Cyclizing radical carboiodination, carbotelluration, and carboaminoxylation of aryl amines

Article abstract of DOI:10.1002/anie.201403968

Radical carboiodination of various aryl amines is reported. Aryl diazonium salts, generated in situ from the corresponding aryl amines, are reacted with Bu₄NI to provide the corresponding aryl radicals which undergo 5-exo or 6-exo cyclization. Iodine abstraction eventually affords the carboiodinated products in good to excellent yields. If TEMPO is added, the cascade provides the cyclized carboaminoxylation products. Running the reaction in the presence of PhTeTePh affords the phenyltellurated cyclized products.

Full text of DOI:10.1002/anie.201403968

Angewandte
Chemie
DOI: 10.1002/anie.201403968
Radical Cyclizations
Cyclizing Radical Carboiodination, Carbotelluration, and
Carboaminoxylation of Aryl Amines**
Marcel Hartmann and Armido Studer*
Abstract: Radical carboiodination of various aryl amines is
reported. Aryl diazonium salts, generated in situ from the
corresponding aryl amines, are reacted with Bu4NI to provide
the corresponding aryl radicals which undergo 5-exo or 6-exo
cyclization. Iodine abstraction eventually affords the carboio-
dinated products in good to excellent yields. If TEMPO is
added, the cascade provides the cyclized carboaminoxylation
products. Running the reaction in the presence of PhTeTePh
affords the phenyltellurated cyclized products.
We decided to start with aryl amines, which are trans-
formed in situ to the corresponding aryl diazonium salts, as
efficient C radical precursors.[3] Aryl diazonium salts have
been successfully used in radical cyclization reactions induced
by single-electron-transfer (SET) reagents[4] and also sodium
iodide mediated reactions to give the corresponding iodo-
dediazonation products have been reported.[5] However, not
every aryl amine can be readily transformed to the corre-
sponding aryl diazonium salt due to its limited stability and
due to problems occurring during isolation. Moreover, some
aryl diazonium salts are explosive and care has to be taken
during isolation and storage. Therefore, generating aryl
diazonium salts in situ under conditions where they can
undergo further reaction directly might solve these problems.
In fact, aryl amines have been elegantly used by Wang and
co-workers in radical arylations in the in situ generation of the
corresponding aryl diazonium salts.[6] It is important to note
that carboiodination cannot be achieved by radical iodine
transfer chemistry starting with aryl iodides. This is because
P
alladium-mediated radical carboiodinations of alkenes
using activated alkyl iodides are known.[1a] Recently this
chemistry was extended to aryl iodides by Lautens and
Tong.[1b–e] They showed that appropriately substituted aryl
iodides can be isomerized in good yields to the corresponding
cyclic alkyl iodides (Scheme 1). Experimental and theoretical
À
the C I bond in aryl iodides is stronger than that in alkyl
iodides and because the aryl radicals are high in energy.
Therefore, an alkyl radical cannot abstract an iodine atom
from an aryl iodide.[7] Herein we report useful radical
carboiodinations of various aryl amines and will further
show that the concept can be also applied to carbotellurations
and carboaminoxylations.
Optimization studies were conducted using aryl amine 1a
to provide cyclized alkyl iodide 2a (Table 1). Reactions were
run in acetonitrile and isoamyl nitrite (1.5 equiv) served as the
Scheme 1. Carboiodinations.
studies revealed that these cyclizations occur through the
migrative insertion of the corresponding aryl–Pd intermedi-
ates.[2] Stimulated by these studies we embarked a program on
cyclizing radical carboiodinations using aryl amines as start-
ing materials. One advantage over the existing methods is that
with the radical approach it should be possible to conduct the
carboiodination under transition-metal-free conditions.
Table 1: Reaction optimization.
Entry IÀ source (equiv) R (equiv)
Acid (equiv)
Yield [%]
À
Moreover, a quaternary C center next to the C I bond in
the product iodide is not necessary since in the radical
pathway b-H elimination, which is a problem in the Pd-
mediated process, will not occur.
1
2
3
4
5
6
7
8
NaI (1.5)
KI (1.5)
CsI (1.5)
isoamyl (1.5)
isoamyl (1.5)
isoamyl (1.5)
isoamyl (1.5)
isoamyl (1.5)
isoamyl (1.1)
MeSO3H (1.1)
MeSO3H (1.1)
MeSO3H (1.1)
MeSO3H (1.1)
MeSO3H (1.1)
MeSO3H (1.1)
68
77
94
99
68
88
34[a]
Bu4NI (1.5)
Bu4NI (1.1)
Bu4NI (1.5)
Bu4NI (1.5)
Bu4NI (1.5)
Bu4NI (1.5)
Bu4NI (1.5)
Bu4NI (1.5)
[*] M. Hartmann, Prof. Dr. A. Studer
Organisch-Chemisches Institut
tert-butyl (1.5) MeSO3H (1.1)
isoamyl (1.5)
isoamyl (1.5)
isoamyl (1.5)
isoamyl (1.5)
MeSO3H (0.1) <5
Westfꢀlische Wilhelms-Universitꢀt Mꢁnster
Correnstrasse 40, 48149 Mꢁnster (Germany)
E-mail: studer@uni-muenster.de
9
10
11
MeSO3H (0.3)
p-TosOH (1.1)
CF3CO2H (1.1)
5
92
78
[**] We thank the University of Mꢁnster for financial support.
[a] A complex reaction mixture was obtained containing 34% of 2a as
determined by NMR analysis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201403968.
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reagent for diazonium salt generation. We chose methane-
sulfonic acid to induce the formation of the diazonium salt
from 1a. The I salt was slowly added as a MeCN solution over
1 hour. In cases where the salt was not perfectly soluble in
MeCN a small amount of water was added.
for the exocyclic trapping of the C radical was low and 2i was
isolated in 90% yield as a 1.7:1 diastereoisomer mixture. We
found a propargyl phenyl ether to cyclize in quantitative yield
as determined by NMR spectroscopy. However, during
isolation we realized that product 2j decomposes upon
removal of the solvent.[10] Formation of quaternary C centers
is possible as shown by the preparation of 2k (54%). The
corresponding 6-endo product was not identified in the crude
reaction mixture. Indoline 2l and benzothiophene 2m were
successfully prepared by application of our novel approach,
showing that the method is not restricted to the preparation of
O-heterocycles. Pleasingly, an excellent yield was also ach-
ieved in the 6-exo cyclization and iodide 2n was isolated in
97% yield. However, 7-exo cyclization of the aryl radical
cannot compete with direct iodination under the applied
conditions: aryl iodide 2o was obtained in 76% yield and the
targeted cyclized product was not identified in the crude
reaction mixture.
The initial experiment was conducted with NaI as the
formal SET and radical-trapping reagent. We were very
pleased to find that in situ generation of the aryl diazonium
salt is compatible with aryl radical generation, cyclization, and
trapping. The targeted cyclized iodide 2a was isolated in 68%
yield (Table 1, entry 1). Yield was further improved by
replacing NaI with KI (77%) and CsI (94%, entries 2 and
3) and 2a was obtained quantitatively when Bu4NI[8] served as
the iodide source (entry 4).[9] Lowering the amount of Bu4NI
and nitrite led to reduced yields (entries 5 and 6). Surprisingly,
tBuONO did not work well and a complex reaction mixture
resulted (entry 7). The use of substoichiometric amounts of
MeSO3H provided a clean reaction but low conversion,
showing that a stoichiometric amount of acid is necessary for
complete conversion (entries 8 and 9). p-Toluenesulfonic acid
worked almost as well as MeSO3H; however, with CF3COOH
a lower yield was achieved (entries 10 and 11). The reaction
can also be conducted in the presence of air, albeit a slightly
lower yield was obtained (86%).
We next studied the 1,2-stereoinduction in the carboiodi-
nation using aryl amine 1p as the substrate. Iodide 2p was
obtained in quantitative yield with 10:1 trans/cis diastereose-
lectivity (Scheme 2). A similar result was obtained in the
reaction with aniline 1q.
Under optimized conditions (Table 1, entry 4) the scope
and limitations of the carboiodination using aryl amines as
precursors were investigated (Figure 1). The preparation of
all starting arylamines is described in the Supporting Infor-
mation.
Scheme 2. Diastereoselective carboiodination.
We also investigated whether the intermediate cyclized
radicals can be trapped by fast non-I-based radical-trapping
reagents. Experiments were mainly conducted with 1a. Bu4NI
was replaced by Bu4NBr and Bu4NCl; however, the corre-
sponding carbobromination and carbochlorination products
were not formed. The diazonium salt derived from 1a did not
react with these halide sources.
Therefore, we continued to use Bu4NI (1.5 equiv) for the
clean generation of aryl radicals and added other typical C
radical trapping reagents. Neither 2a nor the carbobromina-
tion product 3a was identified in the presence of N-
bromosuccinimide (10 equiv). However, adding CBr4
(10 equiv) under otherwise identical conditions gave the
targeted bromide 3a in 45% yield along with iodide 2a in
18% yield (Scheme 3). Consequently, we increased the
amount of CBr4 to 30 equiv and obtained 3a and 2a in a 7:1
ratio. Unfortunately, combined yield decreased to 35% under
these conditions. We therefore switched to other efficient
alkyl-radical-trapping reagents and noted that in the presence
of PhSeSePh (4 equiv) the carboiodination product 2a was
formed exclusively (50%).
Figure 1. Alkyl iodides 2b–o obtained by carboiodination of various
aryl amines (isolated yields),[a] Yield determined by 1H NMR spectros-
copy using an internal standard due to composition upon isolation.
Halides at the arene ring in the aryl amine are tolerated
and iodides 2b, 2c, and 2h were isolated in 88 to 99% yield.
CF3-, methyl-, and acetyl-substituted aryl amines work
equally well and the corresponding cyclized dihydrobenzo-
furans 2e–g were obtained in very good to excellent yields.
However, reaction with the methoxy congener (see 2d) was
not as efficient (32%). As expected, the diastereoselectivity
PhTeTePh is known to be a highly efficient alkyl-radical-
trapping reagent.[11] Indeed, after some optimization we
found that when 4 equiv of PhTeTePh was added the
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Scheme 3. Carbobromination and carbotelluration.
telluration product 4a was obtained in excellent yield (98%).
Other carbotelluration products 4b, 4e, and 4g were success-
fully prepared in moderate to excellent yields (43–78%) with
this method. We found that in some cases the reaction works
better with 2 equiv of PhTeTePh (see the Supporting Infor-
mation). As expected based on our results reported above,
high stereoselectivity was achieved for the cyclization of
aniline 1q to give the tellurated benzofuran 4q in quantitative
yield. The benzodihydrothiophene 4m could be successfully
prepared with this method, albeit in lower yield.
The suggested mechanism for the radical carboiodination
and carbotelluration exemplified with substrate 1a is pre-
sented in Scheme 4. Arylamine 1a is first transformed with
isoamyl nitrite in the presence of MeSO3H to the diazonium
salt 5a. Exchange of the anion in 5a with the anion of Bu4NI
provides diazonium iodide 5b. A literature search revealed
only a single X-ray structure of an aryldiazonium iodide,
indicating an interaction of the iodide anion with the terminal
N atom of the diazonium group (Scheme 4).[12] We therefore
assume that the iododiazonium salt 5b is in equilibrium with
its N-iododiazene form 5c. Considering structure 5c, initia-
Scheme 4. Suggested mechanism.
during initiation is not occurring. The IC radical can dimerize
to I2 which can also act as an alkyl-radical-trapping reagent.
However, considering the low concentration of I2 we cur-
rently disfavor I2 or its adduct with an iodide anion (I3À) as the
trapping reagents. In the carbotelluration, cyclized radical 8a
is trapped by PhTeTePh to give tellurated product 4a. The
chain is likely sustained by I abstraction of the PhTeC radical
from 5c.
Finally, as an additional efficient radical-trapping reagent,
we tested TEMPO in the I-induced cyclization reaction.[13]
Pleasingly, with 2 equiv of TEMPO under otherwise identical
conditions TEMPO adduct 9a was isolated in 89% yield
starting with aniline 1a (Scheme 5).[14–16] In analogy, alkoxy-
amine 9r was successfully prepared.
In summary, we introduced highly efficient and practical
radical carboiodination reactions using aryl amines as sub-
strates. Aryl amines are transformed in situ to the corre-
sponding aryl diazonium salts which in turn act as aryl-radical
À
tion may occur by N I homolysis to form I· radical and radical
6a which undergoes fast N2 fragmentation to generate the
aryl radical 7a. Alternatively, SET from the iodide to the
diazonium cation also leads to 6a. 5-exo cyclization of 7a
generates the alkyl radical 8a which likely abstracts an iodine
=
atom from aryl-N N-I (5c) to eventually give product 2a and
the chain-carrying 6a. This I-atom-transfer step must be very
fast and can only be suppressed with highly efficient radical-
trapping reagents. Moreover, successful trapping of 8a with
external reagents such as CBr4 and PhTeTePh shows that the
trapping of 8a in the solvent cage with the IC radical formed
Scheme 5. Cyclizing carboaminoxylation.
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Xu, Z.-J. Liu, X. Lu, L. Liu, Y. Fu, J. Am. Chem. Soc. 2013, 135,
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precursors. Aryl radicals undergo typical 5-exo and 6-exo
cyclization reactions and the cyclized alkyl radicals are then
iodinated in a chain reaction. In the presence of PhTeTePh
and TEMPO the cyclized radicals are efficiently trapped to
provide the corresponding carbotelluration and carboami-
noxylation products, respectively. Experiments are very easy
to conduct and products are obtained in good to excellent
yields.
[7] L. Chaozhong in Encyclopedia of Radicals in Chemistry, Biology
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[8] P. Finkbeiner, B. J. Nachtsheim, Synthesis 2013, 45, 979.
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Org. Lett. 2014, 16, 1216.
Received: April 3, 2014
Published online: && &&, &&&&
Keywords: carboaminoxylation · carboiodination ·
[10] 2k likely isomerizes to 3-iodomethylbenzofuran which readily
decomposes.
.
carbotelluration · diazonium salts · radical cyclization
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[16] Reaction in the absence of TBAI with TEMPO (2 equiv)
provided 9a in 36% yield showing the IÀ to be necessary to get
high yields. If IÀ is added in a catalytic amount (0.1 equiv), 9a
was obtained in 50% revealing that the IÀ is not acting as
a catalyst. We currently assume that reaction proceeds as non-
chain-process via 5c which undergoes I-transfer to TEMPO to
provide TEMPO+/IÀ and 6a. TEMPO+/IÀ is an unknown
compound which may show similar reactivity as other
TEMPO-oxoammonium salts.
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Radical Cyclizations
M. Hartmann, A. Studer*
&&&& — &&&&
Cyclizing Radical Carboiodination,
Carbotelluration, and
Carboaminoxylation of Aryl Amines
Tamed radicals: The carboiodination of
anilines leads to the corresponding
cyclized iodides. The aryl diazonium salts
generated in situ react with IÀ ions to give
the corresponding aryl radicals, which are
cyclized and trapped. When the reaction
is conducted in the presence of TEMPO
and PhTeTePh, the respective carboami-
noxylated and phenyltellurated cyclized
products are obtained.
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