Alkene: Versus alkyne reactivity in unactivated 1,6-enynes: Regio-And chemoselective radical cyclization with chalcogens under metal-And oxidant-free conditions

Article abstract of DOI:10.1039/d0gc00321b

Herein, we have developed metal and oxidant-free visible light-promoted alkene vs. alkyne regio-And chemoselective radical cascade cyclization of electronically unbiased 1,6-enynes with chalcogens to synthesize substituted pyrrolidines bearing chalcogens. The reaction generated three new bonds, namely, C-SO₂, C-C, and C-Se under extremely mild conditions. Furthermore, we achieved regio-And chemoselective mono-addition of aromatic thiophenols with unactivated 1,6-enynes. The key features of this protocol are broad substrate scope, environment-friendly conditions, operational simplicity, atom economy, and amenability to gram-scale synthesis. The mechanistic studies corroborate that the reaction proceeds via a radical pathway.

Full text of DOI:10.1039/d0gc00321b

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DOI: 10.1039/D0GC00321B
ARTICLE
Alkene Versus Alkyne Reactivity in Unactivated 1,6-Enynes: Regio-
and Chemoselective Radical Cyclization with Chalcogens under
metal- and oxidant-free conditions
Received 00th January 20xx,
Accepted 00th January 20xx
Mohana Reddy Mutra,a Vishal Suresh Kudale,a Wu-Hsun Tsaia and Jeh-Jeng Wanga,b*
DOI: 10.1039/x0xx00000x
Herein, we have developed metal and an oxidant free visible light promoted alkene vs alkyne regio- and chemoselective
radical cascade cyclization of electronically unbiased 1,6-enynes with chalcogens to synthesize substituted pyrrolidine
bearing chalcogens. The reaction was generated three new bonds, such as C-SO2, C-C, and C-Se under extremely mild
conditions. Furthermore, we achieved regio- and chemo selective mono-addition of aromatic thiophenols with unactivated
1,6-enynes. The key features of this protocol are broad substrate scope, environment-friendly condition, operational
simplicity, atom economic, and amenability to gram-scale synthesis. The mechanistic studies corroborate reaction is going
via a radical pathway.
activated benzene-tethered enynes via radical cascade
reactions with a diversity of radicals by using either oxidant or
metals.12 But in unactivated enynes, there is a competitive
Introduction
Chalcogens are impressive chemicals that play a significant role
in organic synthesis (nucleophiles, electrophiles, ligands, and
catalysts),1 biochemistry,2 medicinal chemistry,3 and materials
science.1c,4 Accordingly, sustainable methods for the synthesis
of chalcogens containing heterocyclic compounds are attracted
considerable attention for chemists due to wide application in
many fields of science. Among them, pyrrolidine is a versatile
structural scaffold with diverse pharmacological5 and exists in
many natural products.6 Introducing the chalcogen functionality
in the pyrrolidine skeleton may provide an opportunity to
enhance the reactivity of native compounds or drugs. To date,
many endeavours have been made to investigate and develop
innovative methods for preparing more valuable chalcogen
substituted organic molecules.7 In particular, a common
approach is the addition of selenium or sulfur or sulfone groups
to unsaturated compounds (alkenes or alkynes) via a radical
pathway8 or non-radical pathway9 without chemo- and
regioselective issues in the starting materials (Scheme 1, a and
b).
regio- and chemoselectivity in between alkene and alkyne as a
major drawback in the presence of highly reactive radical
species. Recently Wang et al described N-heterocyclic
carbene−boryl radical initiated chemo- and regio-controlled
addition to an alkene or alkyne depends on substituent at R2 in
enynes followed by ring closure (Scheme 1, c and d).13 We also
recently reported the I2/TBHP mediated solvent controlled
regio- and chemoselective radical cascade cyclization with
Well known approachs to functionalize alkenes or alkynes with chalcogens:
R1
R1
O
S
Se
R2
O
O
S
Se
O
S
R2
O
R2
O
O
S
R2
O
R1
Se
R1
Se
or
or
R1
R1
Expensive
photocatalyst,
UV light
or
stoichiometric amount
of oxidant with metals
or without metals
O
S
Se
R2
O
O
S
Se
R2
O
(
)
b
(
)
a
Previous work
: chemo- and regio-controlled radical borylation/cyclization of nitrogen tethered 1,6-enynes
R2 R1 NHC
BH2
R2
NHC R2 R1
H2
R1
NHC-BH2
NHC-BH2
B
R1= Ph
R2= H, aliphatic
R1= Ph
R2= Ph
N
N
Ts
N
Ts
Ts
(
)
d
(
)
c
Our previous work
: using unactivated nitrogen tethered 1,6-enyne to synthesize n-heterocycles
I
R1
O
R1
R3
5-exo-trig
6-endo-trig
I2 (0.5 equiv),
R3
R2
I2 (0.5 equiv),
70% aq. TBHP (3 equiv),
MeOH (0.1 M), 80 °C
R1= H, Ph, R2= Ph,
R3= H
)
R1
70% aq. TBHP (3 equiv),
MeCN (0.1 M),
H2O (15 equiv), 80 °C
TsN
OH
TsN
R2
R2
N
n
1,6-Enynes are versatile substrates to construct cyclic
skeletons or diverse molecular complexity compounds because
of its easy to various functionalities and ready accessibility. The
well documented synthetic approaches for utilizing enynes are
transition metal-mediated/catalyzed or cycloisomerization
reactions.10 As potential radical acceptors,11 the utilization of
enynes in radical cascade cyclization is largely unexplored due
to the regio- and chemoselective issues, especially with
unactivated enynes containing C=C and C≡C bond with hetero-
n
(e)
Ts
(f)
n=1,2,3
(
e
R1= H, aliphatic, aromatic, -COPh heterocylic, R2= aliphatic, aromatic, R3= -H, Ph
R
Present work
: using unactivated nitrogen tethered 1,6-enynes with chalcogens
R
5-exo-dig
R3SH
Acetone (0.1 M),
R
R2
R1
X
S
R2
Y
R1
R3
R
X
R1
Y
RT
R2
R1= aromatic,
TsN
Acetone (0.1 M),
34 W Blue LED, RT
Z
heterocylic
N
Z= NTs, O
5-exo-dig
(h)
R2= aromatic,
Ts
R1= H, aliphatic, aromatic,
heterocylic, R2= aliphatic,
aromatic
R3= aromatic
23 Examples
up to 88% yield
X=SO2,Y=Se or S
(or)
10 Examples
up to 80% yield
(g)
X,Y= Se
No stochiometric oxidant or
expensive photo-catalysts
Chemo- and regioselective products
environment-friendly
Broad substrat scope
di-radicals (such as RSO2 and RSe.). Prof. Li is a pioneer in
.
Atom-economic
No toxic waste
Gram-scale reaction
Scheme 1. Selected previous reports on radical addition or cascade reactions and
our approach on unactivated nitrogen-tethered 1,-6-enynes
a. Department of Medicinal and Applied Chemistry, Kaohsiung Medical University,
No. 100, Shiquan 1st Rd, Sanmin District, Kaohsiung City, 807, Taiwan.
Department of Medical Research, Kaohsiung Medical University Hospital, No.
b.
100 Tzyou 1st Rd, Sanmin District, Kaohsiung City 807, Taiwan..
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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ARTICLE
Journal Name
Unactivated 1,6-enynes (Scheme 1, e and f).14 Nevertheless, the longer reaction time (Table 1, entry 15-17). With the further
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DOI: 10.1039/D0GC00321B
most of the above reports required toxic oxidants, investigation of solvent a combination such as acetone in
stoichiometric amounts of additives, harsh reaction, expensive combination with water also not improved the reaction yield
metal photocatalysts, and regio- and chemoselective issues. (Table 1, entries, 18-22). Next, we investigated reaction in the
The transition metal catalysts in bio-relevant molecules presence of commercially available dry acetone (99.5%
synthesis brings more toxic by-products, which will affect the acetone+<=0.1 ppm water) by using molecular sieves (see the
environment. Thus, the development of green methodologies ESI, S6 for reaction setup) but similar yields were observed
have gained more attention towards industrial production, our (Table 1, entry 23). Based on the above experiments the water
method can be carried out under oxidant and metal-free may not play key role in this transformation. Then the reaction
conditions, atom economic, which completely inhibits toxic performed atmospheric air in absence of light, no desired
waste or residue of the metal ions in the target product. By
Table 1. Studies of the reaction parametersa
considering the above all factors, the importance of chalcogens
bearing heterocycles and in continuation of our interest in
radical cascade reactions for the synthesis of the bioactive
O
S
Ph
Ph
O
S
molecules.15 Herein, we synthesized pyrrolidine bearing
chalcogen functionality via regio- and chemoselective light-
induced reactions with unactivated 1,6-enynes (Scheme 1, g
and h). To the best of our knowledge, this is the first report with
visible light-induced tosyl radical triggered cyclization of
unactivated enynes and simultaneously trapped by phenylsenyl
radical with in situ generated alkenyl radical in the absence of
oxidant and metal. Based on our previous results, we
anticipated radical cascade cyclization of nitrogen-tethered
unactivated 1,6-enynes with unsymmetrical sulfone selenium
or diselenides
Se
O
Solvent (0.1 M)
34 W Blue LED, RT
Ph
Se
Ph
O
TsN
N
Ts
1b
2b
3bb
Initiator
Solvent
T
Time,
h
Yield
(%)b
Trace
Trace
40
62
74
70
-
15
75
15
45
60
82
80
78
Entry
(°C)
RT
80
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
1c
2c
3c
4
5
6
7
8
9
10
11
12
13
14
15
16
17
TBHP
TBHP
TBHP
MeCN
MeCN
MeCN
MeCN
MeOH
EtOH
24
24
10
10
10
10
24
24
10
24
10
15
9
-
-
-
-
-
-
-
-
-
-
-
-
-
-
O
S
R
R2
O
R
R1
Ph
R
Se
O
R1
R
Se
O
S
R
R
O
R
O
S
R
S
R
O
Se
R1
O
Se
PEG-400
S
O
R2
Se
R
(or)
Ph
R2
R
O
TsN
5-exo-dig
Ethylene glycol
DMSO
6-endo-trig
N
N
N
R
Ts
Ts
Ts
(b)
(a)
observed single
product formation
Expected/ not
observed
H2O
DCM
Scheme 2. Initial hypothesis of regio and chemoselective radical cascade
cyclization on 1,6-enynes and observed results
Toluene
Acetone
or thiols can be initiated at alkyne and expected to get the 6-
endo-trig product but we observed selectively 5-exo-dig
product (Scheme 2, a and b).
THF
9
Cyclohexanone
Butan-2-one
3,3-Dimethyl-2-
butanone
Acetone+H2O
Acetone+H2O
Acetone+H2O
Acetone+H2O
15
24
24
60
65
18d
19e
20f
21g
22h
23i
24j
25k
26k
27l
28m
30
-
-
-
-
-
RT
RT
70
RT
RT
RT
RT
RT
70
RT
RT
70
RT
15
15
15
15
15
9
78
76
74
75
77
80
-
-
48
-
Results and discussion
We initiated the studies by the reaction of unactivated 1,6-
enyne (1b) with benzenesulfonoselenoate (2b) in the presence
of 70% aq.TBHP as an oxidant in acetonitrile. But the expected
product (3bb) was observed trace amount (Table 1, entry 1).
Next, we heated the reaction mixture at 80 °C for 24 h (Table 1,
entry 2), the same results were observed. The yield of 3bb was
enhanced when oxidant along with 34W blue LED up to 40%
yield (Table 1, entry 3). The reason for the selection of light is
areneselenosulfonates or diphenyl diselenide excites to form its
electronically excited species which can lead to an -SO2-Se or -
Se-Se bond homolytic cleavage to generate the free
radicals.8d,16 Next, the reaction performed without oxidant
under visible light, surprisingly an increase in the product yield
up to 62% (Table 1, entry 4). Extensive screening of solvent
studies was investigated under visible light (Table 1, entries 5-
14). Among them pleasingly, acetone solvent afforded product
3bb in 82% yields. Furthermore, screening of various ketone
solvents revealed cyclohexanone observed similar yields after
Acetone+H2O (1:1)
Dry acetone
Acetone
-
Air
O2
O2
AIBN
AIBN
AIBN
-
9
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
24
24
24
24
24
24
-
55
-
31n
a Reaction conditions: Compound 1b (0.1 mmol), 2b (0.1 mmol) and acetone (0.1
M) were stirred at room temperature under 34 W blue LED. b Isolated yields. c 70%
aq.TBHP was used. d 5 equivalents of H2O used. e 20 equivalents of H2O used. f 50
equivalents of H2O used. g 100 equivalents of H2O used. h 0.05 M of H2O used. i dry
acetone (99.5% acetone+<=0.1 ppm water) was used. In atmospheric air. O2
balloon was used. l 0.1 equivalence of AIBN used. m 0.5 equivalence of AIBN used.
n Reaction was carried out in the dark.
j
k
2 | J. Name., 2012, 00, 1-3
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Page 3 of 12
Green Chemistry
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Journal Name
ARTICLE
Table-2. Scope of 1,6-enynes and chalcogensa,b,c
products were detected (Table 1, entry 24). The sVaimeweArrtieclaecOtniloinne
tested in the presence of light but we obsDeOrvI:e1d0.l1o0w39e/Dr 0yGieCld0s03d2u1Be
to the low boiling nature of the acetone evaporated from the
reaction mixture. Under O2 atmosphere the reaction was tested
at room temperature and also at 70 °C but no improvement in
the product yield (Table 1, entries 25-26). The other radical
initiators such as AIBN was tested in the reaction but the yields
were not improved (Table 1, entries 27-30). No product 3bb was
formed in the absence of light (Table 1, entry 31). We chose
acetone as a solvent because it is recommended a green solvent
in the organic transformations (Table 1, entry 13). From these
results, light is crucial for homolytic cleavage of the -SO2-Se
bond in the Se-phenyl 4-methylbenzenesulfonoselenoate.
Using the optimized reaction conditions, we turned to
explore the substrate scope of this reaction using a variety of
reagents, and the results are summarized in Table 2. The
reaction worked well with terminal alkyne (3ab) and internal
alkyne with aryl functionalities such as -ph (3bb) m-Me-Ph (3cb),
p-Me-Ph (3db), and p-COMe-Ph (3eb) to afford polysubstituted
pyrrolidine bearing chalcogen derivatives in 68-82% yields
irrespective of their different electronic properties and sites of
groups on the benzene ring were suitable without affecting the
reaction. Substituted TMS groups were tested at R1 In place of
an aryl group to give compound 3fb in 81% yield maintaining
good selectivity and efficiency. Surprisingly, the reaction
worked with the R1 as hetero functionality to produce the
corresponding polysubstituted pyrrolidine bearing chalcogen
3gb in excellent yields (88%). The reaction underwent smooth
conversion when the aryl group in R1 and R2 were replaced with
aliphatic groups to generate 3hb and 3ib in good yields (72-
77%). Furthermore, tried the reaction with unsymmetrical
chalcogen and symmetrical chalcogen in the starting material
(2) with compound 1,6-enyne: interestingly, the reaction
produced in good yields to excellent yields. A series of sulfone
derivatives in unsymmetrical chalcogens such as, -Ph (3ba) and
with aryl functionalities such as p-OMe-Ph (3bc) to afford the
desired products derivatives in 73-77% yields. The
configurations of (Z)-3-(((4-methoxyphenyl)sulfonyl)methyl)-3-
phenyl-4-(phenyl(phenylselanyl)methylene)-1 tosylpyrrolidine
(3bc) further confirmed by X-ray analysis.17 Following, the
reaction checked with electron-withdrawing functionalities
such as p-Cl-Ph (3bd), p-F-Ph (3be), p-CF3-Ph (3bf) to afford the
corresponding product in good to excellent yields in 68-71%.
Furthermore, we replaced a simple aromatic group with the
reaction with an electron-donating group such as p-Me-Ph
(3bh) to afford the desired product in an 80% yield. Next,
applied naphthalene functionality and the reaction working well
to afford desired product 3bg in a 66% yield. Next, we tried
modification in selenium functionality in the starting material 2.
First, we tested with electron-withdrawing group (3bi) and
heteroaromatic functionality in the selenium core (3bj) to
afford the desired products in 62-65% yield. Surprisingly, the
reaction worked with the unsymmetrical chalcogenides (Ts-S-
Ph) combination and observed the desired product (3bk) in 78%
without affecting the reaction efficiency. Then we changed the
starting material with symmetrical diphenyl diselenides and
observed desired products with moderated to goods yields,
R
R
R
X
Y
R2
R1
R
2
X
R1
Y
R2
X=SO2,Y=Se or S
TsN
Acetone (0.1 M)
(or)
X,Y= Se
34 W Blue LED, RT
N
1
3
Ts
O
S
O
S
Ph
H
O
Se
Ph
Se
O
Se
O
S
Ph
O
Ph
N
N
N
Ts
Ts
Ts
3bb
, 82%, 9h
3ab
3cb
, 75%, 8h
, 80%, 10h
O
O
Si
O
O
Ph
Se
Ph
Se
S
S
O
O
S
O
Ph
Se
O
N
N
Ts
Ts
N
Ts
3db
, 78%, 10h
3fb
, 81%, 8h
3eb
, 68%, 12h
O
S
O
S
O
Ph
S
H3C
Se
O
Ph
Se
Se
O
S
O
Ph
N
N
N
Ts
Ts
Ts
3ib
, 72%, 8h
3gb
3hb
, 77%, 8h
, 88%, 10h
O
O
O
Ph
S
Ph
S
O
Se
O
Ph
Se
Ph
N
N
Ts
Ts
3ba
, 77%, 12h
3bc
, 73%, 10h
3bc
Cl
F
F3C
O
S
O
S
O
Ph
Ph
Se
Ph
S
O
Se
Se
O
O
Ph
Ph
Ph
3bf
O
N
N
N
Ts
, 71%, 12h
Ts
Ts
3bd
, 70%, 12h
3be
, 68%, 12h
F
O
S
Ph
Se
O
S
Ph
S
O
Ph
Ph
Se
O
Se
O
Ph
Ph
N
N
Ts
Ts
N
Ts
3bi
, 62%, 10h
3bh
, 80%, 10h
3bg
,
66%, 10h
O
S
Ph
Ph
Se
S
O
S
Se
Ph
S
O
Ph
Se
Ph
O
Ph
N
N
Ts
Ts
N
Ts
3ba'
, 77%, 24h
3bk
, 78%, 9h
3bj
, 65%, 7h
O
O
NO2
S
Ph
Se
Se
Ph
Ph
Se
Ph
Se
Se
Se
Ph
Ph
Ph
Ph
Ph
N
N
Ts
N
Ts
Ts
3ga
Ph
'
3ga'
, 79%, 10h
3ea'
, 55%, 30h
Ph
3ia'
, 50%, 30h
Unsuccessful examples:
Ph
Ph
Ph
Ph
Ph
Ph
TsN
Ph
TsN
1l
TsN
Ph
TsN
N
H
1p
Ph
N
Ts
1k
1m
1n
1o
a Reaction conditions: 1 (0.1 mmol), 2 (0.1 mmol), solvent (0.1 M) were stirred at
room temperature under 34 W blue LED. b Isolated yields. major Z isomer was
formed
c
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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PleaseGdroeennotChaedmjuissttrmy argins
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ARTICLE
Journal Name
such as -Ph (3ba’) m-NO2-Ph (3ia’), p-CO2Me-Ph (3ga’) in 55-77% results are same without affecting the reaction yields. It
View Article Online
DOI: 10.1039/D0GC00321B
yields to afford cascade cyclization. The configurations of (Z)-3- indicates, the light is not necessary for thiol radical generation
phenyl-4-((phenylselanyl)(thiophen-2-yl)methylene)-3-
((phenylselanyl)methyl)-1-tosylpyrrolidine (3ga’)
an open-air or dissolved oxygen may enough to carry out this
further transformation.18 All of these reactions performed without
confirmed by X-ray analysis.17 In all the above reactions we did light. Next, we explored the substrate scope of various 1,6-
not observe the formation of reverse transformation products. enynes in the reactions such as, electron-donation groups (5da),
The probable reason for this selective radical addition due to
Table-4. Gram-scale reactions
highly reactive tosyl radical first reacts with alkene functionality
in enyne and generate the stable tertiary alkyl radical
O
Ph
intermediate (see in Scheme 4, intermediate A). But in the case
of the reverse transformation, the tosyl radical addition to
alkyne generates less stable vinyl radical intermediate under
light irradiation. Thus, the formation of reverse products will
not be favourable.11c Later, we execute the feasibility of this
transformation done by increasing the chain length from one to
two (1k and 1m) and three (1l and 1m) but unfortunately, the
reaction did not work. Internal alkene (1o) and free amine (1p)
in enyne were also not compatible for this transformation.
Next, we thought to apply thiol (2.0 equivalence) as a reagent
in place of RSO2-SeR (2) with 1,6-enynes in the standard
condition under light irradiation, expected to get di-
functionalization in the cascade reaction. But, surprisingly the
reaction afford mono addition exclusively 5-endo-dig product
via radical cascade reaction to afford desired product 5ba in
80% yield (Table 3). The same reaction was repeated in the
absence of light, the
Ph
Se
Ts
S
Se
O
2
Ph
Acetone (0.1 M)
34 W Blue LED, RT
N
Ph
Ts
3bb
, 75%, 12 h
Ph
TsN
SH
Ph
S
1b
Ph
4
1 equiv, 0.4 g
Acetone (0.1 M),
RT
N
Ts
5ba
, 70%, 24 h
electron-withdrawing groups 5ja, 5ia and heterocyclic
functionality 5ga in the R1 to afford desired products in 42-74%
yields. Furthermore, various thiophenol derivatives tested in
the standard reaction and observed desired products 5bb-5bf
in moderate to goods yields 50-77%. Note that the (E)-4-
benzylidene-3-(((2-bromophenyl)thio)methyl)-3-phenyl-1-
tosylpyrrolidine (5bd) was unambiguously confirmed by X-ray
Table-3. Scope of 1,6-enynes and aromatic thiophenolsa,b,c
Ph
O
S
Se
Acetone (0.1 M)
Ph
O
Blue LED, RT, 24h
R1
R2
S
3bb
TsN
(a)
(b)
Radical inhibitor
TEMPO (0%), BHT (trace), 1,4-Cyclohexadiene(trace)
SH
R
Ph
R1
, 0.1 mmol
Ph
2b
, 0.1 mmol
1b
Acetone (0.1 M)
RT
R1 = aromatic
R2 = H, Ph
R
X
O
S
Se
X
5
2b
Ph
1
4
O
Acetone (0.1 M), in
the absence of light,
3bb
TsN
X = NTs, O
X = NTs, O
RT, 24h
2b
, 0.1 mmol
SH
1b
trace amount of product
, 0.1 mmol
Ph
NO2
Ph
F
Acetone (0.1 M),
5ba
Ph
S
S
S
Ph
TsN
S
RT
(c)
(d)
Ph
Ph
Radical inhibitor
Ph
Ph
Ph
Ph
4a
, 0.1 mmol
SH
1b
, 0.1 mmol
Ph
TEMPO (0%), BHT (40%), 1,4-Cyclohexadiene(45%)
N
N
N
N
Ph
Ts
Ts
Ts
Ts
Acetone (0.1 M),
RT, 24h
N2 balloon
5ba
Yield = 48%
Yield = 0%
TsN
5ba,
5da,
5ja,
5ia,
42%, 30h
80%, 15h
61%, 24h
45%, 24h
4a
, 0.1 mmol
1b
, 0.1 mmol
Ph
Br
Ph
S
Ph
S
S
S
S
S
Ph
Ph
Ph
Acetone (0.1 M),
RT, 24h
Ph
5ba
(e)
Ph
TsN
N
N
4a
', 0.1 mmol
SH
1b
Ts
, 0.1 mmol
Ph
Ts
N
Ts
5ga,
Ph
5bb,
S
58%, 15h
Ph
5bd
74%, 12h
5bd,
77%, 15h
Ph
Ph
Acetone:D2O (1:1)
(0.1 M), RT, 20h
Ph
D(H)
(f)
Ph
TsN
Ph
Ph
S
Ph
S
4a
, 0.1 mmol
A mixture of D and H;
D is the major
N
Ph
Ph
1b
, 0.1 mmol
Ph
S
Ts
Ph
Br
6
Ph
Ph
S
Ph
Cl
TsN
O
S
Se
N
N
Ts
Ph
Ph
Se Ph
(g)
Solvent (0.1 M)
Blue LED, RT,
20h
3ba
'
Ph
Se
3bb
Ts
O
N
TsN
Observed
Ts
exptected
Yield = <10%
Minor
Yield = 65%
Major
5be,
50%, 24h
5bf,
d
5bc,
60%, 15h
Ph
5bf'
48%, 12h
1b
, 0.1 mmol
Ph
2b
2a
, 0.1 mmol
O
', 0.1 mmol
S
Ph
Se
S
SH
S
Ph
Ph
Solvent (0.1 M)
Blue LED, RT,
20h
Ts
O
3bb
5ba
(h)
(i)
S
N
TsN
Ph
Yield = 15%
Minor
Yield = 58%
Major
O
N
1b
, 0.1 mmol
2b
4a
, 0.1 mmol
, 0.1 mmol
SH
Ts
5oa
5oa'
Observed, 61%, 12h
Ph
Ph
Solvent (0.1 M)
5ba
Yield = 52%
3ba
5bg,
'
55%, 12h
Expected
Se Ph
Se
Blue LED, RT,
20h
TsN
Ph
2a
Yield = 20%
Minor
Major
1b
, 0.1 mmol
2b 4a 2a
'
reactivity =
>
>
4a
', 0.1 mmol
, 0.1 mmol
a Reaction conditions: 1 (0.1 mmol), 4 (0.1 mmol), solvent (0.1 M). b Isolated yields.
c major E isomer was formed. d The reaction heated at 60 °C
Scheme 3. Control experiments
4 | J. Name., 2012, 00, 1-3
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Page 5 of 12
Green Chemistry
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Journal Name
crystallography.17 In the case of triphenylmethanethiol (4f) at
ARTICLE
Based on the previous reports8c,8d,16,18,19 and control
View Article Online
DOI: 10.1039/D0GC00321B
room temperature major starting material was observed in TLC. experiments, a plausible mechanism for the reaction was
Thus, the reaction mixture was heated at 60 °C expected to get proposed in Scheme 4. Firstly, in the presence of photo-
5bf but unexpectedly further cascade reaction to afford 5bf’ in irradiation of Se-phenyl 4-methylbenzenesulfonoselenoate 2ba
48% yield. The reaction also worked with oxygen tethered 1,6- produce tosyl (a) and phenylselenyl (b) free radicals8c,8d
enyne 5b with 4a to get a 55% yield. The reaction tested R2 as followed by regio- and chemoselective tosyl radical addition to
hydrogen and expected to 5oa but the addition to alkene the substrate 1b provide an alkyl radical intermediate A. The
product 5oa’ was observed in 61% yield. To demonstrate the resulting alkyl radical A participates selectively in 5-exo-dig
synthetic application of the method, reaction scale-up cascade to afford intermediate B, simultaneously, the vinyl
experiments were performed (Table 4). The desired radical intermediate (B) captured by phenylselenyl (b) radical to
polysubstituted pyrrolidine bearing chalcogen 3bb and 5ba deliver the desired product 3bb. In the case of product 5ba
were formed in a 75-70% yield without affecting the quantity of formation, the radical generates from thiophenols in the
the reaction.
presence of air or dissolved oxygen in the solvent to give thio-
radical c.18 The generated thio-radical (c) reacts selectively with
1,6-enyne (1b) of the alkene to generate alkyl radical C.
To explore the reaction mechanism, preliminary control
experiments were carried out, as shown in Scheme 3. The
reaction between 1b and 2b in the presence of radical
scavengers like TEMPO, BHT and 1,4-cyclohexadiene under the
standard conditions TEMPO inhibited the reaction and in BHT,
1,4-cyclohexadiene afford trace-amount of product 3bb
(Scheme 3, a). These experiments suggest that the reaction
proceeds through a radical pathway. Furthermore, investigation
of the reaction at room temperature in the absence of light. But,
the reaction did not afford the desired product (Scheme 3, b). It
reveals the light is necessary for the homolytic cleavage of the
–SO2-Se, -SO2-S, and Se-Se bond. Next, we tested 1b and 4a with
radical scavengers such as TEMPO, BHT and 1,4-cyclohexadiene
(Scheme 3, c). In TEMPO the reaction did not afford the desired
product 5ba. However, the BHT and 1,4-cyclohexadiene lower
the desired product 40-45% yields. These reactions suggesting
that existence of a radical mechanism. Furthermore, the
reaction 1b with 4a under nitrogen atmosphere but the reaction
affords lower yield 48% (Scheme 3, d). It indicates the dissolved
O2 is necessary for the generation of thioradical.18 Then, we
synthesized the disulfide compounds 4a’ according to the
literature procedure and the reaction was performed with 1b
(Scheme 3, e). But the reaction did not afford the desired
product, TLC shown major starting material intact in the
reaction. It confirmed that disulfide (4a’) may not be an
intermediate in the reaction. The formed thiophenol radical
directly attacking alkene functionality of the enyne 1. The same
reaction performed with a 1:1 ratio of acetone and D2O
(Scheme 3, f, see ESI, S4 for detail). We observed major D
inserted products in alkene functionality. From this we
speculate water may provide the hydrogen source in the
product. Furthermore, we performed a series of reactions with
compounds 1 with 2 and 4 to know the reactivity of the
generated radicals. First, we chosen 1b with 2b and 2a’
combination (Scheme 3, g). In this reaction major 3bb in 65%
yield and minor 3ba’ in below 10% yield. Furthermore, we
selected 1b with 2b and 4a (Scheme 3, h). This reaction affords
the desired product with a major 3bb in 58% yield and minor
5ba in 15%. Next, we tested the reaction with a combination of
1b with 2a’ and 4a (Scheme 3, i). We observed major 5ba in 52%
yield and minor 3ba’ in 20% yield. These results have given an
idea of the reactivity of the chalcogen group in the reaction. The
order of reactivity is 2b>4a>2a’.
Furthermore, the alkyl radical intermediate
C
the
intramolecular 5-exo-dig radical cascade affording vinyl radical
intermediate D. Finally it will generate 5ba via hydrogen atom
transfer (HAT) from water.19
O
S
O
S
Se
Se
O
O
34 W Blue LED
2ba
a
b
O
S
O
S
Ph
Ph
O
S
Ph
Se
O
Ph
b
Ph
O
Ts
a
O
Ph
N
Ph
Ph
N
N
Ts
A
N
Ts
1b
Ts
B
3bb
SH
S
air
4
c
Ph
Ph
S
Ph
S
S
Ph
H
H2
O
Ph
Ph
N
N
N
Ts
Ts
Ts
5ba
C
D
Scheme 4. Plausible mechanism
Conclusions
In summary, a regio- and chemoselective visible light-induced
radical cascade cyclization of unactivated nitrogen-tethered
1,6-enynes with chalcogens have been achieved in 5-exo-dig
fashion to substituted pyrrolidine bearing chalcogens. In the
presence of aromatic thiophenol, mono addition product was
observed. This reaction system showed a mild reaction
condition, environment-friendly condition, generation, good
tolerance with diverse functional groups, broad scope,
moderate to good yields, and no toxic waste generation.
Furthermore, the gram-scale reaction was conducted which
shows the synthetic value of our methodology.
Experimental section
General procedure (A) for the synthesis of (Z)-3-phenyl-4-
(phenyl(phenylselanyl)methylene)-3((phenylsulfonyl)methyl)
1-tosylpyrrolidine derivatives (3).
In an oven-dried screw-capped 5 mL vial equipped with a
magnetic stir bar was charged with 1,6-enyne 1 (1.0 equiv)
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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PleaseGdroeennotChaedmjuissttrmy argins
Page 6 of 12
ARTICLE
Journal Name
chalcogen 2 (1.0 equiv), and acetone (0.1 M) was added. The (m, 8H), 7.01-6.98 (m, 2H), 6.71-6.67 (m, 2H), 6.32 (s, 1H), 6.03
View Article Online
resulting reaction mixture was stirred up to starting material (s, 1H), 4.37 (d, J = 14.0 Hz, 1H), 4.08 (d,DJO=I:1104..1003H9z/D, 01GHC),0043.0212B-
completion at room temperature under a blue LED light. After 3.96 (m, 2H), 3.48 (d, J = 14.8 Hz, 1H), 3.32 (d, J = 14.8 Hz, 1H),
that, the crude reaction mixture was diluted water and 2.49 (s, 3H), 2.39 (s, 3H), 1.86 (s, 3H). 13C NMR (101 MHz, CDCl3)
extracted with ethyl acetate. The organic layer was dried over δ 144.36, 143.88, 143.15, 140.48, 138.41, 136.96, 136.48,
Na2SO4, filtered, and concentrated. The residue was purified by 135.54, 131.84, 130.07, 130.03, 129.77, 129.63, 128.43, 128.16,
flash chromatography to obtained product 3.
128.10, 128.06, 127.93, 127.72, 127.32, 126.92, 126.91, 126.15,
General procedure (B) for synthesis of (E)-4-benzylidene-3- 126.08, 61.33, 59.23, 54.61, 52.37, 21.64, 21.52, 20.92; IR (neat)
phenyl-3-((phenylthio)methyl)-1-tosylpyrrolidine derivatives λ max 3056, 2926, 1592, 1484, 1445, 1344, 1155, 1091, 824,
(5)
740, 697, 555; HRMS (ESI) calcd for C39H38NO4S2Se [M+H]+
In an oven-dried screw-capped, 5 mL vial equipped with a 728.1407; found: 728.1409.
magnetic stir bar was charged with 1,6-enyne (1.0 equiv) (Z)-3-phenyl-4-((phenylselanyl)(p-tolyl)methylene)-1-tosyl-3-
aromatic thiols (1.0 equiv), acetone (0.1 M) was added. The (tosylmethyl)pyrrolidine (3db): The title compound was
resulting solution was stirred up to starting material completion prepared according to the general procedure A to obtain as a
at room temperature. After that, the crude reaction mixture white solid (57 mg, yield = 78%); Mp. 176.1-176.6 °C; 1H NMR
was diluted water and extracted with ethyl acetate. The organic (400 MHz, CDCl3) δ 7.76 (d, J = 8.2 Hz, 2H), 7.42-7.38 (m, 4H),
layer was dried over Na2SO4, filtered, and concentrated. The 7.17 (d, J = 8.0 Hz, 2H), 7.10-7.09 (m, 8H), 7.02-6.98 (m, 2H),
residue was purified by flash chromatography.
6.61 (d, J = 8.0 Hz, 2H), 6.36 (d, J = 6.8 Hz, 2H), 4.32 (d, J = 14.0
Hz, 1H), 4.08 (d, J = 14.4 Hz, 1H), 4.03 (d, J = 10.0 Hz, 1H), 3.92
(d, J = 10.4 Hz, 1H), 3.45 (d, J = 14.4 Hz, 1H), 3.31 (d, J = 14.8 Hz,
(Z)-3-phenyl-4-((phenylselanyl)methylene)-1-tosyl-3-
(tosylmethyl)pyrrolidine (3ab): The title compound was 1H), 2.49 (s, 3H), 2.38 (s, 3H), 2.10 (s, 3H). 13C NMR (101 MHz,
prepared according to the general procedure A to obtain as a CDCl3) δ 144.28, 143.85, 142.62, 140.83, 138.24, 136.89,
1
white solid (48 mg, yield = 75%); Mp. 150.5-151.0 °C; H NMR 135.25, 134.47, 131.92, 129.90, 129.77, 129.55, 129.07, 128.54,
(400 MHz, CDCl3) δ 7.77 (d, J = 8.0 Hz, 2H), 7.38-7.31 (m, 6H), 128.16, 128.10, 127.83, 127.72, 127.32, 126.97, 126.29, 61.63,
7.28-7.26 (m, 3H), 7.20-7.18 (m, 2H), 7.11-7.08 (m, 3H), 7.05 (d, 59.00, 54.55, 52.51, 21.63, 21.51, 20.98; IR (neat) λ max 3049,
J = 8.0 Hz, 2H), 6.43 (s, 1H), 4.62 (d, J = 10.4 Hz, 1H), 3.99 (d, J = 2933, 1912, 1594, 1467, 1329, 1158, 1083, 900, 818, 742, 674,
14.8 Hz, 1H), 3.70 (qd, J = 14.4, 2.4 Hz, 2H), 3.46 (d, J = 14.8 Hz, 553; HRMS (ESI) calcd for C39H38NO4S2Se [M+H]+ 728.1407;
1H), 3.37 (d, J = 10.4 Hz, 1H), 2.47 (s, 3H), 2.34 (s, 3H).13C NMR found: 728.1400.
(101 MHz, CDCl3) δ 144.25, 143.91, 137.11, 136.98, 132.44, (Z)-4-(((3-fluorophenyl)selanyl)(phenyl)methylene)-3-phenyl-
132.15, 129.89, 129.53, 129.46, 128.47, 127.84, 127.71, 127.61, 1-tosyl-3-(tosylmethyl)pyrrolidine (3eb): The title compound
127.19, 126.66, 114.89, 63.55, 55.85, 52.16, 50.61, 21.60, 21.50; was prepared according to the general procedure A to obtain as
1
IR (neat) λ max 3053, 2924, 1590, 1483, 1445, 1103, 1337, 1226, a white solid (52 mg, yield = 68%); Mp. 88.4-89.0 °C; H NMR
1156, 1088, 1033, 821, 739 695, 669, 593, 557, 515, 466; HRMS (400 MHz, CDCl3) δ 7.79 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.4 Hz,
(ESI) calcd for C32H32NO4S2Se [M+H]+ 638.0938; found: 2H), 7.41 (d, J = 8.0 Hz, 4H), 7.24 (d, J = 8.0 Hz, 2H), 7.13-7.07
638.0936.
(m, 6H), 7.03-6.98 (m, 4H), 6.44 (s, 2H), 4.48 (d, J = 14.0 Hz, 1H),
4.17 (d, J = 14.4 Hz, 1H), 4.11 (d, J = 10.0 Hz, 1H), 3. 87 (t, J = 4.0
(Z)-3-phenyl-4-(phenyl(phenylselanyl)methylene)-1-tosyl-3-
(tosylmethyl)pyrrolidine (3bb): The title compound was Hz, 1 H), 3.82 (s, 3H), 3.46 (d, J = 14.4 Hz, 1H), 3.31 (d, J = 14.4
prepared according to the general procedure A to obtain as a Hz, 1H), 2.49 (s, 3H), 2.41 (s, 3H). 13C NMR (101 MHz, CDCl3) δ
white solid (61 mg, yield = 82%); Mp. 165.8-166.6 °C; 1H NMR 166.38, 144.64, 144.00, 143.42, 142.14, 141.75, 138.33, 135.62,
(400 MHz, CDCl3) δ 7.78 (d, J = 8.4 Hz, 2H), 7.42 (t, J = 8.4 Hz, 131.73, 129.80, 129.11, 128.73, 128.35, 128.31, 128.17, 127.29,
4H), 7.18 (d, J = 7.6 Hz, 2H), 7.13-7.07 (m, 8H), 7.01-6.97 (m, 2H), 127.19, 125.92, 61.01, 59.58, 55.11, 52.35, 52.04, 21.66, 21.55;
6.91-6.87 (m, 1H), 6.79 (t, J = 8.0 Hz, 2H), 6.44 (s, 2H), 4.36 (d, J IR (neat) λ max 3057, 1719, 1597, 1441, 1280, 1155, 1100, 822,
= 14.0 Hz, 1H), 4.10 (d, J = 14.4 Hz, 1H), 4.02 (d, J = 10 Hz, 1 H), 741, 597, 552; HRMS (ESI) calcd for C40H38NO6S2Se [M+H]+
3.96 (d, J = 10.4 Hz, 1H), 3.48 (d, J = 14.8 Hz, 1H), 3.32 (d, J = 14.4 772.1306; found: 772.1306.
Hz, 1H), 2.50 (s, 3H), 2.39 (s, 3H). 13C NMR (101 MHz, CDCl3) δ (Z)-3-phenyl-4-((phenylselanyl)(trimethylsilyl)methylene)-1-
144.35, 143.91, 142.70, 140.51, 138.31, 137.23, 135.63, 131.93, tosyl-3-(tosylmethyl)pyrrolidine (3fb): The title compound was
130.05, 129.81, 129.63, 128.55, 128.20, 128.17, 128.01, 127.93, prepared according to the general procedure A to obtain as a
1
127.35, 127.07, 17.00, 126.26, 61.58, 59.19, 54.58, 52.54; IR white solid (58 mg, yield = 81%); Mp. 171.6-172.1 °C; H NMR
(neat) λ max 3055, 2931, 2589, 2309, 1904, 1808, 1739, 1592, (400 MHz, CDCl3) δ 7.71 (d, J = 8.4 Hz, 2H), 7.45-7.41 (m, 4H),
1330, 1158, 1084, 1030, 891, 743, 683, 561; HRMS (ESI) calcd 7.35 (d, J = 7.6 Hz, 2H), 7.29-7.24 (m, 6H), 7.21-7.19 (m, 5H),
for C38H36NO4S2Se [M+H]+ 714.1251; found: 714.1250.
4.30 (d, J = 15.6 Hz, 1H), 4.12 (d, J = 9.2 Hz, 1H), 3.90-3.85 (m,
(Z)-3-phenyl-4-((phenylselanyl)(m-tolyl)methylene)-1-tosyl-3- 3H), 3.43 (d, J = 9.2 Hz, 1H), 2.46 (s, 3H), 2.41 (s, 3H), 0.08 (s,
(tosylmethyl)pyrrolidine (3cb): The title compound was 9H). 13C NMR (101 MHz, CDCl3) δ 160.77, 144.80, 143.78,
prepared according to the general procedure A to obtain as a 143.50, 138.77, 132.47, 131.76, 130.99, 130.69, 130.03, 129.45,
white solid (59 mg, yield = 80%); Mp. 147.5-147.9 °C; 1H NMR 129.19, 128.58, 128.00, 127.53, 127.45, 126.83, 126.35, 62.95,
(400 MHz, CDCl3) δ 7.78 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.0 Hz, 61.68, 59.40, 53.46, 21.62, 21.59, 1.15; IR (neat) λ max 3057,
2H), 7.40 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 7.13-7.09 2955, 1590, 1483, 1443, 1344, 1251, 1155, 1089, 1029, 840,
6 | J. Name., 2012, 00, 1-3
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Page 7 of 12
Green Chemistry
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ARTICLE
672, 598, 556; HRMS (ESI) calcd for C35H39NO4S2NaSiSe [M+Na]+ 6.90-6.86 (m, 1H), 6.79 (t, J = 7.6 Hz, 2H), 6.45 (s, 2H), 4.34 (d, J
View Article Online
732.1153; found: 732.1152.
= 14.0 Hz, 1H), 4.12 (d, J = 14.4 Hz, 1H), 4D.0O5I:(1d0,.1J0=391/0D.00GHC0z,0132H1)B,
3.95 (d, J = 10.2 Hz, 1H), 3.50 (d, J = 14.6 Hz, 1H), 3.34 (d, J = 14.6
(Z)-3-phenyl-4-((phenylselanyl)(thiophen-2-yl)methylene)-1-
tosyl-3-(tosylmethyl)pyrrolidine (3gb): The title compound was Hz, 1H), 2.49 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 143.92,
prepared according to the general procedure A to obtain as a 142.40, 141.13, 140.31, 137.16, 135.65, 133.36, 131.89, 130.14,
1
light brown solid (64 mg, yield = 88%); Mp. 94.6-95.4 °C; H 129.81, 129.21, 129.03, 128.55, 128.21, 128.14, 128.03, 127.85,
NMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 8.4 127.25, 127.11, 127.07, 126.26, 61.60, 59.14, 54.46, 52.55,
Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 7.24-7.14 (m, 10H), 7.10-7.05 21.65; IR (neat) λ max 3477, 3058, 2930, 1895, 1746, 1590,
(m, 2H), 6.92 (dd, J = 5.2, 1.2 Hz, 1H), 6.39 (dd, J = 5.2, 3.6 Hz, 11448, 11335, 1155, 1088, 883, 826, 742, 693, 592, 552, 461;
1H), 5.93 (dd, J = 3.6, 1.2 Hz, 1H), 4.47 (d, J = 14.8 Hz, 1H), 4.09 HRMS (ESI) calcd for C37H34NO4S2Se [M+H]+ 700.1094; found:
(d, J = 10.0 Hz, 1H), 4.02 (d, J = 14.8 Hz, 1H), 3.92 (d, J = 10.0 Hz, 700.1087.
1H), 3.62 (d, J = 14.8 Hz, 1H), 3.55 (d, J = 14.8 Hz, 1H), 2.48 (s, (Z)-3-(((4-methoxyphenyl)sulfonyl)methyl)-3-phenyl-4-
3H), 2.40 (s, 3H).13C NMR (101 MHz, CDCl3) δ 144.59, 144.51, (phenyl(phenylselanyl)methylene)-1-tosylpyrrolidine (3bc):
143.95, 143.52, 139.23, 138.11, 134.57, 132.69, 129.79, 129.67, The title compound was prepared according to the general
128.95, 128.79, 128.73, 128.54, 128.12, 127.90, 127.51, 127.29, procedure A to obtain as a white solid (53 mg, yield = 73%); Mp.
126.47, 126.10, 125.66, 60.16, 59.49, 55.78, 52.87, 21.64, 21.56; 173.8-174.3 °C; 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.0 Hz,
IR (neat) λ max 3057, 2935, 1919, 1802, 1593, 1457, 1328, 1158, 2H), 7.46 (d, J = 9.2 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H), 7.13-7.06
1083, 822, 687, 564; HRMS (ESI) calcd for C36H34NO4S3Se (m, 8H), 7.00-6.97 (m, 2H), 6.92-6.88 (m, 1H), 6.85-6.78 (m, 4H),
[M+H]+ 720.0815; found: 720.0815.
(Z)-3-phenyl-4-(1-(phenylselanyl)ethylidene)-1-tosyl-3-
6.45 (s, 2H), 4.34 (d, J = 14.4 Hz, 1H), 4.10 (d, J = 14.4 Hz, 1H),
4.03 (d, J = 10.4 Hz, 1H), 3.95 (d, J = 10.4 Hz, 1H), 3.83 (s, 3H),
(tosylmethyl)pyrrolidine (3hb): The title compound was 3.47 (d, J = 14.8 Hz, 1H), 3.32 (d, J = 14.8 Hz, 1H), 2.50 (s, 3H).
prepared according to the general procedure A to obtain as a 13C NMR (101 MHz, CDCl3) δ 163.40, 143.91, 142.51, 140.48,
white solid (50 mg, yield = 77%); Mp. 94.8-95.3 °C; 1H NMR (400 137.20, 135.63, 132.77, 131.87, 130.02, 129.81, 129.53, 129.25,
MHz, CDCl3) δ 7.72 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 8.4 Hz, 2H), 128.55, 128.19, 128.16, 128.01, 127.90, 127.07, 127.01, 126.30,
7.41-7.38 (m, 3H), 7.35 (d, J = 5.6 Hz, 2H), 7.33 (s, 1H), 7.29-7.26 114.18, 61.84, 59.12, 55.65, 54.51, 52.52, 21.66; IR (neat) λ max
(m, 4H), 7.25-7.20 (m, 4H), 4.31 (dd, J = 13.6, 1.6 Hz, 1H), 4.16 3468, 3057, 2933, 2584, 2509, 2404, 2305, 2050, 1898, 1805,
(d, J = 9.6 Hz, 1H), 3.97-3.93 (m, 1H), 3.90 (d, J = 2.0 Hz, 2H), 3.53 1745, 1589, 1447, 1328, 1154, 1091, 1030, 826, 741, 686, 559;
(d, J = 9.6 Hz, 1H), 2.47 (s, 3H), 2.46 (s, 3H), 1.37 (s, 3H). 13C NMR HRMS (ESI) calcd for C38H36NO5S2Se [M+H]+ 730.1200; found:
(101 MHz, CDCl3) δ 144.74, 143.89, 143.16, 139.42, 138.41, 730.1199.
134.23, 131.64, 129.98, 129.70, 129.15, 128.74, 128.67, 128.15, (Z)-3-(((4-chlorophenyl)sulfonyl)methyl)-3-phenyl-4-
127.80, 127.57, 127.30, 126.56, 125.83, 61.58, 60.94, 55.97, (phenyl(phenylselanyl)methylene)-1-tosylpyrrolidine (3bd):
52.24, 22.15, 21.65; IR (neat) λ max 3057, 2926, 1591, 1483, The title compound was prepared according to the general
1444, 1405, 1343, 1152, 1091, 1029, 824, 738, 697, 663, 592, procedure A to obtain as a white solid (52 mg, yield = 71%); Mp.
549; HRMS (ESI) calcd for C33H34NO4S2Se [M+H]+ 652.1094; 142.6-114.4 °C; 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.0 Hz,
found: 652.1095.
2H), 7.44-7.40 (m, 4H), 7.38-7.31 (m, 2H), 7.13-7.07 (m, 8H),
(Z)-3-methyl-4-(phenyl(phenylselanyl)methylene)-1-tosyl-3-
7.01-6.90 (m, 3H), 6.83 (t, J = 8.0 Hz, 2H), 6.47 (s, 2H), 4.26 (d, J
(tosylmethyl)pyrrolidine (3ib): The title compound was = 14.4 Hz, 1H), 4.12 (d, J = 10.4 Hz, 1H), 4.09 (d, J = 6.0 Hz, 1H),
prepared according to the general procedure A to obtain as a 3.87 (d, J = 10.4 Hz, 1H), 3.49 (d, J = 14.4 Hz, 1H), 3.33 (d, J = 14.4
1
white solid (47 mg, yield = 72%); Mp. 69.5-70.8 °C; H NMR Hz, 1H), 2.50 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 144.00,
(400 MHz, CDCl3) δ 7.75 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.4 Hz, 141.62, 140.08, 139.89, 139.39, 137.09, 135.78, 134.14, 131.89,
2H), 7.39 (d, J = 8.0 Hz, 2H), 7.26-7.23 (m, 2H), 7.14-7.11 (m, 3H), 130.38, 129.85, 129.28, 129.26, 128.81, 128.57, 128.26, 128.14,
7.09-6.99 (m, 5H), 6.73 – 6.71 (m, 2H), 4.13 (d, J = 14.4 Hz, 1H), 127.71, 127.21, 127.15, 126.39, 62.07, 58.90, 54.23, 52.61,
3.88 (d, J = 14.4 Hz, 1H), 3.59 (d, J = 10.0 Hz, 1H), 3.33 (d, J = 9.6 21.66; IR (neat) λ max 3060, 2929, 1898, 1745, 1647, 1583,
Hz, 1H), 3.00 (d, J = 14.4 Hz, 1H), 2.92 (d, J = 14.0 Hz, 1H), 2.48 1397, 1334, 1158, 1088, 1025, 828, 753, 692, 597, 550, 4664;
(s, 3H), 2.41 (s, 3H), 1.19 (s, 3H). 13C NMR (101 MHz, CDCl3) δ HRMS (ESI) calcd for C37H33NO4S2ClSe [M+H]+ 734.0705; found:
144.43, 143.90, 141.11, 138.18, 137.52, 135.97, 131.65, 129.79, 734.0713.
129.71, 129.10, 128.62, 128.23, 128.15, 127.62, 127.49, 127.39, (Z)-3-(((4-fluorophenyl)sulfonyl)methyl)-3-phenyl-4-
127.25, 61.92, 59.45, 53.80, 46.31, 24.41, 21.61, 21.56; IR (neat) (phenyl(phenylselanyl)methylene)-1-tosylpyrrolidine (3be):
λ max 3056, 2979, 2934, 2863, 1812, 1731, 1593, 1454, 1329, The title compound was prepared according to the general
1156, 1086, 1049, 819, 740, 670, 572; HRMS (ESI) calcd for procedure A to obtain as a white solid (48 mg, yield = 68%); Mp.
C33H34NO4S2Se [M+H]+ 652.1094; found: 652.1091.
(Z)-3-phenyl-4-(phenyl(phenylselanyl)methylene)-3-
148.9-149.4 °C; 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.4 Hz,
2H), 7.53-7.50 (m, 2H), 7.41 (d, J = 8.0 Hz, 2H), 7.13-7.05 (m, 9H),
((phenylsulfonyl)methyl)-1-tosylpyrrolidine (3ba): The title 7.03-7.00 (m, 2H), 6.98-6.97 (m, 1H), 6.93-6.89 (m, 1H), 6.82 (t,
compound was prepared according to the general procedure A J = 8.0 Hz, 2H), 6.47 (s, 2H), 4.27 (d, J = 14.4 Hz, 1H), 4.11 (t, J =
to obtain as a white solid (54 mg, yield = 77%); Mp. 165.2-166.25 14.0 Hz, 2H), 3.89 (d, J = 10.0 Hz, 1H), 3.50 (d, J = 14.4 Hz, 1H),
°C; 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.2 Hz, 2H), 7.55-7.51 3.34 (d, J = 14.8 Hz, 1H), 2.50 (s, 3H). 13C NMR (101 MHz, CDCl3)
(m, 3H), 7.42-7.37 (m, 4H), 7.13-7.07 (m, 8H), 7.00-6.97 (m, 2H), δ 165.4 (d, JC-F = 254.6 Hz) 143.99, 140.83 (d, JC-F = 170.1 Hz),
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137.12, 135.76, 131.89, 130.32, 130.25, 130.15, 129.84, 129.25, 2929, 2301, 1909, 1742, 1597, 1472, 1330, 1156, 1088, 818,
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128.57, 128.24, 128.13, 127.73, 127.17, 127.12, 126.39, 116.26 679, 558; HRMS (ESI) calcd for C39H38NO4DSO2SI:e10[M.10+3H9/]D07G2C80.10430217B;
(d, JC-F = 22.6 Hz) 62.10, 58.91, 54.25, 52.63, 21.65; IR (neat) λ found: 728.1406.
max 3416, 3062, 2927, 1741, 1655, 1590, 11484, 1336, 1232, (Z)-4-(((3-fluorophenyl)selanyl)(phenyl)methylene)-3-phenyl-
1154, 1089, 833, 752, 681, 554, 550; HRMS (ESI) calcd for 1-tosyl-3-(tosylmethyl)pyrrolidine (3bi): The title compound
C37H33NO4S2SeF [M+H]+ 718.1000; found: 718.0999.
(Z)-3-phenyl-4-(phenyl(phenylselanyl)methylene)-1-tosyl-3-
(((4-(trifluoromethyl)phenyl)sulfonyl)methyl)pyrrolidine
was prepared according to the general procedure A to obtain as
a white solid (44 mg, yield = 62%); Mp. 141.6-142.3 °C; 1H NMR
(400 MHz, CDCl3) δ 7.78 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.4 Hz,
(3bf): The title compound was prepared according to the 2H), 7.41 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 7.17-7.05
general procedure A to obtain as a white solid (53 mg, yield = (m, 5H), 7.01-6.90 (m, 3H), 6.84-6.81 (m, 4H), 6.47 (s, 2H), 4.39
70%); Mp. 138.4-139.5 °C; 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J (d, J = 14.0 Hz, 1H), 4.11 (d, J = 14.4 Hz, 1H), 4.02-3.97 (m, 2H),
= 8.3 Hz, 2H), 7.59 (s, 3H), 7.43 (d, J = 7.9 Hz, 2H), 7.15 – 7.06 3.48 (d, J = 14.4 Hz, 1H), 3.33 (d, J = 14.4 Hz, 1H), 2.49 (s, 3H),
(m, 5H), 7.04 (d, J = 4.0 Hz, 4H), 7.02 – 6.98 (m, 2H), 6.95 (dt, J = 2.40 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 161.89 (d, JC-F = 247.9
8.6, 1.3 Hz, 1H), 6.86 (t, J = 7.7 Hz, 2H), 6.50 (d, J = 6.1 Hz, 2H), Hz), 144.45, 144.01, 142.40 (d, JC-F = 120.3 Hz) 137.70 (d, JC-F
=
4.18 (dt, J = 23.5, 12.4 Hz, 3H), 3.84 (d, J = 10.3 Hz, 1H), 3.52 (t, 116.4 Hz), 131.82, 130.86 (d, JC-F = 3.1 Hz), 129.83, 129.74,
J = 12.8 Hz, 1H), 3.36 (d, J = 14.8 Hz, 1H), 2.52 (s, 3H). 13C NMR 129.67, 129.57, 129.50, 129.24, 129.19, 128.23 (d, JC-F = 13.6
(101 MHz, CDCl3) δ 144.14, 142.46 (d, JC-F = 318.2 Hz), 138.27 (d, Hz), 127.35, 127.32, 127.20, 127.12, 126.13, 122.05, 121.86,
JC-F = 247.7 Hz), 135.90, 131.91, 130.58, 129.89, 129.31, 128.59, 115.14, 114.93, 61.27, 59.30, 54.82, 52.46, 21.66, 21.55; IR
128.27, 128.23, 128.04 (d, JC-F = 100.0 Hz), 127.59, 127.31 s(d, (neat) λ max 3056, 2937, 1919, 1588, 1464, 1328, 1158, 1080,
JC-F = 1.9 Hz), 127.21, 126.47, 126.10, 126.07, 62.28, 58.66, 829, 746, 681, 558; HRMS (ESI) calcd for C38 H35NO4S2SeF [M+H]+
53.99, 52.64, 21.67; IR (neat) λ max 3060, 2931, 1592, 1484, 732.1157; found: 732.1151.
1444, 1402, 1326, 1162, 1096, 1058, 832,745, 700, 664, 598, (Z)-3-phenyl-4-(phenyl(thiophen-2-ylselanyl)methylene)-1-
550; HRMS (ESI) calcd for C38H33NO4S2SeF3 [M+H]+ 768.0968; tosyl-3-(tosylmethyl)pyrrolidine (3bj): The title compound was
found: 768.0962.
(Z)-3-((naphthalen-1-ylsulfonyl)methyl)-3-phenyl-4-
prepared according to the general procedure A to obtain as a
yellow solid (47 mg, yield = 65%); Mp. 98.2-99.1 °C; 1H NMR (400
(phenyl(phenylselanyl)methylene)-1-tosylpyrrolidine (3bg): MHz, CDCl3) δ 7.81 (d, J = 8.4 Hz, 2H), 7.43 (dd, J = 8.4, 2.0 Hz,
The title compound was prepared according to the general 2H), 7.19-7.17 (m, 2H), 6.94 (t, J = 7.2 Hz, 2H), 6.85-6.83 (m, 2H),
procedure A to obtain as a white solid (49 mg, yield = 66%); Mp. 6.69-6.65 (m, 2H), 6.44 (s, 2H), 4.36 (d, J = 14.4 Hz, 1H), 4.11 (d,
166.2-166.8 °C; 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 1.6 Hz, J = 14.0 Hz, 1H), 4.03 (d, J = 10.4 Hz, 1H), 3.95 (d, J = 10.0 Hz,
1H), 7.88 (dd, J = 7.2, 4.0 Hz, 2H), 7.83 (d, J = 8.4 Hz, 1H), 7.79- 1H), 3.47 (d, J = 14.8 Hz, 1H), 3.31 (d, J = 14.4 Hz, 1H), 2.50 (s,
7.77 (m, 2H), 7.67-7.59 (m, 2H), 7.49 (dd, J = 8.8, 2.0 Hz, 1H), 3H), 2.39 (s, 3H).13C NMR (101 MHz, CDCl3) δ 144.36, 143.98,
7.37 (d, J = 8.0 Hz, 2H), 7.11-7.07 (m, 5H), 7.02-6.96 (m, 5H), 142.29, 139.31, 138.28, 137.88, 136.32, 132.27, 132.02, 131.17,
6.90-6.86 (m, 1H), 6.79 (t, J = 8.0 Hz, 2H), 6.46 (s, 2H), 4.32 (d, J 129.85, 129.64, 129.28, 128.17, 127.55, 127.35, 127.21, 127.09,
= 14.4 Hz, 1H), 4.14 (d, J = 4.4 Hz, 1H), 4.11 (d, J = 8.0 Hz, 1H), 127.00, 126.29, 121.33, 61.66, 58.98, 53.86, 52.65, 21.66, 21.54;
3.97 (d, J = 10.4 Hz, 1H), 3.58 (d, J = 14.8 Hz, 1H), 3.40 (d, J = 14.6 IR (neat) λ max 3056, 2932, 1915, 1597, 1468, 1331, 1156, 1085,
Hz, 1H), 2.49 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 143.91, 1034, 902, 825, 702, 555; HRMS (ESI) calcd for C36H34NO4S3Se
142.10, 140.29, 137.88, 137.17, 135.69, 135.00, 131.94, 131.87, [M+H]+ 720.0815; found: 720.0814.
130.19, 129.82, 129.42, 129.35, 129.27, 129.22, 128.55, 128.14, (Z)-3-phenyl-4-(phenyl(p-tolylthio)methylene)-1-tosyl-3-
128.12, 128.05, 127.80, 127.58, 127.10, 126.31, 121.91, 61.78, (tosylmethyl)pyrrolidine (3bk): The title compound was
59.15, 54.40, 52.66, 21.66; IR (neat) λ max 3057, 2926, 1956, prepared according to the general procedure A to obtain as a
1815, 1743, 1592, 1482, 1452, 1331, 1156, 1085, 824, 752, 671, white solid (53 mg, yield = 78%); Mp. 159.7-160.3 °C; 1H NMR
596, 550, 490; HRMS (ESI) calcd for C41H36NO4S2Se [M+H]+ (400 MHz, CDCl3) δ 7.79 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.0 Hz,
750.1251; found: 750.1249.
(Z)-3-phenyl-4-(phenyl(p-tolylselanyl)methylene)-1-tosyl-3-
2H), 7.41 (d, J = 7.6 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 7.14-7.09
(m, 5H), 6.94-6.89 (m, 3H), 6.84-6.79 (m, 4H), 6.49 (d, J = 6.0 Hz,
(tosylmethyl)pyrrolidine (3bh): The title compound was 2H), 4.50 (d, J = 14.4 Hz, 1H), 4.18 (d, J = 14.4 Hz, 1H), 3.99 (d, J
prepared according to the general procedure A to obtain as a = 10.0 Hz, 1H), 3.93 (d, J = 10.0 Hz, 1H), 3.47 (d, J = 14.4 Hz, 1H),
1
white solid (58 mg, yield = 80%); Mp. 135.8-136.5 °C; H NMR 3.29 (d, J = 14.8 Hz, 1H), 2.49 (s, 3H), 2.40 (s, 3H), 2.19 (s, 3H).
(400 MHz, CDCl3) δ 7.78 (d, J = 8.2 Hz, 2H), 7.43-7.41 (m, 4H), 13C NMR (101 MHz, CDCl3) δ 144.39, 143.91, 143.40, 140.65,
7.17 (d, J = 8.0 Hz, 2H), 7.11-7.06 (m, 5H), 6.96 (d, J = 8.4 Hz, 2H), 138.37, 137.87, 136.23, 133.60, 131.87, 129.80, 129.71, 129.65,
6.92-6.88 (m, 1H), 6.82-6.78 (m, 4H), 6.44 (s, 2H), 4.33 (d, J = 129.25, 128.27, 128.22, 128.12, 127.38, 127.29, 127.12, 127.04,
14.0 Hz, 1H), 4.10 (d, J = 14.0 Hz, 1H), 4.03 (d, J = 10.4 Hz, 1H), 126.18, 61.26, 59.28, 53.69, 52.14, 21.68, 21.56, 21.04; IR (neat)
3.94 (d, J = 10.0 Hz, 1H), 3.47 (d, J = 14.4 Hz, 1H), 3.31 (d, J = 14.8 λ max 3046, 2933, 2586, 1910, 1798, 1713, 1596, 1476, 1332,
Hz, 1H), 2.49 (s, 3H), 2.38 (s, 3H), 2.19 (s, 3H). 13C NMR (101 1156, 1084, 908, 819, 748, 676, 555; HRMS (ESI) calcd for
MHz, CDCl3) δ 144.31, 143.88, 142.52, 140.02, 138.29, 138.12, C39H38NO4S3 [M+H]+ 680.1963; found: 680.1963.
137.26, 135.71, 131.93, 130.38, 129.78, 129.60, 129.34, 129.24, (Z)-3-phenyl-4-(phenyl(phenylselanyl)methylene)-3-
128.15, 127.33, 127.03, 127.00, 126.94, 126.30, 124.21, 61.69, ((phenylselanyl)methyl)-1-tosylpyrrolidine (3ba’): The title
59.11, 54.44, 52.53, 21.65, 21.52, 21.07; IR (neat) λ max 3050, compound was prepared according to the general procedure A
8 | J. Name., 2012, 00, 1-3
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to obtain as a lite yellow solid (55 mg, yield = 77%); Mp. 171.2- Hz, 1H), 3.71 (d, J = 9.2 Hz, 1H), 3.56 (d, J = 9.3 Hz, 1H), 3.33 (d,
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1
171.7 °C; H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 8.4 Hz, 2H), J = 12.2 Hz, 1H), 3.22 (d, J = 12.2 Hz, 1H)D, 2O.I4: 180.(1s0,339H/D)0. GCC00N3M21RB
7.33-7.29 (m, 4H), 7.26-7.22 (m, 3H), 7.19-7.12 (m, 6H), 7.05- (101 MHz, CDCl3) δ 147.04, 145.18, 143.71, 139.44, 134.53,
6.99 (m, 4H), 6.87 (tt, J = 8.8, 1.2 Hz, 1H), 6.74 (t, J = 8.0 Hz, 2H), 132.73, 131.46, 131.43, 129.71, 129.13, 128.90, 128.77, 128.47,
6.37 (s, 2H), 4.47 (d, J = 14.4 Hz, 1H), 4.06 (d, J = 14.4 Hz, 1H), 128.43, 128.11, 127.85, 127.10, 126.97, 126.29, 126.20, 125.49,
3.73 (d, J = 13.2 Hz, 1H), 3.57 (d, J = 9.2 Hz, 1H), 3.24 (d, J = 12.0 121.88, 61.77, 56.90, 55.74, 35.15, 21.64; IR (neat) λ max 3061,
Hz, 1H), 3.03 (d, J = 12.0 Hz, 1H), 2.48 (s, 3H). 13C NMR (101 MHz, 2937, 2866, 1731, 1592, 1527, 1462, 1347, 1245, 1165, 1089,
CDCl3) δ 145.10, 143.70, 142.85, 137.43, 135.29, 132.66, 1023, 918, 820, 737, 683, 554, 464; HRMS (ESI) calcd for
131.55, 131.33, 129.71, 129.48, 129.11, 128.94, 128.58, 128.16, C35H32NO2S2Se2 [M+H]+ 722.0205; found: 722.0204.
127.84, 127.04, 126.86, 126.80, 126.72, 126.23, 61.86, 56.15, (E)-4-benzylidene-3-phenyl-3-((phenylthio)methyl)-1-
55.02, 35.88, 21.64; IR (neat) λ max 3442, 3057, 2926, 1740, tosylpyrrolidine (5ba): The title compound was prepared
1672, 1586, 1447, 1346, 1161, 1094, 918, 880, 821, 743, 692, according to the general procedure B to obtain as a white solid
1
592, 553, 505, 465; HRMS (ESI) calcd for C37H34NO2SSe2 [M+H]+ (40 mg, yield = 80%); Mp. 140.2-140.9 °C; H NMR (400 MHz,
716.0641; found: 716.0643.
(Z)-4-((3-nitrophenyl)(phenylselanyl)methylene)-3-phenyl-3-
CDCl3) δ 7.61 (d, J = 8.0 Hz, 2H), 7.31-7.26 (m, 4H), 7.25-7.22 (m,
2H), 7.20-7.14 (m, 3H), 7.02-6.99 (m, 5H), 6.82 (d, J = 6.8 Hz, 2H),
((phenylselanyl)methyl)-1-tosylpyrrolidine (3ia’): The title 6.64 (s, 1H), 4.33 (dd, J = 13.6, 2.0 Hz, 1H), 3.98 (dd, J = 14.0, 2.4
compound was prepared according to the general procedure A Hz, 1H), 3.69 (d, J = 9.6 Hz, 1H), 3.61 (d, J = 8.4 Hz, 1H), 3.37-3.30
to obtain as a yellow solid (38 mg, yield = 50%); Mp. 82.1-83.5 (m, 2H), 2.44 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 144.34,
°C; 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.0 Hz, 2H), 7.66 (ddd, 143.57, 141.10, 137.12, 135.49, 132.16, 129.63, 129.61, 128.82,
J = 8.0, 2.4, 1.2 Hz, 1H), 7.42-7.37 (m, 4H), 7.28-7.26 (m, 3H), 128.58, 128.47, 127.91, 127.71, 127.09, 127.07, 126.45, 126.22,
7.15-7.11 (m, 3H), 7.09-7.07 (m, 3H), 7.03-6.98 (m, 2H), 6.95- 125.87, 61.04, 55.45, 54.06, 40.08, 21.57; IR (neat) λ max 3054,
6.92 (m, 2H), 6.88 (t, J = 8.0 Hz, 1H), 6.66 (s, 1H), 4.42 (d, J = 14.8 2936, 2858, 1950, 1891, 1808, 1662, 1590, 1478, 1343, 1255,
Hz, 1H), 4.20 (d, J = 14.8 Hz, 1H), 3.95 (d, J = 9.6 Hz, 1H), 3.56 (d, 1164, 1092, 1027, 917, 825, 750, 687, 592, 547, 492; HRMS (ESI)
J = 9.6 Hz, 1H), 3.31 (d, J = 11.6 Hz, 1H), 3.06 (d, J = 12.0 Hz, 1H), calcd for C31H30NO2S2 [M+H]+ 512.1718; found: 512.1720.
2.50 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 146.59, 144.72, 144.03, (E)-4-(4-methylbenzylidene)-3-phenyl-3-((phenylthio)methyl)-
138.79, 135.93, 134.66, 133.24, 131.50, 130.72, 129.85, 129.29, 1-tosylpyrrolidine (5da): The title compound was prepared
128.92, 128.61, 128.37, 128.22, 127.64, 127.48, 127.13, 127.05, according to the general procedure B to obtain as a white solid
1
127.00, 126.19, 124.04, 121.43, 61.78, 55.92, 55.16, 36.33, (32 mg, yield = 61%); Mp. 153.4-153.9 °C; H NMR (400 MHz,
21.68; IR (neat) λ max 3061, 2937, 2866, 1731, 1592, 1527, CDCl3) δ 7.60 (d, J = 8.4 Hz, 2H), 7.33-7.24 (m, 7H), 7.20-7.12 (m,
1462, 1347, 1245, 1165, 1089, 1023, 918, 820, 737, 683, 554, 3H), 7.00 (dt, J = 6.4, 1.6 Hz, 2H), 6.86 (d, J = 7.6 Hz, 2H), 6.72 (d,
464; HRMS (ESI) calcd for C37H33N2O4SSe2 [M+H]+ 761.0491; J = 8.0 Hz, 2H), 6.61 (s, 1H), 4.32 (dd, J = 15.6, 2.0 Hz, 1H), 3.96
found: 761.0497.
methyl(Z)-4-((4-phenyl-4-((phenylselanyl)methyl)-1-
tosylpyrrolidin-3-ylidene)(phenylselanyl)methyl)benzoate
(dd, J = 14.0, 2.4 Hz, 1H), 3.66 (d, J = 9.2 Hz, 1H), 3.61 (d, J = 9.6
Hz, 1H), 3.39 (d, J = 12.8 Hz, 1H), 3.32 (d, J = 12.8 Hz, 1H), 2.41
(s, 3H), 2.22 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 144.42, 143.52,
(3ea’): The title compound was prepared according to the 140.19, 137.25, 136.90, 132.54, 132.15, 129.58, 129.54, 128.77,
general procedure A to obtain as a white solid (43 mg, yield = 128.59, 128.43, 128.41, 127.88, 127.04, 126.46, 126.13, 125.85,
55%); Mp. 148.1-148.6 °C; 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J 61.04, 55.49, 54.11, 39.87, 21.56, 21.08; IR (neat) λ max 3049,
= 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.35-7.31 (m, 4H), 7.26 (d, 2931, 2862, 1805, 1731, 1655, 1591, 1480, 1345, 1257, 1164,
J = 1.2, 1H), 7.25-7.24 (m, 2H), 7.16-7.12 (m, 6H), 7.03-6.99 (m, 1095, 1025, 820, 750, 668, 595, 548, 494; HRMS (ESI) calcd for
4H), 6.38 (s, 2H), 4.50 (d, J = 14.6 Hz, 1H), 4.10 (d, J = 14.8 Hz, C32H32NO2S2 [M+H]+ 526.1874; found: 526.1876.
1H), 3.82 (s, 3H), 3.79 (d, J = 9.6 Hz, 1H), 3.57 (d, J = 9.6 Hz, 1H), (E)-4-(2-fluorobenzylidene)-3-phenyl-3-((phenylthio)methyl)-
3.22 (d, J = 12.0 Hz, 1H), 3.01 (d, J = 12.0 Hz, 1H), 2.49 (s, 3H). 1-tosylpyrrolidine (5ja): The title compound was prepared
13C NMR (101 MHz, CDCl3) 166.60, 144.82, 144.02, 143.83, according to the general procedure B to obtain as a white solid
1
142.33, 135.41, 132.88, 131.55, 131.06, 129.76, 129.19, 128.93, (23 mg, yield = 45%); Mp. 137.7-138.3 °C; H NMR (400 MHz,
128.79, 128.29, 128.24, 128.19, 128.08, 127.59, 127.24, 126.95, CDCl3) δ 7.62 (d, J = 8.0 Hz, 2H), 7.28-7.15 (m, 10H), 7.09-7.05
126.19, 61.92, 56.31, 54.99, 52.01, 35.97, 21.65; IR (neat) λ max (m, 3H), 6.84 (td, J = 9.6, 0.8 Hz, 1H), 6.71 (td, J = 7.6, 0.8 Hz,
3056, 2941, 1720, 1593, 1443, 1347, 1279, 1167, 1103, 1026, 1H), 6.62-6.57 (m, 2H), 4.32 (dd, J = 14.0, 2.0 Hz, 1H), 4.01 (dd,
825, 744, 684, 592, 555, 467; HRMS (ESI) calcd for J = 13.6, 2.0 Hz, 1H), 3.73 (d, J = 9.6 Hz, 1H), 3.63 (d, J = 9.6 Hz,
C39H36NO4SSe2 [M+H]+ 774.0695; found: 774.0699.
(Z)-3-phenyl-4-((phenylselanyl)(thiophen-2-yl)methylene)-3-
1H), 3.41 (d, J = 12.8 Hz, 1H), 3.31 (d, J = 12.8 Hz, 1H), 2.44 (s,
3H). 13C NMR (101 MHz, CDCl3) δ 159.82 (d, JC-F = 245.5 Hz),
((phenylselanyl)methyl)-1-tosylpyrrolidine (3ga’): The title 143.67, 143.43, 136.99, 132.05, 129.98 (d, JC-F = 2.7 Hz), 129.66,
compound was prepared according to the general procedure A 129.58, 129.20, 129.12, 128.85, 128.50, 127.86, 126.67 (d, JC-F
=
to obtain as a yellow solid (57 mg, yield = 79%); Mp. 164.2-164.9 84.1 Hz), 126.50, 123.24, 123.08, 123.04, 118.91, 118.88,
°C; 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 8.4 Hz, 2H), 7.32-7.27 115.10, 114.88, 60.81, 55.11, 54.14, 40.05, 21.56; IR (neat) λ
(m, 6H), 7.25-7.19 (m, 5H), 7.17-7.14 (m, 3H), 7.12-7.08 (m, 2H), max 3055, 2942, 2859, 1930, 1802, 1589, 1471, 1341, 1240,
6.94 (dd, J = 5.1, 1.2 Hz, 1H), 6.40 (dd, J = 5.1, 3.6 Hz, 1H), 5.90 1166, 1088, 1031, 823, 679, 583, 556, 479; HRMS (ESI) calcd for
(dd, J = 3.6, 1.2 Hz, 1H), 4.52 (d, J = 15.1 Hz, 1H), 4.00 (d, J = 15.1 C31H29NO2S2F [M+H]+ 530.1624; found: 530.1628.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 9
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ARTICLE
Journal Name
(E)-4-(3-nitrobenzylidene)-3-phenyl-3-((phenylthio)methyl)-1- 143.65, 140.90, 137.95, 135.46, 132.86, 132.02, 129.69, 129.61,
View Article Online
DOI: 10.1039/D0GC00321B
tosylpyrrolidine (5ia): The title compound was prepared 128.60, 128.41, 127.86, 127.66, 127.62, 127.17, 127.12, 127.05,
according to the general procedure B to obtain as a lite yellow 126.89, 126.34, 126.13, 124.80, 61.05, 58.78, 55.36, 53.50,
solid (23 mg, yield = 42%); Mp. 74.2-74.9 °C; 1H NMR (400 MHz, 39.42, 21.54; IR (neat) λ max 3052, 2939, 2862, 2298, 1914,
CDCl3) δ 7.88 (dd, J = 8.4, 1.6 Hz, 1H), 7.66 (d, J = 8.4 Hz, 2H), 1806, 1746, 1670, 1590, 1445, 1340, 1259, 1092, 1027, 922,
7.58 (s, 1H), 7.31 (d, J = 4.0 Hz, 2H), 7.22-7.16 (m, 9H), 7.09-7.06 829, 743, 682, 584, 554; HRMS (ESI) calcd for C31H29NO2S2Br
(m, 3H), 6.60 (s, 1H), 4.34 (dd, J = 14.0, 2.0 Hz, 1H), 4.07 (dd, J = [M+H]+ 590.0823; found: 590.0823.
14.0, 2.4 Hz, 1H), 3.77 (d, J = 9.6 Hz, 1H), 3.57 (d, J = 9.6 Hz, 1H), (E)-4-benzylidene-3-(((4-chlorophenyl)thio)methyl)-3-phenyl-
3.39 (d, J = 12.8 Hz, 1H), 3.27 (d, J = 12.8 Hz, 1H), 2.46 (s, 3H). 1-tosylpyrrolidine (5bc): The title compound was prepared
13C NMR (101 MHz, CDCl3) δ 147.44, 144.82, 143.87, 143.36, according to the general procedure B to obtain as a white solid
1
136.86, 136.43, 134.23, 131.90, 129.92, 129.72, 128.96, 128.76, (32 mg, yield = 60%); Mp. 188.5-189.3 °C; H NMR (400 MHz,
128.45, 127.96, 127.42, 126.63, 126.29, 123.43, 123.40, 121.77, CDCl3) δ 7.61 (d, J = 7.2 Hz, 2H), 7.28-7.25 (m, 7H), 7.14-7.05 (m,
109.97, 61.21, 55.50, 53.98, 40.24, 21.61; IR (neat) λ max 3064, 5H), 6.93-6.90 (m, 2H), 6.81 (d, J = 7.1 Hz, 2H), 6.64 (s, 1H), 4.31
2932, 2861, 2294, 1950, 1805, 1729, 1590, 1527, 1471, 1345, (dd, J = 14.0, 2.0 Hz, 1H), 3.99 (dd, J = 13.6, 2.0 Hz, 1H), 3.62 (q,
1164, 1092, 1029, 915, 821, 744, 689, 592, 548, 489; HRMS (ESI) J = 9.2 Hz, 2H), 3.31 (s, 2H), 2.44 (s, 3H). 13C NMR (101 MHz,
calcd for C31H29N2O4S2 [M+H]+ 557.1569; found: 557.1570.
CDCl3) δ 144.05, 143.65, 140.85, 135.54, 135.42, 132.25,
(E)-3-phenyl-3-((phenylthio)methyl)-4-(thiophen-2-
132.17, 131.01, 129.60, 128.91, 128.64, 128.47, 127.88, 127.73,
ylmethylene)-1-tosylpyrrolidine (5ga): The title compound was 127.16, 127.14, 126.42, 126.01, 61.00, 55.41, 54.08, 40.36,
prepared according to the general procedure B to obtain as a 21.57; IR (neat) λ max 3053, 2937, 2860, 1897, 1734, 1659,
lite yellow solid (38 mg, yield = 74%); Mp. 63.3-64.0 °C; 1H NMR 1595, 1473, 1341, 1164, 1092, 1025, 922, 823, 747, 680, 588,
(400 MHz, CDCl3) δ 7.63 (d, J = 8.4 Hz, 2H), 7.35-7.26 (m, 8H), 549, 497; HRMS (ESI) calcd for C31H29NO2S2Cl [M+H]+ 546.1328;
7.23-7.14 (m, 3H), 7.10-7.07 (m, 3H), 6.73 (dd, J = 5.2, 3.6 Hz, found: 546.1328.
1H), 6.66 (s, 1H), 6.44 (d, J = 3.6 Hz, 1H), 4.29 (dd, J = 13.6, 1.6 (E)-4-benzylidene-3-(((4-bromophenyl)thio)methyl)-3-
Hz, 1H), 4.00 (dd, J = 13.6, 2.0 Hz, 1H), 3.79 (d, J = 13.2 Hz, 1H), phenyl-1-tosylpyrrolidine (5be): The title compound was
3.75 (d, J = 9.2 Hz, 1 H), 3.54 (d, J = 9.6 Hz, 1H), 3.50 (d, J = 13.2 prepared according to the general procedure B to obtain as a
1
Hz, 1H), 2.44 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 143.70, white solid (29 mg, yield = 50%); Mp. 183.9-184.4 °C; H NMR
143.36, 140.68, 137.47, 137.03, 131.80, 129.90, 129.63, 128.84, (400 MHz, CDCl3) δ 7.60 (d, J = 8.0 Hz, 2H), 7.28-7.23 (m, 9H),
128.78, 128.04, 128.02, 127.26, 126.69, 126.59, 126.35, 118.50, 7.10-7.02 (m, 3H), 6.86-6.60 (m, 4H), 6.64 (s, 1H), 4.31 (dd, J =
61.64, 56.13, 54.12, 39.64, 21.58; IR (neat) λ max 3057, 2931, 14.0, 2.0 Hz, 1H), 3.99 (dd, J = 13.6, 2.0 Hz, 1H), 3.65-3.59 (m,
2860, 2299, 1888, 1679, 1591, 1463, 1341, 1254, 1165, 1092, 2H), 3.35-3.28 (m, 2H), 2.44 (s, 3H). 13C NMR (101 MHz, CDCl3)
1032, 827, 696, 590, 549; HRMS (ESI) calcd for C29H28NO2S3 δ 146.99, 144.03, 143.65, 140.84, 136.24, 135.40, 132.16,
[M+H]+ 518.1282; found: 518.1281.
(E)-4-benzylidene-3-phenyl-3-((p-tolylthio)methyl)-1-
131.81, 131.13, 129.60, 128.64, 128.45, 127.87, 127.73, 127.16,
127.15, 126.41, 126.01, 120.09, 102.90, 61.00, 55.40, 54.06,
tosylpyrrolidine (5bb): The title compound was prepared 40.14, 21.57; IR (neat) λ max 3060, 2942, 2858, 2584, 2504,
according to the general procedure B to obtain as a white solid 2411, 2309, 1947, 1900, 1813, 1760, 1660, 1590, 1465, 1334,
1
(30 mg, yield = 58%); Mp. 151.1-151.6 °C; H NMR (400 MHz, 1165, 1093, 1015, 825, 743, 604, 549; HRMS (ESI) calcd for
CDCl3) δ 7.62 (d, J = 8.4 Hz, 2H), 7.29-7.23 (m, 7H), 7.10-7.03 (m, C31H29NO2S2Br [M+H]+ 590.0823; found: 590.0822.
3H), 7.00-6.98 (m, 2H), 6.93-6.91 (m, 2H), 6.82-6.80 (m, 2H), 3,6a-diphenyl-5-tosyl-4,5,6,6a-tetrahydro-1H-thieno[3,4-
6.63 (s, 1H), 4.32 (dd, J = 13.6, 2.0 Hz, 1H), 3.98 (dd, J = 13.6, 2.0 c]pyrrole (5bf’): The title compound was prepared according to
Hz, 1H), 3.71 (d, J = 9.2 Hz, 1H), 3.59 (d, J = 9.2 Hz, 1H), 3.34 (d, the general procedure B to obtain as a white solid (22 mg, yield
1
J = 12.8 Hz, 1H), 3.27 (d, J = 12.8 Hz, 1H), 2.44 (s, 3H), 2.29 (s, = 48%); Mp. 133.4-134.5 °C; H NMR (400 MHz, CDCl3) δ 7.50-
3H). 13C NMR (101 MHz, CDCl3) δ 144.43, 143.56, 141.07, 7.47 (m, 2H), 7.41-7.39 (m, 4H), 7.38-7.36 (m, 1H), 7.30-7.25 (m,
136.43, 135.51, 133.42, 132.17, 130.43, 129.59, 128.55, 128.48, 5H), 7.13-7.10 (m, 2H), 4.20 (d, J = 14.4 Hz, 1H), 4.16 (d, J = 9.2
127.93, 127.68, 127.05, 127.01, 126.44, 125.80, 61.03, 55.49, Hz, 1H), 4.04 (d, J = 14.0 Hz, 1H), 3.74 (d, J = 10.8 Hz, 1H), 3.40
54.15, 40.88, 21.58, 20.97; IR (neat) λ max 3041, 2932, 2862, (d, J = 9.6 Hz, 1H), 3.10 (d, J = 11.2 Hz, 1H), 2.35 (s, 3H). 13C NMR
2296, 1901, 1811, 1658, 1487, 1343, 1257, 1164, 1093, 1029, (101 MHz, CDCl3) δ 143.34, 141.23, 135.35, 133.78, 132.49,
922, 816, 753, 675, 592, 547, 497; HRMS (ESI) calcd for 132.20, 129.58, 129.01, 128.83, 128.73, 128.15, 127.37, 127.11,
C32H32NO2S2 [M+H]+ 526.1874; found: 526.1876.
126.07, 102.90, 67.64, 59.61, 58.81, 47.76, 44.57, 21.45; IR
(E)-4-benzylidene-3-(((2-bromophenyl)thio)methyl)-3-phenyl- (neat) λ max 3055, 2981, 2921, 2116, 1892, 1810, 1742, 1646,
1-tosylpyrrolidine (5bd): The title compound was prepared 1596, 1541, 1489, 1447, 1401, 1339, 1270, 1223, 1160, 1097,
according to the general procedure B to obtain as a white solid 1056, 1013, 913, 863, 815, 759, 688, 608, 542, 460; HRMS (ESI)
1
(45 mg, yield = 77%); Mp. 141.8-142.3 °C; H NMR (400 MHz, calcd for C25H24NO2S2 [M+H]+ 434.1248; found: 434.1247.
CDCl3) δ 7.62 (d, J = 8.0 Hz, 2H), 7.46 (dd, J = 7.6, 1.2 Hz, 1H), (E)-4-benzylidene-3-phenyl-3-
7.33-7.23 (m, 7H), 7.13-6.96 (m, 5H), 6.86 (dd, J = 7.6, 1.6 Hz, ((phenylthio)methyl)tetrahydrofuran
(5bg):
The
title
1H), 6.83-6.81 (m, 2H), 6.67 (s, 1H), 4.35 (dd, J = 14.0, 2.0 Hz, compound was prepared according to the general procedure B
1H), 4.00 (dd, J = 13.6, 2.0 Hz, 1H), 3.71-3.65 (m, 2H), 3.31-3.25 to obtain as a white solid (20 mg, yield = 55%); Mp. 109.4-110.1
(m, 2H), 2.42 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 144.31, °C; 1H NMR (400 MHz, CDCl3) δ 7.38-7.36 (m, 5H), 7.32-7.28 (m,
10 | J. Name., 2012, 00, 1-3
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Green Chemistry
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Journal Name
ARTICLE
Reibenspies, M. B. Hall and M. Y. Darensbourg,VJie.wAAmrti.clCe hOenlmine.
2H), 7.25-7.19 (m, 2H), 7.18-7.18 (m, 2H), 7.14-7.05 (m, 4H),
6.62 (s, 1H), 4.79 (dd, J = 13.2, 2.0 Hz, 1H), 4.69 (dd, J = 12.8, 2.0
Hz, 1H), 4.38 (d, J = 8.8 Hz, 1H), 4.05 (d, J = 8.8 Hz, 1H), 3.54 (d,
J = 12.4 Hz, 1H), 3.47 (d, J = 12.4 Hz, 1H). 13C NMR (101 MHz,
CDCl3) δ 145.38, 145.05, 137.51, 135.91, 129.49, 128.80,
128.53, 128.48, 127.68, 126.77, 126.72, 126.56, 126.03, 122.72,
81.60, 75.20, 54.02, 39.04; IR (neat) λ max 3053, 2944, 2848,
1566, 1478, 1318, 1249, 1165, 1069, 939, 843, 704, 624, 499;
HRMS (ESI) calcd for C24H23OS [M+H]+ 359.1470; found:
359.1472.
Soc., 2019, 141, 15338-15347. (c) L. Shao, Y. Li, J. Lu and X.
DOI: 10.1039/D0GC00321B
Jiang, Org. Chem. Front., 2019, 6, 2999-3041; (d) X. Peng, C.
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and O. Onomura, Acc. Chem. Res., 2020, 53, 105-120. (c) F. An,
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2
4-methyl-N-(3-phenylprop-2-yn-1-yl)-N-(3-
(phenylthio)propyl)benzenesulfonamide (5oa’): The title
compound was prepared according to the general procedure B
to obtain as a white solid (27 mg, yield = 61%); Mp. 125.3-125.7
°C; 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 8.4 Hz, 2H), 7.32-7.25
(m, 8H), 7.21-7.16 (m, 3H), 7.08 (dt, J = 6.0, 1.6 Hz, 2H), 3.89 (d,
J = 15.6 Hz, 1H), 3.44 (dd, J = 16.4, 2.0 Hz, 1H), 3.32 (dd, J = 11.6,
4.4 Hz, 1H), 3.12 (dd, J = 11.6, 4.0 Hz, 1H), 2.84-2.80 (m, 1H),
2.43 (s, 3H), 1.06 (d, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3)
δ 148.55, 143.64, 139.73, 134.49, 133.15, 129.67, 129.17,
128.87, 128.05, 127.97, 127.67, 127.52, 126.41, 122.45, 49.58,
48.94, 36.98, 21.52, 17.82; IR (neat) λ max 3055, 2969, 2925,
2864, 1807, 1731, 1661, 1588, 1459, 1342, 1237, 1164, 1092,
1023, 940, 809, 754, 687, 561, 471; HRMS (ESI) calcd for
C25H25NO2S2 [M+H]+ 436.1426; found: 436.1451.
3
4
5
6
7
(E)-3-phenyl-4-(phenylmethylene-d)-3-((phenylthio)methyl)-
1-tosylpyrrolidine (6): The title compound was prepared
according to the general procedure B to obtain as a white solid
1
(28 mg, yield = 58%); Mp. 140.8-141.2 °C; H NMR (400 MHz,
CDCl3) δ 7.62 (d, J = 8.2 Hz, 2H), 7.32-7.23 (m, 7H), 7.21-7.11 (m,
3H), 7.11-6.98 (m, 5H), 6.85- 6.80 (m, 2H), 4.33 (d, J = 13.7 Hz,
1H), 3.99 (d, J = 13.7 Hz, 1H), 3.70 (d, J = 9.5 Hz, 1H), 3.62 (d, J =
9.5 Hz, 1H), 3.39-3.30 (m, 2H), 2.44 (s, 3H). 13C NMR (101 MHz,
CDCl3) δ 144.33, 143.56, 140.97, 137.11, 135.41, 132.17,
129.64, 129.60, 128.81, 128.58, 128.48, 127.90, 127.70, 127.09,
127.07, 126.45, 126.22, 125.87, 61.05, 55.42, 54.03, 40.07,
21.57; IR (neat) λ max 3055, 2933, 2858, 1951, 1889, 1807,
1746, 1658, 1590, 1479, 1343, 1257, 1163, 1092, 1027, 914,
825, 692, 591, 546, 487; HRMS (ESI) calcd for C31H28DNO2S2
[M+H]+ 513.1781; found: 513.1780.
8
9
(a) S. Huang, H. Li, T. Xie, F. Wei, C.-H. Tung and Z. Xu, Org.
Chem. Front., 2019, 6, 1663-1666; (b) S. Huang, Z. Chen, H.
Mao, F. Hu, D. Li, Y. Tan, F. Yang and W. Qin, Org. Biomol.
Chem., 2019, 17, 1121-1129; (c) K. Sun, X. Wang, F. Fu, C.
Zhang, Y. Chen and L. Liu, Green Chem., 2017, 19, 1490-1493.
Conflicts of interest
“There are no conflicts to declare”.
10 For recent reviews on enyne reactions see: (a) K. J. Romero,
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Acknowledgements
The authors gratefully acknowledge funding from the Ministry of
Science and Technology (MOST), Taiwan, and the Centre for
Research and Development of Kaohsiung Medical University for
400 MHz NMR, LC-MS and GC-MS analyses.
Notes and references
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