Direct synthesis of isothiocyanates from isonitriles by molybdenum-catalyzed sulfur transfer with elemental sulfur

Article abstract of DOI:10.1021/jo026042i

The direct molybdenum-catalyzed sulfuration of a variety of isonitriles with elemental sulfur or propene sulfide as sulfur donors affords the corresponding isothiocyanates in good yields and under mild reaction conditions. A catalytic cycle is suggested, in which the molybdenum oxo disulfur complex operates as the active sulfur-transferring species. A novel adduct between the isonitrile and the molybdenum complex has been characterized by X-ray analysis and its association constant determined by UV-vis spectroscopy, but this adduct appears not to be involved in the sulfur-transfer process.

Full text of DOI:10.1021/jo026042i

Dir ect Syn th esis of Isoth iocya n a tes fr om Ison itr iles by
Molybd en u m -Ca ta lyzed Su lfu r Tr a n sfer w ith Elem en ta l Su lfu r †
Waldemar Adam,‡ Rainer M. Bargon,*,‡ Sara G. Bosio,‡ Wolfdieter A. Schenk,§ and
Dietmar Stalke§
Institut fu¨r Organische Chemie and Institut fu¨r Anorganische Chemie, Universita¨t Wu¨rzburg,
Am Hubland, D-97074 Wu¨rzburg, Germany,
adam@chemie.uni-wuerzburg.de
Received J une 11, 2002
The direct molybdenum-catalyzed sulfuration of a variety of isonitriles with elemental sulfur or
propene sulfide as sulfur donors affords the corresponding isothiocyanates in good yields and under
mild reaction conditions. A catalytic cycle is suggested, in which the molybdenum oxo disulfur
complex operates as the active sulfur-transferring species. A novel adduct between the isonitrile
and the molybdenum complex has been characterized by X-ray analysis and its association constant
determined by UV-vis spectroscopy, but this adduct appears not to be involved in the sulfur-
transfer process.
In tr od u ction
operate as the sulfur-transfer agent. Such a direct
synthesis of isothiocyanates has been documented in the
sulfuration of isonitriles by an as yet unidentified sulfur-
containing metalloenzyme6b and would correspond to a
biomimetic methodology.6
In striking contrast to the variety of effective metal
catalysts that are known for oxygen transfer reactions,1
analogous sulfur-transfer processes are to date still
rather scarce. So far, only three cases for the metal-
catalyzed episulfidation of alkenes have been reported,
namely the ruthenium-catalyzed episulfidation of cyclo-
hexene,2a the rhodium-catalyzed episulfidation of nor-
bornene and norbornadiene,2b and the molybdenum-
catalyzed episulfidation of strained cyclic alkenes.2c
Recently, Chandrasekaran and co-workers used a mo-
lybdenum complex to transform alkyl halides to disul-
fides, with latter added in situ to Michael acceptors such
as R,â-unsaturated enones.3 An attempted preparation
of isothiocyanates by sulfur transfer to isonitriles with a
stoichiometric amount of a molybdenum-disulfido com-
plex was also reported, but instead of isothiocyanates,
the corresponding thioureas were obtained.4
The synthesis of isothiocyanates,7 which exist in nature
as marine sesquiterpenes,8 has been extensively studied
over the past decades, since they play an important role
as anti-proliferatives9 and in the therapy of blood can-
cer,10 as enzyme inhibitors for the HIV virus,11 and as
herbicides.12 They may be prepared from amines,13
organic halides,14 alkenes,15 aldehydes,16 and isonitriles.17
These methods require stoichiometric amounts of re-
agents and often the hazardous thiophosgene or its
derivatives need to be utilized.13 In regard to the direct
(5) McDonald, J . W.; Newton, W. E. Inorg. Chim. Acta 1980, 44,
L81-L83.
(6) (a) Simpson, J . S.; Garson, M. J . Tetrahedron Lett. 2001, 42,
4267-4269. (b) Simpson, J . S.; Garson, M. J . Tetrahedron Lett. 1998,
39, 5819-5822.
(7) (a) Guy, R. G. In The Chemistry of Cyanates and their Thio
Derivatives; Patai, S., Ed.; J ohn Wiley & Sons: New York, 1977; Part
2, pp 819-886. (b) Gilmore, J .; Gallagher, P. T. In Comprehensive
Organic Functional Group Transformations, 1st ed.; Katritzky, A. R.,
Meth-Cohn, O., Rees, C. W., Eds.; Elsevier Science Ltd.: New York,
1995; Vol. 5, pp 1021-1051.
Our encouraging results in the metal-catalyzed episulfi-
dation2c of cyclic olefins motivated us to assess whether
isonitriles may be catalytically sulfurated by elemental
sulfur with molybdenum-oxo complex 2 as catalyst;
presumably a molybdenum disulfur complex5 would
(8) Chang, C. W. J . Prog. Chem. Org. Nat. Prod. 2000, 80, 1-186.
(9) Nastruzzi, C.; Cortesi, R.; Esposito, E.; Menegatti, E.; Leoni, O.;
Iori, R.; Palmieri, S. J . Agric. Food Chem. 2000, 48, 3572-3575.
(10) Xu, K.; Thornalley, P. J . Biochem. Pharmacol. 2000, 60, 221-
231.
(11) Zhang, X.; Neamati, N.; Lee, Y. K.; Orr, A.; Brown, R. D.;
Whitaker, N.; Pommier, Y.; Burke, T. R. Bioorg. Med. Chem. 2001, 9,
1649-1657.
(12) Lemin, A. J . U.S. Patent 3,449,112, 1969 [Chem. Abstr. 1969,
71, 37845w].
(13) (a) L’Abbe, G. Synthesis 1987, 525-531. (b) Zhang, X.; Lee, Y.
K.; Kelley, J . A.; Burke, T. R. J . Org. Chem. 2000, 65, 6237-6240.
(14) Gurudutt, K. N.; Rao, S.; Srinivas, P. Indian J . Chem. 1991,
30B, 343-344.
(15) Margarita, R.; Mercanti, C.; Parlanti, L.; Piancatelli, G. Eur.
J . Org. Chem. 2000, 10, 1865-1870.
(16) Kim, J . N.; J ung, K. S.; Lee, H. J .; Son, J . S. Tetrahedron Lett.
1997, 38, 1597-1598.
† This work was presented in part at the XIXth International
Symposium on Organic Chemistry of Sulfur, Sheffield, J une 25-30,
2000.
‡ Institut fu¨r Organische Chemie.
§ Institut fu¨r Anorganische Chemie.
(1) Sheldon, R. A.; Kochi, J . K. Metal-Catalyzed Oxidations of
Organic Compounds; Academic Press: New York, 1981.
(2) (a) Khan, M. M. T.; Siddiqui, M. R. H. Inorg. Chem. 1991, 30,
1157-1159. All our efforts to repeat this work failed under the reported
catalytic conditions with the poorly reactive cyclohexene and even the
highly reactive (E)-cyclooctene as sulfur acceptors. (b) Blake, A. J .;
Cooke, P. A.; Kendall, J . D.; Simpkins, N. S.; Westaway, S. M. J . Chem.
Soc., Perkin Trans. 1 2000, 153-163. (c) Adam, W.; Bargon, R. M.
Chem. Commun. 2001, 1910-1911.
(3) Prabhu, K. R.; Sivanand, P. S.; Chandrasekaran, S. Angew.
Chem., Int. Ed. Engl. 2000, 39, 4316-4319.
(4) Byrne, J . J .; Vallee, Y. Tetrahedron Lett. 1999, 40, 489-490.
10.1021/jo026042i CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/04/2002
J . Org. Chem. 2002, 67, 7037-7041
7037

Adam et al.
TABLE 1. Ca ta lytic Su lfu r a tion of Ison itr iles 4 w ith
Elem en ta l Su lfu r (S8) a s Su lfu r Don or
SCHEME 1. P r ep a r a tion of th e Molybd en u m
Com p lexes 2 a n d 3
method with elemental sulfur, only the selenium- and
tellurium-catalyzed sulfurations of isonitriles have been
reported,17 but the toxicity of these chalcogens limits their
use. These drawbacks we have now circumvented by
developing the first direct molybdenum-catalyzed sulfu-
ration of isonitriles with elemental sulfur, to afford a
variety of isothiocyanates in good yields. Herein we report
the results of this novel sulfuration and offer a mecha-
nism for the catalytic sulfur-transfer process.
a
Yield of pure isolated isothiocyanate after distillation, except
b
5d , which was isolated by silica gel chromatography. 0.05 equiv
Resu lts
of catalyst 2 were used; 100% consumption of the isonitrile 4 after
23 h.
Molybdenum disulfur complex 3 was prepared accord-
ing to the literature procedure in three steps from sodium
molybdate (Scheme 1).5,18,19 Ligation of diethyl dithiocar-
bamate with molybdate yielded dioxo complex 1 in 80%
yield,18 which was readily reduced by triphenylphosphine
to air-sensitive oxo complex 2 in 80% yield.19 The latter
was heated in refluxing acetone with a stoichiometric
amount of elemental sulfur to afford disulfur complex 3,
which acts as the active sulfur-transferring agent.5
Treatment of isonitriles 4 with an excess of elemental
sulfur and a catalytic amount (0.01 equiv) of molybde-
num-oxo complex 2 in refluxing acetone under an inert
atmosphere of argon gas resulted in isothiocyanates 5
in up to 93% yield (Table 1). The consumption of isoni-
triles 4 was complete within 72 h, as monitored by TLC
and 13C NMR spectroscopy. This long reaction time could
be reduced to 23 h for isonitrile 4b (compare entries 2
and 3), with only a small decrease in the yield when 0.05
equiv of catalyst 2 was used.
Isothiocyanates 5 were purified by Kugelrohr distilla-
tion and the heat-sensitive derivatives by silica gel
chromatography. When in a control experiment molyb-
denum catalyst 2 was omitted, the direct reaction of
isonitrile 4b with elemental sulfur in refluxing acetone
gave only traces (<5%) of isothiocyanate 5b even after
69 h, as detected by 13C NMR spectroscopy. Thus, for the
first time a variety of aliphatic and aromatic isonitriles
4 have been catalytically sulfurated with elemental
sulfur. This catalytic sulfur-transfer process tolerates
functionalities such as the trimethylsiloxy group in
isonitrile 4e (entry 6) and the carbon-carbon double bond
in isonitrile 4g (entry 8). The yields of the isolated
products are generally good to excellent (Table 1).
Alkenyl isonitrile 4j and isonitrile 4k with an electron-
withdrawing substituent could not be transformed to
their isothiocyanates 5 with elemental sulfur under the
conditions given in Table 1. The failure of this sulfur-
transfer method with elemental sulfur is due to the fact
that isonitrile 4j and isothiocyanate 5k do not persist in
boiling acetone in the presence of Lewis acid.20 However,
when propene episulfide was used as the sulfur donor,
the catalytic sulfuration was achieved in very good yield
already at 20-25 °C in methylene chloride (Table 2).
As in the case of 4g, the carbon-carbon double bond
of isonitrile 4j is not attacked under these sulfur-transfer
conditions. Even base- or acid-sensitive functional groups
as the hydroxy group in isonitrile 4l and the acetal
functionality in 4m are easily transformed in good yields
to their isothiocyanates 5.
To assess whether in this unprecedented catalytic
sulfuration process the molybdenum disulfur complex 3
operates as a sulfur-transferring species, complex 3 was
independently synthesized (Scheme 1) and allowed to
react with isonitrile 4b. As anticipated, the authentic
molybdenum disulfur complex 3 effects the sulfuration
of isonitrile 4b (Scheme 2). When stoichiometric amounts
of complex 3 and isonitrile 4b were employed, TLC
(17) (a) Fujiwara, S.; Shin-Ike, T.; Okada, K.; Aoki, M.; Sonoda, N.
Tetrahedron Lett. 1992, 33, 7021-7024. (b) Fujiwara, S.; Shin-Ike, T.;
Okada, K.; Aoki, M.; Sonoda, N. Tetrahedron Lett. 1991, 32, 3503-
3506. (c) Tanaka, S.; Uemura, S.; Okano, M. Bull. Chem. Soc. J pn.
1977, 50, 2785-2788.
(18) Moore, F. W.; Larson, M. L. Inorg. Chem. 1967, 6, 998-1003.
(19) Chen, G. J .-J .; McDonald, J . W.; Newton, W. E. Inorg. Chem.
1976, 15, 2612-2615.
(20) Hoppe, D.; Follman, R. Chem. Ber. 1976, 109, 3047-3061.
7038 J . Org. Chem., Vol. 67, No. 20, 2002

Direct Synthesis of Isothiocyanates from Isonitriles
1490, and 936 cm-1, of which the first one is assigned to
the bound isonitrile and the other three to the sym-
metrical and unsymmetrical CN and molybdenum oxo
vibrations of the 2/4h adduct; the characteristic band at
967 cm-1 of free oxo complex 2 was absent.
TABLE 2. Ca ta lytic Su lfu r a tion of th e F u n ction a lized
Ison itr iles 4 w ith 2-Meth ylth iir a n e a s Su lfu r Don or
The association constant (Kc) of adduct 2/4h was
determined photometrically (see Supporting Informa-
tion): Kc ) 140 ( 10 M-1. Similarly, with isonitrile 4d ,
Kc ) 18.4 ( 6.8 M-1 was obtained for adduct 2/4d . These
results indicate that in concentrated solutions of isonitrile
4 in the presence of a catalytic amount of complex 2, the
essentially exclusive species is isonitrile adduct 2/4.
Under these favorable conditions, it was anticipated that
a crystalline adduct could be obtained for X-ray structural
analysis. Indeed, when a hot, saturated solution of oxo
complex 2 in neat isonitrile 4d was allowed to cool to
room temperature under the rigorous exclusion of air,
after several days of standing, adduct 2/4d between
isonitrile 4d and oxo complex 2 crystallized out, whose
X-ray structure is shown in Figure S6 (Supporting
Information). The isonitrile ligand occupies an equatorial
position of the distorted octahedron with a Mo-C bond
of 2.12 Å, which is typical for similar molybdenum(IV)-
oxo/isonitrile complexes.22 One of the dithiocarbamates
exhibits different Mo-S bond lengths of 2.52 and 2.71 Å
to the molybdenum center and coordinates as a Et2NC-
(dS)S- ligand. This fact rationalizes the two CN vibra-
tions in the IR spectrum. The equatorial dithiocarbamate
ligand shows two equivalently bonded sulfur atoms with
nearly identical Mo-S bond lengths of 2.42 and 2.46 Å;
a
Yield of pure isolated isothiocyanate after silica gel chroma-
b
tography. Yield of pure isolated isothiocyanate after distillation.
SCHEME 2. Stoich iom etr ic Su lfu r a tion of th e
Ison itr ile 4b w ith th e P r efor m ed Disu lfu r
Com p lex 3
-
it acts as a Et2NC(S)2 ligand.
monitoring revealed that 0.5 equiv of disulfur complex 3
was consumed and isonitrile 4b was completely converted
to isothiocyanate 5b; the latter was isolated in 70% yield.
Evidently, both sulfur atoms of the disulfur ring in the
molybdenum complex are active for sulfur transfer. Thus,
we propose that elemental sulfur and propene sulfide
transform in situ molybdenum complex 2 to the active
sulfur-transferring species 3, which reacts in a 1:2 stoi-
chiometry with isonitrile 4 to afford isothiocyanate 5.
The possibility of ligation of isonitrile substrate 4 with
the molybdenum-oxo catalyst 2 to generate the 2/4
adduct was probed spectroscopically. When the two were
mixed in dry dichloromethane, a sudden color change
from red to dark green was observed; the UV-vis
absorption spectrum (see Figure S1, Supporting Informa-
tion) exhibits two absorption bands at 362 and 504 nm.
On gradual addition of isonitrile 4h to a 10-4 M solution
of complex 2 in dichloromethane, the absorption band at
504 nm decreased proportionally in intensity; but even
on addition of 100 equiv of isonitrile, the absorption band
of free complex 2 at 384 nm still persisted. Evidently,
isonitrile and the oxo complex are in equilibrium with
their adduct 2/4h . Indeed, at a significantly higher con-
centration (0.38 M) of complex 2, only 3 equiv of isonitrile
4h was sufficient to convert complex 2 nearly completely
to its isonitrile adduct 2/4h , since no absorption of free
complex 2 was observed in the FTIR spectrum (Figure
S2, Supporting Information). Free isonitrile 4h possesses
a characteristic sharp vibration at 2122 cm-1, the free
molybdenum-oxo complex 2 at 1520 and 967 cm-1; the
latter are assigned21 to the two degenerate CN and the
oxo vibrations. Adduct 2/4 between isonitrile 4h and oxo
complex 2 displays four new sharp bands at 2118, 1511,
Discu ssion
The above experimental data for the molybdenum-
mediated sulfuration of isonitriles by elemental sulfur
is mechanistically rationalized in terms of the catalytic
cycle proposed in Scheme 3. First, molybdenum complex
2 reacts with elemental sulfur to generate disulfur
complex 3, the active sulfur-transferring species in the
catalytic sulfuration of isonitriles 4. Complex 3 is then
desulfurized successively by two isonitrile molecules back
to complex 2 through intermediate A, as previously
suggested for complex 3 in its reaction with triphen-
ylphosphine.23 Furthermore, similar molybdenum oxo-
sulfido complexes have been isolated with sterically
demanding ligands.24
The mechanistic details for the sulfur transfer in the
catalytic cycle are offered in Scheme 4, in which only the
sulfur transfer by the disulfur functionality is being
considered.
The mechanistically simpler option (path a) involves
direct intermolecular attack of the nucleophilic isocya-
nide25 on the disulfur ring of complex 3 (generated from
2 by sulfuration) and subsequent sulfur transfer to
(21) J owitt, R. N.; Mitchell, P. C. H. J . Chem. Soc. A 1969, 2632-
2636.
(22) (a) Lippard, S. J . Prog. Inorg. Chem. 1976, 21, 91-103. (b) Lam,
C. T.; Lewis, D. L.; Lippard, S. J . Inorg. Chem. 1976, 15, 989-991. (c)
Carmona, E.; Galindo, A.; Guille-Photin, C.; Sanchez, L. Polyhedron
1988, 7, 1767-1771. (d) Arzoumanian, H.; Corao, C.; Krentzien, H.;
Lopez, R.; Teruel, H. J . Chem. Soc., Chem. Commun. 1992, 856-858.
(23) Xiaoquing, S.; Huixing, Y.; Degang, H. Int. J . Chem. Kinet.
1989, 21, 749-755.
(24) Young, C. G.; Laughlin, L. J .; Colmanet, S.; Scrofani, S. D. B.
Inorg. Chem. 1996, 35, 5368-5377.
J . Org. Chem, Vol. 67, No. 20, 2002 7039

Adam et al.
SCHEME 3. Ca ta lytic Cycle for th e
Molybd en u m -Med ia ted Su lfu r a tion of Ison itr iles 4
w ith Elem en ta l Su lfu r a s Don or
F IGURE 1. σ bonding and π donation by the disulfur
functionality.
reasons: Although our spectral studies have demon-
strated the coordination of isocyanide 4 to the electron-
deficient molybdenum center of oxo complex 2 to afford
adduct 2/4 (Figure S6), such ligation is expected to
diminish the nucleophilic character of the isocyanide,
which expectedly reduces its reactivity toward acceptance
of the sulfur atom from the disulfur ring. To suppose that
the electronic roles of the reacting partners are reversed,
that is, the sulfur atom of the disulfur ring acts as
nucleophile and the sulfur atom is transferred nucleo-
philically to the electrophilically activated isonitrile
ligated at the molybdenum metal center, is in conflict
with the electronic nature of the disulfur functionality:
In disulfur complex 3, the molybdenum is in its +VI
oxidation state such that the electron-deficient d0 metal
center accepts an electron pair from the disulfur unit by
σ bonding as well as by π donation (Figure 1). The latter
reduces the π*-antibonding character of the disulfur
ligand and activates electrophilically this functionality
in the disulfur molybdenum oxo disulfur complex 3
toward nucleophilic attack, in the present case by the
isonitrile nucleophile.27 The reduced bond length (2.01
Å28) and, consequently, increased π bond order (0.4329)
for the sulfur-sulfur bond in the disulfur ring, as well
as the lower negative charge at the sulfur atoms,27
substantiate the electrophilic nature of the disulfur
functionality in molybdenum oxo complex 3. It is, there-
fore, quite unlikely that sulfur transfer takes place when
the isonitrile is ligated to complex 3 (path b) and
presumably the direct nucleophilic attack (path a) oper-
ates preferably. Consequently, analogous to triphenylphos-
phine and other inorganic nucleophiles,23,30 we propose
that direct nucleophilic attack of the isonitrile on the
electrophilic disulfur functionality (path a in Scheme 4)
affords the isothiocyanate 5 product.
SCHEME 4. Mech a n istic Op tion s for th e Su lfu r
Tr a n sfer a
a
Path a involves the direct nucleophilic attack on the molyb-
denum complex 3 (L ) -S-C(dS)-NEt2) by the isonitrile 4 and
Path b is for the isonitrile adduct 2/4.
Con clu sion
We have demonstrated that the molybdenum-catalyzed
sulfur-atom transfer to isonitriles proceeds under mild
reaction conditions to afford a variety of isothiocyanates
in good yields without the need of base. This unprec-
edented catalytic method provides a promising economi-
cal access to isothiocyanates from readily available
isonitriles and elemental sulfur; the latter is the most
abundant and cheapest sulfur source. In the catalytic
cycle, a molybdenum oxo disulfur complex operates as
the active sulfur-transferring species and the sulfur atom
release isothiocyanate 5 and complex A. In the more
involved option, the sequence of the mechanistic events
is reversed: Isonitrile 4 first ligates to the molybdenum
atom of complex 2 to form the observed 2/4 adduct (Fig.
S6) and subsequently, after sulfuration, the intramolecu-
lar sulfur transfer takes place (path b). The latter process
implies a template effect,26 since both the sulfur acceptor
(the isocyanide) and the activated sulfur donor (disulfur
ring) are bound to a common molybdenum metal center.
Of these two mechanistic options, the direct sulfur
transfer (path a) is favored electronically for the following
(27) Mu¨ller, A.; J aegermann, W.; Enemark, J . H. Coord. Chem. Rev.
1982, 46, 245-280.
(25) (a) Halleux, A. Angew. Chem., Int. Ed. Engl. 1964, 3, 752. (b)
Avetisyan, E. A.; Gambaryan, N. P. Izv. Akad. Nauk SSSR, Ser. Khim.
1973, 11, 2559-2562.
(26) Adam, W.; Korb, M. N.; Roschmann, K. J .; Saha-Mo¨ller, C. R.
J . Org. Chem. 1998, 63, 3423-3428.
(28) Dirand, J .; Ricard, L.; Weiss, R. Inorg. Nucl. Chem. Lett. 1975,
11, 661-664.
(29) Nordvik, A. Acta Chem. Scand. 1966, 20, 1885-1891.
(30) Leonard, K.; Plute, K.; Haltiwanger, R. C.; Rakowski Dubois,
M. Inorg. Chem. 1979, 18, 3246-3251.
7040 J . Org. Chem., Vol. 67, No. 20, 2002

Direct Synthesis of Isothiocyanates from Isonitriles
Su p p or tin g In for m a tion Ava ila ble: Full reaction pro-
cedures, spectroscopic and elemental analytical data on iso-
lated compounds, and details of the X-ray structure determi-
nation. This material is available free of charge via the
Internet at http://pubs.acs.org.
is transposed during the direct nucleophilic attack of the
isonitrile on the electrophilically activated disulfur func-
tionality.
Ack n ow led gm en t. We thank the Deutsche Fors-
chungsgemeinschaft and the Fonds der Chemischen
Industrie for generous financial support.
J O026042I
J . Org. Chem, Vol. 67, No. 20, 2002 7041