Direct vicinal disubstitution of diaryliodonium salts by pyridine N-oxides and N-amidates by a 1,3-radical rearrangement

Article abstract of DOI:10.1002/anie.201303347

Paired off: The title reaction leads to a series of o-pyridinium phenols (1) and anilines (2). The experimental and computational studies indicate that the key step involves homolytic cleavage to give a radical pair, which undergoes solvent-cage recombination to give the product. Copyright

Full text of DOI:10.1002/anie.201303347

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DOI: 10.1002/anie.201303347
Radical Reactions
Direct Vicinal Disubstitution of Diaryliodonium Salts by Pyridine
N-oxides and N-amidates by a 1,3-Radical Rearrangement**
Jing Peng, Chao Chen,* Yong Wang, Zhenbang Lou, Ming Li, Chanjuan Xi, and Hui Chen*
Diaryliodonium salts, Ar2I+XÀ, are an important and appeal-
ing class of aromatic iodine(III) derivatives, and recently have
received considerable attention because of their powerful
arylation of a wide range of nucleophiles to synthesize
valuable aromatic compounds.[1] They can be directly sub-
stituted by various nucleophiles under ecological and mild
reaction conditions.[1,2] In the presence of transition metals,
diaryliodonium salts are often applied in cross-coupling
reactions and even substituted by weak nucleophiles such as
alkenes, alkynes, arenes.[1b,3–5] The generation and trapping of
the benzyne intermediates from ortho-silyl diaryliodonium
salts exhibits an efficient way to produce aromatic compounds
having a unique substitution manner.[6] Since there exists
a vast and long-term demand for the synthesis of arenes with
various substitutents, the development of new strategic
substitution modes of diaryliodonium salts to produce val-
uable aromatic compounds will be of great importance.
Recently, we reported a three-component reaction of diaryl-
iodonium salts, nitriles, and alkynes to synthesize quinolines,
where ipso and ortho positions of the arene in the diaryl-
iodonium salts were substituted consecutively in the annula-
tion.[7] As a result of our ongoing project, we herein report
a novel vicinal disubstituion of diaryliodonium salts by the
pyridine N-oxides 1 and N-amidates 2 by an interesting 1,3-
radical rearrangement [Eq. (1)]. The direct vicinal disubsti-
tution reaction of diaryliodonium salt produces a series of
pyridinium phenols (4) and anilines (5), which are important
synthetic intermediates, valuable optical materials, and com-
ponents of natural products.[8–10]
The study commenced using a mixture of pyridine N-
oxide (1a) and diphenyliodonium hexafluorophosphate (3a;
1.0 equiv), which in solution gave an unstable complex
assumed to be the diphenyliodonium pyridine N-oxide l3
complex (Scheme 1).[11] When the mixture was heated to
Scheme 1. Tf =trifluoromethanesulfonyl.
1208C, a new product, 2-pyridinium phenol hexafluorophos-
phate (4aa), was obtained in 17% yield after column
chromatography on silica gel. The reaction of 2-picoline N-
oxide (1b) with 3a gave the analogue 4ba (8% yield), whose
molecular structure was confirmed by X-ray diffraction
À
studies. The crystal structure clearly shows the N O bond
has been broken with insertion of a phenylene group from the
fragmentation of diphenyliodinium salt (Figure 1; for details
[*] J. Peng, Prof. Dr. C. Chen, Y. Wang, Z. Lou, Prof. Dr. C. Xi
Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical
Biology (Ministry of Education), Department of Chemistry
Tsinghua University, Beijing 100084 (China)
E-mail: chenchao01@mails.tsinghua.edu.cn
Y. Wang, Z. Lou, Prof. Dr. M. Li
College of Chemistry and Molecular Engineering, Qingdao Univer-
sity of Science and Technology, Qingdao, 266042 (China)
À
Figure 1. X-ray Crystal structure of 4ba. Hydrogen atoms and PF6 are
Prof. Dr. H. Chen
omitted for clarity. For ORTEP drawing the thermal ellipsoids shown at
35% probability.[20]
Beijing National Laboratory for Molecular Sciences (BNLMS), CAS
Key Laboratory of Photochemistry, Institute of Chemistry, Chinese
Academy of Sciences, Beijing, 100190 (China)
E-mail: chenh@iccas.ac.cn
see the Supporting Information). Considering the low sol-
ubility of 4aa and 4ba in nonpolar solvents, K2CO3 (1.0 equiv)
was added after the reaction was stopped. Thus, after work-up
the betaine 6aa was isolated in 91% yield and 6ba in 65%
yield (for reaction optimization and details, see the Support-
ing Information). To determine the exact substitution position
on the phenyl ring, di(4-chlorophenyl)iodonium triflate (3b)
[**] This work was supported by the National Natural Science
Foundation of China (21102080 and 21290194), the Tsinghua
University Initiative Scientific Research Program (2011Z02150), and
the Chinese Academy of Sciences.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201303347.
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Table 1: The vicinal disubstitution of diaryliodonium salts with 1.[a,b,c]
was chosen to react with 1a under the same reaction
conditions, and 6ab was isolated in 61% yield (Scheme 1).
Further investigation of 6ab by two-dimensional NMR
spectroscopy has proved that the ipso-carbon atom of 3a is
linked to an oxygen atom and the ortho-carbon atom linked to
the nitrogen atom.
The products, o-pyridinium phenolates, have already been
investigated as an important class of optical materials[9] and
have also been found in naturally occuring pyridine alka-
loids.[10] However, present approaches to pyridinium pheno-
lates are of low generality and only suitable for specific
backbones.[9b,12] Encouraged by the above finding, we
attempted to synthesize more fuctionalized o-pyridinium
phenols by the vicinal disubstitution of diaryliodonium salts.
Reactions of various pyridine N-oxides and diaryliodinium
salts have been performed and representative results are
shown in Table 1. Gratifyingly, various methyl pyridine
N oxides, as well as fluoro pyridine, 2,6-lutidine, cyano
pyridine, and benzoisoquinoline N oxides all reacted with
3a to give the expected products (entry 1–7). Most reactions
gave the products in good yields except the 2,6-lutidine N-
oxide, probably because of the steric bulk. The iodonium salts
bearing methyl, fluoro, and tert-butyl groups on the phenyl
ring (entry 7–9, 11, and 12) worked well and the iodonium
salts with substituents at the ortho position (entry 10 and 13)
gave the desired products, albeit in relatively low yields. The
products were isolated in the betaine form except 4ha
(sensitive to base). The vincinal substitution took place on
the less hindered ring of unsymmetric iodonium salts (3g).[3,13]
The diaryl iodonium salt 3h having a CF3 group, a strong
electron-withdrawing group, did not work. In some cases, we
observed pyridine as the by-product (e.g. 2-benzyl-pyridine in
15% yield; entry 8).
The scope of this reaction was further demonstrated by its
application to the synthesis of two b-carboline natural
products, reticulatol and 14-bromoreticulatol (Scheme 2),
Scheme 2. The synthesis of reticulatol and 14-bromoreticulatol.
which were isolated (3mg) as new fascaplysin derivatives
and reported to show significant bioactivity for human
leukemia.[10] For this goal, the b-carboline N-oxide 1j was
readily prepared by a known method.[12] A 1:1 mixture of 1j
(1 mmol) and 3a (1 mmol) was heated at 1208C for 48 hours
and purified to give the betaine form of reticulatol (6ja) in
90% yield upon isolation. Analogously, the betaine form of
14-bromoreticulatol (6ji) was obtained in 87% yield.
Inspired by the successful vicinal disubstitution of diaryl-
iodonium salts by pyridine oxides, the scope was extended to
the pyridine amidates[14] 2 as substrates. To our delight, the
disubstitution was also realized and the desired products, the
[a] The reaction of 1 (1.0 mmol) and 3 (1.0 mmol) was carried out in 1,2-
dichloroethane at 1208C for 2 days. [b] The anion of 3c–h is triflate.
[c] Yields are those of isolated products. [d] The reduced pyridines were
observed. For example, 2-benzyl pyridine was isolated in 15% yield
(entry 8). Mes=2,4,6-trimethylphenyl.
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Scheme 4. Proposed mechanism of the vicinal disubstitution of diaryl-
iodoniums with the pyridine N-oxides 1 and N-amidates 2.
bond in A was homolytically cleaved upon heating to give
a radical pair comprising the pyridine cationic radical B[15] and
the heteroatom aryl radical C (phenoxyl radical[16] and anilino
radical[17]); 3) conceivably, the radical on the heteroatom of C
is easily rearranged to the carbon atom at the ortho or
para- position of the phenyl ring (D); 4) solvent-cage radical
recombination favored the bond formation between B and
the ortho position of D to give E; 5) the tautomerization of E
resulted in the final product.
In the kinetic isotope effect experiment, [D5]-3a was
synthesized and subjected to the reaction with 1a. The
phenolate 4aa and [D4]-4aa were both observed with a ratio
of 1:1 [Eq. (4)].
Scheme 3. The vicinal disubstitution of diaryliodonium salts with 2.
o-pyridinium anilines 5, were formed in good yields
(Scheme 3; Ts = 4-toluenesulfonyl, Bs = benzenesulfonyl).
During the synthesis of 5, we observed the by-product 7 in
trace amounts. To identify whether 7 was the intermediate of
the reaction, we prepared 7 separately. Excitingly, when 2d
was heated with 3c at 808C for 12 h in the presence of
Cu(OTf)2 (10 mol%), 7dc was obtained in 88% yield
[Eq. (2)]. Analogously, 7cc was obtained in 85% yield.
To shed more light on the reaction mechanism at the
molecular level, density functional theory (DFT) calculations
were conducted. As shown in Figure 2, our computations
Interestingly, upon heating 7dc and 7cc at 1208C for
24 hours, complete conversion into 5dc and 5cc, respectively,
were observed.
Additionally, a 1:1 mixture of 7dc and 7cc was heated and
only a mixture of 5dc and 5cc was observed without any
formation of 5a or 5b [Eq. (3)]. This suggested the rearrange-
ment of 7 to 5 was an intramolecular process.
Based on the above-mentioned results, we propose
a mechanism for the reaction as depicted in Scheme 4 (for
clarity, the substituents are omitted except the para-group on
phenyl ring): 1) the pyridine N-oxide 1 or N-amidate 2 was
arylated by diaryliodonium salts to give the intermediate A
Figure 2. DFT calculated pathway of prototype reaction of pyridine N-
oxides with diaryliodonium salts to generate 2-pyridinium phenols. The
calculated relative energies labeled for each species in kcalmolÀ1 and
include zero-point energy (ZPE) corrections. The superscript before the
label represents spin multiplicity.
À
À
[isolated as 7dc and 7cc; Eq. (2)]; 2) the N O or N N single
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3 mL of DCE were added to a mixture of the pyridine N-oxide
suggest that the reaction is initiated from the diphenyliodo-
1
nium pyridine N-oxide l3 complex RC by arylation of the
1 (1.0 mmol) and diaryliodonium salt 3 (1.0 mmol) under a nitrogen
atmosphere in a Schlenk tube with screw-cap. Then the mixture was
sealed and stirred at 1208C for 48 h. The mixture was cooled to room
temperature. Then 1 mmol of K2CO3, 2 mL of methanol, and silica gel
(ca. 1 g) were added to the reaction mixture. All the volatiles were
removed by rotatory evaporation and the product 6 was obtained by
column chromatography (elution: CH2Cl2/petroleum ether/metha-
nol = 10:5:3) as a highly hygroscopic solid. The details of DFT
computations are given in the Supporting Information.
pyridine N-oxide through a reductive elimination via tran-
1
sition-state TSOC having a barrier of 20.8 kcalmolÀ1. Then,
through thermolysis, the in situ formed N-aryloxy pyridinium
cation intermediate INO generates the radical pair intermedi-
ate Iradical comprising the pyridine cationic radical and
3
phenoxyl radical. The triplet-state radical pair Iradical is
slightly lower in energy than the singlet 1Iradical, thus it is
likely that radical pair will convert from the singlet state into
the triplet state by spin flipping. From 3Iradical, subsequent
attack of the pyridine cationic radical on the ortho position of
the phenoxyl radical occurs with only a small barrier of
8.5 kcalmolÀ1 via the transition-state 3TSNC, whereby the
radical pair recombines to reach the triplet adduct 3Iadduct first
Received: April 20, 2013
Published online: June 12, 2013
Keywords: arenes · iodonium · radicals · rearrangement ·
synthetic methods
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1
and then the more stable singlet adduct Iadduct. Finally two
molecules of the singlet adduct exchange their protons to
reach the final product, 2-pyridinium phenol or aniline. The
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1
1
intramolecular H shift from Iadduct to PC is not preferred
because of very high calculated reaction barrier of 55 kcal
molÀ1.
Considering the irreversibility of first step in the reaction
pathway (Figure 2), it is obvious that this arylation of pyridine
N oxide, without direct involvement of the H on the aryl
group, will determine the aryl ring selectivity from the
diaryliodonium salt. This theoretical result explains the
experimental observation shown in Equation (4). Upon
inspection of the entire reaction profile, the thermolysis of
the 1INO and subsequent product-oriented radical pair combi-
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1
effective activation energy of about 30 kcalmolÀ1 from INO
.
1
Once the radical pair adduct Iadduct is formed, it is very
unlikely to go back to 1INO as a result of the large barrier of the
reverse reaction. Thus transition to the final product from
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In conclusion, the direct vicinal disubstitution of the
diaryliodonium salts 3 by pyridine N-oxides 1 and N-amidates
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Diaryliodonium salts (3) were easily synthesized according to
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and 3 f. 1,2-Dichloroethane (DCE) was dried over 4 ꢀ M.S. before
use.
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