Selenoimidoylation of alcohols with selenium and isocyanides and its application to the synthesis of selenium-containing heterocycles

Article abstract of DOI:10.1021/jo0496704

The reaction of alcohols with selenium and isocyanides in the presence of DBU gave oxyimidoylselenoates 6. Trapping of 6 with BuI resulted in high-yield formation of selenocarbonimidates 4. When alk-2-yn-1-ols 9 were allowed to react with selenium and iso

Full text of DOI:10.1021/jo0496704

Selen oim id oyla tion of Alcoh ols w ith
Selen iu m a n d Isocya n id es a n d Its
Ap p lica tion to th e Syn th esis of
Selen iu m -Con ta in in g Heter ocycles
Previously described methods for the preparation of
selenoimidates 1 are (i) alkylation of selenoamides with
6
alkyl halides, (ii) reaction of imidoyl chlorides with
selenols,7 (iii) reaction of imidoyl radicals with diaryl
8
diselenides, (iv) three-component radical coupling reac-
9
tions of diselenides with isocyanides and alkynes, (v)
†
,‡
,†
Yoshiaki Asanuma, Shin-ichi Fujiwara,*
transition-metal-catalyzed addition of diaryl diselenide
‡
Tsutomu Shin-ike, and Nobuaki Kambe*
10
to isocyanide, and (vi) reaction of oxime sulfonates with
4
organoaluminum selenolates. Isoselenoureas 2 can also
Department of Molecular Chemistry, Graduate School of
Engineering, Osaka University,
Suita, Osaka 565-0871, J apan, and
Department of Chemistry, Osaka Dental University,
Hirakata, Osaka 573-1121, J apan
be prepared by the reaction of selenoureas with alkyl
halides1
1,5a,d,e,g,h
or an alkyl sulfate.
12
fujiwara@cc.osaka-dent.ac.jp;
kambe@chem.eng.osaka-u.ac.jp
Received February 26, 2004
Abstr a ct: The reaction of alcohols with selenium and
isocyanides in the presence of DBU gave oxyimidoylsele-
noates 6. Trapping of 6 with BuI resulted in high-yield
formation of selenocarbonimidates 4. When alk-2-yn-1-ols
9
were allowed to react with selenium and isocyanides under
similar conditions, new selenium-containing heterocycles 10,
-imino-4-alkylidene-1,3-oxaselenolanes, were obtained via
We have recently shown that the reaction of benzyl-
lithiums or lithium amides with selenium and isocya-
nides provides the corresponding selenoimidates 1 (eq 1)
or isoselenoureas 2 (eq 2), respectively, in high yields
2
cycloaddition of oxyimidoylselenoates 13 generated in situ
by intramolecular addition of selenolates to carbon-carbon
triple bonds.
13,14
after trapping with alkyl iodide electrophiles.
Similarly, we have also reported that benzyllithiums
react readily with isoselenocyanates at low temperatures
Organoselenium compounds have been recognized not
only as useful intermediates in synthetic chemistry but
1
also as important materials in biological and medicinal
chemistry. As for the compounds containing a selenoimi-
(5) (a) Chu, S.; Mautner, H. G. J . Org. Chem. 1962, 27, 2899. (b)
Chen, G. C.; Banks, C. H.; Irgolic, K. J .; Zingaro, R. A. J . Chem. Soc.,
Perkin Trans. 1 1980, 2287. (c) Burutus, M.; Mollier, Y.; Stavaux, M.
Nouv. J . Chim. 1986, 10, 51; Chem. Abstr. 1987, 106, 195792. (d)
Mirabelli, C. K.; Hill, D. T.; Faucette, L. F.; McCabe, F. L.; Girard, G.
R.; Bryan, D. B.; Sutton, B. M.; Bartus, J . O.; Crooke, S. T.; J ohnson,
R. K. J . Med. Chem. 1987, 30, 2181. (e) Hideg, K.; S a´ r, C. P.;
Hankovszky, O. H.; J erkovich, G. Synthesis 1991, 616. (f) Hideg, K.;
S a´ r, C. P.; Hankovszky, O. H.; Tam a´ s, T.; J erkovich, G. Synthesis 1993,
390. (g) K a´ lai, T.; Balog, M.; J ek o¨ , J .; Hideg, K. Synthesis 1999, 973.
2
doyl skeleton (Se-CdN), selenoimidates 1 have been
3
synthesized and used as precursors of imidoyl radicals
4
and iminoethers. Isoselenoureas 2 have been employed
for the generation of selenolate anions under mild condi-
4
tions by treatment with bases such as NaOH and Bu -
5
NOH; however, selenocarbonimidate 3 has never been
prepared. We now report a high-yield selenoimidoylation
method of alcohols with isocyanides and elemental
selenium under mild conditions.
(
h) Manh, G. T.; Purseigle, F.; Dubreuil, D.; Prad e` re, J . P.; Guingant,
A.; Danion-Bougot, R.; Danion, D.; Toupet, L. J . Chem. Soc., Perkin
Trans. 1 1999, 2821. (i) J honston, B. D.; Pinto, B. M. J . Org. Chem.
2
000, 65, 4607. (i) Russel, H. E.; Luke, R. W. A.; Bradley, M.
Tetrahedron Lett. 2000, 41, 5287. (j) Blum, T.; Ermwrt, J .; Coenen, H.
H. J . Labelled Comp. Radiopharm. 2001, 44, 587; Chem. Abstr. 2001,
1
35, 344558.
6) (a) Cava, M. P.; Saris, L. E. J . Chem. Soc., Chem. Commun. 1975,
(
6
1
17. (b) Meese, C. O.; Walter, W.; Mrotzek, H.; Mirzai, H. Chem. Ber.
976, 109, 956.
(
7) (a) Detty, M. R.; Wood, G. P. J . Org. Chem. 1980, 45, 80. (b)
Kohler, R.; Beyer, L.; Hantschmann, A.; Hoyer, E. Z. Chem. 1990, 30,
02.
(8) Yamago, S.; Miyazoe, H.; Goto, R.; Yoshida, J . Tetrahedron Lett.
1
†
Osaka University.
Osaka Dental University.
‡
1999, 40, 2347.
(
1) (a) Liotta, D., Ed. Organoselenium Chemistry; J ohn Wiley &
(9) Ogawa, A.; Doi, M.; Tsuchii, K.; Hirao, T. Tetrahedron Lett. 2001,
42, 2317-2319.
Sons: New York, 1987. (b) Back, T. G., Ed. Organoselenium Chemis-
try: A Practical Approach; Oxford University Press: Oxford, 1999. (c)
Wirth, T., Ed. Topics in Current Chemistry 208: Organoselenium
Chemistry; Springer: Berlin, 2000.
(10) Kuniyasu, H.; Maruyama, A.; Kurosawa, H. Organometallics
1998, 17, 908.
(11) (a) Zingaro, R. A.; Bennett, F. C. J r.; Hammer, G. W. J . Org.
Chem. 1953, 18, 292. (b) Warner, J . S.; Page, T. F., J r. J . Org. Chem.
1966, 31, 606. (c) Lloyd, D.; Miller, R. W. Tetrahedron 1977, 33, 1379.
(d) K a´ lai, T.; B a´ r a´ cz, N. M.; J erkovich, G.; Hankovszky, O. H.; Hideg,
K. Synthesis 1995, 1278.
(2) (a) Wendel, A., Ed. Selenium in Biology and Medicine; Springer-
Verlag: Berlin, 1989. (b) N e` ve, J ., Favier, A., Eds. Selenium in
Medicine and Biology; Walter de Gruyter: Berlin, 1989.
(
3) (a) Bachi, M. D.; Denenmark, D. J . Am. Chem. Soc. 1989, 111,
1
886. (b) Kim, S.; Lee, T. A. Synlett 1997, 950. (c) Fujiwara, S.;
(12) Wolfrom, M. L.; Rice, F. A. H. J . Am. Chem. Soc. 1947, 69, 1833.
(13) Fujiwara, S.; Maeda, H.; Matsuya, T.; Shin-ike, T.; Kambe, N.;
Sonoda, N. J . Org. Chem. 2000, 65, 5022.
Matsuya, T.; Maeda, H.; Shin-ike, T.; Kambe, N.; Sonoda, N. J . Org.
Chem. 2001, 66, 2183.
(
4) Maruoka, K.; Miyazaki, T.; Ando, M.; Matsumura, Y.; Sakane,
(14) Maeda, H.; Matsuya, T.; Kambe, N.; Sonoda, N.; Fujiwara, S.;
Shin-ike, T. Tetrahedron 1997, 53, 12159.
S.; Hattori, K.; Yamamoto, H. J . Am. Chem. Soc. 1983, 105, 2831.
1
0.1021/jo0496704 CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/09/2004
J . Org. Chem. 2004, 69, 4845-4848
4845

TABLE 1. Syn th eses of Selen oca r bon im id a tesa
SCHEME 1. P la u sible Rea ction P a th w a y
run
R1
R2
product
yieldd (%)
b
1
2
3
4
5
6
7
8
9
Me
Me
Bu
c-Hex
Xy
c-Hex
Xy
Xy
4a
4b
4c
4d
4e
4f
4g
4h
4i
92
85
64
82
45
0
76
94
86
c
Bu
s-Bu
t-Bu
Allyl
Bn
in lower yield and tert-butyl alcohol did not provide
selenocarbonimidate 4f, probably due to steric reasons.
All selenocarbonimidates shown in Table 1 could easily
be isolated as single stereoisomers.17
We carried out the following control experiments in
order to examine the reaction pathways. Under the
conditions indicated in Table 1, cyclohexyl isocyanide
reacted with selenium and methanol to afford 4a in 92%
yield. When the reaction time was shortened from 20 to
Xy
c-Hex
c-Hex
Xy
Bn
a
Conditions: Se (1 mmol), alcohol (2 mmol), isocyanide (1
mmol), DBU (1 mmol), THF (1 mL) rt, 20 h, then BuI (2 mmol), 1
b
c
d
h. Cyclohexyl. 2,6-Xylyl. Isolated yields based on Se used.
to give selenoimidates 1 in high yields after trapping with
alkyl iodides (eq 3).15
3
h, 4a was formed in 36% yield together with 59% of
cyclohexyl isoselenocyanate 5a (eq 6). Next, the reaction
of selenium with cyclohexyl isocyanide in the presence
of DBU for 3 h resulted in the formation of 5a in 98%
(
eq 7).18 Finally, 5a reacted with methanol in the presence
of DBU to give 4a in 88% yield (eq 8).
Aiming at the synthesis of selenocarbonimidates 3, we
attempted the reaction of 2,6-xylyl isoselenocyanate with
a lithium enolate of propiophenone under the conditions
shown in eq 3; however, no reaction took place. The first
example of the synthesis of selenocarbonimidate was
realized by carrying out a similar reaction in the presence
of HMPA at 0 °C to afford 3a in 46% yield together with
selenoimidates 1c (eq 4).15
By combining these steps, we propose the reaction
pathway shown in Scheme 1. Isocyanide react with
selenium to give the corresponding isoselenocyanate 5.
Alkoxide attack at the carbon center of 5 produces
oxyimidoylselenoate 6, which is trapped by BuI to yield
selenocarbonimidate 4.
We recently reported that 1-amino-2-alkynes 7 reacted
with selenium and carbon monoxide in the presence of
DBU to yield 5-alkylideneselenazolin-2-ones 8 stereose-
lectively (eq 9).19 We then attempted to apply this
principle to the preparation of 4-alkylidene-1,3-oxasele-
nolanes 10 from alk-2-yn-1-ols 9, selenium, and isocya-
nides (eq 10).
To develop a more convenient synthetic procedure, we
stirred a mixture of methanol (2 mmol), cyclohexyl isocy-
anide (1 mmol), and selenium (1 mmol) in THF (1 mL)
in the presence of DBU (1 mmol) at room temperature.
The black suspension became a yellow homogeneous solu-
tion within 3 h. Quenching the reaction with BuI after
2
0 h and subsequent workup afforded the expected
selenocarbonimidate 4a in 92% yield based on selenium
used (eq 5).
Results of the reactions performed using several alco-
hols are summarized in Table 1.16 Both aliphatic and
aromatic isocyanides were applicable to the present
reaction. Primary alcohols such as n-butanol, allyl alco-
hol, and benzyl alcohol provided the corresponding sele-
nocarbonimidates 4c-d ,g-i in good to excellent yields
under similar conditions. sec-Butanol, however, gave 4e
(
17) Low-temperature 1H NMR of 4b showed a set of peaks assign-
able to a single isomer. However, we could not determine the stereo-
chemistry of the carbon-nitrogen double bond because a nuclear
Overhauser effect was not observed when we irradiated methyl protons
of 2,6-xylyl group in 4b.
(18) Triethylamine promoted the reaction of selenium with isocya-
nides to yield isoselenocyanates; see: Sonoda, N.; Yamamoto, G.;
Tsutsumi, S. Bull. Chem. Soc. J pn. 1972, 45, 2937.
(
15) Maeda, H.; Kambe, N.; Sonoda, N. Fujiwara, S.; Shin-ike, T.
Tetrahedron 1996, 52, 12165.
16) Selenocarbonimidate 4b was also obtained in 72% yield when
(
the reaction was carried out under conditions similar to those shown
in eqs 1 and 2 by starting with MeOLi.
4
846 J . Org. Chem., Vol. 69, No. 14, 2004

TABLE 2. Syn th esis of Selen iu m -con ta in in g
SCHEME 2. Rea ction P a th w a y for th e F or m a tion
of Z-Im in o-4-a lk ylid en e-1,3-d ioxa selen ola n es
a
Heter ocycles fr om 9
run substrate
R3
R4
R5
Xy
Xy
Xy
Xy
Xy
Xy
product yield (%)
1
2
3
4
5
6
7
8
9a
9b
9c
9d
9e
9f
Ph
H
H
H
H
H
H
10a
10b
10c
10d
10e
10f
12g
10h
92
88
91
96
69
85 (13)
68
85
p-MeC6H4
p-MeOC6H4
p-ClC6H4
b
c
H
Me
H
9g
9a
Ph Xy
c-Hex
Ph
H
a
Conditions: Se (1 mmol), isocyanide (1 mmol), alk-2-yn-1-ol 9
b
(
1 mmol), DBU (1 mmol), THF (1 mL), rt, 4 h. 11e was also
obtained (21%). With CuI (1 mmol).
c
3
-Phenyl-2-propyn-1-ol 9a (1 mmol) was allowed to
react with selenium (1 mmol) and 2,6-xylyl isocyanide
1 mmol) in the presence of DBU (1 mmol) in THF (1 mL)
(
at room temperature for 4 h. Purification of the reaction
mixture by silica gel column chromatography provided
2
-imino-4-alkylidene-1,3-oxaselenolane 10a in 92% yield
(run 1 of Table 2).
When p-methyl-, p-methoxy-, or p-chlorophenyl prop-
argylic alcohols were employed, the expected products
selenoimidoylation by the reaction with selenium and
isocyanide to yield oxyimidoylselenoate 13. The stereo-
selectivity of the CdC double bonds of the products can
be explained by a trans addition mechanism (13 f 14 f
1
9
1
0b-d were also obtained in high yields. Prop-2-yn-1-ol
e gave 10e in 69% yield along with 21% of its isomer
1e.
1
0), where proton coordination to the carbon-carbon
triple bond facilitates nucleophilic addition of selenium
to the triple bond from the opposite site. 2-Selenoxo-1,3-
oxolidine 11e is formed by the nucleophilic addition of
2
2
nitrogen to the carbon-carbon triple bond of 13.
When the reaction of but-3-yn-1-ol 16 was conducted
under similar conditions as eq 10 and Table 2, the
expected six-membered heterocycle 17, 4-methylidene-
1,3-selenane, was not formed at all. However, addition
of CuI and subsequent heating of the reaction mixture
at reflux afforded 17 in 41% yield.
Finally, the yield was boosted to 65% by diluting the
reaction mixture with 9 mL of additional THF before
addition of CuI (eq 12).
The reaction of but-2-yn-1-ol 9f afforded 10f in only
3% yield. Since it is known that CuI promotes the
1
intramolecular cyclization of O-propargyl thiocarbon-
ates20 and N-propargyl selenocarbamates, we added 1
equiv of CuI to the resulting mixture of the reaction of
19
9
f with 2,6-xylyl isocyanide and selenium and heated the
mixture at reflux for 1 h. This procedure led to efficient
production of 10f in 85% yield (eq 11, run 6).
Propargyl alcohol having a phenyl group at the R-car-
bon 9g underwent selenoimidoylation to give a cyclized
product in 68% yield; however, the product isolated was
In summary, alcohols were selenoimidoylated with
selenium and isocyanides under mild conditions to give
selenocarbonimidates 4 after trapping with BuI. Fur-
thermore, the reaction of alk-2-yn-1-ols 9 with selenium
and isocyanides produced oxyimidoylselenoates 13, which
underwent intramolecular cycloaddition affording new
selenium-containing heterocycles 10.
2
-imino-1,3-oxaselenole 12g rather than the exomethyl-
2
1
ene isomer 10g. It should be noted that all 2-imino-4-
alkylidene-1,3-oxaselenolanes obtained (10a -f,h ) adopt
a single configuration with respect to carbon-carbon and
carbon-nitrogen double bonds. In the case of 10a , Z-con-
figurations of the carbon-carbon and carbon-nitrogen
double bonds were determined by X-ray analysis.
A reaction mechanism for this transformation is sug-
gested in Scheme 2. First, alk-2-yn-1-ol 9 undergoes
Exp er im en ta l Section
THF was distilled from sodium benzophenone ketyl. Metha-
nol, butanol, sec-butanol, tert-butyl alcohol, allyl alcohol, benzyl
alcohol, BuI, and DBU were distilled from calcium hydride. Alk-
(
19) Fujiwara, S.; Shikano, Y.; Shin-ike, T.; Kambe, N.; Sonoda, N.
J . Org. Chem. 2002, 67, 6275.
20) Mizuno, T.; Nakamura, F.; Ishino, Y.; Nishiguchi, I.; Hirashima,
T.; Ogawa, A.; Kambe, N.; Sonoda, N. Synthesis 1989, 770.
21) A few 2-imino-1,3-oxaselenoles have been synthesized, see: (a)
Robert, A.; Marechal, A. L. J . Chem. Soc., Chem. Commun. 1978, 447.
b) Mar e´ chal, A. M. L.; Robert, A.; Leban, I. J . Chem. Soc., Perkin
Trans. 1 1993, 351.
(
(
(22) The product selectivity observed is due to higher nucleophilicity
of the selenium atom. In fact, the product ratio was almost the same
when the reaction time was shortened to 1 h. Isolated 10e and 11e
were not interconverted under similar reaction conditions.
(
J . Org. Chem, Vol. 69, No. 14, 2004 4847

2
-yn-1-ols 9a ,e,f,g, but-3-yn-1-ol, and cyclohexyl isocyanide were
2-(2,6-Xylyl)im in o-4-p h en ylm eth ylid en e-1,3-oxa selen o-
la n e (10a ): Typ ica l Exp er im en ta l P r oced u r e. Into a 5-mL
flask was placed selenium (1.0 mmol, 78.0 mg), DBU (1 mmol,
163.9 mg), THF (1 mL), 2,6-xylyl isocyanide (1 mmol, 140.4 mg),
and 3-phenyl-2-propyn-1-ol (1 mmol, 140.2 mg), and the mixture
purchased and used without further purification. Other alk-2-
yn-1-ols 9b -d were synthesized by the reaction of propargyl
2
3
alcohol with the corresponding aryl iodides. 2,6-Xylyl isocya-
nide was prepared from 2,6-xylidine via 2,6-xylyl formamide.24
1
-Me t h yl-2-b u t yl-3-c yc loh e xylse le n oc a r b on im id a t e
4
was stirred for 4 h at 20 °C. Saturated NH Cl (aq) (1 mL) was
(
4a ): Typ ica l Exp er im en ta l P r oced u r e. Into a 5-mL flask
then added and the stirring continued for an additional 0.5 h.
The mixture was concentrated and purified by silica gel column
were added selenium (1.0 mmol, 79.5 mg), DBU (1 mmol, 161.8
mg), THF (1 mL), cyclohexyl isocyanide (1 mmol, 115.7 mg), and
methanol (2.1 mmol, 70.5 mg) at room temperature, and the
mixture was stirred for 20 h. BuI (2 mmol, 365.2 mg) was then
added, and stirring was continued for an additional 1 h at room
temperature. n-Hexane was added, and the deposited white
solids were removed by filtration. The filtrate was concentrated
in vacuo and purified by preparative HPLC eluted with CHCl
to give 1-methyl-2-butyl-3-cyclohexylselenocarbonimidate 4a as
a yellow liquid (225.0 mg, 92% based on selenium used):
NMR (400 MHz, CDCl
chromatography to yield 10a as white solid (321.6 mg, 92% based
1
on Se used): mp 114-115 °C; H NMR (400 MHz, CDCl
3
) δ 2.18
(s, 6 H), 5.20 (d, J ) 0.8 Hz, 2H), 6.93-7.33 (m, 9 H); NOE
experiment, irradiation of methylene at δ 5.20 resulted in 10%
enhancement of signal at δ 6.93 (vinyl); 13C NMR (100 MHz,
CDCl
3
) δ 18.2, 78.0, 123.6, 124.1, 127.5, 127.7, 128.1, 128.5,
-
1
3
128.7, 131.3, 135.6, 146.8, 160.7; IR (KBr) 1672 (CdN) cm
;
+
MS (EI) m/z (relative intensity) 343 (M , 19). Anal. Calcd for
17NOSe: C, 63.16; H, 5.01; N, 4.09. Found: C, 62.87; H,
1
H
18
C H
3
) δ 0.92 (t, J ) 7.3 Hz, 3 H), 1.17-1.45
5.28; N, 4.19.
(
3
2
m, 7 H), 1.58-1.75 (m, 7 H), 2.95 (t, J ) 7.4 Hz, 2 H), 3.05-
.11 (m, 1 H), 3.77 (s, 3 H); 1 C NMR (100 MHz, CDCl
3
Ack n ow led gm en t. This work was supported in part
by a Grant-in-Aid from the Ministry of Education,
Science, Sports and Culture, J apan. Thanks are due to
the Instrumental Analysis Center, Faculty of Engineer-
ing, Osaka University.
3
) δ 13.7,
3.0, 24.9, 25.1, 25.9, 33.3, 34.3, 55.6, 60.2, 149.4; IR (NaCl) 1652
-
1
+
(
CdN) cm ; MS (EI) m/z (relative intensity) 277 (M , 2). Anal.
Calcd for C12 23NOSe: C, 52.17; H, 8.39; N, 5.07. Found: C,
1.98; H, 8.31; N, 5.26.
H
5
(
23) 9b,d were prepared by modified reactions of the general
Su p p or tin g In for m a tion Ava ila ble: Detailed character-
ization data of all new compounds and an ORTEP diagram
and X-ray structure data for compound 10a . This material is
available free of charge via the Internet at http://pubs.acs.org.
procedure for synthesis of aryl alkynes reported in the following paper;
Roesch, K. R.; Larock, R. C. J . Org. Chem. 2001, 66, 412.
(
namurthy, S. Tetrahedron Lett. 1982, 23, 3315. Dehydration of 2,6-
xylyl formamide to 2,6-xylyl isocyanide, see: Obrecht, R.; Herrmann,
R.; Ugi, I. Synthesis 1985, 400.
24) Conversion of 2,6-xylidine to 2,6-xylyl formamide, see: Krish-
J O0496704
4
848 J . Org. Chem., Vol. 69, No. 14, 2004