Stereoselective intermolecular nitroaminoxylation of terminal aromatic alkynes: Trapping alkenyl radicals by TEMPO

Article abstract of DOI:10.1021/ol5030585

The vinyl radical is one of the most unstable organic radicals. It is demonstrated that a nitro radical attacks phenylacetylene and makes the phenyl ring deconjugated with a double bond so that the resulting vinyl radical may be stabilized by delocalization to the phenyl rings π orbital and easily trapped by TEMPO. It is noteworthy that all desired products were obtained in moderate to good yields in an (E)-configuration.

Full text of DOI:10.1021/ol5030585

Letter
pubs.acs.org/OrgLett
Stereoselective Intermolecular Nitroaminoxylation of Terminal
Aromatic Alkynes: Trapping Alkenyl Radicals by TEMPO
Hong Yan, Guangwei Rong, Defu Liu, Yang Zheng, Jie Chen, and Jincheng Mao*
Key Laboratory of Organic Synthesis of Jiangsu Province College of Chemistry, Chemical Engineering and Materials Science,
Soochow University, Suzhou 215123, P. R. China
*
S Supporting Information
ABSTRACT: The vinyl radical is one of the most unstable
organic radicals. It is demonstrated that a nitro radical attacks
phenylacetylene and makes the phenyl ring deconjugated with
a double bond so that the resulting vinyl radical may be
stabilized by delocalization to the phenyl ring’s π orbital and
easily trapped by TEMPO. It is noteworthy that all desired
products were obtained in moderate to good yields in an (E)-
configuration.
adical chemistry has recently played a vital role in organic
suggests that the π-system of the phenyl ring is orthogonal to
the π-system of the double bond. Also, the angle of the phenyl
ring and double bond is approximately equal to the angle C6−
C7−C8 which is 129°. The value is larger than expected for the
R
chemistry as an approach widely used in C−H
1,2 1b,e,3
functionalization, cascade cyclization,
and photochemical
4
reactions. TEMPO is usually used as a radical scavenging to
trap radicals or inhibit reactions. This proves that the
mechanisms of these reactions proceed through a radical
2
sp hybridization. It is indicated that the vinyl radical is between
a bent type (120°) and a linear π-type (180°) resonance
5
12a
pathway. Olefins are a series of good radical acceptors. When
stabilized structure.
they are attacked by radicals, alkyl radicals are formed which
can be trapped by TEMPO and produce useful aminoxylative
products. Significant work on intermolecular aminoxylative of
olefins has also been reported (Figure 1, eqs 1 and
These results were encouraging, and therefore a variety of
nitro sources were screened. Inorganic nitrates gave the
aminoxylative product in poor yields (Table 1, entries 1−4).
Gratifyingly, tert-butyl nitrite is the ideal nitro source, affording
6
−10
2).
Further, the benzylic and allylic radical are relatively
3aa in 73% yield (Table 1, entry 5). Increasing and decreasing
stable in comparison to alkyl radicals because of p-π-
conjugation. In contrast, a vinyl radical (eq 3, A) belongs to
σ radicals that cannot disperse the electron density; therefore, it
is highly unstable and has high reactivity and a short lifetime.
Additionally, the vinyl radical can undergo hydrogen abstration
reactions. Therefore, trapping vinyl radicals remains challen-
the temperature reduced the yields (Table 1, entries 6 and 7).
During our studies, we found that solvents had an adverse effect
on the reactions. No product was formed when alcoholic
solvents were used due to oxidative side reactions of the
14
solvent (Table 1, entry 8). The yield was slightly lower when
1
,4-dioxane, acetonitrile, and cyclohexane were used, while a
3a,11
ging.
We envisage that an appropriate radical attack on
slight increase was noted when toluene was used (Table 1,
entries 9−12). THF proved to be the best solvent giving a yield
as high as 80% (Table 1, entry 13). Ultimately, the use of 1.3
equiv of TEMPO gave the best yield (92%, Table 1, entry 14).
A number of alkynes were tested under the optimized test
conditions. The results are displayed in Figure 3. Both para-
substituted methoxy and methyl phenylacetylenes gave the
corresponding products 3ba and 3ca in excellent yields. Para-
substituted electron-withdrawing groups, such as fluoride,
chloride, and bromide, slightly decreased the reactivities,
offering the desired nitroaminoxylative product in 85%, 86%,
and 85% yield, respectively. The yields of para-substituted alkyl
or alkoxyl phenylacetylenes decreased. A decrease in yields is
also observed when the length of the alkyl or alkoxyls is
phenylacetylene will result in the phenyl ring deconjugated with
a double bond and the resulting vinyl radical is stabilized by
12
delocalization to the phenyl ring’s π orbital. It may extend the
radical’s lifetime and increase the possibility for trapping.
On the basis of our assumption, we began our study by
reacting phenylacetylene with a lot of known radicals. After
several unsuccessful attempts, we finally found that when a
13
nitro radical source was used, the vinyl radical is successfully
trapped by TEMPO (eq 3, B). To the best of our knowledge, it
is the first time vinyl radicals have been trapped by TEMPO.
The X-ray structure of 3aa is shown in Figure 2. The phenyl
ring no longer conjugates with the double bond. The nitro
group and the double bond are in the same plane which is
approximately perpendicular to the phenyl ring. The length of
N1−C8 is 1.43 Å, which is between the C−N single bond (1.47
Å) and C−N double bond (1.28 Å). That means the nitro
group is possibly conjugated with a C−C double bond. It
Received: October 18, 2014
Published: December 4, 2014
©
2014 American Chemical Society
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Organic Letters
Letter
Figure 1. Trapping alkyl radicals and alkenyl radical by TEMPO.
Table 1. Optimazation of Nitroaminoxylation of
a
Phenylacetylene
entry
nitro radical source
solvent
DCE
t (°C)
yield (%)
1
2
3
4
5
6
7
8
9
AgNO3
70
70
70
70
70
80
60
70
70
70
70
70
70
70
35
7
Cu(NO ) ·3H O
DCE
3
2
2
(NH ) Ce(NO )
3 6
DCE
45
trace
73
60
49
0
4
2
Co(NO ) ·6H O
DCE
3
2
2
t-BuONO
t-BuONO
t-BuONO
t-BuONO
t-BuONO
t-BuONO
t-BuONO
t-BuONO
t-BuONO
t-BuONO
DCE
DCE
DCE
ethanol
acetonitrile
cyclohexane
1,4-dioxane
toluene
THF
68
69
71
75
80
91
1
1
0
1
Figure 2. X-ray structure of 3aa.
12
1
1
3
4
b
THF
increased (3ga−3ia vs 3ba and 3ca). Ortho- and meta-
a
Conditions: phenylacetylene (0.3 mmol), nitro radical source (0.6
substituted phenylacetylenes were also studied in our system.
b
mmol), TEMPO (0.3 mmol), 24 h. TEMPO (1.3 equiv).
2-Fluoride phenylacetylene showed slightly better reactivity
than 4-fluoride phenylacetylene, and the desired product 3ja
was recovered in 88% yield. To our delight, 3-bromide
phenylacetylene was a very suitable substrate. The correspond-
ing product 3ka resulted in as high as a 90% yield. However, 3-
methyl phenylacetylene was a poorer substrate as compared to
moderate to good yields. The reactivity of alkyl alkynes was
seen to be poor as compared to the other substrates. Despite
this, the desired alkyl products (3pa−3ra) were generated in
poor yields as expected owing to the poor σ-p-hyper-
conjugation of alkyl groups with alkenyl radicals.
4
-methyl phenylacetylene, producing the 3-methyl product 3la
in 87% yield. To be noted, heterocyclic acetylenes afforded the
corresponding nitroaminoxylative product (3ma−3oa) in
Furthermore, diphenyl acetylene was employed as the
substrate. The result showed that it was not a suitable substrate
6
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Organic Letters
Letter
Figure 4. Nitroaminoxylation of phenylacetylene with various
TEMPOs. Conditions: Phenylacetylene (0.3 mmol), TEMPO (1.3
equiv), t-BuONO (2 equiv), THF (2 mL), 24 h. Isolated yield.
in Figure S1. Explanation of stereoselectivity depends on the
computational study of the mechanism. The relevant work is in
progress.
Alkenyl aminoxylative compounds were a series of special
compounds in view of the reactive N−O bond and the enol
type structure. For instance, mild hydrolysis of a nitro-
aminoxylative product produced the α-nitroketone in 60%
yield as shown in Scheme 2. Additionally, another particularly
Scheme 2. Hydrolysis of 3aa To Prepare α-Nitroketone
Figure 3. Nitroaminoxylation of various terminal alkynes with
TEMPO. Conditions: Terminal alkyne (0.3 mmol), TEMPO (1.3
equiv), t-BuONO (2 equiv), THF (2 mL), 24 h. Isolated yield.
11b
under the test conditions due to its large steric hindrance.
useful transformation of the alkenyl aminoxylative compound
Only benzil was isolated in 17% yield as shown in Scheme 1.
was aminolysis in glacial acetic acid, which afforded the β-
nitroenamine in 82% yield as shown in Scheme 3.
15
Scheme 1. Oxidation of Diphenyl Acetylene in Standard
Conditions
Scheme 3. Aminolysis of 3aa To Prepare β-Nitroenamine
We then investigated the kinds of derivatives of TEMPO
under the optimized conditions, and the related results are
listed in Figure 4. The 4-acetylamino TEMPO represents a
moderate trapping ability for radicals and just gave 3ab in 72%
yield. 4-Hydroxyl, 4-alkoxyl, and 4-acetoxyl TEMPO were
excellent substrates producing corresponding products (3ac−
In summary, we have demonstrated for the first time that
vinyl radicals can be trapped by TEMPO. The nitro-
aminoxylation reactions were successfully carried out under
transition-metal-free conditions, and only E-products were
obtained in moderate to good yields. The alkenyl nitro-
aminoxylative product was easily converted to useful building
blocks under mild conditions. More studies to expand the
utility of these products and computation of the mechanism are
ongoing in our laboratory.
3
af) in as high as 93% to 99% yields. However, 4-oxy TEMPO
was less reactive and the nitroaminoxylative product 3ag was
obtained in 69% yield.
Notably, (E)-products were obtained exclusively. No isomer-
ization was obviously observed between stereoisomers from the
1
H NMR spectra. The proposed mechanism was demonstrated
6
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Letter
(
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ASSOCIATED CONTENT
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AUTHOR INFORMATION
■
*
Corresponding Author
E-mail: jcmao@suda.edu.cn.
Notes
5
16. (f) Manna, S.; Maity, S.; Rana, S.; Agasti, S.; Maiti, D. Org. Lett.
012, 14, 1736−1739. (g) Maity, S.; Manna, S.; Rana, S.; Naveen, T.;
The authors declare no competing financial interest.
2
Mallick, A.; Maiti, D. J. Am. Chem. Soc. 2013, 135, 3355−3358.
ACKNOWLEDGMENTS
(h) Manna, S.; Jana, S.; Saboo, T.; Maji, A.; Maiti, D. Chem. Commun.
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013, 49, 5286−5288. (i) Maity, S.; Naveen, T.; Sharma, U.; Maiti, D.
We are grateful for the grants from the Scientific Research
Foundation for the Returned Overseas Chinese Scholars, State
Education Ministry, the Priority Academic Program Develop-
ment of Jiangsu Higher Education Institutions, The Project of
Scientific and Technologic Infrastructure of Suzhou
SZS201207), and the Key Laboratory of Organic Synthesis
of Jiangsu Province.
Org. Lett. 2013, 15, 3384−3387. (j) Naveen, T.; Maity, S.; Sharma, U.;
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