Cyclisation of aryl acetylides with isothiocyanates: new insight into an old reaction

Article abstract of DOI:10.1016/j.tetlet.2016.02.034

The reaction of lithium phenylacetylide with phenyl isothiocyanate followed by the addition of ethanol produces a crystallographically-characterised heterocycle formed by the cyclisation of two molecules each of acetylene and isothiocyanate, and which is identical to the dimer of the acetylenic thioamide PhC[tbnd]CC([dbnd]S)NHPh, described almost a century ago.

Full text of DOI:10.1016/j.tetlet.2016.02.034

Accepted Manuscript
Cyclization of aryl acetylides with isothiocyanates: new insight into an old re-
action
Harry Adams, Hannah Hodson, Michael J. Morris, Gareth A. Venting
PII:
S0040-4039(16)30144-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.02.034
TETL 47307
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
22 January 2016
2 February 2016
9 February 2016
Please cite this article as: Adams, H., Hodson, H., Morris, M.J., Venting, G.A., Cyclization of aryl acetylides with
isothiocyanates: new insight into an old reaction, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.
2
016.02.034
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Graphical Abstract
page 2

Cyclization of aryl acetylides with isothiocyanates: new insight into an old reaction
Harry Adams, Hannah Hodson, Michael J. Morris* and Gareth A. Venting
Department of Chemistry, University of Sheffield,
Sheffield S3 7HF, U.K.
Corresponding author. Tel.: +44-114-2229363; fax: +44-114-2229346.
E-mail address: M.Morris@sheffield.ac.uk
page 3

Abstract
The reaction of phenylacetylide with phenyl isothiocyanate followed by the addition of
ethanol produces a crystallographically-characterised heterocycle formed by the cyclization of two
molecules each of acetylene and isothiocyanate, and which is identical to the dimer of the
acetylenic thioamide PhCCC(=S)NHPh, described almost a century ago.
Keywords
Alkyne; 3-imino-1,2-dithiole; isothiocyanate; heterocycle; thioamide.
The efficient construction of complex heterocyclic ring systems from simple precursors
remains an important objective in synthetic organic chemistry, particularly given that over 90% of
1
new drugs contain such rings. Reactive heterocumulenes such as isocyanates and isothiocyanates
have long been considered as useful building blocks in such reactions, affording useful structural
2
motifs such as (thio)hydantoins.
We have recently described the one-pot production of 1,2-dithiole-3-thiones under very mild
3
,4
conditions from terminal alkynes, CS and elemental sulfur. We also demonstrated that the
2
analogous 3-phenylimino-1,2-dithioles could be similarly prepared in almost quantitative yields
4
from terminal alkynes, phenyl isothiocyanate and sulfur. In one of these reactions, however, we
isolated a second product that prompted us to examine the cyclization of acetylides with
isothiocyanates in greater detail. In fact the reaction between sodium phenylacetylide and phenyl
isothiocyanate in ether was first studied by Worrall nearly a century ago (Scheme 1). Upon
quenching with water he obtained the acetylenic thioamide PhCCC(=S)NHPh (1), which upon
heating with aqueous NaOH in ether or simply heating in ethanol, was found to convert into a
dimer (on the basis of molecular weight measurement); however no structure was suggested for this
5
product. In this paper we show (i) that quenching this reaction with ethanol produces a thiazolidine
heterocycle with an exocyclic thioketone group, identified crystallographically and (ii) that this
compound is identical to Worrall’s dimer, showing that extensive rearrangement of the acetylenic
thioamide takes place during the dimerization process.
page 4

Scheme 1. Worrall’s synthesis of acetylenic thioamide 1.
In the reaction of lithium ferrocenylacetylide with one equivalent of PhNCS followed by
EtOH and S , the major product was the expected 5-ferrocenyl-3-phenylimino-1,2-dithiole 2 in
8
4
7
2% yield (Scheme 2). However an additional purple compound was obtained in 20% yield (based
on PhNCS) and identified as 5-ferrocenylidene-2-phenyliminothiazolidine-4-thione 3 by X-ray
6
crystallography; its structure is shown in Figure 1. This heterocycle is clearly formed by the
incorporation of two isothiocyanate molecules; the harder N-nucleophile of the first attacks the
second PhNCS, whereas the softer S-nucleophile of the second PhNCS then attacks the triple bond.
The same regiochemistry was previously observed in the reaction of a ruthenium acetylide complex
7
with isothiocyanates.
Scheme 2. Cyclization of ferrocenylacetylene with PhNCS.
page 5

Figure 1. Single crystal X-ray structure of FcCH=CC(=S)NPhC(=NPh)S (3).
This result led us to investigate the reaction of lithium phenylacetylide with two equivalents
of PhNCS followed by protonation with EtOH in an attempt to obtain the phenyl analogue of 3, a
8
compound that has recently been prepared in a different way by Erol and Dogan. However, only a
minute quantity of this compound could be isolated from this reaction. The major product
(
typically 55-60% yield), isolated by chromatography as a golden yellow solution yielding a brown
9
solid, was identified as heterocycle 4a (Scheme 3). Repeating the reaction with a 1:1 ratio of the
two reagents gave the same yield of 4a while largely eliminating the EtOC(=S)NHPh by-product
formed from the reaction of the additional isothiocyanate with ethanol. The analogous compound
4
b could be prepared in similar yield from p-tolyl acetylene, but results from other acetylenes (R =
t
Bu, Fc or SiMe ) were less encouraging, with 3-imino-1,2-dithioles formed in addition to low
3
yields of products which could not be conclusively characterised as analogues of 4.
page 6

Scheme 3. Formation of dimer 4.
Figure 2. Molecular structure of 4a.CDCl in the crystal.
3
The crystal structure of compound 4a was determined and is shown in Figure 2. The
heterocycle is clearly constructed from two molecules each of alkyne and isothiocyanate, though
with considerable rearrangement. We propose the mechanism shown in Scheme 4 for the formation
of 4.
page 7

Scheme 4. Proposed mechanism for formation of 4.
Suspecting that the dimer isolated by Worrall might in fact be 4a, we reinvestigated the
synthesis of thioamide 1 by his method. Whereas treatment of a THF solution of LiCCPh with
PhNCS at room temperature for 1 h gave an orange solution, stirring a white ether suspension of
NaCCPh with PhNCS for two days gave an off-white suspension. Both of these, however,
–
evidently contain the same PhCCC(S)NPh ion, as pouring either of them onto a large volume of
1
0
ice-water gave good yields of thioamide 1 after isolation by filtration. Moreover, addition of
ethanol to the ether suspension of Na[PhCCC(S)NPh] caused its immediate dissolution to a dark
orange solution, which then went on to produce 4a in 35% yield. Evidently precipitating thioamide
1
in water stops the reaction at that stage, whereas if it remains in solution in THF/EtOH the
page 8

reaction can proceed to 4. We then repeated the synthesis of the dimer as described by Worrall.
Heating an ether solution of 1 with aqueous sodium hydroxide, or heating 1 at reflux in ethanol,
produced 4a as the major product, in 54% and 33% yield respectively. It is therefore clear that the
dimer obtained by Worrall was actually 4a.
We are currently exploring the reactivity of the dimer 4a compared to the monomeric
thioamide 1. Preliminary studies have revealed that upon heating at reflux in THF, 1 reacts with
additional isothiocyanate to give 5 (the phenyl analogue of 3) as the major product, albeit as yet in
a modest yield of 14% (Scheme 5), whereas 4a is unreactive under the same conditions.
Scheme 5. Reaction of 1 with PhNCS.
Acknowledgements
We thank the University of Sheffield for support, and Prof. Joe Harrity for useful discussions.
Supplementary Data
Crystallographic data for the structure determinations of 3 and 4a have been deposited with
the Cambridge Crystallographic Data Centre, reference numbers CCDC 1432581 and 1432582
respectively. These data can be obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif. Supplementary data associated with this article
(
experimental procedures and characterisation data for the compounds prepared) can be found in
the online version at …
References
page 9

1
2
.
.
Dua, R.; Shrivastava, S.; Sonwane, S.K.; Srivastava, S.K. Adv. Biol. Res. 2011, 5, 120.
(a) Ulrich, H. Cycloaddition reactions of heterocumulenes, Academic Press, New York,
1
967. (b) Ulrich, H. Cumulenes in click reactions, Wiley, Chichester, 2009. (c) Sharma, S.
Sulfur Rep. 1989, 8, 327. (d) Mukerjee, A.K.; Ashare, R. Chem. Rev. 1991, 91, 1.
Adams, H.; Chung, L.-M.; Morris M.J.; Wright, P.J. Tetrahedron Lett. 2004, 45, 7671.
Adams, H.; Hughes, A.J.; Morris M.J.; Quenby, S.I.A. Tetrahedron Lett. 2014, 55, 5285.
(a) Worrall, D.E. J. Am. Chem. Soc. 1917, 39, 697; (b) Worrall, D.E., J. Am. Chem. Soc.,
3
4
5
.
.
.
1
937, 59, 933; (c) Worrall, D.E., J. Am. Chem. Soc. 1937, 59, 1486.
1
6
.
Characterising data for 3: H NMR (250 MHz, CDCl ):  8.14 (s, 1 H, CH), 7.64-7.00 (m, 10
3
1
3
H, Ph), 4.64 (t, J = 1.7 Hz, 2 H, C H ), 4.58 (t, J = 1.7 Hz, 2 H, C H ), 4.26 (s, 5 H, Cp). C
5
4
5
4
NMR (62.8 MHz, CDCl ):  193.3 (C=S), 156.0 (C=N), 149.3 (Cipso of =NPh), 138.6 (C=C),
3
1
38.0 (CHFc), 129.5-120.8 (m, Ph), 125.5 (Cipso of NPh), 78.1 (Cipso of Fc), 72.4, 71.0 (both
+
CH of C H ), 70.0 (Cp). MS: m/z 480 (M ). Analysis Found: C, 64.81; H, 4.44; N, 5.76; S,
5
4
1
3.06. Calcd. for C H FeN S : C, 65.00; H, 4.17; N, 5.83; S, 13.33%.
2
6
20
2
2
7
.
Chang, C.-W.; Lin, Y.-C.; Lee, G.-H.; Huang, S.-L.; Wang, Y. Organometallics 1998, 17,
534.
2
8
9
.
.
Erol, S.; Dogan I. Tetrahedron 2013, 69, 1337.
Synthesis of 4a: A solution of phenylacetylene (0.29 mL, 2.64 mmol) in THF (10 mL) was
cooled to –78 °C and treated with n-BuLi (1.65 mL, 1.6 M solution in hexanes, 2.64 mmol).
After warming to r.t. and stirring for 30 minutes, the solution was recooled to –78 °C for the
addition of PhNCS (0.3 mL, 2.64 mmol). The mixture was warmed to room temperature and
stirred for 1 h, developing an orange colour. It was then cooled to –78 °C for a third time and
ethanol (1.5 mL) was added to quench the reaction. After stirring overnight at r.t., the solvent
was removed in vacuo and the residue absorbed onto a small amount of silica, which was
then loaded onto a chromatography column. Elution with light petroleum and
dichloromethane (7:3) produced an orange-yellow band consisting of EtOC(=S)NHPh, which
was discarded. Elution with a 1:1 mixture of the same solvents gave a large red-brown band
that eluted as a golden yellow solution which was identified as 4a (337.4 mg, 57%). Crystals
1
3
suitable for X-ray diffraction crystallised directly as a CDCl solvate from the C NMR
3
page 10

1
sample. H NMR (400 MHz, CDCl ):  7.66-7.28 (m, Ph), 7.06 (s, br, 2H, Ph), 6.96 (s, 1H),
3
1
3
6
.83 (s, br, 2H, Ph). C NMR (62.8 MHz, CDCl ):  162.3, 147.9, 137.4, 134.5, 130.3-126.7
3
+
(
m, Ph), 123.1, 118.9, 112.0. MS: m/z 474 (M ). Analysis Found: C, 75.75; H, 4.78; N, 5.92;
S, 13.36. Calcd. For C H N S : C, 75.94; H, 4.64; N, 5.64; S, 13.50%.
3
0
22
2
2
1
0. See the ESI for characterisation data for 1.
page 11

Captions for Figures and Schemes
Figure 1. Single crystal X-ray structure of FcCH=CC(=S)NPhC(=NPh)S (3).
Figure 2. Molecular structure of 4a.CDCl in the crystal.
3
Scheme 1. Worrall’s synthesis of acetylenic thioamide 1.
Scheme 2. Cyclization of ferrocenylacetylene with PhNCS.
Scheme 3. Formation of dimer 4.
Scheme 4. Proposed mechanism for formation of 4.
Scheme 5. Reaction of 1 with PhNCS.
page 12