Efficient microwave-assisted formation of functionalized 2,5-dihydropyrroles using ruthenium-catalyzed ring-closing metathesis

Article abstract of DOI:10.1016/j.tetlet.2004.02.100

A rapid method for the formation of functionalized 2,5-dihydropyrroles using ruthenium-catalyzed ring-closing metathesis under microwave irradiation is presented. The diene substrates were efficiently prepared from aza-Baylis-Hillman adducts.

Full text of DOI:10.1016/j.tetlet.2004.02.100

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3089–3092
Efficient microwave-assisted formation of functionalized 2,5-
dihydropyrroles using ruthenium-catalyzed ring-closing metathesis
Daniela Balan and Hans Adolfsson*
Department of Organic Chemistry, Stockholm University, SE-10691 Stockholm, Sweden
Received 18 December 2003; revised 9 February 2004; accepted 19 February 2004
Abstract—A rapid method for the formation of functionalized 2,5-dihydropyrroles using ruthenium-catalyzed ring-closing
metathesis under microwave irradiation is presented. The diene substrates were efficiently prepared from aza-Baylis–Hillman
adducts.
Ó 2004 Elsevier Ltd. All rights reserved.
Ring-closing metathesis (RCM) has become one of the
most powerful and versatile methods for the formation
of cyclic organic structures.1 The increasing popularity
of this technique can be traced to the development of
efficient, commercially available air-stable ruthenium
catalysts (1, 2), which show high tolerance towards a
wide variety of functional groups.2 The increased ther-
mal stability of the GrubbsÕ second generation catalysts,
here exemplified by 2, further improved the usefulness of
this method and allowed for efficient performance of
reactions at elevated temperatures. The latter is partic-
ularly important for the formation of heavily substituted
olefins (tri- and tetra-substituted) carrying electron-
withdrawing groups, since these substrates typically
result in low conversion when reactions are performed at
room temperature.
The formation of heterocyclic compounds represents
one of many applications where RCM has been suc-
cessfully employed.3 One particular transformation, the
ring closure of N,N-diallyl p-toluensulfonamide yielding
N-tosyl-2,5-dihydropyrrole, is often used as a model
reaction in the evaluation of novel RCM catalysts
(Scheme 1).4 However, the formation of substituted 2,5-
dihydropyrrole derivatives using RCM has so far been
limited to a few examples. This is further accentuated
when it comes to the formation of compounds con-
taining electron-withdrawing substituents.5
Naturally, one of the limiting factors for the preparation
of heterocyclic compounds using RCM, is the avail-
ability of the appropriate dienes as starting materials.
One such class of dienes can be obtained easily using
Baylis–Hillman chemistry.6 The Baylis–Hillman reac-
tion as well as its aza-analog, is a powerful method for
the formation of highly functionalized compounds.7;8
Herein we report on the efficient use of aza-Baylis–
Hillman adducts for the formation of 2,5-dihydropyr-
roles using ring-closing metathesis.
N
N
Mes
Cl
Mes
Ph
P(Cy)3
Ru
Cl
Cl
Ru
Cl
Ph
P(Cy)3
P(Cy)3
1
2
RCM
TsN
Keywords: Ring-closing metathesis; 2,5-Dihydropyrroles; Aza-Baylis–
Hillman reaction; Microwave assisted synthesis.
N
Ts
* Corresponding author. Tel.: +46-8-162479; fax: +46-8-150948;
e-mail: hansa@organ.su.se
Scheme 1.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.02.100

3090
D. Balan, H. Adolfsson / Tetrahedron Letters 45 (2004) 3089–3092
O O
S
E
R
N
Ar
2 (5 mol%)
CH2Cl2, 100oC
(µ-wave irradiation)
E
N
S
O
5
Ar
O
R
O O
S
O
3-HQD (15 mol%)
Ti(OiPr)4 (2 mol%)
Ar
H
E
4
R
NH
E
O O
S
Scheme 4.
4Å mol. sieves
iPrOH, r.t.
Ar
R
NH2
3
Scheme 2.
concentration to 0.1 M and performing the reaction at
100 °C resulted in full conversion of the starting
material into 5a in 60 s (Scheme 4). The use of
microwave irradiation has proven to be particularly
effective in a number of chemical transformations.11
Although nonthermal microwave effects have been
claimed to operate in the RCM reaction,12 Kappe and
co-workers recently showed that the reaction pro-
gresses equally well independently of the type of
heating used.13;14 In fact, for simple substrates, the
RCM reaction works sufficiently well even at room
temperature. In our case, however, heating turned out
to be crucial for the reactivity. Performing the RCM
reaction of the electron-deficient substrate 4a at room
temperature resulted in the formation of a small
amount of product 5a, however, after 48 h there was
still a considerable amount of starting material left
unreacted.
We have recently developed an efficient and reliable one-
pot protocol for the aza-Baylis–Hillman (aza-BH)
reaction (Scheme 2).9 In this combined Lewis acid- and
base-catalyzed three-component reaction we successfully
and selectively formed a-methylene-b-amino acid
derivatives starting from arylaldehydes, sulfonamides
and various Michael acceptors. With the aza-BH
adducts in hand, we realized that these compounds,
properly functionalized, would serve as ideal building
blocks for the preparation of 2,5-dihydropyrroles using
RCM. Thus, treating the adducts 3 with allyl bromide
under basic conditions gave the corresponding N-allyl-
ated compounds 4 in a Ôspot to spotÕ reaction, and after
simple extractive workup, the diene-products were iso-
lated in high yields (Scheme 3).10
With the optimized conditions in hand, we submitted
a number of allylated aza-BH adducts (4a–g) to the
RCM reaction and the results are presented in Table 1,15
which shows that most substrates were converted into
the desired ring-closed products (5a–g)16 within 1 min
reaction time. The only exception was the RCM reac-
tion of the sterically more congested tert-butyl ester 4f,
which required an additional 60 s for full conversion
(entry 6). In addition, the 4-nitrosulfonyl derivative 4g
reacted smoothly and furnished the nosyl-functional-
ized 2,5-dihydropyrrole 5g in good yield (entry 7).
There are good opportunities for further synthetic
manipulations of this particular compound since the
conditions required for nosyl removal are signifi-
cantly milder then those available for N-tosyl depro-
tection.17
These diene-substrates were subsequently submitted to
the RCM reaction employing catalyst 2. In an initial
ring-closing experiment, the allylated aza-BH adduct 4a
and catalyst 2 (5 mol %) were dissolved in dichloro-
methane (0.05 M substrate concentration), and the
solution was heated to 125 °C for 10 min using micro-
wave irradiation. The resulting reaction mixture was
evaporated under reduced pressure and the crude
1
product was analyzed by H NMR spectroscopy. The
spectrum obtained revealed no traces of starting
material and the 2,5-dihydropyrrole-derivative 5a was
the only observable compound. In an optimization of
this reaction we found that increasing the substrate
In conclusion, we have demonstrated how N-allylated
aza-Baylis–Hillman adducts can be efficiently trans-
formed into functionalized 2,5-dihydropyrrole-deriva-
tives using ring-closing metathesis under microwave
irradiation. The 2,5-dihydropyrrole products were iso-
lated in high yields after simple filtration of the reaction
mixture to remove the catalyst followed by evaporation
of the solvent. Hence, from a practical point of view,
this is a rapid, convenient and simple method for the
formation of this particular class of heterocyclic com-
pounds.
O O
S
O O
S
allylbromide
K2CO3
R
NH
R
N
E
E
DMF, r.t.
Ar
Ar
3
4
Scheme 3.

D. Balan, H. Adolfsson / Tetrahedron Letters 45 (2004) 3089–3092
Table 1. Efficient formation of 2,5-dihydropyrrole-derivatives catalyzed by 2a
3091
Entry
Diene
Product
CO2Me
Time (s)
60
Yieldb (%)
Ts
N
1
92
CO2Me
Ph
5a
N
Ts
Ph
4a
CO2Me
Ts
N
2
3
4
60
60
60
95
91
78
CO2Me
N
Ts
4b
5b
CO2Me
Ts
N
Cl
Cl
CO2Me
CO2Me
N
Ts
4c
5c
Ts
CO2Me
N
N
Ts
OMe
MeO
Ts
4d
5d
CO2Me
N
5
4e
60
95
CO2Me
CO2But
N
Ts
N
N
5e
CO2But
Ph
Ts
N
6
120
90
N
Ts
5f
4f
CO2Me
O O
S
Ph
N
N
7
60
90
O S
O
CO2Me
O2N
Ph
4g
NO2
5g
a Reaction conditions: a solution of diene 4 (0.5 mmol) and catalyst 2 (5 mol %) in CH2Cl2 (5 mL; [4]¼0.1 M) were microwave irradiated in a sealed
tube for 60 s with the temperature set to reach 100 °C.
b Isolated yields.
€
(b) Furstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012–
3043.
Acknowledgements
2. (a) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am.
Chem. Soc. 1996, 118, 100–110; (b) Scholl, M.; Ding,
S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953–
956.
3. For recent examples on the formation of heterocyclic
compounds using RCM, see: Walters, M. A. In Progress in
Heterocyclic Chemistry; Gribble, G., Joule, J. A., Eds.;
Pergamon, Oxford, 2003; pp 1–36.
This work was supported by the Swedish Research
Council. We are grateful to Personal Chemistry AB
Uppsala, Sweden for providing the microwave equip-
ment, EmryÕse Creator.
References and notes
4. For recent examples, see: (a) Zaja, M.; Connon, S. J.;
Dune, A. M.; Rivard, M.; Buschmann, N.; Jiricek,
J.; Blechert, S. Tetrahedron 2003, 59, 6454–6558; (b)
1. For recent reviews on olefin metathesis, see: (a) Trnka, T.
M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18–29;

3092
D. Balan, H. Adolfsson / Tetrahedron Letters 45 (2004) 3089–3092
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Chem. 2003, 68, 9136–9139.
14. For a recent discussion on the existence of nonthermal
microwave effects, see: Kuhnert, N. Angew. Chem., Int.
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15. General experimental procedure exemplified for the forma-
tion of 5a. A solution of diene 4a (0.5 mmol) and catalyst 2
(5 mol %) in CH2Cl2 (5 mL) was microwave irradiated in a
sealed tube for 60 s at 100 °C (temperature control, fixed
hold time off, normal absorption mode) using an EmryÕse
Creator. The reaction mixture was filtered through a
short plug of silica, followed by evaporation of the solvent
to yield 165 mg (92%) of the pure product (as white
crystals): 1H NMR (400 MHz, CDCl3)
d 7.42 (d,
J ¼ 8:3 Hz, 2H), 7.22–7.25 (m, 5H), 7.14 (d, J ¼ 8:3 Hz,
2H), 6.78 (dd, J ¼ 4:1, 2.4 Hz, 1H), 5.72–5.76 (m, 1H),
4.51 (dt, J ¼ 17:0, 2.4 Hz, 1H), 4.38 (ddd, J ¼ 17:0, 5.7,
1.9 Hz, 1H), 3.58 (s, 3H), 2.37 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 162.2, 143.3, 139.4, 135.8, 135.6,
135.5, 129.5, 128.3, 128.0, 127.8, 127.1, 69.0, 55.0, 51.8,
21.5; MS (MALDI-TOF) ðm=zÞ 396.29 (MKþ) 380.28
(MNaþ) 358.28 (MHþ).
10. The allylated aza-Baylis–Hillman adducts 4a–g were
isolated in yields ranging from 95% to 99%.
11. For a general review on microwave assisted synthesis, see:
16. For an alternative preparative route towards these het-
erocyclic compounds, see: Xu, Z.; Lu, X. J. Org. Chem.
1998, 63, 5031–5041.
€
Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J.
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1995, 36, 6373–6374.