PhI(OAc)2-mediated synthesis of propargylic N, O-acetals by 1, 2-addition of alcohols to allenamides

Article abstract of DOI:10.1016/j.tetlet.2020.151753

A hypervalent iodine mediated electrophilic activation of allenamides was investigated and propargylic N, O-acetals were prepared in moderate to good yields. By the use of PhI(OAc)₂ as oxidant and alcohol as both nucleophile and solvent, allenamides were converted into propargylic N, O-acetals via 1, 2-addition of alcohol to the sulfimide ion intermediate, and no 1, 4-adducts were found.

Full text of DOI:10.1016/j.tetlet.2020.151753

Tetrahedron Letters xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
PhI(OAc) -mediated synthesis of propargylic N, O-acetals
2
by 1, 2-addition of alcohols to allenamides
⇑
Ruohe Huang, Pengyu Xu, Weixiang Wang, Guo Peng, Hui Yu
School of Chemical Science and Engineering, Shanghai Key Lab of Chemical Assessment and Substainability, Tongji University, 1239 Siping Road, Shanghai 200092, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A hypervalent iodine mediated electrophilic activation of allenamides was investigated and propargylic
Received 16 December 2019
Revised 15 February 2020
Accepted 17 February 2020
Available online xxxx
2
N, O-acetals were prepared in moderate to good yields. By the use of PhI(OAc) as oxidant and alcohol as
both nucleophile and solvent, allenamides were converted into propargylic N, O-acetals via 1, 2-addition
of alcohol to the sulfimide ion intermediate, and no 1, 4-adducts were found.
Ó 2020 Published by Elsevier Ltd.
Keywords:
Allenamides
Alcohols
Ph(OAc)
2
N,O-acetals
Introduction
cient approach to the synthesis of amides derivatives [9], and this
methodology could also be applied successfully on the activation of
As an important and versatile building block in organic synthe-
sis, allenamides have attracted much attention for their potential
application in the fields of pharmaceutical and organic chemistry
allenamides (Scheme 1a) [10]. In the presence of NIS, Li explored
the iodofunctionalization of allenamides with alcohols [10b],
imidazoles [10c], and amines [10d] as the nucleophiles, and in
some cases, enamides could be formed as the main products
through the 1, 4-addition process [10e]. On the other hand,
hypervalent iodines were also proved to be efficient reagents for
the activation of carbon-carbon double bonds of enamides, and
the construction of various interesting frameworks has been
achieved by this strategy [11]. To the best of our knowledge, the
electrophilic activation of allenamides with hypervalent iodines
[
1]. Allenamides can be converted into various compounds through
different types of organic transformations, including cycloaddi-
tions [2], transition-metal-catalyzed coupling reactions [3], and
radical reactions [4]. Among these developed methods, 1, 2-addi-
tion of allenamides has emerged as a remarkable strategy for the
synthesis of a-branched N-allylic amides derivatives. For example,
through a gold-catalyzed intermolecular hydroalkoxylation pro-
cess, allylic N, O-acetals could be prepared from allenamides [5];
Catalyzed by gold or palladium, aza-heterocycles such as imidazo-
lidines [6] and quinazolinones [7] could be established via
intramolecular hydroamination or carboamination process; Gold-
catalyzed intramolecular hydroarylation of allenamides provided
a concise access to the construction of tetrahydroisoquinoline scaf-
folds [8]. However, the utilization of these methods in organic syn-
thesis was limited by some certain disadvantages such as low
yields, poor regioselectivity, and the involvement of expensive
transition metals. Thus, the development of an inexpensive and
convenient entry to1, 2-addition of allenamides is still in high
demand.
2
still remains undeveloped. Herein, we report a PhI(OAc) mediated
addition of alcohols to allenamides, affording propargylic N, O-
acetals as the main products (Scheme 1b) [12].
Results and discussion
Initially, N-allenyl-N-benzyl tosylamide (1a) was chosen as the
model substrate to optimize the reaction conditions [10a,13]. As
shown in Table 1, the reaction was firstly examined in MeOH
(
3 4
2.0 mL) with HIO (2a) or HIO (2b) (2.0 equiv) as the
hypervalent iodine at room temperature. One hour later, all the
starting material disappeared monitored by TLC and the product
The activation of carbon-carbon double bonds adjacent to a
nitrogen atom with iodine electrophiles has been known as an effi-
3
a was isolated in 15% and 30% yields (Table 1, entries 1-2).
When iodosylbenzene (2c) and N-tosylimino-phenyliodinane (2d)
was used as the oxidant, the yield of 3a was improved to 45%
and 48% respectively, which indicated that iodine (III) reagent
could serve as a suitable oxidant for this transformation (Table 1,
⇑
Corresponding author.
E-mail address: yuhui@tongji.edu.cn (H. Yu).
https://doi.org/10.1016/j.tetlet.2020.151753
040-4039/Ó 2020 Published by Elsevier Ltd.
0
Please cite this article as: R. Huang, P. Xu, W. Wang et al., PhI(OAc)
2
-mediated synthesis of propargylic N, O-acetals by 1, 2-addition of alcohols to allena-
mides, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151753

2
R. Huang et al. / Tetrahedron Letters xxx (xxxx) xxx
Firstly, a variety of different alcohols were investigated. The reac-
tion of 1a with ethanol was examined, and the product 3b was
obtained in excellent yield (Tables 2 and 3b). Alcohols with longer
carbon chain such as n-propanol, i-propanol, n-butanol, and i-buta-
nol gave moderate yield of the corresponding products (Table 2,
3
c-f). In case of t-butanol, no product could be found and only N-
benzyl tosylamide (BnNHTs, 3g’) was observed (Tables 2 and 3g).
Cylclic alcohol such as cyclobutanol also gave the product in 60%
yield (Tables 2 and 3h). When allylic and benzyl alcohol was sub-
jected to the reaction, the product was isolated in 85% and 64%
yield respectively (Tables 2 and 3i-j). 2-Cyanoethanol and methyl
2
-hydroxyacetate also reacted smoothly with 1a under the present
reaction conditions to afford the corresponding products in 41%
and 59% yields (Tables 2 and 3k-l). Finally, ethylene glycol was
tested under the optimized conditions but the reaction led to com-
plex mixture and no desired product was found (Tables 2 and 3m).
Changing the substituted group on the nitrogen from benzyl to
phenyl gave the corresponding product in 87% yield (Table-
s 2 and 4a). For substrates with methyl group substituted at differ-
ent positions on the phenyl ring, the corresponding products were
also obtained in good yields (Tables 3 and 4b-c). Substrates with
electron-withdrawing group on the phenyl ring also afforded a sat-
isfied yield (Tables 2 and 4d). Substrates with alkyl groups on the
nitrogen performed very well under the standard conditions and
delivered the corresponding products in good yields (Table-
s 2 and 4e-j). N-Acyl and benzoyl protected N-benzyl allenamide
provided the desired products in moderate yields (Table-
s 2 and 4K-I). Furan group was tolerated in this transformation
and the substrate underwent a smooth reaction to afford the pro-
duct in 72% yield (Tables 2 and 4m). Carbamates including benzyl
benzylcarbamate and tert-butyl benzylcarbamate were also tested
using the optimized reaction and the products were obtained in
moderate yields (Tables 2 and 4n-o). Finally, 2-(4-tert-butylphe-
Scheme 1. Synthesis of N, O-acetals from allenamides
2 2
entries 3-4). To our delight, when Ph(OAc) (2e) and Ph(OTFA) (2f)
was used as iodine (III) reagent, all the starting material was
consumed within 0.5 h, and the yield of 3a was improved
significantly and 2e gave better result than 2f (Table 1, entries 5-
6
). Benziodoxoles including 2g and 2h were also examined but to
gave poor yields (Table 1, entries 7-8). The yield of 3a could be
further improved by simply increasing the reaction temperature,
and the best result was obtained when the reaction was carried
out at 50 (Table 1, entries 9–11). K
the reaction but caused lower yield (Table 1, entry 12). When the
amount of PhI(OAc) was reduced to 1.5 equiv, only 55% yield of
a could be isolated (Table 1, entry 13). Changing the solvent to
2 3
CO (1.0 equiv) was added to
2
3
3
a mixture of CH CN and MeOH (1:1) resulted in the formation of
a in only 47 % yield (Table 1, entry 14). On the basis of these
results, entry 10 represents the best conditions.
Under the optimized reaction conditions, the scope of sub-
strates was investigated with the results summarized in Table 2.
3
Table 1
Screening conditionsa
Entry
Oxidant (2.0 equiv)
Solvent (2 mL)
Temp. (°C)
Yield of 3a (%) b
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2e
2e
2e
2e
2e
2e
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
40
50
60
50
50
50
15
30
45
48
63
52
21
23
83
94
72
10
11
12
13
14
c
85
55
47
d
e
CH
3
CN/MeOH = 1:1
a
b
c
The reaction was carried out on 0.2 mmol scale in a tube under air.
Isolated yield.
K
2
CO
Reaction carried out with PhI(OAc)
Reaction carried out in CH CN/MeOH = 1:1.
3
(1.0 equiv) was added to the reaction.
d
e
2
(1.5 equiv).
3
Please cite this article as: R. Huang, P. Xu, W. Wang et al., PhI(OAc)
2
-mediated synthesis of propargylic N, O-acetals by 1, 2-addition of alcohols to allena-
mides, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151753

R. Huang et al. / Tetrahedron Letters xxx (xxxx) xxx
3
Table 2
Reaction scope on alcohols
Table 3
a,b
a,b
Reaction scope on allenamides
a
2
The reaction was performed with 1a (0.2 mmol), PhI(OAc) (0.4 mmol), in ROH
(
2.0 mL) under air at room temperature for 0.5 -1.0 hour in a tube.
Isolated yields.
b
a
The reaction was performed with 1 (0.2 mmol), PhI(OAc)
2
(0.4 mmol), in MeOH
(
2.0 mL) under air at room temperature for 0.5–1.0 h in a tube.
Isolated yields.
nyl)ethenesulfonamide was examined under the optimized reac-
tion conditions to furnish the expected product in 77% yield
b
(Tables 2 and 4p).
Based on our experimental results and precedents in the liter-
ature, [14] a plausible mechanism for the formation of 3 was pro-
posed as depicted in Scheme 2. Initially, the eletrophilic addition
2
of PhI(OAc) to allenamide 1a generated iodo(III) cyclopropane as
the intermediate (Int 1), then Int 1 transformed to conjugated
sulfimide ion (Int 2) via a decyclization process. The key interme-
diate Int 2 underwent reductive elimination of HOAc and
iodobenzene to give Int 3, then 1, 2-nucleophilic addition of alco-
hol to Int 3 gave rise to the final product 3. Theoretically, the 1,
4
-adduct 5 might also be generated as a competitive product
when the reaction was carried out in alcohols with steric hin-
drance, but 5 could not be isolated for its instability, and only
its hydrolysis product N-benzyl tosylamide 3g’ could be found.
This might be the main reason that no desired product was iso-
lated in case of t-butanol.
Scheme 2. Possible mechanism.
Declaration of Competing Interest
Conclusions
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
In conclusion, we have demonstrated a hypervalent iodine
mediated activation of allenamides in alcohols and propargylic N,
O-acetals were obtained in high yields with excellent regioseleciv-
ity. This methodology proceeds rapidly under mild conditions and
is tolerant of broad scope of alcohols and substrates. The mecha-
nism was also discussed and the attempt to prepare the 1, 4-
adducts with other nucleophiles is still currently underway in
our laboratory.
Acknowledgment
Financial support from Tongji University (20123231) is grate-
fully acknowledged.
Please cite this article as: R. Huang, P. Xu, W. Wang et al., PhI(OAc)
2
-mediated synthesis of propargylic N, O-acetals by 1, 2-addition of alcohols to allena-
mides, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151753

4
R. Huang et al. / Tetrahedron Letters xxx (xxxx) xxx
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Please cite this article as: R. Huang, P. Xu, W. Wang et al., PhI(OAc)
2
-mediated synthesis of propargylic N, O-acetals by 1, 2-addition of alcohols to allena-
mides, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151753