A new efficient synthesis of isothiocyanates from amines using di-tert-butyl dicarbonate

Article abstract of DOI:10.1016/j.tetlet.2008.03.045

Alkyl and aryl amines are converted smoothly to the corresponding isothiocyanates via the dithiocarbamates in good to excellent yields using di-tert-butyl dicarbonate (Boc₂O) and 1-3 mol % of DMAP or DABCO as catalyst. As most of the byproducts are volatile, the work-up involves simple evaporation of the reaction mixture.

Full text of DOI:10.1016/j.tetlet.2008.03.045

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3117–3119
A new efficient synthesis of isothiocyanates
from amines using di-tert-butyl dicarbonate
Henrik Munch a, Jon S. Hansen a, Michael Pittelkow a, Jørn B. Christensen a, Ulrik Boas a,b,
*
a Department of Chemistry, University of Copenhagen, Universitetsparken 5, DK-2100 Copenhagen, Denmark
b National Veterinary Institute, Technical University of Denmark, Bu¨lowsvej 27, DK-1790 Copenhagen, Denmark
Received 18 January 2008; revised 19 February 2008; accepted 7 March 2008
Available online 12 March 2008
Abstract
Alkyl and aryl amines are converted smoothly to the corresponding isothiocyanates via the dithiocarbamates in good to excellent
yields using di-tert-butyl dicarbonate (Boc2O) and 1–3 mol % of DMAP or DABCO as catalyst. As most of the byproducts are volatile,
the work-up involves simple evaporation of the reaction mixture.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Isothiocyanate; Di-tert-butyl dicarbonate; Thiourea; Amine
Isothiocyanates constitute an important functional class
in natural products and pharmaceutically active com-
pounds. Furthermore, isothiocyanates are widely applied
as chemoselective electrophiles in bioconjugate chemistry
because of their tolerance towards aqueous reaction condi-
tions,1 and they are key intermediates in the synthesis of
sulfur-containing heterocycles.2,3 Therefore, numerous
methods have been developed to synthesise isothiocya-
nates, the most well known being based on thiophosgene,4,5
and later refinements of ‘thiocarbonyl transfer’ reagents
such as thiocarbonylditriazole,6 thiocarbonyldiimidazole7
and dipyridyl-thionocarbonate (DPT).8 Albeit, these
reagents are found to be effective in the specific formation
of isothiocyanates and occasionally as desulfurylating
agents for thioureas, they are somewhat limited in scope,
and lead to extensive formation of the corresponding thio-
urea as a byproduct in the case of less reactive amines. To
avoid this side reaction, the desulfurylation of dithiocarb-
amates has been carried out by various reagents such as
uronium- and phosphonium-based peptide coupling
reagents,9–11 triphenylphosphine dibromide12 and tosyl
chloride.3 Although the previous methods are efficient, we
were keen to develop a synthesis of isothiocyanates which
would proceed cleanly without intermediate work-up, such
as extraction or column chromatography, and which would
leave no, or only traces of byproducts. A desulfurylation
reagent leaving only gases and volatile byproducts should
fit this purpose. Di-tert-butyl dicarbonate (Boc2O) seemed
a good candidate for the desulfurylation of the correspond-
ing dithiocarbamate as this reagent may evolve CO2 and
COS during the reaction, and residual carbon disulfide
and tert-butanol together with the solvent should be
removed easily by evaporation. As the formation of dithio-
carbamate in the case of most amines proceeds rapidly, the
isothiocyanate can be synthesised directly from the amine
in the presence of excess carbon disulfide.
In addition to Boc2O, we found that a catalytic amount
of DMAP or DABCO (1–3 mol %) increased the reaction
rate significantly, with visible evolution of gas from the
reaction mixture. The formation of an isothiocyanate from
the corresponding amine was, in the case of aliphatic and
activated aromatic amines, complete within a few minutes.
In the reaction pathway, the electrophilic Boc2O presum-
ably reacts with the dithiocarbamate with evolution of
*
Corresponding author. Tel.: +4535320159; Fax: +4572346001.
E-mail address: ubo@vet.dtu.dk (U. Boas).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.045

3118
H. Munch et al. / Tetrahedron Letters 49 (2008) 3117–3119
Table 1
CO2 to form an unstable ‘mixed dithiocarbamate/
carbonate’ adduct that rapidly decomposes to the isothio-
cyanate, COS and tert-butanol (Scheme 1). One equivalent
of triethylamine was needed for the stabilisation and com-
plete formation of the dithiocarbamate in agreement with
the earlier reports.13 The reaction is usually carried out
under polar conditions ethanol, aqueous ethanol or meth-
anol, although it proceeds equally well in apolar solvents
such as DCM, THF or in dipolar solvents like acetone or
DMF.
Boc2O was added in nearly stoichiometric amounts
(0.99 equiv) to avoid residual di-tert-butyl dicarbonate as
a byproduct. Although the reaction may proceed via other
pathways, such as Boc-protection of the amine or conver-
sion of the amine to the isocyanate,14 these side reactions
were rarely observed. However, formation of the Boc-pro-
tected amine was observed to some extent (14% in GCMS)
in the case of 1-adamantylamine and poorly soluble aryl-
amines, such as naphthyl and anthryl amines, and also in
the case of deactivated aryl amines, for example, para-bro-
moaniline (8%). The Boc-protection of 1-adamantylamine
(Table 1, entry 5) could, however, be avoided by cooling
the dithiocarbamate prior to the addition of Boc2O and
catalyst.
Entry
Isothiocyanate
N=C=S
N=C=S
N=C=S
N=C=S
Yield (%)
115
216
63
98
H
317
91
O
N
O
418
519
Quant
82
N=C=S
N=C=S
620
86
0
7
N=C=S
N=C=S
N=C=S
821
98
S
OMe
922
Quant
In the case of entry 12 the desulfurylation proceeded
without the addition of DMAP, albeit at a slower speed.
In contrast, reaction with triphenylmethylamine did not
give any isothiocyanate product even after prolonged reac-
tion times.
OMe
1023
93
81
N=C=S
N=C=S
MeO
O
ButO
1110
In the cases of amines having weak nucleophilic groups
b to the amino functionality, for example, 2-(Boc-amino)-
ethylenediamine, ethanolamine or in peptide substrates,
the formation of a cyclised product was a competing reac-
tion (e.g., formed in a 1:1 mixture with the isothiocyanate
in the case of 2-(Boc-amino)-ethylenediamine).32 Also in
substrates containing electrophilic groups at the b-position
such as 2-chloroethylamine, the cyclic dithiocarbamate was
formed as the predominant product.
As an alternative, we applied dimethyl carbonate
(DMC) instead of di-tert-butyl dicarbonate as the desul-
furylating agent. However, DMC yielded the correspond-
ing thioureas as the sole products. The formation of
thiourea may be due to the lower reactivity of DMC com-
pared to that of Boc2O.
O
O
12
Quant
Quant
BocHN
S=C=N
O
O
O
O
N=C=S
N=C=S
1324
N=C=S
1425
1526
Quant
Quant
N=C=S
MeO
MeO
MeO
N=C=S
N=C=S
1627
Quant
OMe
O
1728
1829
Quant
Quant
S
O
S
Boc2O
CS2/NEt3
R
N
R
R-NH2
N
S
OBut
H
N
S
HNEt3
+
N=C=S
H
H
+
tBuOH + NEt3 + CO2
N=C=S
R
N
H
ButO
S
O
O
1930
80
96
B
R-N=C=S + tBuOH + COS
S
O
MeO S=C=N
2031
Scheme 1. Suggested mechanism for the base catalysed synthesis of iso-
thiocyanates from the corresponding amines using di-tert-butyl dicarbon-
ate. B: Base catalyst.
N=C=S OMe

H. Munch et al. / Tetrahedron Letters 49 (2008) 3117–3119
3119
17. Kneeland, D. M.; Ariga, K.; Lynch, V. M.; Huang, C.-Y.; Anslyn, E.
V. J. Am. Chem. Soc. 1993, 115, 10042–10055.
CS2/NEt3/Boc2O
Catalyst (1-3 mol%)
R-NH2
18. Spurlock, L. A.; Porter, R. K.; Cox, W. G. J. Org. Chem. 1972, 37,
1162–1168.
R: Alkyl or Aryl
R-N=C=S
EtOH/ 15 min/ r.t.
19. Stetter, H.; Wulff, C. Chem. Ber. 1962, 95, 2302–2304.
20. Hofmann, A. W. Chem. Ber. 1868, 1, 201–202.
Scheme 2.
21. Analytical data for entry 8: 1H NMR (300 MHz, CDCl3): d 7.35 (dd,
3J 3 Hz, 3J 5 Hz, 1H), 7.25 (s, 1H), 7.05 (d, 3J 5 Hz, 1H), 4.70 (s, 2H);
13C NMR (100 MHz, CDCl3): d 135.2, 130.1, 127.4, 126.4, 123.0,
44.5. GCMS m/z 155. Anal. Calcd for C6H5NS2 (155.24): C, 46.42; H,
3.25; N, 9.02. Found: C, 46.63; H, 3.43; N, 8.97.
22. Kjaer, A.; Jensen, R. B. Acta Chem. Scand. 1956, 10, 141–142.
23. Yamasaki, T.; Kawaminami, E.; Uchimura, F.; Okamoto, Y.;
Okawara, T.; Furukawa, M. J. Heterocycl. Chem. 1992, 29, 825–829.
24. Lukyaneko, N. G.; Kirichenko, T. I.; Scherbakov, S. V. J. Chem.
Soc., Perkin Trans. 1 2002, 2347–2351.
In summary, a mild and chemoselective method for a
rapid and clean preparation of isothiocyanates in high
yields and purity without the need for subsequent work-
up has been developed (Scheme 2).33 The reaction proceeds
within 15 min with aliphatic and activated aromatic
substrates; however, deactivated arylamines need longer
reaction times for the complete formation of the dithiocar-
bamate in order to prevent side reactions such as Boc-pro-
tection of the amine or thiourea formation. This method
constitutes an interesting alternative in the synthesis of iso-
thiocyanates (and thioureas) in complex synthetic
sequences where a minimum work-up of the intermediate
isothiocyanate should be carried out.
25. Hofmann, A. W. Chem. Ber. 1869, 2, 120.
26. Braun, J.; Deutsch, H. Ber. Dtsch. Chem. Ges. 1912, 45, 2188–2198.
27. Slotta, K. H.; Tschesche, R.; Dressler, H. Chem. Ber. 1930, 63, 208–
222.
28. Bolsen, C. E.; Hartshorn, E. B. J. Am. Chem. Soc. 1923, 45, 2349–
2355.
29. Mull, R. J. Am. Chem. Soc. 1955, 77, 581–583.
30. Analytical data for entry 19: Purified by filtering the crude through a
plug of silica using 1:1 CH2Cl2/hexane containing 2% Et3N. Pale
brown oil, yield: 80%, 1H NMR (400 MHz, CDCl3, filtered through
Al2O3 before use): 4.00–4.04 (m, 2H), 4.07–4.11 (m, 2H), 5.77 (s, 1H),
7.13 (d, 3J 7.5 Hz, 1H), 7.29 (t, 3J 7.5 Hz, 1H), 7.32–7.35 (m, 1H),
7.46–7.48 (m, 1H). 13C NMR (100 MHz, CDCl3): 65.4, 104.7, 125.1,
125.2, 126.1, 130.4, 132.1, 137.0, 138.9. HRMS (ESI+): [MH+]: calcd
for C10H10NO2S (m/z): 208.0432. Found: 208.0463.
Acknowledgement
U.B. thanks the Danish Research Council for Techno-
logy and Production Sciences (Grant Nos.: 23-04-0086
and 23-02-011) for financial support.
31. Analytical data for entry 20: 1H NMR (400 MHz, CDCl3): d 7.16 (m,
2H), 7.03–7.07 (m, 4H); 4.00 (s, 6H). 13C NMR (100 MHz, CDCl3): d
156.1; 140.3; 125.6; 120.4; 119.4; 110.1; 56.0. GCMS m/z 328. Anal.
Calcd for C16H12N2O2S2 (328.42): C, 58.52; H, 3.68; N, 8.53. Found:
C, 58.42; H, 3.82; N, 8.71.
References and notes
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32. The cyclisation was indicated by elemental analysis, and in the 1H
t
NMR by two separate Bu signals.
33. General procedure: Absolute ethanol (2–5 mL) was added to the amine
(4.40 mmol). CS2 (3.34 g, 44 mmol) and Et3N (444 mg, 4.40 mmol, in
the case of amine hydrochlorides an extra equivalent of triethylamine
was added) were added while stirring, resulting in the precipitation of
the dithiocarbamate. The reaction mixture was stirred for 5–30 min at
room temperature and then cooled on an ice bath. Boc2O (950 mg,
4.36 mmol), dissolved in absolute ethanol (1 mL), was added followed
by the immediate addition of a catalytic amount of DMAP or
DABCO (1–3 mol %) in absolute ethanol (1 mL). The reaction
mixture was kept in the ice bath for 5 min, and was then allowed to
reach room temperature. After evolution of gas from the reaction
mixture had ceased (approximately 10 min), the reaction mixture was
stirred for a further 5 min at rt and evaporated thoroughly in vacuo.
In the case of amine hydrochlorides, the residue was taken up in
diethyl ether and triethylammonium hydrochloride was filtered off,
and the filtrate was evaporated in vacuo to afford the desired
isothiocyanate in high purity.
5. Dyson, G. M.; George, H. J. J. Chem. Soc. 1924, 125, 1702–1708.
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