Regioselective iodoazidation of alkynes: Synthesis of α,α-diazidoketones

Article abstract of DOI:10.1021/acs.orglett.5b00395

Aryl alkyl alkynes reacted with N-iodosuccinimide (NIS) and trimethylsilyl azide (TMSN₃), leading to α,α-diazidoketones via the regioselective addition of IN₃ to alkynes. Huisgen cyclization of α,α-diazidoketones generated bis-triazo

Full text of DOI:10.1021/acs.orglett.5b00395

Letter
pubs.acs.org/OrgLett
Regioselective Iodoazidation of Alkynes: Synthesis of α,α-
Diazidoketones
Noriko Okamoto, Takuya Sueda, Hideki Minami, Yoshihisa Miwa, and Reiko Yanada*
Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hirokoshingai, Kure, Hiroshima 737-0112, Japan
S
* Supporting Information
ABSTRACT: Aryl alkyl alkynes reacted with N-iodosuccinimide
(NIS) and trimethylsilyl azide (TMSN3), leading to α,α-
diazidoketones via the regioselective addition of IN3 to alkynes.
Huisgen cyclization of α,α-diazidoketones generated bis-triazole
compounds.
lkynes have the potential to be transformed into various
functional groups and are considered as one of the most
to afford α,α-diazidoketone 38 via alkene 2,9 which was
assumed to be an intermediate (Table 1). Alkene 2 was
A
important compounds.1−3 We explored the development of
novel tandem reactions utilizing alkyne reactivity.4 We recently
reported the cleavage of an alkyne triple bond into two nitriles
in the absence of a metal catalyst (Scheme 1).4b Triple bond
a
Table 1. Optimization of Reaction Conditions
Scheme 1. Synthesis of α,α-Diazidoketone and Huisgen
Cyclization
NIS
TMSN3
(equiv)
time
entry (equiv)
conditions
under N2
(day)
2 (%) 3 (%)
1
2
3
4
5
6
7
8
9
2.2
1.1
1.1
2.2
3
2.2
1.1
2.2
1.1
3
2
4
42
9
under N2
under N2
under N2
under N2
under N2
under N2
under N2
under N2
under N2
under N2
2
66
2
60
13
15
<35
38
<26
69
65
12
70
66
2
63
2
trace
7
b
c
2.2
2.2
2.2
1.1
0.5
1.1
1.1
2.2
2.2
2.2
2.2
2.2
2.2
2.2
1
1
19
0.4
0.4
8
trace
trace
35
10
11
12
cleavage of diarylalkynes tends to proceed in the presence of at
least one electron-donating group (EDG) on the benzene ring.
The reaction of aryl alkyl substituted alkynes is somewhat
complicated, generating nitriles in low yield. Thus, we
investigated the reactivity of other alkynes and found that a
novel reaction of aryl alkyl substituted alkynes with N-
iodosuccinimide (NIS) and trimethylsilyl azide (TMSN3)
yielded α,α-diazidoketones regioselectively. The cleavage of
an alkyne triple bond or the formation of α,α-diazidoketone
depends on the electron-donating ability of substituents on the
aromatic ring. This transformation represents the formal
addition of two heteroatoms on each alkyne sp carbon, which
represents the first synthesis of α,α-diazidoketones from
alkynes. Several methods to access α,α-diazido carbonyl
compounds with NaN3 and other reagents have been reported.5
Herein, we describe highly regioselective iodoazidation of
alkynes to α,α-diazidoketones6 by NIS and TMSN3. These
diazidoketones are relatively stable and could be subjected to
Huisgen cyclization2,7 (Scheme 1).
d
0.4
0.4
trace
trace
in the dark
under air
a
Alkyne 1 (0.6 mmol) in MeCN/DCE (1.5 mL/1.5 mL) was used.
50 °C. 0.56 equiv of H2O was added. 0.1 M.
b
c
d
unstable in solution under irradiation with visible light. The
stereochemistry of the C−C double bond of 2 was Z geometry
based on X-ray crystallography.10 As the reaction proceeded,
the color of the reaction mixture changed from yellow-orange11
of iodine azide (IN3) to dark purple of iodine. For the
formation of 3, 2.2 equiv of each reagent were required (entries
1−4). Attempts to improve the yield of 3 (by increasing the
amount of each reagent, changing the reaction temperature,
and adding water) were not successful (entries 5−7). While
examining the reaction conditions, we found that the reaction
was faster and cleaner under air than under nitrogen (entry 8).
The reaction of alkyne 1 with TMSN3 and NIS was
performed under a nitrogen atmosphere at room temperature
Received: February 6, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00395
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Even 1.1 equiv of NIS was sufficient to complete the reaction,
but a catalytic amount of NIS was insufficient (entry 9 vs 10).
The yield of 3 was highest when the concentration of 1 was
decreased to 0.1 M (entry 11). The reaction in a dark room
under air also proceeded smoothly to afford 3 (entry 9 vs 12).
This may imply that α,α-diazidoketone 3 is not formed by a
radical process.12 The above-described results can be
summarized as follows: (1) Oxygen in air is required for α,α-
diazidoketone formation and is thought to oxidize iodide ions
to iodine (entry 3 vs 9), (2) water added to the reaction
mixture interferes with the reaction because of the facile
hydrolysis of TMSN3 (entry 1 vs 7), (3) moisture in air is
needed for the formation of 3, and (4) the source of carbonyl
oxygen and the reaction mechanism remain unclear.
Table 3. Scope of Alkyne 7
entry
7
R
time (day)
8 (%)
b
9 (%)
1
2
7a
7b
7c
7d
7e
7f
4-MeO
4-Me
4-F
1.2
1.2
2
0
trace
trace
trace
9b, 72
9c, 66
9d, 50
3
4
4-CF3
4-NO2
3-MeO
2-Me
2-i-Pr
2-Ph
7
c
5
7
0
6
0.4
0.4
0.4
trace
9f, 65
Using these optimized conditions, the substrate scope was
explored (Table 2). Regarding the protecting group of alcohol,
7
7g
7h
7i
(Z)-8g, 81
8h, 77
8i, 80
0
0
0
0
8
9
a
Table 2. Scope of Alkyne 4
10
7j
R-C6H4 = 1-naphthyl
1
8j, 79
a
Alkynes 7 (0.3 mmol) in MeCN/DCE (1.5 mL/1.5 mL) was used.
2-Iodo-1-(4-methoxyphenyl)prop-2-en-1-one 10 was obtained in
b
c
51% yield. Complex mixture.
exhibited an AB system for allylic protons, suggesting the
existence of atropisomerism.15
We performed the following experiments with the aim of
obtaining an understanding of the reaction mechanism. When
isolated (Z)-2 was treated with NIS and TMSN3 under air,
diazidoketone 3 was formed in a similar yield, indicating that 2
was an intermediate in the diazidoketone formation (Scheme 2,
entry
4
R1
R2
R3
time (day)
5 (%)
1
4a
4b
4c
4d
4e
4f
OAc
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
1.2
1.2
2
5a, 68
5b, 72
5c, 73
5d, 17
5e, 35
5f, 62
5g, 58
5h, 62
5i, 36
5j, 70
5k, 58
2
OCO2Et
3
OCOC6H4p-Br
OBn
4
7
5
OTBS
7
6
CH2CH2OBz
CH2CH2CH2OBz
Pr
0.4
0.4
0.4
3
7
4g
4h
4i
Scheme 2. Mechanistic Studies
8
9
−CH2CH2CH2CH2CH2−
10
11
12
4j
OBz
OBz
OBz
Me
1
4k
4l
Ph
1
b
Me
7
0
a
Alkynes 4 (0.3 mmol) in MeCN/DCE (1.5 mL/1.5 mL) were used.
2-Iodo-3-methyl-1-phenylbut-2-en-1-one 6 was obtained in 73%
b
yield.
the reaction was tolerant to acyl-type protecting groups (entries
1−3). The structure of α,α-diazidoketone was determined using
X-ray crystallographic analysis of 5c.13 Ether-type protecting
groups were not suitable (entries 4 and 5). Internal alkynes
excluding propargyl alcohol derivatives could also be used
(entries 6−8), but cyclohexyl-substituted 4i afforded 5i in low
yield (entry 9). Secondary propargyl alcohol derivatives also
yielded 5j and 5k (entries 10 and 11). Tertiary propargyl
alcohol derivative 4l underwent elimination of benzoate to
afford α-iodo-α,β-unsaturated ketone 6 (entry 12).
We next examined the effect of an aromatic substituent
(Table 3). Alkynes that have substituents (excluding a strong
EDG and EWG (electron-withdrawing group)) on the aromatic
ring could afford diazidoketones 9 (entries 2−4 and 6). The use
of methoxy-substituted 7a resulted in elimination, similar to 4l
(entry 1). Nitro-substituted 7e showed low reactivity and
yielded a complex mixture, probably due to a decrease in the
electron density of the alkyne triple bond (entry 5). We found
that ortho-substituted aryl alkynes 7g−7j did not afford
diazidoketones; alkenes 8g−8j were the major products
(entries 7−10). The structure of 8g was also determined
using X-ray crystallography.14 1H NMR spectra of 8g−8j
eq 1). When the reaction of 7g was quenched after 15 min, an
inseparable 1:1 mixture of (Z)- and (E)-8g was obtained (eq
2). Treatment of this mixture for a further 3 h with NIS and
TMSN3 yielded (Z)-8g as a major product (eq 3). These
results suggest isomerization of the C−C double bond of 8g,
although the reasons are not yet clear. Computational studies
indicated that (E)-8g was 2.2 kcal/mol higher in energy than
(Z)-8g.16 A similar trend was observed, and (E)-2 was
calculated to be 1.8 kcal/mol higher than the (Z)-isomer.
The higher stability of the Z-alkenes may be a manifestation of
the “cis-effect”.17 The use of NBS instead of NIS afforded α,α-
dibromoketone 11 as the result of a normal ionic addition18−21
B
DOI: 10.1021/acs.orglett.5b00395
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
but did not complete the reaction to recover the starting
material (eq 4).
A plausible reaction mechanism for the formation of α,α-
diazidoketone is shown in Scheme 3. Initially, alkyne 1 reacts
the reaction of 7a is strongly influenced by the effect of the
methoxy group, and regioselective addition of IN3 exclusively
affords alkene G. The key difference between alkene G and
substrates in our previous report4b is the existence of the
leaving group: a benzoyloxy group. Because of the two EDGs
(methoxyphenyl and azido groups), the benzoyloxy group is
easily eliminated to afford 10.
Scheme 3. Plausible Reaction Mechanism
Finally, α,α-diazidoketone 5a underwent Huisgen cyclization
(Table 4). Two azido groups of α,α-diazidoketone reacted with
Table 4. Huisgen Cyclization of α,α-Diazidoketone
entry
R′
time (h)
12 (%)
1
2
3
4
5
6
n-Bu
i-Pr
2
3
12a, 87
12b, 82
12c, 89
12d, 57
trace
cyclopropyl
t-Bu
3
24
24
7
TMS
4-MeC6H4
12e, 85
the terminal alkyne, providing bis-triazole compound 12. Both
alkyl- and aryl-substituted alkynes can be used. However, the
use of trimethylsilylacetylene resulted in decreased reactivity
and recovery of some of the substrate (entry 5). The reaction of
5a with 1 equiv of alkyne resulted in the low yield of 12 and
recovery of 5a, not affording the monotriazole compound.
In conclusion, we described a novel transformation of aryl
alkyl alkynes not having strong EDG and EWG substituents on
the aromatic ring to α,α-diazidoketones using NIS and TMSN3.
Although the mechanism of this reaction is still unclear, the
reaction probably proceeds via the addition of IN3 to an alkyne.
Huisgen cyclization of α,α-diazidoketones afforded bis-triazoles
in good yield.
with NIS and TMSN3 to form regiochemically unusual alkene
(Z)-2 or (E)-2 via syn or anti addition of the azide ion to
intermediate A. Hassner et al. reported that the regioselectivity
of the addition of IN3 to aryl alkyl alkyne is opposite to the
predicted regioselectivity based on the electronic effect and that
IN3 addition results in the formation of two stereoisomers.22
We performed the reaction of alkyne 1 with IN3 produced by
Hassner’s method.11 The 1H NMR time courses for the
conversion of alkyne 1 into alkenes 2 and diazidoketone 3 were
similar, indicating that the active species from the reaction of
NIS and TMSN3 is ionic IN3. The reaction of B with an azide
ion affords C. Thus, C is subjected to the following through
hydrolysis by moisture from the air and elimination of HI to
generate diazidoketone 3 by way of intermediate D. Oxygen
oxidizes HI to iodine, which acts as the I+ source to add to the
remaining 2. Ortho-substituents of 8g−8j likely complicated the
second IN3 addition. When NBS was used, the addition of
BrN3 may proceed in the normal regiochemical manner,
forming alkenes with a higher reactivity toward BrN3 than the
starting alkyne. For these reasons, double addition of BrN3 to
alkyne followed by hydrolysis at the benzylic position afforded
α,α-dibromoketone 11. For alkyne 4l, alkene F is formed
because of the steric hindrance of E.11 Formation of 6 appears
to be due to SN2′ attack of H2O in alkene F. On the other hand,
ASSOCIATED CONTENT
* Supporting Information
Experimental details, spectral data for all new compounds, and
X-ray data. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: ryanada@ps.hirokoku-u.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge a Grant-in-Aid for Scientific
Research (C) from JSPS KAKENHI (23590032 to R.Y.) and
a Grant-in-Aid for Young Scientist (B) from JSPS KAKENHI
(25870983 to N.O.). We are grateful to Dr. M. Yamaguchi at
Setsunan University for obtaining LRMS and HRMS data.
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