N-arylation followed by incipient azetidinium (6) forma-
tion and then cleavage of the CÀN bond to give the
products. As part of our efforts to define new, synthetically
useful pathways in aryne chemistry,3a,4,7 we chose to
investigate thioureas as substrates in an analogous process.
The more nucleophilic sulfur atom would be expected to
out-compete the N-arylation pathway, setting up an alter-
native insertion pathway resulting in cleavage of the CÀS
π-bond rather than the acyl CÀN σ-bond. To test the idea
we heated thiourea 10a (1 equiv) with benzyne precursor 1
(2.1 equiv) in the presence of cesium fluoride (Scheme 2).
Somewhat surprisingly, we observed the formation of two
separate compounds containing one and two additional
benzene rings, respectively. NMR and X-ray analysis
characterized the structures as the insertion/arylation ami-
dine product 11a (70%, major) and the simple S-arylated
compound 12a (20%, minor). As expected, the sulfur atom
preferentially adds to benzyne to give the formal π-inser-
tion product, which in the presence of excess aryne under-
goes a second S-arylation to afford 11a as the major
product.
(Table 1). The combined yields of 11 and 12 were generally
excellent, with the selectivity between the two products
correlating with the electronic properties of the aryl sub-
stituent. Electron-releasing groups in the para position
(Me, Et, t-Bu and OMe, entries 1À4) were noticeably
selective for the insertion product 11. The most electron-
rich substrate 10e gave a 9:1 selectivity for 11e in an
excellent 89% isolated yield. Electron-withdrawing groups
in the para position tended to increase the amount of
simple arylation product 12, with F, CN, NO2, OCF3,
and CO2Me substituents (entries 5, 7À10) all producing 11
and 12 in ratios from 0.9:1 (NO2, entry 8) to 1.4:1 (F, entry 5).
The reaction was successful for ortho (entry 11) and meta
(Supporting Information) MeO groups, with product
ratios being close to 1:1. Finally, we were pleased to see
that the pyridyl derivative 10m underwent successful in-
sertion (entry 12), with no problems of side reactions3k
from the nucleophilic azine nitrogen.
We extended the scope of the thiourea substrates to
encompass alternative alkyl groups on either thiourea
nitrogen atom. The sterically hindered iPr and cyclohexyl
derivatives were productive, producing the insertion
products 11o and 11p in moderate yields (Table 1,
entries 14 and 15). Replacing the aryl group and using
an all alkyl-substituted thiourea was likewise success-
ful, with the cyclohexyl and benzyl derivatives 10r and
10s undergoing insertion in good yield (entries 17 and
18). Cyclic thiourea 10t is directly analogous to Hiya-
ma’s urea substrate that undergoes CÀN σ-insertion.6
Here, we see the expected CÀS insertion to form the
novel amidine 11t in 75% yield and with >4:1 selectiv-
ity relative to simple arylation. Finally, 3-methoxyben-
zyne proved equally effective as simple benzyne,
affording the functionalized amidine 11u in high yield
as a single diastereoisomer (entry 20).
Scheme 2. Insertion of Benzyne into Thioureas
To clarify the relationship between the two products 11
and 12 in the mechanistic pathway of the reaction, we re-
exposed arylation products 12a and 12k to the reaction
conditions. Interestingly, no reaction was observed in
either case, with both substrates undergoing slow decom-
position over prolonged heating. It appears, therefore, that
12 is not a precursor to 11 in the reaction. A possible
mechanism taking account of this observation is presented
in Scheme 3.
Following initial reaction with benzyne, zwitterionic
intermediate 13 may undergo quenching via intermolecu-
lar proton transfer from the acetonitrile co-solvent and
subsequent proton loss from the iminium ion. The result-
ing S-phenyl isothioureas 12 are then much less reactive
substrates for a second aryne insertion.
Amidines are useful heterocyclic building blocks, as well
as important motifs in medicinal chemistry in their own
right.8 Classical methods of amidine synthesis usually
involve nucleophilic addition to nitriles (Pinner reaction
for primary and secondary amidines) or desulfurizing
thioamides with stoichiometric mercury in the presence
of amine nucleophiles.9 The reaction at hand offers a new
approach that requires no transition metals, as well as
accessing an interesting motif whereby the sulfur atom in
the starting material is transposed in the amidine product,
offering possibilities for further functionalization.
To explore the scope of this amidine synthesis we first
prepared a series of N,N-dimethyl-N-arylthioureas and
examined the affect of varying the aryl substituents
The insertion products 11 presumably arise from inter-
mediate 13 in the usual fashion for aryne insertion chem-
istry, formation of a four-membered intermediate 14,
(8) (a) DeKorver, K. A.; Johnson, W. L.; Zhang, Y.; Hsung, R. P.;
Dai, H.; Deng, J.; Lohse, A. G.; Zhang, Y.-S. J. Org. Chem. 2011, 76,
5092–5103 and references therein. (b) Zhang, Y.; DeKorver, K. A.;
Lohse, A. G.; Zhang, Y.-S.; Huang, J.; Hsung, R. P. Org. Lett. 2009, 11,
899–902.
(9) Dunn, P. J. Amidines and N-Substituted Amidines. In Compre-
hensive Organic Functional Group Transformations II; Katritzky, A. R.,
Taylor, R. J. K., Eds.; Elsevier: New York, 2005; Vol. 5, pp 655À699.
(10) S-Arylation of thiols with benzyne: (a) Scardiglia, F.; Roberts,
J. D. Tetrahedron 1958, 3, 197–208. (b) Bunnett, J. F.; Brotherton, T. K.
J. Org. Chem. 1958, 23, 904–906. (c) Bates, R. B.; Janda, K. D. J. Org.
Chem. 1982, 47, 4374–4376. (d) Lin, W.; Sapountzis, I.; Knochel, P.
Angew. Chem., Int. Ed. 2005, 44, 4258–4261. (e) Cano, R.; Ramon, D. J.;
Yus, M. J. Org. Chem. 2011, 76, 654–660.
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