50
S. Azad et al. / Tetrahedron Letters 50 (2009) 48–50
Table 3
References and notes
High-pressure-promoted aza-Michael reaction of ureas with enonesa
1. High-Pressure Organic Chemistry, Part 34, Part 33: Uddin, Md. I.; Nakano, K.;
Ichikawa, Y.; Kotsuki, H. Synlett 2008, 1402.
2. Reviews: (a) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis;
Pergamon: New York, 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.
O
O
O
p
-TsOH•H2O (10 mol%)
O
R
+
N
NH2
0.6 GPa, 60 °C
R
H
N
H
N
H
MeCN
3. See Ref. 1, and references cited therein.
4
2
5
4. (a) Ahn, K. H.; Lee, S. J. Tetrahedron Lett. 1994, 35, 1875; (b) Goumri-Magnet, S.;
Guerret, O.; Gornitzka, H.; Cazaux, J. B.; Bigg, D.; Palacios, F.; Bertrand, G. J. Org.
Chem. 1999, 64, 3741; (c) Takasu, K.; Nishida, N.; Ihara, M. Synlett 2004, 1844;
(d) Lin, Y.-D.; Kao, J.-Q.; Chen, C.-T. Org. Lett. 2007, 9, 5195.
Entry
1
Urea
Enone
Yield 5b (%)
70 (5a)
5. (a) Gaunt, M. J.; Spencer, J. B. Org. Lett. 2001, 3, 25; (b) Kobayashi, S.; Kakumoto,
K.; Sugiura, M. Org. Lett. 2002, 4, 1319; (c) Wabnitz, T. C.; Spencer, J. B.
Tetrahedron Lett. 2002, 43, 3891; (d) Wabnitz, T. C.; Spencer, J. B. Org. Lett. 2003,
5, 2141; (e) Wabnitz, T. C.; Yu, J.-Q.; Spencer, J. B. Synlett 2003, 1070; (f) Xu, L.-
W.; Li, L.; Xia, C.-G.; Zhou, S.-L.; Li, J.-W.; Hu, X.-X. Synlett 2003, 2337; (g)
Srivastava, N.; Banik, B. K. J. Org. Chem. 2003, 68, 2109; (h) Xu, L.-W.; Xia, C.-G.;
Hu, X.-X. Chem. Commun. 2003, 2570; (i) Wabnitz, T. C.; Yu, J.-Q.; Spencer, J. B.
Chem. Eur. J. 2004, 10, 484; (j) Xu, L.-W.; Xia, C.-G. Synthesis 2004, 2191; (k) Xu,
L.-W.; Xia, C.-G. Tetrahedron Lett. 2004, 45, 4507; (l) Palomo, C.; Oiarbide, M.;
Halder, R.; Kelso, M.; Gómez-Bengoa, E.; García, J. M. J. Am. Chem. Soc. 2004,
126, 9188; (m) Ménand, M.; Dalla, V. Synlett 2005, 95; (n) Bartoli, G.; Bartolacci,
M.; Giuliani, A.; Marcantoni, E.; Massaccesi, M.; Torregiani, E. J. Org. Chem.
2005, 70, 169; (o) Raje, V. P.; Bhat, R. P.; Samant, S. D. Tetrahedron Lett. 2005, 46,
835; (p) Yang, L. Y.; Xu, L.-W.; Xia, C.-G. Tetrahedron Lett. 2005, 46, 3279; (q)
Raje, V. P.; Bhat, R. P.; Samant, S. D. Synlett 2006, 2676; (r) Loreto, M. A.;
Migliorini, A.; Tardella, P. A. J. Org. Chem. 2006, 71, 2163; (s) Chen, Y. K.;
Yoshida, M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 9328; (t) Smitha,
G.; Reddy, Ch. S. Catal. Commun. 2007, 8, 434; (u) Yeom, C.-E.; Kim, M. J.; Kim, B.
M. Tetrahedron 2007, 63, 904; (v) Jensen, R. S.; Umeda, K.; Okazaki, M.; Ozawa,
F.; Yoshifuji, M. J. Organomet. Chem. 2007, 692, 286; (w) Yang, L.; Xu, L.-W.; Xia,
C.-G. Tetrahedron Lett. 2007, 48, 1599; (x) Zhao, G.-L.; Córdova, A. Tetrahedron
Lett. 2007, 48, 5976; (y) Hayashi, A.; Okazaki, M.; Ozawa, F.; Tanaka, R.
Organometallics 2007, 26, 5246; (z) Fustero, S.; Jiménez, D.; Moscardó, J.;
Catalán, S.; del Pozo, C. Org. Lett. 2007, 9, 5283; (aa) Carlson, E. C.; Rathbone, L.
K.; Yang, H.; Collett, N. D.; Carter, R. G. J. Org. Chem. 2008, 73, 5155. See also: Ref
4d.
4a
2a
NHCONH2
2
3
4a
4a
4a
4a
4a
4b
2b
2c
2d
2e
2f
59 (5b)
93 (5c)
Complex (5d)
56 (5e)e
74 (5f)
4c
5d
6f
7f
2g
73 (5g)
8
9
2a
2a
58 (5h)
53 (5i)
H3C
NHCONH2
4b
CH2NHCONH2
4c
10d
11f
C4H9NHCONH2 4d
(C2H5)2NCONH2 4e
2a
2a
72 (5j)
86 (5k)
12g
2a
60 (5l)
NCONH2
4f
6. Busca, G. Chem. Rev. 2007, 107, 5366.
7. As peculiar examples, the use of nucleobases as Michael donors is known: (a)
Khalafi-Nezhad, A.; Zarea, A.; Soltani Rad, M. N.; Mokhtari, B.; Parhami, A.
Synlett 2005, 419; (b) Firouzabadi, H.; Iranpoor, N.; Jafari, A. A. Adv. Synth. Catal.
2005, 347, 655; (c) Qu, G.-R.; Zhang, Z.-G.; Geng, M.-W.; Xia, R.; Zhao, L.; Guo,
H.-M. Synlett 2007, 721; (d) Liu, B. K.; Wu, Q.; Qian, X. Q.; Lv, D. S.; Lin, X. F.
Synthesis 2007, 2653.
8. Review: Kotsuki, H.; Kumamoto, K. J. Synth. Org. Chem., Jpn. 2005, 63, 770.
9. For a related work on high-pressure-promoted aza-Michael reactions of
amines, see: Rulev, A. Yu.; Yenil, N.; Pesquet, A.; Oulyadi, H.; Maddaluno, J.
Tetrahedron 2006, 62, 5411 and references cited therein.
10. All new compounds gave satisfactory spectral data.
a
Unless otherwise noted, all the reactions were performed at 0.6 GPa and 60 °C
for 8 h in MeCN (1.5 mL) using 4 (1.0 mmol) and 2 (1.2 mmol) in the presence of p-
TsOHÁH2O (0.1 mmol).
b
Isolated yield.
c
At 0.6 GPa, rt for 10 h.
d
For 24 h.
e
Trans/cis = 4:1 by 1H NMR.
f
At 0.8 GPa, 50 °C for 55 h.
At 0.6 GPa, rt for 55 h.
g
11. General procedure: A mixture of amide 1 or urea 4 (1.0 mmol) and enone 2
(1.2 mmol) in MeCN (ca. 1.3 mL) containing 10 mol % p-TsOHÁH2O was placed
in a Teflon reaction vessel (1.5 mL volume), and the mixture was allowed to
react at 0.6 GPa at 60 °C for a certain period of time to complete the reaction.
After the reaction mixture was cooled and the pressure was released, the
mixture was evaporated in vacuo. The crude product was purified by silica gel
column chromatography (elution with hexane/EtOAc) to afford the pure
adduct 3 or 5.
2–7). p-Tolylurea (4b) and mono-substituted aliphatic ureas, such
as 4c and 4d, could also react with 2a to afford the desired adducts
5h–j in moderate to good yields (53–72%) (Table 3, entries 8–10).
Efficient reactions were observed for N,N-dialkyl-substituted ureas,
such as 4e and 4f, with 2a after longer reaction times (Table 3,
entries 11 and 12). These results clearly demonstrate the power
of the present method, since it is the only method known for effec-
tively preparing b-N-ureido-substituted ketone derivatives.
In conclusion, we have developed a simple and expeditious
method for the aza-Michael reaction of amides and ureas as
weakly reactive nucleophiles by combining Brønsted acid catalysis
and high-pressure conditions. This method should be valuable for
deriving novel types of b-N-amide- and b-N-ureido-substituted
carbonyl compounds, starting from readily available substrates.18
Further studies to extend the scope of this new method are now
in progress in our laboratory.
12. Compound 3a:4c,d mp 128.0–128.5 °C (from hexane–CHCl3; FTIR (KBr)
m 3323,
1713, 1633, 1530 cmÀ1 1H NMR (400 MHz, CDCl3) d 1.78–1.90 (2H, m), 1.98–
;
2.08 (1H, m), 2.17–2.24 (1H, m), 2.29–2.49 (3H, m), 2.82 (1H, dd, J = 13.9,
4.9 Hz), 4.47 (1H, m), 6.06 (1H, br), 7.44 (2H, t, J = 7.1 Hz), 7.49 (1H, m), 7.74
(2H, d, J = 7.1 Hz); 13C NMR (100 MHz, CDCl3) d 22.2, 30.8, 41.0, 47.6, 49.0,
126.9 (Â2), 128.6 (Â2), 131.7, 134.3, 166.8, 208.7.
13. The role of hydrated p-TsOHÁH2O is unclear at present.
14. We recently found that microwave irradiation was effective for the homo-
conjugate addition of N-heteroaromatics: Uddin, Md. I.; Mimoto, A.; Nakano,
K.; Ichikawa, Y.; Kotsuki, H. Tetrahedron Lett. 2008, 49, 5867.
15. We found that the reaction was quite sensitive to the steric environment for
both donor and acceptor molecules. For example, no products were formed for
the reaction of C6H5CONHMe with 2a or 1a with 3-methyl-2-cyclohexen-1-
one.
16. The same reaction under microwave irradiation (100 W, 150 psi, 100 °C,
35 min) produced 5a in only 20% isolated yield.
Acknowledgments
17. Compound 5a: mp 179.0–181.5 °C (from AcOEt); FTIR (KBr)
m 3313, 1716,
1628, 1574 cmÀ1 1H NMR (400 MHz, CDCl3) d 1.69–1.83 (2H, m), 1.89–2.00
;
(1H, m), 2.06–2.13 (1H, m), 2.22–2.32 (2H, m), 2.35–2.43 (1H, m), 2.73 (1H, dd,
J = 14.2, 4.9 Hz), 4.23 (1H, m), 4.94 (1H, d, J = 7.3 Hz; exchangeable by D2O),
6.60 (1H, br; exchangeable by D2O), 7.10 (1H, m), 7.26–7.34 (4H, m); 13C NMR
(100 MHz, CDCl3) d 22.1, 31.0, 41.1, 48.1, 49.4, 120.6 (Â2), 123.7, 129.3 (Â2),
138.5, 155.1, 210.0.
This work was supported in part by grants for Scientific Re-
search on Priority Areas (18037053 & 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 their
financial support. One of the authors (S.A.) is grateful for a Sasaka-
wa Scientific Research Grant from the Japan Science Society.
18. Despite the extreme activity of the present method, however, no reaction was
observed for 1a with methyl acrylate, methyl cinnamate, or acrylonitrile under
the standardized conditions.