Synthetic evolutions in the nucleophilic addition to alkynes

Article abstract of DOI:10.1016/j.jorganchem.2010.09.025

This short account describes our efforts to transform the simple nucleophilic addition of alkynes into a more efficient, selective and environmentally benign synthetic tool. We have circumvented the lack of regioselectivity in the gold-catalyzed triple bond addition of water through neighboring group participation and in the process we developed a 'functionalized hydration' (multiple bond formation and hydration in a one-pot process) using fluorine-engendered cationic gold catalysis. In addition, we have conducted the synthesis of O-heterocycles through a gold-catalyzed tandem addition/cycloisomerization sequence, the synthesis of N-heterocycles through a copper-catalyzed cyclization-triggered addition of alkynes, and a green synthesis of thioethers 'on water' without catalyst or initiator. These nucleophilic synthetic evolutions, catapulted by a simple addition to an alkyne, will surely contribute to provide a wider synthetic access to sophisticated biological targets.

Full text of DOI:10.1016/j.jorganchem.2010.09.025

Journal of Organometallic Chemistry 696 (2011) 269e276
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Synthetic evolutions in the nucleophilic addition to alkynes
*
*
Bo Xu , Weibo Wang, Le-Ping Liu, Junbin Han, Zhuang Jin, Gerald B. Hammond
Department of Chemistry, University of Louisville, Louisville, KY 40292, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
This short account describes our efforts to transform the simple nucleophilic addition of alkynes into
a more efficient, selective and environmentally benign synthetic tool. We have circumvented the lack of
regioselectivity in the gold-catalyzed triple bond addition of water through neighboring group partici-
pation and in the process we developed a ‘functionalized hydration’ (multiple bond formation and
hydration in a one-pot process) using fluorine-engendered cationic gold catalysis. In addition, we have
conducted the synthesis of O-heterocycles through a gold-catalyzed tandem addition/cycloisomerization
sequence, the synthesis of N-heterocycles through a copper-catalyzed cyclization-triggered addition of
alkynes, and a green synthesis of thioethers ‘on water’ without catalyst or initiator. These nucleophilic
synthetic evolutions, catapulted by a simple addition to an alkyne, will surely contribute to provide
a wider synthetic access to sophisticated biological targets.
Received 25 August 2010
Received in revised form
7 September 2010
Accepted 8 September 2010
Available online 17 September 2010
Keywords:
Alkyne
Gold catalysis
Copper catalysis
O-heterocycles
N-heterocycles
‘On water’ reactions
Ó 2010 Elsevier B.V. All rights reserved.
1. Introduction
account, we will present some recent developments in our laboratory
on alkyne addition that addresses the limitations listed above.
Chemical synthesis plays a major role in medicine, agricultural
and material research. Chemists need new synthetic reactions to
cope with the increasing complexity of target molecules and new
environmental demands. The addition of nucleophilic species to the
carbon-carbon multiple bonds is arguably one of the most widely
used chemical reaction for the functionalization of alkenes, alkynes
and allenes. Such chemical transformations fulfill the principle of
“green chemistry” since they ideally occur with 100% atom economy.
More specifically, our recent research has focused on the trans-
formations that involve addition of nucleophilic species to alkynes.
Alkynes are widely available starting materials and common
synthetic intermediates. In addition, the alkyne functionalityhas very
good functional group tolerance, that is, it is chemically inert toward
various reaction conditions such as acid and base; a reaction of an
alkyne usually occurs only in the presence of certain catalysts like
alkynophilic coinage metals (e.g. gold or copper). This is particularly
beneficial in the late steps of a synthesis. But a simple addition of
nucleophiles to alkynes has its own limitations: (i) regioselectivity
issues; (ii) a simple addition generates only a vinyl adduct. In this
Our overarching goal is to transform the simple nucleophilic
addition of alkynes into a more efficient, selective and environ-
mentally benign synthetic tool (Scheme 1). In the following
sections, we will demonstrate our approach to circumvent the
regioselectivity issue through neighboring group participation; the
development of ‘functionalized hydration’ (multiple bond forma-
tion and hydration in a one-pot process) using a fluorine-engen-
dered cationic gold catalyst; the synthesis of O-heterocycles
through
sequence; the synthesis of N-heterocycles through a copper-cata-
lyzed cyclization-triggered addition of alkynes; and green
a gold-catalyzed tandem addition/cycloisomerization
a
synthesis of thioethers ‘on water’ without catalyst or initiator.
These nucleophilic synthetic evolutions catapulted by a simple
addition to an alkyne will contribute to a wider synthetic access to
sophisticated biological targets.
2. Regioselective hydration of alkynes through neighboring
group participation [1]
The addition of water to alkynes generates carbonyl compounds
such as ketones or aldehydes [1]. Unlike other syntheses of carbonyl
compounds, the hydration of alkynes is an atom-economical addi-
tion of water without energy-intensive redox chemistry [2]. But the
hydration of internal alkynes is sluggish and non-regioselective.
Usually only terminal alkynes show good regioselectivity
* Corresponding authors.
E-mail addresses: Bo.Xu@louisville.edu (B. Xu), gb.hammond@louisville.edu (G.
B. Hammond).
0022-328X/$ e see front matter Ó 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2010.09.025

270
B. Xu et al. / Journal of Organometallic Chemistry 696 (2011) 269e276
Scheme 1. Synthetic evolutions of nucleophilic addition of alkynes.
(Markovnikov products), and most reactions need elevated
temperatures or strong acid co-catalysts. In general, the regiose-
lective hydration of internal alkynes may only proceed in the pres-
ence of a directing functionalitydheteroatoms or aromatic rings in
close proximity [2]. We proposed that with internal alkynes pos-
sessing a nucleophilic site Nu nearby (Scheme 2), this nucleophilic
site could attack a metal (e.g. gold)-activated triple bond to form two
regioisomeric cyclic intermediates. Although both carbons in the
triple bond are prone to nucleophilic attack, one cyclic intermediate
may be favored over the other according to Baldwin’s rules [3]. The
subsequent nucleophilic attack by water yields a single hydration
product (Scheme 2).
Our model reaction is the neighboring carbonyl group-assisted
hydration of internal alkynes in the presence of a gold(III) catalyst
that yields 1,4-dicarbonyl compounds. We chose the latter because
they are convenient starting materials and intermediates in many
important natural products and synthetic drug syntheses [4e8],
but, unlike their 1,3 or 1,5-counterparts, the disconnection of 1,4-
dicarbonyl compounds, especially of highly substituted 1,4-dicar-
3-alkynoates 1, provided this transformation can be carried out
regioselectively, under mild conditions, and with good functional
group tolerance [1]. After screening various metal and solvent
combinations, we concluded that NaAuCl4$2H2O (5%) in EtOH/H2O
(4:1) offered the best conditions for the hydration of alkyne 1. The
hydration proceeded smoothly in high yield and regioselectivity,
and was tolerant of ether, double bond, and other ester function-
alities (Table 1). Indeed, only one regioisomer was detected in all
the crude products examined.
The proposed mechanism for the reaction, based on similar
systems, is shown in Scheme 3. First, the gold(III) catalyst coordi-
nates with alkyne 1, activating the triple bond, and triggering the
participation of the carbonyl group nearby; this acts as a nucleo-
phile, attacking the triple bond to form a cyclized vinyl gold
intermediate of type int-A or int-B. According to Baldwin’s rules
Table 1
Au(III)-catalyzed hydration of internal 3-alkynoates.
bonyl compounds such as
trivial [4e10]. A tactical approach that enables a one-step discon-
nection of highly substituted g-keto esters is the direct hydration of
g-keto-a,a-substituted esters, is not
R2
O
R2
COOR4
R3
NaAuCl4.H2O (5%)
COOR4
R3
R1
R1
EtOH/H2O (4;1), r.t. / 12-18h
2
1
O
O
O
COOEt
n-C6H13
COOEt
n-C6H13
2d
COOEt
OMe
Ln
n-C6H13
LnAu
Au
n-C8H17
89%
LnAu
R
2b 93%
R
AuLn
2a, 78%
n
n
Nu
R
or
R
n
n
O
Nu
Nu
O
Nu
COOEt
O
n-C6H13
n-C6H13
COOEt
COOEt
H2O
O
H2O
Ph
2g
2f 91%
58%
2e
H
91%
H
O
O
n
or
n
O
R
H
Nu
R
Nu
COOMe
H
OEt
n-C6H13
C6H13
O
OCH3
O
COOEt
2i 80%
CO2Et
92%
O
2h
Scheme 2. Directed gold-catalyzed hydration of alkynes through neighboring group
2j
74%
assistance.

B. Xu et al. / Journal of Organometallic Chemistry 696 (2011) 269e276
271
R1
OR2
1
O
Au(III)
(III)Au
R1
(III)Au
R1
4-exo-dig
(III)
Au
OR2
H2O
OR2
disfavored
O
Int-A
O
R1
OR2
(III)Au
R1
(III)Au
R1
O
5-endo-dig
favored
OR2
O
OR2
int-B
O
1. H2O
2. -R2OH
(III)Au
R1
H
H
H
H
H2O
R1
OR2
R1
OR2
R1
O
OR2
HO
O
O
3
O
O
2
OH O
Scheme 3. Proposed mechanism for the hydration of 3-alkynoates.
[3], if the carbonyl oxygen attacks the
a 4-exo-dig process, which is disfavored. But if the carbonyl oxygen
attacks the -carbon, it would then be a 5-endo-dig attack, which is
b
-carbon, it is considered
active, they are effective mimics of
probes in various biological processes, and enzyme inhibitors
[12,14]. They also provide configurationally stable substituents for
a
-hydroxy ketones, useful
g
regarded as favored. Thus, int-B should be the predominating
intermediate. Water attack on int-B furnished the g-keto ester 2. A
competing side reaction, namely the elimination of R2OH from int-
B, is also possible. This would account for the trace amounts of
cyclic byproduct 3 obtained in some cases.
molecules containing a tertiary chiral carbon atom next to
a carbonyl group, an important structural motif in medicinal
chemistry [14]. This one-pot tandem addition/oxidative coupling/
fluorination sequencedusing readily available starting materials
(alkyne, water, organoboronic acid and Selectfluor)dhas clear
advantages over literature methods, all of which require multiple
synthetic steps [23e26].
3. Functionalized hydration of alkynes [11]
We first examined the reaction of 4a with phenyl boronic acid
(Table 2). Various metal catalysts were screened. Gold(I) catalyst
(Ph3PAuCl) gave the best result, and other transition metals like
copper, silver or palladium could not catalyze this transformation
under similar conditions. On exploring the scope of this novel func-
tionalized hydration, we found that functionalized and unfunction-
alized internal alkynes reacted with aryl boronic acid, giving very
A major shortcoming of the transition metal-catalyzed hydra-
tion of alkynes is that it only adds the elements of H2O to an alkyne
[11] (Scheme 4a). We propose that the vinyl metal complex
hydration intermediate can react further during the hydration
process to give an a,a-disubstituted ketone (Scheme 4b) in a one-
pot reaction. We coined this process ‘functionalized hydration’. We
speculated that if a vinyl gold intermediate could react with an
organoboronic acid (reagent X) and an electrophilic fluorine source
good yields of a-substituted ketones, with moderate regioselectivity
(Table 2, entries 1e12). With electron-rich 4-methoxy or 3,4-dime-
thoxyphenylboronic acids, we observed by-products arising from
fluorination or oxidation of the electron-rich aromatic rings by
Selectfluor [27,28]. Steric and electronic effects determine the
regioselectivity [2,29]. For internal alkynes possessing a nucleophilic
site nearby (e.g. the ester group in 4a), this site may influence the
regioselectivity through neighboring group participation [1,2,29].
Our proposed mechanism is shown in Scheme 5. Initially, water
attacks the gold-activated alkyne to form a vinyl gold complex C
[30], which reacts with a metal reagent RM (e.g., PhB(OH)2)
through a transmetalation process, to give intermediate D. We
believe that the strong BeF bond and the weak AueF bond are the
driving forces behind this transmetalation. Reductive elimination
of D gives E. And E may be fluorinated by Selectfluor to give the
functionalized ketone 6 [31]. Because we had never isolated 8 in all
cases, it is also possible that intermediate D reacts with Selectfluor
first to give F, and, following reductive elimination, gives the final
product 6. The transmetalation of AuIeCl complex with boronic
acid has been demonstrated by Hashmi and coworkers in a recent
paper [32]. Zhang and others have also proposed the trans-
metalation of AueF with boronic acid in their gold-catalyzed
oxidative-coupling reactions [33e37].
such as Selectfluor (reagent Y) it would afford
roketone in one-pot (Scheme 4b). Our proof of principle was the
synthesis of functionalized -fluoroketonesdwell-known targets
and important synthetic intermediates [12e22]. Tertiary -fluori-
nated ketones have received much attention recently because
a-aryl-a-fluo-
a
a
compounds having an
a
-fluorocarbonyl moiety are biologically
R2
H
R2
(a)
(b)
R1
H2O
MLn
LnM
O
R1
OH
R2
simple hydration
R1
R2
R1
OH
R2
R2
X
Y
reagent
X
Y
H2O
reagent X
R1
OH
R1
O
transformative hydration
Cl
-
N
N
F
2BF4
cat.
F
O
(c)
R1
R2 + H2O + R3B(OH)2
+
R1
R2
R3
Selectfluor
Scheme 4. Concept of functionalized hydration.

Table 2
Scope of the functionalized hydration.a
a
4 (0.4 mmol), 5 (0.8 mmol), Selectfluor (1.0 mmol), ClAuPPh3 (5%), 3 mL CH3CN/water (20:1), rt, 18e24 h. Selectfluoro: 1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo
[2.2.2]-octane bis(tetrafluoroborate).

B. Xu et al. / Journal of Organometallic Chemistry 696 (2011) 269e276
273
Table 3
Gold-catalyzed transformation of diols 10 to ketals 11 or tetrahydropyrans 12.a
Entry
R1/R2/R3/R4
x mol%/Time
Yield [%]b,c
1
2
3
n-C6H13/Me/H/H 10a
t-Bu/Me/H/H 10b
10b
6 mol%/24 h
2 mol%/10 min
6 mol%/24 h
12a, 91
11b, 52(99)
12b, 52
4
5
CypCH2/Me/H/H 10c
1c
2 mol%/10 min
6 mol%/24 h
11c, 87(99)
12c, 83
6
7
C6H5/Me/H/H 10d
10d
2 mol%/10 min
6 mol%/24 h
11d, 84(99)
12d, 88
Scheme 5. Proposed mechanism for the functionalized hydration.
8
9
p-CH3OC6H4/Me/H/H 10e
10e
2 mol%/10 min
6 mol%/24 h
11e, 80(99)
12e, 86
10
11
12
13
14
15
16
17
p-ClC6H4/Me/H/H 10f
10f
2 mol%/10 min
6 mol%/24 h
11f, 77(99)
12f, 65
O
Cat. 5%
(a)
(b)
n-C6H13/Et/H/H 10g
n-C6H13/Me/C6H5/H 10h
n-C6H13/Me/H/Me 10i
Me/Me/H/H 10j
i-Pr/Me/H/H 10k
Bn/Me/H/H 10l
2 mol%/10 min
2 mol%/10 min
2 mol%/10 min
2 mol%/10 min
2 mol%/10 min
2 mol%/10 min
11g, 86(99)
11h,d 68(99)
11i,e 79(99)
11j, 46(99)
11k, 75(99)
11l, 82(99)
Selectfluor 1.5 equiv
CH3CN:water (20:1)
H
F
7a
rt, 24h
4c
1. ClAu(PPh3)
2. IPrAuCl/AgBF4
3. ClAu(CF3Ph3P)
46%
21%
25%
a
Ph
General conditions: 2-alkynyl-1,5-diols 10 0.20 mmol, AuCl 1.0 mg (2 mol%),
CH2Cl2 1.0 mL; or 2-alkynyl-1,5-diols 10 0.20 mmol, AuCl 3.0 mg (6 mol%), CH2Cl2
1.0 mL.
ClAu(PPh3) 5%
O
O
O
O
PhB(OH)2 (2 equiv),
O
O
b
Selectfluor (1.5 equiv)
Isolated yields.
NMR yields.
Mixture of diaseteroisomers in 1.4:1 ratio.
Mixture of diaseteroisomers in 1:1 ratio.
4i
9, 45%
rt, 24h
c
CH3CN:water (20:1)
d
e
Scheme 6. Synthesis of fluoroketones and oxidative coupling of alkynes.
To probe our proposed mechanism, we conducted two control
experiments (Scheme 6). According to Scheme 5, fluoroketones 7
could be formed in the absence of a coupling partner R3M, in which
case, the vinyl metal complex C undergoes reductive elimination or
fluorodemetalation15 to give fluoroketone 7. This was the case
experimentally, although so far only moderate yields have been
obtained. The reaction of terminal alkyne 4i with 5a gives the
oxidative-coupling product 9 [38]. The formation of 6 hints toward
a tandem mechanism that involves fluorination of the gold complex,
transmetalation with boronic acid or terminal alkyne, and reductive
elimination. It is interesting to note that gold catalysts undergo
transmetalation and reductive elimination readily, although they are
not able to undergo oxidative insertion e as Pd does in coupling
reactions.
The key step of this mechanism is the generation of cationic gold
species A by fluorination (Scheme 5). Our preliminary experiments
show that Selectfluor did react with gold(I) complex at room temper-
ature. For example, when CH3CN was used as solvent, AuCl readily
reacted with Selectfluor at room temperature; the net result should be
the transfer of fluorine from Selectfluor to gold (Scheme 5). The change
of oxidation state of gold has been verified by X-ray photoelectron
spectroscopy (XPS) and high resolution ESI-mass spectroscopy [11].
R2
LnAu
O
R2
R1
R1
O Au
O
O
C
A
AuLn
R2
R2
AuLn
R1
R1
O
R1
R2
O
O
O
O
AuLn
O
11
O
12
E
AuLn
O
R2
OAuLn
R1
O
AuLn
R2
D
R1
B
Scheme 7. Plausible mechanism for the transformation of 11 to 12.
4. Synthesis of O-heterocycles through a tandem addition/
cycloisomerization sequence [39]
Bicyclic O-heterocycles like ketals or their heterobicyclic
counterparts [40] are intriguing structural motifs, not only from
the perspective of chemical diversity or biological potential, but
Scheme 8. Cyclization-triggered alkynylation.

Table 4
Scope of the tandem amination/alkynylation reaction.a
a
13 (0.5 mmol), 14 (2.0 mmol), 1 mL dioxane.

B. Xu et al. / Journal of Organometallic Chemistry 696 (2011) 269e276
275
also because of the stimulating transformations that they could
engender. During our investigations on the regioselective func-
tionalization of allenoates [41e46], we pondered whether these
could also open up a manifold of non-trivial transformations.
Taking a cue from Genet and coworkers’ gold-catalyzed cyclo-
isomerization of bis-homopropargylic diols to strained dioxabi-
cyclic ketals [47], and using 10 e promptly obtained by LAH
reduction of the parent diester [46] e as our substrate, we
screened various gold salts. To our satisfaction, with gold(I)
chloride, the reaction proceeded very smoothly in dichloro-
methane at room temperature, and was completed in 10 min; the
desired ketal 11, was isolated in excellent yield (Table 3). During
our investigation, we found that tetrahydropyran derivative 12
accompanied the formation of 11 when the reaction time was
prolonged. Initially, we thought that this rearrangement could be
induced by acidic conditions, but no tetrahydropyran was
observed when various Brønsted acids were employed to catalyze
the conversion of 11 to 12. We were positively surprised to
discover that tetrahydropyran 12 could be obtained in good to
excellent yields by simply increasing the gold catalyst loading and
prolonging the reaction time, as summarized in Table 3.
internal alkynes, and terminal alkynes have also been reported by
Bertrand et al. [57]. On the other hand, Li et al. have reported the
tandem addition of an amine and alkyne to a,b-unsaturated esters
through an iminium intermediate [58]. We envisioned a broader
scope for our tandem hydroamination/alkynylation process,
namely, the amination of inactive alkynes (terminal or internal) in
the presence of a single metal catalyst operating on both, the
hydroamination and alkynylation steps.
Among the various coinage metal catalysts screened, copper
catalyst was the best, and Cu(I) catalyst was better than Cu(II). The
scope of this tandem amination/alkynylation reaction is outlined in
Table 4. The reaction worked extremely well in all cases producing
near quantitative chemical yields of five-, six-, and seven-
membered ring compounds. Complete regioselectivity was
observed in all cases. When N-methyliminodiacetic acid (MIDA)
boronate [59] alkyne 14f was used, the terminal alkyne product 15k
was obtained (Table 4, entry 11); this may be due to cleavage of
MIDA boronate during the reaction. The regioselectivity obeyed
Baldwin’s rules [3]. The cyclization of 3-yn-amine 13b and 13a gave
five-membered ring products through 5-endo-dig and 5-exo-dig
processes [60]. And the reactions of 5-yn-amine (e.g., 13c) and 6-
yn-amine (e.g., 13e) yielded six-membered and seven-membered
rings, through 6-exo-dig and 7-exo-dig processes, respectively. The
cycloisomerization of 1,n-enynes and 1,n-diynes is currently
a highly competitive field in organic synthetic chemistry [61]. Our
newly found method provides direct entry to functionalized 1,n-
enynes, as showcased by the synthesis of 1,6-enyne (15e) in high
yield in a single step (Table 4, entry 5).
A plausible mechanism for the gold-catalyzed transformation of
dioxabicyclo[4.2.1] ketal 11 to tetrahydropyran 12 is outlined in
Scheme 7. Gold activates one of the oxygen atoms to form the
intermediate A or B, which may rearrange to the oxonium inter-
mediate C or D. These intermediates undergo an intramolecular
attack to give intermediate E, which produces the tetrahydropyran
product 12 and regenerates the gold catalyst.
5. Synthesis of N-heterocycles through a cyclization-triggered
addition of alkynes [48]
6. Green synthesis of vicinal dithioethers and alkenyl
thioethers from the reaction of alkynes and thiols in water
[62]
In the search for bioactivity, N-heterocycles of different ring sizes,
with different substitution patterns, are among the most important
structure classes [48e53]. A large percentage of drugs in the market
contain one or more N-heterocycles. Although the synthesis of
heterocycles has been around for over a century and a variety of
well-established methods are available, there are still unmet needs
for concise and efficient synthesis of structurally more complex
N-heterocycles, especially when larger amounts of material are
required for extensive biological studies or clinic trials [54]. The
desire to map new chemical spaces through tandem or cascade
reactions in atom-economical fashion inspired us to develop
a strategy to access biologically important heterocycles through
alkynophilic coinage metals capable of catalyzing tandem additions/
cyclization of alkynes. This new tandem strategy may enable us to
rapidly generating biological important N-heterocycles like cyclic
amino-acids with a facility unmatched by previous methodologies.
The transition metal-catalyzed intramolecular amination
(cyclization) of alkene/allene/alkyne is a well-established method
to generate N-heterocycles, but this method doesn’t introduce new
functionality to the heterocycles for further manipulation. We
proposed a flexible strategy to generate N-heterocycles in tandem
fashion: first, an intramolecular hydroamination of amino-alkynes
13 generates an activated enamine or imine in situ, capable of
reacting with a functionalized carbon nucleophile to give double
addition products (Scheme 8) in one pot. In this manner, we not
only accomplished the construction of N-heterocycles, but also
introduced a new functional group onto the ring system through
a carbonecarbon forming reaction, this being particularly advan-
tageous when constructing complex ring systems.
Thioethers have become increasingly important as the role of
sulfur is probed deeper in biological processes, new materials, and
chemical synthesis in general [62,63]. One of the most straight-
forward syntheses of thioethers is the addition of thiol to alkynes
(Scheme 9). Due to the increasing environmental consciousness
among the scientific community, we chose water as our reaction
medium. It was surprising to us that water was able to speed-up
this addition considering that both, starting material and product,
are virtually insoluble in water. And this reaction doesn’t need any
catalyst or initiator. According to Sharpless and co-workers, reac-
tion rates that are accelerated when insoluble reactants are stirred
in aqueous suspension are denoted as “on water” conditions [64].
Thus, this reaction could be considered as an ‘on water’ reaction.
R1
R2
rt or 60 oC
H2O
R1
R2
+
R3-SH
17
R3S
SR3
18
R1, R2 = Alkyl
R3 =Alkyl, Aryl
10 examples
(31% to 96%)
S R3
OH
rt
R4
R3-SH
17
R5
+
R4
OH
R5
R6
H2O
R6
19
R4 not H,
13 examples
R4, R5, R6 = Alkyl, Aryl
R3 =Aryl
Che and coworkers have reported a gold(I)-catalyzed tandem
synthesis of pyrrolo[1,2-a]quinolines [55,56], but their reaction
requires aromatic amines and terminal alkynes. The gold-catalyzed
one-pot synthesis of 1,2-dihydroquinoline derivatives from amines,
(17% to 78%)
(E:Z=9:1 to 100:0)
Scheme 9. Green synthesis of vicinal dithioethers and alkenyl thioethers.

276
B. Xu et al. / Journal of Organometallic Chemistry 696 (2011) 269e276
[26] G.E. Heasley, C. Codding, J. Sheehy, K. Gering, V.L. Heasley, D.F. Shellhamer,
T. Rempel, J. Org. Chem. 50 (2002) 1773e1776.
[27] P.T. Nyffeler, S.G. Duron, M.D. Burkart, S.P. Vincent, C.-H. Wong, Angew.
Chem., Int. Ed. 44 (2005) 192e212.
Various alkynes reacted with thiols in water to give vicinal
dithioethers 18 in good yields, and non-terminal propargyl alcohols
reacted with phenyl thiols to produce a highly regio and stereo-
selective monohydrothiolation product, E-alkenyl thioether 19
(Scheme 9).
[28] M. Schueler, Spec. Chem. Mag. 26 (2006) 20.
[29] N. Marion, R.S. Ramon, S.P. Nolan, J. Am. Chem. Soc. 131 (2009) 448e449.
[30] L.-P. Liu, B. Xu, M.S. Mashuta, G.B. Hammond, J. Am. Chem. Soc. 130 (2008)
17642e17643.
[31] D. Enders, M.R.M. Hüttle, Synlett (2005) 991 The fluorination of a ketone
bearing aromatic ring has been reported:.
7. Concluding remarks
[32] A.S.K. Hashmi, T.D. Ramamurthi, F. Rominger, J. Organomet. Chem. 694 (2009)
592e597.
[33] G. Zhang, Y. Peng, L. Cui, L. Zhang, Angew. Chem., Int. Ed. 48 (2009)
3112e3115.
[34] P. Garcia, M. Malacria, C. Aubert, V. Gandon, L. Fensterbank, ChemCatChem 2
(2010) 493e497.
[35] A.D. Melhado, W.E. Brenzovich, A.D. Lackner, F.D. Toste, J. Am. Chem. Soc. 132
(2010) 8885e8887.
[36] W.E. Brenzovich, D. Benitez, A.D. Lackner, H.P. Shunatona, E. Tkatchouk,
F.D. Toste, Angew. Chem., Int. Ed. 49 (2010) 5519e5522.
[37] G. Zhang, L. Cui, Y. Wang, L. Zhang, J. Am. Chem. Soc. 132 (2010) 1474e1475.
[38] F. Yang, Y. Wu, Eur. J. Org. Chem. 2007 (2007) 3476e3479.
[39] L.-P. Liu, G.B. Hammond, Org. Lett. 11 (2009) 5090e5092.
[40] (a) P.A. Bartlett, M. Entzeroth (Eds.), Exploiting chemical diversity for drug
discovery, Royal Society of Chemistry, Cambridge, UK, 2006;
(b) P.-C. Kuo, T.-H. Kuo, A.G. Damu, C.-R. Su, E.-J. Lee, T.-S. Wu, R. Shu,
C.-M. Chen, K.F. Bastow, T.-H. Chen, K.-H. Lee, Org. Lett. 8 (2006) 2953.
[41] B. Xu, G.B. Hammond, Synlett 2010 (2010) 1442e1454.
[42] J.C. Aponte, G.B. Hammond, B. Xu, J. Org. Chem. 74 (2009) 4623e4625.
[43] H. Yang, B. Xu, G.B. Hammond, Org. Lett. 10 (2008) 5589e5591.
[44] B. Xu, G.B. Hammond, Angew. Chem., Int. Ed. 47 (2008) 689e692.
[45] W. Wang, B. Xu, G.B. Hammond, Org. Lett. 10 (2008) 3713e3716.
[46] L.-P. Liu, B. Xu, G.B. Hammond, Org. Lett. 10 (2008) 3887e3890.
[47] S. Antoniotti, E. Genin, V. Michelet, J.-P. Genet, J. Am. Chem. Soc. 127 (2005)
9976e9977.
[48] J. Han, B. Xu, G.B. Hammond, J. Am. Chem. Soc. 132 (2010) 916e917.
[49] C. Zhang, C.K. De, R. Mal, D. Seidel, J. Am. Chem. Soc. 130 (2008) 416e417.
[50] B.M. Trost, N. Maulide, R.C. Livingston, A. Ruthenium-Catalyzed, J. Am. Chem.
Soc (2008) 16502e16503.
[51] S. Fustero, J. Moscardo, D. Jimenez, M.D. Perez-Carrion, M. Sanchez-Rosello,
C. Del Pozo, Chemistry 14 (2008) 9868e9872.
[52] J.L. Vicario, D. Badia, L. Carrillo, New methods for the asymmetric synthesis of
nitrogen heterocycles 2005. Research Signpost, Kerala, India, 2005.
[53] E.S.H. El Ashry, A. El-Nemr, Synthesis of naturally occurring nitrogen
heterocycles from carbohydrates. Blackwell Publications, Oxford, UK, Ames,
Iowa, 2005.
[54] N.T. Patil, Y. Yamamoto, Chem. Rev. 108 (2008) 3395e3442.
[55] X.-Y. Liu, C.-M. Che, Angew. Chem., Int. Ed. 47 (2008) 3805e3810.
[56] X.-Y. Liu, C.-M. Che, Angew. Chem., Int. Ed. 48 (2009) 2367e2371.
[57] X. Zeng, G.D. Frey, R. Kinjo, B. Donnadieu, G. Bertrand, J. Am. Chem. Soc. 131
(2009) 8690e8696.
The nucleophilic addition of alkyne is a synthetic tool that is
evolving to meet the needs for more efficient and environmentally
benign synthesis of synthetic targets. We have demonstrated that
the regioselectivity can be controlled by the formation of cyclic
intermediates, and that tandem chemistry can enable quick access
to a diverse set of oxygen and nitrogen heterocycles. Developing the
full potential of these reactions, including their asymmetrical
versions is currently a priority in our laboratory.
Acknowledgment
We are grateful to the National Science Foundation for financial
support (CHE-0809683).
References
[1] W. Wang, B. Xu, G.B. Hammond, J. Org. Chem. 74 (2009) 1640e1643.
[2] L. Hintermann, A. Labonne, Synthesis (2007) 1121e1150.
[3] J.E. Baldwin, J. Chem. Soc., Chem. Commun (1976) 734e736.
[4] A.G. Csaky, J. Plumet, Chem. Soc. Rev. 30 (2001) 313e320.
[5] G. Piancatelli, M. D’Auria, F. D’Onofrio, Synthesis (1994) 867e889.
[6] Y. Kubota, H. Nemoto, Y. Yamamoto, J. Org. Chem. 56 (1991) 7195e7196.
[7] S. Aoki, E. Nakamura, Tetrahedron 47 (1991) 3935e3946.
[8] S. Aoki, E. Nakamura, Synlett (1990) 741e742.
[9] S. Muthusamy, P. Srinivasan, Tetrahedron Lett. 47 (2006) 6297e6300.
[10] A.I. Meyers, R.H. Wallace, M. Harre, R. Garland, J. Org. Chem. 55 (1990)
3137e3143.
[11] W. Wang, J. Jasinski, G.B. Hammond, B. Xu, Angew. Chem. Int. Ed. 49 (2010)
7247e7252.
[12] Y. Guo, B. Twamley, J.N.M. Shreeve, Org. Biomol. Chem. 7 (2009) 1716e1722.
[13] K.-Y. Kim, B.C. Kim, H.B. Lee, H. Shin, J. Org. Chem. 73 (2008) 8106e8108.
[14] G.K.S. Prakash, P. Beier, Angew. Chem., Int. Ed. 45 (2006) 2172e2174.
[15] E.C. Burger, B.R. Barron, J.A. Tunge, Synlett (2006) 2824e2826.
[16] F.A. Davis, W. Han, C.K. Murphy, J. Org. Chem. 60 (1995) 4730e4737.
[17] V.Reutrakul, T.Kruahong, M.Pohmakotr,TetrahedronLett.35 (1994)4853e4856.
[18] W.R. Dolbier Jr., S.K. Lee, O.I.V. Phanstiel, Tetrahedron 47 (1991) 2065e2072.
[19] E. Differding, G.M. Ruegg, R.W. Lang, Tetrahedron Lett. 32 (1991) 1779e1782.
[20] C. Tarnus, M.J. Jung, J.M. Remy, S. Baltzer, D.G. Schirlin, FEBS Lett. 249 (1989)
47e50.
[21] P. Bravo, E. Piovosi, G. Resnati, J. Chem. Res., Synop. (1989) 134e135.
[22] P. Bravo, G. Resnati, J. Chem. Soc., Chem. Commun. (1988) 218e219.
[23] R.S. Neale, J. Am. Chem. Soc. 86 (2002) 5340e5342.
[24] L. Benati, P.C. Montevecchi, P. Spagnolo, Tetrahedron Lett. 29 (1988)
2381e2384.
[58] L. Zhou, H.-F. Jiang, C.-J. Li, Adv. Synth. Catal. 350 (2008) 2226e2230.
[59] E.P. Gillis, M.D. Burke, J. Am. Chem. Soc. 129 (2007) 6716e6717.
[60] X. Zeng, R. Kinjo, B. Donnadieu, G. Bertrand, Angew. Chem. Int. Ed. 49 (2010)
942e945.
[61] V. Michelet, P.Y. Toullec, J.-P. Genet, Angew. Chem., Int. Ed. 47 (2008)
4268e4315.
[62] Z. Jin, B. Xu, G.B. Hammond, Eur. J. Org. Chem (2010) 168e173.
[63] R.J.W. Cremlyn, An Introduction to Organosulfur Chemistry. Wiley, Chichester,
New York, 1996.
[64] A. Chanda, V.V. Fokin, Chem. Rev. 109 (2009) 725e748.
[25] K. Tamao, K. Maeda, Tetrahedron Lett. 27 (1986) 65e68.