Optimized access to alkyl thiocyanates

Article abstract of DOI:10.1016/S0040-4039(01)01846-9

Functionalized alkyl thiocyanates are synthesized in high yields from corresponding halides via in situ formation of tetra n-butylammonium thiocyanate. Use of this mild but efficient thiocyanation reagent limits the amounts of by-products.

Full text of DOI:10.1016/S0040-4039(01)01846-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8479–8481
Optimized access to alkyl thiocyanates
Pierre-Yves Renard,a,b,* Herve´ Schwebel,a Philippe Vayron,a,b Eric Leclerc,a Sonia Diasa,c and
Charles Mioskowskia,c,
*
aService des Mole´cules Marque´es, DBCM, Baˆt. 547, CEA, CE-Saclay, F-91191 Gif-sur-Yvette Cedex, France
bDGA/DCE PHD/PH2D CE du Bouchet BP3, 91710 Vert le Petit, France
cUniversite´ Louis Pasteur, Faculte´ de Pharmacie, Laboratoire de Synthe`se Bioorganique (UMR 7514),
74, route du Rhin, 67401 Illkirch-Graffenstaden, France
Received 20 July 2001; accepted 3 October 2001
Abstract—Functionalized alkyl thiocyanates are synthesized in high yields from corresponding halides via in situ formation of
tetra n-butylammonium thiocyanate. Use of this mild but efficient thiocyanation reagent limits the amounts of by-products.
© 2001 Elsevier Science Ltd. All rights reserved.
Alkyl thiocyanates are one of the most important syn-
thetic intermediates for the preparation of sulfur-con-
taining organic compounds. Not only natural products
containing the thiocyanate group have attracted atten-
tion,1 but this functional group can also be used as a
masked mercapto group or a precursor for sulfur-con-
taining heterocycle compounds. Yet the low nucle-
ophilicity of the NCS- ion, compared to that of simple
thiols, requires relatively harsh reaction conditions. To
introduce the thiocyanate group into an organic
molecule, the use of metal thiocyanate on organic
halides or sulfonate has been generalized (usually K-
SCN, Na-SCN or in situ formed Zn(SCN)2).2 However,
the thiocyanate group is poorly stable when heated or
submitted to acidic conditions. A simple chromatogra-
phy on silica gel or a prolonged heating over 50°C can
cause an intramolecular rearrangement to thermody-
namically favored isothiocyanate isomers (this rear-
rangement occurs preferentially with primary
thiocyanates, thus for such fragile compounds, heating
or use of a dissociative solvent such as HMPA or DMF
should be avoided).3 Ammonium thiocyanate was also
successfully used for such a halogen substitution, but
this reagent is sensitive and explosion hazards have
been reported.4 This substitution could also be per-
formed using trimethylsilyl isothiocyanate, but only on
activated benzylic compounds using HMPA as solvent5
or under activation with a stoichiometric amount of a
strong Lewis acid such as TiCl4.6 In any case, high
amounts of contaminating isothiocyanates were also
formed. Thiocyanates can also be obtained from alco-
hols,7 silyl ethers8 or amines9 using in situ formed
electrophilic phosphorane Ph3P(SCN)2. However, the
results are unreliable and not reproducible because of
the low thermal stability of the required intermediate
(SCN)2. Once again various amounts of rearranged
isothiocyanate by-product are observed. The toxicity of
the starting material Pb(SCN)2 is also a major draw-
back for this thiocyanation method.
Silica gel chromatography increases the amount of rear-
rangement by-products, so we aimed our efforts at
finding a simple nucleophilic reagent with a higher
reactivity than metal thiocyanate (as KSCN or
NaSCN) and that would enable a straightforward
experimental procedure in order to prevent aqueous
treatment or silica gel chromatography.
Two recent papers have attracted our attention. In
order to proceed to a nucleophilic substitution of an
organic halide by an azide function,10 the authors intro-
duced the conjugated use of trimethylsilyl azide and a
‘milder Lewis acid and silicon containing compounds
activator’ such as tetrabutylammonium fluoride. This
use of nBu4NF was also applied to the epoxide ring
opening using trimethylsilyl isothiocyanate.11 No mech-
anistic investigations were reported in these papers.
Keywords: thiocyanates; nucleophilic substitution; trimethylsilyl
isothiocyanate.
In order to extend this method to the nucleophilic
substitution of organic halides, we tested the use of
TMSNCS/n-Bu4NF on benzyl bromide. We were
* Corresponding authors. Tel.: +33 169 085 487; fax: +33 169 087 991
(P.-Y.R.); tel.: +33 390 244 297; fax: +33 390 244 306 (C.M.);
e-mail: pierre-yves.renard@cea.fr; mioskow@aspirine.u-strasbg.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01846-9

8480
P.-Y. Renard et al. / Tetrahedron Letters 42 (2001) 8479–8481
pleased to note that in THF and at room temperature,
the substitution reaction occurred within minutes
(quantitative yield in less than 1 h). No trace of rear-
rangement benzyl isothiocyanate was detected using
GC/MS. As far as the reaction procedure is concerned,
the resultant ammonium salts could be removed by
filtration after successive precipitation with diethyl
ether and pentane. Solvent evaporation yielded ben-
zylthiocyanate of very high purity (>98% as checked by
GC/MS), which could be used without further purifica-
tion (Scheme 1).
ingly, high yields were obtained with alcohols (Table 1
entry 13) and amines (Table 1 entries 11 and 12),
whereas other thiocyanation methods failed or gave
<50% yields.
Table 1. Formation of thiocyanates. The reaction was per-
formed with 1.1 equiv. of TMSNCS and 1.1 equiv. of
nBu4NF, substrate 0.1 M in THF. Yields of isolated thio-
cyanate
Me3SiN=C=S
N
nBu4NF
THF
98%
Br
S
Scheme 1. Thiocyanation of benzyl bromide.
Mechanistic studies were then undertaken. In order to
detect the active species, reaction product of a stoichio-
metric mixture of TMSNCS and n-Bu4NF was ana-
lyzed. Not surprisingly, the tetrabutylammonium
thiocyanate salt was detected as the major product.
This salt was also formed and isolated using a previ-
ously described procedure (KSCN+n-Bu4NBr).12 Using
this preformed salt, the reaction with primary alkylbro-
mides proceeds smoothly in THF at room temperature,
albeit at a slightly lower rate. Note that this salt is very
hygroscopic and has to be freshly prepared and kept
under a neutral atmosphere. The best yields were
obtained with the in situ formation of tetra-
butylammonium thiocyanate, requiring only 1.1 equiv.
of each reactant instead of 1.5 equiv. of the commer-
cially available salt (Aldrich or Fluka). We also experi-
mentally checked that in both previously described
reactions,10,11 the active species were also the in situ
formed tetrabutylammonium salts (azide or thio-
cyanate).
THF, DMF, and, to a lesser extent DME, acetonitrile
and diethyl ether proved to be the best solvents for this
reaction. Using either of the two methods, we could
perform very mild thiocyanation of activated or unacti-
vated primary bromides and iodides (Table 1). The
reaction occurs at room temperature, and no trace of
isothiocyanates was detected in GC/MS. The highest
yields were obtained when a simple precipitation of
resulting ammonium salts could be performed (with
diethyl ether or pentane for iodides and pentane for
bromides). When needed, flash chromatographies could
be undertaken, lowering the yields to 65–85% (entries
8–12). A typical reaction procedure is illustrated for
amide 11a.13
Not surprisingly, iodides are readily substituted, then
bromides, and displacement of a chlorine atom is less
favorable. Sensitive functions such as cyanides, phenols,
aromatic nitrites, carboxylic acids, dioxolanes, and
amides did not interfere in the reaction process. In any
case, this procedure favorably competes with those
using conventional thiocyanation procedures. Interest-

P.-Y. Renard et al. / Tetrahedron Letters 42 (2001) 8479–8481
Table 2. Formation of secondary thiocyanates. Reaction
8481
References
was led with 1.5 equiv. of TMSNCS and 1.5 equiv. of
nBu4NF, substrate 0.1 M in THF. Yields of isolated thio-
cyanate
1. (a) Benn, M. Pure Appl. Chem. 1977, 49, 197; (b) Pham,
A. T.; Ichida, T.; Yoshida, W. Y.; Scheuer, P. J.; Uchida,
T.; Tanaka, J.; Higa, T. Tetrahedron Lett. 1991, 32, 4843.
2. (a) Bacon, R. G. R. In Organic Sulfur Compounds;
Kharasch, N., Ed.; Pergamon Press: New York, 1961;
Vol. 1, Chapter 27, p. 304; (b) Guy, R. G. In The
Chemistry of Cyanates and Their Thio Derivatives; Patai,
S., Ed.; Wiley: New York, 1977; p. 819; (c) Metzer, J. B.
In Comprehensive Heterocyclic Chemistry; Katrizki, A.,
Ed.; Pergamon: Oxford, 1984; Vol. 6, p. 235.
3. Bacon, R. G. R.; Guy, R. G. J. Chem. Soc. 1961, 2428,
2436 and 2447.
4. (a) Pavlik, J. W.; Tongcharoensirikul, P.; Bird, N. P.;
Day, A. C.; Barltrop, J. A. J. Am. Chem. Soc. 1994, 116,
2292–3000; (b) Dangerous Prop. Ind. Mater. Rep. 1995,
15, 493–503.
5. Nishiyama, K.; Oba, M. Bull. Chem. Soc. Jpn. 1987, 60,
2692.
6. Sasaki, T.; Nakanishi, A.; Ohno, M. J. Org. Chem. 1981,
46, 5445–5447.
7. (a) Tamura, Y.; Kawasaki, T.; Adachi, M.; Tanio, M.;
Kita, Y. Tetrahedron Lett. 1977, 18, 4417; (b) Burski, J.;
Kiesowski, J.; Michalski, J.; Pakulski, M.; Skowronska,
A. Tetrahedron 1983, 39, 4175.
8. Iranpoor, N.; Firouzabadi, H.; Shaterian, H. Synlett
2000, 10, 65.
9. Molina, P.; Alajarin, M.; Ferao, A.; Lindon, M. J.;
Fresneda, P. M.; Vilaplana, M. J. Synthesis 1982, 472.
10. Ito, M.; Koyakumaru, K. I.; Ohta, T.; Takaya, H. Syn-
thesis 1995, 376–378.
As another example for the comparison with conven-
tional thiocyanation methods, when dioxolanone 15a
was treated with potassium thiocyanate, the best yields
(53%) were obtained by heating overnight at 118°C in
methyl isobutyl ketone, whereas treatment with
trimethylsilyl isothiocyanate and tetrabutylammonium
fluoride at room temperature in THF gave an 85% yield
in less than 1 h.
11. Tanabe, Y.; Mori, K.; Yoshida, Y. J. Chem. Soc., Perkin
Trans. 1 1997, 671–675.
12. Dehmlow, E. V.; Vehre, B.; Broda, W. Synthesis 1985,
508–509.
Substitution was then assayed using secondary halogen
compounds (Table 2). Unexpectedly, iodide compounds
gave mainly degradation products (Table 2, entry 3).
Activated (allylic or benzylic) bromides were substi-
tuted in good yields (Table 2, entries 1 and 5), and
unactivated bromides required moderate heating (60°C)
and longer reaction times. In one case (Table 2, entry
6), higher reaction temperature was required (100°C, in
DMF) leading to contamination with ca. 5% rear-
ranged isothiocyanates (as estimated by GC/MS analy-
sis of the crude reaction product). A modest 42% yield
of pure thiocyanate 21b was then isolated after careful
flash chromatography.
13. A typical experimental procedure: Trimethylsilyl isothio-
cyanate (140 mL, 1.1 mmol) was added at room tempera-
ture to a solution of bromide 11a (222 mg, 1.0 mmol,
prepared using a conventional literature procedure from
commercially available 2-aminoethanol) in dry THF (10
mL). Tetrabutylammonium fluoride (1.1 mL of a 1.0 M
solution in THF) was then added dropwise. The reaction
course was monitored by TLC, and after stirring for 16 h,
THF was evaporated, and the reaction mixture was tritu-
rated with pentane. Filtration followed by removal of the
solvants under vacuo yielded thiocyanate 11b as a yellow
oil (174 mg, 87% yield, 95% pure as estimated by GC/
MS) which could either be used directly or submitted to
flash chromatography on silica gel (CH2Cl2/MeOH, 98/2)
yielding 124 mg (62%) of a pale yellow oil. IR u (cm−1):
2154 (SCN), 1639 (CꢀO); 1H NMR (300.15 MHz,
In conclusion, we have developed an optimized thiocya-
nation method, which requires only a moderate reac-
tion temperature, and a very easy isolation procedure,
thus limiting the amount of undesired degradation
products.
3
3
CDCl3), l, ppm: 1.15 (t, J 7.5 Hz, 3H), 1.25 (d, J 6.5
3
3
Hz, 6H), 2.39 (q, J 7.5 Hz, 2H), 3.15 (t, J 5 Hz, 2H),
3.55 (t, 3J 5 Hz, 2H), 4.10 (quint, 3J 6.5 Hz, 1H); 13C
NMR (75.4 MHz, CDCl3), l, ppm: 9.44, 21.30, 26.87,
31.56, 41.24, 48.42, 53.49, 112.24 (SCN), 174.12; m/z (IC,
NH3,): 201 ([M+H]+), 218 ([M+NH4]+).
Acknowledgements
Financial support by De´le´gation Ge´ne´rale pour l’Arme-
ment is gratefully acknowledged.