Thermally Induced Carbohydroxylation of Styrenes with Aryldiazonium Salts

Article abstract of DOI:10.1002/anie.201601656

The radical carbohydroxylation of styrenes with aryldiazonium salts has been achieved under mild thermal conditions. A broad range of aryldiazonium salts was tolerated, and the reaction principle based on a radical–polar crossover mechanism could be exten

Full text of DOI:10.1002/anie.201601656

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201601656
German Edition: DOI: 10.1002/ange.201601656
Carbohydroxylation
Thermally Induced Carbohydroxylation of Styrenes with
Aryldiazonium Salts
Stephanie Kindt, Karina Wicht, and Markus R. Heinrich*
Abstract: The radical carbohydroxylation of styrenes with
aryldiazonium salts has been achieved under mild thermal
conditions. A broad range of aryldiazonium salts was toler-
ated, and the reaction principle based on a radical–polar
crossover mechanism could be extended to carboetherification
as well as to a two-step, metal-free variant of the Meerwein
arylation leading to stilbenes.
The results from a series of optimization experiments with
4-chlorophenyldiazonium tetrafluoroborate (1a) and a-
methylstyrene (2a) are summarized in Table 1. To avoid the
attack of aryl radicals onto unconverted diazonium ions, slow
addition of 1a was combined with elevated reaction temper-
Table 1: Optimization of reaction conditions.
O
ver the last decade, the Meerwein arylation has become
a broadly applicable reaction for the functionalization of
alkenes.[1] The product scope has been increased through the
introduction of new radical acceptors and aryl radical sources.
Besides this, the reaction conditions have been improved
through the development of catalytic,[2] photocatalytic,[3] and
metal-free versions.[4] Seminal examples are the TEMPO/
sodium-mediated carboaminohydroxylation by Studer et al.[5]
and the remazol-catalyzed hydroperoxyarylation by Leow
et al. (Scheme 1).[6–8] Inspired by new carboamination reac-
tions,[9] we investigated whether basic conditions—which have
so far mainly been applied in Gomberg–Bachmann reac-
tions[1e,10,11]—could also add to the attractiveness of Meer-
wein-type carbohydroxylations.
Entry
Reaction conditions[a]
Yield 3a [%][b]
1
2
3
4
5
6
7
8
9
Na2CO3, 508C
Na2CO3, 508C, under oxygen atmosphere
Na2CO3, 708C
Na2CO3, 708C, 2a (3 equiv)
Na2CO3, 708 C, 2a (12 equiv)
KOAc, 708C
KOAc, CH3CN/H2O (1:1)
KOAc, under nitrogen atmosphere
No base, 708C
60
56
72
61
58
85 (82)[c]
81
78
83 (86)[c]
[a] General reaction conditions: 1a (1.0 mmol) in CH3CN/H2O (5:1,
4 mL) added slowly over 5 min to a mixture of the base (1.5 mmol) and
2a (3–12 mmol) in CH3CN/H2O (5:1, 5 mL) under air. [b] Yield
determined by 1H NMR spectroscopy using dimethyl terephthalate as an
internal standard. [c] Yield after purification by column chromatography.
atures, as both measures reliably decrease the concentration
of 1a in the reaction mixture. Potassium acetate[10b] (Table 1,
entries 6–8) was found to be a better suited base than sodium
carbonate (Table 1, entries 1–5), and in the former case the
reaction under nitrogen gave a slightly lower yield of alcohol
3a than that under air (Table 1, entries 6 and 8). The lower
yield obtained under oxygen atmosphere (Table 1, entry 2)
already indicated at an early stage that radical trapping by
Scheme 1. Meerwein-type carbooxygenation reactions.
oxygen
is—in
contrast
to
many other
carbo-
oxygenations[6,7g,k]—at least not the major mechanistic path-
way. The use of twice as much alkene 2a (12 equivalents) did
not further increase the yield, as the reaction was then
complicated by phase separation (Table 1, entry 5). The
strong base sodium hydroxide, which largely converts aryl-
diazonium ions into aryl diazotates,[11d] led to low yields in the
range of 16–41% (see the Supporting Information), thus
suggesting that a certain amount of free diazonium ions is
required for the desired reaction course. Finally, a control
experiment in the absence of base provided 3a in 86% yield
and revealed thermal initiation as a useful alternative to
weakly basic conditions.[1e]
[*] M. Sc. S. Kindt, K. Wicht, Prof. Dr. M. R. Heinrich
Department of Chemistry and Pharmacy, Pharmaceutical Chemistry
Friedrich-Alexander-Universitꢀt Erlangen-Nꢁrnberg
Schuhstrasse 19, 91052 Erlangen (Germany)
E-mail: Markus.Heinrich@fau.de
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201601656.
ꢂ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co.
KGaA. This is an open access article under the terms of the Creative
Commons Attribution Non-Commercial NoDerivs License, which
permits use and distribution in any medium, provided the original
work is properly cited, the use is non-commercial, and no
modifications or adaptations are made.
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With optimized conditions A and B available (Table 1,
entries 6 and 9, respectively), we then explored the scope and
limitations regarding the substitution pattern on the diazo-
nium salt (Scheme 2). Good to high yields of the racemic
alcohols 3 were obtained with few exceptions. The 4-
reaction scope could be extended to a substituted naphtha-
lene 3dd, tetrahydronaphthalene 3ee, and thiophene 3 ff. If
one compares conditions A and B, it appears that the main
advantage of potassium acetate (conditions A) is to protect
acid-labile alcohols 3. Reactions in the absence of base
(conditions B) were found to be strongly acidic (pH ꢀ 1) after
the complete addition of 1, so that donor-substituted alcohols
(e.g. 3t, 3z, R3 = OMe) can decompose via their related
cations 5. Acid-stable alcohols 3, as is the case in Scheme 2,
benefit from base-free conditions B as more free diazonium
ions 1 are then available for chain propagation.[10a] Radical
arylations in which solely the diazonium ions act as chain
carriers have been described so far for only enol ethers, enol
esters, and some aromatic systems.[17] In related carbo-
amination reactions of styrenes reported by Kçnig et al.,[7e]
an additional photocatalyst is required.[3d]
Extension of the reaction principle to obtain the carbo-
etherfication product 7[7f] was possible in two ways, either by
exchanging the cosolvent acetonitrile for methanol (Path I,
Scheme 5) or by treating alcohol 3a with catalytic amounts of
acid in methanol (Path II).[18] The latter sequence did not
require intermediate purification of 3a. The synthesis of
stilbenes 8a–e, which offers an attractive alternative to known
transition-metal-catalyzed[19] and radical reactions,[3d,20] could
Scheme 2. Carbohydroxylation: variation of substituents on the aryl-
diazonium salt. See the Experimental Section for general procedures A
and B. Yields determined after purification by column chromatography.
[a] Yield from reaction under base-free conditions B. [b] Reaction time:
18 h.
fluorophenyldiazonium salt used for the synthesis of
3b is likely to undergo nucleophilic aromatic substitu-
tion under conditions A rather than enter the radical
reaction,[12] so that a good yield could only be achieved
under base-free conditions B. Reactions of the unsub-
stituted phenyldiazonium ion, such as that leading to
alcohol 3k, appear under some conditions to be
complicated by effects like aggregation.[13] The low
yield obtained for 3l can be explained by the underlying
mechanism (Scheme 3), in which the donor-substituted
4-methoxyphenyldiazonium ion (1, R1 = OMe) is unable
to effectively propagate the radical chain through
oxidation of radical 4 to cation 5.[14] In a tandem
reaction combining carbohydroxylation and lactoniza-
tion, the 2-methyloxycarbonyl-substituted diazonium
salt directly provided isochromanone 3s. A repetition
of the synthesis of 3a on a larger scale (10 mmol,
conditions A) led to a yield of 66% (1.39 g).
Scheme 3. Plausible reaction mechanism.
The radical–polar crossover step[15] in the assumed
reaction mechanism (Scheme 3), in which basically an
electron acts as a catalyst to form the new aryl radical
6,[16] was further supported by the results obtained with
different styrenes (Scheme 4). Substituents leading to
a comparable or increased stabilization of cation 5, such
as R3 = OMe (3t), R3 = Cl (3u), and R2 = Ph (3w),
support product formation. Destabilizing substituents
like R3 = NO2 (3v) and R2 = H (3x), on the other hand,
lead to low yields. The lack of the methyl group in R2 is
not counterbalanced by a more reactive diazonium ion
(3y, R1 = NO2), but is counterbalanced by a donor
substituent R3 (3z–3cc, R3 = OMe). Donor substitution
(R3 = OMe) then even allowed a successful reaction
with the electron-rich 4-methoxyphenyldiazonium salt
Scheme 4. Carbohydroxylation: variation of the alkene. See the Experimental
Section for general procedures A and B. Yields determined after purification
by column chromatography. [a] Yield from reaction under base-free conditions
(R1 = OMe) to give alcohol 3bb. Furthermore, the B. [b] Yields determined by 1H NMR spectroscopy.
2
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Keywords: carbohydroxylation · diazonium ions ·
Meerwein arylation · radical reactions · styrene
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In summary, we have shown that carbohydroxylation of
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Experimental Section
General procedures A and B for the carbohydroxylation of styrenes
with aryldiazonium tetrafluoroborate salts: A stirred solution of
styrene 2 (6.00 mmol) and KOAc (147 mg, 1.50 mmol, only for
conditions A, no base is added for conditions B) in CH3CN/H2O (5:1,
5 mL) at 708C was treated by the dropwise addition of a solution of
the aryldiazonium tetrafluoroborate salt 1 (1.00 mmol) in CH3CN/
H2O (5:1, 4 mL) over 5 min. After stirring for 10 min at 708C, the
reaction mixture was diluted with water (10 mL), cooled to room
temperature, and extracted with diethyl ether (3 ꢀ 30 mL). The
combined organic layers were washed with aqueous acetate buffer
(only for conditions B) and brine (30 mL), and dried over Na2SO4.
The solvents were removed under reduced pressure and the product
was purified by column chromatography on silica gel.
Acknowledgements
We gratefully acknowledge financial support from the
Deutsche Forschungsgemeinschaft (DFG) and the helpful
comments of the referees.
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Received: February 16, 2016
Revised: April 21, 2016
Published online: && &&, &&&&
4
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Communications
Carbohydroxylation
S. Kindt, K. Wicht,
M. R. Heinrich*
&&&& — &&&&
Thermally Induced Carbohydroxylation of
Styrenes with Aryldiazonium Salts
From radical to cation: The radical car-
bohydroxylation of styrenes with aryldia-
zonium salts has been achieved under
mild thermal conditions. A broad range of
aryldiazonium salts was tolerated and the
reaction principle based on a radical–
polar crossover mechanism could be
extended to carboetherification as well as
to a two-step, metal-free variant of the
Meerwein arylation leading to stilbenes.
Angew. Chem. Int. Ed. 2016, 55, 1 – 5
ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!