Organoselenium-catalyzed synthesis of oxygen- and nitrogen-containing heterocycles

Article abstract of DOI:10.1021/acs.orglett.5b03543

A new and efficient approach for the synthesis of oxygen and nitrogen heterocycles by organoselenium catalysis has been developed. The exo-cyclization proceeded smoothly under mild conditions with good functional group tolerance and excellent regioselectivity. Mechanistic studies revealed that 1-fluoropyridinium triflate is key for oxidative cyclization.

Full text of DOI:10.1021/acs.orglett.5b03543

Letter
pubs.acs.org/OrgLett
Organoselenium-Catalyzed Synthesis of Oxygen- and Nitrogen-
Containing Heterocycles
Ruizhi Guo, Jiachen Huang, Haiyan Huang, and Xiaodan Zhao*
Institute of Organic Chemistry & MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry and Chemical
Engineering, Sun Yat-Sen University, Guangzhou 510275, P. R. China
S
* Supporting Information
ABSTRACT: A new and efficient approach for the synthesis
of oxygen and nitrogen heterocycles by organoselenium
catalysis has been developed. The exo-cyclization proceeded
smoothly under mild conditions with good functional group
tolerance and excellent regioselectivity. Mechanistic studies
revealed that 1-fluoropyridinium triflate is key for oxidative
cyclization.
or many years, selenium reagents have frequently been
applied in organic synthesis.1 In particular, diselenides, an
of diselenide and N-fluorobenzenesulfonimide (NFSI) as the
oxidant.10c,14 The reported PhSeSePh/NFSI catalytic systems
were limited in the synthesis of benzoheterocycles. However,
valuable oxygen- and nitrogen-containing heterocycles such as
tetrahydrofurans and -pyrans, pyrrolidines, and piperidines have
not been synthetically explored with diselenide as the catalyst
or precatalyst. The development of an efficient selenium-
catalyzed reaction system to prepare them is highly desirable.
Herein, we report our discovery that they can be synthesized by
a new and efficient catalytic system PhSeSePh/1-fluoropyr-
idinium triflate (FP-OTf)/NaF via exo-trig cyclization.
Oxygen- and nitrogen-containing heterocycles exist in a
variety of biologically active molecules as well as natural
products.15 Developing new and efficient methods for their
synthesis remains a long-standing interest to organic chem-
ists.16 Cyclization of alkene-tethered nucleophiles, e.g., −OH
and −NHTs, as the substrates is a straightforward way to form
heterocycles.17 Thus, we attempted to produce heterocycles by
the cyclization with unsaturated alcohol 1a (E/Z = 4:1) as a
model substrate.
The classical oxidants PhI(OAc)2, PhI(OCOCF3)2, and
(NH4)2S2O8 did not result in any desired cyclization product
2a at room temperature (Table 1, entries 1−3) although they
were effective in the synthesis of furans, dihydrofurans,11 and
intramolecular lactones.12 Only trace amounts of 2a were
generated when the reaction was carried out at 60 °C using
(NH4)2S2O8 as the oxidant. The yield improved using a low-
cost oxidant hydrogen peroxide−urea adduct (UHP) (Table 1,
entry 4). Notably, the use of NFSI as the oxidant selectively
furnished the E-configured cyclization product 2a in 59% yield
along with the rearrangement product 3a (Table 1, entry 6).
The formation of 3a was facilitated by HF in the reaction. In
this reaction, byproducts other than 3a were observed.18 By
continuing the search for a more efficient oxidant, FP-OTf
F
important class of organoselenium compound, possess unique
properties and are readily available. Diselenides as the catalysts
or precatalysts have garnered considerable attention in a
number of different reactions,2 e.g., dihydroxylation of alkenes,3
Baeyer−Villiger oxidation,4 halogenation,5 dehydration of
aldoximes,6 amination of alkenes,7 etc.,8 due to the mild
reaction conditions, good functional group tolerance and
excellent regioselectivity. Importantly, some valuable com-
pounds inaccessible by other catalytic methods could be
prepared by using catalytic amounts of diselenides. For
example, Denmark recently developed an elegant approach to
make syn-dichlorides with diselenide as the precatalyst.9
Although some achievements have been made in this area,
reactions by using diselenides as the catalysts or precatalysts are
not broad, and many others remain unexplored. The study of
this area is still in its infancy.
Our group has devoted considerable effort to the develop-
ment of new and efficient reactions by selenium catalysis,10 and
we noticed that cyclizations with diselenides as the catalysts or
precatalysts are rare. In the literature, only some specific
heterocycles have been produced. In the 1990s, Tiecco
reported synthesis of furans and dihydrofurans with catalytic
amounts of diselenide and (NH4)2S2O8 as the oxidant.11 In
these transformations, an electron-withdrawing group such as
an ester group had to be installed in the substrates to promote
the 5-endo-trig cyclizations. Eight years ago, Wirth and co-
workers described the cyclization of unsaturated carboxylic
acids to afford five- or six-membered intramolecular lactones by
a catalytic system PhSeSePh/PhI(OCOCF3)2.12 Their methods
are efficient for unsaturated carboxylic acid substrates, but they
pointed out that the method did not work for cyclizations of
γ,δ-unsaturated alcohols at different temperatures in the
paper.12b Recently, synthesis of isobenzofuranones was
demonstrated by Breder using olefinic carboxylic acids as the
substrates.13 Furthermore, we and Breder independently
reported synthesis of indole derivatives using catalytic amounts
Received: December 14, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03543
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Organic Letters
Letter
a
Table 1. Condition Optimization
Scheme 1. Formation of Tetrahydrofurans and -pyrans from
Olefinic Alcohols
a
b
yield (%)
entry
X (mol %)
oxidant
base
2a
3a
1
10
10
10
10
10
10
10
10
10
−
PhI(OAc)2
PhI(OCOCF3)2
(NH4)2S2O8
UHP
−
−
−
−
−
−
−
NaF
Et3N
NaF
NaF
NaF
−
−
−
23
16
59
64
92
−
−
−
−
−
−
19
15
−
−
−
−
−
2
3
4
5
Selectfluor
NFSI
6
7
FP-OTf
8
FP-OTf
9
FP-OTf
10
11
FP-OTf
−
92
5
FP-OTf
c
12
5
FP-OTf
98 (96)
a
Conditions: 1a (0.1 mmol), oxidant (0.12 mmol), base (1 equiv),
b
CH3CN (2.0 mL), rt, 18 h. Determined by 400 MHz NMR with
1,3,5-trimethoxybenzene as the internal standard. Isolated yield shown
in parentheses. Solvent, 5.0 mL.
c
resulted in the generation of 2a in 64% yield (Table 1, entry
7).19 Due to direct fluorination, only 16% products were
formed with Selectfluor as the oxidant (Table 1, entry 5). To
eliminate HF in the reaction, the base NaF, an excellent
adsorbent of HF, was added. Pleasingly, the yield improved to
92% with FP-OTf (Table 1, entry 8). No seven-membered
byproduct 3a was observed. Other inorganic bases, i.e., Na2CO3
and NaHCO3, led to lower yields. Organic base Et3N inhibited
the reaction (Table 1, entry 9). When PhSeSePh was absent or
replaced by other chalcogenide catalysts, i.e., PhSePh,
BnSeSeBn, and PhSSPh, trace or no desired product was
observed (Table 1, entry 10). Product 2a could eventually be
obtained in 96% isolated yield with only 5 mol % catalyst
loading (Table 1, entry 12). Importantly, the cyclization
proceeded efficiently under mild conditions with the formation
of a quaternary center. Additionally, both the E- and Z-isomers
of 1a were completely converted to the E-olefinic tetrahy-
drofuran.
With the optimal conditions identified, we went on to
demonstrate the substrate scope (Scheme 1). The size of the R1
substituent had little influence on the cyclization. The R2
substituent could be hydrogen, alkyl, or an aromatic group.
Functional groups such as −Cl and −OBn were well tolerated
in the cyclization (2e, 86%; 2f, 88%). Interestingly, when R2
was hydrogen only the exo-product (2g, E/Z = 5:1) was formed
in 71% yield; the endo-cyclization product was not observed.
When R2 were electron-neutral and -deficient aromatic rings,
the cyclization proceeded efficiently to produce the desired
products (2h−o, 74−91%). When R2 were electron-rich
aromatic rings, i.e., (4-MeO)C6H4−, the corresponding
tetrahydrofuran products were obtained in low yields and
most tetrahydrofuran products were rearranged to 3a analogues
despite of the presence of 1 equiv of NaF. Olefinic secondary
and tertiary alcohols underwent cyclization to generate the
corresponding products in good yields under similar conditions
(2p, 79%; 2q, 67%). Although the diastereoselectivity was poor
for 2p, it was possible to improve it by condition optimization.
Furthermore, tetrahydropyran products could be obtained in
a
Conditions: substrate 1 (0.1 mmol), PhSeSePh (5 mol %), FP-OTf
(1.2 equiv), NaF (1 equiv), CH3CN (5 mL), rt, 18 h.
good to excellent yields by similar cyclization (2r, 79%; 2s,
96%).
This protocol was successfully applied to the cyclization of
olefinic sulfonamides. The corresponding five- and six-
membered tosyl amines were formed in 54−93% yields
(Scheme 2). The reactions were sensitive to solvent and acid.
Not only five-membered amines but also their rearrangement
products, azepine derivatives, were formed using acetonitrile as
the solvent and 1 equiv of base. By simply changing the solvent
to 1,2-dichloroethane five-membered amines were generated in
the presence of stoichiometric NaF. To afford 5b, as much as
possible, it was essential to replace NaF by NaHCO3. The
cyclization reactions using 0.5 equiv of NaF produced seven-
membered amines 6a−c in 45−82% yields from the
corresponding sulfonamides. The formation of 6a−c can be
rationalized via the rearrangement of 5a−c, respectively,
facilitated by the HF remaining in the reactions.
When the alcohol 7 was treated with PhSeSePh as the
catalyst in the presence of FP-OTf, the hydroxy group
selectively added to the double bond to generate tetrahy-
drofuran 8 (dr = 1:1) in 72% yield (Scheme 3).20 Intriguingly,
the protected allylic alcohol moiety was not affected in the
cyclization, and no cyclization product was observed where
addition of the hydroxyl group to the other double bond had
occurred. In contrast, when the alcohol was treated with
palladium catalyst, the hydroxy group added to the other
double bond to give product 9 (dr = 5:1) in almost quantitative
yield as one would predict.21 These results show that selenium
catalysis can occur with excellent regioselectivity, in a way
complementary to metal catalysis in organic synthesis.
B
DOI: 10.1021/acs.orglett.5b03543
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Formation of N-Heterocycles from Olefinic
a
Sulfonamides
We have therefore proposed the reaction mechanism
depicted in Scheme 4. Reaction of PhSeSePh with fluoropyri-
Scheme 4. Proposed Mechanism
a
Conditions: substrate 4 (0.1 mmol), PhSeSePh (10 mol %), FP-OTf
b
(1.2 equiv), NaF (1 equiv), DCE (2 mL), rt, 21 h. NaHCO3 (0.8
equiv) instead of NaF. NaF: 0.5 equiv.
c
Scheme 3. Selenium Catalysis vs Metal Catalysis
dium triflate produces PhSeX (X = F, OTf) species. Highly
active PhSeX easily interacts with the double bond of olefinic
alcohol 1a to form seleniranium ion 11, and then intra-
molecular attack of the hydroxy group leads to three-membered
ring opening to yield intermediate 10. The PhSe group on 10
was oxidized by FP-OTf to generate intermediate 12.
Participation of base assists proton elimination and removal
of the selenium moiety to give the desired product 2a and
regenerate the species PhSeX. Acid promotes the rearrange-
ment of 2a toward 3a. Based on the aforementioned
experiments, the formation of 2a from 10 is likely through
the oxidation of FP-OTf, not by the active species PhSeF and
PhSeOTf. At present, it is unclear whether pyridine in the
reaction can stabilize PhSe+ or inhibit the oxidation of
substrates.
In summary, we have developed an efficient approach to the
synthesis of O- and N-hereocycles using organoselenium
catalysis. The reactions proceeded smoothly without special
care and with good functional group tolerance and excellent
regioselectivity. Our mechanistic studies have revealed that FP-
OTf is the key for the oxidative cyclization. This method is
supplemental to metal catalysis in organic synthesis. Develop-
ment of an asymmetric version of cyclization is ongoing in our
laboratory.
NMR experimental studies in acetonitrile-d3 were conducted
to elucidate the mechanism. First, PhSeSePh was treated with a
stoichiometric oxidant FP-OTf in CD3CN to verify whether it
could be oxidized to generate PhSe+.22 The reaction was
1
monitored by H, 19F, and 77Se NMR (see the Supporting
Information). After 4 h, the 1H NMR spectrum clearly showed
that new compounds were formed. A signal at δ = 48.2 ppm
assigned to FP-OTf in the 19F NMR spectrum almost
disappeared, which revealed that most FP-OTf was decom-
posed. Meanwhile, a signal at δ = 465.8 ppm assigned to
PhSeSePh disappeared and a signal at δ = 1440.6 ppm appeared
in 77Se NMR spectrum, which indicated that diselenide was
converted to another species. The signal at δ = 1440.6 ppm was
assigned to PhSeX (X = F, OTf).23,24 We attempted to trap it.
Another reaction of PhSeSePh with FP-OTf was run, and then
1a was added after 4 h to see if 1a could be cyclized (eq 1). As
expected, PhSe-functionalized intermediate 10 was observed in
61% NMR yield. This indicated that FP-OTf can oxidize
PhSeSePh to form PhSeX.25 Next, removal of the PhSe group
from the intermediate 10 was investigated. The cyclic ether 10
was treated with different oxidants, FP-OTf, pregenerated
PhSeF from PhSeBr and AgF, pregenerated PhSeOTf from
PhSeBr and AgOTf, and even PhSeBr. Only FP-OTf as the
oxidant led to the formation of 2a in 82% isolated yield (eq 2).
The other oxidants only resulted in no or trace 2a. Thus, the
organoselenium catalyzed synthesis of heterocycles is consid-
ered to proceed through a PhSe-addition and PhSe-elimination
sequence. FP-OTf is key for the transformation.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03543.
Experimental details, characterization data, mechanistic
studies, and NMR spectra of new compounds (PDF)
C
DOI: 10.1021/acs.orglett.5b03543
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(14) Ortgies, S.; Breder, A. Org. Lett. 2015, 17, 2748.
AUTHOR INFORMATION
■
(15) For selected reviews on oxygen heterocycles, see: (a) Elliott, M.
C. J. Chem. Soc., Perkin Trans. 1 2002, 2301. (b) Lorente, A.;
Lamariano-Merketegi, J.; Albericio, F.; Alvarez, M. Chem. Rev. 2013,
113, 4567. For nitrogen heterocycles, see: (c) O’Hagan, D. Nat. Prod.
Rep. 2000, 17, 435. (d) Michael, J. P. Nat. Prod. Rep. 2001, 18, 520.
(e) Gupton, J. T. Top. Heterocycl. Chem. 2006, 2, 53. (f) Robertson, J.;
Stevens, K. Nat. Prod. Rep. 2014, 31, 1721.
Corresponding Author
*E-mail: zhaoxd3@mail.sysu.edu.cn.
Notes
The authors declare no competing financial interest.
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Commandeur, C.; Commandeur, M.; Reymond, S.; Guerinot, A.;
Cossy, J. Acc. Chem. Res. 2015, 48, 761.
(17) For selected examples on metal-catalyzed synthesis of
heterocycles, see: (a) Hosokawa, T.; Uno, T.; Inui, S.; Murahashi, S.
J. Am. Chem. Soc. 1981, 103, 2318. (b) Uozumi, Y.; Kato, K.; Hayashi,
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ACKNOWLEDGMENTS
■
We thank Sun Yat-Sen University, the “One Thousand Youth
Talents” Program of China, and the Natural Science
Foundation of Guangdong Province (Grant No.
2014A030312018) for financial support.
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