An efficient conjugate hydrocyanation of chalcones and related enones with TMSCN under solvent- and additive-free microwave conditions

Article abstract of DOI:10.1016/j.tetlet.2006.12.145

A first example of solvent- and additive-free 1,4-addition reaction of α,β-unsaturated ketones such as chalcones, 3-nonen-2-one and benzalacetone with trimethylsilyl cyanide (TMSCN) is described. The addition of TMSCN to chalcones, 3-nonen-2-one, and benzalacetone under microwave irradiation in the absence of Lewis or Br?nsted acids and solvents, yielded the corresponding β-cyanoketones in good to moderate yields, as quite rapidly as in 5 min. No systematic substituent effect of chalcones on the yields was observed. No reaction of α,β-unsaturated esters such as methyl cinnamate with TMSCN took place under the same conditions.

Full text of DOI:10.1016/j.tetlet.2006.12.145

Tetrahedron Letters 48 (2007) 2037–2039
An efficient conjugate hydrocyanation of chalcones and
related enones with TMSCN under solvent- and
additive-free microwave conditions
Hirokazu Iida, Tatsuya Moromizato, Hiroshi Hamana* and Kiyoshi Matsumoto*
Faculty of Pharmacy, Chiba Institute of Science, Shiomi-cho 15-8, Choshi, Chiba 288-0025, Japan
Received 24 October 2006; revised 17 December 2006; accepted 28 December 2006
Available online 5 January 2007
Abstract—A first example of solvent- and additive-free 1,4-addition reaction of a,b-unsaturated ketones such as chalcones, 3-nonen-
2-one and benzalacetone with trimethylsilyl cyanide (TMSCN) is described. The addition of TMSCN to chalcones, 3-nonen-2-one,
and benzalacetone under microwave irradiation in the absence of Lewis or Brønsted acids and solvents, yielded the corresponding b-
cyanoketones in good to moderate yields, as quite rapidly as in 5 min. No systematic substituent effect of chalcones on the yields was
observed. No reaction of a,b-unsaturated esters such as methyl cinnamate with TMSCN took place under the same conditions.
Ó 2007 Published by Elsevier Ltd.
Conjugate hydrocyanation of a,b-unsaturated carbonyl
compounds is useful reactions in organic chemistry,
because the resulting b-cyanoadducts can be converted
to c-aminobutyric acids (GABA analogues and deriva-
tives) under reducing conditions. One of the most pow-
erful and ubiquitous methods for introduction of a
cyano group would be the reactions of ketones with
TMSCN. Specifically, the reaction of p-benzoquinones
with TMSCN afforded only 1,2-adducts which serve as
a carbonyl protection.1 It is reported that the reactions
of enones with TMSCN in the presence of base catalysts
gave almost selectively 1,2-adducts.2–4 In contrast,
employing Lewis acid catalysts such as Et2AlCN,5
Et3Al,6 AlCl3,7 and SnCl2,7 the selective 1,4-additions
took place. Recently, two excellent methods of catalytic
enantioselective conjugate addition of cyanide using
TMSCN were reported by Jacobsen and co-workers8
and Shibasaki and co-workers.9 As far as we searched,
acid additives were essential for selective 1,4-addition
reactions of enones with TMSCN.
products.10 We have reported the enantioselective tri-
methylsilylcyanation of acetophenone catalyzed by
Ti-triol under high pressure.11 In continuation of our
studies using non-conventional methods, it occurred
to us that microwave irradiation might assist such 1,2-
and/or conjugate additions using TMSCN without
additive and solvent. This was indeed the case.12 Quite
interestingly, under microwave conditions, a variety of
chalcones underwent rapidly and regioselectively
conjugate additions with TMSCN without additive
and solvent. This is a subject of the present Letter.
Representatively, the reaction of (E)-chalcone (1 equiv)
and TMSCN (2 equiv) without solvent and any additive,
proceeded smoothly by the irradiation of microwave
and completed within 5 min. The crude mixture was
subjected to evaporation in vacuo to remove TMSCN,
and the resulting mixture in THF was treated by TBAF
for 5 min to give a single product after column chroma-
1
tography on SiO2. An inspection of H and 13C NMR
established that the product was not the 1,2-adduct
but 1,4-adduct 1, no 1,2-adduct being observed in the
present case (Scheme 1).13
We have been interested in the organic reactions under
non-conventional conditions such as high pressure and
microwave irradiation. These reaction conditions accel-
erate reaction rates and sometimes yield unexpected
Further successful examples of the reactions of (E)-chal-
cones with TMSCN under the same conditions13 are
illustrated in Table 1. Curious substituent effects on
the yields should be noted. Thus, the chalcones with
such groups as H, CH3, OCH3, and F either at 4 or
40, the 1,4-adducts were obtained in good to moderate
*
Corresponding authors. Tel./fax: +81 479 30 4615 (K.M.); tel.: +81
479 30 4616; fax: +81 479 30 4740 (H.H.); e-mail addresses:
hhmana@cis.ac.jp; kmatsumoto@cis.ac.jp
0040-4039/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2006.12.145

2038
H. Iida et al. / Tetrahedron Letters 48 (2007) 2037–2039
of 3-nonen-2-one, and benzalacetone with TMSCN gave
O
the 1,4-adduct albeit in a 20% yield with 38% recovery of
benzalacetone. Unfortunately, however, a,b-unsatu-
rated esters such as methyl cinnamate did not undergo
1,4-addition at all, the starting material being recovered
(Scheme 2).
2eq. TMSCN
no solvent
microwave
5 min
10% aq. TBAF
THF
R2
5 min
R1
O
CN
In conclusions, we disclosed a highly efficient 1,4-addi-
tion reactions of chalcones and the related enones with
TMSCN under microwave irradiation. Without additive
and solvent, the reactions proceed rapidly and regio-
selectively to give the corresponding 1,4-adducts gener-
ally in good to moderate yields. Further investigations
employing other kinds of enones such as a,b-unsatu-
rated steroid hormones are under way and will be
reported in due course.
R2
R1
1
Scheme 1. Microwave assisted reactions of chalcones with TMSCN.
Table 1. b-Cyanoketones 1 from chalcones and TMSCN
Entry R1
R2
H
Yielda,b (%) mpc (°C)
1
H
87
122.5–125
(lit. 126–127 (EtOH))14
71–73
2
3
p-CH3
H
H
CH3
69 (13)
68 (13)
135–137
(lit. 135–136 (EtOH))14
Oil
Acknowledgments
4
5
6
7
8
9
p-OCH3
H
p-F
H
p-Cl
H
H
72 (10)
OCH3 65 (11)
This work was supported in part by a Grant-in-Aid for
Scientific Research (C, No. 18244120) from the Ministry
of Education, Culture, Sports, Science, and Technology,
Japan (to H.H.). This work was also supported in part
by Grant-in-Aid for Encouragement of Young Scientists
(B, No. 16710157) from the Japan Society for the Pro-
motion of Science (to H.I.). Finally, the financial sup-
ports from Chiba Institute of Science (Special Grants:
Education and Research Grants in 2004 and 2006 to
K.M. and H.I. respectively) are greatly acknowledged.
113–114
132–135
97–100.5
116–118 (lit. 122)15
112–113
H
F
H
Cl
75 (12)
71 (10)
72 (20)
27 (33)
(lit. 115–117 (EtOH))14
122–124 (lit. 124)15
86–87
10
11
12
p-Br
m-Br
H
H
H
Br
27 (36)
62 (15)
13 (59)
122–123
a Isolated yields and not optimized.
b Recovered starting material was shown in the parenthesis.
c Analytically pure samples were obtained by recrystallization from
ethanol.
References and notes
yields (Table 1, entries 1–7), whereas the chalcones pos-
sessing a halogen group such as Cl and Br either at 4 or
40 position, the 1,4-adducts were obtained only in low
yields (Table 1, entries 8–10, 12). However, the chalcone
having Br at 3 position gave the adduct in a pretty good
yield (entry 11). In any event, no 1,2-adduct was ob-
tained in our hands and the starting materials were
recovered.
1. Evans, D. A.; Hoffman, J. M.; Truesdale, L. K. J. Am.
Chem. Soc. 1973, 95, 5822–5823.
2. Baeza, A.; Najera, C.; Retamosa, M de G.; Sansano, J. M.
Synthesis 2005, 2787–2797.
3. He, B.; Li, Y.; Feng, X.; Zhang, G. Synlett 2004, 1776–
1778.
4. Higuchi, K.; Onaka, M.; Izumi, Y. Bull. Chem. Soc. Jpn.
1993, 66, 2016–2032.
5. Nagata, W.; Yoshioka, M. Org. React. 1977, 25, 255, and
the references cited therein.
In order to help clarify the scope and limitation of the
present method, some reactions of the enones other than
chalcones were performed under the same conditions.
For instances, 3-nonen-2-one with TMSCN afforded
the 1,4-adduct in a 65% yield along with 24% recovery
6. Utimoto, K.; Obayashi, M.; Shishiyama, Y.; Inoue, M.;
Nozaki, H. Tetrahedron Lett. 1980, 21, 3389–3392.
7. Utimoto, K.; Wakabayashi, Y.; Horie, T.; Inoue, M.;
Shishiyama, Y.; Obayashi, M.; Nozaki, H. Tetrahedron
1983, 39, 967–973.
O
O
CN
O
2eq. TMSCN
microwave
10% aq. TBAF
THF
O
CN
2eq. TMSCN
microwave
10% aq. TBAF
THF
O
2eq. TMSCN
microwave
10% aq. TBAF
THF
OCH3
No reactions
Scheme 2. Microwave assisted reactions of some enones other than chalcones.

H. Iida et al. / Tetrahedron Letters 48 (2007) 2037–2039
2039
8. (a) Sammis, G. M.; Jacobsen, E. N. J. Am. Chem. Soc.
2003, 125, 4442; (b) Sammis, G. M.; Danjo, H.; Jacobsen,
E. N. J. Am. Chem. Soc. 2004, 126, 9928.
9. Mita, T.; Sasaki, K.; Kanai, M.; Shibasaki, M. J. Am.
Chem. Soc. 2005, 127, 514–515.
10. (a) Matsumoto, K.; Acheson, R. M. Organic Synthesis at
High Pressure; John Wiley & Sons: New York, 1991; (b)
Matsumoto, K.; Hamana, H.; Iida, H. Helv. Chim. Acta
2005, 88, 2033–2234.
11. Choi, M. C. K.; Chan, S.-S.; Chan, M.-K.; Matsumoto,
K. Tetrahedron Lett. 1997, 38, 6669–6672; Choi, M. C. K.;
Chan, S.-S.; Chan, M.-K.; Kim, J. C.; Iida, H.; Matsu-
moto, K. Heterocycles 2004, 62, 643–653.
12. For normal 1,2-additions of TMSCN with aldehydes and
ketones under additive- and solvent-free microwave con-
ditions: Iida, H.; Hamana, H.; Matsumoto, K. Synth.
Commun., in press.
13. Representative experimental procedure: A mixture of (E)-
chalcone (1 mmol) and TMSCN (2 mmol) were irradiated
(CEM Discover, 200 °C) for 5 min. After cooling to rt,
the mixture was evaporated in vacuo and dissolved in
THF (5 mL) to which 10% aqueous solution of TBAF
(0.5 mL) was added at rt, and then the solution was
stirred for 5 min at rt. Water (5 mL) was added to the
solution, and the organic layer was extracted with ethyl
acetate (10 mL). The organic layer was washed by brine
(10 mL), and dried over MgSO4. Ethyl acetate was
evaporated and the resulting oil was subjected to a short
column chromatography on SiO2 using ethyl acetate and
hexane (1:1) as the eluent to afford 1,4-adduct. All
isolated products gave satisfactory elemental and spectral
data (1H NMR, 13C NMR, Anal) and were in agreement
with those reported in the literature.14 The selected
spectral data of the 1,4-adduct: Compound 1 (R1 = H,
R2 = H): colorless needles, mp 122.0–125.0 (EtOH), 1H
NMR (CDCl3) d: 3.51 (1H, dd, J = 6.0, 17.9 Hz), 3.73
(1H, dd, J = 7.9, 17.9 Hz), 4.58 (1H, dd, J = 6.0, 7.9 Hz),
7.31–7.54 (8H, m), 7.57–7.64 (1H, m), 7.92–7.96 (1H, m);
13C NMR (CDCl3) d: 31.9, 44.5, 120.6, 127.5, 128.1,
128.4, 128.8, 129.3, 133.9, 135.3, 135.7, 194.7, Anal.
Calcd for C16H13NO: C, 81.68; H, 5.57; N, 5.95. Found:
C, 81.27; H, 5.38; N, 5.95.
14. Ciller, J. A.; Seoane, C.; Soto, J. L. Liebigs Ann. Chem.
1985, 51–57.
15. Allen, C. F. H.; Frame, G. F. Can. J. Res. 1932, 6, 605–
613.