Reduction of arenediazonium salts by tetrakis(dimethylamino)ethylene (TDAE): Efficient formation of products derived from aryl radicals

Article abstract of DOI:10.3762/bjoc.5.1

Tetrakis(dimethylamino)ethylene (TDAE 1), has been exploited for the first time as a mild reagent for the reduction of arenediazonium salts to aryl radical intermediates through a single electron transfer (SET) pathway. Cyclization of the aryl radicals produced in this way led, in appropriate substrates, to syntheses of indolines and indoles. Cascade radical cyclizations of aryl radicals derived from arenediazonium salts are also reported. The relative ease of removal of the oxidized by-products of TDAE from the reaction mixture makes the methodology synthetically attractive.

Full text of DOI:10.3762/bjoc.5.1

Reduction of arenediazonium salts by
tetrakis(dimethylamino)ethylene (TDAE): Efficient
formation of products derived from aryl radicals
Mohan Mahesh1, John A. Murphy*,1, Franck LeStrat1
and Hans Peter Wessel2
Full Research Paper
Open Access
Address:
Beilstein Journal of Organic Chemistry 2009, 5, No. 1.
1WestCHEM, Department of Pure and Applied Chemistry, University
of Strathclyde, 295, Cathedral Street, Glasgow G1 1XL, U.K. and
2Pharma Research, Discovery Chemistry, F. Hoffmann-La Roche
Ltd., Basel, CH-4070, Switzerland
doi:10.3762/bjoc.5.1
Received: 19 November 2008
Accepted: 24 December 2008
Published: 12 January 2009
Email:
John A. Murphy* - john.murphy@strath.ac.uk
© 2009 Mahesh et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
cyclization; electron transfer; indole; indoline; radical
Abstract
Tetrakis(dimethylamino)ethylene (TDAE 1), has been exploited for the first time as a mild reagent for the reduction of arene-
diazonium salts to aryl radical intermediates through a single electron transfer (SET) pathway. Cyclization of the aryl radicals
produced in this way led, in appropriate substrates, to syntheses of indolines and indoles. Cascade radical cyclizations of aryl
radicals derived from arenediazonium salts are also reported. The relative ease of removal of the oxidized by-products of TDAE
from the reaction mixture makes the methodology synthetically attractive.
Introduction
Arenediazonium salts have long proved useful as sources of such as dihydrobenzofurans, indolines and indoles have been
aryl radicals in many reactions featuring carbon-carbon (e.g., synthesized using this methodology and the radical-polar meth-
Meerwein [1], Pschorr [2,3], Gomberg [3] reactions) and odology has been employed successfully in the total synthesis
carbon-heteroatom bond (e.g., Sandmeyer [4]) formation. The [10] of aspidospermidine (15), the alkaloid of the Aspido-
radical-polar crossover reaction [5-15] of arenediazonium salts, sperma genus (Scheme 2). In line with our interests in gener-
developed in our group since 1993, also features aryl radical ating aryl radicals by reduction of arenediazonium salts with
intermediates and is a more recent addition to these reactions. It tetrathiafulvalenes [5-16] 4 and dithiadiazafulvalenes [16,17]
involves a novel splicing of radical and polar reactions in one (DTDAF) 6 (Scheme 1) and later by electrochemical means
pot, employing tetrathiafulvalene (TTF, 4a, Scheme 1) as elec- [18], we were keen to compare the outcomes of these reactions
tron donor. A number of functionalised heterocycles [5-17] of diazonium salts with those arising from the use of alternative
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Beilstein Journal of Organic Chemistry 2009, 5, No. 1.
Scheme 1: Aza- and thia-substituted electron donors.
Scheme 2: Radical-polar crossover reaction of arenediazonium salts by TTF.
neutral organic electron donors [19,20]. An interesting member TDAE (1), has been widely exploited as a strong electron donor
of these alternative reagents is the commercially available and [21-59] to electron-poor aliphatic and benzylic halides, notably
economically attractive tetrakis(dimethylamino)ethylene those derived from organofluorine sources. Burkholder, Dolbier
(TDAE, 1). This paper describes the results of our investiga- and Médebielle reported [28] that the electrochemical oxidation
tions on reactions of TDAE as a neutral organic electron donor of TDAE in acetonitrile occurs in two reversible one-electron
with arenediazonium salts.
oxidation steps, to TDAE+• 2 and TDAE++ 3 at −0.78 V and
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Beilstein Journal of Organic Chemistry 2009, 5, No. 1.
−0.61 V vs saturated calomel electrode (SCE). Recently, The experiments were of heightened interest because of the
TDAE-promoted reduction of electron-deficient o- and recent report by Andrieux and Pinson [60] on the standard
p-nitrobenzyl chlorides [44-47], 1,2-bis(bromomethyl)arenes reduction potential of the phenyl radical (formed by electro-
[48], mono and trichloromethyl azaheterocycles [49,50], chemical reduction of the arenediazonium cation) to the phenyl
2-(dibromomethyl)quinoxaline [51], α-bromoketones [52] have anion (+0.05 V vs SCE). Thus, it had long been noted that
been reported. Vanelle and co-workers recently reported a cyclic voltammetry of aryl halides, particularly iodides, can
photoinduced reduction of p-nitrobenzaldehyde in the presence give rise to a single two-electron wave in the reductive part of
of TDAE [53].
the cycle. The first electron converts the aryl iodide to the
corresponding aryl radical, while the second electron trans-
The utility of TDAE as a strong electron donor in specific forms the aryl radical to an aryl anion. The two-electron single
organometallic reactions, such as the chromium-mediated reductive wave arises because the transfer of the second elec-
allylation of aldehydes and ketones [54,55] and the palladium- tron is easier than the first. Andrieux and Pinson reasoned that
catalyzed reductive homo-coupling of aryl halides to afford the in order to determine the potential for the conversion of aryl
corresponding biaryls [56-59] illustrate further versatility of the radical to aryl anion, a substrate other than an aryl halide would
reagent.
need to be used. As the one-electron reduction of an arene-
diazonium salt occurs [60] at much more positive potentials (Ep
The fact that formation of aryl radicals had never been reported 0.16 V vs SCE) than for aryl iodides [61] (Ep −2.2 V vs SCE),
using TDAE meant that we were keen to compare its reactions this gives a much better chance to observe a second reductive
with those of the structurally related TTF (4a). Thus, as shown peak in cyclic voltammetry and to determine the potential for
in Scheme 2, the radical-cation of TTF intercepts intermediates conversion of aryl radicals to aryl anions. In the event, their
with the formation of C-S bonds in the radical-polar crossover study [60] showed two reductive peaks for benzenediazonium
reaction; would the analogous chemistry be seen with TDAE tetrafluoroborate (Ep 0.16 V and −0.64 V vs SCE). Through
where no sulfur atoms are present?
detailed analysis, Andrieux and Pinson showed that this second
Scheme 3: Studies on the reductive radical cyclization of arenediazonium salt 16 by TDAE.
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Beilstein Journal of Organic Chemistry 2009, 5, No. 1.
peak was consistent with reduction of the aryl radical to aryl electron-transfer by a mediator in solution [63] is frequently
anion and derived a value for the standard potential of this step more easily achieved (less negative potential) than would be
as E0 = +0.05 V.
expected from the bare electrochemical data. In the light of
these facts, and given that TDAE is a much more powerful
The reduction potentials determined by Andrieux and Pinson donor than TTF (by about 1.1 V for the transfer of the first elec-
would be consistent with the chemistry that we had observed tron), there is a danger that aryl radicals formed from arene-
using TTF, in that TTF had been able to achieve the easier step diazonium salts using this reagent would be further converted
of reducing arenediazonium salts to aryl radicals, but not the into aryl anions, if the second electron transfer were suffi-
more difficult step (aryl radicals to aryl anions). The redox ciently rapid. Therefore, we proposed to examine cyclization
potentials associated with TTF are +0.32 V and +0.71 V vs SCE reactions of aryl radicals produced in this way to investigate this
[62] so, even transferring one electron to the diazonium salts point.
would superficially appear difficult, but it is well known that
Table 1: Reductive radical cyclization of arenediazonium salt 16 by TDAE.
Entry
Equivalents of TDAE
Solvent
Temperature (°C)
Time
Yield (%) of
20a
20b
21
(i)
(ii)
(iii)
1.0
1.0
2.5
Acetonitrile
Methanol
25
−40 to 25
25
24 h
24 h
11
4
11
5
50
64
–a
Acetonitrile
10 min
12
17
a[TDAE]++ 2[BF4−] salt 21 was not isolated from the reaction
Scheme 4: Preparation of the arenediazonium salts 31a–d. Reagents and conditions: (a) 23, NaH, THF, 0 °C, 0.5 h, then TBDPS-Cl, 0 °C to 25 °C, 4
h, 85%; (b) 25, DIAD, PPh3, THF, 0 °C to 25 °C, 12 h, 80% (26a), 64% (26d); (c) TBAF, THF, 25 °C, 1.5 h, 85% (27a), 0.5 h, 97% (27d); (d) PBr3,
DCM, 0 °C to 25 °C, 1 h, 99% (28a), 93% (28d); (e) PhSH, NaH, THF, 0 °C to 25 °C, 1 h, then 28, 25 °C, 5 h, 98% (29a), 94% (29d); (f) Cu(acac)2,
NaBH4, EtOH, 25 °C, 15 h, 70% (30a), SnCl2·2H2O, MeOH, 65 °C, 4 h, 91% (30d); (g) NOBF4, CH2Cl2, −20 °C to −10 °C, 1.5 h, 98% (31a), 100%
(31d); (h) NaIO4, MeOH/H2O, r.t., 1 h 15 min, 92%; (i) SnCl2, MeOH, 65 °C, 4 h, 71%; (j) NOBF4, CH2Cl2, −20 °C to −10 °C, 1.5 h, 100%; (k) NaIO4,
MeOH/H2O (1:1), r.t., 72 h, 82%; (l) SnCl2·2H2O, MeOH, 3.5 h, 83%; (m) NOBF4, CH2Cl2, −20 °C to −10 °C, 1.5 h, 100%.
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Beilstein Journal of Organic Chemistry 2009, 5, No. 1.
Results and Discussion
Preparation of indolines
although the yields of the products 20 were not high. Non-
observation of 22 illustrates that TDAE+•, unlike TTF+•, does
Our initial studies reacted TDAE with simple arenediazonium not provide an efficient termination of radical processes, and the
salt 16 (Scheme 3). On addition of TDAE to a solution of the low yields of isolated compounds could be consistent with
arenediazonium tetrafluoroborate salt 16 in acetonitrile [Table radical chemistry where efficient termination was lacking. With
1, entries (i) and (ii)], or, alternately, on addition of the arene- this as guidance to our thinking, the remaining substrates below
diazonium salt to excess TDAE (2.5 equiv) [Table 1, entry (iii)] were designed to provide internal termination routes for the
the reaction mixture underwent effervescence as it turned from radical chemistry.
deep red to pale orange. In each case, the reaction yielded an
inseparable mixture of indolines 20a and 20b in approximately One way to achieve clean termination of the radical process
equal yield. In entry (iii) of that table, these yields were estim- would be by providing a radical leaving group adjacent to the
ated from a calibrated NMR determination; following this, the cyclised radical 19. Appropriate groups might be sulfide,
mixture was subjected to epoxidation with mCPBA, leading to sulfoxide and sulfonyl groups [64,65]. Accordingly, arene-
isolation of 20b and the epoxide 20c (not shown in Scheme 3) diazonium salts 31a–d were prepared bearing appropriate
derived from 20a. From this series of experiments, the oxidized terminal radical leaving groups (Scheme 4) and treated with 1
product of TDAE, namely octamethyloxamidinium bis(tetra- equivalent of TDAE under different solvent conditions and
fluoroborate) (21) was isolated in up to 64% yield as an off- temperature. As expected, the aryl radical generated from the
white powder. The structure of the salt 21 was characterized by reduction of the arenediazonium salts, underwent facile self-
NMR studies and also by mass spectrometry.
terminating 5-exo-trig aryl radical-alkene cyclization to afford
the indolines 20a, 32 as the sole products in very high yields
The formation of the indolines 20a and 20b could then be (Table 2). Owing to the sensitive nature of the arenediazonium
envisaged through an intermolecular radical disproportionation salts 31a–d, they were usually generated in situ from the corres-
reaction of two cyclised radical intermediates 19 as explained in ponding amines 30a–d by treatment with nitrosonium tetra-
Scheme 3. No evidence was seen for the formation of salt 22 fluoroborate. One of the notable features of these cyclizations is
Table 2: Reductive radical cyclization of arenediazonium salts 31a–d by TDAE.
Entry
Diazonium Salt
Equivalents of
TDAE
Solvent
Temperature (°C)
Time
Isolated Yield (%) of
20a/32
33
21
(i)
31a
31a
31a
31a
31a
31b
31c
31d
1.0
0
Acetonitrile
Acetonitrile
Acetonitrile
Acetone
25
25
5 min
5 min
5 min
5 min
2 h
88
0
82
0
12
0
(ii)a
(iii)b,d
(iv)
3.0
1.0
1.0
1.0
1.0
1.0
25
85
84
81
81
63
88
39
78
34
0
–c
17
71
24
41
35
25
(v)
Methanol
Acetone
0 to 25
25
(vi)d
(vii)d
(viii)d
5 min
5 min
5 min
Acetone
25
0
Acetone
25
55
aControl reaction performed in the absence of TDAE reagent. bThis experiment was conducted by adding a solution of the diazonium salt in dry MeCN
to a solution of TDAE in dry MeCN, while the other experiments in this table all featured addition of the TDAE to the diazonium salt. c[TDAE]++ 2[BF4−]
salt 21 was not isolated from the reaction. dIn these experiments, the arenediazonium salts 31a–d were made in situ from their corresponding amines
30a–d, while all the other experiments in this table featured direct use of arenediazonium salt.
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Beilstein Journal of Organic Chemistry 2009, 5, No. 1.
the ease of purification of the product from the reaction Preparation of indoles
mixture. The oxidized product of TDAE, namely octamethylox- Following the successful implementation of the methodology
amidinium bis(tetrafluoroborate) (21), was easily removed on the synthesis of indolines, we next sought to harness the aryl
either by filtration or by simple work-up with water.
radicals in the synthesis of indoles by a radical-based addition-
elimination strategy [66,67]. However, our initial attempts in
this area upon cyclization of arenediazonium salt 49a were not
Cascade cyclizations
To determine the scope of the TDAE-mediated reduction of fruitful as the reactions afforded a mixture of the exocyclic
arenediazonium salts, we sought to extend this methodology to alkene 50a and the alcohol 52a [Table 3, entry (i)]. We
more complex substrates, namely 42 and 44. Pleasingly, the expected that the aryl radical 53a generated by the reduction of
arenediazonium salts 42 and 44, prepared in situ from the arenediazonium salt 49a by TDAE would undergo 5-exo-trig
amines 41 and 43 respectively upon treatment with 1 equi- radical cyclization onto the vinyl bromide to afford the alkyl
valent of TDAE, underwent facile cascade radical cyclizations radical intermediate 54a, from which Br• would be eliminated
to afford the bicyclized product 47 in 85% and 77% yield to afford the exocyclic alkene 50a (Scheme 6). Such alkenes
respectively (Scheme 5). The ability of TDAE to mediate such tautomerise easily to the corresponding indoles (in this case
efficient cascade cyclizations via two C-C bond formations 51a) in the presence of a trace of acid. Alcohol 52a can arise by
reactions in one pot from the aryl radical 45 was significant 1,2-bromine shift [66,68,69] from radical 54a followed by
considering the fact that our previous studies on similar either (a) loss a hydrogen atom from the resulting benzylic
substrates by TTF [5,8,16,17] and TMTTF [16] had shown radical 56a in collision with another radical or, less likely, (b)
competitive trapping of the intermediate alkyl radical 46 by oxidation of 56a by electron transfer to an arenediazonium
TTF+• or TMTTF+•.
cation. Loss of a proton from the cation so formed would yield
Scheme 5: Cascade radical cyclizations of arenediazonium salts 42 and 44 by TDAE. Reagents and conditions: (a) 23, NaH, THF, 0 °C, 0.5 h, then
TBDPS-Cl, 0 °C to 25 °C, 4 h, 85%; (b) NBS, Me2S, CH2Cl2, −30 °C, 0.5 h, then 24, −30 °C to r.t., 3 h, 95%; (c) 23, NaH, THF, 0 °C to r.t., 1 h, then
34, 72 h, 61%; (d) N-(2-nitrophenyl)methanesulfonamide (25a), DIAD, PPh3, THF, 0 °C to r.t., 1 h, 98%; (e) TBAF, THF, r.t., 20 min, 90%; (f) NBS,
PPh3, CH2Cl2, −25 °C, 20 min, then 37, −25 °C to r.t., 40 min, 96%; (g) PhSH, NaH, THF, 0 °C to r.t., 1 h, then 38, r.t., 12 h, 86%; (h) NaIO4, H2O,
MeOH, r.t., 76 h, 73%; (i) SnCl2, CH3OH, H2O, reflux, 3.5 h to 4 h, 95% (41), 78% (43); (j) NOBF4, CH2Cl2, −15 °C to 0 °C, 1.5 h; (k) NOBF4, CH2Cl2,
−15 °C to 0 °C, 1.5 h; (l) TDAE (1.0 equiv), acetone, 10 min, r.t., 85% 47, 46% 33, 52% 21 in two steps, from 41; 77% 47, 46% 21 in two steps, from
43.
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Beilstein Journal of Organic Chemistry 2009, 5, No. 1.
Table 3: Initial optimization studies of cyclization of arenediazonium salt 49a.
Entry
Diazonium Salt
Equivalents of
TDAE
Solvent
Temperature (°C)
Time
Isolated Yielda (%)
of
51a
52a
(i)
49a
49a
1.0
1.5
Acetone
25
25
30 min
10 min
39b
68c
40
0
(ii)
DMF (anhydrous)
aAll isolated yields were calculated on the basis of the quantity of the starting aryl amine 48a. bThe product 51a was isolated directly from the reaction
mixture after auto-tautomerisation of 50a to indole 51a during storage of reaction mixture prior to flash chromatography. cThe product 51a was obtained
by treatment of the intermediate exocyclic alkene 50a with p-toluenesulfonic acid monohydrate in dichloromethane at r.t. for 12 h.
Scheme 6: TDAE-mediated radical based addition-elimination route to indoles.
bromoalkylindole 57a and subsequent hydrolysis would result diazonium salts 49b–d on treatment with 1.5 equivalents of
in the alcohol 52a. However, when the same reaction was TDAE in anhydrous DMF yielded the indoles 51b–d in 63%,
re-examined in anhydrous DMF as the solvent with 1.5 equival- 43% and 64% yields (in three steps from the corresponding aryl
ents of TDAE, it afforded the unstable exocyclic alkene 50a as amines 48b–d) respectively (Scheme 7). The indole 51d
the sole product, which after treatment with p-toluenesulfonic bearing a fused 9-membered ring was of particular interest to us
acid tautomerised to the indole 51a in an overall 68% yield in because the important anticancer drugs vinblastine (58a) and
three steps from 48a. Adopting the optimized procedure, the vincristine (58b) contain such a system.
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Beilstein Journal of Organic Chemistry 2009, 5, No. 1.
Scheme 7: Cyclization of the arenediazonium salts 49b–d by TDAE. Reagents and conditions: (a) NOBF4, CH2Cl2, −10 °C to 0 °C, 1.5 h; (b) TDAE
(1.5 equiv), anhydrous DMF, r.t., 10 min; (c) p-toluenesulfonic acid monohydrate, CH2Cl2, r.t., 12 h, 63% (51b, in three steps from 48b), 43% (51c, in
three steps from 48c); (d) NOBF4, CH2Cl2, −10 °C to 0 °C, 1.5 h; (e) TDAE (1.5 equiv), anhydrous DMF, r.t., 10 min, 74% 50d; (f) p-toluenesulfonic
acid monohydrate, CH2Cl2, r.t., 12 h, 64% (overall yield in three steps, from 48d).
Scheme 8: Cyclization of the arenediazonium salt 62 by TDAE. Reagents and conditions: (a) 2-Nitrobenzenesulfonyl chloride, DMAP, pyridine, 0 °C
then 110 °C, 27 h, 57%; (b) H2, Pd/C, EtOAc, 3 h, 98%; (c) 61, NOBF4, CH2Cl2, −10 °C, 1.5 h, 95%; (d) TDAE, CH3OH/acetone (1:1), 25 °C, 10 min,
33% 63, 5% 64, 60% 65.
Aryl C-C bond formation
Initial SET from TDAE to the arenediazonium salt 62 afforded
As a final extension of this methodology, we probed the feasib- the aryl radical 67, with release of molecular nitrogen. The aryl
ility of this methodology in aryl-aryl C-C bond formation reac- radical 67 would be expected [3,11,70] to cyclise onto the aryl
tions. Accordingly, the diazonium salt 62 was prepared from ring A either through 5-exo or 6-endo cyclization. The radicals
indoline (59), and treated with one equivalent of TDAE in 68 and 69 could interconvert. Alternatively, aryl radical 67
acetone as solvent. The reaction mixture instantaneously turned could also undergo direct formation of the radical 69. Rearo-
deep red, with accompanying effervescence of nitrogen, and matization from 69 might then occur through a number of path-
afforded the tetracyclic sulfonamide 65 in 60% yield along with ways; in one of these, the radical intermediate 69 would lose a
indole (63) and indole sulfonamide 64 in 33% and 5% yield proton to yield the radical anion 70 which, upon oxidation by
respectively (Scheme 8).
loss of single electron to the starting diazonium salt 62, would
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Beilstein Journal of Organic Chemistry 2009, 5, No. 1.
Scheme 9: Mechanism for the formation of the tetracyclic sulfonamide 65.
Scheme 10: Possible mechanism for the formation of indole (63) and indole sulfonamide 64.
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Beilstein Journal of Organic Chemistry 2009, 5, No. 1.
result in the formation of the tetracyclic sulfonamide 65 Acknowledgments
(Scheme 9).
We thank Universities UK (CVCP) for the award of Overseas
Research Scholarship (ORS), University of Strathclyde for an
Indole (63) and indole sulfonamide 64 can be formed via the International Research Scholarship, and F. Hoffmann-La
indolinyl radical intermediate 71 (Scheme 10). The formation of Roche, Ltd., Basel for a CASE award to M.M.; EPSRC for
the indolinyl radical 71 could be envisaged by abstraction of the funding; EPSRC National Mass Spectrometry Service, Swansea
hydrogen atom (1,5-hydrogen translocation) by the aryl radical for the mass spectral analysis and Dr. John A. Parkinson,
67 from the carbon atom in the α-position to the nitrogen atom University of Strathclyde for NOE NMR experiments.
of the indoline nucleus within the same molecule. The indolinyl
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