) B. D. Roth, C. J. Blankley, A. W.
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3
a) C. D’Silva, D. A. Walker, J. Org. Chem. 1998, 63, 6715. b) C.
Paal, Ber. Dtsch. Chem. Ges. 1885, 18, 367. c) L. Knorr, Ber. Dtsch.
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C8H17TsN
5
4
5
a) V. Kameswaran, B. Jiang, Synthesis 1997, 530. b) A. Hantzsch,
Ber. Dtsch. Chem. Ges. 1890, 23, 1474.
a) J. T. Binder, S. F. Krisch, Org. Lett. 2006, 8, 2151. b) Y.
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C8H17TsN
Ph
10 mol%Bi(OTf)3
+
OEt
ð1Þ
toluene (0.5 M)
100 °C, 22 h
O
O
O
O
Ph
OEt
not obtained
2h
10 mol%Bi(OTf)3
1 equiv additive
Ts
Ts
N
Ph
N
Ph
J. Gilmore, Chem. Commun. 1998, 2207. e) A. Furstner, H. Szillat,
¨
toluene (0.5 M)
B. Gabor, R. Mynott, J. Am. Chem. Soc. 1998, 120, 8305. f) S. E.
Korostova, A. I. Mikhaleva, A. M. Vasilt’sov, B. A. Trofimov, Russ.
J. Org. Chem. 1998, 34, 911.
CO2Et
100 °C
CO2Et
6
3h
ð2Þ
E
/
Z
ratio of 6
Additive
H2O
Time / h Yield / %
6
Examples for direct synthesis of pyrroles: a) Y.-F. Wang, K. K. Toh,
S. Chiba, K. Narasaka, Org. Lett. 2008, 10, 5019. b) W. S. Bremner,
M. G. Organ, J. Comb. Chem. 2008, 10, 142. c) D. J. S. Cyr, N.
Martin, B. A. Arndtsen, Org. Lett. 2007, 9, 449. d) B. Ramanathan,
A. J. Keith, D. Armstrong, A. L. Odom, Org. Lett. 2004, 6, 2957.
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Tellado, M. L. Rodrꢀguez, J. Am. Chem. Soc. 2004, 126, 8390.
f) H. Saikachi, T. Kitagawa, H. Sasaki, Chem. Pharm. Bull. 1979,
27, 2857.
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Takahashi, K. Takaki, Org. Lett. 2008, 10, 5119. c) K. Komeyama,
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100/0
5
80
100/0
67/33
0/100
none
H2O
H2O
17
10
22
37
61
21
Based on these results, we proposed the reaction mechanism
in Scheme 2. In the initial step (i), the bismuth catalyst would act
as a Lewis acid for the enamine formation to provide the meta-
lated 3-aza-1,5-enyne B. In contrast, ꢁ-acidity of the same cata-
lyst would accelerate the cycloisomerization of the enyne unit of
B to give the zwitterion intermediate C (ii), which could sponta-
neously deprotonate or deacylate to liberate the two types of
products and the catalyst (iii). In this step, the deprotonation
could occur in the case of ꢂ-keto ester due to instability of
þC(O)OR. About effect of water, it might induce other pyrrole
route via N,O-acetal D.
In conclusion, we have demonstrated a new method for the
direct synthesis of multisubstituted pyrroles from simple 2-pro-
pynylamine and various 1,3-diketones or ꢂ-keto esters by the
bismuth catalyst. The transformation depended on the presence
of water generated in the initial step. Moreover, the stereochem-
istry of the 3-aza-1,5-enyne intermediate influenced the reaction
efficiency, i.e., the E isomer was more active than the Z isomer.
7
8
9
Bi(ClO4)3 and Bi(BF4)3 were prepared in situ from the reaction of
BiCl3 and 3 equivalent of AgClO4 and AgBF4 at room temperature
for 1 h, respectively. Detail on the catalyst screening was summa-
rized in Table S1 (see Supporting Information).12
General procedure for synthesis of 3a and 4a catalyzed by Bi(OTf)3:
2,4-Pentanedione (2a) (51.5 mg, 0.51 mmol) was added to a solution
of N-tosyl-2-propynylamine (1a) (52.4 mg, 0.25 mmol) and Bi(OTf)3
(16 mg, 24 mmol, 10 mol %) in anhydrous toluene (0.5 mL), and the
reaction vial was sealed. After stirring at 100 ꢁC for 9 h, the mixture
was cooled to ambient temperature, passed through a short silica-gel
column, and concentrated to leave the reddish black residue. Purifi-
cation of the residue by column chromatography on silica gel (hex-
ane/ethyl acetate = 20/1) gave pyrroles 3a and 4a as a yellow solid
(Mp.: 85.0–86.0 ꢁC, 20 mg, 27%) and a yellow oil (29 mg, 47%),
respectively.
We thank Dr. Eigo Miyazaki for the X-ray structure deter-
mination of the pyrrole 3i. This work was supported in part by
Electronic Technology Research Foundation of Chugoku and a
Grant-in-Aid for Scientific Research from the Ministry of Edu-
cation, Culture Sports, Science and Technology of Japan.
Ts
N
Ts
N
R1
R1
O
O
+
TsHN
or
10 Bismuth-catalyzed formation of enamines from amines and ketones.
See: A. R. Khosropour, M. M. Khodaei, M. Kookhazadeh, Tetrahe-
dron Lett. 2004, 45, 1725.
11 Under the silver/gold catalyst system or microwave conditions, 3-
hetero-1,5-enynes undergo the 2-propynyl-Claisen rearrangement
to give the allene intermediate, which followed by sequent cycliza-
tion to afford the pyrrole skeleton different from the present products.
See: Refs. 5a and 6b.
R1
R2
C(O)R2
2
1a
4
3
[Bi]
(ii)
(iii)
(i)
H2O
Ts
Ts
OH
R1
H
Ts
N
N
R1
N
R1
C(O)R2
H2O
-H2O
H
[Bi]
H
C(O)R2
C(O)R2
[Bi]
D
C
B
12 Supporting Information is available electronically on the CSJ-
Journal Web site, http://www.csj.jp/journals/chem-lett/index.html.
Scheme 2. Plausible reaction mechanism.
Published on the web (Advance View) January 31, 2009; doi:10.1246/cl.2009.224