Mild generation of selenolate nucleophiles by thiol reduction of diselenides: Convenient syntheses of selenyl-substituted aryl aldehydes

Article abstract of DOI:10.1016/j.tetlet.2011.10.075

Various selenyl-substituted aryl aldehydes were obtained using dithiothreitol (DTT) as a reducing agent for diselenides in the presence of a base. For electron-deficient haloaryl aldehydes, a weak base, such as K ₂CO₃, performed well. However, for electron-rich haloaryl aldehydes, a stronger base, such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), was required for successful substitution. The selenyl-substitution of heteroaryl substrates were also investigated to obtain satisfactory yields of the desired products.

Full text of DOI:10.1016/j.tetlet.2011.10.075

Tetrahedron Letters 52 (2011) 6839–6842
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Mild generation of selenolate nucleophiles by thiol reduction
of diselenides: convenient syntheses of selenyl-substituted aryl aldehydes
Rashmi Dubey a, Hangeun Lee a, Do-Hyun Nam b, Dongyeol Lim a,
⇑
a Department of Chemistry, Sejong University, Seoul 143-747, Republic of Korea
b Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Various selenyl-substituted aryl aldehydes were obtained using dithiothreitol (DTT) as a reducing agent
for diselenides in the presence of a base. For electron-deficient haloaryl aldehydes, a weak base, such as
K2CO3, performed well. However, for electron-rich haloaryl aldehydes, a stronger base, such as 1,8-diaza-
bicyclo[5.4.0]undec-7-ene (DBU), was required for successful substitution. The selenyl-substitution of
heteroaryl substrates were also investigated to obtain satisfactory yields of the desired products.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 23 September 2011
Revised 11 October 2011
Accepted 13 October 2011
Available online 18 October 2011
Keywords:
Diselenide reduction
Dithiothreitol
Aryl selenide
Selenolate nucleophile
Introduction
agents.17 Several catalytic procedures have been reported for the
reduction of diselenides. However, these catalytic procedures often
Organoselenium compounds are useful in organic syntheses,1
and organic diselenidesare being investigated as useful syntheticre-
agents and intermediates in organoselenium chemistry. These com-
pounds are easy to handle and are naturally stable, and they are
reactive enough to yield electrophilic, nucleophilic, and radicophilic
species.2 Organoselenium compounds are similarto their sulfurana-
logues.3 The enhanced reactivity of selenium-containing com-
pounds relative to their sulfur analogues has led to new versatile
synthetic methods in organic chemistry.4 Despite the obvious
advantages of selenium-heterocycles, only a few preparative routes
have been reported compared to sulfur heterocycles.5 Selenium-
containing aryl aldehydes are good intermediates for the synthesis
of various biologically active benzoselenophenes.6 To avoid the
use of unstable selenols and other unstable reagents, diselenides
have been used to develop selenium anions by reducing the Se–Se
bonds during the reaction.7 The reduction of the Se–Se bond in disel-
enides to generate selenolate intermediates (RSeꢀ) can be accom-
require harsh reaction conditions and are only applicable to a lim-
ited set of substrates.18 Therefore, mild, convenient, and economical
reagents applicable to a diverse set of substrates are necessary for
organoselenium synthesis. The generation and synthetic use of
benzeneselenolate ion as produced from diphenyl diselenide via
an excess of N-acetylcysteine has been explored.19 In this study,
we describe an efficient synthesis of various selenyl-substituted aryl
aldehydes using dithiothreitol (DTT) as the reducing agent.
Results and discussion
The desired aryl methyl selenide (1a) was synthesized under
various reaction conditions to determine the experimental condi-
tions that afforded the best yields (Table 1). Dimethyl diselenide
(DMDS) and 5-nitro-2-chloro-benzaldehyde were used as a repre-
sentative reaction for optimization. Initially, the reaction was per-
formed in an EtOH solvent, while NaBH4 was used to reduce the
Se–Se bond of DMDS (Table 1, entry 1).10 However, the aldehyde
group was reduced to an alcohol instead of forming the desired
product. Variations in the reaction conditions (e.g., the solvent,
reaction time, temperature, and amount of base and reducing
agent) did not alter the reaction (Table 1, entries 1–5). However,
when DTT was used as the reducing agent,20 the yield of the
desired product increased dramatically, and reduction of the alde-
hyde group was not observed (Table 1, entries 6–9). Good yields
were obtained for various bases, such as K2CO3 and 1,8-diazabicy-
clo[5.4.0]undec-7-ene (DBU), and solvents. When we replaced the
plished via reducing agents, such as N2H4ꢁH2O,8 R4NþBH
,
9
ꢀ
4
NaBH4,10 and LiEt3BH.11 In addition, indium,12 lanthanum,13 samar-
ium,14 and other metals15 have been used to cleave the Se–Se bond.
Direct coupling of a simple organohalide with a diselenide has been
performed using zinc dust and an ionic liquid.16 However, in the
presence of a free aldehyde group, the substitution of halides with
selenolate anions is difficult using the aforementioned reducing
⇑
Corresponding author.
E-mail address: dylim@sejong.ac.kr (D. Lim).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.075

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R. Dubey et al. / Tetrahedron Letters 52 (2011) 6839–6842
Table 1
Synthesis of 2-methylselenyl-5-nitro-benzaldehyde under various conditions
O2N
CHO
O2N
CHO
Cl
DMDS, reducing agent
base, solvent
SeMe
1a
Entry
DMDS (equiv)
Reducing agent (equiv)
Base (equiv)
Solvent
Time (h)
Temp (°C)
Yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
1
2
2
1
1
1
1
1
1
1
1
1
1
NaBH4 (1 equiv)
NaBH4 (2 equiv)
NaBH4 (2 equiv)
NaBH4 (1 equiv)
—
DTT (1 equiv)
DTT (2 equiv)
DTT (1 equiv)
DTT (1 equiv)
N-Acetyl cysteine (2 equiv)
N-Acetyl cysteine (2 equiv)
1,4-Butanedithiol (2 equiv)
1,4-Butanedithiol (2 equiv)
NaOEt (2 equiv)
—
—
EtOH
EtOH
DMF
THF
DMF
EtOH
DMF
DMF
DMF
DMF
DMF
DMF
DMF
5
24
24
6
14
4
1
1
3
1
60
rt
rt
60
0
rt
rt
rt
rt
rt
rt
rt
rt
0b
3b
5b
—
0b
K2CO3 (2.5 equiv)
NaOEt (2 equiv)
NaOEt (2 equiv)
K2CO3 (2.5 equiv)
DBU (2 equiv)
NaOEt (2 equiv)
DBU (2 equiv)
NaOEt (2 equiv)
DBU (2 equiv)
No rxn
85
85
85
80
79
73
82
76
3
2
3
a
Isolated yield.
An alcohol was obtained as the major product.
b
reducing agent with other thiols, such as N-acetylcysteine or 1,4-
butanedithiol, the desired product was also obtained in good yield
(Table 1, entries 10–13).
observed and yielded the ethylether analogue as the major product
A simple pathway for the formation of methylselenolate by DTT
reduction is shown in Figure 1. The thiol-diselenide interchange
reaction is fast under basic conditions because the thiolate anion
(RSꢀ) is more reactive toward diselenide. Therefore, a base is
required for the reaction to proceed (the pKa values of the thiol
groups in DTT are 9.2 and 10.1). When the free methylselenolate
is formed, it attacks the aryl group and a nucleophilic substitution
takes place within 1 h.
Table 2
Synthesis of 2-selenyl-5-nitrobenzaldehydes
RSeSeR (0.6 eq), DTT (1 eq)
K2CO3, DMF, 80 oC, 1 h
O2N
CHO
SeR
O2N
CHO
Cl
1b-1g
Entry
R
Product
Yielda (%)
Because thiols selectively reduced DMDS in the presence of a
formyl group, we extended the application of the above reaction
to different diselenides. DTT was selected because it is a better
reducing agent than the monothiol, and the product could be easily
separated. When diphenyl diselenide or dibenzyl diselenide was
used, the reaction proceeded slowly at room temperature. There-
fore, we increased the reaction temperature and observed comple-
tion of the substitution reaction within 1 h (Table 2). When we
compared the same reaction with dibenzyldiselenides containing
various substituents on the phenyl ring,21 the reaction with the
electron-rich diselenides produced higher yields of 1f and 1g
(Table 2, entries 2–6). A general procedure for the synthesis of
selenyl-substituted aryl aldehydes is described in Ref. 22.
Because the selenyl substitutions proceeded smoothly with the
DTT reducing agent for the various diselenides studied, the same
reaction was performed on an electron-rich substrate (Table 3).
Upon the addition of sodium ethoxide, formation of the desired
product was not observed when DTT was used as the reducing
agent (Table 3, entries 1 and 2). At an elevated temperature and
upon addition of DTT/NaOEt, an ethoxide substitution was
1
2
3
4
5
6
Ph
Bn
4-Cl-Bn
4-NO2-Bn
3-Me-Bn
3,5-DiMe-Bn
1b
1c
1d
1e
1f
97
69
68
60
96
96
1g
a
Isolated yield.
(Table 3, entry 3). However, when DBU was used in the presence of
thiol reducing agents, the desired methyl selenide, 2a, was
obtained in good yield (Table 3, entries 4–7). The same reaction
with diphenyl diselenide and dibenzyl diselenide required a higher
temperature to produce 2b and 2c, respectively, in moderate yields
(Table 4, entries 1 and 2). The faster reaction with DMDS is
probably due to smaller steric effects from the methyl selenolate
compared to the phenyl or benzyl selenolate. Another explanation
for the faster reaction might be the use of excess DMDS, due to its
volatile nature. Specifically, when only a slight excess of DMDS was
used, some of the starting materials remained in the final reaction
mixture.
H3C
Se Se
CH3
HS
Se CH3
-S
S
HO
HO
base
base
S
S
HO
2 CH3Se-
+
HO
HO
OH
OH
OH
SH
S-
SH
Figure 1. Formation of methylselenolate from the thiol-diselenide interchange reaction.

R. Dubey et al. / Tetrahedron Letters 52 (2011) 6839–6842
6841
Table 3
Synthesis of 4,5-methylenedioxy-2-methylselenylbenzaldehyde under various conditions
CHO
CHO
O
O
MeSeSeMe, reducing agent
base, solvent
O
O
SeMe
Br
2a
Entry
Reducing agent
Base
Solvent
DMDS (equiv)
Time (h)
Temp (°C)
Yielda (%)
1
2
3
4
5
6
7
DTT (1 equiv)
DTT (1 equiv)
DTT (1 equiv)
DTT (1 equiv)
DTT (1 equiv)
N-Acetylcysteine (2 equiv)
1,4-Butanedithiol (2 equiv)
NaOEt (2 equiv)
NaOEt (2 equiv)
NaOEt (2 equiv)
DBU (2 equiv)
DBU (2.5 equiv)
DBU (2.5 equiv)
DBU (2.5 equiv)
EtOH
DMF
DMF
DMF
DMF
DMF
DMF
1
1
1
1
1.2
1.5
1.5
24
24
24
1
1
3
rt
rt
60
rt
rt
rt
rt
Byproduct
Byproduct
b
80
82
56
60
3
a
Isolated yield.
Arylethylether was obtained as the major product.
b
The results from the synthesis of various selenyl-substituted
increase the electron density on the 2-position of the benzaldehyde
more than on the aldehyde carbon. Indeed, we observed unidenti-
fied byproducts resulting from the nucleophilic attack on the alde-
hyde carbon.
In addition, we attempted to extend this reaction to heteroaryl
haloaldehydes. Using DTT/K2CO3 in DMF at room temperature,
haloaldehydes of pyridine, furan, and thiophene generated the de-
sired products in reasonable yields (Table 5).
In summary, we obtained various selenyl-substituted aryl alde-
hydes using diselenide/DTT/base in DMF as a general reaction con-
dition. For electron-withdrawing substituents on the haloaryl
aldehydes, a weak base, such as K2CO3, works well. However, for
electron-donating substituents on the haloaryl aldehydes, a stron-
ger base, such as DBU, delivered more than 60% of the desired prod-
ucts. In addition, room temperature was adequate for DMDS, but
higher temperatures were necessary for both diphenyl diselenide
and dibenzyl diselenide to produce the desired products.
aryl aldehydes using DTT/base/DMF conditions are provided in
Table 4. Substrates containing no substituent, bromo- and flu-
oro-benzaldehyde, afforded the corresponding products in satis-
factory yields (Table 4, entries 3–6). For electron-withdrawing
substituents, i.e., 6-nitro- and 5-trifluoromethyl substituents,
the reaction proceeded well to give the desired product with var-
ious diselenides (Table 4, entries 7–13). For substrates with
electron-donating substituents, i.e., 5-methyl-, 3-methoxy-, 4-
methoxy-, 5-methoxy-, and 4,5-dimethoxy aldehydes, we
obtained the desired products in fair to good yields (Table 4,
entries 14–20).
When the electron-donating group is located at the 5-position
of the benzaldehyde, it was difficult to substitute the halo group
by benzyl selenolate, and we observed lower yields for the substi-
tuted products (Table 4, entries 2 and 19). These low yields proba-
bly resulted from the electronic effects of the substituents, which
Table 4
Synthesis of 2-selenyl-substituted arylaldehydes
6
CHO
X
R'SeSeR', DTT (1 eq)
5
4
CHO
SeR'
1
R
R
Condition, DMF
2
3
2-10
a
Entry
R
X
R0
Conditionb
Product
Yieldc (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
4,5-Methylenedioxy
4,5-Methylenedioxy
H
H
H
Br
Br
Br
Br
Br
F
Br
Cl
Cl
Cl
Cl
Cl
Cl
F
Cl
F
Br
Br
Br
F
Ph
Bn
Me
Ph
Bn
Me
Me
Me
Ph
Bn
4-Cl-Bn
3-Me-Bn
A
A
B
A
A
B
C
C
C
C
C
C
C
B
B
B
B
A
A
B
2b
2c
3a
3b
3c
3a
4
5a
5b
5c
5d
5e
5f
6
7
8
9a
9b
9c
10
60
40
84
80
58
97
79
75
74
73
68
70
71
85
60
92
60
62
39
67
H
6-Nitro
5-Trifluoromethyl
5-Trifluoromethyl
5-Trifluoromethyl
5-Trifluoromethyl
5-Trifluoromethyl
5-Trifluoromethyl
5-Methyl
3-Methoxy
4-Methoxy
5-Methoxy
5-Methoxy
5-Methoxy
4,5-Dimethoxy
3,5-DiMe-Bn
Me
Me
Me
Me
Ph
Bn
Me
a
b
c
1.2 equiv (R0 = Me) and 0.6 equiv (R0 = Ph and Bn) used.
Conditions: (A) DBU (2.5 equiv), 80 °C, 1 h. (B) DBU (2.5 equiv), rt, 1 h. (C) K2CO3 (2.5 equiv), rt, 1 h.
Isolated yield.

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R. Dubey et al. / Tetrahedron Letters 52 (2011) 6839–6842
2. (a) Liotta, D.; Monahan, R. Science 1986, 231, 356–361; (b)Organoselenium
Table 5
Chemistry-A Practical Approach; Back, T. G., Ed.; Oxford University Press: Oxford,
1999.
Synthesis of selenyl-substituted heteroaryl aldehydes
3. (a) Cecchini, M. A.; Giesbrecht, E. J. Org. Chem. 1956, 21, 1217–1220; (b)
Hanson, R. N.; Davis, M. A. J. Heterocycl. Chem. 1981, 18, 205–206.
4. Ip, C.; Ganther, H. E. Carcinogenesis 1992, 13, 1167–1170.
CHO
CHO
SeR
RSeSeR, DTT (1 eq)
Ar
X
Ar
5. (a) Litvinow, V. P.; Dyachenko, V. D. Russ. Chem. Rev. 1997, 66, 923–951; (b)
Renson, M. In The Chemistry of Organic Selenium and Tellurium Compounds;
Patai, S., Rappoport, Z., Eds.; J. Wiley & Sons: New York, 1986; Vol. 1, p 399;
(c)Organic Selenium Compounds: Their Chemistry and Biology; Klayman, D. L.,
Günter, W. H. H., Eds.; J. Wiley & Sons: New York, 1973. 379.
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(b) Jakobs, A. E.; Christiaens, L. E.; Renson, M. J. Tetrahedron 1994, 50, 9315–
9324.
K2CO3 (2.5 eq), DMF, rt, 1h
heteroaryl
11-13
heteroaryl
Entry
1
Substrate
CHO
Ra
Product
Yieldb (%)
CHO
7. Iwaoka, M.; Tomoda, S. Top. Curr. Chem. 2000, 208, 55–80.
8. Syper, L.; Młochowski, J. Synthesis 1984, 439–442.
Me
70
N
Cl
N
SeMe
9. Bergman, J.; Engman, L. Synthesis 1980, 569.
(11a)
10. Sharpless, K. B.; Lauer, R. F. J. Am. Chem. Soc. 1973, 95, 2697.
11. Gladysz, J. A.; Hornby, J. L.; Garbe, J. E. J. Org. Chem. 1978, 43, 1204.
12. Zheng, Y.; Bao, W.; Zhang, Y. Synth. Commun. 1997, 27, 79.
13. Nishino, T.; Okada, M.; Kuroki, T.; Watanabe, T.; Nishiyama, Y.; Sonoda, N. J.
Org. Chem. 2002, 67, 8696.
CHO
Cl
CHO
2
3
4
Ph
62
78
92
N
N
SePh
(11b)
O
14. Chen, R. E.; Su, W. K. J. Ind. Chem. Soc. 2005, 82, 958.
15. (a) Hoye, T. R.; Caruso, A. J. Tetrahedron Lett. 1978, 19, 4611; (b) Liotta, D.;
Sunay, U.; Santiesteban, H.; Markiewicz, W. J. Org. Chem. 1981, 46, 2605; (c)
Yoshimatsu, M.; Sato, T.; Shimizu, H.; Hori, M.; Kataoka, T. J. Org. Chem. 1994,
59, 1011; (d) Ranu, B. C.; Mandal, T.; Samanta, S. Org. Lett. 2003, 5, 1439; (e)
Ranu, B. C.; Mandal, T. J. Org. Chem. 2004, 69, 5793; (f) Cohen, R. J.; Fox, D. L.;
Salvatore, R. N. J. Org. Chem. 2004, 69, 4265; (g) Bonaterra, M.; Martín, S. E.;
Rossi, R. A. Tetrahedron Lett. 2006, 47, 3511; (h) Dowsland, J.; McKerlie, F.;
Procter, D. J. Tetrahedron Lett. 2000, 41, 4923; (i) Su, W.; Gao, N.; Zhang, Y. J.
Chem. Res. Synop. 2002, 4, 168; (j) Taniguchi, N.; Onami, T. J. Org. Chem. 2004,
69, 915; (k) Andrade, F. M.; Massa, W.; Peppe, C.; Uhl, W. J. Organomet. Chem.
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K.; Hirano, M.; Tanaka, K. Org. Lett. 2005, 7, 4193; (n) Movassagh, B.;
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CHO
CHO
O
Me
Me
Br
SeMe
CHO
(12)
S
CHO
Br
S
SeMe
(13)
a
1.2 equiv (R = Me) and 0.6 equiv (R = Ph) used.
Isolated yield.
b
16. Narayanaperumal, S.; Alberto, E. E.; Gul, K.; Rodrigues, O. E. D.; Braga, A. L. J.
Org. Chem. 2010, 75, 3886.
Acknowledgments
17. Sakakibara, M.; Kastsumata, K.; Watanabe, Y.; Toru, T.; Ueno, Y. Synthesis 1992,
377.
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7338.
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This work was supported by a grant from the Korea Healthcare
Technology R&D Project, Ministry for Health and Welfare Affairs,
Republic of Korea (A092255).
21. The symmetrical dibenzyl diselenides (entries 3–6 in Table 4) were prepared
by the literature procedure: Du, J.; Surzhykov, S.; Lin, J. S.; Newton, M. G.;
Cheng, Y.-C.; Schinazi, R. F.; Chu, C. K. J. Med. Chem. 1997, 40, 2991.
22. General procedure: Diselenide was added to a solution of thiol (equivalents are
given in table) in 2 mL of anhydrous solvent under a N2 atmosphere. The
reaction mixture was stirred for 30 min at a given temperature in table. The
haloaryl aldehyde (100 mg) was added to the reaction mixture in a portion and
the mixture was stirred at a given temperature for 15 min. A base (equivalents
are given in table) was added to the reaction mixture and stirring was
continued for an additional 15 min. The progress of the reaction was followed
by TLC analysis. When the starting material was disappeared, the mixture was
concentrated in vacuo and the residue was extracted with CH2Cl2 (3 ꢂ 25 mL).
The combined organic layer was dried over anhydrous MgSO4 and the solvent
was removed in vacuo. The crude product was purified by silica-gel column
chromatography, eluting with an ethyl acetate–hexane solution. Yields are
given in table.
Supplementary data
Supplementary data (spectroscopic data (1H and 13C NMR and
MS) for compounds 1a–13) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2011.10.075.
References and notes
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A.; Wirth, T. Eur. J. Org. Chem. 2009, 1649; (d) Wirth, T.; Nishibayashi, Y.;
Uemura, S. Organoselenium Chemistry; Springer: Berlin/Heidelberg, 2000. pp
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