A practical variation on the Leuckart reaction

Article abstract of DOI:10.1016/j.tetlet.2004.12.042

S-Aryldiazo xanthates, derived from the corresponding diazonium salts by reaction with potassium O-ethyl xanthate, undergo a radical chain reaction with loss of nitrogen; the intermediate aromatic radical can be captured by an internal olefin to give bicy

Full text of DOI:10.1016/j.tetlet.2004.12.042

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 971–973
A practical variation on the Leuckart reaction
Lucie Tournier and Samir Z. Zard*
` ´
Laboratoire de Synthese Organique associe au CNRS, Ecole Polytechnique, F-91128 Palaiseau, France
Received 22 October 2004; revised 29 November 2004; accepted 8 December 2004
Available online 25 December 2004
Abstract—S-Aryldiazo xanthates, derived from the corresponding diazonium salts by reaction with potassium O-ethyl xanthate,
undergo a radical chain reaction with loss of nitrogen; the intermediate aromatic radical can be captured by an internal olefin to
give bicyclic xanthates in good overall yield.
ꢀ 2004 Elsevier Ltd. All rights reserved.
One of the oldest methods for the synthesis of thiophe-
nols is the Leuckart reaction.1 In this reaction, an aryl
diazonium salt 1 is treated with potassium O-ethyl xan-
thate to give an aryl xanthate 2, which is then cleaved
with alkali into the thiophenol 3 (Scheme 1). This syn-
thesis, however, comes with a serious warning of an
explosion hazard2 and this has presumably hindered
mechanistic studies to understand the workings of the
process and, perhaps even more, its application for the
large scale preparation of thiophenols.
As part of a wider study on the reduction of aryldiazon-
ium salts, Beckwith and co-workers3 examined the case
of thiolates and concluded that the thiodediazoniation
proceeded via an SRN1 type mechanism: electron trans-
fer, followed by loss of nitrogen and formation of aro-
matic radicals. The latter could indeed be intercepted
by an internal olefin. One example involved a xanthate
salt as the thiolate component.3a In contrast to other thio-
Scheme 2.
lates, however, it is possible to propose an alternative
mechanism, outlined in Scheme 2, which could be oper-
ating in the case of xanthates. The S-aryldiazo xanthate
4, formed when the diazonium salt is combined with
potassium O-ethyl xanthate, can in fact undergo a chain
reaction similar to the one we have proposed for ali-
phatic xanthates and upon which much of our recent re-
search has been based.4 The chain process would be
expected to be highly effective in view of the weakness
Scheme 1.
of the N–S bond.
In the original Leuckart process, the ice-cold solution
Keywords: Leuckart reaction; Diazonium salt; Aromatic radical;
Xanthate.
of the requisite aniline in aqueous mineral acid is
diazotised by addition of sodium nitrite followed by
addition of potassium O-ethyl xanthate.1,2 The
*
Corresponding author. Tel.: +33 0169334872; fax: +33
0169333851; e-mail: zard@poly.polytechnique.fr
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.12.042

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L. Tournier, S. Z. Zard / Tetrahedron Letters 46 (2005) 971–973
This modification of the Leuckart reaction was applied
to various substituted anilines. The results are compiled
in the Table 1.5 The yields, calculated from the free ani-
line, are generally synthetically quite acceptable. Five-
or six-membered rings, containing an oxygen, nitrogen
or a sulfur, can be constructed, and various substituents
are tolerated on the aromatic ring. The internal olefinic
trap can also be substituted. In this respect, the case of
24 is especially interesting since the terminal carbon
has now the oxidation level of an aldehyde. For com-
pounds 14, 22, 24, 28 and 30, we observed, not surpris-
ingly, little stereoselectivity and an essentially 1:1
mixture of diastereoisomers was obtained. It is also wor-
Table 1. Internal capture of aryl radicals (Xa = EtOCSS–)
Scheme 3.
13, R = H, R0 = Me;
15, R = R0 = Me
14, R = H, R0 = Me (49%);
16, R = R0 = Me (64%)
formation of the S-aryldiazo xanthate intermediate
4 must be rapid and, since it is usually not water
soluble, it would in most cases separate from the
solution. If a spontaneous initiation takes place, by
adventitious radicals generated, for example, by the
ambient lighting or by a slight decomposition of the dia-
zonium salt, then an exceedingly efficient chain process
sets in the essentially neat material causing an exother-
mic evolution of nitrogen, leading in some cases to an
explosion. The danger of an explosion obviously
increases with the scale at which the Leuckart reaction
is performed.
17
18 (52%)
19, R =R0 = Me;
21, R = H, R0 = Me;
23, R = H, R0 = Cl
20, R =R0 = Me (55%);
22, R = H, R0 = Me (66%);
24, R = H, R0 = Cl (58%)
In order to remedy this problem, and at the same time to
exploit the synthetic potential of the intermediate aryl
radical, we decided to modify the experimental proce-
dure and perform the reaction in a two phase system.
Thus, an inert organic solvent would be added before
incorporating the xanthate salt. In this way, the S-aryl-
diazo xanthate never accumulates and the radical chain
reaction takes place on the diluted substance, in the or-
ganic phase. It would, moreover, be easy to regulate its
concentration by controlling the rate of addition of the
xanthate salt.
25
26 (68%)
27, R =MeO;
29, R = CF3
28, R =MeO (61%);
30, R = CF3 (73%)
We tested the feasibility of this modification using
O-prenylated 2-aminophenol 7 as the aniline partner.
Once the diazotisation was complete, cyclohexane
was added and the medium deoxygenated by bub-
bling nitrogen to avoid interference by triplet oxygen.
The potassium O-ethyl xanthate was then incorporated
in portions and with vigorous stirring. Thin layer chro-
matography examination of the organic phase indi-
cated the presence of an intermediate, presumably the
putative diazo xanthate 8, which smoothly evolved into
the expected dihydrobenzofuran 12. The latter was
isolated in overall 64% yield based on the starting
aniline 7.6 The intermediate aryl radical 10 is captured
by the internal olefin, but the chain is otherwise
propagated in the expected manner, as depicted in
Scheme 3.
31
32 (59%)
33
35
34 (68%)
36 (68%)

L. Tournier, S. Z. Zard / Tetrahedron Letters 46 (2005) 971–973
973
References and notes
1. Leuckart, R. J. Prak. Chem. 1890, 41, 179–224; For
reviews, see: (a) Baguley, P. A.; Walton, J. C. Angew.
Chem., Int. Ed. 1998, 37, 3072; (b) Studer, A. Synthesis
2003, 835.
2. See, for example: Vogel, A. I. Practical Organic Chemistry,
3rd ed.; Longman: London, 1970; p 597; For a review on
the radical chemistry of arenediazonium salts, see: Galli, C.
Chem. Rev. 1988, 88, 765–792.
3. (a) Meijs, G. F.; Beckwith, A. L. J. J. Am. Chem. Soc. 1986,
108, 5890–5893; For related work from the same group, see:
(b) Abeywickrema, A. N.; Beckwith, A. L. J. J. Am. Chem.
Soc. 1986, 108, 8227–8229.
4. (a) Zard, S. Z. Angew. Chem., Int. Ed. 1997, 36, 672–685;
(b) Quiclet-Sire, B.; Zard, S. Z. Phosphorus, Sulfur, Silicon
1999, 153–154, 137–154; (c) Zard, S. Z. In Radicals in
Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-
VCH: Weinheim, 2001; Vol. 1, pp 90–108.
5. Typical procedure: to a mixture of the corresponding aniline
(n mmol) and ice (0.5n g) was added concentrated HCl
(1.9n mmol) dropwise at 0 ꢁC. The medium was deoxygen-
ated by bubbling nitrogen. Adeoxygenated solution of
sodium nitrite (1.05n mmol) was added dropwise while
strictly maintaining the reaction temperature at 0 ꢁC. The
reaction mixture was stirred for 1 h at 0 ꢁC. Once the
diazotisation was complete, cold, deoxygenated cyclohexane
(2n mL) was added to the aqueous solution. Xanthate salt
(1.2n mL) was carefully added, in portions and with
vigorous stirring. The reaction was stirred another 5 min
and quenched with ice. The reaction was diluted with ether
(20 mL), and washed with water (2 · 10 mL) and brine
(10 mL). The organic layer was dried over MgSO4, concen-
trated in vacuo and purified by flash chromatography.
6. When this compound was prepared using the usual
Leuckart reactions, the yield was only 40% instead of
64% under our modified conditions. We thank Dr. Gilles
Ouvry for performing this reaction.
7. (a) Cheung, M.; Hunter, R. N., III; Peel, M. R.; Lackey, K.
E. Heterocyles 2001, 55, 1583–1590, and references cited
therein; (b) Ting, P. C.; Kaminski, J. J.; Sherlock, M. H.;
Tom, W. C.; Lee, J. F.; Bryant, R. W.; Watnick, A. S.;
McPhail, A. T. J. Med. Chem. 1990, 33, 2697–2706; (c)
Kumar, V.; Dority, J. A.; Bacon, E. R.; Singh, B.; Lesher,
G. Y. J. Org. Chem. 1992, 25, 6995–6998; For a recent
approach to such structures involving radical addition to
Scheme 4.
thy of note that the process is compatible with a pyridine
ring and azaindolines such as 36 are readily accessible.
Such derivatives are currently in great demand by
medicinal chemists in view of their potential as kinase
inhibitors.7
Experimentally, the process is extremely easy to per-
form. The reagents are cheap and readily available,
and no heavy metals are involved. Little waste is gener-
ated and scale up should be straightforward since the is-
sue of a chain reaction taking place in neat S-aryldiazo
xanthate has been completely circumvented. Although
cyclohexane was suitable for the examples described
herein, other solvents (toluene, chlorobenzene, etc.)
could also be used in principle.
Last but not least, the adducts are highly functional-
ised. The xanthate group can be converted into a
number of other functionalities or serve as a conve-
nient entry into the rich chemistry of sulfur. It can, of
course, also act as a starting point for another radical
sequence. Compound 34 embodies a portion of the
structure of welwitindolinones,8 which loses the
xanthate group upon heating in 1,2-dichloroethane to
give unsaturated oxindole 37 in 75% yield (Scheme 4).
In this case, b-elimination is especially favoured due to
the acidity of the hydrogen on C-3 of the oxindole
structure.
´
the pyridine ring, see: (d) Bacque, E.; El Qacemi, M.; Zard,
S. Z. Org. Lett. 2004, 6, 3671–3674.
8. Isolation and structure: (a) Stratmann, K.; Moore, R. E.;
Bonjouklian, R.; Deeter, J. B.; Patterson, G. M. L.; Shaffer,
S.; Smith, C. D.; Smitka, T. A. J. Am. Chem. Soc. 1994,
116, 9935–9942; (b) Jimenez, J. I.; Huber, U.; Moore, R. E.;
Patterson, G. M. L. J. Nat. Prod. 1999, 62, 569–572; For
published synthetic approaches, see: (c) Ready, J. M.;
Reisman, S. E.; Hirata, M.; Weiss, M. M.; Tamaki, T.;
Ovaska, T. V.; Wood, J. L. Angew. Chem., Int. Ed. 2004, 43,
1270–1272; (d) Wood, J. L.; Holubec, A. A.; Stoltz, B. M.;
Weiss, M. M.; Dixon, J. A.; Doan, B. D.; Shamji, M. F.;
Chen, J. M.; Heffron, T. P. J. Am. Chem. Soc. 1999, 121,
6326–6327; (e) Jung, M. E.; Slowinski, F. Tetrahedron Lett.
2001, 42, 6835–6838; (f) Deng, H. P.; Konopelski, J. P. Org.
Lett. 2001, 3, 3001–3004; (g) Lopez-Alvarado, P.; Garcia-
Granda, S.; Alvarez-Rua, C.; Avenando, C. Eur. J. Org.
Chem. 2002, 1702–1707.
Acknowledgements
One of us (L.T.) gratefully acknowledges generous
financial support from Rhodia. We thank Drs. Jean-
Marc Paris and Franc¸ois Metz of Rhodia for friendly
discussions.