Radical allylations by reaction of azides with allylindium dichloride

Article abstract of DOI:10.1039/c001848a

Allylindium dichloride is an effective reagent for carrying out photolytically initiated radical allylation reactions, as also proved by EPR experiments. In the presence of suitable azides that can give rise to electrophilic radicals, a homolytic chain reaction occurs with formation of allylated compounds. With δ-azido esters and chlorides generation of primary indiumaminyl radicals is followed by a very efficient 1,5-H shift process that gives rise to electrophilic carbon-centred radicals, whose subsequent allylation by the starting indium reagent, followed by aqueous workup, eventually affords allylated nitrogen heterocycles in good yields. Some comparative theoretical calculations accounted for the observation that analogous reactions with an organoallyltin reagent did not work at all. The results show that the reaction with allylindium dichloride seems strongly favoured by both a lower BDE of the allyl-metal bond and a considerably faster, exothermic 1,5-H migration step. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/c001848a

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Radical allylations by reaction of azides with allylindium dichloride†‡
Giorgio Bencivenni, Tommaso Lanza, Matteo Minozzi, Daniele Nanni,* Piero Spagnolo and Giuseppe Zanardi
Received 28th January 2010, Accepted 16th April 2010
First published as an Advance Article on the web 1st June 2010
DOI: 10.1039/c001848a
Allylindium dichloride is an effective reagent for carrying out photolytically initiated radical allylation
reactions, as also proved by EPR experiments. In the presence of suitable azides that can give rise to
electrophilic radicals, a homolytic chain reaction occurs with formation of allylated compounds. With
d-azido esters and chlorides generation of primary indiumaminyl radicals is followed by a very efficient
1,5-H shift process that gives rise to electrophilic carbon-centred radicals, whose subsequent allylation
by the starting indium reagent, followed by aqueous workup, eventually affords allylated nitrogen
heterocycles in good yields. Some comparative theoretical calculations accounted for the observation
that analogous reactions with an organoallyltin reagent did not work at all. The results show that the
reaction with allylindium dichloride seems strongly favoured by both a lower BDE of the allyl-metal
bond and a considerably faster, exothermic 1,5-H migration step.
of indium radicals to the azide moiety. Indium radicals would then
Introduction
behave in a similar way to the tin congeners similarly affording
stannylaminyl radicals,8 which are key intermediates in numerous
worthwhile azide processes including, inter alia, reductions as well
as cyclisations onto suitable radicophilic groups.6a,c,8d–g,m
Radical reactions are now recognised as very powerful tools for
synthetic organic chemists1 and, rather than further establishing
their synthetic value, many of the current efforts to exploit radical
reactions are devoted to discovering novel, efficient procedures
that avoid using toxic metal reagents or, especially, the organotin
compounds that still play a dominant role in radical chemistry.2
In recent years, indium metal, indium halides, and
organoindium reagents have been employed as benign, green
alternatives to other metal-based catalysts.3 In the field of radical
reactions, indium hydrides and allylindium derivatives have been
successfully used as valid alternatives to organostannanes in
many radical processes.4 Allylindium compounds, in particular,
althoughrarely employed, have given excellentresults in allylations
of electrophilic radicals,4o as suitable allylstannane substitutes,
and in cyclisations of the corresponding allyl radicals.4p,r The
reactions can be triggered by either standard radical initiators,
e.g. BEt3/O2,4o or photolysis.4p,r,5
Following our interest in the synthetic utility of azides and their
radical reactions,6 we have recently shown that organic azides are
easily converted by dichloroindium hydride to the corresponding
amines under very mild conditions and in a highly chemoselective
fashion.7 Furthermore, in the presence of side chains bearing
cyano groups, they give rise to outstanding 5-membered cyclisa-
tions affording pyrrolidin-2-imines. Both processes probably entail
the intermediacy of indium-aminyl radicals arising from addition
These encouraging results prompted us to study different
conditions for carrying out radical decompositions of azides,
mainly by avoiding the use of rather unstable indium hydrides and,
at the same time, by accessing final reaction products that could
be even more synthetically interesting. From this point of view,
allylindium reagents were in principle very good candidates, since,
compared to the corresponding hydrides, they are more readily
accessible and also much less sensitive to both water and oxygen.
Furthermore, like allylstannanes, they allow introduction of the
allyl moiety into the final products. Here we report the preliminary
results obtained by reacting some organic azides with allylindium
dichloride under photolytic initiation.
Results and discussion
Synthesis and mechanistic discussion
Allylindium dichloride was prepared by treatment of indium
trichloride with allylmagnesium chloride in THF, as previously
described.4o After replacement of THF with benzene and addition
of a suitable substrate, photolysis was performed at r.t. with a 150
W medium pressure Hg vapour lamp with a pyrex filter. At the
outset of the present work there was just one example of allyl
radical generation by photolysis of organoindium compounds,
in particular allylindium sesquihalides produced from allylic
(cinnamyl) derivatives and indium metal.4p Therefore, before
reacting the azides, we decided to try our photolytic conditions
on the radical allylation reaction reported by Oshima under
triethylborane initiation.4o We actually found that photolysis at r.t.
of allylindium dichloride in the presence of ethyl a-bromoacetate
brought to ethyl a-allylacetate in virtually quantitative yield, hence
proving that our initiation method can be a very good substitute
for chemical initiators.
Dipartimento di Chimica Organica "A. Mangini", Universita` di Bologna,
Viale Risorgimento 4, I-40136, Bologna, Italy. E-mail: nanni@ms.fci.
unibo.it; Fax: +39 051 2093654; Tel: +39 051 2093623
† Electronic supplementary information (ESI) available: Calculation de-
tails, calculated values for the BDEs of tetraalkylstannanes, plot of calcu-
lated BDEs vs. experimental values, calculated BDEs of allyltrimethylstan-
nane and allylindium dichloride, reaction pathway and calculated energies
for the species involved in 1,5-H transfer of indium- or tin-substituted
aminyl radicals, cartesian coordinates of all compounds, intermediates,
and transition states. See DOI: 10.1039/c001848a
‡ This paper is heartily dedicated to Prof. Rino Leardini on the occasion
of his retirement.
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Since no direct evidence for homolytic cleavage of the carbon-
indium bonds had been obtained to date, with the exception of
alkylindium(III) tetraphenylporphyrin,9 we also tried to demon-
strate the possible generation of allyl and indyl radicals upon pho-
tolysis of allylindium dichloride by means of EPR spectroscopic
experiments. When a degassed solution of allylindium dichloride
in tert-butylbenzene was photolysed at -13 ◦C with a 500 W
super pressure Hg arc lamp inside the EPR resonant cavity, the
unambiguous spectrum of the allyl radical was recorded.10 Fig. 1
shows the spectrum obtained after 30 scans (upper panel) and the
corresponding simulation (lower panel): the latter was obtained
with hyperfine splitting constants [a(1H) = 4.0 G, a(2H) = 13.9 G,
a(2H) = 14.8 G] and g-factor (2.00254) i.e. virtually identical to
those reported in the literature.11
Fig. 2 Azides reacted with allylindium dichloride under photolysis.
However, all attempts to detect ensuing aminyl radicals were
unsuccessful, the allyl radical being the only identifiable species.
Presumably, decomposition of indium-aminyl radicals was fast
enough to lower their concentration below the limit for detection.
Indeed, as it will be shown below, sulfonyl/acyl azides 1,2 can form
electrophilic aminyl (and sulfonyl) radicals capable of initiating an
effective chain reaction with the allylindium reagent, whereas alkyl
azides 3,4 could form nucleophilic aminyl radicals highly able to
rearrange to electrophilic carbon radicals, which were again prone
to promote a fair chain reaction with allylindium dichloride.
When azide 1 was reacted for 3 h with allylindium dichlo-
ride in benzene solution at r.t. with photolytic initiation12 it
gave, besides small amounts of unreacted starting material (ca.
10%), benzenesulfonamide 9, allylsulfonylbenzene 10, and N-allyl
benzenesulfonamide 12. 1H-NMR spectroscopic analysis revealed
that 9 and 10 were the major products in a ca. 1 : 1 ratio, whereas
the N-allyl derivative 12 was a minor product (12/10 ª 1/2). These
results are clearly consistent with the radical mechanism shown
in Scheme 1, which is analogous to that previously invoked for
similar reactions of arenesulfonyl azides with allylstannanes under
thermal conditions.13
Fig. 1 Upper panel: EPR spectrum of the allyl radical (MW frequency:
9.5 GHz; 260 K; power: 2.0 mW; modulation amplitude 0.6 Gpp, 1st
derivative; 30 scans). Lower panel: simulation obtained with a(1H) = 4.0 G,
a(2H) = 13.9 G, and a(2H) = 14.8 G.
This experiment provided the first evidence of generation of allyl
radicals, and thence, indirectly, of dichloroindium radicals, from
photolysis of an allylindium compound.
Scheme 1 Reaction mechanism of sulfonyl azide 1 with allylindium
dichloride.
It is worth noting that the quite weak signal observed (30 scans
were needed in order to record a reasonable quality spectrum)
could be due to a somewhat inefficient photolysis process or,
more likely, to reversible scission of the In–CH2 bond that,
without any trapping of dichloroindyl radicals, could keep the
concentration of free allyl radicals low, due to the recombination
process. However, this photochemical outcome should not spoil
the possible efficiency of synthetic applications, since any trap of
the indium-centred radicals would shift the reagent dissociation
equilibrium and, moreover, photolysis would be just needed for
bringing about initiation of the chain reaction.
Photolysis of allylindium dichloride in the presence of various
azides (i.e. azides 1–4, Fig. 2) showed evident evolution of small gas
bubbles inside the reaction mixtures and concomitant, although
not complete, disappearance of the starting azide. This strongly
suggested that the experimental conditions triggered decomposi-
tion of those azides to the corresponding indium-aminyl radicals.
Indeed, after initial generation of 1,3-(5) and/or 3,3-
substituted-(6) triazenyl radicals, allylsulfonylbenzene 10 can be
easily accounted for through a radical deazidation pathway
followed by allylation of the resulting sulfonyl radical 7 by the
starting allylindium dichloride (AllInCl2). Competing formation
of indium-sulfonamidyl radical 8 by nitrogen extrusion, followed
by reaction with the starting allylindium reagent and final
hydrolysis, explains the formation of allylsulfonamide 12. The
additional formation of 9, entailing hydrogen abstraction by
radical 8 followed by hydrolysis, was not unexpected, since it was
also observed to a certain extent in related radical reactions of
azide 1 with allylstannanes.13 However, preferential production
of compound 9 at the expense of 12 was rather surprising. For
unclear reasons radical 8 would prefer to undergo allylic hydrogen
atom abstraction from the starting allylindium reagent rather
than alternative allylation.13,14 Also, product 10 occurred to a
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greater extent than in the allylstannane-mediated reactions: this
suggests that indyl radicals are more prone to perform attack at the
terminal azide nitrogen, resulting in deazidation, than the stannyl
congeners.15
This radical protocol therefore provides a novel, appealing one-
pot synthesis of allylated nitrogen heterocycles such as 18 and 19
using easily available azido precursors.18
By way of contrast, deazidation was not observed at all for
azide 2, which furnished again the reduced benzamide 13 as the
major reaction product together with minor amounts of N-allyl
benzamide 14 (13/14 ratio ca. 3 : 1) (Scheme 2). Unfortunately, this
reaction was not very significant, since it also yielded considerable
amounts of unidentified by-products. In such case the resultant
electrophilic benzamidyl radical would be even less selective than
sulfonamidyl 8 in bringing about the radical chain.
Theoretical calculations
It is worth noting that the reactions of azides 3 and 4 described in
the above section could not be carried out by replacing allylindium
dichloride with allyltributylstannane: prolonged photolysis of the
reaction mixtures in the presence of the latter reagent gave mostly
unreacted starting material. These findings were quite unexpected,
since allylstannanes are well-known photolytical initiators of
radical allylation chain reactions.19,20 We then became interested
in ascertaining the reasons why the allylindium and allyltin
compounds could behave so differently with azides 3 and 4.
A preliminary approach could be to turn our attention to the
All-In and All-Sn BDEs (bond dissociation energies). Unfortu-
nately, no experimental data are available for either metallorganic
compounds, and hence we evaluated the respective energies by
performing some theoretical calculations. These were carried out
with the Gaussian03 package;21 Density Functional Theory (DFT)
was employed at the B3LYP level22 using the LanL2DZ basis
set with Effective Core Potentials (ECP) on all atoms23 (see
ESI†). These options have already been exploited for calcula-
tions involving group XIII and XIV organometallic compounds
(including organoindium derivatives) and seemed therefore both
the best level and basis set for our study.24 Nonetheless, before
attempting calculations of the BDEs of allylindium dichloride
and allyltrimethyltin (the simplest model for allyltributyltin), we
initially derived the BDEs of a series of simple tetraalkylstannanes
for which experimental BDE values are available.25 Actually,
DFT calculations allowed a quite careful estimation of the
tin-alkyl BDEs of methyl-, ethyl-, iso-propyl-, and tert-butyl-
trimethylstannane, with deviations from the experimental values
ranging from 1.8% (iso-propyl) to 6.7% maximum (methyl). It is
worth pointing out that the same calculations carried out by an
analogous HF method, while well reproducing the relative bond
weakening by passing from methyl to tert-butyl, totally failed to
estimate the absolute values, with deviations ranging from 25.3%
(methyl) to so much as 31.3% (tert-butyl) (see ESI for details†).
Persuaded we had a dependable tool in our hands, we turned
back to the allyl derivatives and calculated the BDEs of the All-In
and All-Sn bonds in allylindium dichloride and allyltrimethyltin
as 42.3 and 49.8 kcal mol-1, respectively, with a quite noteworthy
difference of 7.5 kcal mol-1 in favor of the indium compound. Once
again, HF calculations properly predicted the trend (DBDE =
7.7 kcal mol-1) but were completely unreliable as to the absolute
values, estimating energies (19.0 and 26.7 kcal mol-1 for All-In and
All-Sn bonds, respectively) that are evidently far away from reality.
Theoretical data clearly suggest that the indium-allyl bond in
allylindium dichloride is significantly weaker than the tin-allyl
bond of an allyltrialkylstannane, and hence the radical allylation
performed with the former reagent seems to be appreciably
favoured, at least as far as the initiation step is concerned. These
results, though, do not seem sufficient to explain thoroughly the
dramatically different behaviours of tin and indium allyls. Indeed,
if an efficient radical chain reaction were to start by scission of
the metal-allyl bond, in principle even very few radicals would
be capable of bringing about the whole process, and at least
Scheme 2 Reaction products of acyl azide 2 with allylindium dichloride.
More interesting results were obtained with azides 3 and 4.16
These azides were chosen on the assumption that, in general,
indiumaminyl radicals would give very fast hydrogen abstraction
reactions. Even faster reactions are expected to occur whenever
intramolecular H-shifts are feasible, especially if polar effects can
operate in the transition state,17 as when nucleophilic aminyls
abstract a hydrogen atom vicinal to an electron-withdrawing
group. The resulting electrophilic carbon radicals should in turn
add quickly to allylindium dichloride, hence bringing about the
radical chain. Our overall results obtained with azides 3 and 4 are
depicted in Scheme 3.
Scheme 3 Reaction mechanism of alkyl azides 3 and 4 with allylindium
dichloride.
Addition of dichloroindium radicals to the azides gives rise to
(nucleophilic) indium-aminyl radicals 15 able to undergo 1,5-H
shifts affording (electrophilic) a-halo- (from 3) and a-carbonyl-
(from 4) substituted alkyl radicals 16. Allylation of the latter by
the starting allylindium dichloride yields allylated N-indylamines
17, which, upon aqueous basic workup, are finally converted into
mixtures of the respective amines and their (ionic) cyclisation
products 18 (from 3) and 19 (from 4). When the aqueous workup
mixtures were stirred overnight at r.t., 2-allylpyrrolidine 18 and
3-allylpiperidin-2-one 19 were obtained as the exclusive reaction
products in 60% and 65% yield, respectively. Side products derived
from other possible reactions of radicals 15, such as N-allylation
and/or intermolecular H-abstraction, were not observed at all.
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some products would be observed. Consequently, either all of
the (few) tin radicals arising from the allylstannane are scavenged
by pathways competitive with addition to the azide moiety (but
it seems unlikely),20,26 or a different step is responsible for the
profoundly altered reaction outcome.
Therefore, we were prompted to turn our attention to the 1,5-
H migration transforming metal-aminyls 15 into carbon-centred
radicals 16, which are the crucial intermediates for the effectiveness
of the chain reaction.12 Theoretical calculations were carried out
on radical intermediates A, B, and C (Metal = Me3Sn or Cl2In)
and the transition states connecting them (Scheme 4, see ESI
for details†).27 On the basis of the previous results, calculations
were performed with the DFT method at the spin-unrestricted
UB3LYP level (LanL2DZ ECP basis set), but a HF method was
again employed as well to test as before the consistency of relative
data. Fig. 3 shows the reaction profiles obtained by DFT with the
two different metal moieties.
the corresponding activation barriers, which differ by about 3 kcal
mol-1 (tin: Ea = 10.8 kcal mol-1 [DFT] or 29.6 kcal mol-1 [HF];
indium: Ea = 8.0 kcal mol-1 [DFT] or 26.0 kcal mol-1 [HF]).28
Such a significant difference in activation energies suggests
that, under our conditions, 1,5-H shift of aminyls, besides being
enthalpically favoured, is much faster in indium-substituted rad-
icals with respect to the tin-congeners. Even taking into account
a possible reversibility of this step, the equilibrium converting
stannylaminyls into the corresponding carbon-centred radicals
would be expected to be strongly shifted towards the former
species, thus preventing a useful concentration of the latter to be
formed. On the contrary, with indiumaminyls the rearrangement
equilibrium would unquestionably be shifted towards the carbon-
centred radicals, hence strongly favouring the formation of the
species that are crucial for the effectiveness of the whole radical
chain reaction.
The reason why so remarkable a difference between tin-
and indium-substituted aminyls is observed (and theoretically
predicted) remains so far rather obscure. Since intramolecular
radical hydrogen migrations are supposed to occur through
transition states entailing significant charge separation developing
on both the involved atoms, we thought that tin or indium
moieties could bring significant differences on the nucleophilicity
of the corresponding aminyl, and hence on the extent of charge
separation in the 1,5-H shift transition state. Unfortunately,
calculations predicted for TS B-C charge density maps strictly
independent of the presence of tin or indium moieties,29 hence
making this hypothesis unlikely for explaining experimental and
theoretical evidences. Currently, the only noticeable distinction
between tin- and indium-aminyls can be found in hybridation of
the corresponding nitrogen atom, which, while being nearly planar
in TS B-C (Metal = Cl2In), appears slightly pyramidal in TS B-C
(metal = Me3Sn): this could appreciably affect orbital overlapping
in the transition state and hence the reaction rate. This is, though,
just a preliminary account and further studies are definitely needed
to develop a more consistent explanation.
Scheme 4 Intermediates and transition states (TS) involved in calcula-
tions on 1,5-H migration of tin- and indium-aminyl radicals (Metal =
Me3Sn, Cl2In).
Conclusions
Allylindium dichloride was shown to be an effective reagent for
photolytically initiated radical allylation of azido compounds.
Photolysis in the presence of azido chloride 3 and azido ester
4 led to eventual occurrence of allylated pyrrolidine/pyperidinone
products 18 and 19, respectively, primarily due to a tandem radical
process entailing 1,5-H transfer reaction of initial (nucleophilic)
indium-aminyl radicals, followed by allylation of the (electrophilic)
translocated carbon radicals by the allylindium reagent. These
findings provide the first example of valuable synthetic use of
an allylindium compound triggered by photochemical homolytic
fragmentation of the carbon-indium bond.
Some comparative theoretical calculations allowed us to ac-
count for the observation that analogous azide reactions are
totally prevented when using an organoallyltin reagent in place
of allylindium dichloride. The results show that the reaction with
allylindium dichloride seems strongly favoured with respect to the
one carried out with an allylstannane by both a lower BDE of
the allyl-metal bond and a considerably faster, exothermic 1,5-H
migration step. When the latter process is hindered, as calculations
suggest is the case of the allylstannane, the formation of the crucial
Fig. 3 Reaction profiles for 1,5-H shift of tin- and indium-aminyls
(UB3LYP, LanL2DZ ECP).
When metal = Me3Sn, conversion of A into B is a nearly
isoenthalpic process, with an activation barrier of about 2 kcal
mol-1 (DH = -0.2 kcal mol-1, Ea = 1.9 kcal mol-1 [DFT], DH =
0.2 kcal mol-1, Ea = 2.5 kcal mol-1 [HF]). When metal = Cl2In
the conformational transformation becomes slightly endothermic
by about 1 kcal mol-1, with an activation energy comparable to
that estimated for tin (DH = 0.8 kcal mol-1, Ea = 2.2 kcal mol-1
[DFT], DH = 1.5 kcal mol-1, Ea = 2.7 kcal mol-1 [HF]). Hence,
calculations suggest that this process does not seem to justify any
difference between tin and indium in this crucial step.
More significant divergencies were observed instead for the
subsequent step, i.e. the key hydrogen shift. Indeed, with tin the
rearrangement is somewhat endothermic (DH = 0.6 kcal mol-1
[DFT] or = 2.6 kcal mol-1 [HF]), whereas with indium it becomes
notably exothermic (DH = -4.9 kcal mol-1 [DFT] or = -2.6 kcal
mol-1 [HF]). An even more significant difference was also found in
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carbon-centred radical is seriously hampered and the radical chain
cannot be sustained.
Studies are underway to fully exploit the synthetic potential
of our radical allylation reactions of azides with allylindium
dichloride.
solvent was removed in vacuo and replaced by benzene (3 mL);34
the azide (1 mmol) was then added and the resulting solution was
photolysed for 3 h with the 150 W medium pressure Hg arc UV
lamp. The reaction crude was treated with an alkaline (NaOH)
aqueous solution, extracted with diethyl ether and purified by
column chromatography.
Experimental
Photolytic reactions of azides with allylindium dichloride: results
General procedures
Azide
1 afforded unreacted starting material (10%), N-
1H and 13C NMR spectra were recorded in deuteriochloroform
on a Varian Mercury Plus 400 instrument (1H: 400 MHz, 13C:
100 MHz) using the residual solvent signal (1H NMR spectra,
d 7.26 ppm; 13C NMR spectra, d 77.0) as the internal standard.
In reporting spectral data, the following abbreviations were used:
m = multiplet, br s = broad singlet. IR spectra were recorded
in CHCl3 on a FT-IR Perkin Elmer Spectrum RXI instrument.
Mass spectra were recorded either by the electron spray ionization
(ESI) method or under electron impact (EI, 70 eV) conditions with
Waters–Micromass ZQ4000 and Thermo–Finnigan MAT95 XP
instruments, respectively. GC-MS analyses were carried out using
a ThermoFisher–Focus DSQ system. Column chromatography
was performed on ICN silica gel (70–230 or 230–400 mesh) by
gradual elution with mixtures of light petroleum (bp 40–70 ◦C)
and diethyl ether or dichloromethane or methanol and final elution
with methanol. Photolyses were performed with a 150 W medium
pressure Hg arc UV lamp or with a 500 W super high pressure
Hg arc UV lamp (ESR). ESR spectra were obtained with a
Bruker EMX 10/12 spectrometer operating at 9.5 GHz with 100
kHz modulation (power 2.0 mW, modulation amplitude 0.6 Gpp).
Samples were contained in quartz capillary tubes (ca. 1 mm i.d.),
deaerated by bubbling nitrogen for ca. 15 min. Simulations were
carried out with the Bruker Simfonia software package. Anhy-
drous indium trichloride was commercially available (Aldrich) and
was dried prior to each reaction by heating at 130 ◦C under argon
for 1 h. Allylindium dichloride was prepared by treatment of dry
indium trichloride with allylmagnesium chloride (1 eq) in THF,
according to a reported procedure.30 Azides 1,13 2,31 3,32 and 433
were prepared according to previous literature procedures.
allylbenzenesulfonamide 12 (15%), benzenesulfonamide 9 (30%),
and allyl phenyl sulfone 10 (33%). All products were identified by
spectral comparison with authentic samples.13
Azide 2 yielded N-allylbenzamide 14 (19%), identified by
spectral comparison with an authentic sample,35 and benzamide
13 (60%).36
Azide 3 gave a reaction crude that, after usual workup,
contained (GC-MS analysis) a mixture of pyrrolidine 18 and its
presumable precursor 17 (X = Cl, NHInCl2 = NH2). The latter
compound [m/z 108 (M+ + 2 - 41, 30%), 106 (M+ - 41, 100%)]
could not be isolated and the whole reaction mixture was stirred
overnight with an aqueous NaOH solution to transform 17 into
the allylated heterocycle 18. After extraction with diethyl ether and
chromatography, 2-allylpyrrolidine 18 was isolated in 60% yield
and identified by spectral comparison with an authentic sample;
1H NMR d 1.70–1.83 (m, 1H), 2.02–2.19 (m, 2H), 2.24–2.30 (m,
1H), 2.46–2.53 (m, 1H), 2.61–2.67 (m, 1H), 3.33–3.45 (m, 2H),
3.70–3.76 (m, 1H), 3.80–3.94 (br s, 1H, NH), 5.26–5.37 (m, 2H),
5.88–6.00 (m, 1H);37 13C NMR d 26.0 (CH2), 32.4 (CH2), 39.2
(CH2), 48.3 (CH2), 63.2 (CH), 122.1 (CH2), 138.5 (CH) [lit.37 13C
NMR (CDCl3, 62.5 MHz) d 24.0, 30.4, 36.9, 45.2, 59.7, 119.4,
133.0];38 m/z (EI, rel. abund.) 70 (M+ - 41, 100), 68 (15), 43 (10),
41 (10).
Azide 4 analogously afforded a reaction crude containing a
mixture of piperidinone 19 and its probable precursor 17 (X =
CO2Et, NHInCl2 = NH2), which could not be isolated. The whole
reaction mixture was stirred overnight with an aqueous NaOH
solution to completely transform 17 into the allylated heterocycle
19. After extraction with diethyl ether and chromatography, 3-
allylpiperidin-2-one 19 was isolated in 65% yield and identified by
spectral comparison with an authentic sample; 1H NMR d 1.45–
2.35 (m, 7H), 3.21–3.51 (m, 2H), 4.88–5.21 (m, 2H), 5.52–6.15 (m,
1H), 6.65 (br s, 1H, NH);39 13C NMR d 22.3 (CH2), 27.0 (CH2),
37.2 (CH2), 42.0 (CH2), 43.8 (CH), 118.0 (CH2), 137.8 (CH), 175.3
(CO).39
Photolysis of allylindium dichloride: ESR analyses
A 1.0 M THF solution of allylmagnesium chloride (1 mmol) was
added dropwise under argon at r.t. to a stirred solution of dry
indium trichloride (1 mmol) in dry THF (2 mL). After 20 min the
solvent was removed in vacuo and replaced by tert-butylbenzene
(2 mL); the resulting solution was degassed with nitrogen and
transferred into a quartz tube, which was then sealed, inserted
into the ESR cavity, and photolysed with the 500 W super high
pressure Hg arc UV lamp. The optimised spectrum reported in
Acknowledgements
We gratefully thank Prof. J. C. Walton (University of St. Andrews,
UK) for help with the EPR spectra. We also acknowledge financial
support from the University of Bologna and MIUR (2008 PRIN
funds for “Properties and reactivity of free radicals in complex
environments and their role in oxidative processes and in organic
synthesis”).
◦
Fig. 1 was obtained at -13 C. In some experiments carried out
in the presence of various azides no species other than the allyl
radical could be detected.
Photolytic reactions of azides with allylindium dichloride: general
procedure
Notes and references
A 1.0 M THF solution of allylmagnesium chloride (2 mmol) was
added dropwise under argon at r.t. to a stirred solution of dry
indium trichloride (2 mmol) in dry THF (3 mL). After 20 min the
1 For a comprehensive review on synthetic radical chemistry, see:
Radicals in Organic Synthesis, vol. 1 and 2, ed. P. Renaud and M. P. Sibi,
Wiley-VCH, Weinheim, 2001.
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2 For recent papers on this subject, see: (a) P. A. Baguley and J. C. Walton,
Angew. Chem., Int. Ed., 1998, 37, 3072; (b) F. Gagosz, C. Moutrille and
S. Z. Zard, Org. Lett., 2002, 4, 2707; (c) S. Kim and C. J. Lim, Angew.
Chem., Int. Ed., 2002, 41, 3265; (d) F. Gagosz and S. Z. Zard, Org.
Lett., 2002, 4, 4345; (e) S. Kim and H.-J. Song, Synlett, 2002, 2110;
(f) A. Studer and S. Amrein, Synthesis, 2002, 835; (g) G. Ouvry and
S. Z. Zard, Chem. Commun., 2003, 778; (h) L. Benati, G. Calestani, R.
Leardini, M. Minozzi, D. Nanni, P. Spagnolo and S. Strazzari, Org.
Lett., 2003, 5, 1313; (i) J. Boivin, R. Jrad, S. Juge and V. T. Nguyen,
Org. Lett., 2003, 5, 1645; (j) A.-P. Schaffner and P. Renaud, Angew.
Chem., Int. Ed., 2003, 42, 2658; (k) Y. M. Osornio, R. Cruz-Almanza,
V. Jimenez-Montano and L. D. Miranda, Chem. Commun., 2003, 2316;
(l) A. Studer, S. Amrein, F. Schleth, T. Schulte and J. C. Walton, J. Am.
Chem. Soc., 2003, 125, 5726; (m) A. Studer, Chem. Soc. Rev., 2004, 33,
267; (n) L. Benati, R. Leardini, M. Minozzi, D. Nanni, R. Scialpi, P.
Spagnolo, S. Strazzari and G. Zanardi, Angew. Chem., Int. Ed., 2004,
43, 3598; (o) K. Molawi, T. Schulte, K. O. Siegenthaler, C. Wetter and
A. Studer, Chem. Eur. J., 2005, 11, 2335; (p) C. M. Jessop, A. F. Parsons,
A. Routledge and D. J. Irvine, Eur. J. Org. Chem., 2006, 1547; (q) L.
Benati, G. Bencivenni, R. Leardini, M. Minozzi, D. Nanni, R. Scialpi,
P. Spagnolo and G. Zanardi, J. Org. Chem., 2006, 71, 3192; (r) S.-H.
Ueng, M. Makhlouf Brahmi, E. Derat, L. Fensterbank, E. Lacoˆte, M.
Malacria and D. P. Curran, J. Am. Chem. Soc., 2008, 130, 10082; (s) G.
Bencivenni, T. Lanza, R. Leardini, M. Minozzi, D. Nanni, P. Spagnolo
and G. Zanardi, Org. Lett., 2008, 10, 1127.
3 (a) B. C. Ranu, Eur. J. Org. Chem., 2000, 2347; (b) K. Takami, H.
Yorimitsu, H. Shinokubo, S. Matsubara and K. Oshima, Org. Lett.,
2001, 3, 1997; (c) M. Bandini, P. G. Cozzi, A. Garelli, P. Melchiorre
and A. Umani-Ronchi, Eur. J. Org. Chem., 2002, 3243; (d) B. Gotov,
J. Kaufmann, H. Schumann and H.-G. Schmalz, Synlett, 2002, 361;
(e) M. Iasuda, S. Yamasaki, Y. Onishi and A. Baba, J. Am. Chem. Soc.,
2004, 126, 7186; (f) M. Bandini, M. Fagioli, A. Melloni and A. Umani-
Ronchi, Adv. Synth. Catal., 2004, 346, 573; (g) S. Juan, Z.-H. Hua, S.
Qi, S.-J. Ji and T.-P. Loh, Synlett, 2004, 829; (h) D. H. Cho and D. O.
Jang, Tetrahedron Lett., 2004, 45, 2285; (i) J. Lu, S.-J. Ji and T.-P. Loh,
Chem. Commun., 2005, 2345; (j) H. Miyabe and T. Naito, Org. Biomol.
Chem., 2004, 2, 1267.
4 Indium hydrides: (a) T. Miyai, K. Inoue, M. Yasuda, I. Shibata and A.
Baba, Tetrahedron Lett., 1998, 39, 1929; (b) K. Inoue, A. Sawada, I.
Shibata and A. Baba, Tetrahedron Lett., 2001, 42, 4661; (c) K. Inoue,
A. Sawada, I. Shibata and A. Baba, J. Am. Chem. Soc., 2002, 124,
906; (d) K. Takami, H. Yorimitsu and K. Oshima, Org. Lett., 2002,
4, 2993; (e) K. Takami, S. Mikami, H. Yorimitsu, H. Shinokubo and
K. Oshima, Tetrahedron, 2003, 59, 6627; (f) K. Takami, S. Mikami,
H. Yorimitsu, H. Shinokubo and K. Oshima, J. Org. Chem., 2003, 68,
6627; (g) N. Hayashi, I. Shibata and A. Baba, Org. Lett., 2004, 6, 4981;
(h) N. Hayashi, I. Shibata and A. Baba, Org. Lett., 2005, 7, 3093; (i) K.
Miura, M. Tomita, Y. Yamada and A. Hosomi, J. Org. Chem., 2007,
72, 787; (j) K. Miura, M. Tomita, J. Ichikawa and A. Hosomi, Org.
Lett., 2008, 10, 133; indium metal (SET processes): (k) H. Miyabe,
M. Ueda, A. Nishimura and T. Naito, Org. Lett., 2002, 4, 131; (l) H.
Miyabe and T. Naito, Org. Biomol. Chem., 2004, 2, 1267; organoindium
reagents: (m) S.-I. Usugi, T. Tsuritani, H. Yorimitsu, H. Shinokubo and
K. Oshima, Bull. Chem. Soc. Jpn., 2002, 75, 841; (n) K. Takami, H.
Yorimitsu and K. Oshima, Org. Lett., 2004, 6, 4555; (o) K. Takami,
S.-I. Usugi, H. Yorimitsu and K. Oshima, Synthesis, 2005, 824; (p) T.
Hirashita, J. Tanaka, A. Hayashi and S. Araki, Tetrahedron Lett., 2005,
46, 289; (q) B. C. Ranu and T. Mandal, Tetrahedron Lett., 2006, 47,
2859; (r) T. Hirashita, A. Hayashi, M. Tsuji, J. Tanaka and S. Araki,
Tetrahedron, 2008, 64, 2642; (s) N. Hayashi, Y. Hirokawa, I. Shibata,
M. Yasuda and A. Baba, Org. Biomol. Chem., 2008, 6, 1949.
5 Although toxicity data on organoindium compounds are not available
to a great extent, it is worth admitting that the few accessible
information suggest there could be no significant improvement, as far
as toxicity is strictly concerned, by substituting tin with indium. The
greenness of organoindium compounds is rather a matter of workupand
purification of reaction products. Employment of dichloroindium
hydride or allylindium dichloride results in inorganic, water-soluble
metal byproducts that can be easily, quantitatively removed from the
reaction crude: this prevents noteworthy contamination of organic
reaction products, hence overcoming the main problems associated
with use of organotin reagents.
2002, 58, 3485; (c) L. Benati, G. Bencivenni, R. Leardini, M. Minozzi,
D. Nanni, R. Scialpi, P. Spagnolo, G. Zanardi and C. Rizzoli, Org. Lett.,
2004, 6, 417; (d) L. Benati, G. Bencivenni, R. Leardini, M. Minozzi, D.
Nanni, R. Scialpi, P. Spagnolo and G. Zanardi, J. Org. Chem., 2005, 70,
3046; (e) L. Benati, G. Bencivenni, R. Leardini, M. Minozzi, D. Nanni,
R. Scialpi, P. Spagnolo and G. Zanardi, J. Org. Chem, 2006, 71, 434;
(f) L. Benati, G. Bencivenni, R. Leardini, M. Minozzi, D. Nanni, R.
Scialpi, P. Spagnolo and G. Zanardi, J. Org. Chem, 2006, 71, 5822; (g) G.
Bencivenni, T. Lanza, R. Leardini, M. Minozzi, D. Nanni, P. Spagnolo
and G. Zanardi, J. Org. Chem, 2008, 73, 4721; (h) T. Lanza, R. Leardini,
M. Minozzi, D. Nanni, P. Spagnolo and G. Zanardi, Angew. Chem. Int.
Ed, 2008, 47, 9439; (i) M. Minozzi, D. Nanni and P. Spagnolo, Chem.
Eur. J., 2009, 15, 7830.
7 L. Benati, G. Bencivenni, R. Leardini, M. Minozzi, D. Nanni, R.
Scialpi, P. Spagnolo and G. Zanardi, Org. Lett., 2006, 8, 2499.
8 (a) M. Frankel, D. Wagner, D. Gertner and A. Zikha, J. Organomet.
Chem, 1967, 7, 518; (b) M. C. Samano and M. J. Robins, Tetrahedron
Lett., 1991, 32, 6293; (c) N. E. Poopeiko, T. I. Pricota and I. A.
Mikhailopulo, Synlett, 1991, 342; (d) S. Kim, G. H. Joe and J. Y. Do,
J. Am. Chem. Soc., 1993, 115, 3328; (e) S. Kim, G. H. Joe and J. Y.
Do, J. Am. Chem. Soc., 1994, 116, 5521; (f) S. Kim, S. and J. Y. Do,
J. Chem. Soc., Chem. Commun., 1995, 1607; (g) S. Kim, S. S. Kim,
H. S. Seo and K. S. Yoon, Tetrahedron, 1995, 51, 8437; (h) H.-S. Dang
and B. P. Roberts, J. Chem. Soc., Perkin Trans. 1, 1996, 1493; (i) S.
Kim, K. M. Yeon and K. S. Yoon, Tetrahedron Lett., 1997, 38, 3919;
(j) A. M. Hornemann and I. Lundt, J. Org. Chem., 1998, 63, 1919;
(k) P. C. Montevecchi, M. L. Navacchia and P. Spagnolo, Eur. J. Org,.
Chem., 1998, 1219; (l) D. S. Hays and G. C. Fu, J. Org. Chem., 1998, 63,
2796; (m) A. J. Moreno-Vargas and P. Vogel, Tetrahedron Lett., 2003,
44, 5069.
9 M. Yamaji, Y. Hama, S. Arai and M. Oshino, Inorg. Chem., 1987, 26,
4375.
∑
10 Detection of a good signal of InCl2 radical was very unlikely, due to
the broadening effect of the Indium quadrupole moment; hence all
efforts were devoted to detection of the radical counterpart, i.e. the
allyl radical. The optimal temperature of -13 ◦C was determined after
several attempts at various temperatures.
11 J. K. Kochi and P. J. Krusic, J. Am. Chem. Soc, 1968, 90,
7157.
12 Photolytic self-decomposition of those azides does not occur to a
significant extent under our experimental conditions. Normal alkyl
or aryl azides (the latter even with electron-withdrawing substituents)
were recovered completely unreacted upon treatment after many hours
with allylindium dichloride under photolytic initiation; in this case, the
radical chain reaction is probably hindered by the low electrophilicity
of the intermediate indiumaminyl radicals, which, by analogy with
other metal-substituted congeners, are actually supposed to be slightly
nucleophilic (see ref. 6e,f, 7, and 8i).
13 H.-S. Dang and B. P. Roberts, J. Chem,. Soc., Perkin Trans. 1, 1996,
1493.
14 Hydrogen abstraction from allylindium dichloride could also account
for the observed non-complete conversion of the starting azide, since
this process would consume part of the allyl indium reagent in a route
that would not furnish the ·InCl2 radicals required for the allylation
process.
15 For radical azido-transfer reactions, see: P. Panchaud, L. Chabaud, Y.
Landais, C. Ollivier, P. Renaud and S. Zigmantas, Chem. Eur. J., 2004,
10, 3606.
16 It is worth noting that, whereas the reactions of azides 1 and 2 were
not substantially affected by the solvent (THF or benzene), those of
azides 3 and 4 showed a dramatic effect: in THF the starting azides were
recovered substantially unchanged after prolonged photolysis, whereas,
after 3 h in benzene solution, we observed complete conversion into the
products reported in Scheme 3. This impressive difference could be due
to either the hydrogen donor features of THF, which may quench the
initial aminyl radicals in a chain-breaking reaction, or the complexing
properties of this solvent, which could alter the real structure of the
allylindium reagent and thence its reactivity towards these particular
azides.
17 (a) B. Giese, Radicals in Organic Synthesis: Formation of Carbon-
Carbon Bonds, Pergamon Press, Oxford, 1986, Chp. 2; (b) K. Heberger
and A. Lopata, J. Org. Chem, 1998, 63, 8646; (c) H. Fischer and L.
Radom, Angew. Chem., Int. Ed, 2001, 40, 1340; (d) F. De Vleeschouwer,
V. Van Speybroeck, M. Waroquier, P. Geerlings and F. De Proft, Org.
Lett., 2007, 9, 2721, and references therein.
6 (a) L. Benati, D. Nanni, C. Sangiorgi and P. Spagnolo, J. Org. Chem.,
1999, 64, 7836; (b) L. Benati, R. Leardini, M. Minozzi, D. Nanni,
P. Spagnolo, S. Strazzari, G. Zanardi and G. Calestani, Tetrahedron,
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18 Compounds 18 and 19 have been previously synthesised in multistep
protocols entailing starting materials that were always more structurally
complicated with respect to our simple azides; even our yields, albeit
not exceptionally high, are however comparable with the overall yields
obtained in literature methods.
19 See, for example: (a) G. E. Keck and J. B. Yates, J. Am. Chem. Soc., 1982,
104, 5829; (b) G. E. Keck, E. J. Enholm, J. B. Yates and M. R. Wiley,
Tetrahedron, 1985, 41, 4079; (c) J. Fiandor and S. Y. Tam, Tetrahedron
Lett., 1990, 31, 597; (d) H. Rolland, P. Potin, J.-P. Majoral and G.
Bertrand, Tetrahedron Lett., 1992, 33, 8095.
24 For some recent examples, see: (a) G. K. Rothschopf, J. S. Perkins,
S. Li and D.-S. Yang, J. Phys. Chem. A, 2000, 104, 8178; (b) W. Uhl,
A. El-Hamdan, M. Pro¨tt, P. Spuhler and G. Frenking, Dalton Trans.,
2003, 1360; (c) W. Miao, L. W. Chung, Y.-D. Wu and T. H. Chan,
J. Am. Chem. Soc., 2004, 126, 13326; (d) G. Fontana, G. Savona and F.
Ferrante, Lett. Org. Chem., 2006, 3, 98; (e) Y.-P. Tong and Y.-W. Lin,
Inorg. Chim. Acta, 2009, 362, 2033.
25 Y.-r. Luo, Handbook of Bond Dissociation Energies in Organic Com-
pounds, CRC Press, Boca Raton, 2003, p. 297.
26 We are currently aiming at investigating by theoretical calculations the
intermolecular addition of metal-centred radicals, including certainly
tin- and indium-centred ones, to azides.
27 Structures A and B are just conformers but it is important to verify
whether the two different metal moieties bring about any peculiar
hindrance in converting the presumably more stable linear A into the
conformer B that can undergo 1,5-H migration.
28 The Ea values obtained by HF calculations are unmistakably far away
from reality but, like in the case of the BDEs reported above, it is worth
pointing out that they confirm the relative trend, giving differences
in enthalpies and activation barriers strictly comparable with those
obtained by DFT, hence providing further support to the mechanistic
discussion.
29 The notable difference in electropositivity between tin and indium,
which should be expected to affect nucleophilicity of the corresponding
aminyl radical, is probably balanced by thepresence of electronreleasing
and electronwithdrawing groups on tin (alkyl moieties) and indium
(chlorine atoms), respectively.
20 Although addition of tin radicals to azides is normally carried out at
80 ◦C or above, it seems very unlikely that at r.t. this reaction would
slow down enough to inhibit the whole reaction. For a few examples
of reactions performed below 80 ◦C, see: M. Frankel, D. Wagner, D.
Gertner and A. Zilkha, J. Organomet. Chem., 1967, 7, 518, where the
poorer results obtained by lowering the temperature seem just a matter
of initiator inefficiency rather than rate of addition of tin radicals to
the azide (or even intervention of alternative mechanisms).
21 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb,
J. R. Cheeseman, J. A. Montgomery, Jr., T. Vreven, K. N. Kudin, J. C.
Burant, J. M. Millam, S. S. Iyengar, J. Tomasi, V. Barone, B. Mennucci,
M. Cossi, G. Scalmani, N. Rega, G. A. Petersson, H. Nakatsuji, M.
Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T.
Nakajima, Y. Honda, O. Kitao, H. Nakai, M. Klene, X. Li, J. E.
Knox, H. P. Hratchian, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo,
R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi,
C. Pomelli, J. W. Ochterski, P. Y. Ayala, K. Morokuma, G. A. Voth,
P. Salvador, J. J. Dannenberg, V. G. Zakrzewski, S. Dapprich, A. D.
Daniels, M. C. Strain, O. Farkas, D. K. Malick, A. D. Rabuck, K.
Raghavachari, J. B. Foresman, J. Ortiz, Q. Cui, A. G. Baboul, S. Clifford,
J. Cioslowski, B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I.
Komaromi, R. L. Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C. Y.
Peng, A. Nanayakkara, M. Challacombe, P. M. W. Gill, B. Johnson,
W. Chen, M. W. Wong, C. Gonzalez and J. A. Pople, Gaussian 03,
revision E.01; version EM 64L-G03, Gaussian, Inc., Wallingford, CT,
2004.
30 K. Takami, S.-i. Usugi, H. Yorimitsu and K. Oshima, Synthesis, 2005,
824.
31 D. S. Bose and A. V. N. Reddy, Tetrahedron Lett., 2003, 44, 3543.
32 L. Yao, B. T. Smith and J. Aube´, J. Org. Chem., 2004, 69, 1720.
33 N. Khoukhi, M. Vaultier and R. Carrie´, Tetrahedron, 1987, 43, 1811.
34 Benzene is very toxic and carcinogenic (R45) and every possible
precaution must be taken when handling this solvent. However, our
reactions can be effectively carried out by replacing benzene with other
aromatic hydrocarbons such as tert-butylbenzene or toluene.
35 L. E. Fisher, J. M. Muchowski and R. D. Clark, J. Org. Chem., 1992,
57, 2700.
22 (a) C. Lee, W. Yang and R. G. Parr, Phys. Rev. B, 1988, 37, 785; (b) A. D.
Becke, J. Chem. Phys., 1993, 98, 1372; (c) A. D. Becke, J. Chem. Phys.,
1993, 98, 5648.
23 (a) T. H. Dunning, Jr. and P. J. Hay, in Modern Theoretical Chemistry,
H. F. Schaefer, III, Ed.; Plenum, New York, 1976; Vol. 3, pp 1-28;
(b) P. J. Hay and W. R. Wadt, J. Chem. Phys., 1985, 82, 270; (c) W. R.
Wadt and P. J. Hay, J. Chem. Phys., 1985, 82, 284; (d) P. J. Hay and
W. R . Wa d t , J. Chem. Phys., 1985, 82, 299.
36 Commercially available.
37 S. H. Park, H. J. Kang, S. Ko, S. Park and S. Chang, Tetrahedron:
Asymmetry, 2001, 12, 2621.
38 S. Hong, A. M. Kawaoka and T. J. Marks, J. Am. Chem. Soc., 2003,
125, 15878.
39 N. Khoukhi, M. Vaultier and R. Carrie´, Tetrahedron, 1987, 43, 1811.
3450 | Org. Biomol. Chem., 2010, 8, 3444–3450
This journal is
The Royal Society of Chemistry 2010
©