Iodine-promoted cyclization of N-propynyl amides and N-allyl amides via sulfonylation and sulfenylation

Article abstract of DOI:10.1039/c6cc05138c

An iodine-promoted regioselective cyclization of N-propynyl/allyl amides with sulfonyl hydrazides has been developed for the synthesis of 5-methyl-arylsulfonyloxazoles and 5-methyl-arylthiooxazolines via sulfonylation and sulfenylation reactions. The notable features of this reaction are the formation of new C-S and C-O bonds, the broad functional group tolerance, and its applicability to alkyl sulfonyl hydrazides as well as internal alkynes.

Full text of DOI:10.1039/c6cc05138c

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Iodine‐promoted cyclization of N‐propynyl amides and N‐allyl
amides via sulfonylation and sulfenylation
Gopal Chandru Senadi,†,a Bing‐Chun Guo,†,a Wan‐Ping Hu,b and Jeh‐Jeng Wang*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
An iodine‐promoted regioselective cyclization of N‐propynyl/allyl such as aryl,8 peroxy,9 azide,10 trifluoromethyl,10 sulfonyl10 and
amides with sulfonyl hydrazides has been developed for the allylic alkylation11 at the endo carbon of N‐propargylamides
synthesis of 5‐methyl‐arylsulfonyloxazoles and 5‐methyl‐ under transition‐metal catalysis (Scheme 1a). Similarly, the
arylthiooxazolines via sulfonylation and sulfenylation reactions. synthesis of oxazolines from N‐allylamides has been achieved
The notable features of this reaction are the formation of new C‐S with the insertion of a variety of functional groups12 under
and C‐O bonds, the broad functional group tolerance, and its metal‐catalysed as well as metal‐free conditions (Scheme 1a).
applicability to alkyl sulfonyl hydrazides as well as internal
alkynes.
Recently, sulfonyl hydrazides have been used to install
sulfonyl or thioether functional groups in organic molecules,
depending on reaction conditions.13,14 As part of our ongoing
research in metal‐free reactions and oxaza heterocycle
synthesis,15,5a we wish to extend the utilization of sulfonyl
Sulfones and thioethers are important classes of functional
groups with diverse applications as bioactive substituents.1
Likewise, oxazoles and oxazolines are pivotal classes of oxaza
heterocycles because of their widespread use in chemistry and
biological applications.2 Therefore, sulfur‐containing oxaza
heterocyles are of potential biological interest (Figure 1).3
hydrazides to generate ‐iodovinylsulfones from N‐propargyl
amides with I2/TBHP, followed by intramolecular cyclization in
the presence of 1,8‐Diazabicycloundec‐7‐ene (DBU) in a
sequential one‐pot method (Scheme 1b), for the synthesis of
2,5‐disubstituted oxazoles. In addition, we disclose the
synthesis of oxazolines from N‐allylamides through
electrophilic addition to an in situ generated sulfenyl iodide
(Scheme 1c).
Previous work
O
Fe, Cu, Zn, Pd, Ag, Au, Mn, [I]
ref 8-12
O
R
R1
(a)
N
R
N
H
R1 = Ar, OOH, N3, CF3, SO2PhCF3, I, Br,
Cl, SPh, SePh, OH, OAc
Figure 1. Bioactive sulfur‐containing oxazole and oxazoline heterocycles.
1. I2 50 mol%
This work
R2
In the last decade, N‐propargyl amides have gained
significant popularity in the synthesis of oxazoles and
oxazolines;4,5 however, difficulties in controlling exo vs endo
selectivity6 and low feasibility with internal alkynes7 are major
drawbacks. Recently, an alternative strategy was used to
overcome this issue by in situ installation of functional groups
TBHP (2.0 equiv)
CH3CN, 90 o
N
O
S
(b)
C
R1
O
R3
2. DBU (2.0 equiv)
THF
O
O
R2
R3
O
S
NH2
O
Metal-free
N
H
R1
N
N
H
I2 (1.0 equiv)
Toluene
reflux
(c)
R3
S
R1
O
Scheme 1. Previous studies and this work towards the in situ functionalization of
a. Department of Medicinal and Applied Chemistry, Kaohsiung Medical University,
No. 100, Shiquan 1st Rd, Sanmin District, Kaohsiung City, 807, Taiwan.
b. Department of Biotechnology, Kaohsiung Medical University, No. 100, Shiquan 1st
Rd, Sanmin District, Kaohsiung City, 807, Taiwan.
† These two authors contributed equally.
Electronic Supplementary Information (ESI) available: [details of any
N‐propynyl or N‐allyl amide
Our preliminary investigation began with propargyl amide
1a and tosyl hydrazide 2a as model substrates, as shown in
supplementary information available should be included here]. See Table 1. To our surprise, N‐((E)‐2‐iodo‐3‐tosyl‐allyl)benzamide
DOI: 10.1039/x0xx00000x
3aa was obtained in 67% when these substrates were treated
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Table 1. Optimization of the reaction conditionsa
The scope of this methodology was investigated by
screening N‐propynylamides and aryl sulfonyl
hydrazides ) under the standard conditions, as shown in
1(a‐m)
2(a‐h
Table 2. The reaction worked well with benzene sulfonyl
hydrazide (2b) as well as with a series of substituents of aryl
functionalities such as p‐MeO (2c), p‐F (2d), p‐Cl (2e), p‐Br (2f),
yield (%)
3aab
I source (x
equiv)
oxidant (y
equiv)
and p‐CF3 (2g) to afford oxazole derivatives
4(ab‐ag) in 50‐95%
entry
solvent
4aac
62
20
21
70
45
54
60
59
35
‐
‐
‐
‐
‐
‐
‐
‐
yield. Surprisingly, the reaction worked with mesyl hydrazide
1
2
3
4
5
6
7d
8
9e
NIS (50)
TBAI (50)
KI (50)
I2 (50)
I2 (25)
I2 (50)
I2 (50)
I2 (50)
I2 (50)
I2 (50)
I2 (50)
I2 (50)
I2 (50)
I2 (50)
I2 (50)
I2 (50)
I2 (50)
I2 (50)
I2 (50)
I2 (50)
I2 (50)
I2 (50)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (1.5)
TBHP (2)
CHP (2)
TBHP(2)
DTBP (2)
H2O2 (2)
K2S2O8 (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
1,4‐dioxane
THF
67
25
26
75
50
60
65
64
40
<10
<10
<10
15
<5
0
(
2h) to produce the corresponding alkyl derivative 4ah, albeit
in low yield. Substituted phenyl groups were tested at R1,
including electron‐donating groups such as p‐Me (1b), p‐MeO
(
1c) and m‐MeO (1d), as well as electron‐withdrawing groups
such as p‐F (1e), p‐Cl (1f), p‐Br (1g), p‐I (1h), p‐CF3 (1i) and p‐
NO2 1j). The reaction proceeded well to give compounds
ba ja) at 40‐74% yields. Cumene hydroperoxide (CHP) was
(
4(
‐
required for p‐MeO (1c) and p‐I (1h) due to low yields with
TBHP. The reaction underwent smooth conversion when the
10
11f
12
13
14
15
16
17
18g
19h
20i
21j
22k
23
aryl group was replaced with alkyl (1k) and heteroaryl (1m
groups to generate ka la) in moderate yields. Finally, the
reaction also worked well with internal alkyne 1m to produce
4ma at a 68% yield. The structures of compounds 4ab 4ac
4ad 4af
4ag and 4ma were confirmed by X‐ray analysis.16
)
4( ‐
,
,
DMSO
DMF
,
,
0
toluene
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
<10
75
75
75
75
75
‐
Table 2. Scope of N‐propynylamides and sulfonyl hydrazidesa,b
21
30
45
63
64
‐
a
Reaction condition: 1a (1.0 mmol), 2a (2.0 mmol), iodine source (x equiv),
oxidant (y equiv), solvent (2.0 mL) and stirred for 2 h at 90 ꢀ, then cooled to rt
and diluted with THF (1.0 mL) followed by addition of DBU (2.0 equiv) and stirred
at rt for another 2h unless otherwise noted. b Determined by GC‐mass analysis. c
Isolated yields. d 1.5 mmol of 2a was used e TBHP (5‐6 M in decane). f 30% H2O2. g
h
i
DABCO (2.0 equiv). K2CO3 (2.0 equiv). Cs2CO3 (2.0 equiv). j 1.0 equiv DBU was
used. k DBU (2.0 equiv) was added without THF.
with NIS (50 mol %) and TBHP (2.0 equiv) in acetonitrile for 2 h
at 90 °C. The resultant compound was further treated with 2.0
equiv of DBU and THF (1.0 mL) to yield 2‐phenyl‐5‐
(tosylmethyl)oxazole 4aa in 62% yield in a sequential one‐pot
reaction (Table 1, entry 1). The structure of compound 4aa was
confirmed using X‐ray analysis.16 Subsequent work (Table 1,
entries 2‐4) revealed that 50 mol% I2 followed by treatment
with DBU gave 4aa at a 70% yield. Lowering the quantities of
I2, TBHP, and tosyl hydrazide, or screening other oxidants such
as CHP, TBHP (5‐6 M decane), DTBP, 30% H2O2, and K2S2O8,
resulted in lower yields (Table 1, entries 5‐12). The effect of
solvents was tested using dioxane, THF, DMSO, DMF, and
toluene (Table 1, entries 13‐17). However, no solvents resulted
in improved yields. Bases besides DBU, such as DABCO, K2CO3
and Cs2CO3, led to lower conversion (Table 1, entries 18‐20).
The yield of 4aa was reduced when only 1.0 equiv of DBU was
used or when THF was omitted (Table 1, entries 21‐22). The
reaction gave a complex mixture in the absence of iodine
(Table 1, entry 23). Thus, of the reaction conditions screened
in Table 1, entry 4 was chosen as the optimum conditions.
a
Reaction conditions: compound 1a‐m (1.0 mmol), sulfonyl hydrazide 2a‐h (2.0
mmol), I2 (50 mol%), TBHP (2.0 equiv), CH3CN (2.0 mL), 90 °C, 2‐5 h, then DBU
b
c
(2.0 equiv), THF (1.0 mL), rt, 2‐5 h. isolated yields. CHP was used instead of
TBHP. c Without the addition of DBU the intermediate 3ja' was isolated at a 45%
yield; the structure was confirmed by X‐ray. After adding DBU (2.0 equiv)
reaction was stirred for 24 h at 80 oC.
d
The synthetic feasibility of this procedure was extended to
the reaction of '‐disubstituted propynyl amides 1(n‐o) with
tosyl hydrazide (2a) for the synthesis of vinyl sulfones as
shown in Scheme 2 (eqs. 1 and 2). The reaction went smoothly
to produce vinyl sulfones 4na
structure of 4oa was confirmed by X‐ray analysis.16
‐oa in 50‐53% yields. The
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under the standard conditions from Table 3 with TEMPO gave
the compound 5aa at a 55% yield (Scheme 3, eq. 5). These
results suggest that the sulfonylation reaction proceeds via
radical reaction and that the sulfenylation proceeds through a
non‐radical pathway.
Scheme 2. Synthesis of vinyl sulfones.
Following the successful synthesis of the oxazole
derivatives, we investigated the scope of the reaction between
N‐allyl benzamide (5a) and tosyl hydrazide (2a) using the
standard conditions. However, the desired oxazoline was not
obtained; instead, N‐(2‐hydroxy‐3‐tosylpropyl)benzamide 6aa’
was isolated at low yields.17 Interestingly, 5‐((p‐
Scheme 3. Control studies.
tolylthio)methyl)‐4,5‐dihydro‐2‐phenyloxazole
6aa
was
A plausible mechanism for the formation of oxazoles and
oxazolines based on control studies and previously reported
literatures13,14e,f is shown in Scheme 4. The reaction is
isolated at 65% yields when the conditions were changed to I2
(1.0 equiv) in toluene at 120 °C for 5 h (Table 3).18 Next, the
scope the reaction between allyl amides and aryl hydrazides
was evaluated using benzene sulfonyl hydrazide (2b) and 4‐
bromo benzene sulfonyl hydrazide (2f). The reaction was
successful in both the cases, affording oxazoline derivatives
6ab and 6af at 62% and 50% yields, respectively. The reaction
also worked for mesyl hydrazide (2h) to give corresponding
alkylthioethers 6ah and 6bh in moderate yields. Finally, the
reaction also proceeded with the R1 substituted aryls p‐Me
proposed to involve a sulfonyl radical
the reaction of I2 with TBHP through the elimination of N2. The
attack of the resulting sulfonyl radical to N‐propynylamide
gives the vinyl radical . The vinyl radical is trapped by I2 to
afford Then, the reaction of the
‐iodovinylsulfone G 13e
iodovinylsulfone with DBU gives the 5‐exo‐trig product . The
followed by the
19b (Scheme 4A).
E, which is generated by
E
1
F

.
‐
H
elimination of HI from intermediate
isomerization gave the oxazole derivative
H
4
(
5b) and p‐F (5c), to produce 6(ba‐ca) at 40‐43% yields.
Table 3. Scope of N‐allylamides and sulfonyl hydrazidesa,b
O
N
N
O
R3
I2 1.0 (equiv)
S
S
S
NH2
O
R3
N
H
R1
N
Toluene
120 oC , 5-12 h
R1
O
H
2a, b, f, h
6
5a-c
N
N
S
S
O
O
O
6aa, 65%(0%)c
6ab, 62%
6af, 50%
Br
N
N
N
S
S
O
S
O
O
6bh, 45%
6ah, 40%
6ba, 43%
N
O
S
F
6ca, 40%
a Reaction conditions: compounds 5a‐c (1.0 mmol), sulfonyl hydrazide 2a, b, f, h
(1.5 mmol), I2 (1.0 equiv), toluene (2.0 mL) at 120 °C for 5‐7 h. b isolated yields. c
In the absence of iodine, S‐(p‐tolyl) 4‐methylbenzenesulfonothioate was isolated
as major product and 1,2‐di‐p‐tolyldisulfane was isolated as minor product with
recovery of 5a.
Scheme 4. Proposed mechanism for oxazoles and oxazolines.
To understand the reaction mechanism, the control
experiments shown in Scheme 3 were carried out. The
reaction of N‐propargyl amide 1a with S‐p‐tolyl‐4‐methyl
benzene sulfonothioate 2a' under the standard condition
without DBU gave trace amounts of N‐((E)‐2‐iodo‐3‐
tosylallyl)benzamide 3aa (Scheme 3, eq. 3). This result suggests
that 2a' is not a key intermediate formed in the reaction.19a
Next, the reaction of 1a and 2a under standard conditions
from Table 2 in the presence of TEMPO gave trace or no
product (Scheme 3, eq. 4). Finally, the reaction of 5a and 2a
On the other hand, upon reaction with iodine, sulfonyl
hydrazide undergoes sequential eliminations of HI and HOI
to form sulfenyl iodide via arylthiodiazonium salt
14e,f The
electrophilic addition of sulfenyl iodide to N‐allylamide
gives the sulfonium intermediate . The 5‐exo‐tet‐cyclization
of intermediate gives the intermediate which is
deprotonated to give the oxazoline derivative
2
N
M.
N
5
O
O
P,
6
.
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Diomedi, R. Giovannini, M. Mari, L. Marsili and E.
Marcantoni, Eur. J. Org. Chem. 2012, 630.
In conclusion, we have developed a metal‐free approach
for the synthesis of 5‐methyl‐arylsulfonyloxazoles by iodine‐
promoted sulfonylation of N‐propynyl amides with sulfonyl
hydrazides followed by DBU‐mediated cyclization. Similarly,
the oxysulfenylation of N‐allyl amides, which proceeded via
the electrophilic addition of in situ generated sulfenyl iodide,
produced 5‐methyl‐arylthiooxazolines. The key features of
these reactions are broad functional group tolerance, mild
conditions, the formation of two new bonds (C‐S and C‐O) and
applicability to alkyl sulfonyl hydrazides as well as to internal
alkynes.
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16 The CCDC number for the compounds 4aa (1465160), 4ab
(1465161), 4ac (1465166), 4ad (1465163), 4af (1465164),
4ag (1465165), 4ma (1465167), 4oa (1465162), and 3ja’
(1473425).
17 When N‐allylbenzamide 5a and tosylhydrazides 2a was
treated with I2/TBHP, the desired oxazoline was not isolated
instead N‐(2‐hydroxy‐3‐tosylpropyl)benzamide 6aa’ was
isolated in less than 10% along with other unidentified
compounds.
18 For complete optimization of reaction condition (see the
ESI†).
2
, 542. (d) A. Alhalib and W. J. Moran, Org. Biomol. Chem.,
19 (a) The sulfonyl radical does not form via the intermediate S‐
p‐tolyl‐4‐methylbenzenesulfonothioate 2a' as proposed in
2014, 12, 795.
6
7
(a) X. Meng and S. Kim, Org. Biomol. Chem., 2011, 9, 4429;
(b) A. S. K. Hashmi, A. M. Schuster, M. Schmuck, and F.
Rominger, Eur. J. Org. Chem., 2011, 4595.
ref 13c; (b) Intermediate
H was proposed based on the
acidity of the methylene proton and result obtained from
Scheme 2.
(a) P. Wipf, Y. Aoyama, and T. E. Benedum, Org. Lett., 2004,
6
, 3593; (b) E. Merkul and T. J. J. Muller, Chem. Commun.,
2006, 4817; (c) G. Bartoli, C. Cimarelli, R. Cipolletti, S.
4 | J. Name., 2012, 00, 1‐3
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