Thiocarbonyl compounds as regulating reagent in the radical addition of tertiary amines with alkenes using photoelectron transfer conditions

Article abstract of DOI:10.1039/b600220j

The effect of thiocarbonyl compound addition to a reaction mixture on the efficiency of the photoinduced radical addition of tertiary amines to oleifinic double bonds was investigated. Various aromatic ketones in combination with different tertiary amines

Full text of DOI:10.1039/b600220j

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Thiocarbonyl compounds as regulating reagent in the radical addition of
tertiary amines with alkenes using photoelectron transfer conditions†
Dominique Harakat, Jens Pesch, Sinisˇa Marinkovic´ and Norbert Hoffmann*
Received 9th January 2006, Accepted 1st February 2006
First published as an Advance Article on the web 14th February 2006
DOI: 10.1039/b600220j
The efficiency of the photoinduced radical addition of tertiary
amines to olefinic double bonds is significantly enhanced
and the stereoselectivity is influenced when thiocarbonyl
compounds are added to the reaction mixture.
all significant values like triplet quenching rates were of the
same order of magnitude.
Therefore, we wondered whether we could influence the in-
terplay between the different radical intermediates involved in
the mechanism. In the field of radical polymerization, it is well
known that regulating reagents like thiocarbonyl compounds can
trap a terminal radical of a growing chain and thus start a new
one.9 Furthermore, it has been recently shown in the radical
addition of xanthates to alkenes that the xanthate group can
reversibly add to reactive radical intermediates in such a way as
to stabilize these intermediates.10 In contrast to the previously
investigated reactions, none of the substrates of our reaction
contained a thiocarbonyl function. We therefore decided to add
simple thiocarbonyl compounds to the reaction mixture. Their
influence on the reactivity and stereoselectivity are described in
this paper.
We started our investigation with the addition of triethylamine
2 to furanone 1 (Scheme 1). The irradiation was carried out
at k = 350 nm and 4,4ꢀ-dimethoxybenzophenone was used as
the sensitizer. Under standard reaction conditions as described
in ref. 4 no significant reaction was observed. However, in the
presence of the dithiocarbamate 3 (5 equiv. with respect to 1), a
fast reaction was observed and the diastereomeric adducts 4 were
isolated in high yields.‡ The amine was added in excess [1 : 1 (v/v)
mixture with acetonitrile as solvent]. Preliminary tests revealed the
thiocarbonyl derivative 3 to be a particularly efficient regulator. In
the case of dimethylisopropylamine 5, two regioisomers 6 and 7
were isolated. It should be mentioned that the addition occurred
preferentially at the isopropyl substituent which indicates that
the thermodynamically more stable tertiary radical is more easily
added. This observation is in contrast to previous ones where
the formation of the a-aminoalkyl radicals occurred under kinetic
conditions and the kinetic products (in our case 6) were favored.11
Therefore, not only the reactivity but also the regioselectivity is
affected by the presence of the thiocarbonyl compound.
Radical reactions have become an important tool in organic
chemistry.1,2 Much research in this field presently concerns
the investigation or the improvement of selectivity, especially
stereoselectivity.3
Radical addition of simple tertiary amines to alkenes represents
an interesting example. Despite the great variety of resulting
products possessing biological activity, this reaction has rarely
been applied to organic synthesis since the products are often
isolated in low or moderate yields. Recently, we have developed
an efficient method for performing such transformations.4
A
photochemically-induced electron transfer step using an electron
donor-substituted aromatic ketone as a sensitizer in catalytic
amounts was used to initiate the radical chain reaction. In this
way, a-aminoalkyl radicals were generated and added to electron
deficient alkenes. In contrast to using conventional sensitizers
like benzophenone or acetophenone, high yields (up to 94%)
were observed and the sensitizer could be recovered up to 80%
after the reactions. Heterogeneous catalysis using an inorganic
semiconductor as a sensitizer was also successfully applied with
yields of up to 98%.5 The reaction could be performed with
a large variety of electron deficient alkenes. More complex
transformations like radical tandem addition cyclization reactions
have also been carried out.6 For a recent application of this method
in the field of catalytic enantioseletive reactions see ref. 7.
Although a large variety of nitrogen-containing heterocycles
were accessible, only a restricted number of tertiary amines, mainly
cyclic compounds, could be transformed. In order to enhance
the scope of our method, we became particularly interested in
extending the reaction to tertiary amines possessing only a weak
reactivity under our standard conditions. In such cases, the
primary photochemical processes should also take place. One
possibility of optimization might be structure variation of the
sensitizer in order to influence these primary processes. Therefore,
we investigated various aromatic ketones in combination with
different tertiary amines, reactive and unreactive ones.8 However,
Using the same reaction conditions, the cyclic tertiary amines
8 and 9 were successfully transformed. In the absence of 3 these
transformations were significantly slower and unselective so that
no pure product could be isolated. The sensitizer, although used
in catalytic amounts (0.1 equiv.) was recovered up to 90%. The
regulating reagent 3 was recovered up to 70%. Compound 3
absorbed at k = 350 nm, but this compound was not capable
of sensitizing the reaction. In the presence of the thiocarbonyl
compound and in the absence of the sensitizer, no significant
transformation took place.
Laboratoire des Re´actions Se´lectives et Applications, UMR CNRS et
Universite´ de Reims Champagne-Ardenne, UFR Sciences, B.P. 1039,
F-51687 Reims, cedex 02 France. E-mail: norbert.hoffmann@univ-reims.fr;
Fax: +33 (0)3 26 91 31 66; Tel: +33 (0)3 26 91 31 96
Using the same reaction conditions, the amines 2, 8, 9 and
10 were added to the acrylamide 11 (Scheme 2). Owing to the
restricted Michael acceptor activity, this alkene possessed only low
† Electronic supplementary information (ESI) available: NMR data of
radical addition products of tertiary amines and mass spectra from 16 and
17. See DOI: 10.1039/b600220j
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Scheme 2
Scheme 1
reactivity with respect to the addition of nucleophilic a-aminoalkyl
radicals. Consequently, no significant reactivity was observed in
the absence of the dithiocarbamate 3. However, in the presence
of 3, the adducts were obtained in good yields. Owing to its
enhanced reactivity, the addition of N-methylpyrrolidine 10 4,5 was
particularly efficient. In these cases, the reaction was carried out in
a 1 : 1 (v/v) mixture of acetonitrile and the corresponding amine.
Using the more sensitive menthyloxyfuranone 12 as the olefinic
reaction partner and dithiocarbamate 3 as the regulator, the
reaction was less efficient. Although a transformation took place,
product isolation in the presence of 3, even in small quantities,
caused problems since the amine adducts partially decomposed
during workup. In this case, the reaction could be efficiently
performed using the xanthate 13 (11 equiv. with respect to 12)
(Scheme 3). In the presence of the thiocarbonyl compound and the
absence of the sensitizer, no significant transformation took place.
The radical addition occurred stereospecifically anti with respect
to the menthyloxy substituent. As with furanone 1 (Scheme 1),
the configuration of the chiral center in the a-position of the
nitrogen was not controlled. The regioselectivity of the reaction
of dimethylisopropylamine 5 was almost the same as for 1. For
the addition of N-methylpiperidine 8, we have shown that the
presence of a thiocarbonyl compound in the reaction mixture also
affects the stereoselectivity of the reaction. In the absence of such
a compound, only diastereoisomer 14 was formed, however, in
lower yield.4 The corresponding isomer 15 was not detected.
Scheme 3
At this stage, we can only present a restricted mecha-
nistic interpretation of all of these observations. Using 4,4ꢀ-
dimethoxybenzophenone as an efficient sensitizer, nucleophilic a-
aminoalkyl radicals A are first generated by photoinduced electron
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Scheme 4 Possible reversible trapping of radical intermediates by thiocarbonyl compounds.
transfer (equation 1, Scheme 4). They add easily to the alkene,
and electrophilic oxoallyl radicals B are generated (equation 2,
Scheme 4) (see refs. 4 and 5 and refs. cited therein). After hydrogen
abstraction from the tertiary amine, the final product is obtained
and a-aminoalkyl radicals A are generated. Frequently, radical
intermediates are unstable and their formation is reversible. For
these reasons, the radical chain process is not always efficient
for the radical addition of tertiary amines. Only low quantum
yields have been measured.4 Thiocarbonyl compounds like 3 or
13 are able to reversibly trap such intermediates and stabilize
them (D, E). Such an effect is well established as ‘persistent
radicals’.9,10,12 In this way, equilibria of the radical chain are
shifted. After demethylation, the thiocarbonyl derivative 16 can
be formed. Indeed, using electropray mass spectrometry, we were
able to detect this product in the reaction mixture containing
triethylamine at a concentration of 6 × 10−2 mol L−1. Using
the MS/MS technique, we were able to record the fragmentation
and the high resolution spectra were also obtained. Both were in
accordance with the proposed molecular structure. We observed
that the signal intensity in the mass spectrum of the intermediate
16 decreased considerably when the concentration of triethylamine
2 was increased to 23.5 × 10−2 mol L−1 and the signal intensity
increased when the amine concentration was diminished to 1.3 ×
10−2 mol L−1. The reductive elimination of the xanthate function
in the presence of hydroxyalkyl radicals has been previously
described.10 An increased concentration of 2 and the correspond-
ing a-aminoalkyl radicals should act in the same way to generate
the final product 4 from 16. The thiocarbamade derivative 17
was also detected by electrospray mass spectrometry which proves
that a-aminoalkyl radicals A can add to thiocarbonyl compounds
like 3 or 16. An interaction of the thicarbonyl compounds with
the radical ion pair or ketyl radicals C of the starting reaction is
also possible and could affect the efficiency of this reaction step.
Further mechanistic investigations will be carried out in order to
explain the influence on reactivity, regio- and stereo-selectivity.
It will be checked whether or not the addition of thiocarbonyl
compounds more generally affects radical reactions, in particular
those initiated by other means (BEt3, AIBN, . . .).
In summary, the photoinduced radical addition of tertiary
amines with olefins is significantly accelerated by the presence
of thiocarbonyl compounds like dithiocarbamates or xanthates.
Regio- and stereo-selectivity are also affected. Otherwise unreac-
tive amines have also been efficiently added. Very likely, persistent
radical effects are involved in the mechanism.
S. M. thanks the Ministe`re de l’Education Nationale, de
l’Enseignement Supe´rieur et de la Recherche for a doctoral
fellowship. This work was funded by the CNRS and the Deutsche
Forschungsgemeinschaft in the context of a bilateral French
German research project.
Notes and references
‡ Typical procedure: 84 mg (1.00 mmol, 1.0 equiv.) of 2,4-dihydrofuran-
2-one 1, 24 mg (0.10 mmol, 0.1 equiv.) of 4,4ꢀ-dimethoxybenzophenone,
817 mg (5.00 mmol, 5.0 equiv.) of 3 and 50 mL of the appropriate amine
are dissolved in 50.0 mL of absolute acetonitrile. The solution is evenly
distributed to four Pyrex tubes (Ø = 2 cm) and degassed with argon for
20 min. After irradiation under UV-light (Rayonet, k = 350 nm) for 15–
30 min, the solvent and the excess amine are removed in vacuo. The pure
products are obtained after flash chromatography on silica gel or neutral
alumina.
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