Microwave-assisted and Ln(OTf)3-catalyzed homo-conjugate addition of N-heteroaromatics to activated cyclopropane derivatives

Article abstract of DOI:10.1016/j.tetlet.2008.07.142

A new expeditious method for the homo-conjugate addition of nitrogen heteroaromatics to 1,1-cyclopropanedicarboxylates was developed in the presence of La(OTf)₃ as an efficient Lewis acid catalyst under microwave irradiation.

Full text of DOI:10.1016/j.tetlet.2008.07.142

Tetrahedron Letters 49 (2008) 5867–5870
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave-assisted and Ln(OTf)3-catalyzed homo-conjugate addition
of N-heteroaromatics to activated cyclopropane derivatives
*
Md. Imam Uddin, Akiko Mimoto, Keiji Nakano, Yoshiyasu Ichikawa, Hiyoshizo Kotsuki
Laboratory of Natural Product Chemistry, Faculty of Science, Kochi University, Akebono-cho, Kochi 780-8520, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A new expeditious method for the homo-conjugate addition of nitrogen heteroaromatics to 1,1-cyclopro-
panedicarboxylates was developed in the presence of La(OTf)3 as an efficient Lewis acid catalyst under
microwave irradiation.
Received 10 July 2008
Accepted 18 July 2008
Available online 29 July 2008
Ó 2008 Elsevier Ltd. All rights reserved.
The conjugate addition reactions of amine–nucleophiles includ-
ing nitrogen heterocycles to ,b-unsaturated carbonyl compounds,
N-heteroaromatics in the presence of an appropriate Lewis acid
catalyst (Scheme 1).6
a
so-called aza-Michael reactions, are a convenient way to prepare a
pharmacologically important family of b-amino carbonyl com-
pounds.1 Recently, we found that reactions of this type could be
efficiently promoted in water, even in the absence of catalysts,
by applying a high-pressure technique.2 In our continuing efforts
to extend this methodology to other less common Michael accep-
tors, we have been very interested in the homo-conjugate addition
of nitrogen heteroaromatics (N-heteroaromatics) to activated
cyclopropanes.
Although the ring-opening reaction of activated cyclopropane
derivatives with relatively strong nucleophiles is well-established,3
the direct transformation using N-heteroaromatics as donor mole-
cules still remains a challenging subject mainly due to their low
nucleophilicity.4
Table 1
Homo-conjugate addition of pyrazole (1a) with diethyl 1,1-cyclopropanedicarboxy-
late (2a) under microwave irradiationa
CO2Et
CO2Et
N
N
H
N
N
3a
1a
+
cat LA (20 mol%)
+
MeCN, 120 W, 10 min
CO2Et
100 °C, 50 psi
X
N
N
CO2Et
2a
Our preliminary experiments to realize this strategy using
uncatalyzed and high-pressure conditions were all unsuccessful.
Gratifyingly, however, we found that microwave irradiation5
provided an efficient and expeditious tool for achieving the desired
cyclopropane ring-opening reactions with weakly nucleophilic
EtO2C
CO2Et
CO2Et
CO2Et
3b (X = OTf)
Entry
Cat LA
Yieldsb (%)
3a
3b
Microwave
cat LA
CO2R
1c
2
3
4
5
6
7
8
9
—
FeCl3
ZnCl2
Yb(OTf)3
La(OTf)3
Nd(OTf)3
Gd(OTf)3
Dy(OTf)3
Sc(OTf)3
NRd
NRd
Trace
72
76
72
75
72
69
—
—
—
19
14
16
12
16
21
R' R''
R''
R'
+
CO2R
CO2R
N
CO2R
NH
3
1
2a: R = Et, R', R" = H
2b: R = Et, R', R" = Me
2c: R = Me, R' = Ph, R'' = H
2d: R = Et, R', R'' = -(CH2)5-
a
All reactions were carried out using 1a (1.5 mmol), 2a (1.0 mmol), and LA
Scheme 1.
(20 mol%) in MeCN (ca. 2 mL).
b
Isolated yield based on 2a.
Reaction was continued for 30 min.
c
* Corresponding author. Tel.: +81 88 844 8298; fax: +81 88 844 8359.
E-mail address: kotsuki@kochi-u.ac.jp (H. Kotsuki).
d
No reaction.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.142

5868
M. I. Uddin et al. / Tetrahedron Letters 49 (2008) 5867–5870
Table 2
Homo-conjugate addition of N-heteroaromatics to 1,1-cyclopropanedicarboxylates under microwave irradiationa
Entry
Substrate
Acceptor
Time (min)
Products (Yield, %)b
CO2Et
CO2Et
CO2Et
CO2Et
N
N
H
1a
1
10
N
N
2b
3c (83)
C6H5 CO2Me
C6H5
CO2Me
CO2Me
2
3
4
1a
10
40
10
N
CO2Me
3d (89)
N
2c
CO2Et
CO2Et
CO2Et
1a
N
CO2Et
3e (37)c
2d
N
CO2Et
CO2Et
CO2Et
EtO2C
N
TfO
CO2Et
CO2Et
N
N
2a
2b
2a
N
H
N
N
3f (40)
3h (41)
1b
3g (36)
EtO2C
EtO2C
CO2Et
CO2Et
TfO
CO2Et
N
N
5
1b
10
N
CO2Et
N
N
3i (28)
CO2Et
CO2Et
CO2Et
EtO2C
TfO
N
CO2Et
CO2Et
N
N
6
10
N
N
N
H
1c
3j (48)
3k (26)
CO2Et
CO2Et
CO2Et
CO2Et
N
N
CO2Et
EtO2C
N
TfO
N
3l (37)
N
N
H
N
N
7
2a
40
CO2Et
N
1d
3n (21)
N
CO2Et
N
3m (33)
CO2Et
CO2Et
EtO2C
EtO2C
N
CO2Et
CO2Et
N
TfO
N
3o (37)
N
N
8
1d
2b
10
CO2Et
N
3q (19)
N
CO2Et
N
N
3p (20)

M. I. Uddin et al. / Tetrahedron Letters 49 (2008) 5867–5870
5869
Table 2 (continued)
Entry Substrate
Acceptor
Time (min)
Products (Yield, %)b
CO2Et
CO2Et
CO2Et
TfO
CO2Et
N
N
EtO2C
N
9
2a
10
N
CO2Et
N
H
N
3r (45)
1e
3s (22)
CO2Et
CO2Et
CO2Et
TfO
N
N
CO2Et
CO2Et
N
N
N
EtO2C
N
10
2a
10
N
H
N
N
3t (52)
1f
3u (33)
CO2Et
CO2Et
N
CO2Et
CO2Et
N
N
N
N
N
N
N
N
N
3x (trace)
N
3v (41)
11
2a
5
N
or
N
N
N
CO2Et
N
N
H
1g
N
CO2Et
CO2Et
N
CO2Et
N
3w (33)
a
All reactions were carried out using 1 (1.5 mmol), 2 (1.0 mmol), and La(OTf)3 (20 mol %) in MeCN (ca. 2 mL) at 120 W, 100 °C under 50 psi.
Isolated yield based on 2.
33% of the recovered 2d was observed, accompanied by considerable decomposition of substrates.
b
c
We describe here the microwave-assisted homo-conjugate
addition of a variety of N-heteroaromatics 1 to cyclopropanedi-
carboxylates 2.
due to the steric hindrance around the nitrogen atom of a pyrazole
ring in the adducts.
Interestingly, the reaction of imidazole (1b) and 2-methylimid-
azole (1c) with 2a or 2b gave the corresponding adducts 3f, 3h, and
3j in good yields along with a considerable amount of their corre-
sponding imidazolium salts 3g, 3i, and 3k (Table 2, entries 4–6).
When 1,2,4-triazole (1d) was reacted with 2a and 2b, the expected
regioisomeric products 3l and 3m (or 3o and 3p) were obtained in
good yields in an almost 1:1 ratio along with the corresponding
triazolium salts 3n and 3q (Table 2, entries 7 and 8). In a similar
manner, benzimidazole (1e) and benzotriazole (1f) reacted
smoothly with 2a to produce mixtures of 3r and 3s, and 3t and
3u, respectively, in good combined yields (Table 2, entries 9 and
10).
To optimize the reaction conditions, we examined the reaction
of pyrazole (1a, 1.5 equiv) with diethyl 1,1-cyclopropanedicarb-
oxylate (2a) in the presence of different Lewis acid catalysts under
microwave irradiation. The results are summarized in Table 1.7,8
The results demonstrated that the use of classical Lewis acids
such as FeCl3 and ZnCl2 did not catalyze the reaction (entries 2
and 3, Table 1). On the other hand, in agreement with our previous
observations,9,10 lanthanide triflates showed remarkable catalytic
activities in terms of product yields (Table 1, entries 4–9). Thus,
the best result was obtained when the reaction was conducted in
the presence of 20 mol % of La(OTf)3 in MeCN at 120 W and
100 °C for 10 min, and 3a was produced in 76% yield along with
its pyrazolium salt 3b in 14% yield (Table 1, entry 5).11,12 The for-
mation of the latter ionic liquid-type compound can be easily
understood by considering the facile quaternization of 3a with
another molecule of 2a. No reaction occurred in the absence of cat-
alysts (Table 1, entry 1).
CO2Et
CO2Et
CO2Et
+
N
CO2Et
N
3a
2a (1 equiv)
With these results in hand, we then sought to clarify the general
scope of this method with various combinations of substrates, and
the results are summarized in Table 2.7,8
TfO
The reaction of pyrazole (1a) with cyclopropanedicarboxylates
2b and 2c gave the corresponding adducts 3c and 3d in high yields,
but the sterically crowded 2d reacted very slowly to give 3e in
reduced yield (Table 2, entries 1–3). Consistent with the reported
examples, the nucleophilic attack of 1a occurred exclusively at
the more-substituted carbon center vicinal to the diester moiety
on the cyclopropane ring.13 Importantly, in these examples the
formation of pyrazolium salts could not be detected probably
N
N
La(OTf)3 (20 mol%)
EtO2C
CO2Et
MeCN, 120 W, 10 min
100 °C, 50 psi
CO2Et
CO2Et
3b (22% conversion yield)
Scheme 2.

5870
M. I. Uddin et al. / Tetrahedron Letters 49 (2008) 5867–5870
10. For related works on Ln(OTf)3-catalyzed cyclopropane ring-opening reactions,
The reaction of purine (1g) with 2a gave a mixture of N9- and
see: (a) Kang, Y.-B.; Tang, Y.; Sun, X.-L. Org. Biomol. Chem. 2006, 4, 299; (b)
Karadeolian, A.; Kerr, M. A. J. Org. Chem. 2007, 72, 10251; (c) Perreault, C.;
Goudreau, S. R.; Zimmer, L. E.; Charette, A. B. Org. Lett. 2008, 10, 689; (d)
Carson, C. A.; Young, I. S.; Kerr, M. A. Synthesis 2008, 485; (e) Jackson, S. K.;
Karadeolian, A.; Driega, A. B.; Kerr, M. A. J. Am. Chem. Soc. 2008, 130, 4196. and
references cited therein.
N7-substituted regioisomers 3v and 3w in respective yields of
41% and 33%, along with a trace amount of N3 (or N1)-substituted
3x (Table 2, entry 11).14
To confirm the ease of formation of ionic liquid-type salts dur-
ing the cyclopropane ring-opening process, stepwise conversion
was examined (Scheme 2).15 Thus, treatment of pre-formed adduct
3a with 1 equiv of 2a in the presence of La(OTf)3 (20 mol %) under
the standard conditions (MeCN, 120 W, 10 min, 100 °C, 50 psi)
gave 3b in 22% conversion (15% isolated) yield. This suggests that
the in situ-generated zwitterionic intermediate should be proton-
ated spontaneously during the work-up procedure.
In conclusion, we have developed a novel method for the homo-
conjugate addition of a variety of nitrogen heteroaromatics to
activated cyclopropanes in the presence of La(OTf)3 as an efficient
Lewis acid catalyst under microwave irradiation.16 This method
11. Compound 3a: Colorless oil; FTIR (neat)
m ;
1747, 1732, 1515 cmÀ1 1H NMR
(CDCl3, 400 MHz) d 1.26 (6H, t, J = 7.1 Hz), 2.45 (2H, q, J = 7.1 Hz), 3.28 (1H, t,
J = 7.1 Hz), 4.19 (2H, q, J = 7.1 Hz), 4.20 (2H, q, J = 7.1 Hz), 4.23 (2H, t, J = 7.1 Hz),
6.24 (1H, dd, J = 2.2, 1.9 Hz), 7.38 (1H, d, J = 2.2 Hz), 7.51 (1H, d, J = 1.9 Hz); 13
C
NMR (CDCl3, 100 MHz) d 13.9 (Â2), 29.2, 48.8, 49.2, 61.5 (Â2), 105.4, 129.3,
139.6, 168.7 (Â2).
Compound 3b: Colorless oil; FTIR (neat)
m ;
1728, 1283, 1254, 1032 cmÀ1 1H
NMR (CDCl3, 400 MHz) d 1.28 (12H, t, J = 7.1 Hz), 2.47 (4H, q, J = 6.8 Hz), 3.60
(2H, t, J = 6.8 Hz), 4.15–4.27 (8H, m), 4.74 (4H, t, J = 6.8 Hz), 6.75 (1H, t,
J = 2.9 Hz), 8.30 (2H, d, J = 2.9 Hz); 13C NMR (CDCl3, 100 MHz) d 13.9 (Â4), 28.1
(Â2), 47.9 (Â2), 48.2 (Â2), 62.2 (Â4), 108.3, 137.8 (Â2), 168.2 (Â4).
12. The reaction of 1a with the Meldrum acid derivative 4 in the presence of
20 mol % of La(OTf)3 under the similar conditions gave
accompanied by acylation and decarboxylation
5 in 66% yield
will provide a new rapid method for preparing c-amino carbonyl
compounds, which are known to be important building blocks
for natural products and synthetic drugs.17 Further studies to
extend the scope of this new method are now in progress in our
laboratory.
N
1a (2.5 equiv)
La(OTf)3 (20 mol%)
N
O
N
N
H
+
MeCN, 120 W, 60 min
Acknowledgements
100 °C, 50 psi
O
O
O
N
This work was supported in part by a Scientific Research on Pri-
ority Areas (18037053 and 18032055) from MEXT, as well as by a
Special Research Grant for Green Science from Kochi University.
We also thank the Asahi Glass Foundation for financial support
of this work.
N
O
4
5 (66% yield)
Compound 5: mp 52–53 °C; FTIR (KBr)
m ;
1739, 1420, 1388 cmÀ1 1H NMR
(CDCl3, 400 MHz) d 2.36 (2H, quintet, J = 6.8 Hz), 3.15 (2H, t, J = 6.8 Hz), 4.28
(2H, t, J = 6.8 Hz), 6.24 (1H, t, J = 2.0 Hz), 6.44 (1H, dd, J = 2.7, 1.4 Hz), 7.41
(1H, d, J = 2.0 Hz), 7.50 (1H, d, J = 2.0 Hz), 7.69 (1H, d, J = 1.4 Hz), 8.24 (1H, d,
J = 2.7 Hz); 13C NMR (CDCl3, 100 MHz) d 25.0, 30.8, 50.8, 105.4, 109.6, 128.2,
129.2, 139.5, 144.0, 171.2.
References and notes
1. Reviews: (a) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis;
Pergamon, 1992; p 114; (b) Liu, M.; Sibi, M. P. Tetrahedron 2002, 58, 7991; (c)
Vicario, J. L.; Badía, D.; Carrillo, L. Org. Prep. Proc. Int. 2005, 37, 513; (d) Xu,
L.-W.; Xia, C.-G. Eur. J. Org. Chem. 2005, 633.
2. Uddin, Md. I.; Nakano, K.; Ichikawa, Y.; Kotsuki, H. Synlett 2008, 1402.
3. Reviews: (a) Danishefsky, S. Acc. Chem. Res. 1979, 12, 66; (b) Wong, H. N. C.;
Hon, M.-Y.; Tse, C.-W.; Yip, Y.-C.; Tanko, J.; Hudlicky, T. Chem. Rev. 1989, 89,
165; (c) Reissig, H.-U.; Zimmer, R. Chem. Rev. 2003, 103, 1151; (d) Yu, M.;
Pagenkopf, B. L. Tetrahedron 2005, 61, 321.
4. For related works on base-promoted transformations, see: (a) Franco, F.;
Greenhouse, R.; Muchowski, J. M. J. Org. Chem. 1982, 47, 1682; (b) Ortiz, C.;
Greenhouse, R. Tetrahedron Lett. 1985, 26, 2831; (c) Gibson, C. L.; La Rosa, S.;
Ohta, K.; Boyle, P. H.; Leurquin, F.; Lemacon, A.; Suckling, C. J. Tetrahedron 2004,
60, 943; (d) Kalayanov, G.; Jaksa, S.; Scarcia, T.; Kobe, J. Synthesis 2004, 2026; (e)
Torii, T.; Yamashita, K.; Kojima, M.; Suzuki, Y.; Hijiya, T.; Izawa, K. Nucleosides,
Nucleotides Nucleic Acid 2006, 25, 625; (f) Tanaka, M.; Ubukata, M.; Matsuo, T.;
Yasue, K.; Matsumoto, K.; Kajimoto, Y.; Ogo, T.; Inaba, T. Org. Lett. 2007, 9, 3331.
5. (a) The enormous power of microwave irradiation reactions has been well
established in a wide range of organic transformations. See: Microwave Assisted
Organic Synthesis; Tierney, J. P., Lidström, P., Eds.; CRC Press: USA and Canada,
2005; (b) Microwave Methods in Organic Synthesis; Larhed, M., Olofsson, K., Eds.;
Springer: Berlin, 2006.
13. The higher reactivity at the more-substituted carbon center vicinal to the
diester moiety on the cyclopropane ring has been well established. For
example, see Ref. 3a.
14. Assignments of N-9 (3v) versus N-7 (3w) isomers can be made from the 13C
NMR signals of the C-4 and C-5 peaks; for 3v: d 134.0 and 151.4; for 3w: d
125.1 and 160.8. For comparison, see: (a) Gómez, J. A.; Campos, J.; Marchal, J.
A.; Trujillo, M. A.; Melguizo, C.; Prados, J.; Gallo, M. A.; Aránega, A.; Espinosa, A.
´
Tetrahedron 1997, 53, 7319; (b) Núnez, M. C.; Pavani, M. G.; Dıaz-Gavilán, M.;
Rodr´ıguez-Serrano, F.; Gómez-Vidal, J. A.; Marchal, J. A.; Aránega, A.; Gallo, M.
A.; Espinosa, A.; Campos, J. M. Tetrahedron 2006, 62, 11724.
Compound 3v: Colorless oil; FTIR (neat)
m ;
1745, 1731, 1597, 1580 cmÀ1 1H
NMR (CDCl3, 400 MHz) d 1.26 (6H, t, J = 7.1 Hz), 2.55 (2H, q, J = 7.1 Hz), 3.35
(1H, t, J = 7.1 Hz), 4.12–4.24 (4H, m), 4.44 (2 H, t, J = 7.1 Hz), 8.13 (1H, s), 9.00
(1H, s), 9.16 (1H, s); 13C NMR (CDCl3, 100 MHz) d 14.0 (Â2), 28.7, 41.4, 48.9,
61.9 (Â2), 134.0 (C-4), 145.2, 148.7, 151.4 (C-5), 152.7, 168.3 (Â2).
Compound 3w: Pale yellow oil; FTIR (neat)
m ;
1742, 1729, 1605, 1561 cmÀ1 1H
NMR (CDCl3, 400 MHz) d 1.27 (6H, t, J = 7.1 Hz), 2.51 (2H, q, J = 7.1 Hz), 3.34
(1H, t, J = 7.1 Hz), 4.15–4.27 (4H, m), 4.44 (2H, t, J = 7.1 Hz), 8.23 (1H, s), 9.05
(1H, s), 9.18 (1H, s); 13C NMR (CDCl3, 100 MHz) d 14.0 (Â2), 28.9, 43.6, 48.5,
62.1 (Â2), 125.1 (C-4), 140.0, 147.9, 153.5, 160.8 (C-5), 168.1 (Â2).
6. We also examined the reaction of the Na salt of 1a with 2a (1.2 equiv) in
refluxing DMF for 12 h, but no product formation was observed.
7. Microwave irradiation was carried out in
15. The use of microwave techniques for the preparation of ionic liquid-type salts
has been reported previously. For example, see: Fu, S.-K.; Liu, S.-T. Synth.
Commun. 2006, 36, 2059 and related references cited therein.
a
discovery microwave heating
apparatus with a temperature controller.
16. The reaction using indole itself as an N-heteroaromatic under the standardized
conditions caused only C-alkylation even in low yield (ca. 6%). For similar
findings, see: (a) Harrington, P.; Kerr, M. A. Tetrahedron Lett. 1997, 38, 5949; (b)
Kerr, M. A.; Keddy, R. G. Tetrahedron Lett. 1999, 40, 5671; (c) England, D. B.;
Kuss, T. D. O.; Keddy, R. G.; Kerr, M. A. J. Org. Chem. 2001, 66, 4704.
General procedure:
A mixture of N-heteroaromatic 1 (1.5 mmol), cyclo-
propanedicarboxylate 2 (1.0 mmol) and La(OTf)3 (0.2 mmol) in MeCN (ca.
2.0 mL) was placed in a microwave reaction vessel, and the mixture was
allowed to react at 120 W, 100 °C and 50 psi for a period indicated in Tables 1
and 2. After cooling to rt, the mixture was purified by silica gel column
chromatography (elution with CH2Cl2–i-PrOH) to afford the adduct 3 in some
cases together with its salt.
´
17. (a) Vicario, J. L.; Rodriguez, M.; Badıa, D.; Carrillo, L.; Reyes, E. Org. Lett. 2004, 6,
3171; (b) Chi, Y.; Guo, L.; Kopf, N. A.; Gellman, S. H. J. Am. Chem. Soc. 2008, 130,
5608 and related references cited therein.
8. All new compounds gave satisfactory spectral data.
9. Kotsuki, H.; Arimura, K.; Maruzawa, R.; Ohshima, R. Synlett 1999, 650.