Lithium naphthalenide induced reductive selenenylation of α-cyano ketones: A regiocontrolled process for α-phenylseleno ketones and one-pot conversion into enone system

Article abstract of DOI:10.1055/s-2007-977448

An efficient procedure for the regiocontrolled synthesis of α-phenylseleno ketones has been developed, making use of the lithium naphthalenide induced reductive selenenylation of the α-cyano ketone system as a key operation. Moreover, seleno ketones thus generated in situ, upon subsequent treatment with hydrogen peroxide and acetic acid, could be further converted into the corresponding enones with a high degree of regioselectivity, presumably due to the lithium salt mediated selenoxide syn-elimination process. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-977448

1274
LETTER
Lithium Naphthalenide Induced Reductive Selenenylation of a-Cyano
Ketones: A Regiocontrolled Process for a-Phenylseleno Ketones and One-Pot
Conversion into Enone System
R
a
eductive
i
Selene
a
nylation of
-
a
-Cyano
L
K
etone
s
iang Zhu,*a Yen-Chun Ko,a Chun-Wei Kuo,b Kak-Shan Shia*b
Department of Chemistry, National Dong-Hwa University, Hualien 974, Taiwan, R.O.C.
Fax +886(38)633570; E-mail: jlzhu@mail.ndhu.edu.tw
b
Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350, Taiwan, R.O.C.
Fax +886(37)586456; E-mail: ksshia@nhri.org.tw
Received 29 January 2007
selenenylating agent, a-selenenylation was effected, re-
sulting in the specific replacement of the cyano group
with a phenylseleno group. A typical experiment is de-
picted in Scheme 1.14 However, it is noteworthy that
Abstract: An efficient procedure for the regiocontrolled synthesis
of a-phenylseleno ketones has been developed, making use of the
lithium naphthalenide induced reductive selenenylation of the a-cy-
ano ketone system as a key operation. Moreover, seleno ketones
thus generated in situ, upon subsequent treatment with hydrogen among several phenylselenenylating agents investigated,
peroxide and acetic acid, could be further converted into the corre-
phenylselenyl bromide is superior to its counterparts such
sponding enones with a high degree of regioselectivity, presumably
as phenylselenyl chloride (65% yield) and diphenyl
due to the lithium salt mediated selenoxide syn-elimination process.
diselenide (52% yield) in offering compound 2.
Key words: lithium naphthalenide, a-phenylseleno ketones, regio-
selectivity, a-cyano ketones, reductive selenenylation
O
O
LN (5 equiv), THF, 20 min, –40 °C
CN
SePh
Ph
then PhSeBr (1.2 equiv), 30 min
90%
Ph
a-Phenylseleno ketones are of great importance in syn-
thetic chemistry where they are commonly used as the
substrates for preparation of a,b-unsaturated ketones1 or
the intermediates for synthesizing polycyclic compounds
via a free-radical cyclization process.2 In addition to their
synthetic versatility, a specific series of a-phenylseleno
ketones as reported by Cotgreave et al.3 has been shown to
possess glutathione peroxidase-like biological properties,
indicating that a-phenylseleno ketones might have poten-
tial to serve as anticancer, antiviral and anti-inflammatory
agents,4 and/or as the selenium source of selenoproteins,
which are essential for human immune system and known
to play a critical role in reducing the incidence of a wide
variety of cancers, particularly that of the prostate.5,6
1
2
Scheme 1
This reductive selenenylation process proved to be gener-
al as outlined in Table 1. In all cases examined, the reac-
tions proceeded smoothly and the desired products were
obtained in synthetically useful yields (75–92%). Sub-
strates 1 and 3–9 are prepared by alkylation of the corre-
sponding a-cyano ketones using an appropriate alkylating
agent and lithium hydride (LiH) in THF at room tempera-
ture for 24 hours, which are readily accessible via the
Thorpe–Ziegler reaction,15 the base-induced rearrange-
ment of isoxazoles16 or the a-cyanation of ketones.17 On
the other hand, substrates 10 and 11 were constructed
from Diels–Alder reaction of 2,2-dimethyl-1-cyanoben-
zoylethene with isoprene and 2,3-dimethyl-1,3-butadiene,
respectively, in the presence of ZnCl2 as catalyst,18 and
substrate 12 was prepared according to the procedure
reported in the literature.13
While a number of procedures are accessible to provide a-
phenylseleno ketones, an efficient control over the regio-
selectivity remains problematic for unsymmetrical ke-
tones with the a and a¢ carbons to a ketone carbonyl
equally susceptible to selenenylation.7–11 Herein, we wish
to report that a convenient synthetic method, making use
of the lithium naphthalenide (LN)12 induced reductive
selenenylation of a-cyano ketones as a key operation, has
been developed to facilitate the formation of the corre-
sponding a-phenylseleno ketones with complete regiose-
lectivity. It was found that a-cyano ketones could be
readily reduced with LN under mild conditions (–40 °C)
to give the corresponding ketone enolates.13 When the
reduction was followed by the addition of a phenyl-
In addition to providing a direct access to a variety of
a-phenylseleno ketones which are otherwise difficult to
synthesize, the aforementioned reductive selenenylation
process also found a synthetic application in converting
a-cyano ketones into enones by modification of the phen-
ylseleno group. It was found that the keto selenides thus
obtained via reductive selenenylation, without isolation,
could be directly oxidized to give the corresponding
enones with high regiocontrol of the double–bond forma-
tion, presumably due to the intermediacy of rich lithium
salts derived from the preceding reaction (vide infra). This
one-pot selenenylation–oxidative-elimination process
was found to be general as illustrated in Table 2. In terms
SYNLETT 2007, No. 8, pp 1274–1278
1
6.
0
5.
2
0
0
7
Advanced online publication: 08.05.2007
DOI: 10.1055/s-2007-977448; Art ID: W01807ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Reductive Selenenylation of a-Cyano Ketones
1275
Table 1 Reductive Selenenylation of a-Cyano Ketones with
of cyclic a-cyano ketones examined (entries 1–6 and 11),
with the exception of a six-membered-ring substrate
(entry 3) which gave a mixture of endo- and exocyclic
enones in 2:1 ratio, the procedure was found to proceed
with regioselectivity to provide the exocyclic products
exclusively in good to excellent yields (72–95%).
Lithium Naphthalenide (continued)
O
O
LN (5 equiv), THF, 20 min
CN
SePh
R
R
then PhSeBr (1.2 equiv), 30 min
Entry a-Cyano ketone
Product
Temp
(°C)
Yield
(%)a
Table 1 Reductive Selenenylation of a-Cyano Ketones with
Lithium Naphthalenide
O
O
CN
SePh
O
O
LN (5 equiv), THF, 20 min
Ph
Ph
SePh
R
CN
9
–40
–40
91
R
then PhSeBr (1.2 equiv), 30 min
Entry a-Cyano ketone
Product
Temp
(°C)
Yield
11
(%)a
O
O
CN
SePh
O
O
10
89c
CN
SePh
1
–40
–40
85
12
3
a Yields are for isolated, chromatographically pure products.
O
O
b 7.0 equiv of LN and 2.2 equiv of PhSeBr were required to complete
the reaction.
CN
Ph
SePh
Ph
c cis-Addition product is temporarily assigned based on previously
closely resembled examples.13
2
87
87
88
4
As for acyclic substrates (entries 7 and 8), in each case
only a single regioisomer (E-form) was formed in quanti-
tative yield (90–95%). All enones obtained were charac-
terized by spectroscopic methods and where applicable,
NOE experiments were extensively performed to deter-
mine the stereochemistry assigned. As well, the spectral
data of compounds 13–17 are in good agreement with
those reported in the literature.9b,19–22 As a typical exam-
ple, a-phenylseleno ketone 2 thus generated in situ fol-
lowing the protocol in Scheme 1 was further treated with
acetic acid (4 equiv) and H2O2 (8 equiv) at –40 °C to give
the corresponding enone product 13 in 85% yield over
two steps.14 Mechanistically, the regioselectivity ob-
served in compound 13 might be tentatively explained by
invoking the intermediacy of the lithium ion to stabilize
the preferred conformation of the selenoxide intermediate
required for introducing the exo double bond via syn-elim-
ination (Figure 1). This proposal is supported by the fol-
lowing preliminary findings. When isolated compound 2
was treated with 5 equivalents of LiBr followed by addi-
tion of acetic acid (4 equiv) and H2O2 (8 equiv) in CH2Cl2
at 0 °C, a mixture of exo- and endocyclic products were
O
O
CN
SePh
Ph
Ph
3
–40
–40
5
O
O
O
CN
SePh
SePh
4
6
O
CN
5
–40
–40
–40
–40
75b
85
92
86
7
O
O
6
CN
SePh
8
O
O
CN
SePh
Ph
7
8
Ph
H
H
9
O
O
Se
SePh
CN
O
O
Ph
Ph
Li
Figure 1
10
Synlett 2007, No. 8, 1274–1278 © Thieme Stuttgart · New York

1276
J.-L. Zhu et al.
LETTER
Table 2 One-Pot Conversion of a-Cyano Ketones into a,b-Unsatur-
formed in 7:1 ratio (86% yield); however, for comparison,
when the same reaction was carried out in the absence of
LiBr, the desired exo- and endocyclic 13 were obtained in
1:1.5 ratio (81% yield).
ated Ketones (continued)
LN (5 equiv), THF, 20 min, –40 °C
O
O
then PhSeBr (1.2 equiv), 30 min
CN
R
R
then AcOH (4 equiv), H2O2 (8 equiv)
–40 °C to 0 °C, 40 min
Table 2 One-Pot Conversion of a-Cyano Ketones into a,b-Unsatur-
ated Ketones
LN (5 equiv), THF, 20 min, –40 °C
Entry a-Cyano ketone Product
Yield
(%)a
O
O
then PhSeBr (1.2 equiv), 30 min
CN
R
R
then AcOH (4 equiv), H2O2 (8 equiv)
–40 °C to 0 °C, 40 min
O
O
O
CN
CN
Ph
Ph
Ph
9
98
Entry a-Cyano ketone Product
Yield
(%)a
22
O
O
O
O
O
O
H
H
O
CN
1
2
85
75
Ph
Ph
Ph
95
10
11
13
14
23
CN
CN
O
O
CN
77b
O
O
24
Ph
Ph
Ph
a Yields are for isolated, chromatographically pure products.
3
97
b Only a single diastereomer was formed; its stereochemistry remains
to be determined.
15
16
endo/exo (E) 67:33
A similar observation on the product distribution (exo/
endo = 1:1.3) has also been made previously by Reich et
al., where the oxidation reaction was conducted under
treatment with H2O2 without the presence of lithium
salts.23 The results disclosed above appear to be of great
significance in the enone-synthesis chemistry, thus
prompting us to undergo a systematical investigation on
the phenylselenoxide syn-elimination process mediated
with different lithium salts as well as other relevant metal
salts. A detailed account of the mechanistic study will be
published elsewhere in due course.
H
O
O
CN
Ph
4
5
95
91
Ph
17
O
O
H
O
CN
18
As described above, we have developed a highly efficient
and completely regiocontrolled procedure for the prepara-
tion of a-phenylseleno ketones starting from readily avail-
able a-cyano ketones. Moreover, a-phenylseleno ketones
thus formed, without isolation, could be further oxidized
to afford the corresponding a,b-unsaturated ketones with
high regioselectivity, presumably due to the intermediacy
of the lithium salts provided by the preceding reductive
selenenylation. This newly developed one-pot process for
direct conversion of a-cyano ketones into enone system is
expected to have broad synthetic utility in light of the high
degree of regiocontrol and operational simplicity.
H
O
CN
6
7
8
72
90
95
19
O
O
O
CN
CN
H
20
O
Ph
Acknowledgment
H
Ph
We are grateful to the National Health Research Institutes and
National Science Council of the Republic of China for financial
support.
21
Synlett 2007, No. 8, 1274–1278 © Thieme Stuttgart · New York

LETTER
Reductive Selenenylation of a-Cyano Ketones
1277
J = 18.1, 8.1, 2.0 Hz, 1 H), 3.08 (d, J = 13.7 Hz, 1 H), 3.27
(d, J = 13.7 Hz, 1 H), 7.08–7.11 (m, 2 H), 7.19–7.25 (m, 3
H), 7.30–7.35 (m, 2 H), 7.39–7.45 (m, 1 H), 7.52–7.61 (m, 2
H). 13C NMR (75 MHz, CDCl3): d = 18.4, 33.0, 36.1, 41.0,
59.5, 126.5, 126.6, 128.3, 129.0, 129.6, 130.5, 137.6, 138.0,
211.6. MS (EI): m/z = 331.2 [M + 1]. Instead of quenching
with sat. aq NH4Cl, after ketone 2 was generated in situ
following the aforementioned protocol, AcOH (0.13 mL,
2.21 mmol) and H2O2 (0.43 mL of 35% H2O2, 4.41 mmol)
were sequentially added to the above reaction mixture at
–40 °C. The resulting solution was then warmed to 0 °C in
40 min and quenched with sat. aq NaHCO3 followed by
extraction with EtOAc (2 × 10 mL). The combined organic
layers were washed with H2O, brine, dried with Na2SO4, and
concentrated to give the crude product, which was purified
by flash chromatography on silica gel (EtOAc–n-hexane,
1:25) to give exo-(E)-139a,b (81 mg) in 85% yield over two
steps.
(E)-2-Benzylidenecyclopentanone (13): IR (neat): 1706,
1622, 1487 cm–1. 1H NMR (300 MHz, CDCl3): d = 2.04 (m,
2 H), 2.42 (t, J = 7.9 Hz, 2 H), 2.98 (dt, J = 7.2, 2.7 Hz, 2 H),
7.36–7.44 (m, 4 H), 7.54 (dd J = 7.4, 1.1 Hz, 2 H). 13C NMR
(75 MHz, CDCl3): d = 20.2, 29.4, 37.8, 128.7, 129.3, 130.5,
132.3, 135.6, 136.1, 208.0. HRMS (EI): m/z calcd for
C12H12O: 172.0889; found: 172.0877.
2-Allyl-2-phenylselenocycloheptanone (6a): IR (KBr):
3072, 2926, 2855, 1686, 740, 691 cm–1. 1H NMR (300 MHz,
CDCl3): d = 1.14–1.27 (m, 1 H), 1.33–1.46 (m, 2 H), 1.61
(dd, J = 14.7, 10.7 Hz, 1 H), 1.73–1.94 (m, 3 H), 2.21–2.30
(m, 2 H), 2.40–2.48, (m, 2 H), 3.17 (td, J = 11.2, 2.4 Hz, 1
H), 5.06 (br d, J = 17.1 Hz, 1 H), 5.14 (br d, J = 10.5 Hz, 1
H), 5.92–6.05 (ddm, J = 17.1, 10.5 Hz, 1 H), 7.26–7.31 (tm,
J = 7.2 Hz, 2 H), 7.34–7.41 (m, 1 H), 7.41–7.46 (dm, J = 7.2
Hz, 2 H). 13C NMR (75 MHz, CDCl3): d = 24.9, 26.3, 30.4,
32.1, 36.9, 39.6, 60.7, 118.2, 127.2, 129.0, 129.4, 135.1,
137.5, 207.3. LC-MS (ES): m/z = 331 [M + 23]+.
References and Notes
(1) For leading references, see: (a) Larock, R. C.
Comprehensive Organic Transformation, 2nd ed.; Wiley:
New York, 1999. (b) Liotta, D.; Barnum, C.; Puleo, R.;
Zima, G.; Bayer, C.; Kezar, H. S. III J. Org. Chem. 1981, 46,
2920. (c) Bernardi, A.; Karamfilova, K.; Sanguinetti, S.;
Scolastico, C. Tetrahedron 1997, 53, 13009. (d) Honda, T.;
Rounds, B. A.; Gribble, G. W.; Suh, N. Y.; Wang, P.; Sporn,
M. P. Bioorg. Med. Chem. Lett. 1998, 20, 2711. (e) Smith,
N. D.; Hayashida, J.; Rawal, V. H. Org. Lett. 2005, 7, 4309.
(2) (a) Kusuda, S.; Watanabe, Y.; Ueno, Y.; Toru, T. J. Org.
Chem. 1992, 57, 3145. (b) Back, T. G. Organoselenium
Chemistry: A Practical Approach; Oxford University Press:
New York, 1999.
(3) Cotgreave, I. A.; Moldeus, P.; Brattsand, R.; Hallberg, A.;
Andersson, C. M.; Engman, L. Biochem. Pharmacol. 1992,
43, 793.
(4) (a) Mugesh, G.; duMont, W. W.; Sies, H. Chem. Rev. 2001,
101, 2125. (b) Nogueira, C. W.; Zeni, G.; Rocha, J. B. T.
Chem. Rev. 2004, 104, 6255.
(5) In humans, 25 selenoproteins have been identified, many of
which possess unknown functions and remain to be
explored. For the leading references, see: (a) Kryukov, G.
V.; Castellano, S.; Novoselov, S. V.; Lobanov, A. V.;
Zehtab, O.; Guigo, R.; Gladyshev, V. N. Science 2003, 300,
1439. (b) May, S. W. Exp. Opin. Invest. Drugs 1999, 8,
1017. (c) Medina, D.; Thompson, H.; Ganther, H.; Ip, C.
Nutr. Cancer. 2001, 40, 12.
(6) Navsariwala, V. D.; Prins, G. S.; Swanson, S. M.; Birch, L.
A.; Ray, V. H.; Hedayat, S.; Lantyit, D. L.; Diamond, A. M.
Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 8179.
(7) For recent examples, see: Wang, J.; Li, H.; Mei, Y.; Lou, B.;
Xu, D.; Xie, D.; Guo, H.; Wang, W. J. Org. Chem. 2005, 70,
5678; and references cited therein.
(8) Girlanda, J. C.; Keyling, B. F.; Schmitt, G.; Luu, B.
Tetrahedron 1998, 54, 7735.
(E)-2-Allylidenecycloheptanone (18): IR (neat): 1699,
1613, 1579 cm–1. 1H NMR (300 MHz, CDCl3): d = 1.62–
1.80 (m, 6 H), 2.47–2.57 (m, 2 H), 2.62–2.68 (m, 2 H), 5.49
(dd, J = 9.9, 1.7 Hz, 1 H), 5.63 (dd, J = 16.7, 1.7 Hz, 1 H),
6.63 (ddd, J = 16.7, 11.5, 9.9 Hz, 1 H), 7.00 (d, J = 11.5 Hz,
1 H). 13C NMR (75 MHz, CDCl3): d = 25.3, 27.5, 29.8, 31.3,
43.4, 125.4, 131.6, 135.2, 140.3, 204.8. LC-MS (ES): m/z =
151 [M + 1]+.
(9) (a) Reich, H. J.; Renga, J. M.; Reich, I. L. J. Am. Chem. Soc.
1975, 97, 5434. (b) Wang, W.; Mei, Y.; Li, H.; Wang, J.
Org. Lett. 2005, 7, 601. (c) Reich, H. J.; Reich, I. L.; Renga,
J. M. J. Am. Chem. Soc. 1973, 95, 5813. (d) Clive, D. L. J.
Chem. Commun. 1973, 695. (e) Liotta, D.; Saindane, M.;
Monahan, R. III; Brothers, D.; Fivush, A. Synth. Commun.
1986, 16, 1461.
(10) Cossy, J.; Furet, N. Tetrahedron Lett. 1993, 48, 7755.
(11) Torii, S.; Uneyama, K.; Handa, K. Tetrahedron Lett. 1980,
21, 1863.
(15) Marshall, J. A.; Peterson, J. C.; Lebioda, L. J. Am. Chem.
Soc. 1984, 106, 6006.
(16) Seishiand, T.; Hiroyuki, Y. Yakugaku Zasshi 1959, 79, 467.
(17) Kahne, D.; Collum, D. B. Tetrahedron Lett. 1981, 22, 5011.
(18) 1-Benzoyl-4,6,6-trimethylcyclohex-3-enecarbonitrile
(10): IR (KBr): 2232, 1692, 1596, 1578 cm–1. 1H NMR (300
MHz, CDCl3): d = 1.12 (s, 3 H), 1.21 (s, 3 H), 1.72 (br s, 3
H), 1.96 (d, J = 17.9 Hz, 1 H), 2.31 (d, J = 17.9 Hz, 1 H),
2.58 (br d, J = 17.8 Hz, 1 H), 2.90 (br d, J = 17.8 Hz, 1 H),
5.32 (br s, 1 H), 7.42–7.48 (tm, J = 7.3 Hz, 2 H) 7.52–7.58
(12) For preparing a stock solution of LN, see: Liu, H. J.; Yip, J.;
Shia, K. S. Tetrahedron Lett. 1997, 38, 2253.
(13) Zhu, J. L.; Shia, K. S.; Liu, H. J. Chem. Commun. 2000,
1599.
(14) Satisfactory spectral and LC-MS or HRMS analytical data
were obtained for all new compounds. A typical experiment
is outlined as follows: To a solution of a-cyano ketone 1
(110 mg, 0.55 mmol) in THF (10 mL) at –40 °C was added
LN (7.5 mL, 0.365 M, 2.75 mmol) dropwise. The resulting
dark green solution was stirred at the same temperature for
20 min followed by addition of phenylselenyl bromide (156
mg, 0.66 mmol) in one portion. The resulting mixture was
continued to stir for additional 30 min at –40 °C and then
quenched with sat. aq NH4Cl and extracted with EtOAc
(2 × 10 mL). The combined extracts were washed with
brine, dried with Na2SO4, and concentrated to give the crude
residue, which was subjected to flash chromatography on
silica gel (EtOAc–n-hexane, 1:50) to afford the
(tm, J = 7.3 Hz, 1 H), 8.04–8.08 (dm, J = 7.3 Hz, 2 H). 13
NMR (75 MHz, CDCl3): d = 22.7, 23.8, 27.7, 33.1, 36.7,
C
44.0, 53.2, 115.2, 121.7,128.4, 129.1, 132.9, 133.9, 137.5,
195.3. LC-MS (ES): m/z = 253 [M]+.
1-Benzoyl-3,4,6,6-tetramethylcyclohex-3-enecarbonitrile
(11): IR (KBr): 2232, 1692, 1595, 1578 cm–1. 1H NMR (300
MHz, CDCl3): d = 1.08 (s, 3 H), 1.20 (s, 3 H), 1.66 (br s, 6
H), 1.90 (d, J = 17.8 Hz, 1 H), 2.38 (br d, J = 18.0 Hz, 1 H),
2.44 (d, J = 17.8 Hz, 1 H), 2.88 (br d, J = 18.0 Hz, 1 H),
7.43–7.48 (tm, J = 7.8 Hz, 2 H), 7.53–7.59 (tm, J = 7.8 Hz,
1 H), 8.04–8.08 (dm, J = 7.8 Hz, 2 H). 13C NMR (75 MHz,
CDCl3): d = 18.4, 19.0, 22.5, 27.7, 36.6, 38.6, 45.7, 51.4,
120.3, 121.8, 125.2, 128.4, 129.1, 132.8, 137.8, 195.4. LC-
MS (ES): m/z = 267 [M]+.
corresponding a-phenylseleno ketone 2 as a colorless oil
(165 mg, 90%). IR (neat): 1729, 1604, 1577 cm–1. 1H NMR
(300 MHz, CDCl3): d = 1.72–2.13 (m, 5 H), 2.59 (ddd,
Synlett 2007, No. 8, 1274–1278 © Thieme Stuttgart · New York

1278
J.-L. Zhu et al.
LETTER
(19) Kishi, N.; Mikami, K.; Nakai, T. Tetrahedron 1991, 47,
8111.
(20) Negishi, E.; Tan, Z.; Liou, S. Y.; Liao, B. Tetrahedron 2000,
56, 10197.
(21) Kreher, U. P.; Rosamilia, A. E.; Raston, C. L.; Scott, J. L.;
Strauss, C. R. Org. Lett. 2003, 5, 3107.
(22) Yanagisawa, A.; Goudu, R.; Arai, T. Org. Lett. 2004, 6, 428.
(23) It was reported by Reich et al.,9a that treatment of compound
2 with H2O2 (8.8 equiv) in CH2Cl2 containing a small portion
of pyridine at 25 °C gave rise to a mixture of the exo- and
endocyclic enones in a ratio of 1:1.3.
Synlett 2007, No. 8, 1274–1278 © Thieme Stuttgart · New York

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