Gold(I)-catalyzed selective heterocyclization of propargylic thioureas: Mechanistic study of competitive gold-activation mode

Article abstract of DOI:10.1002/chem.201500466

A new selective gold(I)-catalyzed intramolecular heterocyclization of propargylic thioureas has been developed, efficiently affording two kinds of cycloadducts in moderate to excellent yields with a broad substrate scope. Further mechanistic investigation

Full text of DOI:10.1002/chem.201500466

DOI: 10.1002/chem.201500466
Communication
&
Gold Catalysis
Gold(I)-Catalyzed Selective Heterocyclization of Propargylic
Thioureas: Mechanistic Study of Competitive Gold-Activation
Mode
Yu Jiang,[a] Yin Wei,[b] Xiang-Ying Tang,*[b] and Min Shi*[a, b]
Abstract: A new selective gold(I)-catalyzed intramolecular
heterocyclization of propargylic thioureas has been devel-
oped, efficiently affording two kinds of cycloadducts in
moderate to excellent yields with a broad substrate scope.
Further mechanistic investigations indicate that competi-
tive different gold activation modes feature in these cycli-
zation processes. Kinetic experiments reveal that the gold
activation mode is influenced by the ligand of the gold
catalyst and the reaction conditions.
Gold(I)-catalyzed activation of multiple bonds, for example,
carbon–carbon triple bonds, has attracted much attention and
has also witnessed significant developments within the past
decade.[1] Recently, mechanistic investigation of the activation
modes of these reactions has emerged at the forefront of cur-
rent research. Several activation modes have been proposed to
date (Scheme 1), by the groups of Toste, Zhang, and Hashmi:
Scheme 1. Gold activation modes.
a) The p-activation mode (Scheme 1a), in which alkyne moiet-
ies are first activated by p-coordination with the gold catalyst
and then accept the attack of nucleophiles, is well-established
and accepted in gold catalysis; b) the dual s,p-activation con-
cept[2–7] was first proposed by Toste, Houk et al.[3a] Later, the
groups of Hashmi[4] and Zhang[5] independently discovered
a new dual gold activation mode in the cyclization of diynes,
whereby one alkyne moiety is activated by p-coordination,
while the other is activated by s-coordination (Scheme 1b);
c) more recently, Hashmi reported the s-activation mode,[8]
whereby the alkyne moiety is activated by s-coordination to
the gold catalyst (gold–acetylide), increasing the nucleophilici-
ty of the b-carbon atom (Scheme 1c). The field of gold cataly-
sis chemistry has been significantly enriched by knowledge of
these three modes of gold activation. However, to our knowl-
edge, few examples to date concern ligand-controlled gold ac-
tivation.[12g]
Alkynyl compounds bearing amide,[9,10] carbamate,[11] or
urea[12,13] functional groups have been extensively investigated
in gold-catalyzed intramolecular cyclizations.[14] Because of the
multiple nucleophilic atoms in the aforementioned functional
groups, they are excellent candidates to explore the different
cyclization pathways and activation modes involved in gold
catalysis. In 2013, the Asensio and co-workers[12g] reported that
(o-ethynylaryl)ureas could selectively undergo either 6-exo-dig
or 5-endo-dig cyclization (both N-attack) to give different cyclo-
adducts depending on the choice of gold(I) catalyst. Herein,
we report our findings on the gold catalyzed selective hetero-
cyclization of propargylic thioureas, affording N- or S-cycload-
ducts (N-attack or S-attack) from different cyclization pathways
due to the different activation modes governed by the ligands
and the reaction conditions (Scheme 2).
[a] Y. Jiang, Prof. Dr. M. Shi
Key Laboratory for Advanced Materials and Institute of Fine Chemicals
East China University of Science and Technology
Meilong Road No. 130, Shanghai, 200237 (P.R. China)
We initially utilized 3-isothiocyanato-1-methyl-3-(prop-2-yn-
yl)indolin-2-one 1a (0.10 mmol, 1.0 equiv) and benzylamine 2a
(0.12 mmol, 1.2 equiv) as the substrates by carrying out the re-
action in toluene in the presence of [PPh3AuCl]/AgOTf
(10 mol%) at 508C to examine the reaction outcome (Table 1).
The corresponding N-attack cycloadduct 3aa and S-attack cy-
cloadduct 4aa were obtained in 25% and 45% yields, respec-
[b] Dr. Y. Wei, Prof. Dr. X.-Y. Tang, Prof. Dr. M. Shi
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
345 Lingling Road, Shanghai, 200032 (P.R. China)
E-mail: siocxiangying@mail.sioc.ac.cn
mshi@mail.sioc.ac.cn
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201500466.
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be the common intermediate for
N
and S-cyclization reactions
(Table 1, entry 4). To assess the
influence of the AgI salt,
[PPh3AuNTf2] and [PPh3AuOTf]
were synthesized and used as
catalysts for the reaction, afford-
ing 3aa/4aa in 29%/20% and
31%/25% yields, respectively,
alongside 5aa in 33 and 35%
yields, respectively (Table 1, en-
tries 5 and 6). Interestingly, using
[Me4tBuXPhosAuNTf2] as the cat-
alyst
(Me4tBuXPhos=2-di-tert-
Scheme 2. Gold-catalyzed selective cyclization of propargylic thioureas.
Table 1. Optimization of the reaction conditions.
butylphosphino-3,4,5,6-tetra-
methyl-2’,4’,6’-triisopropyl-1,1’-bi-
phenyl) afforded 4aa as the
major product in 47% yield
alongside 5aa in 15% yield
(Table 1, entry 7). The use of
[IPrAuNTf2] as the catalyst afford-
ed 5aa as the sole product
(Table 1, entry 8, see the Sup-
porting Information for details).
Subsequently, the reaction tem-
perature and solvent were exam-
ined using [PPh3AuOTf] or
[Me4tBuXPhosAuNTf2] as the cat-
alyst. Consequently, 6-exo-dig N-
attack cycloadduct 3aa could be
obtained as the sole product in
91% yield in the presence of
10 mol% of [PPh3AuOTf] at room
temperature in dichloromethane
(DCM; Table 1, entry 13). Using
[Me4tBuXPhosAuNTf2] as the cat-
alyst led to the formation of 6-
exo-dig S-attack cycloadduct 4aa
as the only product in 92% yield
in DCM at 808C (Table 1,
entry 18).
Entry[a]
Catalyst
Solvent
t [h]
T [8C]
Yield [%][b]
4aa
3aa
5aa
1
2
3
4
5
6
7
8
none
AgOTf
[PPh3AuCl]/AgOTf
[PPh3AuCl]
[PPh3AuNTf2]
[PPh3AuOTf]
[Me4tBuXPhosAuNTf2]
[IPrAuNTf2]
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DCM
CH3CN
DCE
THF
DCM
DCM
6
6
12
6
6
6
6
6
6
6
80
80
50
50
50
50
50
50
50
50
50
50
RT
RT
RT
RT
50
80
–
–
25
19
29
31
–
–
74
18
37
41
95 (91[d]
)
21
10
2
–
74
45
trace
20
25
47
–
5
6
13
14
–
93
–
13
68
33
35
15
85
19
64
38
30
–
75
40
20
13
–
9
[PPh3AuOTf]
[PPh3AuOTf]
[PPh3AuOTf]
[PPh3AuOTf]
10
11
12
13
14[c]
15
16
17
18
6
6
[PPh3AuOTf]
[PPh3AuOTf]
[Me4tBuXPhosAuNTf2]
[Me4tBuXPhosAuNTf2]
[Me4tBuXPhosAuNTf2]
[Me4tBuXPhosAuNTf2]
48
48
24
24
12
6
–
THF
DCM
DCM
DCM
35
65
72
97 (92[d]
–
–
)
[a] Unless otherwise specified, all reactions were performed with 1a (0.12 mmol), 2a (0.10 mmol), and catalyst
(0.01 mmol); [b] yields were determined by 1H NMR spectroscopy using mesitylene as an internal standard;
[c] 2.5 mol% [PPh3AuOTf] was used. [d] yields of isolated product.
With optimal reaction condi-
tions in hand, we surveyed the
substrate scope by varying the
structure of oxindole derivatives
1 as well as amines 2 (Table 2).
tively, alongside the corresponding thiourea product 5aa in
13% yield on the basis of 1H NMR spectroscopy (Table 1,
entry 3). The structures of 3aa and 4aa were unambiguously
determined by X-ray diffraction (for ORTEP drawings and CIF
data, see the Supporting Information).[15] The control experi-
ments indicated that upon heating, the thiourea product 5aa
was the only isolated product (93% yield; Table 1, entry 1).
AgOTf could also catalyze the cyclization, exclusively giving
the S-attack product 4aa in 74% yield (Table 1, entry 2).
[PPh3AuCl] afforded 5aa as the major product in 68% yield,
alongside 3aa and 4aa in low yields, suggesting that 5aa may
In all cases except 1k, the desired S-cyclization products 4
were obtained in excellent yields ranging from 83% to 96%
under condition B and the reactions were completed within
6 h. For condition A, in all cases except 1k, the desired N-cycli-
zation products 3 were formed as the sole product in moder-
ate to excellent yields. With substrate 1b, bearing 5-Cl and 7-
Me aromatic substituents, or with nBuNH2 as the nucleophile,
the desired N-cyclization products 3ba and 3af were produced
in moderate yields of 52% and 63% after 24 or 48 h, respec-
tively (Table 2, entries 2 and 15). It should be also noted that,
when 1k bearing an internal alkyne was used for the reaction,
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Table 2. Reaction scope: synthesis of heterocyclic products 3 and 4.
Entry[a]
1
R1
R2
2/R3
Product, yield [%],[b]
t
Condition A
Condition B[d]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1 f
H
Me
Me
Me
Me
Me
Me
Me
Bn
2a/Bn
2a/Bn
2a/Bn
2a/Bn
2a/Bn
2a/Bn
2a/Bn
2a/Bn
3aa, 91, 24 h
3ba, 52, 24 h
3ca, 79, 12 h
3da, 82, 20 h
3ea, 94, 12 h
3 fa, 94, 12 h
3ga, 89, 12 h
3ha, 82, 24 h
4aa, 92
4ba, 93
4ca, 87
4da, 94
4ea, 94
4 fa, 94
4ga, 87
4ha, 92
5-Cl, 7-Me
5-F
6-Br
5-Me
6-Me
5-OMe
H
1g
1h
9
1i
H
2a/Bn
3ia, 85, 24 h
4ia, 91
10
1j
H
2a/Bn
3ja, 63, 24 h
4ja, 93
11
12
13
14
15
1a
1a
1a
1a
1a
H
H
H
H
H
Me
Me
Me
Me
Me
2b/4-MeC6H4CH2
2c/2,4-Me2C6H3CH2
2d/4-ClC6H4CH2
2e/nPr
3ab, 90, 24 h
3ac, 77, 24 h
3ad, 91, 10 h
3ae, 73, 48 h
3af, 63, 48 h
4ab, 96
4ac, 90
4ad, 91
4ae, 83
4af, 89
2 f/nBu
16
1k
2a/Bn
N.D.[c]
N.D.[c]
Condition A: [PPh3AuOTf] (10 mol%), DCM, RT; condition B: [Me4tBuXPhosAuNTf2] (10 mol%, DCM, 808C. [a] Unless otherwise specified, all reactions were
performed with 1 (0.12 mmol), 2 (0.10 mmol), and catalyst (0.01 mmol); [b] yields of isolated product; [c] N.D.=not detected, thiourea compound 5ka was
obtained instead of 3ka or 4ka.; [d] all reactions under condition B were all performed within 6 h.
only 5ka resulted under the both conditions, suggesting that
the acetylenic proton (ꢀCÀH) played an important role. This
phenomenon prompted us to further investigate the reaction
mechanism.
The mechanistic investigations were initiated by evaluation
of the chemical behavior of the isolated common intermediate
5aa. Upon treatment of 5aa under the conditions A and B, dif-
ferent results were observed. As shown in Scheme 3a and 3b,
S-cyclization product 4aa was given smoothly with condi-
tion B, while trace of N-cyclization product 3aa could be ob-
tained with condition A. This unexpected phenomenon led to
examine the function of benzylamine in the reaction. More-
over, when 5aa was treated with [PPh3AuOTf] in the presence
of BnNH2 (10 mol%), 3aa was isolated in 79% yield
(Scheme 3c). Replacing benzylamine with triethylamine or pro-
pylamine could also afford 3aa in 82% or 78% yield, respec-
tively, indicating that BnNH2 may also act as a base in this reac-
tion (see the Supporting Information).
Scheme 3. Reaction of 5aa.
Therefore, [D1]5aa (97% D), deuterated at the terminal ace-
tylenic proton, was prepared to probe the possible reaction
pathway. Compound [D1]5aa was subjected to 10 mol% of
[PPh3AuOTf] and BnNH2 in DCM at room temperature, giving
undeuterated 3aa in 80% yield without deuterium incorpora-
tion (Scheme 4a). The complete loss of deuterium implied an
acetylenic CÀH bond cleavage process in the [PPh3AuOTf]-cata-
lyzed reaction. In comparison, treating [D1]5aa with
[Me4tBuXPhosAuNTf2] in DCM at 808C provided [D1]4aa in
94% yield with 69% deuterium incorporation (Scheme 4b).
Subsequently, BnND2 was prepared and used in this reaction.
The treatment of 5aa with 1.0 equivalent of BnND2 in DCM in
the presence of [PPh3AuOTf] (10 mol%) gave [D2]3aa in 77%
yield along with 25% deuterium incorporation equally at the
two terminal olefinic positions (see the Supporting Informa-
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a gold–acetylide species as an intermediate (Scheme 4a). Fur-
thermore, in the deuterium labeling experiment (Scheme 4c),
equal deuterium incorporation at the two terminal olefinic po-
sitions suggests that the N-attack cyclization process may un-
dergo the s,p-activation mode (see below; Scheme 7, interme-
diate B).
Subsequently, [PPh3AuÀacetylide] complex 6a (see the Sup-
porting Information for X-ray diffraction[15]) was prepared by
treating 1a with [PPh3AuCl] in the presence of Et3N.[4c] Interest-
ingly, treatment of 6a with 1.0 equivalent of BnNH2 afforded
a new gold species 7aa, which was identified by 1H and
13C NMR spectroscopy and high-resolution mass spectrometry
(see the Supporting Information for details), rather than a thio-
urea-tethered [PPh3AuÀacetylide] compound (Scheme 5). This
result was significantly different from Asensio’s finding,[12 g] in
which a stable urea-tethered gold–acetylide compound was
produced. Attempts to obtain a single crystal of this gold com-
plex failed because it was very sensitive to ambient moisture.
Purification of 7aa by column chromatography on silica gel di-
rectly gave 3aa in 80% yield. The reaction of substrate 6d,
having a 6-Br substituent on the aromatic , with 2d also pro-
duced the corresponding gold species 7dd in 95% yield
(Scheme 5).
However,
attempts
to
synthesize
a [Me4tBuXPhosAuÀacetylide] complex all failed, indicating
that in the S-cyclization process, p-coordination of
[Me4tBuXPhosAu]+ with the alkyne moiety is favored.
Scheme 4. Deuteration experiments.
tion). Moreover, when 3.0 equiv-
alents of BnND2 was used,
[D2]3aa could be obtained in
78% yield along with 38% deu-
terium incorporation equally at
the two terminal olefinic posi-
tions (Scheme 4c). The use of
[Me4tBuXPhosAuNTf2]
under
these conditions gave [D2]4aa in
93% yield alongside 28% and
60% deuterium incorporation at
the two terminal olefinic posi-
tions (Scheme 4d).
The greater deuterium reten-
tion at the terminal olefinic posi-
tion syn to the
S atom in
[D1]4aa, as well as that at the
Scheme 5. Synthesis of gold complexes 7aa and 7dd.
terminal olefinic position anti to
S atom in [D2]4aa (Scheme 4b
and d), clearly indicate that the S-attack cyclization undergoes
the classical p-activation mode. The 31P NMR spectroscopy of
[Me4tBuXPhosAuNTf2] with 5aa is also consistent with this acti-
vation mode by observation of a new signal at 83.066 ppm
(see Figure S1 in the Supporting Information). Moreover, the
partial loss or incorporation of deuterium (Scheme 4b and
Scheme 4d, respectively) also suggest the reversible acetylenic
CÀH bond cleavage in S-attack cyclization processes (see
below; Scheme 7).
More importantly, gold–acetylide complex 6a or gold com-
plex 7aa can successfully catalyze the N-cyclization of 5aa to
give 3aa in moderate yield, indicating that this triphenylphos-
phine gold–acetylide complex is indeed the active species in
the [PPh3AuOTf]-catalyzed reaction (Scheme 6). This result also
suggests that the catalytically active AuI species for N-cycliza-
tion can be released upon intermolecular protodeauration of
6a or 7aa by 5aa, possibly due to the different pKa values of
the NÀH moiety in urea and thiourea compounds.[17] The lower
pKa values of thioureas can lead to the intra- or intermolecular
protodeauration taking place more readily.
In the N-attack cyclization process, the necessity of a base
and the acetylenic CÀH bond cleavage raised the possibility of
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Scheme 6. Reaction of 5aa with 6a and 7aa.
According to the above experiments, the product distribu-
tion of 3aa and 4aa was highly dependent on the gold cata-
lyst, base, and reaction temperature. Thus, we set out to accu-
rately analyze the pathways of these gold(I)-catalyzed transfor-
mations by NMR spectroscopy. Upon adding 5aa, gold catalyst
and BnNH2 into a NMR tube using CDCl3 as the solvent, the re-
sulting reaction mixtures were heated at appropriate tempera-
ture, and their 1H NMR spectra were recorded every 30 mi-
nutes. The yields of 3aa and 4aa as a function of time were
then recorded (Figure 1).
Under the catalysis of [PPh3AuOTf] (10 mol%) with BnNH2
(10 mol%) at 408C, the heterocyclization of 5aa proceeded
smoothly (Figure 1A, lines b, b’), giving the N-cyclization prod-
uct 3aa and S-cyclization product 4aa simultaneously, while
the reaction rate of N-cyclization was faster than that of S-cycli-
zation. After 5 h, 3aa and 4aa were given in 91% and 8%
yields, respectively. On raising the reaction temperature to 60
or 808C (Figure 1A, lines c, c’ and lines d, d’), the initial rate of
3aa formation increased over the first hour, but soon de-
creased because of the same increased rate of 4aa formation
and, after 5 h, yields of 3aa are lower than that for the reac-
tion at 408C. However, the rate of formation of 4aa at elevated
temperature was fairly comparable over the full 5 hour period.
Lowering the reaction temperature to 208C led to no forma-
tion of 4aa, with 3aa as the sole product (Figure 1A, lines
a, a’). This result showed clearly that high temperature favored
S-cyclization. Next, the base effect in this competitive reaction
was also examined. In the absence of BnNH2, product 4aa was
the main product (Figure 1B, lines a, a’). However, in the pres-
ence of BnNH2, N-cyclization was favored, suggesting that the
presence of BnNH2 in any amount is required to form product
3aa in respectable yield (Figure 1B, line b b’ and lines c, c’).
This phenomenon indicates that the formation of [PPh3AuÀ
acetylide] is promoted in the presence of BnNH2, subsequently
Figure 1. Kinetics of the transformations of 5aa in the presence of gold cat-
alyst under various conditions. All experiments were performed at
0.10 mmol scale in 1.0 mL CDCl3 (containing 0.033 mmol of 1,3,5-trimethoxy-
benzene as an internal standard). A) [PPh3AuOTf] (10 mol%) and BnNH2
(10 mol%), at 20, 40, 60, or 808C; B) [PPh3AuOTf] (10 mol%) and BnNH2 (0, 5,
or 10 mol%) at 808C; C) [PPh3AuOTf] or [Me4tBuXPhosAuNTf2] (10 mol%)
and BnNH2 (10 mol%) at 808C.
favoring
the
N-cyclization
process.
Finally,
using
tion, whereas the presence of base favored the formation of
the gold–acetylide compound, leading to N-cyclization.
[Me4tBuXPhosAuNTf2] instead of [PPh3AuOTf] led to 4aa as the
only product at 808C, despite the presence of BnNH2 (Fig-
ure 1C), indicating that it is difficult to form [Me4tBuXPhosAu–
acetylide] complex, presumably due to the steric effect. These
kinetic experiments demonstrated that reaction conditions can
influence the gold activation mode. Sterically bulky
Me4tBuXPhos ligand and high temperature promoted S-cycliza-
Based on monitoring by NMR spectroscopy and control ex-
periments, a plausible mechanism for this reaction has been
proposed using 1a and BnNH2 2a as model substrates
(Scheme 7). At first, compound 5aa is formed as the common
intermediate. Using [PPh3AuOTf] as the catalyst, acetylenic CÀ
H bond cleavage of 5aa in the presence of base (BnNH2) gen-
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In summary, we have found
that propargylic thioureas can
selectively give the S-, or N-cycli-
zation products under gold(I)
catalysis. Further mechanistic
study indicated that competitive
activation modes operated in
the different reaction pathways,
through p-activation or dual s,p-
coordination with the gold cata-
lyst. More importantly, new gold
complex intermediates 7aa and
7dd were identified by spectro-
scopic data. Kinetic experiments
revealed the gold activation
mode was influenced by gold
catalyst ligand selection and the
reaction conditions. Triphenyl-
phosphine, low temperature,
and the presence of base favor
the dual s,p-activation of al-
kynes.
Acknowledgements
Scheme 7. Proposed reaction mechanism.
We are grateful for the financial
support from the National Basic
Research Program of China (973-
2015CB856603), the National
erates the s,p-activated intermediate A. The next N-attack cyc-
lization takes place to give the gem-diauraalkene intermediate
B.[3] Subsequent intramolecular protodeauration generates the
gold complex C, which can be intramolecularly protodeaurated
again to give 7aa,[16] in which one Au atom may have weak in-
teraction with sulfur. Intermolecular deprotonation of 5aa by
7aa gives intermediate A alongside the final product 3aa. In
the control experiment (Scheme 5), gold complex 6a can also
give the desired N-cyclization product in the presence of
BnNH2. This phenomenon is different from Asensio’s findings,
in which the urea-tethered gold–acetylide complex is stable
and its activation requires additional gold catalyst because of
the different pKa values of the NÀH moieties in ureas and thio-
ureas. Furthermore, in this catalytic cycle, BnNH2 also acts as
Natural Science Foundation of China (20472096, 21372241,
21361140350, 20672127, 21421091, 21372250, 21121062,
21302203 and 20732008).
Keywords: gold · heterocycles · homogeneous catalysis ·
reaction mechanisms · thioureas
[1] For selected reviews: a) E. Jimꢁnez-NfflÇez, A. M. Echavarren, Chem.
Commun. 2007, 333–346; b) D. J. Gorin, B. D. Sherry, F. D. Toste, Chem.
Rev. 2008, 108, 3351–3378; c) A. S. K. Hashmi, M. Rudolph, Chem. Soc.
Rev. 2008, 37, 1766–1775; d) A. S. K. Hashmi, Angew. Chem. Int. Ed.
2010, 49, 5232–5241; Angew. Chem. 2010, 122, 5360–5369; e) S. Sen-
gupta, X. Shi, ChemCatChem 2010, 2, 609–619; f) P. Kothandaraman, W.
Rao, S. J. Foo, P. W. H. Chan, Angew. Chem. Int. Ed. 2010, 49, 4619–4623;
Angew. Chem. 2010, 122, 4723–4727; g) A. Corma, A. Leyva-Pꢁrez, M. J.
Sabater, Chem. Rev. 2011, 111, 1657–1712; h) J. Xiao, X. Li, Angew.
Chem. Int. Ed. 2011, 50, 7226–7236; Angew. Chem. 2011, 123, 7364–
7375; i) N. Krause, C. Winter, Chem. Rev. 2011, 111, 1994–2009; j) W. Rao,
D. Susanti, P. W. H. Chan, J. Am. Chem. Soc. 2011, 133, 15248–15251;
k) M. Rudolph, A. S. K. Hashmi, Chem. Soc. Rev. 2012, 41, 2448–2462;
l) A. S. K. Hashmi, F. D. Toste, Modern Gold-Catalyzed Synthesis Wiley-
VCH, Weinheim, 2012, pp. 1–402; m) W. Rao, M. J. Koh, P. Kothandara-
man, P. W. H. Chan, J. Am. Chem. Soc. 2012, 134, 10811–10814; n) W.
Rao, M. J. Koh, D. Li, H. Hirao, P. W. H. Chan, J. Am. Chem. Soc. 2013,
135, 7926–7932; o) D.-H. Zhang, X.-Y. Tang, M. Shi, Acc. Chem. Res.
2014, 47, 913–924; p) L. Fensterbank, M. Malacria, Acc. Chem. Res.
2014, 47, 953–965; q) W. Yang, A. S. K. Hashmi, Chem. Soc. Rev. 2014,
43, 2941–2955.
a
base
to
initiate
the
catalytic
cycle.
When
[Me4tBuXPhosAuNTf2] is used as the catalyst, the cyclization
may undergo a classical p-activation mode. The p-coordination
of gold catalyst to 5aa gives intermediate D, which undergoes
nucleophilic attack by the sulfur atom to generate intermedi-
ate E. Intramolecular protodeauration gives product 4aa and
the gold catalyst to complete the catalytic cycle. It should be
noted that 5aa can also undergo an acetylenic CÀH bond
cleavage to form the unstable gold complex F (this process is
reversible), which leads to the partial loss of acetylenic deuteri-
um in the control experiment (Scheme 3b). Anyhow, the intra-
molecular cyclization of intermediate D takes place faster than
the acetylenic CÀH bond cleavage of intermediate F.
[2] For selected reviews of dual gold activation: a) A. Gómez-Suµrez, S. P.
Nolan, Angew. Chem. Int. Ed. 2012, 51, 8156–8159; Angew. Chem. 2012,
124, 8278–8281; b) A. S. K. Hashmi, Acc. Chem. Res. 2014, 47, 864–876.
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&
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www.chemeurj.org
6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Communication
[3] a) P. H-Y. Cheong, P. Morganelli, M. R. Luzung, K. N. Houk, F. D. Toste, J.
Am. Chem. Soc. 2008, 130, 4517–4626; b) A. Simonneau, F. Jaroschik, D.
Lesage, M. Karanik, R. Guillot, M. Malacria, J.-C. Tabet, J.-P. Goddard, L.
Fensterbank, V. Gandon, Y. Gimbert, Chem. Sci. 2011, 2, 2417.
[4] a) A. S. K. Hashmi, I. Braun, M. Rudolph, F. Rominger, Organometallics
2012, 31, 644–661; b) A. S. K. Hashmi, M. Wieteck, I. Braun, P. Nçsel, L.
Jongbloed, M. Rudolph, F. Rominger, Adv. Synth. Catal. 2012, 354, 555–
562; c) A. S. K. Hashmi, I. Braun, P. Nçsel, J. Schädlich, M. Wieteck, M. Ru-
dolph, F. Rominger, Angew. Chem. Int. Ed. 2012, 51, 4456–4460; Angew.
Chem. 2012, 124, 4532–4536; d) M. M. Hansmann, M. Rudolph, F. Ro-
minger, A. S. K. Hashmi, Angew. Chem. Int. Ed. 2013, 52, 2593–2598;
Angew. Chem. 2013, 125, 2653–2659.
[5] a) L. Ye, Y. Wang, D. H. Aue, L. Zhang, J. Am. Chem. Soc. 2012, 134, 31–
34; b) Y. Wang, A. Yepremyan, S. Ghorai, R. Todd, D. H. Aue, L. Zhang,
Angew. Chem. Int. Ed. 2013, 52, 7795–7799; Angew. Chem. 2013, 125,
7949–7953.
[6] For other examples of dual gold complexes: a) Y. Odabachian, X. F.
Le Goff, F. Gagosz, Chem. Eur. J. 2009, 15, 8966–8970; b) A. Grirrane, H.
García, A. Corma, E. lvarez, ACS Catal. 2011, 1, 1647–1653; c) T. J.
Brown, D. Weber, M. R. Gagnꢁ, R. A. Widenhoefer, J. Am. Chem. Soc.
2012, 134, 9134–9137; d) D. D. Vachhani, M. Galli, J. Jacobs, L. Van
Meervelt, E. V. Van der Eycken, Chem. Commun. 2013, 49, 7171–7173;
e) A. Grirrane, H. Garcia, A. Corma, E. lvarez, Chem. Eur. J. 2013, 19,
12239–12244; f) I. Braun, A. M. Asiri, A. S. K. Hashmi, ACS Catal. 2013, 3,
1902–1907.
269–272; d) A. Varela-Fernµndez, J. A. Varela, C. Saµ, Adv. Synth. Catal.
2011, 353, 1933–1937; e) M. Hellal, G. D. Cuny, Tetrahedron Lett. 2011,
52, 5508–5511; f) T. Saito, S. Ogawa, N. Takei, N. Kutsumura, T. Otani,
Org. Lett. 2011, 13, 1098–1101; g) T. Miura, K. Hiraga, T. Toyoshima, M.
Yamauchi, M. Murakami, Chem. Lett. 2012, 41, 798–800.
[11] a) S. Ritter, Y. Horino, J. Lex, H.-G. Schmalz, Synlett 2006, 3309–3313;
b) A. Buzas, F. Gagosz, Synlett 2006, 2727–2730; c) R. Robles-Machín, J.
Adrio, J. C. Carretero, J. Org. Chem. 2006, 71, 5023–5502; d) A. S. K.
Hashmi, R. Salathꢁ, W. Frey, Synlett 2007, 1763–1766; e) E. S. Lee, H. S.
Yeom, J. H. Hwang, S. Shin, Eur. J. Org. Chem. 2007, 3503–3507; f) F. M.
Istrate, A. K. Buzas, I. D. Jurberg, Y. Odabachian, F. Gagosz, Org. Lett.
2008, 10, 925–928; g) T. Enomoto, S. Obika, Y. Yasui, Y. Takemoto, Synlett
2008, 1647–1650; h) T. Enomoto, A-L. Girard, Y. Yasui, Y. Takemoto, J.
Org. Chem. 2009, 74, 9158–9164; i) N. Gouault, M. Le Roch, C. Corneꢁ,
M. David, P. Uriac, J. Org. Chem. 2009, 74, 5614–5617; j) S. Fustero, I.
IbµÇez, P. Barrio, M. A. Maestro, S. Catalµn, Org. Lett. 2013, 15, 832–835.
[12] a) D. Ye, J. Wang, X. Zhang, Y. Zhou, X. Ding, E. Feng, H. Sun, G. Liu, H.
Jiang, H. Liu, Green Chem. 2009, 11, 1201–1208; b) A. Gimeno, M.
Medio-Simón, C. Ramírez de Arellano, G. Asensio, A. B. Cuenca, Org. Lett.
2010, 12, 1900–1903; c) V. S. Peshkov, O. P. Pereshivsko, S. Sharma, T.
Meganathan, V. S. Parmar, D. D. Ermolatꢁv, E. V. Van der Eycken, J. Org.
Chem. 2011, 76, 5867–5872; d) O. P. Pereshivko, V. S. Peshkov, J. Jacobs,
L. Van Meervelt, E. V. Van der Eycken, Adv. Synth. Catal. 2013, 355, 781–
789; e) P. P. Sharp, M. G. Banwell, J. Renner, K. Lohmann, A. C. Willis, Org.
Lett. 2013, 15, 2616–2619; f) A. Gimeno, A. B. Cuenca, M. Medio-Simón,
G. Asensio, Adv. Synth. Catal. 2014, 356, 229–236; g) A. Gimeno, A. B.
Cuenca, S. Suarez-Pantiga, C. R. D. Arellano, M. Medio-Simón, G. Asen-
sio, Chem. Eur. J. 2014, 20, 683–688.
[7] a) T. N. Hooper, M. Green, C. A. Russell, Chem. Commun. 2010, 46, 2313–
2315; b) T. J. Brown, R. A. Widenhoefer, Organometallics 2011, 30, 6003–
6009.
[8] J. Bucher, T. Wurm, K. S. Nalivela, M. Rudolph, F. Rominger, A. S. K.
Hashmi, Angew. Chem. Int. Ed. 2014, 53, 3854–3858; Angew. Chem.
2014, 126, 3934–3939.
[13] For gold-catalyzed cyclization of allenyl- and alkenylureas, see: a) C. F.
Bender, R. A. Widenhoefer, Org. Lett. 2006, 8, 5303–5305; b) Z. Zhang,
S. D. Lee, R. A. Widenhoefer, J. Am. Chem. Soc. 2009, 131, 5372–5373;
c) H. Li, R. A. Widenhoefer, Org. Lett. 2009, 11, 2671–2674; d) R. L. La-
Londe, W. E. Brenzovich, D. Benitez, E. Tkatchouk, K. Kelley, W. A. God-
dard, F. D. Toste, Chem. Sci. 2010, 1, 226–233; e) H. Li, S. D. Lee, R. A.
Widenhoefer, J. Organomet. Chem. 2011, 696, 316–320; f) H. Seo, D. R.
Snead, K. A. Abboud, S. Hong, Organometallics 2011, 30, 5725–5730;
g) M. Kojima, K. Mikami, Synlett 2012, 23, 57–61.
[14] For other selected examples of gold-catalyzed cyclization of allenyl-
and alkenylamides, see: a) X. Han, R. A. Widenhoefer, Angew. Chem. Int.
Ed. 2006, 45, 1747–1749; Angew. Chem. 2006, 118, 1779–1781; b) C. F.
Bender, R. A. Widenhoefer, Chem. Commun. 2006, 4143–4144; c) X.-Y.
Liu, C.-H. Li, C.-M. Che, Org. Lett. 2006, 8, 2707–2710; d) Z. Zhang, C.
Liu, R. E. Kinder, X. Han, H. Qian, R. A. Widenhoefer, J. Am. Chem. Soc.
2006, 128, 9066–9073; e) H. Li, F. Song, R. A. Widenhoefer, Adv. Synth.
Catal. 2011, 353, 955–962; f) P. Mukherjee, R. A. Widenhoefer, Angew.
Chem. Int. Ed. 2012, 51, 1405–1407; Angew. Chem. 2012, 124, 1434–
1436; g) S. D. Lee, J. C. Timmerman, R. A. Widenhoefer, Adv. Synth. Catal.
2014, 356, 3187–3192.
[9] For examples of gold catalyzed heterocyclizations involving alkynyla-
mides, see: a) A. S. K. Hashmi, J. P. Weyrauch, W. Frey, J. W. Bats, Org.
Lett. 2004, 6, 4391–4394; b) C. Ferrer, A. M. Echavarren, Angew. Chem.
Int. Ed. 2006, 45, 1105–1109; Angew. Chem. 2006, 118, 1123–1127; c) D.
Aguilar, M. Contel, R. Navarro, T. Soler, E. P. Urriolabeitia, J. Organomet.
Chem. 2009, 694, 486–493; d) Y. Zhou, E. Feng, G. Liu, D. Ye, J. Li, H.
Jiang, H. Liu, J. Org. Chem. 2009, 74, 7344–7348; e) J. P. Weyrauch,
A. S. K. Hashmi, A. Schuster, T. Hengst, S. Schetter, A. Littmann, M. Ru-
dolph, M. Hamzic, J. Visus, F. Rominger, W. Frey, J. W. Bats, Chem. Eur. J.
2010, 16, 956–963; f) L. Zhang, D. Ye, Y. Zhou, G. Liu, E. Feng, H. Jiang,
H. Liu, J. Org. Chem. 2010, 75, 3671–3677; g) A. S. K. Hashmi, A. M.
Schuster, M. Schmuck, F. Rominger, Eur. J. Org. Chem. 2011, 4595–4602;
h) A. S. K. Hashmi, A. M. Schuster, S. Gaillard, L. Cavallo, A. Poater, S. P.
Nolan, Organometallics 2011, 30, 6328–6337; i) A. S. K. Hashmi, C. Loth-
schütz, K. Graf, T. Häffner, A. Schuster, F. Rominger, Adv. Synth. Catal.
2011, 353, 1407–1412; j) Y. Long, Z. She, Z. X. Liu, Y. Chen, J. Org. Chem.
2013, 78, 2579–2588; k) D. Ye, X. Zhang, Y. Zhou, D. Zhang, L. Zhang,
H. Wang, H. Jiang, H. Liu, Adv. Synth. Catal. 2009, 351, 2770–2778; l) J.
Zhu, H. Xie, Z. Chen, S. Li, Y. Wu, Org. Biomol. Chem. 2012, 10, 516–523;
m) D. D. Vachhani, V. P. Mehta, S. G. Modha, K. Van Hecke, L. Van Meer-
velt, V. Van der Eycken, Adv. Synth. Catal. 2012, 354, 1593–1599;
n) A. S. K. Hashmi, M. C. Blanco Jaimes, A. M. Schuster, F. Rominger, J.
Org. Chem. 2012, 77, 6394–6408; o) A. S. K. Hashmi, A. Littmann, Chem.
Asian J. 2012, 7, 1435–1442.
[15] CCDC 941698 (3aa), 931872 (4aa), and 979552 (6) contain the supple-
mentary crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif
[16] G. Banditelli, A. L. Bandini, M. A. Cinellu, G. Minghetti, M. Scandola, P.
Traldi, Inorg. Chim. Acta 1991, 183, 51.
[17] F. G. Bordwell, D. J. Algrim, J. A. Harrelson Jr., J. Am. Chem. Soc. 1988,
110, 5903–5904.
[10] For other transition-metals catalyzed heterocyclizations involving alky-
nylamides, see: a) M. Costa, N. D. Cà, N. B. Gabriele, C. Massera, G. Sale-
rno, M. Soliani, J. Org. Chem. 2004, 69, 2469–2477; b) G. Liu, Y. Zhou, D.
Ye, D. Zhang, X. Ding, H. Jiang, H. Liu, Adv. Synth. Catal. 2009, 351,
2605–2610; c) M. Bian, W. Yao, H. Ding, C. Ma, J. Org. Chem. 2010, 75,
Received: February 5, 2015
Published online on && &&, 0000
Chem. Eur. J. 2015, 21, 1 – 8
www.chemeurj.org
7
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Communication
COMMUNICATION
&
Gold Catalysis
Y. Jiang, Y. Wei, X.-Y. Tang,* M. Shi*
&& – &&
Gold(I)-Catalyzed Selective
Heterocyclization of Propargylic
Thioureas: Mechanistic Study of
Competitive Gold-Activation Mode
Plan of attack: A new selective gold(I)-
catalyzed intramolecular heterocycliza-
tion of propargylic thioureas has been
developed with a broad substrate
scope, whereby two kinds of gold acti-
vation mode efficiently afford different
cyclization products in moderate to ex-
cellent yields (see scheme).
&
&
Chem. Eur. J. 2015, 21, 1 – 8
www.chemeurj.org
8
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!