Selenocystine Peptides Performance in 5-endo-dig Reactions

Article abstract of DOI:10.1002/ejoc.201901548

Herein, we present methods for the generation of selenocysteinyl electrophile by weak Lewis acids or oxidants. The electrophilic selenium species were further utilized in 5-endo-dig cyclization reactions with 2-ethynyl phenols, anisoles, and anilines, yie

Full text of DOI:10.1002/ejoc.201901548

A Journal of
Accepted Article
Title: Selenocystine peptides performance in 5-endo-dig reactions
Authors: Sindija Lapcinska and Pavel Arsenyan
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10.1002/ejoc.201901548
European Journal of Organic Chemistry
FULL PAPER
Selenocystine peptides performance in 5-endo-dig reactions
Sindija Lapcinska[a] and Dr. Pavel Arsenyan[a]*
Abstract: Herein we present methods for the generation of
selenocysteinyl electrophile by weak Lewis acids or oxidants. The
electrophilic selenium species were further utilized in 5-endo-dig
cyclization reactions with 2-ethynyl phenols, anisoles and anilines
yielding substituted benzo[b]furans and indoles bearing short
selenocysteine-containing peptides. Copper(II) bromide promoted
5-endo-dig cyclization can be successfully applied for protected and
unprotected peptides in high yields. Elaborated protocol allows the
construction of phenylindeno[1,2-c]chromene moiety in 5-endo-
dig/6-endo-dig cascade reactions.
on the electrophilic character of (5-nitropyridylthio)-Sec peptides
and was used in Sec-peptide and small molecule (including some
indoles) late stage conjugation. Recently, our group
demonstrated novel copper(II) bromide mediated method[25] for
the generation of selenocysteinyl electrophile from selenocystine
containing peptides. The electrophilic species were used in
5-endo-dig cyclization with 2-propargyl N-pyridines forming
corresponding indolizinium salts whereas 6-endo-dig cyclization
with 2-ethynylbiaryls led to formation of polyaromatic systems
containing Sec peptides. In continuation of our research we would
like to present the formation of selenocysteine containing
benzo[b]furans and indoles via 5-endo-dig cyclization utilizing
copper(II) bromide or oxidant induced generation of Sec
electrophile. Notably, methods are tolerant to both unprotected
and protected selenocystine containing peptides. Moreover,
developed protocol allows the formation of phenylindeno[1,2-
c]chromene moiety in 5-endo-dig/6-endo-dig cascade reactions.
Introduction
Benzo[b]furan[1] and indole[2] are among the most important
heterocycles found in many natural products. Due to the biological
activity of natural and synthetic derivatives of these heterocycles
they are relevant scaffolds for pharmaceuticals.[3,4] Furthermore,
both - benzo[b]furan and indole - are considered as “privileged
structures” thanks to their ability to act as ligands for various
receptors.[5]
O
O
O
H
H
AA
AA
H
AA
N
N
N
AA
AA
N
N
AA
N
AA
AA
AA
H
H
H
Se
Se
Se
R
Se
H
X
AA
O
N
The most popular approaches for introduction of selenium atom
in benzo[b]furan and indole moieties is either direct selenylation[6-
AA
N
AA
H
5-endo-dig
O
> 20 examples,
10]
of these heterocycles or electrophilic cyclization of 2-(1-
protected and
unprotected Sec peptides
mild conditions
up to quantitative yields
5-endo-dig/6-endo-dig
alkynyl)anisoles/phenols and 2-(1-alkynyl)anilines in the
presence of selenium electrophile. [11] The electrophilic species
usually employed are arylselanyl chloride[12,13] or arylselanyl
iodide generated in situ from diselenides using I2,[14] Fe/I2,[15] KI/m-
CPBA system[6] or copper(I) iodide. [16] Copper(I) iodide has also
been used as catalyst for the generation of selenium electrophile.
Results and Discussion
[17]
Knowing that copper(II) bromide is a suitable promoter for the Sec
electrophile generation, we continued our research in purpose to
expand the application scope of this method in 5-endo-dig
cyclization reactions. Initially we chose 2-(phenylethynyl)anisole
(1a) and diphenyl diselenide as model substrates employing
previously established optimal reaction conditions (Scheme 1).
Copper(II) bromide (1.2 equiv.) was added to a solution of Ph2Se2
(1.0 equiv.) in CH2Cl2 followed by addition of anisole 1a
(1.2 equiv.) after 30 min of stirring. After 24 hours we were
delighted to observe the formation of product 2a, however, the
diselenide still remained in the reaction mixture therefore we
elevated the reaction temperature to 40 °C, which resulted in full
consumption of the diselenide in 16 hours and the product 2a was
obtained in 83% yield. Furthermore, the structure of 2a was
unambiguously confirmed by x-ray analysis (Figure 1, CCDC
1943954). Interestingly, that Kazmierczak et al., who developed
method for synthesis of 3-selanyl benzo[b]furans via 5-endo-dig
cyclization of 2-alkynyl phenols using diaryl diselenide and
copper(I) iodide,17 stated that the reaction of diphenyl diselenide
and 2-(phenylethynyl)phenol in the presence of CuBr2 in DMSO
provides the product 2a in only 9% yield. They hypothesized that
Lewis acid (FeCl3) mediated generation of selenium
electrophile has been used for preparation of 3-selanyl
benzo[b]furans[18] and indoles[19] as well. Very recently, Perin et al.
reported the synthesis of 2,3-dichalcogenyl substituted
benzo[b]chalcogenophenes employing oxone induced generation
[20]
of selenium electrophile.
Another sulfur-containing oxidant
(persulfates) induced generation of selenium electrophile has
been used for the direct selenylation of indole[8] and arenofurans.
[9] It is noteworthy that previous research has only focused on the
use of simple diaryl diselenides except for Cohen et al. who
reported a sophisticated method[21,22] for the generation of
selenocysteine[23,24] (Sec, U) electrophile. This approach is based
[a]
Latvian Institute of Organic Synthesis, 21 Aizkraukles Str., Riga, LV-
1006, Latvia; е-mail: pavel@osi.lv
URL: osi.lv/en/laboratories/pharmacomodulators-synthesis-group/
Supporting information for this article is given via a link at the end of
the document. SI contains copies of 1H, 13C, 77Se NMR spectra and
HRMS for all new compounds
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10.1002/ejoc.201901548
European Journal of Organic Chemistry
FULL PAPER
the halogen atom plays a crucial role. Probably, less polar solvent
elongates the existence of diphenyl diselenide – copper(II)
bromide adduct in the reaction mixture providing an increase of a
product yield up to 83%. Analogously, 3-chalcogenyl
benzo[b]furans 2b and 2c were synthesized employing dibenzyl
diselenide and diphenyl ditelluride. Previously 2b and 2c have
been obtained only by Zeni et al. using FeCl3 promoted cyclization
of 2-phenylethynyl anisole.18 Inspecting both methods, it could be
concluded that in case of 2b the yields are similar (60% - CuBr2
method, 64% - FeCl3). However, CuBr2 promoted cyclization led
to the formation of 2-phenyl-3-(phenyltellanyl)benzo[b]furan (2c)
in 50% yield which is a considerable improvement comparing to
FeCl3 promoted phenyltellanyl electrophile generation (36%).
Based on previous studies25 we believe that electrophilic
selenium species are formed via CuBr2-diselenide adduct A.
of aryl group stabilized vinyl cation thus preventing 5-endo-dig
cyclization. The desired 2-butyl-3-selanylbenzo[b]furan 4c formed
in low yield forcing us to search for a different method for the
generation of Sec electrophile. It is known that selenium
electrophile can be generated from diselenides using inorganic
and organic oxidants. The choice of reagent depends on the
substrate and its functional groups.[27] We tested several of the
most popular oxidation agents used for diselenide oxidation to see
whether it is possible to employ oxidant for generation of Sec
electrophile from Sec containing peptide and use it further in
5-endo-dig cyclization for benzo[b]furan ring formation. Among
the most popular oxidants for selenium electrophile generation
are persulfates producing strongly electrophilic alkyl or aryl
selanyl sulfate which has been proposed by Tiecco et al.[28] and
[29]
[9,28-31]
proven by Kumar et al.
based on 77Se NMR data.
Interestingly, Kumar et al. emphasized that TFA is crucial for
phenylselanyl electrophile generation in the presence of K2S2O8.
Probably, it is related with the fact that diphenyl diselenide
reaction with persulfate is very slow, furthermore, the solubility of
K2S2O8 in organic solvents is low as well. Tiecco et al. also
reported[31] that addition of TfOH to a mixture of Ph2Se2 and
ammonium persulfate in acetonitrile resulted in completion of
reaction in just several minutes. Although most likely that under
these conditions the selanylating agent was a mixture of
phenylselanyl sulfate and phenylselanyl triflate.[31] Unfortunately,
the addition of TFA was prohibited since it would remove
protecting groups from peptide. Furthermore, Hajra et al. in 2017
reported direct selanylation of arenofuranes using Na2S2O8
mediated oxidation of diaryl diselenide[9] without addition of any
acid. Utilization of only 1.2 equivalents of oxidant was enough for
reaction completion. Treating mixture of dipeptide 3a and 2-
(hexynyl)phenol (1d) in MeCN with 5 equiv. of K2S2O8 resulted in
selective, but slow formation of the product 4c. Ammonium
persulfate provided similar results, yet it was slightly less effective
and required more time for full conversion of 3a. In case of
potassium iodate, the reaction was even slower compared to
persulfates whereas oxone provided complex mixture of
unidentified compounds and only traces of product.
Unsatisfactory results were also obtained employing m-CPBA,
NaIO4, cerium ammonium nitrate and (diacetoxyiodo)benzene.
Therefore, K2S2O8 is the most suitable oxidant for 2-alkyl-3-
selanylbenzo[b]furan formation. Next, the necessary quantity of
oxidant for the reaction completion was studied (1, 2, 3 and 5
Ph
YR
Ph
O
OMe
2
1a
2a Y = Se, R = Ph 83%
2b Y = Se, R = Bn 60%
2c Y = Te, R = Ph 50%
CuBr2
[RY-CuBr]
RY-YR
CuBr2
CuBr
R2Y2
Scheme 1. 3-Selanyl and 3-tellanyl benzo[b]furans formation: feasibility studies.
Reaction conditions: 1a (1.2 equiv.), R2Y2 (1.0 equiv.), CuBr2 (1.2 equiv.),
CH2Cl2, 40 °C.
Figure 1. ORTEP molecular structure of 2a
Satisfied with the results, we turned our attention to preparation
of Sec containing benzo[b]furans. Gratifyingly, generation of
selenium electrophile from bis-dipeptide (Boc)Sec-Gly-OBn 3a
with CuBr2 and reaction with anisole 1a finalized with the isolation
of 4a in 62% yield (Scheme 2). Similarly, 2-(phenylethynyl)phenol
(1b) provided product 4b in 68% yield. Since dipeptide 3a was
convenient for the benzo[b]furan formation process, we decided
equiv. of K2S2O8). According to experimental results,
5
equivalents of oxidant were required for full conversion of starting
material in the shortest period (3 days). It should be noted that 5
equivalent excess of oxidant is acceptable for the further studies
only because potassium persulfate is a very cheap inorganic
reagent. The solvent change from MeCN to CH2Cl2 and
temperature increase to 40 °C did not give any improvement, so
we settled reaction conditions on more environmentally friendly
solvent at room temperature. Next, we were focused on the scope
and limitations studies. Reaction of 3a with 2-(hex-1-yn-1-
yl)phenol (1d) proceeded smoothly to yield 2-butyl-3-
selanylbenzo[b]furan 4c in very good yield (87%). The use of
2-(hex-1-yn-1-yl)anisole (1c) resulted in even higher yield of 4c
(95%). We also prepared previously obtained compound 4a to
to
test
more
complicated
system
–
bis-tripeptide
selenoglutathione 3b
–
a
seleno-analogue of natural
glutathione.[26] Under the same reaction conditions benzo[b]furan
4d with selenoglutathione moiety was isolated in almost
quantitative yield (98% employing 1a, 91% - 1b). Obviously, the
complexity of the diselenide does not interfere with the reaction
yield. However, treatment of 2-(hex-1-yn-1-yl)phenol (1d) with
dipeptide 3a in the presence of CuBr2 led to the formation of a
mixture of unidentified compounds probably due to the formation
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10.1002/ejoc.201901548
European Journal of Organic Chemistry
FULL PAPER
compare the impact of alkyl and aryl substituents attached to the
triple bond. Both substituents were equally suitable for the
preparation of 2-substituted benzo[b]furans. It is worth mentioning
that product 4a was prepared in significantly higher yield than
employing CuBr2 mediated cyclization.
Elaborated reaction conditions using 2-ethynyl substituted
anilines were tested in purpose to obtain Sec-containing indoles.
Previously, Zeni’s group reported an elegant FeCl3 promoted
cyclization19 of o-alkynyl anilines with diphenyl diselenide,
unfortunately, this method led to a very low conversion of peptide
3a. Similarly to benzo[b]furan formation, the treatment of
(Boc)Sec-Gly-OBn 3a with N-tosyl-2-(phenylethynyl)aniline 5a in
the presence of CuBr2 in CH2Cl2 at room temperature was slow.
However, elevation of the temperature to 40 °C led to full
consumption of diselenide within 16 hours yielding 6a in 87% yield
(Scheme 3). Under the optimal reaction conditions, substrate
scope of alkynyl anilines was examined. Nosyl protected 2-
(phenylethynyl)aniline 5c showed even better result compared to
tosyl aniline. Corresponding N-nosylindole 6c was isolated in 91%
yield after treatment with TFA. Notably, 2,4-dinitro-
benzenesulfonyl protection (5e) resulted in loss of reactivity, the
reaction mixture showed only traces of product 6e. Pleasingly,
Boc protected 2-(phenylethynyl)aniline 5f produced indole 6f in
62% yield after treatment with TFA. However, the developed
method does not allow the use of unprotected 2-
(phenylethynyl)aniline as a starting material: only a mixture of
unidentified compounds was obtained. Additionally, N,N-
dimethyl- and N,N-dibenzyl 2-(phenylethynyl)anilines 5h and 5i
were tested with the aim to improve the substrate scope. In both
cases complex mixture of unidentified compounds was obtained.
The
same
was
observed
employing
N-benzyl-2-
(phenylethynyl)aniline 5j. Under the optimal reaction conditions,
we prepared selenoglutathione-indole conjugates 6j, 6l, 6m.
Again, we observed that the use of selenoglutathione 3b showed
superior yield (75-90%) compared to (Boc)Sec-Gly-OBn 3a
probably due to steric hindrance of the Boc protecting group in 3a.
Treatment of peptide 3a with 2-(hexynyl)aniline 5b in the
presence of CuBr2 led to formation of a mixture of unidentified
compounds showing only traces of product. Thus, an oxidant-
promoted selenium electrophile generation was utilized for
preparation of 2-alkyl-3-selanylindoles. Tosyl and nosyl anilines
were well tolerated under the chosen reaction conditions
providing corresponding 3-selanyl indoles in good yields (75 –
98%). However, (2,4-dinitrophenylsulfonyl), Boc and Bn protected
anilines were not suitable substrates, as well as dimethyl and
dibenzyl anilines. Remarkably, selenocysteinyl indoles 6n-p were
obtained in quantitative yield employing 50 equiv. of K2S2O8. Boc-
Sec moiety containing benzo[b]furans and indoles are without
doubt important building blocks that can be easily used for
synthesis of more sophisticated structures.
Scheme 2. 3-selanyl benzo[b]furan formation: scope and limitation studies.
Reaction conditions: a) 1. CuBr2 (1.5 equiv.), CH2Cl2, 40 °C; (2. TFA, CH2Cl2,
0 °C); b) K2S2O8 (5 equiv.), MeCN, rt; c) K2S2O8 (50 equiv.), MeCN, rt.
Although both methods for Sec electrophile generation provided
products in good yields and the substrate scope was quite broad,
obviously the main limitation of this reaction to be used for more
sophisticated peptides is the employment of protecting groups.
Consequently, we decided to test the reaction between Ts-aniline
5a and unprotected dipeptide Sec-Gly-OBn 3aa, although we did
not have high expectations. However, the reaction in the presence
of CuBr2 led to selective formation of corresponding 3-Sec-indole
due to protonation of amino group that prevented the formation of
Notably, selenoglutathione-benzo[b]furan conjugate 4e was
obtained from phenol 1d in 80% yield whereas the use of anisole
1c resulted in preparation of 4e in almost quantitative yield (98%).
Unfortunately, neither CuBr2, nor K2S2O8 was suitable for the
generation of respective sulfenyl electrophile from sulfur analogue
of 3b with consequent formation of glutathione containing
benzo[b]furan. Treatment of Boc-Sec with 1a in the presence of
CuBr2 or K2S2O8 (5 equiv.) led only to traces of the desired product
4f even after several days. However, increasing the amount of
oxidant up to 50 equiv. led to selective formation of 4f only in 16
hours providing the product in high yield. Product 4g was obtained
analogously, but in lower yield.
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10.1002/ejoc.201901548
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Scheme 3. Scope and limitation studies in synthesis of 3-selanylindoles. Reaction conditions: a) 1. CuBr2 (1.5 equiv.), CH2Cl2, 40 °C; (2. TFA, CH2Cl2, 0 °C); b)
K2S2O8 (5 equiv.), MeCN, rt; c) K2S2O8 (50 equiv.), MeCN, rt. 5a R1 = Ph, R2 = Ts, R = H; 5b R1 = Bu, R2 = Ts, R = H; 5c R1 = Ph, R2 = Ns, R = H; 5d R1 = Bu, R2 =
Ns, R = H; 5e R1 = Ph, R2 = (2,4-dinitrophenylsulphonyl), R = H; 5f R1 = Ph, R2 = Boc, R = H; 5g R1 = Bu, R2 = Boc, R = H; 5h R1 = Ph, R2 = R= Me; 5i R1 = Ph, R2
= R = Bn; 5j R1 = Ph, R2 = Bn, R = H.
complex with copper salt. Increase of temperature to 40 °C
provided the product 6r in very good yield (74%) (Scheme 4). The
product was also formed employing K2S2O8, however, with
considerably lower yield and formation of side products.
Next, the substrate scope was determined, and we found out that
only Ts-aniline 5a and anisole 1a were suitable substrates for
5-endo-dig cyclization. In both cases, the use of unprotected
dipeptide 3aa resulted in excellent yields, furthermore, they
exceeded the ones obtained employing protected dipeptide 3a.
This observation encouraged us to test more complex Sec
peptides. Unprotected selenoglutathione Glu-Sec-Gly-OBn 3ba
provided benzo[b]furan 4i and indole 6s in excellent yields (85%
and quantitative yield, correspondingly). Tetrapeptide dimer Tyr-
Sec-Gly-Phe-NH2 3ca that mimics the active site of glutathione
peroxidase32 (GPx-4) gave corresponding benzo[b]furan 4j in
quantitative yield. Tripeptide Sec-Lys-Phe-NH2 3da provided
benzo[b]furan 4k in lower yield due to complications in purification
process.
Next, we were interested to see whether it is possible to generate
selenium electrophile and perform cascade reaction due to the
attractive nature of such transformation. This route allows the
formation of multiple bonds in a single step providing polycyclic
structures. The main advantages of cascade reaction are atom
economy, short reaction time and less waste supporting the basic
principles of green chemistry. We chose to utilize anisole-
containing aryldiyne
7 for the construction of indeno[1,2-
c]chromene skeleton. Chromene moiety is often found in
biologically active natural products, furthermore, compounds
containing indeno[1,2-c]chromene core show high potential for
use in dye-sensitized photovoltaic cells.[34] Notably, only few
methods exist for the construction of indeno[1,2-c]chromene
moiety. Previously, TfOH mediated cascade reaction of anisole 7
has been performed for the synthesis of 6-phenylindeno[1,2-
[34]
c]chromene,
while halogen-mediated cascade reaction has
been reported by Chen et al. for the synthesis of halogenated 6-
phenylindeno[1,2-c]chromenes. [35]
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10.1002/ejoc.201901548
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Scheme 4. Preparation of benzo[b]furans and indoles employing unprotected Sec peptides. Reaction conditions: CuBr2 (2.5 equiv.), CH2Cl2/MeCN, 40 °C.
Initially, we tested the reaction of Ph2Se2 with 7 in the presence
of CuBr2. However, only 11-bromo-6-phenylindeno[1,2-
c]chromene was detected in the reaction mixture. Potassium
persulfate induced electrophile generation lead only to the traces
of the desired product even employing 50 equiv. of oxidant. Next,
we decided to test Bn2Se2. Fortunately, the reaction of Bn2Se2
The structure of 8a was unambiguously confirmed by x-ray
analysis (Figure 2, CCDC 1949753).Similarly, the use of peptides
3a and 3b led to the formation of Sec containing 6-
phenylindeno[1,2-c]chromenes as the major product. However,
complicated purification of products 8b and 8c was responsible f
or the low yield of products. Unfortunately, Boc-Sec was not
suitable substrate for this reaction. The plausible mechanism for
this transformation includes following steps: selanyl electrophile
coordinates to the more electron rich double bond forming
selenirenium cation I. Next, the other triple bond attacks the
selenirenium cation with the closure of indene cycle (intermediate
II). Methoxy group then attacks the carbocation giving cyclization
intermediate III that after demethylation provides the product 8.
Chen et al. [35] performed DFT studies to confirm the cyclization
path for o-methoxy aryldiynes and stated that the pathway for o-
amino, thio and carboxy substituents would be different due to the
nucleophilic attack of heteroatom to the coordinated triple bond.
with anisole
7 in the presence of K2S2O8 provided 11-
(benzylselanyl)-6-phenylindeno[1,2-c]chromene (8a) (Scheme 5).
Ph
RSe
R2Se2
O
Ph
8
OMe
7
OSO3Me
(RSe)2SO4
RSe
RSe
R
Se
Ph
O
Ph
O
OMe
Ph
Me
Me
SO42
I
II
III
O
OtBu
NHBoc
BnO
O
O
O
H
N
Ph
BnO
NHBoc
N
H
N
H
Se
O
O
Se
Se
O
Ph
O
O
Ph
Ph
8a 51%
8b 45%
8c 36%
Scheme 5. Plausible mechanism for cascade 5-endo/6-endo-dig cyclization.
Reaction conditions: K2S2O8 (5 equiv.), MeCN, rt.
Figure 2. ORTEP molecular structure of 8a
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10.1002/ejoc.201901548
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2M HCl and brine, dried over Na2SO4. After filtration and evaporation, the
residue was purified by flash chromatography (PE/EtOAc 10:1 – 3:1) to
give the title compound 5d (0.43 g, 69%) as yellow solid. 1H NMR (400
MHz, CDCl3) δ 8.24 (d, J = 8.9 Hz, 2H), 7.91 (d, J = 9.0 Hz, 2H), 7.60 (d,
J = 7.9, 1H), 7.30 – 7.21 (m, 3H), 7.07 (td, J = 7.6, 1.2 Hz, 1H), 2.38 (t, J
= 7.0 Hz, 2H), 1.60 – 1.51 (m, 2H), 1.49 – 1.37 (m, 2H), 0.96 (t, J = 7.3 Hz,
3H). 13C NMR (101 MHz, CDCl3) δ 150.4, 144.8, 136.4, 132.4, 129.2,
128.6, 125.6, 124.2, 120.9, 116.1, 98.4, 75.2, 30.7, 22.2, 19.3, 13.7. HRMS
(ESI/Q-TOF) m/z: [M+H]+ calcd for [C18H19N2O4S]+ 359.1066; found
359.1071.
Conclusions
Preparation of 2-aryl- as well as 2-alkyl-3-selanylbenzo[b]furans
and indoles by ring closure via 5-endo-dig cyclization employing
CuBr2 and K2S2O8 mediated generation of Sec electrophile was
presented. Copper(II) bromide is effective promoter for the
generation of Sec electrophile from protected and unprotected
peptides for the formation of 2-aryl-3-Sec-benzo[b]furans and
indoles up to quantitative yields. However, utilization of CuBr2 is
not suitable for preparation of 2-alkyl-3-Sec-benzo[b]furans and
indoles. Out of all tested oxidants, potassium persulfate is the top
choice for the Sec electrophile generation to provide both 2-alkyl-
and 2-aryl-3-Sec benzo[b]furans and indoles as well. Although the
reaction is rather slow and more than equimolar amount of oxidant
is required, the yields are excellent and superior to the ones
obtained by CuBr2 promoted reaction. Oxidant induced Sec
electrophile generation tolerated anilines with Ts and Ns
protecting groups whereas CuBr2 promoted cyclization tolerated
also Boc aniline. Moreover, based on optimized conditions
construction of indeno[1,2-c]chromene skeleton is possible. As a
result, the use of selenocystine containing peptides results in the
formation of Sec containing 6-phenylindeno[1,2-c]chromenes. To
sum up, the elaborated methods are efficient for the synthesis of
3-Sec-benzo[b]furans, indoles and indeno[1,2-c]chromenes
employing mild conditions, tolerating broad substrate scope and
providing products in good to excellent yields.
2,4-Dinitro-N-(2-(phenylethynyl)phenyl)benzenesulfonamide (5e)
To a solution of 2-(phenylethynyl)aniline (0.3 g, 1.55 mmol, 1 equiv.) in
CH2Cl2 (7 ml) pyridine (0.25 ml, 3.10 mmol, 2 equiv.) and 2,4-
dinitrobenzenesulfonyl chloride (0.51 g, 1.86 mmol, 1.2 equiv.) were added
at 0 °C. The reaction mixture was stirred for 16 h at room temperature,
then it was poured into ice water and extracted with CH2Cl2, washed with
2M HCl and brine, dried over Na2SO4. After filtration and evaporation, the
residue was purified by flash chromatography (PE/EtOAc 10:1 – 3:1) to
give the title compound 5e (0.34 g, 52%) as yellow solid. 1H NMR (400
MHz, CDCl3) δ 8.30 (dd, J = 8.6, 2.2 Hz, 1H), 8.18 (d, J = 2.2 Hz, 1H), 8.05
(s, 1H), 8.00 (d, J = 8.6 Hz, 1H), 7.62 (dd, J = 8.2, 1.2 Hz, 1H), 7.38 – 7.24
(m, 6H), 7.18 – 7.12 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 149.9, 148.1,
138.9, 135.8, 133.0, 132.5, 131.5, 130.0, 129.6, 128.8, 127.0, 126.8, 124.2,
121.6, 121.0 117.2, 96.1, 83.6, 77.5, 77.2, 76.8. HRMS (ESI/Q-TOF) m/z:
[M+H]+ calcd for [C20H14N3O6S]+ 424.0603; found 424.0592.
Preparation of Sec-peptide 3d
Benzyl
tert-butyl
((S)-6-(((S)-1-amino-1-oxo-3-phenylpropan-2-
yl)amino)-6-oxohexane-1,5-diyl)dicarbamate (9)
Experimental Section
To a solution of (S)-2-amino-3-phenylpropanamide hydrochloride (0.79 g,
3.94 mmol, 1.5 equiv.) in DMF (5 ml) at 0 °C was added NMM (0.58 ml,
5.26 mmol, 2 equiv.) and the mixture was stirred for 5 minutes. Then to the
reaction mixture was added a solution of N6-((benzyloxy)carbonyl)-N2-
(tert-butoxycarbonyl)-L-lysine (1 g, 2.63 mmol, 1 equiv.) in DMF (5 ml),
HOBt (0.402 g, 2.63 mmol, 1 equiv.) and EDC×HCl (1 g, 5.26 mmol, 2
equiv.). The reaction mixture was stirred at 0 °C for 10 minutes and at rt
for 2 hours. After evaporation, the residue was purified by reverse phase
chromatography (C-18, MeCN/H2O+AcOH 10-85%) to give the title
compound 9 (1.2 g, 87%) as white solid. 1H NMR (400 MHz, CD3OD) δ
7.39 – 7.15 (m, 10H), 5.07 (s, 2H), 4.63 (dd, J = 8.9, 5.4 Hz, 1H), 3.84 (dd,
J = 8.1, 5.8 Hz, 1H), 3.20 (dd, J = 13.9, 5.4 Hz, 1H), 3.06 (t, J = 6.9 Hz,
2H), 2.95 (dd, J = 13.8, 9.0 Hz, 1H), 1.58 – 1.47 (m, 2H), 1.46-1.34 (m,
11H), 1.30 – 1.12 (m, 2H). 13C NMR (101 MHz, CD3OD) δ 175.9, 175.0,
158.9, 158.2, 138.5, 138.4, 130.4, 129.5, 128.9, 128.8, 127.8, 80.9, 67.3,
56.8, 55.2, 41.3, 38.4, 32.7, 32.4, 30.5, 28.7, 23.8, 23.7, 14.4. HRMS
(ESI/Q-TOF) m/z: [M+H]+ calcd for [C28H39N4O6]+ 527.2870; found
527.2868.
Unless otherwise stated, all reagents were purchased from commercial
suppliers and used without further purification. Thin layer chromatography
(TLC) was performed using MERCK Silica gel 60 F254 plates and
visualized by UV (254 nm) fluorescence. ZEOCHEM silica gel (ZEOprep
60/35-70 microns – SI23501) was used for column chromatography. 1H,
13C and 77Se NMR36 spectra were recorded on a Bruker Avance Neo
spectrometer at 400, 101 and 76 MHz correspondingly at 298 K in CD3OD
or CDCl3. Dimethyl selenide was used as a standard. Infrared (IR) spectra
were recorded with a Prestige-21 FTIR spectrometer (Shimadzu, Kyoto,
Japan). HRMS were recorded on Waters Synapt GII Q-ToF UPLC/MS
system. Single crystals of 2a and 8a were investigated on a Rigaku
XtaLAB Synergy, Dualflex, HyPix diffractometer. The crystal was kept at
140.0(1) K during data collection. Using Olex2,36 the structure was solved
with the olex2.solve37 structure solution program using Charge Flipping
and refined with the ShelXL38 refinement package using Least Squares
minimization.
Boc-L-selenocystine,39 peptides 3a,b,c,25 2-(1-alkynyl)anisoles 1a,40 b,41
2-(1-alkynyl)phenols 1c,d,42 2-(1-alkynyl)anilines 5a-c,43 f,44 g,45 h,i,46 j,47
and 734 were prepared according to literature procedures.
Tert-butyl
(2-(trimethylsilyl)ethyl)
((S)-6-(((S)-1-amino-1-oxo-3-
phenylpropan-2-yl)amino)-6-oxohexane-1,5-diyl)dicarbamate (10)
To a solution of 9 (0.54 g, 1.02 mmol) in MeOH with few drops of AcOH
was added Pd/C (0.11 g, 0.09 mmol) and H2 was bubbled through the
mixture for 1 hour. The product was filtered, evaporated and dissolved in
a mixture of THF (2 ml) and saturated NaHCO3 (2 ml) and Teoc-OSu
(0.396 g, 1.53 mmol, 1.5 equiv.) was added. The resulting reaction mixture
was stirred for 2 hours, followed by evaporation. Residue was extracted
with EtOAc, and washed with brine yielding the title compound (0.4 g, 74%)
as white solid. 1H NMR (400 MHz, CD3OD) δ 7.36 – 7.12 (m, 5H), 4.64 (dd,
N-(2-(hex-1-yn-1-yl)phenyl)-4-nitrobenzenesulfonamide (5d)
To a solution of 2-(hex-1-yn-1-yl)aniline (0.3 g, 1.73 mmol, 1 equiv.) in
CH2Cl2 (7 ml) pyridine (0.28 ml, 3.46 mmol, 2 equiv.) and p-
nitrobenzenesulfonyl chloride (0.48 g, 2.08 mmol, 1.2 equiv.) were added
at 0 °C. The reaction mixture was stirred for 16 h at room temperature,
then it was poured into ice water and extracted with CH2Cl2, washed with
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901548
European Journal of Organic Chemistry
FULL PAPER
J = 8.8, 5.4 Hz, 1H), 4.18 – 4.07 (m, 2H), 3.86 (dd, J = 8.2, 5.7 Hz, 1H),
3.20 (dd, J = 13.9, 5.4 Hz, 1H), 3.03 (t, J = 7.0 Hz, 2H), 2.96 (dd, J = 13.9,
8.9 Hz, 1H), 1.59 – 1.47 (m, 2H), 1.46 – 1.35 (m, 11H), 1.30 – 1.13 (m,
2H), 1.03 – 0.93 (m, 2H), 0.05 (s, 9H). 13C NMR (101 MHz, CD3OD) δ
175.9, 175.0, 159.3, 158.2, 138.5, 130.4, 129.5, 127.8, 80.9, 63.7, 56.8,
55.2, 41.2, 38.4, 32.5, 30.6, 28.7, 23.9, 18.7, -1.4. HRMS (ESI/Q-TOF)
m/z: [M+H]+ calcd for [C26H45N4O6Si]+ 537.3108; found 537.3109.
Colorless crystals (104 mg, 83%). Prepared from Ph2Se2 (112 mg, 0.36
mmol), CuBr2 (97 mg, 0.43 mmol), and 1a (90 mg, 0.43 mmol). Crystallized
from petroleum ether – ethyl acetate. Melting point: 86-87 °C. 1H NMR (400
MHz, CDCl3) δ 8.22-8.16 (m, 2H), 7.56-7.10 (m, 12H).
3-(benzylselanyl)-2-phenylbenzofuran (2b)18
Yellow oil (64 mg, 60%). Prepared from Bn2Se2 (123 mg, 0.36 mmol),
CuBr2 (97 mg, 0.43 mmol), and 1a (90 mg, 0.43 mmol). 1H NMR (400 MHz,
CDCl3) δ 8.11 – 8.02 (m, 2H), 7.60 – 7.56 (m, 1H), 7.52 (m, 1H), 7.44 –
7.24 (m, 5H), 7.16 – 7.02 (m, 5H), 3.98 (s, 2H).
(12S,15S)-16-amino-15-benzyl-2,2-dimethyl-6,13,16-trioxo-5-oxa-
7,14-diaza-2-silahexadecan-12-aminium 4-methylbenzenesulfonate
(11)
2-phenyl-3-(phenyltellanyl)benzofuran (2c)18
To a solution of 10 (0.4 g, 0.75 mmol, 1 equiv.) in Et2O (7 ml) pTsOH (0.156
g, 0.82 mmol, 1.1 equiv.) was added and the mixture was stirred until full
dissolution and then it was evaporated and held at 40 °C for 4 hours. The
residue was purified by reverse phase chromatography (C-18, MeCN/H2O
10-85%) to give the title compound (220 mg, 51%) as white solid. 1H NMR
(400 MHz, CD3OD) δ 7.72 (d, J = 8.2 Hz, 2H), 7.32 – 7.16 (m, 7H), 4.64
(dd, J = 8.8, 6.0 Hz, 1H), 4.12 (t, J = 8.4 Hz, 2H), 3.82 (t, J = 6.3 Hz, 1H),
3.14 (dd, J = 13.9, 6.0 Hz, 1H), 3.08 (t, J = 6.9 Hz, 2H), 2.97 (dd, J = 13.9,
9.0 Hz, 1H), 2.37 (s, 3H), 1.90-1.76 (m, 2H), 1.54 – 1.44 (m, 2H), 1.44 –
1.31 (m, 2H), 1.02 – 0.93 (m, 2H), 0.05 (s, 8H). 13C NMR (101 MHz,
CD3OD) δ 175.5, 170.1, 159.4, 143.5, 141.7, 138.3, 130.3, 129.8, 129.5,
127.9, 127.0, 63.8, 56.1, 54.2, 41.1, 38.8, 32.3, 30.5, 22.9, 21.3, 18.7, -1.5.
HRMS (ESI/Q-TOF) m/z: [M+H]+ calcd for [C21H37N4O4Si]+ 437.2584;
found 437.2586.
Yellow oil (72 mg, 50%). Prepared from Ph2Te2 (148 mg, 0.36 mmol),
CuBr2 (97 mg, 0.43 mmol), and 1a (90 mg, 0.43 mmol). 1H NMR (400 MHz,
CDCl3) δ 8.15-8.10 (m, 2H), 7.57 – 7.52 (m, 2H), 7.50-7.42 (m, 5H), 7.38-
7.30 (m, 2H), 7.18 – 7.07 (m, 3H).
General procedure for preparation of 3-selanyl benzo[b]furans 4a-e
and indoles 6a-m.
Method A. To a solution of Sec-peptide 3 (1 equiv.) in CH2Cl2 CuBr2 (1.5
equiv.) was added and the mixture was stirred for 30 min at rt. Then a
solution of 2-(1-alkynyl)anisole/phenol/aniline (2 equiv.) in CH2Cl2 was
added. Reaction mixture was stirred for 16 h at 40 °C, and then it was
evaporated and purified by reverse phase chromatography (C-18,
MeCN/H2O 10-85%) to give the product.
Di-tert-butyl (2-(trimethylsilyl)ethyl) ((12S,15R,20R,23S)-23-(((S)-1-
amino-1-oxo-3-phenylpropan-2-yl)carbamoyl)-12-(((S)-1-amino-1-
oxo-3-phenylpropan-2-yl)carbamoyl)-2,2-dimethyl-6,14,21-trioxo-5-
oxa-17,18-diselena-7,13,22-triaza-2-silaheptacosane-15,20,27-
triyl)tricarbamate (3d)
Method B. To a solution of peptide 3a or 3b (1 equiv.) and 2-(1-
alkynyl)aniline/phenol/anisole (2 equiv.) in MeCN K2S2O8 (5 equiv.) was
added and the mixture was stirred for 3 days at rt. After evaporation the
mixture was purified by reverse phase chromatography (C-18, MeCN/H2O
10-85%) to give the product.
To a solution of 10 (200 mg, 0.33 mmol, 3 equiv.) in DMF (5 ml) NMM(0.05
ml, 0.45 mmol, 4 equiv.) was added and the mixture was stirred for 5
minutes at 0 °C. Then HOBt (34 mg, 0.22 mmol, 2 equiv.) was added
followed by the addition of solution of Boc-L-selenocystine (60 mg, 0.11
mmol, 1 equiv.) in DMF (3 ml) and EDC×HCl (87 mg, 0.45 mmol, 4 equiv.).
The reaction mixture was stirred for 10 minutes at 0 °C and additionally for
1 hour at rt, then it was evaporated and the residue was purified by reverse
phase chromatography (C-18, MeCN/H2O 10-85%) to give the title
compound (110 mg, 71%) as light yellow solid. 1H NMR (400 MHz,
CD3OD) δ 7.33 – 7.14 (m, 5H), 4.67 (t, J = 7.1 Hz, 1H), 4.48-4.43 (m, 2H),
4.11 (t, J = 8.3 Hz, 2H), 3.30-3.24 (m, 1H), 3.13 (dd, J = 14.0, 6.5 Hz, 1H),
3.04 (t, J = 6.9 Hz, 2H), 2.96 (dd, J = 13.7, 8.3 Hz, 1H), 1.77 – 1.51 (m,
2H), 1.50-1.37 (m, 11H), 1.39 – 1.22 (m, 2H), 1.03 – 0.92 (m, 2H), 0.04 (s,
9H). 13C NMR (101 MHz, CD3OD) δ 175.8, 173.8, 173.3, 159.2, 157.6,
138.3, 130.4, 129.5, 127.8, 80.9, 63.7, 56.2, 55.7, 54.9, 41.4, 39.1, 33.5,
33.0, 30.5, 28.8, 23.9, 18.7, -1.4. HRMS (ESI/Q-TOF) m/z: [M+H]+ calcd
for [C58H97N10O14Se2Si2]+ 1373.5055; found 1373.5100.
Boc and tBu cleavage. To a solution of protected peptide in CH2Cl2 TFA at
0 °C was added. Reaction mixture was stirred until disappearance of
starting material (1-3 hours). After evaporation the mixture was purified by
reverse phase chromatography (C-18, MeCN/H2O 10-80%).
Benzyl (R)-(2-((tert-butoxycarbonyl)amino)-3-((2-phenylbenzofuran-
3-yl)selanyl)propanoyl)glycinate (4a)
White solid. Prepared by method A in 62% yield from 3a (100 mg, 0.12
mmol), CuBr2 (40 mg, 0.18 mmol), alkyne 1a (50 mg, 0.24 mmol), CH2Cl2
(5 ml). Prepared by method B from 3a (100 mg, 0.12 mmol), K2S2O8
(165 mg, 0.61 mmol), alkyne 1a 50 mg, 0.24 mmol) or alkyne 1b (47 mg,
0.24 mmol, MeCN (4 ml) in 95% (70 mg) or 85% (63 mg) yield,
correspondingly. NMR spectra presented in SI are from product obtained
20
by method B using alkyne 1a. [α]D -9.0 (c 0.96, CHCl3). IR νmax (film):
General procedure for CuBr2 promoted cyclization of diorganyl
dichalcogenide and 2-(phenylethynyl)anisole (1a)
3064, 2978, 2933, 1751, 1686, 1517, 1253, 1178. 1H NMR (400 MHz,
CDCl3) δ 8.21 – 8.10 (m, 2H), 7.61 – 7.52 (m, 1H), 7.45 – 7.32 (m, 3H),
7.32 – 7.13 (m, 8H), 6.64 (s, 1H), 5.14 (d, J = 8.2 Hz, 1H), 5.04 (s, 2H),
4.25 (s, 1H), 3.77 (qt, J = 18.3, 2.7 Hz, 2H), 3.12 (m, 1H), 2.99 (dd, J =
12.6, 5.7 Hz, 1H), 1.22 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 170.7, 169.3,
156.1, 155.4, 153.9, 135.2, 132.0, 130.2, 129.3, 128.7, 128.6, 128.4, 127.8,
125.3, 123.5, 120.8, 111.3, 100.0, 80.5, 67.2, 54.3, 41.4, 29.7, 28.2. 77Se
(76 MHz, CDCl3) δ 68.1. HRMS (ESI/Q-TOF) m/z: [M+H]+ calcd for
[C31H33N2O6Se]+ 609.1504; found 609.1501.
CuBr2 (1.2 equiv.) was added to a solution of diorganyl dichalcogenide (1
equiv.) in CH2Cl2 and the mixture was stirred for 30 min at rt. Then a
solution of 1a (1.2 equiv.) in CH2Cl2 was added. Reaction mixture was
stirred for 16 h at 40 °C, and then it was evaporated and purified by flash
chromatography (petroleum ether/ethyl acetate 10:0-4:1) to give 2a-c.
2-phenyl-3-(phenylselanyl)benzofuran (2a)18
(R)-1-((2-(benzyloxy)-2-oxoethyl)amino)-1-oxo-3-((2-phenylbenzo-
furan-3-yl)selanyl)propan-2-aminium trifluoroacetate (4b)
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901548
European Journal of Organic Chemistry
FULL PAPER
Yellow solid (50 mg, 68%). Prepared by method A from 3a (100 mg, 0.12
mmol), CuBr2 (40 mg, 0.18 mmol), alkyne 1b (71 mg, 0.24 mmol), CH2Cl2
(5 ml). Product was isolated after Boc deprotection. [α]D20 +5.2 (c 1.2,
MeOH). IR νmax (film): 3064, 3031, 2934, 1748, 1674, 1668, 1662, 1512,
1192, 1189. 1H NMR (400 MHz, CD3OD) δ 8.30 – 8.22 (m, 2H), 7.75 –
7.68 (m, 1H), 7.60 – 7.48 (m, 2H), 7.46 – 7.37 (m, 1H), 7.37 – 7.28 (m, 7H),
5.12 (s, 2H), 3.76 (s, 2H), 3.41 (dd, J = 7.3, 5.2 Hz, 1H), 3.12 (dd, J = 12.3,
5.2 Hz, 1H), 2.98 (dd, J = 12.3, 7.3 Hz, 1H). 13C NMR (101 MHz, CD3OD)
δ 175.8, 170.9, 157.5, 155.3, 137.1, 133.4, 131.6, 130.3, 129.6, 129.5,
129.4, 128.8, 126.5, 124.6, 122.0, 112.1, 101.0, 67.9, 55.9, 49.6, 49.4,
49.2, 49.0, 48.8, 48.6, 48.4, 41.9, 34.3. 77Se NMR (76 MHz, CD3OD) δ
59.5. HRMS (ESI/Q-TOF) m/z: [M+H]+ calcd for [C26H25N2O4Se]+
509.0980; found 509.0989.
2.35-2.20 (m, 2H), 2.10-2.00 (m, 1H), 1.88 – 1.78 (m, 1H), 1.71 (p, J = 7.5
Hz, 2H), 1.51 – 1.34 (m, 22H), 0.95 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz,
CD3OD) δ 174.8, 173.3, 170.8, 164.3, 155.8, 137.1, 132.2, 129.6, 129.34,
129.31, 128.3, 128.0, 125.3, 124.2, 121.2, 111.8, 82.8, 80.6, 67.9, 65.2,
55.4, 55.0, 42.1, 41.8, 33.1, 31.6, 28.8, 28.5, 28.3, 27.9, 23.4, 14.2. 77Se
(76 MHz, CD3OD) δ 62.9. HRMS (ESI/Q-TOF) m/z: [M+Na]+ calcd for
[C38H51N3O9SeNa]+ 796.2688; found 796.2698.
Benzyl (R)-(2-((tert-butoxycarbonyl)amino)-3-((2-phenyl-1-tosyl-1H-
indol-3-yl)selanyl)propanoyl)glycinate (6a)
Yellow solid (40 mg, 87%). Prepared by method A from 3a (50 mg, 0.06
mmol), CuBr2 (20.2 mg, 0.09 mmol), alkyne 5a (41.9 mg, 0.12 mmol),
CH2Cl2 (5 ml). [α]D20 -13.1 (c 1.1, MeOH). IR νmax (film): 2982, 2931, 1669,
1448, 1369, 1177, 1091. 1H NMR (400 MHz, CD3OD) δ 8.28 (d, J = 8.3 Hz,
1H), 7.64 (d, J = 7.8 Hz, 1H), 7.49 – 7.24 (m, 13H), 7.15 (d, J = 8.2 Hz,
2H), 5.10 (s, 2H), 4.05 – 3.95 (m, 1H), 3.76 (s, 2H), 2.83 (dd, J = 12.5, 5.1
Benzyl
(R)-(2-amino-3-((2-butylbenzofuran-3-
yl)selanyl)propanoyl)glycinate (4c)
White solid. Prepared by method B from 3a (100 mg, 0.12 mmol), K2S2O8
(165 mg, 0.61 mmol), alkyne 1c (45 mg, 0.24 mmol) or alkyne 1d (42 mg,
0.24 mmol, MeCN (4 ml) in 95% (67 mg) and 87% (62 mg) yield,
correspondingly. [α]D20 -23.0 (c 1.1, CHCl3).IR νmax (film): 3322, 2958, 2930,
1752, 1685, 1523, 1452, 1367, 1251, 1171. 1H NMR (400 MHz, CD3OD) δ
7.58 – 7.53 (m, 1H), 7.46 – 7.40 (m, 1H), 7.37 – 7.18 (m, 7H), 5.13 (s, 2H),
4.14 (dd, J = 9.5, 4.5 Hz, 1H), 3.89 (d, J = 5.7 Hz, 2H), 3.11 (dd, J = 12.8,
4.5 Hz, 1H), 2.99 (td, J = 7.4, 5.4 Hz, 2H), 2.90 – 2.77 (m, 1H), 1.72 (q, J
= 7.6 Hz, 2H), 1.43 (s, 8H), 1.40 – 1.26 (m, 4H), 0.96 (t, J = 7.4 Hz, 3H).
13C NMR (101 MHz, CD3OD) δ 173.9, 170.8, 164.3, 157.5, 155.8, 137.1,
132.2, 129.5, 129.3, 125.2, 124.2, 121.1, 111.8, 100.8, 80.9, 67.9, 56.1,
42.1, 31.6, 30.3, 28.7, 27.9, 23.3, 14.2. 77Se (76 MHz, CD3OD) δ 58.2.
HRMS (ESI/Q-TOF) m/z: [M+H]+ calcd for [C29H37N2O6Se]+ 589.1817;
found 589.1813.
Hz, 1H), 2.69 (dd, J = 12.5, 8.2 Hz, 1H), 2.27 (s, 3H), 1.42-22 (m, 9H). 13
C
NMR (101 MHz, CD3OD) δ 173.4, 170.6, 157.1, 146.8, 145.3, 138.4, 137.1,
136.4, 133.6, 133.2, 132.6, 130.7, 130.1, 129.5, 129.32, 129.29, 128.3,
127.9, 126.6, 125.6, 122.2, 117.0, 111.1, 80.9, 67.9, 55.9, 42.0, 30.0, 28.7,
21.5. 77Se NMR (76 MHz, CD3OD)δ86.3. HRMS (ESI/Q-TOF) m/z: [M+H]+
calcd for [C38H40N3O7SSe]+ 762.1752; found 762.1741.
Benzyl
(R)-(2-((tert-butoxycarbonyl)amino)-3-((2-butyl-1-tosyl-1H-
indol-3-yl)selanyl)propanoyl)glycinate (6b)
Yellow oil (67 mg, 75%). Prepared by method B from 3a (100 mg, 0.12
mmol), K2S2O8 (165 mg, 0.61 mmol), alkyne 5b (80 mg, 0.24 mmol),
MeCN (5 ml). [α]D20 -10°.2 (c 1.12, CHCl3). IR νmax (film): 2959, 2931, 1750,
1686, 1455, 1368, 1173. 1H NMR (400 MHz, CD3OD) δ 8.09 – 8.03 (m,
1H), 7.61 (d, J = 8.4 Hz, 2H), 7.58 – 7.53 (m, 1H), 7.35 – 7.19 (m, 9H),
5.11 (s, 2H), 4.00 (dd, J = 10.0, 4.4 Hz, 1H), 3.86 (s, 2H), 3.36 – 3.32 (m,
2H), 3.08 (dd, J = 12.6, 4.5 Hz, 1H), 2.76 (dd, J = 12.6, 9.9 Hz, 1H), 2.24
(s, 3H), 1.75-1.55 (m, 2H), 1.51 – 1.28 (m, 12H), 0.95 (t, J = 7.3 Hz, 3H).
13C NMR (101 MHz, CD3OD) δ 173.9, 170.7, 157.5, 148.0, 146.6, 138.1
137.0, 136.7, 133.4, 131.1, 129.5, 129.31, 129.26, 127.4, 125.7, 125.2,
121.5, 116.1, 108.8, 80.9, 67.9, 55.7, 42.1, 34.8, 30.3, 29.3, 28.8, 23.7,
21.5, 14.3. 77Se (76 MHz, CD3OD) δ 68.6. HRMS (ESI/Q-TOF) m/z:
[M+Na]+ calcd for [C36H43N3O7SeSNa]+ 764.1885; found 764.1893.
Tert-butyl
N5-((R)-1-((2-(benzyloxy)-2-oxoethyl)amino)-1-oxo-3-((2-
phenylbenzofuran-3-yl)selanyl)propan-2-yl)-N2-(tert-
butoxycarbonyl)-L-glutaminate (4d)
Yellow solid. Prepared by method A from 3b (100 mg, 0.083 mmol), CuBr2
(28 mg, 0.12 mmol), alkyne 1c (35 mg, 0.167 mmol) or alkyne 1d (49 mg,
0.167 mmol), CH2Cl2 (5 ml) in 98% (65 mg) or 91% (60 mg) yield,
correspondingly. IR νmax (film): 3295, 3069, 2978, 2933, 1734, 1653, 1646,
1517, 1455, 1368, 1253, 1154. 1H NMR (400 MHz, CD3OD) δ 8.29 – 8.22
(m, 2H), 7.71 – 7.65 (m, 1H), 7.57 – 7.24 (m, 12H), 5.10 (s, 2H), 4.43 (dd,
J = 9.2, 5.1 Hz, 1H), 3.92 (dd, J = 9.4, 4.7 Hz, 1H), 3.81 (d, J = 2.4 Hz, 2H),
3.25 (dd, J = 12.6, 5.1 Hz, 1H), 2.97 (dd, J = 12.6, 9.1 Hz, 1H), 2.24 – 2.11
(m, 1H), 2.08 – 1.87 (m, 2H), 1.81 – 1.67 (m, 1H), 1.54 – 1.37 (m, 18H).
13C NMR (101 MHz, CD3OD) δ 174.6, 173.3, 173.0, 170.7, 158.1, 157.5,
155.3, 137.1, 133.4, 131.6, 130.3, 129.6, 129.5, 129.3, 128.9, 126.4, 124.6,
122.0, 112.1, 100.8, 82.8, 80.5, 67.9, 55.4, 54.8, 49.4, 42.1, 32.8, 29.8,
28.8, 28.3. 77Se NMR (76 MHz, CD3OD) δ 82.1. HRMS (ESI/Q-TOF) m/z:
[M+H]+ calcd for [C40H49N3O9Se]+ 794.2556; found 794.2559.
(R)-1-((2-(benzyloxy)-2-oxoethyl)amino)-3-((1-((4-
nitrophenyl)sulfonyl)-2-phenyl-1H-indol-3-yl)selanyl)-1-oxopropan-2-
aminium 2,2,2-trifluoroacetate (6c)
Yellow oil (87 mg, 78%). Prepared by method A from 3a (80 mg, 0.1 mmol),
CuBr2 (32.3 mg, 0.16 mmol), alkyne 5c (73 mg, 0.19 mmol), CH2Cl2 (5 ml).
Product was isolated after Boc deprotection. [α]D20 -4.2 (c 1.2, MeOH). IR
νmax (film): 3109, 3028, 1748, 1683, 1532, 1349, 1184, 1088. 1H NMR (400
MHz, CD3OD) δ 8.29 (d, J = 8.2 Hz, 1H), 8.22 (d, J = 8.9 Hz, 2H), 7.73 –
7.63 (m, 3H), 7.54 – 7.37 (m, 7H), 7.32 (s, 5H), 5.12 (s, 2H), 3.70 (d, J =
2.6 Hz, 2H), 3.20 – 3.02 (m, 1H), 2.88 (dd, J = 12.2, 4.5 Hz, 1H), 2.73 –
2.57 (m, 1H). 13C NMR (101 MHz, CD3OD) δ 170.8, 152.3, 145.3, 143.8,
138.3, 137.1, 133.8, 133.2, 132.3, 130.4, 129.6, 129.39, 129.36, 128.6,
127.2, 126.3, 125.4, 122.5, 117.0, 112.3, 67.9, 41.9. 77Se NMR (76 MHz,
Tert-butyl
N5-((R)-1-((2-(benzyloxy)-2-oxoethyl)amino)-3-((2-
butylbenzofuran-3-yl)selanyl)-1-oxopropan-2-yl)-N2-(tert-
butoxycarbonyl)-L-glutaminate (4e)
Yellow oil. Prepared by method A from 3b (100 mg, 0.083 mmol), CuBr2
(28 mg, 0.12 mmol), alkyne 1c (32 mg, 0.17 mmol) or alkyne 1d (29 mg,
0.17 mmol), CH2Cl2 (5 ml) in 98% (63 mg) or 80% (51 mg) yield,
correspondingly. IR νmax (film): 3295, 2977, 2932, 1718, 1646, 1529, 1452,
1367, 1250, 1155. 1H NMR (400 MHz, CD3OD) δ 7.56 – 7.51 (m, 1H), 7.44
– 7.40 (m, 1H), 7.36 – 7.21 (m, 7H), 5.12 (s, 2H), 4.42 (dd, J = 9.4, 4.8 Hz,
1H), 3.98 (dd, J = 9.2, 4.9 Hz, 1H), 3.87 (d, J = 1.2 Hz, 2H), 3.13 (dd, J =
12.7, 4.8 Hz, 1H), 2.96 (t, J = 7.6 Hz, 2H), 2.86 (dd, J = 12.7, 9.5 Hz, 1H),
CDCl3)
δ
332.5. HRMS (ESI/Q-TOF) m/z: [M+H]+ calcd for
[C32H29N4O7SSe]+ 693.0922; found 693.0934.
Benzyl
(R)-(2-((tert-butoxycarbonyl)amino)-3-((2-butyl-1-((4-
nitrophenyl)sulfonyl)-1H-indol-3-yl)selanyl)propanoyl)glycinate (6d)
Yellow oil (90 mg, 95%). Prepared by method B from 3a (100 mg, 0.12
mmol), K2S2O8 (165 mg, 0.61 mmol), alkyne 5d (80 mg, 0.24 mmol),
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901548
European Journal of Organic Chemistry
FULL PAPER
MeCN (5 ml). [α]D20 +5.1 (c 1.06, CHCl3). IR νmax (film): 2960, 2931, 1749,
1684, 1539, 1179. 1H NMR (400 MHz, CD3OD) δ 8.21 (d, J = 8.8 Hz, 2H),
8.07 (d, J = 7.9 Hz, 1H), 7.96 – 7.91 (m, 2H), 7.54 (d, J = 7.1 Hz, 1H), 7.34-
7.22 (m, 8H), 5.11 (s, 2H), 3.85 (s, 2H), 3.75 (dd, J = 10.4, 4.2 Hz, 1H),
3.38-3.32 (m, 2H), 3.06 (dd, J = 12.8, 4.2 Hz, 1H), 2.68 (dd, J = 12.8, 10.4
Hz, 1H), 1.82-1.70 (m, 1H), 1.67-1.58 (m, 1H), 1.51 – 1.33 (m, 12H), 1.33
– 1.25 (m, 1H), 0.96 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CD3OD) δ
173.7, 170.7, 157.6, 152.2, 148.2, 143.9, 138.1, 137.0, 133.5, 129.5,
129.27, 129.26, 129.0, 126.3, 126.0, 125.8, 121.9, 116.3, 110.3, 80.9, 67.9,
55.5, 42.1, 34.7, 29.9, 29.5, 28.8, 23.6, 14.3. 77Se (76 MHz, CD3OD) δ
74.9. HRMS (ESI/Q-TOF) m/z: [M+Na]+ calcd for [C35H40N4O9SeSNa]+
795.1579; found 795.1579.
71.4. HRMS (ESI/Q-TOF) m/z: [M+Na]+ calcd for [C45H58N4O10SeSNa]+
949.2937; found 949.2926.
(S)-4-(((R)-1-((2-(benzyloxy)-2-oxoethyl)amino)-3-((1-((4-
nitrophenyl)sulfonyl)-2-phenyl-1H-indol-3-yl)selanyl)-1-oxopropan-2-
yl)amino)-1-carboxy-4-oxobutan-1-aminium trifluoroacetate (6l)
Yellow solid (30 mg, 89%). Prepared by method A from 3b (50 mg, 0.042
mmol), CuBr2 (14.0 mg, 0.06 mmol), alkyne 5c (39.4 mg, 0.10 mmol),
CH2Cl2 (5 ml). Product was isolated after Boc deprotection. IR νmax (film):
3062, 3028, 2932, 1744, 1653, 1532, 1349, 1184. 1H NMR (400 MHz,
CD3OD) δ 8.32 (d, J = 8.1 Hz, 1H), 8.25 (d, J = 8.8 Hz, 2H), 7.67 (dd, J =
8.0, 3.7 Hz, 3H), 7.59 – 7.25 (m, 12H), 5.14 (s, 2H), 4.06 (d, J = 9.3 Hz,
1H), 3.79 (s, 2H), 3.55 (s, 1H), 3.03 (dd, J = 12.6, 4.4 Hz, 1H), 2.72 – 2.60
(m, 1H), 2.35 (s, 2H). Due to low solubility of 6l only 1H NMR spectra was
acquired. HRMS (ESI/Q-TOF) m/z: [M+H]+ calcd for [C37H36N5O10SSe]+
822.1348; found 822.1346.
(R)-1-((2-(benzyloxy)-2-oxoethyl)amino)-1-oxo-3-((2-phenyl-1H-indol-
3-yl)selanyl)propan-2-aminium 2,2,2-trifluoroacetate (6f)
Yellow oil (45 mg, 62%). Prepared by method A from 3a (100 mg, 0.12
mmol), CuBr2 (40.4 mg, 0.18 mmol), alkyne 5f (71 mg, 0.24 mmol), CH2Cl2
(5 ml). Product was isolated after Boc deprotection. [α]D20 +6.3 (c 1, MeOH).
1H NMR (400 MHz, CD3OD) δ 8.31 – 8.23 (m, 2H), 7.75 – 7.65 (m, 1H),
7.59 – 7.27 (m, 11H), 5.12 (s, 2H), 3.76 (s, 2H), 3.45-3.36 (m, 1H), 3.12
(dd, J = 12.2, 5.0 Hz, 1H), 2.98 (dd, J = 12.3, 7.2 Hz, 1H). 13C NMR (101
MHz, CD3OD) δ 170.9, 157.4, 155.3, 137.1, 133.4, 131.6, 130.3, 129.6,
129.5, 129.3, 128.8, 126.4, 124.6, 122.0, 112.1, 101.0, 67.9, 42.0. 77Se
NMR (76 MHz, CD3OD) δ 59.5. ESI-MS m/z: 508.20 [M+H]+. Elemental
analysis calculated for C26H25N3O3Se ´ TFA ´ 1.3H2O: C, 52.30; H, 4.48;
N, 6.53; found: C, 52.39; H, 4.57; N, 6.38.
Tert-butyl
N5-((R)-1-((2-(benzyloxy)-2-oxoethyl)amino)-1-oxo-3-((2-
phenyl-1H-indol-3-yl)selanyl)propan-2-yl)-N2-(tert-butoxycarbonyl)-l-
glutaminate (6m)
Yellow oil (49 mg, 75%). Prepared by method A from 1c (100 mg, 0.083
mmol), CuBr2 (28.4 mg, 0.124 mmol), alkyne 5f (49 mg, 0.167 mmol),
CH2Cl2 (5 ml). IR νmax (film): 3295, 2977, 2934, 1743, 1645, 1534, 1455,
1367, 1253, 1175, 1172, 1154. 1H NMR (400 MHz, CD3OD) δ 8.30 – 8.21
(m, 2H), 7.67 (dd, J = 7.7, 1.4 Hz, 1H), 7.57 – 7.46 (m, 3H), 7.45 – 7.39
(m, 1H), 7.39 – 7.26 (m, 7H), 5.10 (s, 2H), 4.43 (dd, J = 9.0, 5.0 Hz, 1H),
3.93 (d, J = 4.7 Hz, 1H), 3.80 (d, J = 2.5 Hz, 2H), 3.24 (dd, J = 12.6, 5.1
Hz, 1H), 2.97 (dd, J = 12.6, 9.1 Hz, 1H), 2.24 – 2.13 (m, 1H), 2.08 – 1.89
(m, 2H), 1.80 – 1.67 (m, 1H), 1.45 (d, J = 8.0 Hz, 18H). 13C NMR (101 MHz,
CD3OD) δ 174.6, 173.3, 173.0, 170.7, 158.1, 157.5, 155.3, 137.1, 133.4,
131.6, 130.3, 129.6, 129.5, 129.33, 129.30, 128.9, 126.4, 124.6, 122.0,
112.1, 100.8, 82.8, 80.5, 67.9, 55.4, 54.8, 42.4, 32.8, 29.8, 28.8, 28.3. 77Se
NMR (76 MHz, CD3OD) δ 82.0. HRMS (ESI/Q-TOF) m/z: [M+H]+ calcd for
[C40H49N4O8Se]+ 793.2716; found 794.2537.
Tert-butyl
N5-((R)-1-((2-(benzyloxy)-2-oxoethyl)amino)-1-oxo-3-((2-
phenyl-1-tosyl-1H-indol-3-yl)selanyl)propan-2-yl)-N2-(tert-
butoxycarbonyl)-L-glutaminate (6j)
Yellow oil (76 mg, 90%). Prepared by method A from 3b (100 mg, 0.082
mmol), CuBr2 (27.8 mg, 0.13 mmol), alkyne 5a (87 mg, 0.24 mmol), CH2Cl2
(5 ml). IR νmax (film): 3306, 2 978, 2933, 1739, 1654, 1517, 1368, 1178,
1090. 1H NMR (400 MHz, CD3OD) δ 8.28 (d, J = 8.3 Hz, 1H), 7.64 (d, J =
7.7, 1H), 7.50 – 7.27 (m, 16H), 7.16 (d, J = 8.1 Hz, 2H), 5.11 (s, 2H), 4.23-
4.11 (m, 1H), 3.98-3.90 (m, 1H), 3.76 (d, J = 3.8 Hz, 2H), 2.91 (dd, J =
12.5, 5.4 Hz, 1H), 2.65 (dd, J = 12.5, 8.8 Hz, 1H), 2.29 (s, 3H), 2.20 – 2.09
(m, 1H), 2.09 – 1.98 (m, 1H), 1.98 – 1.91 (m, 1H), 1.80 – 1.70 (m, 1H),
1.46 (m, 18H). 13C NMR (101 MHz, CD3OD) δ 174.5, 173.3, 172.9, 170.7,
158.1, 146.8, 145.6, 138.5, 137.1, 136.3, 133.6, 133.3, 132.6, 130.7, 130.1,
129.6, 129.34, 129.31, 128.3, 127.9, 126.7, 125.7, 122.2, 117.0, 110.9,
82.8, 80.5, 67.9, 55.4, 54.6, 49.4, 42.0, 32.8, 29.2, 28.8, 28.3, 21.5. 77Se
(76 MHz, CD3OD) δ 89.4. HRMS (ESI/Q-TOF) m/z: [M+H]+ calcd for
[C47H55N4O10SSe]+ 947.2804; found 947.2789.
General procedure for preparation of Boc-Sec containing
benzo[b]furans 4f,g and indoles 6n-p.
To a solution of Boc-Sec (100 mg, 0.187 mmol, 1 equiv.) and 2-(1-
alkynyl)aniline/phenol/anisole (0.28 mmol, 1.5 equiv.) in MeCN (10 ml)
K2S2O8 (2.53 g, 9.36 mmol, 50 equiv.) was added and the mixture was
stirred for 16 hours at rt. After filtration and evaporation, the mixture was
purified by reverse phase chromatography (C-18, MeCN/H2O 10-85%) to
give the product.
Tert-butyl N5-((R)-1-((2-(benzyloxy)-2-oxoethyl)amino)-3-((2-butyl-1-
tosyl-1H-indol-3-yl)selanyl)-1-oxopropan-2-yl)-N2-(tert-
butoxycarbonyl)-L-glutaminate (6k)
(R)-2-((tert-butoxycarbonyl)amino)-3-((2-phenylbenzofuran-3-
yl)selanyl)propanoic acid (4f).
White solid (76 mg, 88%). Prepared from alkyne 1a (58 mg). [α]D20 +24.2
(c 1.0, CHCl3). 1H NMR (400 MHz, CD3OD) δ 8.31 – 8.25 (m, 2H), 7.70 –
7.65 (m, 1H), 7.54 – 7.44 (m, 3H), 7.43 – 7.37 (m, 1H), 7.37 – 7.28 (m, 2H),
4.25 (dd, J = 8.0, 4.4 Hz, 1H), 3.34 – 3.26 (m, 1H, overlaps with CD3OD
signal), 3.08 (dd, J = 12.5, 8.0 Hz, 1H), 1.37-1.17 (m, 9H). 13C NMR (101
MHz, CD3OD) δ 174.0, 157.3, 157.2, 155.3, 133.4, 131.6, 130.2, 129.5,
128.7, 126.3, 124.5, 121.9, 112.1, 100.8, 80.6, 55.3, 30.1, 28.6. 77Se (76
Yellow oil (37 mg, 98%). Prepared by method B from 3b (50 mg, 0.04
mmol), K2S2O8 (56 mg, 0.21 mmol), alkyne 5b (27 mg, 0.08 mmol), MeCN
(4 ml). IR νmax (film): 2971, 2931, 1662, 1457, 1369, 1172. H NMR (400
1
MHz, CD3OD) δ 8.09 – 8.05 (m, 1H), 7.67 – 7.61 (m, 2H), 7.59 – 7.53 (m,
1H), 7.37 – 7.23 (m, 10H), 5.12 (s, 2H), 4.37 – 4.28 (m, 1H), 4.04 – 3.98
(m, 1H), 3.87 (s, 2H), 3.10 (dd, J = 12.6, 4.8 Hz, 1H), 2.80 (dd, J = 12.6,
9.7 Hz, 1H), 2.34-2.23 (m, 5H), 2.13-2.02 (m, 1H), 1.96 – 1.84 (m, 1H),
1.75-1.57 (m, 2H), 1.51 – 1.37 (m, 20H), 1.32-1.25 (m, 1H), 0.96 (t, J = 7.4
Hz, 3H). 13C NMR (101 MHz, CD3OD) δ 174.8, 173.3, 173.1, 170.7, 158.1,
147.9, 146.7, 138.1, 137.1, 136.8, 133.4, 131.1, 129.6, 129.34, 129.29,
127.5, 125.8, 125.3, 121.5, 116.2, 108.9, 82.8, 80.6, 67.9, 55.4, 54.5, 42.1,
34.7, 33.1, 29.4, 28.8, 28.3, 23.7, 21.5, 14.3. 77Se (76 MHz, CD3OD) δ
MHz, CD3OD)
[C22H22NO5Se]- 460.0663; found 460.0677.
δ
83.9. HRMS (ESI/Q-TOF) m/z: [M-H]- calcd for
(R)-2-((tert-butoxycarbonyl)amino)-3-((2-butylbenzofuran-3-
yl)selanyl)propanoic acid (4g).
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901548
European Journal of Organic Chemistry
FULL PAPER
Light yellow oil (40 mg, 50%). Prepared from alkyne 1d (46 mg, 0.24 mmol).
[α]D20 +14.1 (c 1.1, CHCl3). 1H NMR (400 MHz, CD3OD) δ 7.59 – 7.53 (m,
1H), 7.45 – 7.39 (m, 1H), 7.29 – 7.22 (m, 2H), 4.19 (dd, J = 8.4, 4.4 Hz,
1H), 3.21 (dd, J = 12.6, 4.4 Hz, 1H), 3.03 – 2.88 (m, 3H), 1.73 (p, J = 7.4
Hz, 2H), 1.49 – 1.25 (m, 11H), 0.96 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz,
CD3OD) δ 174.1, 164.2, 157.5, 155.8, 132.1, 125.2, 124.2, 121.1, 111.8,
100.7, 80.6, 55.3, 31.6, 29.6, 28.6, 27.9, 23.3, 22.1, 14.2. 77Se (76 MHz,
CD3OD) δ 59.0. HRMS (ESI/Q-TOF) m/z: [M-H]- calcd for [C20H26NO5Se]-
440.0976; found 440.0982.
reverse phase chromatography (C-18, MeCN/H2O+HCl 10-85%) to give
the desired product.
Benzyl
(R)-(2-amino-3-((2-phenylbenzofuran-3-
yl)selanyl)propanoyl)glycinate (4h)
White solid (53 mg, 89%). Prepared from 3a (90 mg, 0.11 mmol), CuBr2
(61 mg, 0.27 mmol), alkyne 1a (34 mg, 0.16 mmol), CH2Cl2 (4 ml), MeCN
(1 ml). 1H NMR (400 MHz, CD3OD) δ 8.26 – 8.19 (m, 2H), 7.77 – 7.69 (m,
1H), 7.60 – 7.26 (m, 11H), 5.11 (s, 2H), 4.04 (t, J = 6.2 Hz, 1H), 3.73 (d, J
= 17.8 Hz, 1H), 3.51 (d, J = 17.8 Hz, 1H), 3.28-3.21 (m, 2H).
(R)-2-((tert-butoxycarbonyl)amino)-3-((2-phenyl-1-tosyl-1H-indol-3-
yl)selanyl)propanoic acid (6n).
(S)-4-(((R)-1-((2-(benzyloxy)-2-oxoethyl)amino)-1-oxo-3-((2-
phenylbenzofuran-3-yl)selanyl)propan-2-yl)amino)-1-carboxy-4-
oxobutan-1-aminium chloride (4i)
20
Light yellow solid (115 mg, quant.). Prepared from alkyne 5a (97 mg). [α]D
+12.7 (c 0.93, CHCl3). 1H NMR (400 MHz, CD3OD) δ 8.28 (d, J = 8.3 Hz,
1H), 7.65 (d, J = 7.6 Hz, 1H), 7.51 – 7.26 (m, 9H), 7.15 (d, J = 8.1 Hz, 2H),
4.09-4.01 (m, 1H), 2.95 (dd, J = 12.6, 4.5 Hz, 1H), 2.76 (dd, J = 12.6, 7.6
Hz, 1H), 2.29 (s, 3H), 1.39-1.20 (m, 9H). 13C NMR (101 MHz, CD3OD) δ
173.7, 157.1, 146.7, 145.3, 138.6, 136.3, 133.6, 133.1, 132.6, 130.6, 130.0,
128.3, 127.8, 126.6, 125.7, 122.1, 117.1, 111.2, 80.7, 55.1, 29.4, 28.6,
21.5. 77Se (76 MHz, CD3OD) δ 91.3. HRMS (ESI/Q-TOF) m/z: [M+Na]+
calcd for [C29H30N2O6SSeNa]+ 637.0887; found 637.0909.
White solid (47 mg, 85%). Prepared from 3b (100 mg, 0.083 mmol), CuBr2
(47 mg, 0.21 mmol), alkyne 1a (26 mg, 0.12 mmol), CH2Cl2 (4 ml), MeCN
(1 ml). IR νmax (film): 3280, 3064, 2936, 1743, 1653, 1539, 1200. 1H NMR
(400 MHz, CD3OD) δ 8.28-8.22 (m, 2H), 7.69-7.64 (m, 1H), 7.56 – 7.27 (m,
11H), 5.10 (s, 2H), 4.39 (dd, J = 9.4, 5.1 Hz, 1H), 3.93 (t, J = 6.4 Hz, 1H),
3.80 (s, 2H), 3.25 (dd, J = 12.7, 5.1 Hz, 1H), 2.96 (dd, J = 12.7, 9.3 Hz,
1H), 2.46-2.34 (m, 1H), 2.31-2.19 (m, 1H), 2.12-1.94 (m, 2H). 13C NMR
(101 MHz, CD3OD) δ 174.1, 173.0, 171.4, 170.8, 157.6, 155.3, 137.0,
133.4, 131.6, 130.4, 129.6, 129.59, 129.55, 129.4, 129.32, 129.31, 128.9,
126.5, 124.6, 122.0, 112.2, 100.6, 67.9, 55.0, 53.5, 42.0, 32.3, 29.5, 26.9.
77Se (76 MHz, CD3OD) δ 83.4. HRMS (ESI/Q-TOF) m/z: [M+H]+ calcd for
[C31H32N3O7Se]+ 638.1405; found 638.1409.
(R)-2-((tert-butoxycarbonyl)amino)-3-((1-((4-nitrophenyl)sulfonyl)-2-
phenyl-1H-indol-3-yl)selanyl)propanoic acid (6o).
20
Yellow solid (120 mg, quant.). Prepared from alkyne 5c (106 mg). [α]D
+12.6 (c 0.9, CHCl3). 1H NMR (400 MHz, CD3CN) δ 8.25 (dt, J = 8.4, 0.9
Hz, 1H), 8.21 – 8.10 (m, 2H), 7.73 – 7.60 (m, 3H), 7.60 – 7.39 (m, 7H),
5.25 (d, J = 7.9 Hz, 1H), 4.09 – 3.96 (m, 1H), 2.99 (dd, J = 12.8, 4.6 Hz,
1H), 2.83 (dd, J = 12.8, 7.3 Hz, 1H), 1.39-1.15 (m, 9H). 13C NMR (101 MHz,
CD3CN) δ 172.1, 155.9, 152.0, 144.7, 143.2, 137.8, 133.2, 132.8, 132.0,
130.3, 129.1, 128.5, 127.2, 126.2, 125.5, 122.2, 116.9, 112.1, 80.3, 54.5,
29.1, 28.4. 77Se (76 MHz, CD3CN) δ 91.3. HRMS (ESI/Q-TOF) m/z: [M-H]-
calcd for [C28H26N3O8SSe]- 644.0606; found 644.0645.
(S)-1-(((R)-1-((2-(((S)-1-amino-1-oxo-3-phenylpropan-2-yl)amino)-2-
oxoethyl)amino)-1-oxo-3-((2-phenylbenzofuran-3-yl)selanyl)propan-
2-yl)amino)-3-(4-hydroxyphenyl)-1-oxopropan-2-aminium
(4j)
chloride
White solid (50 mg, 100%). Prepared from (Boc)Tyr-Sec-Gly-Phe-NH2 (83
mg, 0.066 mmol), CuBr2 (44 mg, 0.19 mmol), alkyne 1a (20 mg, 0.098
mmol), CH2Cl2 (2 ml), MeCN (1 ml), MeOH (2 ml). IR νmax (film): 3269,
3032, 1652, 1506, 1214. 1H NMR (400 MHz, CD3OD) δ 8.25 – 8.19 (m,
2H), 7.73 – 7.67 (m, 1H), 7.58 – 7.53 (m, 1H), 7.51-7.45 (m, 2H), 7.43 –
7.29 (m, 3H), 7.27-7.21 (m, 4H), 7.19-7.13 (m, 1H), 7.04 (d, J = 8.5 Hz,
2H), 6.74 (d, J = 8.5 Hz, 2H), 4.59 (dd, J = 9.0, 5.5 Hz, 1H), 4.39 (t, J = 7.2
Hz, 1H), 3.89 (dd, J = 8.4, 5.6 Hz, 1H), 3.79 (d, J = 16.9 Hz, 1H), 3.38 (d,
J = 16.9 Hz, 1H), 3.29 – 3.24 (m, 1H), 3.18 – 3.02 (m, 3H), 2.91 (dd, J =
13.9, 9.1 Hz, 1H), 2.82 (dd, J = 14.4, 8.7 Hz, 1H). 13C NMR (101 MHz,
CD3OD) δ 176.1, 171.7, 170.7, 169.9, 158.3, 157.4, 155.4, 138.4, 133.3,
131.6, 131.5, 130.4, 130.3, 129.6, 129.5, 128.9, 127.8, 126.5, 125.8, 124.6,
122.0, 116.9, 112.2, 101.1, 55.84, 55.78, 55.6, 43.4, 39.0, 37.6, 29.1. 77Se
(76 MHz, CD3OD) δ 83.8. HRMS (ESI/Q-TOF) m/z: [M+H]+ calcd for
[C37H38N5O6Se]+ 728.1987; found 728.1984.
(R)-2-((tert-butoxycarbonyl)amino)-3-((2-butyl-1-((4-
nitrophenyl)sulfonyl)-1H-indol-3-yl)selanyl)propanoic acid (6p).
Yellow oil (117 mg, quant.). Prepared from alkyne 5d (100 mg). [α]D20 28.8
(c 0.97, CHCl3). 1H NMR (400 MHz, CD3OD ) δ 8.31 – 8.25 (m, 2H), 8.12
– 8.05 (m, 1H), 8.01 – 7.93 (m, 2H), 7.60-7.55 (m, 1H), 7.36 – 7.25 (m,
2H), 3.78 (dd, J = 10.0, 4.1 Hz, 1H), 3.36 (t, J = 7.9 Hz, 2H), 3.09 (dd, J =
12.7, 4.1 Hz, 1H), 2.75 (dd, J = 12.7, 10.0 Hz, 1H), 1.83 – 1.72 (m, 1H),
1.69 – 1.58 (m, 1H), 1.50-1.36 (m, 10H), 1.27-1.20 (m, 1H), 0.98 (t, J = 7.4
Hz, 3H). 13C NMR (101 MHz, CD3OD) δ 174.4, 157.6, 152.2, 148.4, 144.0,
138.1, 133.6, 129.0, 126.4, 126.0, 125.8, 121.8, 116.4, 110.2, 80.5, 54.4,
34.7, 29.4, 29.3, 28.8, 23.6, 14.2. 77Se (76 MHz, CD3OD) δ 78.5. HRMS
(ESI/Q-TOF) m/z: [M-H]- calcd for [C26H30N3O8SSe]- 624.0919; found
624.0943.
(S)-6-(((S)-1-amino-1-oxo-3-phenylpropan-2-yl)amino)-5-((R)-2-
ammonio-3-((2-phenylbenzofuran-3-yl)selanyl)propanamido)-6-
oxohexan-1-aminium dichloride (4k)
General procedure for preparation of 3-selanyl benzo[b]furans 4h-k
and indoles 6r,s
To a solution of Sec-peptide 3a-d in CH2Cl2 TFA was added at 0 °C.
Reaction mixture was stirred until disappearance of starting material. After
evaporation the peptides 3aa-3da were used further without additional
purification. To a solution of unprotected Sec-peptide (1 equiv.) in
CH2Cl2/MeCN (and MeOH in the case of peptides 3ca and 3da) CuBr2 (2.5
equiv.) was added and the mixture was stirred for 30 min at rt followed by
addition of a solution of 1a or 5a (1.5 equiv.) in CH2Cl2. Reaction mixture
was stirred for 16 h at 40 °C, and then it was evaporated and purified by
White solid (25 mg, 46%). Prepared from 3d (100 mg, 0.076 mmol), CuBr2
(42 mg, 0.19 mmol), alkyne 1a (24 mg, 0.11 mmol), CH2Cl2 (2 ml), MeCN
(1 ml), MeOH (2 ml). IR νmax (film): 3441, 1646, 1521, 1180, 1142. 1H NMR
(400 MHz, CD3OD) δ 8.29 – 8.20 (m, 2H), 7.81 – 7.72 (m, 1H), 7.61 – 7.50
(m, 3H), 7.49 – 7.43 (m, 1H), 7.42-7.34 (m, 2H), 7.24 – 7.19 (m, 2H), 7.15
(t, J = 7.6 Hz, 2H), 7.08 – 7.01 (m, 1H), 4.60 (dd, J = 8.7, 5.8 Hz, 1H), 4.31
(t, J = 6.9 Hz, 1H), 4.02 (dd, J = 7.8, 5.5 Hz, 1H), 3.24 – 3.05 (m, 3H), 3.00
– 2.84 (m, 3H), 1.80-1.69 (m, 1H), 1.67-1.58 (m, 3H), 1.44-1.30 (m, 2H).
13C NMR (101 MHz, CD3OD) δ 175.8, 172.7, 168.2, 158.1, 155.4, 138.2,
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10.1002/ejoc.201901548
European Journal of Organic Chemistry
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133.0, 131.3, 130.7, 130.3, 129.8, 129.4, 129.0, 127.7, 126.7, 124.9, 121.9,
112.3, 100.2, 55.7, 54.7, 54.2, 40.4, 39.0, 32.5, 29.1, 28.0, 23.3. 77Se (76
Orange oil (77 mg, 45%). Prepared from 3a (200 mg, 0.24 mmol), K2S2O8
(326 mg, 1.21 mmol), alkyne 7 (75 mg, 0.24 mmol), MeCN (7 ml). IR νmax
(film): 3341, 2926, 1748, 1684, 1653, 1456, 1214, 755. [α]D -7.26 (c 1,
20
MHz, CD3OD)
δ
67.9. HRMS (ESI/Q-TOF) m/z: [M+H]+ calcd for
CHCl3). 1H NMR (400 MHz, CD3OD) δ 9.56 (dd, J = 7.6, 2.0 Hz, 1H), 7.85
– 7.74 (m, 3H), 7.72 – 7.62 (m, 3H), 7.56 – 7.43 (m, 3H), 7.39 (ddd, J =
7.9, 7.2, 1.1 Hz, 1H), 7.33 – 7.26 (m, 6H), 7.05 (ddd, J = 8.1, 7.3, 1.1 Hz,
1H), 5.10 (s, 2H), 4.27 – 4.17 (m, 1H), 3.81 (s, 2H), 3.23 (dd, J = 12.7, 4.7
Hz, 1H), 3.14 – 3.05 (m, 1H), 1.29 (s, 10H). 13C NMR (101 MHz, CD3OD)
δ 173.8, 170.7, 154.2, 151.8, 146.3, 137.1, 134.8, 132.3, 132.0, 131.0,
130.6, 130.0, 129.9, 129.5, 129.3, 128.2, 126.8, 126.0, 124.2, 122.4,
121.43, 121.38, 118.9, 118.8, 116.8, 80.8, 67.9, 56.5, 42.1, 28.6. 77Se
NMR (76 MHz, CD3OD) δ 91.7. HRMS (ESI/Q-TOF) m/z: [M+H]+ calcd for
[C39H37N2O6Se]+ 709.1817; found 709.1807.
[C32H38N5O4Se]+ 636.2089; found 636.2079.
(R)-1-((2-(benzyloxy)-2-oxoethyl)amino)-1-oxo-3-((2-phenyl-1-tosyl-
1H-indol-3-yl)selanyl)propan-2-aminium chloride (6r)
White solid (56 mg, 74%). Prepared from 3a (90 mg, 0.11 mmol), CuBr2
(61 mg, 0.27 mmol), alkyne 1a (57 mg, 0.16 mmol), CH2Cl2 (4 ml), MeCN
(1 ml). ). [α]D20 +23.5 (c 1, CHCl3). IR νmax (film): 1738, 1669, 1369, 1175.
1H NMR (400 MHz, CD3OD) δ 8.31 (d, J = 8.3 Hz, 1H), 7.75 – 7.67 (m,
1H), 7.52 – 7.31 (m, 15H), 7.18 (d, J = 8.2 Hz, 2H), 5.13 (d, J = 2.9 Hz,
2H), 3.76 (t, J = 6.4 Hz, 1H), 3.67 (d, J = 17.8 Hz, 1H), 3.48 (d, J = 17.8
Hz, 1H), 2.90 (dd, J = 6.4, 1.5 Hz, 2H), 2.30 (s, 3H). 13C NMR (101 MHz,
CD3OD) δ 170.3, 168.4, 147.0, 145.8, 138.3, 137.0, 136.3, 133.3, 133.1,
132.3, 130.8, 130.4, 129.6, 129.45, 129.42, 128.6, 127.9, 126.9, 125.8,
122.1, 116.9, 109.8, 68.1, 54.0, 41.9, 28.1, 21.5. 77Se (76 MHz, CD3OD) δ
74.8. HRMS (ESI/Q-TOF) m/z: [M+H]+ calcd for [C33H32N3O5SSe]+
662.1228; found 662.1223.
(6S,11R)-benzyl 6-(tert-butoxycarbonyl)-2,2-dimethyl-4,9,12-trioxo-
11-(((6-phenylindeno[1,2-c]chromen-11-yl)selanyl)methyl)-3-oxa-
5,10,13-triazapentadecan-15-oate (8c)
Orange oil (52 mg, 36%). Prepared from 3b (194 mg, 0.16 mmol), K2S2O8
(219 mg, 0.81 mmol), alkyne 7 (50 mg, 0.16 mmol), MeCN (7 ml). IR νmax
(film): 3307, 2978, 1701, 1636, 1455, 1152. 1H NMR (400 MHz, CD3OD) δ
9.51 (dd, J = 7.9, 1.7 Hz, 1H), 7.80 (m, 3H), 7.76 – 7.62 (m, 3H), 7.62 –
7.23 (m, 11H), 7.05 (m, 1H), 5.09 (s, 2H), 4.45 (dd, J = 9.0, 4.8 Hz, 1H),
3.89 (dd, J = 9.4, 4.9 Hz, 1H), 3.78 (d, J = 2.4 Hz, 2H), 3.28 (m, 1H), 3.05
(dd, J = 12.7, 9.2 Hz, 1H), 2.18-2.05 (m, 1H), 2.05 – 1.82 (m, 2H), 1.76-
1.64 (m, =1H), 1.43 and 1.42 (2 s, 18H).13C NMR (101 MHz, CD3OD) δ
174.5, 173.2, 170.7, 158.0, 154.3, 151.7, 146.3, 137.1, 134.8, 132.4, 132.0,
131.0, 130.7, 130.0, 129.9, 129.5, 129.31, 129.29, 128.2, 126.8, 125.9,
124.3, 122.4, 121.5, 121.3, 118.9, 110.0, 82.7, 80.5, 67.9, 55.4, 55.3, 42.1,
32.9, 30.8, 29.9, 28.8, 28.3, 28.2. 77Se NMR (76 MHz, CD3OD) δ 96.2.
HRMS (ESI/Q-TOF) m/z: [M+Na]+ calcd for [C48H51N3O9SeNa]+ 916.2688;
found 916.2653.
(S)-4-(((R)-1-((2-(benzyloxy)-2-oxoethyl)amino)-1-oxo-3-((2-phenyl-1-
tosyl-1H-indol-3-yl)selanyl)propan-2-yl)amino)-1-carboxy-4-
oxobutan-1-aminium chloride (6s)
White solid (69 mg, 100%). Prepared from 3b (100 mg, 0.083 mmol),
CuBr2 (47 mg, 0.28 mmol), alkyne 1a (26 mg, 0.12 mmol), CH2Cl2 (4 ml),
MeCN (1 ml). IR νmax (film): 3376, 3050, 1652, 1517, 1176. 1H NMR (400
MHz, CD3OD) δ 8.29 (dt, J = 8.4, 0.9 Hz, 1H), 7.63 (ddd, J = 7.7, 1.4, 0.7
Hz, 1H), 7.49 – 7.27 (m, 14H), 7.20 – 7.14 (m, 2H), 5.11 (s, 2H), 4.10 (dd,
J = 9.1, 5.3 Hz, 1H), 3.95 (t, J = 6.4 Hz, 1H), 3.75 (s, 2H), 2.92 (dd, J =
12.7, 5.3 Hz, 1H), 2.63 (dd, J = 12.7, 9.1 Hz, 1H), 2.41 – 2.33 (m, 1H), 2.30
(s, 3H), 2.29 – 2.21 (m, 1H), 2.08 (p, J = 7.5, 6.9 Hz, 2H). 13C NMR (101
MHz, CD3OD) δ 174.0, 172.9, 171.5, 170.7, 146.9, 145.7, 138.5, 137.1,
136.3, 133.5, 133.31, 132.6, 130.7, 130.1, 129.6, 129.4, 129.3, 128.3,
127.9, 126.7, 125.7, 122.1, 117.1, 110.6, 67.9, 54.8, 42.0, 32.2, 28.9, 26.9,
21.5.77Se (76 MHz, CD3OD) δ 90.7. HRMS (ESI/Q-TOF) m/z: [M+H]+ calcd
for [C31H32N3O7Se]+ 638.1405; found 638.1409.
Acknowledgments
Financial support from Latvian Institute of Organic Synthesis is
gratefully acknowledged (internal grant: IG-2018-06). Authors
would like to thank Dr. S. Belyakov for x-ray analysis, Dr. M.
Petrova and R. Muhamadejevs for NMR spectra recording.
General procedure for preparation of 11-selanyl-6-phenylindeno[1,2-
c]chromenes
To a solution of diorganyl diselenide (1 equiv.) and alkyne (1 equiv.) in
MeCN K2S2O8 (5 equiv.) was added and the mixture was stirred for 3 days
at rt. After volatiles evaporation residue was purified by flash
chromatography on silica gel (PE/EtOAc 10:1-6:1) (8a) or reverse phase
chromatography (C-18, MeCN/H2O 10-85%) (8b,c) to give the product.
Keywords: diselenide • peptide • selenocysteine • 5-endo-dig •
6-endo-dig
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
FULL PAPER
O
O
O
Selenocysteine electrophile*
S. Lapcinska and P. Arsenyan,*
H
H
AA
AA
H
AA
N
N
N
AA
AA
N
N
AA
N
AA
AA
AA
H
H
H
Se
Se
Se
Page No. – Page No.
R
Se
H
X
AA
O
N
AA
N
Selenocystine peptides performance
AA
H
5-endo-dig
O
in 5-endo-dig reactions
> 20 examples,
protected and
unprotected Sec peptides
mild conditions
up to quantitative yields
5-endo-dig/6-endo-dig
Herein we present copper(II) bromide and oxidant promoted 5-endo-dig and 5-
endo-dig/6-endo-dig cascade reactions yielding substituted benzo[b]furans, indoles
and indeno[1,2-c]chromenes bearing Sec-peptides in position 3. It can be
successfully applied for protected and unprotected peptides in up to quantitative
yields.
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