Metal-free synthesis of unsymmetrical organoselenides and selenoglycosides

Article abstract of DOI:10.1021/acs.orglett.7b02526

A one-pot, metal-free procedure has been developed to synthesize unsymmetrical organoselenides. In the first step of the reaction, arylation of potassium selenocyanate (KSeCN) with an iodonium reagent proceeds in the absence of a metal catalyst to produce

Full text of DOI:10.1021/acs.orglett.7b02526

Letter
pubs.acs.org/OrgLett
Metal-Free Synthesis of Unsymmetrical Organoselenides and
Selenoglycosides
Yong Guan† and Steven D. Townsend*,†,‡
†Department of Chemistry, Vanderbilt University, 7330 Stevenson Center, Nashville, Tennessee 37235, United States
‡Institute of Chemical Biology, Vanderbilt University, 896 Preston Research Building, Nashville, Tennessee 37232-6304, United
States
S
* Supporting Information
ABSTRACT: A one-pot, metal-free procedure has been developed to synthesize unsymmetrical organoselenides. In the first step
of the reaction, arylation of potassium selenocyanate (KSeCN) with an iodonium reagent proceeds in the absence of a metal
catalyst to produce an arylselenocyanate. In the second step, treatment with sodium borohydride unmasks a second selenium
nucleophile that engages an aliphatic electrophile, iodonium reagent, or glycosyl halide. The procedure represents an umpolung
approach to the synthesis of aryl-selenides.
The study began by examining the arylation of potassium
selenocyanate (KSeCN). Given the opportunities available
through arylation with iodonium salts,14 pioneered by the
Olofsson School,15 we hypothesized a diaryliodonium salt
would be sufficiently electrophilic to react with KSeCN.16 We
were not alone in this line of conjecture, as Nikolaienko and
Reuping have demonstrated KSeCN reacts with aryl diazonium
salts under Sandmeyer conditions.17 To gauge the reactivity of
iodonium salts to KSeCN a competition experiment was
conducted (Scheme 1). Iodonium salt (12) and diazonium salt
(13) were reacted with KSeCN at 80 °C in CH3CN. Under
these reaction conditions, iodonium salt (12) outperformed
diazonium salt (13) in a ca. 5:1 ratio.
With this data point in hand, the results of continued probing
of this system are shown in Table 1. Interestingly, the reaction
was tolerant of both ring activation and deactivation as p-nitro-
and p-methoxy-substituted aryl rings reacted with equal
efficiency. High yields were obtained when the reaction was
conducted in acetonitrile (entry 2), ethyl acetate (entry 3), and
dioxane (entry 5). Ethyl acetate was selected as the solvent for
the remaining reactions due to its safety profile and ease of use.
rganoselenides are a longstanding substrate class in
1
Oorganic synthesis.
Diaryldiselenides, for example, are
used to incorporate the arylselenide functional group into
organic molecules. Once installed, the arylselenide is a reactive
handle for installing unsaturation (via oxidative elimination),2
reductive metalation,3 or alkylation4 and α-deprotonation.5
Recently, organoselenides have found use in biological
chemistry as Pentelute and Buchwald have demonstrated the
modification of peptides at a selenium handle.6 The synthesis of
novel selenoglycosides is of increasing importance as new
donors are needed to streamline oligosaccharide synthesis.7 In
addition to their value as reactive handles, organoselenides are
attractive therapeutic leads due to observed antioxidant and
antibacterial activities.8
As a result of this interest a number of approaches to
synthesize organoselenides have been developed. The most
established methods involve Fe,9 Cu,10 Pd,11 or Ni12 catalyzed
C(sp2)−Se bond formation. Additional metal mediated
processes have also been established.13 In the event,
arylselenides are produced by coupling aryl halides, boronic
acids, or diazonium salts with electrophilic selenium species
(Figure 1). Herein, we report the synthesis of organoselenides
and selenoglycosides using a one-pot, metal-free procedure that
involves alkylation, arylation, or alkynylation of selenium
anions.
Received: August 15, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02526
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Organic Letters
Letter
a
Scheme 2. Scope of KSeCN Iodonium Salt Arylation
Figure 1. Selenium arylation reactions.
a
Scheme 1. Competition Arylation Experiment Using KSeCN
as the Nucleophile and Aryliodonium and Diazonium Salts
As Electrophiles
The reaction was conducted using iodonium salt (0.1 mmol) and
b
KSeCN (0.11−0.20 mmol) in EtOAc (1 mL) at 80 °C for 24 h. The
reaction was conducted using iodonium salt (0.20 mmol) and KSeCN
c
(0.40 mmol) in EtOAc (2 mL) at 80 °C for 24 h. When X = Y, the
iodonium salt is symmetrical. Otherwise, Y = mesitylene or anisole.
d
7a was prepared at 1.0 mmol scale.
nontransferable aryl ring is mesitylene (Y = 2,4,6 trimethyl
substitution) the so-called “anti-ortho” effect governs chemo-
selectivity. In this case, approach of the nucleophile to the aryl
ring labeled by X is favored as it avoids steric repulsion from the
ortho-methyl substituents.
Table 1. Solvent Screening for the Arylation of KSeCN
Using Four Diaryl Iodonium Salts
a d
,
7a and 7b were produced in excellent yield. The steric bulk
of a mesitylene group proved to be acceptable as 7c was
isolated in 88% yield. Halogen substituents were also tolerable.
Arylation with electron-deficient iodonium salts produced
compounds such as 7f and 7h in 94% and 91% isolated yields,
respectively. 7i is obtained in 95% yield establishing that
electron-rich aryl rings can undergo transfer when a sym-
metrical salt is used.
After completing the first arylation reaction we anticipated
addition of sodium borohydride (NaBH4) would liberate a
selenol in a Grieco type reduction.1,18 The selenium
nucleophile could then react with a second electrophile. In
this event, shown in Scheme 3, compounds 10a and 10b were
each prepared in 93% isolated yield over two steps by reacting
the selenium anion with an alkynylated iodonium salt (see SI
for a list of iodonium salts used in Schemes 3 and 4).19 The
arylselenides 10c to 10f were isolated in 88−94% yield after
reacting the intermediate arylselenide with aliphatic bromides.
When rac-epi-chlorohydrin was used as the electrophile, 10g
was isolated in 68% yield.
b
b
b
X = H
(%)
X = NO2
X = OMe
(%)
X = Br
(%)
entry
solvent
(%)
1
2
3
4
5
6
1,2-DCE
CH3CN
EtOAc
68
97
95
70
17
86
89
94
39
84
79
94
97
88
27
97
91
95
EtOH
61
46
toluene
1,4-dioxane
91
74
>99
>99
a
The reaction was conducted using iodonium salt (0.05 mmol) and
b
KSeCN (0.10 mmol) in solvent (1 mL) at 80 °C for 24 h. 1H NMR
yields were calculated using 1,2-dibromoethane as the internal
standard. When X = Y, the iodonium salt is symmetrical. Otherwise,
Y = mesitylene or anisole. Substitutions are at position 4.
c
d
Isolated yields for the KSeCN arylation are shown in Scheme
2. Of note is that reactions with unsymmetrical diaryliodonium
reagents take place with complete chemoselectivity. This is
likely due to one of two possible effects. The first concerns
iodonium salts featuring anisole (Y = 4-OMe) as the
nontransferable aryl ring. Based on the principles of
nucleophilic aromatic substitution (SNAr), a nucleophile will
expectedly engage the electron-deficient aryl ring. When the
Next, we studied the generation of unsymmetrical diary-
lselenides using an aryliodonium salt as the second electrophile.
Starting with an anisole derived selenide, reaction with o-, m-,
and p-toluoyl-containing iodonium salts produced 10h, 10i, and
10j in yields ranging from 84% to 86%.20 Exchanging the m-
CH3 group for m-CF3 did not affect reaction efficiency as 10k
was produced in 82% yield. The halogenated compound 10l
was isolated in 78% yield. Electron-withdrawing p-nitro
B
DOI: 10.1021/acs.orglett.7b02526
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a
Scheme 3. One-Pot Synthesis of Unsymmetrical
Organoselenides
Scheme 4. One-Pot Synthesis of Glycosylselenides
a
a
The reaction was conducted by suspending the iodonium (0.20
mmol) and KSeCN (0.40 mmol) in EtOAc (2 mL) and stirring at 80
°C for 24 h. The solvent was removed, and the residue was suspended
in degassed EtOH (1 mL) and treated with NaBH4 (0.40 mmol) and a
glycosyl bromide (0.16 mmol).
ester) gave lower yielding products as is evidenced by 11h, 11i,
and 11j.
a
The reaction was conducted by suspending the iodonium salt (0.10
In summary, a one-pot metal-free procedure has been
developed to synthesize unsymmetrical organoselenides and
selenoglycosides. Future studies are aimed at studying metal
promoted activation of the selenoglycoside donors in
glycosylation reactions and studying the mechanism of the
metal-free arylation of selenolate ions. Results in both regards
will be reported in due course.
mmol) and KSeCN (0.10 mmol) in EtOAc (1 mL) and stirring at 80
°C for 16 h. The solvent was removed, and the residue was suspended
in degassed EtOH (5 mL) and treated with NaBH4 (0.20 mmol) and
an electrophile (0.20 mmol).16b 10a was prepared at 1.0 mmol scale.
substituents were tolerated, as 10m and 10n were produced in
92% and 84% yields, respectively. When an ester was placed on
the aryl selenide, no adverse effects were observed as 10o to
10r were produced in yields ranging from 68% to 90%. Given
that no purification is required after the first step, we observed
yields that were 10−15% higher than previous reported
methodologies.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02526.
Our final goal was to apply the reaction to the synthesis of
selenoglycosides with varying electronic properties for use in
glycosylation reactions (Scheme 4).7b,21 In an orienting set of
experiments, peracetylated α-glucosyl and α-galactosyl bro-
mides were found to be compatible as electrophiles providing
11a and 11b in 85% and 99% yields as their β-anomers.
Presumably, this reaction proceeds with inversion of stereo-
chemistry through an SN2 pathway. Aryl selenocyanates
featuring p-alkylation performed well in the reaction as 11c
was produced in 81% yield. The mesitylene derived nucleophile
provided similar results and generated 11d in 82% yield.
Electron-releasing methoxy and halogen groups were com-
parable in reactivity to alkyl substituents. Not surprisingly,
electron-deficient selenocyanates (substituted by F, NO2, or
Experimental procedures, characterization, and spectra
for new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: steven.d.townsend@vanderbilt.edu.
ORCID
Steven D. Townsend: 0000-0001-5362-7235
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.7b02526
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Letter
ACKNOWLEDGMENTS
■
S.D.T. would like to thank Vanderbilt University and the
Institute of Chemical-Biology for support. The reviewers are
acknowledged for their helpful suggestions.
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