Visible-light-promoted selenofunctionalization of alkenes

Article abstract of DOI:10.1021/ol402753u

A visible-light-promoted method for the selenofunctionalization (and tellurofunctionalization) of alkenes has been developed. This method obviates the prepreparation of moisture-sensitive chalcogen electrophiles. The experimental setup is simple, and supe

Full text of DOI:10.1021/ol402753u

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Visible-Light-Promoted
Selenofunctionalization of Alkenes
Elizabeth S. Conner, Katherine E. Crocker, Ranelka G. Fernando, Frank R. Fronczek,
George G. Stanley, and Justin R. Ragains*
Department of Chemistry, Louisiana State University, Baton Rouge, Louisiana 70803,
United States
jragains@lsu.edu
Received September 23, 2013
ABSTRACT
A visible-light-promoted method for the selenofunctionalization (and tellurofunctionalization) of alkenes has been developed. This method obviates
the prepreparation of moisture-sensitive chalcogen electrophiles. The experimental setup is simple, and superior yields are obtained in the case of
selenofunctionalization(upto99%) whilemoderate togood yields areobtained inthe caseof tellurofunctionalization (53À75%). A varietyof intra- and
intermolecular processes and a short synthesis of the Amaryllidaceae alkaloid (()-γ-lycorane are demonstrated with this method.
Since the publication of seminal reports in the late 1950s
and early 1960s,1 selenofunctionalization and telluro-
functionalization have served as versatile methods for the
synthetic elaboration of alkenes. These methods have been
used in the synthesis of numerous non-natural and natural
products. The preparation of reagents and the synthesis
of target molecules have been the subject of a number
of reviews.2 Organoselenide products of selenofunctiona-
lization are useful synthetic intermediates as they can
be manipulated further (e.g., with selenoxide elimination,3
CÀSe bond homolysis,4 Pummerer rearrangement,5 and
selenone manipulation6). Further, a surge of interest in
organoselenides and organotellurides as potential antic-
ancer agents has been kindled in recent years.7
Selenofunctionalization and tellurofunctionalization are
traditionally accomplished with the use of selenium and
tellurium electrophiles with the general structures ArSeX
and ArTeX3 where “X” is typically a halogen.1,2 These
reagents suffer from numerous shortcomings including
moisture sensitivity and a short shelf life. As such, the in situ
preparation of reagents in this class has become a method of
choice in accomplishing these transformations. Unfortu-
nately, the use of electrophiles such as molecular bromine
in the formation of electrophiles such as PhSeBr from bench-
stable and easily handled PhSeSePh preclude the generation
of these electrophiles in the presence of an alkene substrate.
Methods allowing for the in situ generation of “ArSeX” and
“ArTeX3” in the presence of alkene substrates are very
desirable to accomplish these transformations.
(1) (a) Holze, G.; Jenny, W. Helv. Chim. Acta 1958, 41, 593–603. (b)
de Moura Campos, M.; Petragnani, N. Chem. Ber. 1960, 93, 317–320. (c)
de Moura Campos, M.; Petragnani, N. Tetrahedron 1962, 18, 521–526.
(2) (a) Ranganathan, S.; Muraleedharan, K. M.; Vaish, N. K.;
Jayaraman, N. Tetrahedron 2004, 60, 5273–5308. (b) Petragnani, N.;
Stefani, H. A.; Valduga, C. J. Tetrahedron 2001, 57, 1411–1448. (c)
Tiecco, M. Top. Curr. Chem. 2000, 208, 7–54. (d) Back, T. G. In The
Chemistry of Organic Selenium and Tellurium Compounds; Patai, S., Ed.;
Wiley: New York, 1987; Vol. 2, pp 91À213. (e) Nicolaou, K. C.; Petasis,
N. A. Selenium in Natural Product Synthesis; CIS: Philadelphia, 1984.
(3) Nishibayashi, Y.; Uemura, S. Top. Curr. Chem. 2000, 208, 201–
233.
Unfortunately, methods to form “ArSeX” in the
presence of nucleophile-tethered alkene substrates are
scarce and include chemical,8 electrochemical,9 and
UV photochemical10 protocols. We now report on a
mild, visible-light-promoted method for the seleno- and
(4) Renaud, P. Top. Curr. Chem. 2000, 208, 81–112.
(5) Akai, S.; Kita, Y. Top. Curr. Chem. 2007, 274, 35–76.
(6) Krief, A.; Dumont, W.; Denis, J.-N. J. Chem. Soc., Chem.
Commun. 1985, 571–572.
(7) Seng, H.-L.; Tiekink, E. R. T. Appl. Organometal. Chem. 2012, 26,
655–662.
(8) Tiecco, M.; Testaferri, L.; Tingoli, M.; Bartoli, D.; Balducci, R.
J. Org. Chem. 1990, 55, 429–434.
(9) (a) Konstantinovic, S.; Vukicevic, R.; Mihailovic, M. L. Tetra-
hedron Lett. 1987, 28, 6511–6512. (b) Vukicevic, R.; Konstantinovic, S.;
Mihailovic, M. L. Tetrahedron 1991, 47, 859–865.
r
10.1021/ol402753u
XXXX American Chemical Society

tellurofunctionalization of alkenes via the in situ preparation
of chalcogen electrophiles in the presence of alkene sub-
strates. This method uses bench-stable reagents (PhSeSePh,
PhTeTePh, and tetrahalomethanes) with low reactivity
in the absence of blue light and is marked by operative
simplicity and high (often near quantitative) yields with-
out the use of an inert atmosphere.
Table 1. Solvent Screen for Visible-Light-Promoted
Selenocyclizationa
Recently, we have demonstrated the visible-light-pro-
moted activation of selenoglycosides for O-glycosylation
and determined through 77Se NMR studies that the com-
bination of PhSeSePh and CBr4 with blue LED irradia-
tion results in the formation of PhSeBr.11 We recognized
the potential for these conditions to provide a method for
the in situ generation of PhSeBr in the presence of alkene
substrates. To explore this possibility, we studied the seleno-
cyclization of 5-hexen-1-ol (1, Table 1; see Supporting Infor-
mation for a photo of the experimental setup, Figure S1).
Initial experiments involving the blue LED irradiation of
1 equiv each of PhSeSePh and CBr4 at a concentration of
200 mM resulted in long reaction times (>24 h) with low
and variable yields. Increasing the dilution to 50 mM resulted
in reaction times of 1 day or less and a marked improvement
in yield. Reactions run in THF or diethyl ether resulted
in relatively long reaction times (24.5 h) but high yields of
the selenocyclized product 2 (entries 1, 2). Dichloromethane
and acetonitrile reduced the reaction time substantially and
resulted in excellent yields of 2 (entries 3, 4). Finally, the use
of undistilled alcohol solvents resulted in the shortest ob-
served reaction times (3.5À5.5 h) and, in the case of metha-
nol, a nearly quantitative yield of 2 (entries 5À7). Somewhat
surprisingly, we never observed products of intermolecular
alkoxyselenation resulting from solvent attack on the inter-
mediate seleniranium ion.
We also observed (entry 8) that the tetrahalomethane
Cl3CBr is interchangeable with CBr4, providing a lowered
yield of 2 in MeOH with an increased reaction time.
Importantly, controls run in the absence of both light and
CBr4 (entries 9 and 10) demonstrated the necessity of both.
Finally, none of these experiments were run under an inert
atmosphere (which did nothing to improve yields).
To demonstrate the substrate scope of this method, we
screened a number of alkene substrates for the intra- and
intermolecular selenofunctionalization of alkenes (Table 2).
Formation of the five-membered ether 4a (entry 1) pro-
ceeded in 94% yield while the Boc-protected pyrrolidine 4b
was formed in a modest 62% yield in CH2Cl2 (entry 2) and
not at all in MeOH. Surmising that HBr generated during
the course of selenofunctionalization might result in degra-
dation of both substrate 3b and product 4b, we performed
the selenocyclization of methoxycarbonyl-protected analog
3c that proceeded in an improved 78% yield, demonstrating
the efficacy of this method for the formation of pyrrolidine
derivatives (entry 3). The selenocyclization of 4-pentenoic
acid (3d) in methanol resulted in substantial quantities of
irradiation
yield
(%)
entry
solvent
time (h)
1
THF
24.5
24.5
11
70
84
93
91
85
90
98
82
0
2
Et2O
3
CH2Cl2
CH3CN
iPrOH
EtOH
4
6
5
3.5
5.5
4
6
7
MeOH
MeOH
CH2Cl2
CH2Cl2
8b
9c
10d
7
120
120
0
a All reactions were performed on a 0.6 mmol scale at a concentration
of 50 mM. b Used CBrCl3 instead of CBr4. c Performed in the absence of
light. d Performed in the absence of CBr4.
products of methoxyselenation. The same reaction in di-
chloromethane resulted in a 95% yield of γ-butyrolactone
product 4d (entry 4). The intermolecular methoxyselenation
of cyclohexene resulted in a 97% yield of the product 4e as a
single diastereomer (entry 5), whereas the Ritter reaction12
of cyclohexene resulted in a sluggish reaction and a dis-
appointing 43% yield of amide 4f (entry 6). Methoxyselena-
tion of 1-hexene resulted in a 97% yield of a 3.3:1 mixture of
products favoring the Markovnikov product 4ga (entry 7).
Finally, selenocyclization of 2° alcohol 3g resulted in a 1:1
mixture (99%) of diastereomeric products 4h (entry 8).
Tellurocyclization (Table 3) was also performed on
alkenols in the presence of CBr4 and PhTeTePh. While
methanol gavehigh yieldswithselenocyclization, thissame
solvent afforded none of the predicted tellurofunctionali-
zation products. On the other hand, dichloromethane
afforded 75% and 53% yields of 5 and 6, respectively.
The structure of 5 was confirmed by X-ray crystallography
(Supporting Information, Figure S2).
The mechanism of these chalcogenofunctionalizations
is a subject of continuing investigation. Controls have
demonstrated that these reactions are dependent on both
light and tetrahalomethane. Reaction temperatures are
consistently in the range 25À29 °C, demonstrating that
adventitious heating by the light source does not explain
the reactivity. As mentioned before, we have observed the
formation of PhSeBr upon blue LED irradiation of PhSe-
SePh and CBr4 using 77Se NMR. We propose that blue
LED irradiation of PhTeTePh in the presence of CBr4
results in the formation of PhTeBr3, a reagent known to
promote tellurofunctionalization.13 However, CBr4 does
not absorb at the wavelengths (λmax = 455 nm) of blue
(10) (a) Pandey, G.; Gadre, S. R. Acc. Chem. Res. 2004, 37, 201–210.
(b) Pandey, G.; Soma Sekhar, B. B. V.; Bhalerao, U. T. J. Am. Chem.
Soc. 1990, 112, 5650–5651.
(11) Spell, M.; Wang, X.; Wahba, A. E.; Conner, E.; Ragains, J.
Carbohydr. Res. 2013, 369, 42–47.
(12) Toshimitsu, A.; Aoai, T.; Owada, H.; Uemura, S.; Okano, M.
J. Org. Chem. 1981, 46, 4727–4733.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Substrate Scope of Visible-Light-Promoted
Selenofunctionalizationa
Table 3. Visible-Light-Promoted Tellurofunctionalizationa
a Reactions were performed on a 0.6 mmol scale at a concentration of
50 mM.
(Scheme 1). Nevertheless, a photoinitiated electron transfer10
from diaryldichalcogenide to CBr4 (Mechanism 2, Scheme 1)
is an alternative scenario that cannot be ruled out at this
time. The fate of carbon and the remaining bromine
atoms of CBr4 is also unclear at this time; the formation
of volatile byproducts may explain the lack of isolable
byproducts from these reactions. To this end, GC/MS
analysis of irradiated mixtures of 1, PhSeSePh and CBr4
has been inconclusive regarding the fate of the tribro-
momethyl radical.
Scheme 1. Possible Mechanistic Scenarios
a All reactions were performed on a 0.6 mmol scale at a concentration
of 50 mM. b Reaction performed in CH2Cl2. c Reaction performed in
CH3CN/H2O (13 μL of H2O added to 12.0 mL of CH3CN).
LED irradiation.14 On the other hand, PhSeSePh absor-
bance does tail into the wavelengths produced by blue
LEDs15 while the absorbance of PhTeTePh at 455 nm is
substantial.16 We initially considered the possibility of a
light-promoted homolysis of PhSeSePh and PhTeTePh
preceding abstraction of halogen from tetrahalomethane
by a chalcogen radical (Mechanism 1, Scheme 1). Indeed,
Gaussian 2009 calculations at the 6-311G** level of theory
indicate that phenylselenyl radical abstraction of bromine
from CBr4 to generate phenylselenyl bromide and the
tribromomethyl radical is favorable by À9.3 kcal/mol
We sought to demonstrate the efficacy of this method in
the synthesis of a complex natural product and recognized
its potential to provide a short synthesis of the Amarylli-
daceae alkaloid (()-γ-lycorane17,18 (Scheme 2, Part I).
Reduction of known nitrile 719 to amine 8 followed by
coupling to commercially available acid chloride 9 af-
forded a 63% yield of cyclization substrate 10 (two steps).
(17) Kotera, K. Tetrahedron 1961, 12, 248–261.
(13) Comasseto, J. V.; Ferraz, H. M. C.; Petragnani, N. Tetrahedron
Lett. 1987, 28, 5611–5614.
(14) Zhang, H.; Dvornikov, A. S.; Rentzepis, P. M. J. Phys. Chem. A
(18) For recent syntheses of γ-lycorane, see: (a) Huntley, R. J.; Funk,
R. L. Tetrahedron Lett. 2011, 52, 6671–6674. (b) El Bialy, S. A. A. Nat.
Prod. Res. 2008, 22, 1176–1188. (c) Chapsal, B. D.; Ojima, I. Org. Lett.
2006, 8, 1395–1398. (d) Fujioka, H.; Kenichi, M.; Ohba, Y.; Hirose, H.;
Kita, Y. Chem. Commun. 2006, 832–834. (e) Gao, S.; Tu, Y. Q.; Song, Z.;
Wang, A.; Fan, X.; Jiang, Y. J. Org. Chem. 2005, 70, 6523–6525.
(19) Cochran, B. M.; Michael, F. E. Org. Lett. 2008, 10, 5039–5042.
2005, 109, 5984–5988.
(15) Ito, O. J. Am. Chem. Soc. 1983, 105, 850–853.
(16) Tamai, T.; Nomoto, A.; Tsuchii, K.; Minamida, Y.; Mitamura,
T.; Sonoda, M.; Ogawa, A. Tetrahedron 2012, 68, 10516–10522.
Org. Lett., Vol. XX, No. XX, XXXX
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produce a 37% yield of an inseparable ∼1:1 mixture of
desired 12 and undesired constitutional isomer 13 in addi-
tion to uncyclized 14. Zard and co-workers have observed a
similar effect in an alternative synthesis of (()-γ-lycorane.20
To circumvent this selectivity problem (Scheme 2, Part II),
we synthesized blocked substrate 16 from the requisite
carboxylic acid 1521 and amine 8 in 54% yield. Selenocycli-
zation of 16 in the absence of base was successful; however,
the generation of HBr resulted in protiodesilylation and
none of the desired TMS-protected product 17. Buffering
with the base 2,6-di-tert-butyl-4-methylpyridine (DTBMP),
on the other hand, resulted in the generation of 17 (85%).
Attempted tin-promoted cyclization of 17 (Bu3SnH) resulted
in hydrogen abstraction product 18 (73À77%). Recognizing
that Bu3SnH is too reactive as a hydrogen donor, we turned
to the less reactive tris(trimethylsilyl)silane (TTMSS,
Scheme 2, Part III). Refluxing a solution of TTMSS, AIBN,
and selenide 17 in benzene resulted in a 44% yield of the
desired cyclized product 19 along with 41% of uncyclized
product 18 (the formation of which we were never able to
suppress). Importantly, 13 was never observed in product
mixtures of 18/19. LiAlH4 reduction of amide 19 preceded
TFA-promoted protiodesilylation to furnish (()-γ-lycorane
in 68% (two steps).
Scheme 2. Synthesis of (()-γ-Lycorane
In summary, we have developed a mild method for seleno-
and tellurofunctionalization of alkenes via the visible-light-
promoted in situ generation of chalcogen electrophiles.
These transformations are marked by high yields and ease
of performance (reactions proceed at room temperature, and
an inert atmosphere is not necessary). We have performed
the seleno- and tellurofunctionalization of a variety of
substrates, demonstrating that inter- and intramolecular
processes are possible. The mechanism of these reactions is
still under investigation, and the utility of this method has
been demonstrated in a short synthesis of the Amaryllidaceae
alkaloid (()-γ-lycorane.
Acknowledgment. We would like to thank Ms. Connie
David (LSU) for assistance with HRMS and Dr. Dale
Treleaven (LSU) and Dr. Thomas Weldeghiorghis (LSU)
for assistance with 2D NMR. We thank Louisiana State
University for financial support of this work and the
Louisiana Board of Regents for a fellowship for ESC.
Supporting Information Available. Experimental pro-
cedures and characterization for all intermediates and
products, 1D and 2D NMR spectra, and X-ray crystal
structures for 5. This material is available free of charge
via the Internet at http://pubs.acs.org.
Visible-light-promoted selenocyclization worked best in
CH2Cl2 and afforded a 71% yield of perhydroindole 11,
the stereochemistry of which was confirmed with 2D NMR
(see Supporting Information). Formation of the γ-lycorane
skeleton proceeded via tin-promoted radical cyclization to
(21) Josien, H.; Ko, S.-J.; Bom, D.; Curran, D. P. Chem.;Eur. J.
1998, 4, 67–83.
(20) Cassayre, J.; Zard, S. Z. Synlett 1999, 4, 501–503.
The authors declare no competing financial interest.
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Org. Lett., Vol. XX, No. XX, XXXX