Highly selective double chalcogenation of isocyanides with disulfide-diselenide mixed systems

Article abstract of DOI:10.1021/jo061704f

A highly selective method for introducing thio and seleno groups into a variety of isocyanides has been developed based on the elucidation of the relative reactivities of organic dichalcogenides and chalcogen-centered free radicals. When the reactions of

Full text of DOI:10.1021/jo061704f

Highly Selective Double Chalcogenation of Isocyanides with
Disulfide-Diselenide Mixed Systems
Kaname Tsuchii,† Yasunori Tsuboi,‡ Shin-ichi Kawaguchi,§ Junko Takahashi,†
Noboru Sonoda,‡ Akihiro Nomoto,§ and Akiya Ogawa*,§
Department of Chemistry, Faculty of Science, Nara Women’s UniVersity, Kitauoyanishi-machi, Nara
630-8506, Japan, Department of Applied Chemistry, Faculty of Engineering, Osaka UniVersity, Suita,
Osaka 565-0871, Japan, and Department of Applied Chemistry, Graduate School of Engineering,
Osaka Prefecture UniVersity, Gakuen-cho, Nakaku, Sakai, Osaka 599-8531, Japan
ogawa@chem.osakafu-u.ac.jp
ReceiVed August 16, 2006
A highly selective method for introducing thio and seleno groups into a variety of isocyanides has been
developed based on the elucidation of the relative reactivities of organic dichalcogenides and chalcogen-
centered free radicals. When the reactions of aromatic isocyanides (ArNC) with organic disulfides (R′SSR′)
and diselenides (R′′SeSeR′′) are conducted upon irradiation with a tungsten lamp through Pyrex (hν
>300 nm), simultaneous introduction of both thio and seleno groups into the isocyanides takes place to
provide the corresponding thioselenation products (R′S-C(dNAr)-SeR′′) in good yields with excellent
selectivity. In the cases of aliphatic isocyanides (RCN), a novel diselenide-assisted bisthiolation of RNC
with diaryl disulfides (Ar′SSAr′) proceeds successfully to give the corresponding bisthiolation products
(Ar′S-C(dNR)-SAr′), although the same photoirradiated reaction of RNC with diaryl disulfides does
not occur in the absence of diselenide. These double chalcogenation reactions are assumed to proceed
via the formation of imidoyl radical intermediates by the reaction of isocyanides with relatively reactive
thio radicals (compared with seleno radicals). The obtained thioselenation products can be employed as
useful precursors for the construction of â-lactam framework by the formal [2 + 2] cyclization with
ketene equivalents.
Introduction
Organic disulfides and diselenides have their absorption
maxima based on the n f σ* transition in ultraviolet and
near-UV regions, respectively (Figure 1), and therefore irradia-
tion with these light sources causes homolytic cleavage of the
chalcogen-chalcogen bonds to generate the corresponding
chalcogen-centered radicals as labile species (eq 1).1
FIGURE 1. UV-visible spectra of (PhS)2 and (PhSe)2.
† Nara Women’s University.
When the photolysis of dichalcogenides (PhY-YPh) is
performed in the presence of carbon-carbon unsaturated
compounds such as alkynes, chalcogeno radicals formed in situ
‡ Osaka University.
§ Osaka Prefecture University.
(1) Schmidt, U.; Mu¨ller, A.; Markau, K. Chem. Ber. 1964, 97, 405.
10.1021/jo061704f CCC: $37.00 © 2007 American Chemical Society
Published on Web 12/13/2006
J. Org. Chem. 2007, 72, 415-423
415

Tsuchii et al.
TABLE 1. Radical Addition of Dichalcogenides to Isocyanidesa
may be trapped by unsaturated compounds, affording vicinal
dichalcogenation products, as exemplified in eq 2.2-4
yield, %b
Isocyanides, which bear an isoelectronic structure with carbon
monoxide, are useful C1 units in organic synthesis as well as
building blocks for nitrogen-containing heterocyclic com-
pounds.5 Isocyanides may react with carbon- or heteroatom-
centered radical species (Z•) to generate the corresponding
imidoyl radicals (eq 3).6 However, the development of efficient
synthetic reactions involving chalcogenoimidoyl radicals as key
intermediates has remained largely unexplored.7
entry
R
1
(PhY)2, (equiv)
time, h
2 (4)
3
1
2
3
4
2,6-xylyl
2,6-xylyl
2,6-xylyl
2,6-xylyl
PhCH2
1a
1a
1a
1a
1b
1c
1a
1d
1d
(PhS)2 (1.0)
(PhS)2 (2.0)
(PhS)2 (5.0)
(PhS)2 (5.0)c
(PhS)2 (1.0)
(PhS)2 (1.1)
(PhSe)2 (1.0)
(PhSe)2 (1.2)
(PhSe)2 (3.0)
48
48
16
13
10
15
48
9
17
35
58
74
0
33
24
24
0
5d
6d
7d
8
0
cC6H11
0
0
2,6-xylyl
p-O2N-C6H4
p-O2N-C6H4
0
0
75
90
0
0
9
16
a Reaction conditions: isocyanide (0.25 mmol), CDCl3 (0.5 mL), hV
tungsten lamp (500 W, Pyrex), 40 °C. b Isolated yield. c In the absence of
solvent. d Isocyanide was recovered in almost quantitative yield.
We have investigated in detail the photoirradiated reactions
of isocyanides with organic dichalcogenides, and have found
SCHEME 1. A Possible Pathway for Bisthiolation of
Isocyanides
(2) For a review see: Ogawa, A. In Main Group Metals in Organic
Synthesis; Yamamoto, H., Oshima, K., Eds.; Wiley-VCH: Weinheim,
Germany, 2004; Vol. 2, p 813.
(3) For radical addition reactions of disulfides to alkynes, see for
example: Heiba, E. I.; Dessau, R. M. J. Org. Chem. 1967, 32, 3837.
(4) For radical addition reactions of diselenides to alkynes, see for
example: (a) Back, T. G.; Krishna, M. V. J. Org. Chem. 1988, 53, 2533.
(b) Ogawa, A.; Yokoyama, H.; Yokoyama, K.; Masawaki, T.; Kambe, N.;
Sonoda, N. J. Org. Chem. 1991, 56, 5721. (c) Ogawa, A.; Takami, N.;
Sekiguchi, M.; Yokoyama, H.; Kuniyasu, H.; Ryu, I.; Sonoda, N. Chem.
Lett. 1991, 2241.
(5) For reviews concerning radical reactions of isocyanides, see for
example: (a) Ryu, I.; Sonoda, N.; Curran, D. P. Chem. ReV. 1996, 96, 177.
(b) Nanni, D. In Radicals in Organic Synthesis; Renaud, P., Sibi, M. P.,
Eds.; Wiley-VCH: Weinheim, Germany, 2001; Vol. 2, p 44. (c) Tokuyama,
H.; Fukuyama, T. Chem. Rec. 2002, 2, 37.
that a novel bischalcogenation of isocyanides with organic
dichalcogenides can take place efficiently with high selectivity,
based on the combination of the characteristic features of
individual chalcogen-centered radicals (i.e., thio and seleno
radicals) and dichalcogenides (i.e., disulfides and diselenides).
(6) For the reaction of organophosphorous compounds with isocyanides,
see for example: (a) Saegusa, T.; Ito, Y.; Yasuda, N.; Hotaka, T. J. Org.
Chem. 1970, 35, 4238. For the reaction of organosilicon compounds with
isocyanides, see for example: (b) Chatgilialoglu, C.; Giese, B.; Kopping,
B. Tetrahedron Lett. 1990, 31, 6013. For the reaction of organosulfur
compounds with isocyanides, see for example: (c) Barton, D. H. R.; Ozbalik,
N.; Vacher, B. Tetrahedron 1988, 44, 3501. (d) Nanni, D.; Calestani, G.;
Leardini, R.; Zanardi, G. Eur J. Org. Chem. 2000, 707. (e) Leardini, R.;
Nanni, D.; Zanardi, G. J. Org. Chem. 2000, 65, 2763. For the reaction of
organoselenium compounds with isocyanides, see for example: (f) Ogawa,
A.; Doi, M.; Tsuchii, K.; Hirao, T. Tetrahedron Lett. 2001, 42, 2317. For
the reaction of organotin compounds with isocyanides, see for example:
(g) Saegusa, T.; Kobayashi, S.; Ito, Y.; Yasuda, N. J. Am. Chem. Soc. 1968,
90, 4182. (h) Curran, D. P.; Liu, H. J. Am. Chem. Soc. 1991, 113, 2127. (i)
Curran, D. P.; Liu, H. J. Am. Chem. Soc. 1992, 114, 5863. (j) Curran,
D. P.; Ko, S.-B.; Josien, H. Angew. Chem., Int. Ed. Engl. 1995, 34, 2683.
(k) Curran, D. P.; Liu, H.; Josien, H.; Ko, S.-B. Tetrahedron 1996, 52,
11385. (l) Josien, H.; Curran, D. P. Tetrahedron 1997, 53, 8881. (m) Josien,
H.; Ko, S.-B.; Bom, D.; Curran, D. P. Chem. Eur. J. 1998, 4, 67. (n)
Kobayashi, Y.; Fukuyama, T. J. Heterocycl. Chem. 1998, 35, 1043. (o)
Du, W.; Curran, D. P. Synlett 2003, 1299. (p) Tangirala, R.; Antony, S.;
Agama, K.; Pommier, Y.; Curran, D. P. Synlett 2005, 2843. For the reaction
of organotellurium compounds with isocyanides, see for example: (q)
Yamago, S.; Miyazoe, H.; Goto, R.; Yoshida, J. Tetrahedron Lett. 1999,
40, 2347. (r) Miyazoe, H.; Yamago, S.; Yoshida, J. Angew. Chem., Int. Ed.
2000, 39, 3669. (s) Yamago, S.; Miyazoe, H.; Sawazaki, T.; Goto, R.;
Yoshida, J. Tetrahedron Lett. 2000, 41, 7517. (t) Yamago, S.; Miyazoe,
H.; Goto, R.; Hashidume, M.; Sawazaki, T.; Yoshida, J. J. Am. Chem. Soc.
2001, 123, 3697. (u) Yamago, S.; Miyazoe, H.; Nakayama, T.; Miyoshi,
M.; Yoshida, J. Angew. Chem., Int. Ed. 2003, 42, 117. (v) Kotani, M.;
Yamago, S.; Satoh, A.; Tokuyama, H.; Fukuyama, T. Synlett 2005, 1893.
(7) Z ) S: (a) Saegusa, T.; Kobayashi, S.; Ito, Y. J. Org. Chem. 1970,
35, 2118. (b) Bachi, M. D.; Balanov, A.; Bar-Ner, N. J. Org. Chem. 1994,
59, 7752. (c) Fukuyama, T.; Chen, X.; Peng, G. J. Am. Chem. Soc. 1994,
116, 3127. (d) Minozzi, M.; Nanni, D.; Walton, J. C. Org. Lett. 2003, 5,
901. Z ) S, Se: (e) Minozzi, M.; Nanni, D.; Walton, J. C. J. Org. Chem.
2004, 69, 2056.
Results and Discussion
Photoinduced Bisthiolation and Bisselenation of Isocya-
nides with Dichalcogenide-Single Systems. If the photolysis
of dichalcogenides is performed in the presence of isocyanides,
the formed chalcogen-centered radicals may add to the unsatur-
ated C-N bonds, producing imidoyl radical intermediates. Thus,
we examined the photoinduced reactions of diphenyl dichalco-
genides with isocyanides (Table 1). When the reaction of 2,6-
xylyl isocyanide (1a, 0.5 M) with equimolar amounts of
diphenyl disulfide in CDCl3 was conducted for 48 h upon
irradiation with a tungsten lamp through Pyrex, 1,1-bisthiolation
product (2a, Y ) S, R ) 2,6-xylyl) and 1,1-hydrothiolation
product (3a, Y ) S, R ) 2,6-xylyl) were obtained in 17% and
33% yields, respectively (entry 1). The reaction may proceed
via the formation of imidoyl radical intermediates by the reaction
of 1a with PhS•, and the subsequent SH2 reaction of the imidoyl
radical intermediates with (PhS)2 leads to the 1,1-bisthiolation
product (2a) (Scheme 1).
Since (PhS)2 is known to convert to p-PhS-C6H4-SH gradually
under photoirradiation conditions,8 the formation of 3a may be
explained by the hydrogen abstraction of the imidoyl radical
intermediate from p-PhS-C6H4-SH. With increase of the molar
ratio of (PhS)2/1a, the yields of 2a increased (entries 1-3). In
the absence of solvent (i.e., under higher concentration of the
substrate), the SH2 reaction of the imidoyl radical intermediate
(8) Schaafsma, Y.; Bickel, A. F.; Kooyman, E. C. Tetrahedron 1960,
10, 76.
416 J. Org. Chem., Vol. 72, No. 2, 2007

Highly SelectiVe Double Chalcogenation of Isocyanides
TABLE 2. Bisthiolation of Benzyl Isocyanide with (PhS)2 in the
with (PhS)2 proceeded to provide 2a in a high yield selectively
(entry 4). In contrast to the aromatic isocyanide, aliphatic
isocyanides did not undergo similar bisthiolations at all (entries
5 and 6). This is probably due to the lack of conjugation between
aromatic π-electrons and lone pairs on sulfur through C-N
double bonds (observed in the case of aromatic isocyanides:
C6H5-NdC-S-Ph T C6H5-dN-CdS+-Ph). In the case of
(PhSe)2, the corresponding bisselenation of isocyanides (both
aromatic and aliphatic ones) did not take place at all (entry 7).
Owing to the weakness of the C-Se bond and the relative
stability of PhSe• (compared with PhS•), the imidoyl radical
bearing phenylseleno group easily undergoes reverse reaction
to reform isocyanide and PhSe•. Exceptionally, isocyanide
bearing a nitro group at the para position (1d) underwent the
photoinduced bisselenation effectively to give the corresponding
1,1-bisselenated product (4d) in high yields (entries 8 and 9)
because of the stabilization of radical intermediate by the
inductive effect of the nitro group.
a
Presence of (PhSe)2
(PhSe)2,
equiv
time,
h
isolated (NMR) yield, %
entry
2b
1
1.0
1.0
1.0
0.15
0.23
1.0
15
15
15
22
15
9
53 (81)
65
(72)
(32)
(47)
76
2b
3c
4
5
6d
a Reaction conditions: PhCH2NC (0.25 mmol), (PhS)2 (1 equiv), solvent
(0.5 mL), 40 °C, hV (>300 nm). b Solvent (0.1 mL). c hV (>400 nm).
d Solvent (C6H6).
Diselenide-Assisted Double Thiolation of Isocyanides with
Disulfides. Some kinetic data are of great importance for
predicting the radical addition reactions of (PhY)2 to unsaturated
compounds. The reactivity of the addition of phenylseleno
radical to carbon-carbon unsaturated bonds is relatively lower
by the factor of about 10-50, compared with the corresponding
thiyl radical.9 On the other hand, the rate constants for the SH2
reaction are estimated to be 7.6 × 104 M-1 s-1 for (PhS)2 and
1.2 × 107 M-1 s-1 for (PhSe)2 by using the free radical clock
system of the 5-hexenyl radical.10 These kinetic data indicate
that (PhSe)2 exhibits an excellent carbon radical capturing
ability, compared with (PhS)2, by the factor of approximately
160.
With these kinetic considerations in mind, we next examined
the photoirradiated reactions of aliphatic isocyanides with (PhS)2
in the presence of (PhSe)2. When a mixture of benzyl isocyanide
(1b), (PhS)2, and (PhSe)2 was irradiated with a tungsten lamp
through Pyrex, surprisingly, bisthiolation product (2b), which
could not be obtained by the reaction of aliphatic isocyanides
with (PhS)2 alone, was obtained in a moderate yield without
formation of any selenated products (Table 2, entries 1 and 2).11
The desired bisthiolation could take place even in the presence
of catalytic amounts of (PhSe)2 (entry 5).
FIGURE 2. (PhSe)2-assisted bisthiolation of benzyl isocyanide with
(PhS)2.
5b disappeared gradually, and instead, the yield of 2b increased
in the meantime.
To gain insight into the role of (PhSe)2, the reaction of benzyl
isocyanide (1b) with (PhS)2 and (PhSe)2 was monitored by
taking the 1H NMR spectra over a period of 50 h and the results
are shown in Figure 2. As can be seen from Figure 2,
thioselenation product (5b) was formed in the initial stage, but
As mentioned already, disulfide has its absorption maximum
in the ultraviolet region, whereas diselenide has its absorption
maximum in the near-UV region (Figure 1). Upon irradiation
with a tungsten lamp through Pyrex (>300 nm), therefore,
(PhSe)2 undergoes homolytic cleavage of the Se-Se bond more
easily compared with that of the S-S bond of (PhS)2. Accord-
ingly, thiyl radicals are probably generated by the reaction of
PhSe• with (PhS)2 (Scheme 2). The formed thiyl radical attacks
the carbon of isocyanide to provide imidoyl radical intermediate
(6), which is trapped by (PhSe)2 to give the corresponding
thioselenated product (5) as a kinetic product. In this reaction,
5 is probably unstable under the photoirradiation conditions.
Therefore, the reverse reaction from 5 to 6 may take place, and
6 is trapped with PhSeSPh, yielding bisthiolation product (2)
with regeneration of PhSe•. Alternatively, a thiyl radical attacks
5 to give 6 by the release of PhSSePh, and then 6 provides 2.
Table 3 summarizes the results of a variety of aliphatic
isocyanides with (PhS)2 in the presence of (PhSe)2. When the
reaction of primary alkyl isocyanide (1e) with (PhS)2 and
(PhSe)2 was conducted in the absence of solvent, the desired
bisthiolated product (2e) was obtained in a good yield (entry
(9) (a) Ito, O.; Matsuda, M. J. Am. Chem. Soc. 1979, 101, 1815. (b) Ito,
O.; Matsuda, M. J. Am. Chem. Soc. 1979, 101, 5732. (c) Ito, O.; Matsuda,
M. J. Am. Chem. Soc. 1981, 103, 5871. (d) Ito, O. J. Am. Chem. Soc. 1983,
105, 850. (e) Ito, O.; Matsuda, M. J. Org. Chem. 1984, 49, 17. (f) Ito, O.;
Matsuda, M. Prog. Polym. Sci. 1992, 17, 827. (g) Ito, O. In The Chemistry
of Free Radicals: S-Centered Radicals; Alfassi, Z. B., Ed.; Wiley:
Chichester, UK, 1999; Chapter 6, pp 193-224.
(10) (a) Perkins, M. J.; Turner, E. S. J. Chem. Soc., Chem. Commun.
1981, 139. (b) Russell, G. A.; Tashtoush, H. J. Am. Chem. Soc. 1983, 105,
1398. (c) Russell, G. A.; Ngoviwatchai, P.; Tashtoush, H. I.; Pla-Dalmau,
A.; Khanna, R. K. J. Am. Chem. Soc. 1988, 110, 3530.
(11) For thioselenation of alkenes, see for example: (a) Ogawa, A.;
Tanaka, H.; Yokoyama, H.; Obayashi, R.; Yokoyama, K.; Sonoda, N.
J. Org. Chem. 1992, 57, 111. (b) Ogawa, A.; Obayashi, R.; Ine, H.; Tsuboi,
Y.; Sonoda, N.; Hirao, T. J. Org. Chem. 1998, 63, 881. (c) Ogawa, A.;
Obayashi, R.; Sonoda, N.; Hirao, T. Tetrahedron Lett. 1998, 39, 1577. (d)
Ogawa, A.; Obayashi, R.; Doi, M.; Sonoda, N.; Hirao, T. J. Org. Chem.
1998, 63, 4277. (e) Ogawa, A.; Ogawa, I.; Obayashi, R.; Umezu, K.; Doi,
M.; Hirao, T. J. Org. Chem. 1999, 64, 86.
J. Org. Chem, Vol. 72, No. 2, 2007 417

Tsuchii et al.
SCHEME 2. Possible Pathways for Bisthiolation of
Isocyanides
bisthiolation products clearly indicates that the thioselenation
products derived from aromatic isocyanides are stable under
photoirradiation conditions. A possible reaction pathway is
shown in eq 4. In situ formed thiyl radicals (from (PhS)2 and
PhSe•) may attack the isocyanide carbon of 1a to give imidoyl
radical intermediate (6a), which undergoes SH2 reaction with
(PhSe)2 to provide 5a. Even with the smaller amounts of
disulfide and diselenide, effective thioselenation proceeded
smoothly in CDCl3 in short reaction times (5a: 76%).
Table 4 summarizes the results of thioselenation of various
aromatic isocyanides. Similar conditions can be employed with
a variety of aromatic isocyanides, and the desired thioselenated
products (5) were obtained in excellent yields (entries 1-5).
The thioselenation of aliphatic disulfides and (PhSe)2 also
proceeded effectively, although the yield was slightly reduced
compared with the case of aromatic disulfide (eq 5). This is
partly due to the bond strength of the S-S single bond: the
S-S bond of aliphatic disulfides is stronger than that of aromatic
disulfides.14
TABLE 3. Bisthiolation of Aliphatic Isocyanides with (PhS)2 in the
a
Presence of (PhSe)2
a Reaction conditions: (PhS)2 (1 equiv), (PhSe)2 (1 equiv), 40 °C, hV
(>300 nm). b Isolated (NMR) yield. c hV (>400 nm). d (PhSe)2 (0.5 equiv).
3). On the other hand, in the case of isocyanides bearing a more
bulky substituent (1g), the reaction did not proceed effectively
(entry 7), probably because the imidoyl radical intermediate was
unstable to decompose to tert-butyl radical and PhSCN.6e
Photoinduced Thioselenation of Aromatic Isocyanides
with a (PhS)2-(PhSe)2 Mixed System. We next examined the
reaction of aromatic isocyanides by using a (PhS)2-(PhSe)2
mixed system. When a reaction of 2,6-xylyl isocyanide (1a)
with (PhS)2 and (PhSe)2 was conducted in the absence of
solvent, interestingly, the product was not the bisthiolation
product but the thioselenation product (5a: 95%) (eq 4).12,13
The fact that prolonged photoirradiation did not cause the
conversion of the thioselenation products into the corresponding
Thioselenation Products as Useful Building Blocks for the
Synthesis of â-Lactam Framework. A series of thioselenated
products obtained by the reaction of isocyanides with dichal-
cogenides are expected to convert into the â-lactam framework
by formal [2+2] cyclization with ketene equivalents. When the
[2+2] cyclization of the thioselenated product (5a) and 2 equiv
of phenoxyacetyl chloride (7a) in the presence of triethylamine
was performed, the desired â-lactam derivative (8a) was
(13) When aromatic isocyanides were used in this reaction, the product
(5) was stable relatively because of resonance stabilization between the
aromatic group and the N-C double bonds. Contrary to this, in the case of
aliphatic isocyanides, the product (5) was unstable compared to the product
from aromatic isocyanides.
(12) The syn- and anti-isomers, concerning C-N double bonds, of the
products are in rapid equilibrium with each other at ambient temperature,
and, as a result, the 1H NMR spectra of the products indicate averaged
signals of both isomers, see: (a) Kessler, H. Angew. Chem. 1970, 82, 237.
(b) Kessler, H.; Leibfritz, D. Tetrahedron 1970, 26, 1805.
(14) (a) Lias, S. G.; Bartmess, J. E.; Liebman, J. F.; Holmes, J. L.; Levin,
R. D.; Mallard, W. G. J. Phys. Chem. Ref. Data 1988, 17, Suppl. No. 1.
(b) Stein, S. E.; Lias, S. G.; Liebman, J. F.; Levin, R. D.; Kafafi, S. A.
NIST Standard Reference Data Base 25, NIST Structures and Properties
Version 2.0; U.S. Dept of Commerce: Gaithersburg, MD, 1994.
418 J. Org. Chem., Vol. 72, No. 2, 2007

Highly SelectiVe Double Chalcogenation of Isocyanides
TABLE 4. Selective Thioselenation of Isocyanides with
a
(PhS)2-(PhSe)2
a Reaction conditions: isocyanide (0.25 mmol), (PhS)2 (1 equiv), (PhSe)2
(1 equiv), CDCl3 (0.5 mL), hV tungsten lamp (500 W, Pyrex), 40 °C.
b Isolated yield. c Adduct of diselenide (4d) was formed in 10% yield.
d (PhSe)2 (0.15 mmol). e Adduct of diselenide (4d) was formed in 2% yield.
of 8i with an allyltin compound also took place selectively at
the phenylseleno group, to form â-lactam derivative (10i) in a
good yield (eq 9).
TABLE 5. Synthesis of â-Lactam Bearing Thio and Seleno
Groupsa
7a,
Et3N, CH2Cl2,
yield, %
ratio of
entry equiv equiv
mL
isolated (NMR) stereoisomersb
1
2
2
2
5
2
2
2
5
4
2
4
2
24
46 (54)
(46)
91/9
2
86/14
83/17
89/11
3c
4
52 (79)
a Reaction conditions: 5a (0.2 mmol), -23 °C, 1 h; then room
temperature, 20 h. b The stereochemistry of 8a was not determined. c Reflux,
16 h.
obtained successfully (Table 5, entry 1).15 Higher concentration
of a ketene precursor improved the yield of 8a (entry 4).
When the [2+2] cyclization reactions were attempted by using
further excess amounts of methoxyacetyl chloride (7a′), the
desired cyclization product (8a′) was obtained in 81% yield (eq
6). In the case of the thioselenation product (5i) derived from
p-methoxyphenylisocyanide, the corresponding â-lactam product
(8i) was formed in 91% yield successfully (eq 7).
Since the thus formed â-lactam derivatives (8i) have both
thio and seleno groups, the chemoselective transformation with
8i was demonstrated as follows. When the reaction of 8i with
tin hydride in the presence of AIBN was examined, the
phenylseleno group of 8i could be reduced selectively to give
the â-lactam derivative (9i) in excellent yield (eq 8). Allylation
Moreover, this thioselenation and [2+2] cyclization sequence
is applicable for the synthesis of carbacephems (Scheme 3).16
When the reaction of isocyanide (1k) with (PhS)2 and (PhSe)2
was performed under the photoirradiation conditions, the
corresponding thioselenated compound (5k) was formed in 96%
(15) Two mechanistic pathways have been reported, see: Baldwin,
J. E. In ComprehensiVe Organic Synthesis; Paquette, L. A., Ed.; Pergamon
Press: Oxford, UK, 1991; Vol. 5, Chapter 2, p 63.
(16) Guzzo, P. R.; Miller, M. J. J. Org. Chem. 1994, 59, 4862.
J. Org. Chem, Vol. 72, No. 2, 2007 419

Tsuchii et al.
SCHEME 3. Synthesis of Carbacephem Framework
products of isocyanides was demonstrated by the constraction
of â-lactam flameworks.
Experimental Section
General Comments. Isocyanides,20 aliphatic disulfides,21 and
diphenyl diselenide22 were synthesized according to the literature.
Other materials were obtained from commercial supplies and
purified by distillation or recrystallization before use. Dichlo-
romethane and triethylamine were distilled from CaH2 and KOH,
respectively. Purification of products was performed on a recycling
preparative HPLC (Japan Analytical Industry Co. Ltd., Model LC-
908), equipped with JAIGEL-1H and -2H columns (GPC), using
1
CHCl3 as an eluent. H NMR spectra were recorded on a JEOL
JNM-GSX-270 (270 MHz) spectrometer with CDCl3 as the solvent
and Me4Si as the internal standard. 13C NMR spectra were taken
on a JEOL JNM-GSX-270 (68 MHz) with CDCl3 as the solvent.
Chemical shifts in 1H NMR were measured relative to CDCl3 and
converted to δ (Me4Si) values by using δ (CDCl3) ) 7.26 ppm.
Chemical shifts in 13C NMR were measured relative to CDCl3 and
converted to δ (Me4Si) values by using δ (CHCl3) ) 77.0 ppm. IR
spectra were determined on a Perkin-Elmer Model 1600 spectrom-
eter. Melting points were determined on a Yanagimoto micro
melting point apparatus. Mass spectra were obtained on a JEOL
JMS-DX303 in the analytical section of Osaka University. Elemen-
tal analyses were also performed there.
N-(2,6-Dimethylphenyl)bis(phenylthio)methanimine (2a). In
a Pyrex glass tube (φ ) 5 mm, length ) 180 mm) were placed
2,6-xylyl isocyanide (1a, 32.8 mg, 0.25 mmol) and diphenyl
disulfide (273 mg, 1.25 mmol) under an argon atmosphere.
Irradiation with a tungsten lamp (500 W) was performed at 40 °C
for 13 h. Purification was performed on a recycling preparative
yield.17 The thioselenation product (5k) reacted with methoxy-
acetyl chloride in the presence of triethylamine to give a
â-lactam derivative (8k) in 79% yield. When the reaction of
8k with 3-buten-2-one was conducted in the presence of nBu3-
SnH and AIBN, the seleno group of 8k was selectively
converted into the 3-butanonyl group.18 Then, the desired
carbacephem derivative (11k) was obtained in excellent yield
by the intramolecular Horner-Emmons reaction of 10k.19
1
HPLC, yielding 64.7 mg (74%) of 2a as a white solid. H NMR
(270 MHz, CDCl3): δ 2.10 (s, 6 H), 6.84-6.98 (m, 3 H), 7.35-
7.37 (m, 6 H), 7.54-7.57 (m, 4 H). 13C NMR (68 MHz, CDCl3):
δ 17.8, 123.6, 126.9, 127.8, 129.0, 129.2, 129.7, 136.1, 147.6, 160.1.
IR (KBr): 3066, 2912, 1598, 1579, 1465, 1439, 1199, 1088, 926,
907, 766, 742, 704, 684 cm-1. MS (CI): m/z 349 (M+ + 1, 4).
HRMS calcd for C21H19NS2 349.0959, found 349.0965.
N-(4-Nitropheny)bis(phenylseleno)methanimine (4d). In a
Pyrex glass tube (φ ) 5 mm, length ) 180 mm) were placed
4-nitrophenyl isocyanide (1d, 34.5 mg, 0.23 mmol), diphenyl
diselenide (82.9 mg, 0.27 mmol), and CDCl3 (0.5 mL) under an
argon atmosphere. Irradiation with a tungsten lamp through Pyrex
was performed at 40 °C for 9 h. Purification by preparative TLC
(silica gel, pentane/Et2O ) 10/1, Rf ) 0.37) and the following
recrystallization from hexane provided 79.7 mg (75%) of 4d as an
Conclusion
A series of photoinduced reactions of various isocyanides with
disulfide and/or diselenide were investigated in detail. The
bisthiolation of aromatic isocyanides could be attained by use
of excess amounts of disulfides. In contrast, aliphatic isocyanides
did not undergo bisthiolation with disulfide alone. In the
presence of diselenide, however, the desired bisthiolation of
aliphatic isocyanides was achieved successfully. On the other
hand, the reaction of aromatic isocyanides with (PhS)2 and
(PhSe)2 afforded the corresponding thioselenation products
selectively. Moreover, the synthetic utility of thioselenation
1
orange needle crystal; mp 96.5 °C. H NMR (270 MHz, CDCl3):
δ 6.89 (d, J ) 8.8 Hz, 2 H), 7.31-7.44 (m, 6 H), 7.64 (d, J ) 6.8
Hz, 4 H), 8.13 (d, J ) 9.3 Hz, 2 H). 13C NMR (68 MHz, CDCl3):
δ 119.9, 124.9, 127.0, 129.3 (2C), 129.7, 137.0, 144.2, 156.4. IR
(KBr): 3053, 2361, 1598, 1585, 1512, 1343, 1211, 1110, 872, 858
cm-1. MS (CI): m/z 463 (M+ + 1, 92). Anal. Calcd for C19H14N2O2-
Se2: C, 49.58; H, 3.07; N, 6.09. Found: C, 49.58; H, 3.19; N,
6.16.
N-Benzylbis(phenylthio)methanimine (2b) (General Proce-
dure for the Bisthiolation of Aliphatic Isocyanides). In a Pyrex
glass tube (φ ) 5 mm, length ) 180 mm) were placed benzyl
isocyanide (1b, 29.3 mg, 0.25 mmol), diphenyl disulfide (54.6 mg,
0.25 mmol), diphenyl diselenide (78.0 mg, 0.25 mmol), and C6D6
(0.5 mL) under an argon atmosphere. Irradiation with a tungsten
lamp (500 W) was performed at 40 °C for 9 h. The reaction mixture
(17) The bisthiolated product was assumed to be obtained because of
the reaction of aliphatic isocyanides with (PhS)2 and (PhSe)2. However,
the thioselenated product (5k) was obtained as a sole product. The reason
why 5k was obtained may be explained by the coordination of a
diethoxyphosphoryl group to the seleno group as shown below, which
stabilizes the thioselenation products.
(20) (a) Ugi, I.; Meyr, R. Chem. Ber. 1960, 93, 239. (b) Ugi, I.; Fetzer,
U.; Eholzer, U.; Knupfer, H.; Offermann, K. Angew. Chem. 1965, 77, 492.
(21) Gladysz, J. A.; Wong, V. K.; Jick, B. S. Tetrahedron 1979, 35,
2329.
(22) Reich, H. J.; Renga, J. M.; Reich, I. V. J. Am. Chem. Soc. 1975,
97, 5434.
(18) Mesmaeker, A. De.; Hoffmann, P.; Ernst, B.; Hug, P.; Winkler, T.
Tetrahedron Lett. 1989, 30, 6311.
(19) Grieco, P. A.; Pogonowski, C. S. Synthesis 1973, 425.
420 J. Org. Chem., Vol. 72, No. 2, 2007

Highly SelectiVe Double Chalcogenation of Isocyanides
was treated with preparative TLC on silica gel with pentane/Et2O
(50/1) as an eluent to afford 63.7 mg (76%) of 2b as a white solid;
mp 80.5 °C. 1H NMR (270 MHz, CDCl3): δ 4.72 (s, 2 H), 7.14-
7.40 (m, 13 H), 7.60 (d, J ) 7.8 Hz, 2 H). 13C NMR (68 MHz,
CDCl3): δ 57.0, 126.5, 127.2, 128.1, 128.6, 128.7, 129.2, 129.4,
130.7, 135.0 (2 C), 135.4, 139.6, 156.8. IR (KBr): 3028, 2857,
1595, 1577, 1493, 1472, 1452, 1439, 1353, 1009, 930, 912, 757,
734, 694 cm-1. MS (CI): m/z 336 (M+ + 1, 39). Anal. Calcd for
C20H17NS2: C, 71.60; H, 5.11; N, 4.18. Found: C, 71.13; H, 5.21;
N, 4.15.
121.2 (2 C), 128.9 (2 C), 129.1 (2 C), 129.3, 134.9, 137.4, 143.6,
156.7. IR (KBr): 2998, 1604, 1587, 1574, 1504, 1458, 1439, 1290,
1245, 1030, 893, 738, 689 cm-1. MS (CI): m/z 399 (M+ + 1, 1).
Anal. Calcd for C20H17NOSSe: C, 60.30; H, 4.30; N, 3.52.
Found: C, 60.11; H, 4.40; N, 3.53.
N-(4-Nitrophenyl)(phenylseleno)(phenylthio)methanimine (5d):
1
yellow solid; mp 98.0-98.5 °C. H NMR (270 MHz, CDCl3): δ
6.89 (d, J ) 8.8 Hz, 2 H), 7.33-7.41 (m, 6 H), 7.51-7.54 (m, 2
H), 7.64 (d, J ) 6.8 Hz, 2 H), 8.11 (d, J ) 8.8 Hz, 2 H). 13C NMR
(68 MHz, CDCl3): δ 120.3, 124.8, 124.9, 126.0, 129.1, 129.3,
129.7, 129.9, 135.2, 137.2, 144.1, 155.9, 160.2. IR (KBr): 3066,
N-(Butyl)bis(phenylthio)methanimine (2e): yellow oil. 1H
NMR (270 MHz, CDCl3): δ 0.87 (t, J ) 7.3 Hz, 3 H), 1.39 (sextet,
J ) 7.3 Hz, 2 H), 1.53 (quint, J ) 7.2 Hz, 2 H), 3.50 (t, J ) 6.8
Hz, 2 H), 7.25-7.26 (m, 3 H), 7.32-7.35 (m, 5 H), 7.53 (d, J )
7.3 Hz, 2 H). 13C NMR (68 MHz, CDCl3): δ 13.8, 20.4, 32.4,
53.9, 128.3, 128.5, 128.9, 129.0, 130.0, 131.0, 134.3, 135.0, 154.1.
IR (NaCl): 2930, 1598, 1580, 1475, 887, 745, 705, 689 cm-1. MS
(CI): m/z 302 (M+ + 1, 18). HRMS calcd for C17H19NS2 302.1037,
found 302.1044.
2363, 1597, 1559, 1510, 1475, 1342, 1111, 900, 740, 688 cm-1
.
MS (CI): m/z 415 (M+ + 1, 68). HRMS calcd for C19H14N2O2SSe
415.0019, found 415.0047.
N-(4-Trifluoromethylphenyl)(phenylseleno)(phenylthio)-
1
methanimine (5j): yellow solid. H NMR (270 MHz, CDCl3): δ
6.89 (d, J ) 8.3 Hz, 2 H), 7.29-7.42 (m, 6 H), 7.48-7.53 (m, 4
H), 7.65 (d, J ) 6.8 Hz, 2 H). 13C NMR (68 MHz, CDCl3): δ
119.7, 120.1, 126.1 (JC-F ) 3.4 Hz), 126.1 (JC-F ) 32.5 Hz), 126.3
(JC-F ) 272.2 Hz), 129.1, 129.2, 129.5, 129.7, 135.1, 137.0, 137.3,
153.2, 158.7. IR (KBr): 1622, 1603, 1509, 1475, 1322, 1156, 1123,
1103, 1064, 878, 740, 688 cm-1. MS (CI): m/z 438 (M+ + 1, 13).
HRMS calcd for C20H14F3NSSe 438.0042, found 438.0034.
N-(2,6-Dimethylphenyl)(butylthio)(phenylseleno)-
methanimine (5a′). The photoirradiated reaction of 2,6-xylyl
isocyanide (1a, 26.0 mg, 0.22 mmol) with dibutyl disulfide (54.3
mg, 0.30 mmol) and diphenyl diselenide (76.1 mg, 0.24 mmol) in
CDCl3 (0.5 mL) at 40 °C for 43 h was performed similarly as the
general procedure for the thioselenation of aromatic isocyanides.
Purification by preparative TLC (silica gel, pentane/Et2O ) 50/1,
Rf ) 0.44) provided 66.7 mg (84%) of 5a′ as a yellow oil. 1H NMR
(270 MHz, CDCl3): δ 0.88 (t, J ) 7.3 Hz, 3 H), 1.37 (sextet, J )
7.3 Hz, 2 H), 1.65 (quint, J ) 7.3 Hz, 2 H), 2.17 (s, 6 H), 3.05 (t,
J ) 7.3 Hz, 2 H), 6.96-7.05 (m, 3 H), 7.29-7.41 (m, 3 H), 7.66
(d, J ) 7.3 Hz, 2 H). 13C NMR (68 MHz, CDCl3): δ 13.7, 18.0,
22.1, 31.3, 32.6, 123.9, 125.8, 127.4, 128.1, 129.0, 129.5, 138.1,
148.5, 157.0. IR (NaCl): 2959, 2930, 1598, 1574, 1474, 1438, 916,
890, 740, 689 cm-1. MS (EI): m/z 377 (M+, 1). HRMS calcd for
C19H23NSSe 377.0716, found 377.0718.
N-(Cyclohexyl)bis(phenylthio)methanimine (2c): white solid;
1
mp 73.5 °C. H NMR (270 MHz, CDCl3): δ 1.25-1.68 (m, 10
H), 3.75-3.81 (m, 1 H), 7.24-7.35 (m, 8 H), 7.49 (br s, 2 H). 13
C
NMR (68 MHz, CDCl3): δ 24.1, 25.7, 33.0, 62.5, 128.1, 128.4,
128.9 (2C), 130.5, 131.6, 134.0, 135.0, 151.8. IR (KBr): 3057,
2928, 2853, 1598, 1577, 1438, 1362, 1023, 925, 910, 871, 749,
688 cm-1. MS (CI): m/z 328 (M+ + 1, 35). HRMS calcd for
C19H21NS2 328.1194, found 328.1187.
N-(2-(1-Cyclohexenyl)ethyl)bis(phenylthio)methanimine (2f):
1
yellow oil. H NMR (270 MHz, CDCl3): δ 1.52-1.63 (m, 4 H),
1.87 (br s, 2 H), 1.97 (br s, 2 H), 2.18 (t, J ) 7.1 Hz, 2 H), 3.60
(t, J ) 7.1 Hz, 2 H), 5.37 (br s, 1 H), 7.24-7.37 (m, 8 H), 7.53-
7.56 (m, 2 H). 13C NMR (68 MHz, CDCl3): δ 22.4, 23.0, 25.3,
28.4, 38.5, 53.3, 122.5, 128.4, 128.5, 129.0, 129.1, 130.1, 131.0,
134.4, 135.0, 135.8, 154.5. IR (NaCl): 2925, 2854, 2833, 1599,
1580, 1477, 1440, 886, 744, 705, 688 cm-1. MS (CI): m/z 354
(M+ + 1, 24). HRMS calcd for C21H23NS2 354.1350, found
354.1346.
N-(2,6-Dimethylphenyl)(phenylseleno)(phenylthio)methani-
mine (5a) (General Procedure for the Thioselenation of Aro-
matic Isocyanide). In a Pyrex glass tube (φ ) 5 mm, length )
180 mm) were placed 2,6-xylyl isocyanide (1a, 29.3 mg, 0.22
mmol), diphenyl disulfide (55.4 mg, 0.25 mmol), and diphenyl
diselenide (79.3 mg, 0.25 mmol) under an argon atmosphere.
Irradiation with a tungsten lamp (500 W) was performed at 40 °C
for 5 h. The reaction mixture was treated with preparative TLC
(silica gel, Rf ) 0.59) with pentane/Et2O (25/1) as an eluent to
afford 82.8 mg (95%) of 5a. The product was recrystallized from
N-(2,6-Dimethylphenyl)-3-phenoxy-4-(phenylseleno)-4-(phen-
ylthio)azetidin-2-one (8a) (General Procedure for the Synthesis
of â-Lactam Framework). In a two-necked flask (20 mL) equipped
with a dropping funnel and a magnetic stirring bar were placed
N-(2,6-dimethylphenyl)(phenylseleno)(phenylthio)methanimine (5a,
78.9 g, 0.20 mmol) and dichloromethane (4 mL) under an argon
atmosphere, and the solution was cooled at -23 °C. After the
addition of phenoxyacetyl chloride (7a, 171 mg, 1.0 mmol) to the
solution in one portion, triethylamine (139 µL, 101 mg, 1.0 mmol)
was added slowly. During the addition of Et3N, the white salt was
precipitated. The suspended solution was stirred for 1 h at -23 °C
and then for 20 h at ambient temperature (the solution had a color
varying from initially pale yellow to brown at the end). The resulting
solution was washed with water, dried over MgSO4, and concen-
trated in vacuo. Purification of 8a was performed by a recycling
preparative HPLC and then by preparative TLC (silica gel, pentane/
Et2O ) 25/1, developed two times, Rf ) 0.09), affording 55.3 mg
(52%, 89/11) of 8a: yellow oil. 1H NMR (270 MHz, CDCl3): major
isomer δ 2.50 (s, 3 H), 2.60 (s, 3 H), 5.67 (s, 1 H), 6.95-7.34 (m,
18 H); minor isomer δ 2.55 (s, 3 H), 2.57 (s, 3 H), 5.79 (s, 1 H),
6.95-7.34 (m, 18 H). 13C NMR (68 MHz, CDCl3): major isomer
δ 20.7, 83.1, 90.4, 117.0, 123.1, 127.5, 128.1, 128.2, 128.4, 128.7,
129.0, 129.3, 129.5, 129.6, 132.3, 133.8, 135.2, 136.2, 138.1, 138.8,
157.6, 163.6; minor isomer δ 20.5, 81.9, 91.1, 117.1, 123.1, 127.9,
128.3, 129.6, 132.5, 133.9, 135.2, 137.8, 139.1, 158.2, 164.0. IR
(NaCl): 3060, 1778, 1591, 1494, 1225, 1022, 738, 689 cm-1. MS
(CI): m/z 532 (M+ + 1, 8). HRMS calcd for C29H25NO2SSe
532.0850, found 532.0854.
1
hexane as a white solid; mp 72.0-73.0 °C. H NMR (270 MHz,
CDCl3): δ 2.10 (s, 6 H), 6.88-6.98 (m, 3 H), 7.32-7.35 (m, 6
H), 7.53 (br s, 2 H), 7.69 (d, J ) 7.3 Hz, 2 H). 13C NMR (68
MHz, CDCl3): δ 17.9, 123.8, 126.4, 126.8, 127.9, 128.9, 129.1,
129.4, 129.5, 130.0, 135.6, 137.7, 148.3, 156.2. IR (KBr): 3063,
2912, 1618, 1597, 1583, 1476, 1439, 1190, 1090, 1022, 881, 768,
738, 685 cm-1. MS (CI): m/z 398 (M+ + 1, 10). Anal. Calcd for
C21H19NSSe: C, 63.63; H, 4.83; N, 3.53. Found: C, 63.85; H, 4.91;
N, 3.77.
N-Phenyl(phenylseleno)(phenylthio)methanimine (5h): white
1
solid; mp 130.0-131.0 °C. H NMR (270 MHz, CDCl3): δ 6.84
(d, J ) 7.3 Hz, 2 H), 7.07 (t, J ) 7.6 Hz, 1 H), 7.23-7.39 (m, 8
H), 7.52 (br s, 2 H), 7.69 (d, J ) 6.8 Hz, 2 H). 13C NMR (68
MHz, CDCl3): δ 119.9 (2 C), 124.3, 128.9 (2 C), 129.0, 129.1 (2
C), 129.3, 135.0, 137.5 (2 C), 150.4. IR (KBr): 3048, 1587, 1484,
1474, 1210, 916, 904, 867, 754, 748, 735, 692 cm-1. MS (CI):
m/z 370 (M+ + 1, 8). Anal. Calcd for C19H15NSSe: C, 61.95; H,
4.10; N, 3.80. Found: C, 61.68; H, 4.15; N, 3.81.
N-(4-Methoxyphenyl)(phenylseleno)(phenylthio)methanimine
1
(5i): white solid; mp 133.0 °C. H NMR (270 MHz, CDCl3): δ
3.76 (s, 3 H), 6.82 (s, 4 H), 7.28-7.42 (m, 6 H), 7.51 (br s, 2 H),
N-(2,6-Dimethylphenyl)-3-methoxy-4-(phenylseleno)-4-(phen-
ylthio)azetidin-2-one (8a′). The reaction of N-(2,6-dimethylphen-
7.68 (br s, 2 H). 13C NMR (68 MHz, CDCl3): δ 55.4, 114.1 (2C),
J. Org. Chem, Vol. 72, No. 2, 2007 421

Tsuchii et al.
yl)(phenylseleno)(phenylthio)methanimine (5a, 78.9 g, 0.20 mmol)
with methoxyacetyl chloride (7a′, 217 mg, 2.0 mmol) in the
presence of Et3N (279 µL, 202 mg, 2.0 mmol) in CH2Cl2 (2 mL)
was conducted according to the above general procedure. Isolation
was performed on a recycling preparative HPLC, yielding 76.2 mg
(81%, 81/19) of 8a′ as a yellow oil. 1H NMR (270 MHz, CDCl3):
major isomer δ 2.48 (s, 3 H), 2.56 (s, 3 H), 3.49 (s, 3 H), 4.97 (s,
1 H), 6.92-7.34 (m, 13 H); minor isomer δ 2.50 (s, 3 H), 2.51 (s,
3 H), 3.38 (s, 3 H), 5.16 (s, 1 H), 6.92-7.34 (m, 13 H). 13C NMR
(68 MHz, CDCl3): major isomer δ 20.6, 20.7, 60.0, 84.7, 93.3,
127.4, 127.9, 128.5, 128.7, 128.8, 128.9, 129.3, 129.4, 132.3, 132.6,
133.7, 135.6, 138.0, 138.8, 164.1; minor isomer δ 20.3, 20.6, 60.1,
82.9, 94.3, 128.0, 128.4, 129.1, 129.5, 132.7, 133.0, 133.1, 136.3,
137.6, 139.1, 164.3. IR (NaCl): 2930, 1770, 1472, 1339, 1022,
738, 690 cm-1. MS (EI): m/z 470 (M+, 1). HRMS calcd for C24H23-
NO2SSe 470.0693, found 470.0693.
0.35) of trans-10i and 20.8 mg (24%, Rf ) 0.17) of cis-10i as a
yellow oil. trans-10i: 1H NMR (270 MHz, CDCl3): δ 3.03 (dd, J
) 7.8, 8.3 Hz, 2 H), 3.54 (s, 3 H), 3.83 (s, 3 H), 4.21 (s, 1 H), 5.10
(dd, J ) 9.7, 17.0 Hz, 2 H), 5.94 (m, 1 H), 6.92 (d, J ) 8.8 Hz, 2
H), 7.24-7.39 (m, 5 H), 7.77 (d, J ) 9.3 Hz, 2 H). 13C NMR (68
MHz, CDCl3): δ 38.5, 55.4, 59.9, 75.1, 88.5, 114.3, 119.6, 120.0,
128.8, 129.3, 129.8, 130.2, 131.6, 136.6, 156.6, 162.9. IR (NaCl):
2935, 1756, 1513, 1378, 1298, 1247, 1133, 1021, 832 cm-1. MS
(EI): m/z 355 (M+, 6). HRMS calcd for C20H21NO3S 355.1243,
found 355.1245. cis-10i: 1H NMR (270 MHz, CDCl3): δ 2.97 (dd,
J ) 6.8, 7.3 Hz, 2 H), 3.60 (s, 3 H), 3.80 (s, 3 H), 4.52 (s, 1 H),
5.23 (dd, J ) 11.7, 14.7 Hz, 2 H), 5.77 (m, 1 H), 6.86 (d, J ) 9.3
Hz, 2 H), 7.12-7.27 (m, 3 H), 7.45 (d, J ) 8.3 Hz, 2 H), 7.59 (d,
J ) 9.3 Hz, 2 H). 13C NMR (68 MHz, CDCl3): δ 40.9, 55.4, 59.0,
78.2, 88.3, 114.3, 120.3, 120.9, 128.4, 129.1, 129.2, 129.7, 130.8,
136.6, 156.8, 162.9. IR (NaCl): 2932, 1760, 1514, 1378, 1137,
750 cm-1. MS (EI): m/z 355 (M+, 5). HRMS calcd for C20H21-
NO3S 355.1243, found 355.1261.
3-Methoxy-N-(4-methoxyphenyl)-4-(phenylseleno)-4-(phen-
ylthio)azetidin-2-one (8i). The reaction of N-(4-methoyphenyl)-
(phenylseleno)(phenylthio)methanimine (5i, 0.20 mmol, 79.7 g)
with methoxyacetyl chloride (7a′, 217 mg, 2.0 mmol) in the
presence of Et3N (279 µL, 202 mg, 2.0 mmol) in CH2Cl2 (2 mL)
and the following purification on a recycling preparative HPLC
provide 85.6 mg (91%, 52/48) of 8i as a yellow oil. 1H NMR (270
MHz, CDCl3): major isomer δ 3.56 (s, 3 H), 3.81 (s, 3 H), 4.24
(s, 1 H), 6.85 (d, J ) 9.3 Hz, 2 H), 7.09 (t, J ) 8.1 Hz, 2 H),
7.20-7.38 (m, 5 H), 7.50-7.57 (m, 3 H), 7.79 (d, J ) 8.8 Hz, 2
H); minor isomer δ 3.44 (s, 3 H), 3.81 (s, 3 H), 4.46 (s, 1 H), 6.87
(d, J ) 8.8 Hz, 2 H), 7.12 (t, J ) 8.5 Hz, 2 H), 7.20-7.38 (m, 5
H), 7.47-7.53 (m, 3 H), 7.79 (d, J ) 9.3 Hz, 2 H). 13C NMR (68
MHz, CDCl3): major isomer δ 55.4, 59.0, 76.7, 90.9, 114.1, 120.2,
126.5, 128.5, 129.4, 129.6, 130.0, 136.2, 137.5, 156.8, 161.5; minor
isomer δ 55.4, 59.1, 75.3, 89.0, 114.0, 120.2, 125.8, 128.5, 129.4,
129.6, 130.2, 136.1, 137.9, 156.8, 161.3. MS (EI): m/z 471 (M+,
1). HRMS calcd for C23H21NO3SSe 471.0407, found 471.0436.
3-Methoxy-N-(4-methoxyphenyl)-4-(phenylthio)azetidin-2-
one (9i). In a two-necked flask equipped with a condenser and a
magnetic stirring bar were placed 3-methoxy-N-(4-methoxyphenyl)-
4-(phenylseleno)-4-(phenylthio)azetidin-2-one (8i, 93.9 mg, 0.20
mmol), 2,2′-azobisisobutyronitrile (AIBN, 6.60 mg, 0.04 mmol),
and benzene (3 mL) at ambient temperature under a nitrogen
atmosphere. After the addition of tributyltin hydride (75.3 mg, 0.26
mmol) to the mixture at ambient temperature, the reaction was
conducted under reflux for 3 h. The resulting solution was
condensed under reduced pressure, and the residual mixture was
treated with preparative TLC on silica gel (pentane/Et2O ) 10/1,
three times), yielding 36.6 mg (58%, Rf ) 0.14) of trans-9i and
20.8 mg (33%, Rf ) 0.06) of cic-9i as a yellow oil. 1H NMR (270
MHz, CDCl3): trans-10i δ 3.51 (s, 3 H), 3.82 (s, 3 H), 4.38 (d, J
) 1.5 Hz, 1 H), 5.07 (d, J ) 1.5 Hz, 1 H), 6.92 (d, J ) 9.3 Hz, 2
H), 7.30-7.37 (m, 5 H), 7.48 (d, J ) 9.3 Hz, 2 H); cis-9i δ 3.70
(s, 3 H), 3.78 (s, 3 H), 4.82 (d, J ) 4.4 Hz, 1 H), 5.47 (d, J ) 4.4
Hz, 1 H), 6.80 (d, J ) 8.8 Hz, 2 H), 7.23-7.31 (m, 5 H), 7.46 (d,
J ) 7.3 Hz, 2 H). 13C NMR (68 MHz, CDCl3): trans-9i δ 55.4,
58.2, 64.6, 88.5, 114.5, 119.8, 128.6, 129.3, 129.4, 135.3, 156.9,
162.1; cis-9i δ 55.4, 59.2, 68.4, 84.6, 114.2, 119.8, 128.5, 129.1,
129.4, 131.9, 134.0, 156.7, 162.7. IR (NaCl): 2933, 2836, 1760,
1514, 1385, 1249, 1130, 693 cm-1. MS (EI): m/z 315 (M+, 10).
HRMS calcd for C17H17NO3S 315.0929, found 315.0927.
N-((Diethoxyphosphoryl)methyl)(phenylseleno)(phenylthio)-
methanimine (5k). According to the general procedure for thiose-
lenation of isocyanides, the photoinduced reaction of (diethoxy-
phosphoryl)methyl isocyanide (1k, 34.9 mg, 0.20 mmol) with
diphenyl disulfide (44.3 mg, 0.20 mmol) and diphenyl diselenide
(65.2 mg, 0.21 mmol) in CDCl3 (0.5 mL) at 40 °C for 4 h was
conducted. Purification on a recycling preparative HPLC provided
1
84.9 mg (96%) of 5k as a pale yellow oil. H NMR (270 MHz,
CDCl3): δ 1.18 (t, J ) 7.2 Hz, 6 H), 3.83-4.03 (m, 6 H), 7.25-
7.48 (m, 8 H), 7.64-7.72 (m, 2 H). 13C NMR (68 MHz, CDCl3):
major isomer δ 16.2, 53.8 (JC-P ) 162.1 Hz), 62.4, 126.5, 128.6,
128.8, 129.0, 129.4, 130.8, 134.7, 136.1, 157.0 (JC-P ) 23.9 Hz);
minor isomer δ 16.3, 51.7 (JC-P ) 162.2 Hz), 62.5, 128.5, 128.7,
129.1, 130.2, 136.2, 136.4, 159.1 (JC-P ) 23.9 Hz). IR (NaCl):
3118, 2989, 2854, 1576, 1476, 1440, 1391, 1237, 1162, 1062, 976,
901, 844, 801, 748, 690 cm-1. MS (CI): m/z 444 (M+ + 1, 100).
Anal. Calcd for C18H22NO3PSSe: C, 48.87; H, 5.01; N, 3.17.
Found: C, 49.03; H, 5.11; N, 3.32.
N-((Diethoxyphosphoryl)methyl)-3-methoxy-4-(phenylseleno)-
4-(phenylthio)azetidin-2-one (8k). The reaction of N-((diethoxy-
phosphoryl)methyl)(phenylseleno)(phenylthio)methanimine (5k, 81.2
g, 0.18 mmol) with methoxyacetyl chloride (7a′, 2.0 mmol, 217
mg) in the presence of Et3N (202 mg, 2.0 mmol) in CH2Cl2 (2
mL) was conducted according to the general procedure for the
construction of the â-lactam framework. Isolation was performed
on a recycling preparative HPLC, yielding 73.2 mg (79%, 64/36)
1
of 8k as a pale yellow oil. H NMR (400 MHz, CDCl3): major
isomer δ 1.32 (t, J ) 7.2 Hz, 6 H), 3.20 (dd, J ) 17.0, 17.0 Hz, 1
H), 3.41-3.50 (m, 1 H), 3.45 (s, 3 H), 4.11-4.23 (m, 4 H), 4.39
(s, 1 H), 7.27-7.44 (m, 6 H), 7.67 (d, J ) 7.2 Hz, 2 H), 7.82 (d,
J ) 7.2 Hz, 2 H); minor isomer δ 1.33 (t, J ) 7.2 Hz, 6 H), 3.20
(dd, J ) 4.8, 16.2 Hz, 1 H), 3.41 (s, 3 H), 3.53 (dd, J ) 3.4, 16.2
Hz, 1 H), 4.11-4.23 (m, 4 H), 4.38 (s, 1 H), 7.27-7.44 (m, 6 H),
7.70 (d, J ) 7.2 Hz, 2 H), 7.77 (d, J ) 7.6 Hz, 2 H). 13C NMR (68
MHz, CDCl3): major isomer δ 16.2, 36.2 (JC-P ) 159.0 Hz), 37.4,
58.9, 62.8, 89.2, 126.5, 129.0, 129.5, 130.1, 130.5, 136.0, 137.4,
163.7; minor isomer δ 16.3, 36.4 (JC-P ) 159.0 Hz), 37.6, 58.8,
62.7, 90.8, 127.2, 128.9, 129.5, 129.9, 130.2, 135.9, 137.4, 163.8.
MS (CI): m/z 516 (M+ + 1, 13.0). Anal. Calcd for C21H26NO5-
PSSe: C, 49.03; H, 5.09; N, 2.72. Found: C, 48.98; H, 5.09; N,
2.68.
N-((Diethoxyphosphoryl)methyl)-3-methoxy-4-(phenylthio)-
4-(3-oxabutyl)azetidin-2-one (10k). In a three-necked flask equipped
with a condenser, a dropping funnel, and a magnetic stirring bar
were placed N-((diethoxyphosphoryl)methyl)-3-methoxy-4-(phen-
ylseleno)-4-(phenylthio)azetidin-2-one (8k, 111 mg, 0.22 mmol),
AIBN (7.7 mg, 0.05 mmol), benzene (2 mL), and 3-buten-2-one
(77.1 mg, 1.10 mmol) at room temperature under a nitrogen
atmosphere. The solution of tributyltin hydride (71.2 mg, 0.25
mmol) and 3-buten-2-one (15.4 mg, 0.22 mmol) in benzene (3 mL)
was added dropwise to the reaction mixture over 45 min at 80 °C.
4-Allyl-3-methoxy-N-(4-methoxyphenyl)-4-(phenylthio)azeti-
din-2-one (10i). In a two-necked flask equipped with a condenser
and a magnetic stirring bar were placed 3-methoxy-N-(4-methoxy-
phenyl)-4-(phenylseleno)-4-(phenylthio)azetidin-2-one (8i, 107 mg,
0.23 mmol), AIBN (9.9 mg, 0.06 mmol), and benzene (2 mL) at
room temperature under a nitrogen atmosphere. After the addition
of allyltributyltin (223 mg, 0.67 mmol) to the mixture at room
temperature, the reaction was conducted under reflux for 8 h. The
resulting solution was condensed under reduced pressure, and the
residual mixture was treated with preparative TLC on silica gel
(pentane/Et2O ) 5/1, two times), yielding 36.6 mg (43%, Rf )
422 J. Org. Chem., Vol. 72, No. 2, 2007

Highly SelectiVe Double Chalcogenation of Isocyanides
The reaction was continued at the temperature for an additional 4
h. The resulting solution was condensed under reduced pressure,
and the residual mixture was treated with a recycling preparative
HPLC, yielding 32.1 mg (34%, 52/48) of 10k along with simply
Extraction with diethyl ether (2 × 10 mL) followed by evaporation
afforded a crude product. Purification on a recycling preparative
HPLC yielded 14.8 mg (96%, 53/47) of 11k as a colorless oil (the
ratio of stereoisomers is 53/47). 1H NMR (300 MHz, CDCl3): major
isomer δ 1.74 (s, 3 H), 1.79 (dd, J ) 5.4, 17.7 Hz, 1 H), 2.06 (dd,
J ) 7.2, 10.2 Hz, 1 H), 2.17 (dd, J ) 5.4, 17.7 Hz, 1 H), 2.54-
2.65 (m, 1 H), 3.64 (s, 3 H), 4.20 (s, 2 H), 6.26 (s, 1 H), 7.24-
7.31 (m, 3 H), 7.51-7.54 (m, 2 H); minor isomer δ 1.77 (s, 3 H),
1.99-2.11 (m, 1 H), 2.15-2.24 (m, 2 H), 2.47-2.61 (m, 1 H),
3.43 (s, 3 H), 4.35 (s, 2 H), 6.29 (s, 1 H), 7.32-7.39 (m, 3 H),
7.45-7.49 (m, 2 H). 13C NMR (75 MHz, CDCl3): major isomer δ
20.4, 25.4, 26.9, 58.7, 70.8, 91.5, 114.0, 121.6, 128.4, 128.8, 129.1,
136.6, 162.5; minor isomer δ 20.6, 24.6, 29.6, 59.3, 67.5, 90.4,
113.5, 124.2, 129.0, 129.4, 129.6, 136.3, 161.7. IR (NaCl): 3066,
2921, 1767, 1440, 1387, 1369, 1217, 1085, 1024, 815, 750, 694
cm-1. MS (EI): m/z 275 (M+, 20). HRMS calcd for C15H17NO2S
275.0980, found 275.0984. Anal. Calcd for C15H17NO2S: C, 65.43;
H, 6.22; N, 5.09. Found: C, 65.13; H, 6.65; N, 4.52.
1
deselenated reduction product (55%): pale yellow oil. H NMR
(300 MHz, CDCl3): major isomer δ 1.35 (dt, J ) 3.9, 7.2 Hz, 6
H), 2.18 (s, 3 H), 2.18-2.25 (m, 1 H), 2.32-2.42 (m, 2 H), 2.79-
2.85 (m, 1 H), 3.44 (s, 3 H), 3.62 (dd, J ) 11.7, 16.5 Hz, 1 H),
3.81 (dd, J ) 12.3, 16.5 Hz, 1 H), 4.08 (d, J ) 4.5 Hz, 1 H), 4.21
(dq, J ) 2.4, 7.5 Hz, 4 H), 7.27-7.44 (m, 4 H), 7.60-7.64 (m, 1
H); minor isomer δ 1.31 (dt, J ) 4.9, 7.2 Hz, 6 H), 2.11-2.14 (m,
1 H), 2.19 (s, 3 H), 2.25-2.32 (m, 2 H), 2.67-2.76 (m, 1 H), 3.24
(dd, J ) 11.7, 16.5 Hz, 1 H), 3.47 (dd, J ) 10.9, 16.5 Hz, 1 H),
3.61 (s, 3 H), 4.18 (dq, J ) 2.4, 7.2 Hz, 4 H), 4.36 (d, J ) 4.3 Hz,
1 H), 7.27-7.44 (m, 4 H), 7.60-7.64 (m, 1 H). 13C NMR (75 MHz,
CDCl3): major isomer δ 16.4, 28.7, 30.1, 35.5 (JC-P ) 160.0 Hz),
38.9, 59.0, 62.9, 63.0, 79.8, 88.9, 128.4, 129.0, 129.7, 136.6, 165.1,
206.9; minor isomer δ 16.4, 30.0, 31.5, 35.6, 39.0, 59.5, 62.7, 62.8,
63.0, 77.2, 89.1, 128.7, 129.4, 130.1, 136.6, 165.6, 206.2. IR
(NaCl): 2976, 1769, 1714, 1442, 1371, 1294, 1241, 1164, 1117,
1025, 972, 733, 703 cm-1. MS (CI): m/z 430 (M+ + 1, 36). HRMS
calcd for C19H28NO6PS 430.1453, found 430.1440.
7-Methoxy-3-methyl-6-(phenylthio)-1-aza-bicyclo[4.2.0]oct-2-
en-8-one (11k). In a two-necked flask equipped with a condenser
were placed N-((diethoxyphosphoryl)methyl)-3-methoxy-4-(phen-
ylthio)-4-(3-oxabutyl)azetidin-2-one (10k, 24.1 mg, 0.06 mmol) and
dimethoxyethane (1 mL) at room temperature. After the addition
of sodium hydride (2.64 mg, 0.11 mmol) to the mixture at room
temperature, the mixture was stirred for 0.5 h at room temperature
and then for 1 h at 60-65 °C. The resulting solution was cooled in
an ice-water bath and quenched with saturated NaCl aq at 0 °C.
Acknowledgment. We thank Mr. M. Doi (Osaka University)
for his assistance. This work was supported by a Grant-in-Aid
for Scientific Research on Priority Areas “Advanced Molecular
Transformations of Carbon Resources” from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
Supporting Information Available: UV-vis spectra of cy-
clohexyl isocyanide (1c) and 2,6-xylyl isocyanide (1a). This material
is available free of charge via the Internet at http://pubs.acs.org.
JO061704F
J. Org. Chem, Vol. 72, No. 2, 2007 423