Regioselective iodoamination of terminal ynamides for the synthesis of α-amino-β,β-diiodo-enamides

Article abstract of DOI:10.1039/c6cc00370b

A mild and efficient methodology involving the I₂/TBHP-mediated intermolecular iodoamination of ynamides with amines for the synthesis of α-amino-β,β-diiodo-enamides was developed. This reaction provides the first intermolecular iodoamination o

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Regioselective Iodoamination of Terminal Ynamides
for the Synthesis of αꢀaminoꢀβ,βꢀdiiodoꢀenamides
Cite this: DOI: 10.1039/x0xx00000x
Hai Huang, Luning Tang, Xiaobo Han, Guangke He, Yang Xi, and Hongjun Zhu*
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
stable nature.16 And our group reported a rare 6ꢀexoꢀdig ring closure
A mild and efficient methodology concerning I2/TBHPꢀmediated
intermolecular iodoamination of ynamides with amines for the
synthesis of αꢀaminoꢀβ,βꢀdiiodoꢀenamides was developed. This
reaction provides the first intermolecular iodoamination of
terminal alkynes to diiodoꢀenamines and can be easily applied to
a wide range of substrates.
reaction of ynamides, in which we achieved an intermolecular
iodocyclization of ynamides using acetonitrile as nitrogen
nucleophile reagent.17 More recently, Baell’s group developed regioꢀ
and stereoselective iodoacyloxylations of alkynes and ynamides, by
utilizing a combination of iodobenzene dicarboxylate and iodine as
iodonium reagent.18 Inspired by those results, we envisioned the
possibility of the synthesis of enmines through an iodineꢀmediated
intermolecular iodoamination of ynamides with amines. Following
our ongoing efforts in exploring the reactivity of ynamides,19 We
herein report that intermolecular iodoamination of ynamides could
be achieved under I2/TBHP condition and this iodoamination
revealed a rare entry to 1ꢀdiiodoenamines from terminal alkynes.
1,1ꢀDihaloꢀ1ꢀalkenes are not only important structural motifs
frequently occurring in natural compounds and pharmaceuticals,1 but
also useful and versatile building blocks for organic synthesis,
widening the road to the synthesis of heterocyclic compounds like
the synthesis of 2ꢀoxazolones,2 indoles,3 benzofurans,4
benzothiophenes5 and others.6 The most popular synthesis of 1,1ꢀ
dihaloꢀ1ꢀalkenes concerns the Wittig type reaction between carbonyl
compounds and tetrahalocarbon.7 However, this protocol was always
limited to the synthesis of some special structures. Thus, the
development of other practical synthetic methods for 1,1ꢀdihaloꢀ1ꢀ
alkenes is highly desirable. And up to now, numerous efforts have
been devoted to the achievement of such a goal. For examples, headꢀ
toꢀtail coupling of 1ꢀiodoalkynes,8 iodine mediated electrophilic
addition of 1ꢀiodoalkynes9 and others.10
Enamines on one hand are versatile tools providing key
intermediates for the synthesis of nitrogenꢀcontaining compounds in
organic synthesis.11 And the most popular synthesis of 1,2ꢀ
disubstituted enamines was focused on the condensation of amines
with ketones or aldehydes12 and metal catalyzed hydroamination of
alkynes.13 On the other hand, as shown in Scheme 1, intramolecular
iodoamination (iodine mediated addition of amines to alkynes) of
alkynes is one of the most powerful methodologies for the creation
of azoꢀring structures and further functionalizable iodo components
(path a).14 In path b, although generation of iodoꢀenamines via
intermolecular iodoamination of alkynes would be an alternative
method for the contribution of enamines, it remains a highly
challenging task, which may face the major hurdle that iodine would
generate Nꢀiodoamines in the present of amines rather than activate
the alkynes.15 Despite this, we assumed the type of the
intermolecular iodoamination mentioned above would be achieved if
active alkynes and suitable iodonium reagent were appropriately
chosen. Over the past decade, ynamides have been established as the
ultimate synthetic units because of their electronꢀrich and relatively
Scheme 1. Current achievements and challenges of iodoamination
In the initial experiments, reaction conditions were focused on
optimizing a variety of reaction parameters by a model reaction
between terminal ynamide (1a) and morpholine. First of all, different
normal systems of active iodide ion, such as I2/tertꢀbutyl hydrope
roxide (TBHP), KI/TBHP, Bu4NI/TBHP, NIS, bis(2,4,6ꢀ
collidine)iodonium hexafluorophosphate [I(coll)2·PF6], were tested
(Table 1, entries 1ꢀ5). We found that only I2/TBHP exhibited the
obvious reactivity, and desired intermolecular iodoamination product
2a was isolated in 23% yield along with byproduct 1,2,2ꢀ
triiodovinylamide 3a in 43% yield. Other oxidants including H2O2,
PhI(OAc)2, Oxone, mꢀCPBA were subsequently tested, and none of
them could promote this novel reaction (Table 1, entries 6ꢀ9).
Besides no desired product 2a was observed when the model
reaction was carried out in the presence of I2 without TBHP (Table 1,
entry 10). Next, we screened the reaction in the presence of different
solvents in order to further improve the yield of 2a. When the
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reaction performed in the presence of polar solvent, the desired confirmed via singleꢀcrystal Xꢀray diffraction (For details, see ESI).
product 2a was afforded in poor yields while 3a in moderate to good Terminal ynamides with methyl on the orthoꢀposition in the Nꢀaryl
yield. To our delight, 61%ꢀ66% yield of 2a was isolated when the ring were converted into the corresponding diiodoꢀenamide 2b in
model reaction was carried out in nonpolar solvent, such as benzene acceptable yield (Table 2, entry 2). Ynamides with other groups,
and toluene (Table 1, entries 18ꢀ19). Reduce the amount of such as Me, F, Cl, Br, MeO and CF3 substituted on the metaꢀposition
morpholine form 3.0 to 2.0 equiv, the reaction could form the of the Nꢀaryl ring were able to be converted into the corresponding
desired product 2a but in lower yield (Table 1, entry 20). The effect diiodoꢀenamides in moderate to good yields, and ynamide with
of the loading of I2 showed that 3.0 equiv of I2 gave the lower yield strongly electronꢀwithdrawing group gave higher yield (Table 2,
(Table 1, entry 21). Last, the effect of TBHP loading showed that 3.0 entries 5ꢀ8). Meanwhile, the paraꢀeffect was not obvious for methyl,
equiv of TBHP gave the highest yield (71%) (Table 1, entries 22ꢀ23). bromo or chloro groups on the paraꢀposition of the Nꢀaryl ring, and
corresponding products in the reactions were obtained in 63ꢀ68%
Table 1. Optimization of reaction conditionsa
yields (Table 2, entries 9ꢀ11). Ynamides possessing 2ꢀnaphthyl,
benzo[d][1,3]dioxolꢀ5ꢀyl and benzyl on the Nꢀatom could also
succeed in affording the desired oxazolidineꢀ2,4ꢀdiones in 52ꢀ62%
yields (Table 2, entries 12ꢀ15).
Table 2. I2/TBHP mediated iodoamination of terminal ynamidesa
[I]
Oxidant
(equiv)
Yieldb
2a/3a
nr
Entry
Solvent
(2.0 equiv)
1
2
NIS
I(coll)2·PF6
ꢀꢀ
ꢀꢀ
DCM
DCM
nr
3
4
5
6
KI
Bu4NI
I2
aq.TBHP(2.0)
aq.TBHP(2.0)
aq.TBHP(2.0)
H2O2(2.0)
DCM
DCM
DCM
DCM
nr
nr
23/43
nr
Entry
1
R
Product
Isolated yield (%)
71
73b
34
65
69
70
72
44
76
68
63
66
62
54
52
53
I2
Ph
2a
7
8
9
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
Oxone(2.0)
PhI(OAc)2(2.0)
mꢀCPBA(2.0)
ꢀꢀ
DCM
DCM
DCM
DCM
nr
nr
nr
2
3
4
5
6
7
8
9
10
11
12
13
14
15
oꢀMePh
mꢀMePh
mꢀFPh
mꢀClPh
mꢀBrPh
mꢀMeOPh
mꢀCF3Ph
pꢀMePh
pꢀClPh
pꢀBrPh
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
10
11
12
13
14
15
16
17
18
19
20c
21d
22
23
ꢀꢀ/54
ꢀꢀ/ꢀꢀ
ꢀꢀ/51
ꢀꢀ/52
13/47
ꢀꢀ/71
15/46
24/51
61/12
66/9
59/14
53/19
71/ꢀꢀ
64/ꢀꢀ
aq.TBHP(2.0)
aq.TBHP(2.0)
aq.TBHP(2.0)
aq.TBHP(2.0)
aq.TBHP(2.0)
aq.TBHP(2.0)
aq.TBHP(2.0)
aq.TBHP(2.0)
aq.TBHP(2.0)
aq.TBHP(2.0)
aq.TBHP(2.0)
aq.TBHP(3.0)
aq.TBHP(4.0)
DMF
CH3OH
CH3CN
Dioxane
THF
EA
DCE
benzene
toluene
toluene
toluene
toluene
toluene
2ꢀnaphthyl
benzo[d][1,3]dioxolꢀ5ꢀyl
Bn
pꢀMeOBn
a) Reaction conditions: 1 (0.3 mmol), morpholine (3.0 equiv), I2 (2.0
equiv), and aq. TBHP (3.0 equiv), in toluene (2.0 mL) at rt for 12 h.
b) Scaleꢀup experiment with 3.0 mmol 1a loading.
I2
a) Reaction conditions: 1a (0.3 mmol), morpholine (3.0 equiv), I2 (2.0
equiv), and aq. TBHP (2.0 equiv), in toluene (2.0 mL) at rt for 12 h;
nr = No Reaction; aq. TBHP (70 % in H2O) was used; H2O2 (30% in
H2O) was used. b) Isolated yield. c) morpholine (2.0 equiv) was used.
d) I2 (3.0 equiv) was used.
Under the optimum conditions, we next explored the scope and
limits of various ynamides and amines (Table 3). Ethyl
ethynyl(phenyl)carbamate 1p gave the corresponding product in 65%
yield (Table 3, 2p). Terminal ynesulfonamides were also effective
substrates, and their reactions provided the expected products 2qꢀ2r
in moderate yields (Table 3, 2qꢀ2r). Bearing nꢀbutyl on the Nꢀatom,
terminal ynesulfonamides could also afford the product NꢀbutylꢀNꢀ
(2,2ꢀdiiodoꢀ1ꢀmorpholinovinyl)ꢀ4ꢀmethylbenzenesulfonamide 2s in
33% yield (Table 3, 2s). In addition, substituted indole was
examined and could be transformed into the corresponding products
in 78% yield (Table 3, 2t). By investing a range of amines, we found
that the iodoamination also reacted with thiomorpholine and form
product 2ab in 74 % yield (Table 3, 2ab). tertꢀButyl piperazineꢀ1ꢀ
Scheme 2. Synthesis of terminal ynamides. a) NBS (1.25 equiv),
AgNO3 (5 mol%), acetone, rt; b) CuSO4·5H2O (5 mol%), 1,10ꢀPhen
(10 mol%), K3PO4 (2.0 equiv), toluene, 85 oC; c) TBAF (1.1 equiv),
THF, 0 oCꢀrt.
We synthesized some terminal yanmides 1aꢀ1t to further examine carboxylate was employed in the reaction to give the corresponding
the flexibility of this transition according to the previously reported diiodoenamide 2ac in moderate yield (Table 3, 2ac). Although the
methodology (Scheme 2).20
reaction between 1a and piperidine did work by checking in TLC, no
corresponding diiodoenamides was isolated probably due to the
With the optimum reaction conditions in hand, we next examined
the scope and generality of various ynamides in this transformation, unstable of product 2ad (Table 3, 2ad). On the contrary, ester groups
and the results are summarized in Table 2. It is noteworthy that this in the 4ꢀposition of the piperidine increased the reactivity of
reaction could be scaled up to 3.0 mmol in high yield with similar piperidine and achieved accepted yields of the diiodoenamides 2af
and 2ag (Table 3, 2aeꢀ2af).
efficiency (Table 1, entry 1). And the structure of 2a was further
2 | J. Name., 2014, 00, 1-3
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Table 3. I2/TBHP mediated iodoamination of terminal ynamides
added (Scheme 3, Condition 2). The reaction also gave poor results
only with addition of morpholine (Scheme 3, Condition 3). When
morpholine and TBHP were added, a relatively higher yield of
corresponding product 2a was obtained (Scheme 3, Condition 4).
When I2 and TBHP were utilized for this reaction, the desired
product 2a could not be produced (Scheme 3, Condition 5). All the
results above indicated that Nꢀiodomorpholine is the important
iodonium reagent rather than I2. We also confirmed that the
iodoamination proceeded smoothly to form tertꢀbutyl (2,2ꢀdiiodoꢀ1ꢀ
morpholinovinyl)(phenyl)carbamate 2a in 64ꢀ68% yields in the
presence of radical scavengers like TEMPO and BHT, which
strongly rules out a radical process (Scheme 3, III).
I
O
I
O
I
O
N
N
N
I
I
I
O
N
Ph
O
N
O
N
Ph
S
S
O
O
O
(2p, 65%)
2q
2r
(
I
, 61%)
(
, 58%)
I
O
I
O
I
S
N
N
N
N
N
I
I
O
O
N
O
S
O
O
O
2t
(2s, 33%)
(
, 78%)
2ab
, 74%)
(
O
Boc
R'
I
N
I
I
O
N
N
N
N
I
I
I
O
N
O
O
O
N
O
O
(2ac, 56%)
2ad
, trace)
(
2ae
2af
: R' = Me, 34%
: R' = Et, 36%
a) Reaction conditions: 1 (0.3 mmol), morpholine (3.0 equiv), I2 (2.0
equiv), and TBHP (3.0 equiv), in toluene (2.0 mL) at rt for 12 h.
Then, we started to investigate the synthetic utility of the 1ꢀ
diiodoenmides obtained by our method. To our delight, we found
that tertꢀbutyl (2,2ꢀdiiodoꢀ1ꢀmorpholinovinyl)carbamates was an
ideal structure for the contribution of 3,4,5ꢀmultisubstituted
oxazolones. For example, an interesting SuzukiꢀMiyaura crossꢀ
coupling/cyclization product 4ꢀmorpholinoꢀ3,5ꢀdiphenyloxazolꢀ
2(3H)ꢀone 4a was generated in 62% yield under general Suzuki
condition. Similarly, 2a could afford the Heck crossꢀ
coupling/cyclization product 4b in moderate yield under general
Heck condition.
Scheme 3. Experiments for Mechanistic Study
Scheme 4. Proposed mechanism for the iodoamination of terminal
ynamides.
Although the exact mechanism of this reaction and the actual role
of TBHP in this transition cyclization have not been very clear so
far, a possible tandem reaction pathway was proposed on the basis of
our experimental data above and reported literatures, as shown in
Scheme 4. When treated with Nꢀiodomorpholine generated from the
reaction of I2 with morpholine, terminal ynmaides can produce the
Scheme 3. Pdꢀcatalyzed crossꢀcoupling/cyclization of tertꢀbutyl
(2,2ꢀdiiodoꢀ1ꢀmorpholinovinyl)carbamates.
15b
corresponding 1ꢀiodoynamides intermediate A.8a,
And in the
presence of I+ as a weak Lewis acid, A can next produce iodonium
intermediate B, which is also characterized by keteniminium forms
B′ to increase their electrophilicity and regioselectivity.16 Finally, B′
undergoes a nucleophilic attack by morpholine21 or iodide anion to
produce 1ꢀdiiodoenmides 2 or byproduct 1,2,2ꢀtriiodovinylamides 3.
To understand the mechanism of the reaction, several control
experiments were performed. 1,2,2ꢀtriiodovinylamide 3a could not
produce 2a under recommended reaction conditions, which indicated
that the formation of C−N bond might be formed through a
nucleophilic addition instead of nucleophilic substitution (Scheme 3,
I). Generally, the reaction of iodine and morpholine normally affords
Nꢀiodomorpholine.15 We further our examination to determine
whether Nꢀiodomorpholine plays any role in this novel
transformation system. Thus Nꢀiodomorpholine hydroiodide was
synthesized and further investigated. Only 21% yield of 2a was
given in the reaction between Nꢀiodomorpholine and ynmaides 1a
(Scheme 3, Condition 1), and a 56% yield was obtained when TBHP
22
Probably due to oxidizability of TBHP, iodide anion would be
oxidized decreasing the generation of byproducts 3.23
Conclusions
In summary, we have developed a novel and efficient protocol for
the synthesis of αꢀaminoꢀβ,βꢀdiiodoꢀenamides by I2/TBHP mediated
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intermolecular iodoamination.
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This
method
not
only
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The authors greatly acknowledge the financial support in part by
Provincal Natural Science Foundation of Jiangsu, China (NO.
BK20140937), Postgraduate Innovation Fund of Jiangsu Province
(2015, KYLX15_0797).
,
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, 6
,
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Notes and references
Department of Applied Chemistry, College of Chemistry and Molecular
Engineering, Nanjing Tech University, Nanjing 211816, People’s Republic of
China, Eꢀmail: zhuhj@njtech.edu.cn
,
,
,
,
†
Footnotes should appear here. These might include comments
relevant to but not central to the matter under discussion, limited
experimental and spectral data, and crystallographic data.
Electronic Supplementary Information (ESI) available: [details of any
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