Synthesis of 3-selena-1-dethiacephems and selenazepines via iodocyclization

Article abstract of DOI:10.1021/ol801010y

(Chemical Equation Presented) A convenient approach to synthesize novel selenium-β-lactams, 3-selena-1-dethiacephems and selenazepines, was accomplished via the regioselective iodocyclization reaction. The substituent of allenyl moieties dramatically infl

Full text of DOI:10.1021/ol801010y

ORGANIC
LETTERS
2008
Vol. 10, No. 15
3319-3322
Synthesis of 3-Selena-1-dethiacephems
and Selenazepines via Iodocyclization
Dinesh R. Garud† and Mamoru Koketsu‡,*
Department of Chemistry, Faculty of Engineering, Gifu UniVersity, Gifu-501-1193,
Japan, and DiVision of Instrumental Analysis, Life Science Research Center, Gifu
UniVersity, Gifu-501-1193, Japan
koketsu@gifu-u.ac.jp
Received May 23, 2008
ABSTRACT
A convenient approach to synthesize novel selenium-ꢀ-lactams, 3-selena-1-dethiacephems and selenazepines, was accomplished via the
regioselective iodocyclization reaction. The substituent of allenyl moieties dramatically influenced the regiochemical outcome in the iodocyclization
of allene-selenourea derivatives.
In recent years, interest in synthesis of selenium-containing
compounds has increased because of their interesting reac-
tivities1 and their potential biological activities. The biologi-
cal and medicinal properties of selenium and organoselenium
compounds are increasingly appreciated, mainly due to their
antioxidant, antitumor, antimicrobial, and antiviral proper-
ties.2 The ꢀ-lactam (2-azetidinone) skeleton is the key
structural element of the most widely employed class of
antibacterial agents, the ꢀ-lactam antibiotics.3 There is
considerable interest in the modification of the ring system
of ꢀ-lactams by placing a heteroatom at the 2 or 3 position.
In this regard, several groups have published the synthesis
of ꢀ-lactams differing from the penam and cephem systems.4
However, it is surprising to note that only a few reports are
available in the literature for the synthesis of selenium-
† Department of Chemistry.
‡ Division of Instrumental Analysis.
(1) (a) Krief, A. In ComprehensiVe Organometallic Chemistry; Abel,
W. W., ; Stone, F. G. A., ; Wilkinson, G., Eds.; Pergamon: Oxford, 1995;
Vol. 11, p 515. (b) Organoselenium Chemistry: A Practical Approach; Back,
T. G., Ed.; Oxford University Press: U.K., 1999. (c) Wirth, T. Angew. Chem.
2000, 112, 342; Angew. Chem., Int. Ed. Engl. 2000, 39, 3740. (d)
ComprehensiVe Heterocyclic Chemistry III; Katritzky, A. R., ; Ramsden,
C. A., ; Scriven, F. V., ; Taylor, J. K., Eds.; Elsevier: Oxford, 2008.
(2) (a) Mehta, S.; Andrews, J. S.; Johnson, B. D.; Svensson, B.; Pinto,
B. M. J. Am. Chem. Soc. 1995, 117, 9783. (b) Mugesh, G.; du Mont, W.-
W.; Sies, H. Chem. ReV. 2001, 101, 2125. (c) Back, T. G.; Moussa, Z.
J. Am. Chem. Soc. 2003, 125, 13455. (d) Nogueira, C. W.; Zeni, G.; Rocha,
J. B. T. Chem. ReV. 2004, 104, 6255. (e) Nishina, A.; Sekiguchi, A.;
Fukumoto, R.; Koketsu, M.; Furukawa, S. Biochem. Biophys. Res. Commun.
2007, 352, 360.
(3) For some reviews on ꢀ-lactam antibiotics, see: (a) Chemistry and
Biology of ꢀ-Lactam Antibiotics; Morin, R. B., ; Gorman, M., Eds.;
Academic Press: New York, 1982; Vols. 1-3. (b) Southgate, R.; Branch,
C.; Coulton, S.; Hunt, E. In Recent Progress in the Chemical Synthesis of
Antibiotics and Related Microbial Products; Luckacs, G., Ed.; Springer-
Verlag: Berlin, 1993; Vol. 2, pp 621. (c) Southgate, R. Contemp. Org. Synth.
1994, 1, 417.
(4) For papers and reviews, see:(a) Sakurai, O.; Ogiku, T.; Takahashi,
M.; Hayashi, M.; Yamanaka, T.; Horikawa, H.; Iwasaki, T. J. Org. Chem.
1996, 61, 7889. (b) Anada, M.; Watanabe, N. Chem. Commun. 1998, 1517.
(c) Hwu, J. R.; Tsay, S.-C.; Hakimelahi, S. J. Med. Chem. 1998, 41, 4681.
(d) Alcaide, B.; Almendros, P. Curr. Med. Chem. 2004, 11, 1921. (e)
Brabandt, W. V.; Vanwalleghem, M.; D’hooghe, M.; Kimpe, N. D. J. Org.
Chem. 2006, 71, 7083.
10.1021/ol801010y CCC: $40.75
Published on Web 07/04/2008
2008 American Chemical Society

Our retrosynthetic disconnection approach (Figure 1)
suggests that a variety of selenium-ꢀ-lactams can be easily
prepared from allene- or alkyne-selenoureas via an iodocy-
clization reaction.
The key starting materials, alkyne-selenoureas 1, for our
approach were readily prepared by the N-alkylation reaction
of the corresponding previously known propargyl-azetidi-
nones10 with a wide variety of isoselenocyanates11 under
basic conditions (Table 1, entries 1a-1h).
Table 1. Synthesis of 3-Selena-1-dethiacephem 2 via
Iodocyclizationa
Figure 1. Retrosynthesis of selenium-ꢀ-lactam.
containing ꢀ-lactams because of difficulties involved in their
preparations.5 Only one report is available in the literature
for the preparation of isodethiaselenapenam and isodethi-
aselenacephems by Hakimelahi et al. with limited biological
activity.6 The prepared compounds possessed functionality
that compromised their biological activity. To the best of
our knowledge, the 3-selena-1-dethiacephem has never been
described in the literature thus far. Recently, we have reported
a TSE-protection approach for the synthesis of a variety of
selenium-ꢀ-lactams.7 In continuation of the above investiga-
tions, we recently decided to search for a new procedure
that would allow us to synthesize selenium-containing
ꢀ-lactams having a selenium atom at the 3 or 4 position.
Iodocyclization of an unsaturated C-C bond with a wide
variety of nucleophiles, including N, O, and S nucleophiles,
has been extensively studied and has become a powerful tool
for the construction of various heterocycles.8 In contrast, only
a few examples for the synthesis of selenium hererocycles
via electrophilic cyclization have been reported in the
literature,9 and to the best of our knowledge, the electrophilic
cyclization of alkyne-selenoureas or allene-selenoureas has
never been described thus far. We describe herein, for the
first time, an approach to place the selenium to the 3 or 4
position in the ꢀ-lactam ring system by a regioselective
iodocyclization reaction of alkyne- and allene-selenoureas
resulting in the synthesis of selenium-ꢀ-lactams.
entry
R1
R2
yield (%) time (h) yield (%)
1
2
3
4
5
6
7
8
H
p-ClC6H4
C6H5
p-CH3C6H4
2-naphthyl
benzyl
97 (1a)
96 (1b)
95 (1c)
92 (1d)
93 (1e)
6.5
10
11
8
11
11.5
6.5
10
92 (2a)
91 (2b)
88 (2c)
93 (2d)
82 (2e)
84 (2f)
95 (2g)
92 (2h)
H
H
H
H
H
cyclo-C6H11 85 (1f)
C6H5 p-ClC6H4
C6H5 p-CH3C6H4
98 (1g)
99 (1h)
a All iodocyclization reactions were conducted at room temperature with
1.25 equiv of I2 in CH2Cl2.
First, we examined the reaction of ꢀ-alkyne-selenourea
(1a) with 1.05 equiv of iodine or NIS in THF at room
temperature. We found that the reaction was highly depend-
ent on the type of electrophile used. With NIS, we obtained
the desired 3-selena-1-dethiacephem 2a along with 3-aza-
4-selenoxo-1-dethiacephem 3a and 3-aza-4-oxo-1-dethia-
cephem 4a (Figure 2, R1 ) H, R2 ) p-ClC6H4). The 3-aza-
(5) (a) Alpegiani, M.; Bedeschi, A.; Perrone, E.; Franceschi, G.
Tetrahedron Lett. 1986, 27, 3041. (b) Brown, G. A.; Anderson, K. M.;
Murray, M.; Gallagher, T.; Hales, N. J. Tetrahedron 2000, 56, 5579. (c)
Brown, G. A.; Anderson, K. M.; Large, J. M.; Planchenault, D.; Urban,
D.; Hales, N. J.; Gallagher, T. J. Chem. Soc. Perkin Trans. 1 2001, 1897.
(d) Carland, M. W.; Martin, R. L.; Schiesser, C. H. Tetrahedron Lett. 2001,
42, 4737. (e) Carland, M. W.; Martin, R. L.; Schiesser, C. H. Org. Biomol.
Chem. 2004, 2, 2612.
(6) Hwu, J. R.; Lai, L.-L.; Hakimelahi, G. H.; Davari, H. HelV. Chim.
Acta 1994, 77, 1037.
Figure 2. Iodocyclization reaction products of 1.
(7) Garud, D. R.; Ando, H.; Kawai, Y.; Ishihara, H.; Koketsu, M. Org.
Lett. 2007, 9, 4455.
(8) For a two-part review of iodocyclization, see:(a) Frederickson, M.;
Grigg, R. Org. Prep. Proc. Int. 1997, 2, 33. (b) ibid, p 63. (c) Martins da
Silva, F.; Jones, J., Jr.; de Mattos, M. C. S. Curr. Org. Synth. 2005, 2, 393.
(9) (a) Bui, C. T.; Flynn, B. L. J. Comb. Chem. 2006, 8, 163. (b) Koketsu,
M.; Kiyokuni, T.; Sakai, T.; Ando, H.; Ishihara, H. Chem. Lett. 2006, 35,
626. (c) Kesharwani, T.; Worlikar, S. A.; Larock, R. C. J. Org. Chem. 2006,
71, 2307. (d) Alves, D.; Luchese, C.; Nogueira, C. W.; Zeni, G. J. Org.
Chem. 2007, 72, 6726. (e) Garud, D. R.; Makimura, M.; Ando, H.; Ishihara,
H.; Koketsu, M. Tetrahedron Lett. 2007, 48, 7764.
4-oxo-1-dethiacephem 4a was formed by the decomposition
(10) Propargyl- or allenyl-azetidinones were prepared according to the
literature. See: Lee, P. H.; Kim, H.; Lee, K.; Kim, M.; Noh, K.; Kim, H.;
Seomoon, D. Angew. Chem., Int. Ed. 2005, 44, 1840.
(11) See the review:Garud, D. R.; Koketsu, M.; Ishihara, H. Molecules
2007, 12, 504.
3320
Org. Lett., Vol. 10, No. 15, 2008

3
of 3a. However, when the reaction was carried out using
1.05 equiv of iodine, the desired product 2a was exclusively
produced in good isolated yield (84%) with only a trace
amount of byproduct 3a (as indicated by TLC). To improve
the yield of cyclization, different reaction conditions were
then screened (see Supporting Information). CH2Cl2 was
found to be the best solvent for the cyclization reaction.
Furthermore, the reaction was heavily influenced by the
amount of iodine added, and the best result was obtained
when 1.25 equiv of iodine was used (92% yield). The
structures of 2a, 3a, and 4a were confirmed by IR, 1H NMR,
13C NMR, and HRMS spectra. There was no seven-
membered ring product 5a detected in all cases (Figure 2).
On the basis of the above results, the iodocyclization of
other alkyne-selenoureas 1 with 1.25 equiv of iodine was
conducted in CH2Cl2 at room temperature, and the results
are summarized in Table 1. A variety of 3-selena-1-
dethiacephems 2 were obtained in good to excellent yields.
The nature of the R2 group on the selenourea had very little
effect on the reaction rate or product yields. Aryl-substituted
selenoureas (entries 1-4) gave slightly higher yield than
alkyl-substituted selenoureas (entries 5 and 6). The aryl
substitution at alkynes was also well accommodated and
afforded the cyclized products 2g and 2h in excellent yields
(entries 7 and 8).
shows coupling with the trans proton H6b, J(77Se-1H) )
34.3 Hz exclusively (Scheme 1). Thus, this important spectral
feature confirms our current findings. We anticipate that this
spectral feature may become an important tool for confirming
the structure of selenium-containing compounds.
Next, we turned our attention toward the iodocyclization
of allene-selenoureas 8 (Table 2). Allenes are a versatile class
Table 2. Synthesis of 3-Selena-1-dethiacephems and
Selenazepines via Iodocyclizationa
time
(h)
entry
R1
R2
C6H5
yield (%)
yield (%)
1
H
61% (8a)
3
67 (9a)
The reaction shows high regioselectivity for six-membered
ring selenacephems 2. Seven-membered ring products 5 were
never detected under these reaction conditions. The structures
of 2 were confirmed by spectroscopic methods (see Sup-
porting Information) and chemically. Thus, the palladium-
catalyzed triethylammonium formate reduction of the iodide
2a12 provided only compound 6 but not compound 7. The
same product 6 can be alternatively obtained by the intramo-
lecular cyclization of 1a (Scheme 1).13 It was relatively easy
2
H
p-CH3C6H4 61% (8b) 3.5
69 (9b)
3
H
p-ClC6H4
67% (8c)
4
4
8
6
8
7
65 (9c)
4
H
2-naphthyl 36% (8d)
69 (9d)
5
H
benzyl
45% (8e)
85% (8f)
61 (9e)
6
CH3
CH3
p-ClC6H4
55 (10f) + 7b
62 (10g) + 8b
41 (10h) + 10c
69 (10i)
7
p-CH3C6H4 83% (8g)
8
C2H5
p-ClC6H4
93% (8h)
9
C2H5
p-CH3C6H4 96% (8i) 10
p-ClC6H4 92% (8j) 10
p-CH3C6H4 96% (8k) 10
10
11
12
n-C5H11
50 (10j)
52 (10k)
n-C5H11
1-naphthyl p-ClC6H4
96% (8l) 2 days complex mixture
a All iodocyclization reactions were conducted at room temperature with
1.25 equiv of I2 in CH2Cl2. b Isodethiaselenapenam was isolated as an
inseperable mixture. c Isodethiaselenapenam was isolated in 10% yields.
Scheme 1
of organic compounds that feature numerous patterns of
reactivities.15 Allenamides are a subclass of allenes that have
recently received much attention in the synthetic com-
munity.16 The key intermediates, allene-selenoureas 8, for
the iodocyclization reaction were readily prepared by the
reaction of previously known allenyl-azetidinones10 with
isoselenocyanates under basic conditions in good to excellent
yields (Table 2, entries 8a-8l).
We first examined the iodocyclization reaction of unsub-
stituted allene-selenoureas using iodine under standard
conditions (Table 2). The iodine reaction resulted in the
formation of 3-selena-1-dethiacephems 9 as the major
product with traces of the five-membered product as con-
firmed by TLC (Table 2, entries 1-5).17 Good yields were
to distinguish the isomers 6 and 7 by an NMR study.
Recently, we found that selenium shows strong coupling with
the trans proton of the exocyclic double bond, whereas
similar coupling with the cis proton was not observed.9e,14
We found the same observation in compound 6; i.e., selenium
(15) Schuster, H. E.; Coppola, G. M. Allenes in Organic Synthesis; John
Wiley and Sons: New York, 1984.
(12) (a) Cacchi, S.; Ciattini, P. G.; Morera, E.; Ortar, G. Tetrahedron
Lett. 1986, 27, 5541. (b) Peng, A.-Y.; Ding, Y.-X. Org. Lett. 2004, 6, 1119.
(13) The reaction time can be shortened by the use of base such as DBU,
but reaction gave the product in slightly lower yield.
(16) For reviews on allenamides, see: (a) Saalfrank, R. W.; Lurz, C. J.
In Methoden Der Organischen Chemie (Houben-Weyl); Kropf, H., ;
Schaumann, E., Eds.; Georg Thieme Verlag: Stuttgart, 1993; p 3093. (b)
Wei, L.-L.; Xiong, H.; Hsung, R. P. Acc. Chem. Res. 2003, 36, 773.
(17) Iodocyclization reaction of 9c using NIS resulted in the formation
of multiple spots.
(14) Koketsu, M.; Sakai, T.; Kiyokuni, T.; Garud, D. R.; Ando, H.;
Ishihara, H. Heterocycles 2006, 68, 1607
.
Org. Lett., Vol. 10, No. 15, 2008
3321

obtained in all cases, irrespective of the nature of the
substituent present on the selenourea group (entries 1-5).
Seven-membered ring products were not detected under these
reaction conditions. Thus, these reaction conditions show
high regioselectivity toward six-membered rings.
Scheme 2
To further test the scope of the cyclization, allenesele-
noureas bearing alkyl or aryl groups at the allenyl position
are examined with iodine (Table 2, entries 6-12). We are
pleased to find that regiochemistry in the iodocyclization
reaction is affected by the nature of the R1 group at the allenyl
position. The reaction of methyl-substituted alleneselenoureas
8f and 8g with 1.25 equiv of iodine afforded selenazepines
10f and 10g along with corresponding five-membered
isodethiaselenapenams as inseperable mixtures (entries 6 and
7). The reaction of ethyl-substituted alleneselenourea 8h gave
10h in 41% yield and the corresponding isodethiaselenapem
in 10% yield (entry 8). The reaction of the alleneselenoureas
8i-8k afforded the selenazepines 10i-10k as the major
product with trace amounts of five-membered product as
confirmed by TLC (entries 9-11),18 whereas the cyclization
reaction of 1-naphthyl-substituted alleneselenourea 8l gave
a complex mixture (entry 12). The synthesis of seven-
membered selenium heterocycles has been found to be very
difficult. To the best of our knowledge, there are only three
reports7,19 on the preparation of seven-membered selenium-
containing heterocycles, that is, 1,3-selenazepines. Our
iodocyclization method provides a novel approach for the
synthesis of seven-membered selenium-containing hetero-
cycles.
product 11 was isolated in excellent yield (Scheme 3). The
imine group in the 3-selena-1-dethiacephem 2, 6, and 9 and
selenazepine 10 is advantageous for further functionalization.
Scheme 3
A plausible mechanism is proposed for the formation of
9 and 10 as illustrated in Scheme 2. The reaction of 8 with
iodine gave iodonium A and released an iodine anion at the
same time. With the assistance of the iodine anion, intramo-
lecular nucleophilic attack of selenium in the selenourea
group on the center carbon of allene (when R1 ) H) in the
favored exo mode affords the corresponding cyclization
product 9, whereas attack of selenium in the selenourea group
on the terminal carbon of allene (when R1 ) CH3, C2H5, or
n-C5H11) in the favored endo mode affords the corresponding
cyclization product 10 accompanied by the simultaneous
elimination of hydrogen iodide.
The presence of iodine in the 3-selena-1-dethiacephem 2a
allows further structural elaboration, most notably using
palladium-catalyzed coupling reactions. For example, when
compound 2a was exposed to Sonogashira coupling condi-
tions20 with phenylacetylene, the corresponding coupling
In conclusion, we have developed a pivotal approach to
prepare a variety of selenium-containing ꢀ-lactams, using
an iodocyclization reaction with high regioselectivity. The
regiochemical outcome of the iodocyclization of allene-
selenourea was found to depend on the nature of the
substituent on allenyl moieties. Further expansion of current
strategies is in progress.
Acknowledgment. This work was supported by a Grant-
in-Aid for Science Research from the Ministry of Education,
Culture, Sports, Science, and Technology of Japan (No.
20590005) to which we are grateful.
(18) The reaction of ethyl-substituted alleneselenourea 8i using 2.0 equiv
of NIS afforded two different products of six-membered 3-selena-1-
dethiacephems (see Supporting Information).
(19) (a) Nurbaev, K. I.; Zakhidov, K. A.; Oripov, E. O.; Smiev, R. A.;
Shakhidoyatov, K. M. Uzb. Khim. Zh. 1996, 1-2, 96; Chem. Abstr. 1996,
126, 47303. (b) Sommen, G. L.; Linden, A.; Heimgartner, H. Tetrahedron
Supporting Information Available: Experimental details
for the synthesis and 1H and 13C NMR spectra of compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Lett. 2005, 46, 6723
.
(20) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 23, 4467. (b) Sonogashira, K. ComprehensiVe Organic Synthesis;
Trost, B. M., ; Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 3, p
521.
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